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These conditions are thought to be rare causes of ischemic stroke in adults, but may be more important causes of ischemic stroke in children. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Hematologic'.) The 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines note that it is uncertain whether testing for these hematologic traits is beneficial in the context of secondary stroke prevention [14]. Suspicion for hypercoagulable states as the cause of stroke may be heightened in younger patients with cryptogenic stroke, a history or family history of unprovoked thrombosis, prior spontaneous abortion, or concomitant systemic signs and symptoms suggestive of hypercoagulability. The same guidelines note that for patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable to reduce the risk of recurrent stroke or TIA [14]. The evaluation and management of these conditions is discussed in greater detail separately. (See "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A" and "Overview of homocysteine" and "Cerebral venous thrombosis: Treatment and prognosis".) Cancer-related hypercoagulable state Patients with cancer may be at increased risk for stroke due to hypercoagulability and other potential mechanisms, including compression or invasion of blood vessels, marantic endocarditis, infections, paraneoplastic disorders, and complications of cancer therapies [28,29]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".) For patients with TIA or ischemic stroke attributed to cancer hypercoagulability, optimal treatment for secondary stroke prevention is unknown, and data are limited [29]. Empiric treatment with low molecular weight heparin is often used, but the clinical risk and benefit compared with antiplatelets remains uncertain [30]. In patients with venous thromboembolism (VTE) and cancer, anticoagulant therapy is the mainstay of treatment. Low molecular weight heparin or DOACs are preferred in patients without renal insufficiency, whereas warfarin is the preferred treatment in patients with renal insufficiency (eg, creatinine clearance <30 mL/minute). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) The 2021 AHA/ASA guidelines note only that in the setting of atrial fibrillation and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke prevention [14]. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 12/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate CRYPTOGENIC STROKE Cryptogenic stroke is variably defined and generally designates the category of brain infarction that is not attributed to an established source of cardioembolism, large artery atherosclerosis, small artery disease, or other determined cause of stroke. However, the term cryptogenic stroke has been applied to patients with an incomplete diagnostic evaluation, a complete but unrevealing evaluation, or an evaluation that identifies multiple potential causes of stroke. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Classification'.) Embolic stroke of undetermined source (ESUS) is a subcategory of cryptogenic stroke defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources; ESUS requires a full standardized stroke evaluation to exclude other causes. While the less well- defined term of cryptogenic stroke has been reported to account for approximately 25 to 40 percent of ischemic strokes, the more specific term of ESUS consistently accounts for approximately 20 percent of ischemic strokes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) For secondary prevention, most patients with a cryptogenic ischemic stroke or TIA should be treated with blood pressure control, low-density lipoprotein cholesterol lowering therapy, and lifestyle modification. Initial antiplatelet therapy is advised while awaiting the results of long- term cardiac monitoring. For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, anticoagulant therapy with warfarin or a direct oral anticoagulant is advised rather than antiplatelet therapy. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Fibromuscular dysplasia".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 13/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Transient ischemic attack (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Large artery disease Secondary prevention for ischemic stroke or transient ischemic attack (TIA) attributed to large artery disease may include the following measures: Symptomatic internal carotid stenosis In addition to medical management, revascularization is generally beneficial for patients with recently symptomatic internal carotid artery atherosclerotic stenosis with 50 to 99 percent luminal narrowing. In the setting of complete carotid occlusion, medical management is the only practical option. (See 'Symptomatic carotid stenosis' above.) Extracranial vertebral artery In most cases, ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment with multifactorial risk reduction. (See 'Extracranial vertebral artery stenosis' above.) Intracranial atherosclerosis Aggressive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis. (See 'Intracranial large artery atherosclerosis' above.) Arterial dissection Antithrombotic therapy with either antiplatelet or anticoagulant agents is used for the secondary prevention of ischemic stroke and TIA caused by cervical arterial dissection. (See 'Dissection' above.) https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 14/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Small artery disease Antiplatelet therapy and treatment of modifiable risk factors is the mainstay for secondary stroke prevention in patients with lacunar stroke or TIA due to small artery disease. (See 'Small artery disease' above.) Cardiogenic embolism Virtually all patients with atrial fibrillation who have a history of stroke or TIA should be treated with oral anticoagulation in the absence of contraindications. (See 'Atrial fibrillation' above.) Other cardiac sources of embolism for which anticoagulation is often indicated include: Left ventricular thrombus (see 'Left ventricular thrombus' above) Cardiomyopathy (see 'Cardiomyopathy' above) Prosthetic heart valves (see 'Valvular disease' above) Moderate to severe mitral stenosis, even in the absence of atrial fibrillation (see 'Valvular disease' above) Congenital heart disease (see 'Congenital heart disease' above) Patent foramen ovale (PFO) device closure is more effective than medical therapy alone for select patients with a PFO-associated stroke. Evaluation and treatment are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Aortic atherosclerosis The optimal treatment for the prevention of ischemic stroke and TIA attributed to aortic arch atherosclerosis is not clear. Medical management with antiplatelet and low-density lipoprotein cholesterol lowering therapy is reasonable. (See 'Aortic atherosclerosis' above.) Sickle cell disease Stroke is a frequent complication of sickle cell disease, and the risk of recurrent stroke is high. Stroke risk can be reduced with chronic transfusion therapy. (See 'Sickle cell disease' above and "Prevention of stroke (initial or recurrent) in sickle cell disease".) Hypercoagulable states Anticoagulation with warfarin is the gold standard for patients with antiphospholipid syndrome and arterial thromboembolism; some experts add low- dose aspirin for selected patients with arterial events who also have additional risk factors for atherosclerotic vascular disease. With TIA or ischemic stroke attributed to cancer hypercoagulability, the optimal treatment for secondary stroke prevention is unknown. Inherited thrombophilias are thought to be rare causes of ischemic stroke in adults. For patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 15/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable. (See 'Hypercoagulable states' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges J Philip Kistler, MD, Hakan Ay, MD, and Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Klijn CJ, Kappelle LJ, Tulleken CA, van Gijn J. Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors. Stroke 1997; 28:2084. 2. Klijn CJ, Kappelle LJ, Algra A, van Gijn J. Outcome in patients with symptomatic occlusion of the internal carotid artery or intracranial arterial lesions: a meta-analysis of the role of baseline characteristics and type of antithrombotic treatment. Cerebrovasc Dis 2001; 12:228. 3. Khazaal O, Neale N, Acton EK, et al. Early neurologic deterioration with symptomatic isolated internal carotid artery occlusion: a cohort study, systematic review, and meta- analysis. Stroke Vasc Interv Neurol 2022; 2. 4. Myrcha P, Gloviczki P. A systematic review of endovascular treatment for chronic total occlusion of the internal carotid artery. Ann Transl Med 2021; 9:1203. 5. Jovin TG, Gupta R, Uchino K, et al. Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate. Stroke 2005; 36:2426. 6. Barnett HJ. Delayed cerebral ischemic episodes distal to occlusion of major cerebral arteries. Neurology 1978; 28:769. 7. Barnett HJ, Peerless SJ, Kaufmann JC. "Stump" on internal carotid artery a source for further cerebral embolic ischemia. Stroke 1978; 9:448. 8. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985; 313:1191. 9. Powers WJ, Clarke WR, Grubb RL Jr, et al. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA 2011; 306:1983. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 16/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 10. Rainer WG, Cramer GG, Newby JP, Clarke JP. Fibromuscular hyperplasia of the carotid artery causing positional cerebral ischemia. Ann Surg 1968; 167:444. 11. Choi PM, Singh D, Trivedi A, et al. Carotid Webs and Recurrent Ischemic Strokes in the Era of CT Angiography. AJNR Am J Neuroradiol 2015; 36:2134. 12. Boesen ME, Eswaradass PV, Singh D, et al. MR imaging of carotid webs. Neuroradiology 2017; 59:361. 13. Mac Grory B, Emmer BJ, Roosendaal SD, et al. Carotid web: an occult mechanism of embolic stroke. J Neurol Neurosurg Psychiatry 2020; 91:1283. 14. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 15. Coward LJ, McCabe DJ, Ederle J, et al. Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial. Stroke 2007; 38:1526. 16. Jenkins JS, Patel SN, White CJ, et al. Endovascular stenting for vertebral artery stenosis. J Am Coll Cardiol 2010; 55:538. 17. Stayman AN, Nogueira RG, Gupta R. A systematic review of stenting and angioplasty of symptomatic extracranial vertebral artery stenosis. Stroke 2011; 42:2212. 18. Markus HS, Harshfield EL, Compter A, et al. Stenting for symptomatic vertebral artery stenosis: a preplanned pooled individual patient data analysis. Lancet Neurol 2019; 18:666. 19. Xu R, Zhang X, Liu S, et al. Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis. Cochrane Database Syst Rev 2022; 5:CD013692. 20. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993. 21. Gornik HL, Persu A, Adlam D, et al. First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 2019; 24:164. 22. Arboix A, Alio J. Acute cardioembolic cerebral infarction: answers to clinical questions. Curr Cardiol Rev 2012; 8:54. 23. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 24. Homma S, Di Tullio MR, Sciacca RR, et al. Effect of aspirin and warfarin therapy in stroke patients with valvular strands. Stroke 2004; 35:1436. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 17/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 25. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 26. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e576S. 27. Amarenco P, Davis S, Jones EF, et al. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke 2014; 45:1248. 28. Salazar-Camelo RA, Moreno-Vargas EA, Cardona AF, Bayona-Ortiz HF. Ischemic stroke: A paradoxical manifestation of cancer. Crit Rev Oncol Hematol 2021; 157:103181. 29. Dearborn JL, Urrutia VC, Zeiler SR. Stroke and Cancer- A Complicated Relationship. J Neurol Transl Neurosci 2014; 2:1039. 30. Navi BB, Iadecola C. Ischemic stroke in cancer patients: A review of an underappreciated pathology. Ann Neurol 2018; 83:873. Topic 1119 Version 29.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 18/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate GRAPHICS Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 19/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Graphic 131695 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 20/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 21/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 22/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low Apical akinesia ejection fraction (<28%) Dilated cardiomyopathy (prior established diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) Wall motion abnormalities (hypokinesia, akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 23/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 24/25 7/6/23, 12:09 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Shadi Yaghi, MD, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 25/25

7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pathophysiology of ischemic stroke : Arshad Majid, MB, ChB, FRCP, Mounzer Kassab, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 23, 2022. INTRODUCTION The term ischemic stroke is used to describe a variety of conditions in which blood flow to part or all of the brain is reduced, resulting in tissue damage. Although in some cases this may be a chronic condition, most strokes occur acutely. Research over the last four decades has resulted in a significant expansion of our knowledge and understanding of the molecular and cellular processes that underlie ischemia-induced cellular injury. The goal of this review is to provide an overview of the underlying factors, such as the hemodynamic changes and molecular and cellular pathways, which are involved in stroke- related brain injury. A better understanding of these processes may help in the development of new therapies that are needed to treat this devastating disease. STROKE SUBTYPES The etiology and clinical classification of ischemic stroke subtypes is reviewed here briefly and discussed in greater detail separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Brain ischemia' and "Clinical diagnosis of stroke subtypes".) Acute ischemic stroke subtypes are often classified in clinical studies using a system developed by investigators of the TOAST trial, based upon the underlying cause ( table 1) [1]. Under this system, strokes are classified into the following categories: Large artery atherosclerosis https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 1/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Cardioembolism Small vessel occlusion Stroke of other, unusual, determined etiology Stroke of undetermined etiology Ischemic strokes are due to a reduction or complete blockage of blood flow [2]. This reduction can be due to decreased systemic perfusion, severe stenosis, or occlusion of a blood vessel. Decreased systemic perfusion can be the result of low blood pressure, heart failure, or loss of blood. Determination of the type of stroke can influence treatment to be used. The main causes of ischemia are thrombosis, embolization, and lacunar infarction from small vessel disease. Ischemic strokes represent approximately 80 percent of all strokes. (See "Stroke: Etiology, classification, and epidemiology", section on 'Epidemiology'.) Thrombosis refers to obstruction of a blood vessel due to a localized occlusive process within a blood vessel [2]. The obstruction may occur acutely or gradually. In many cases, underlying pathology such as atherosclerosis may cause narrowing of the diseased vessel. This may lead to restriction of blood flow gradually, or in some cases, platelets may adhere to the atherosclerotic plaque forming a clot leading to acute occlusion of the vessel. Atherosclerosis usually affects larger extracranial and intracranial vessels. In some cases, acute occlusion of a vessel unaffected by atherosclerosis may occur because of a hypercoagulable state. (See "Stroke: Etiology, classification, and epidemiology", section on 'Thrombosis'.) Embolism refers to clot or other material formed elsewhere within the vascular system that travels from the site of formation and lodges in distal vessels causing blockage of those vessel and ischemia [2]. The heart is a common source of this material, although other arteries may also be sources of this embolic material (artery to artery embolism). In the heart, clots may form on valves or chambers. Tumors, venous clots, septic emboli, air, and fat can also embolize and cause stroke. Embolic strokes tend to be cortical and are more likely to undergo hemorrhagic transformation, probably due to vessel damage caused by the embolus. Emboli from venous sources such as a deep venous thrombosis (DVT) can also cause stroke if the emboli are able to migrate to the arterial system through a patent foramen ovale (PFO) or an arteriovenous (AV) shunt such as pulmonary AV fistulae. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) Lacunar infarction occurs as a result of small vessel disease. Smaller penetrating vessels are more commonly affected by chronic hypertension leading to hyperplasia of the tunica media of these vessels and deposition of fibrinoid material leading to lumen narrowing and occlusion [2]. Lacunar strokes can occur anywhere in the brain but are typically seen in https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 2/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate subcortical areas. Atheroma can also encroach on the orifices of smaller vessels leading to occlusion and stroke. (See "Lacunar infarcts".) Nonatherosclerotic abnormalities of the cerebral vasculature, whether inherited or acquired, predispose to ischemic stroke at all ages, but particularly in younger adults and children. These can be divided into noninflammatory and inflammatory etiologies. The following list, though not exhaustive, highlights the major nonatherosclerotic vasculopathies associated with ischemic stroke: Arterial dissection ( figure 1) Fibromuscular dysplasia (see "Clinical manifestations and diagnosis of fibromuscular dysplasia") Vasculitis (see "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Incidence and classification") Moyamoya disease (see "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis") Sickle cell disease arteriopathy (see "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease") Focal cerebral arteriopathy of childhood (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Focal cerebral arteriopathy') Decreased systemic perfusion due to systemic hypotension may produce generalized ischemia to the brain [2]. This is most critical in the borderzone (or watershed) areas, which are territories that occupy the boundary region of two adjacent arterial supply zones. The ischemia caused by hypotension may be asymmetric due to preexisting vascular lesions. Areas of the brain commonly affected include the hippocampal pyramidal cells, cerebellar Purkinje cells, and cortical laminar cells discussed below. (See "Stroke: Etiology, classification, and epidemiology", section on 'Systemic hypoperfusion'.) Despite extensive testing to identify the etiology of the stroke, no clear cause is found in approximately 25 percent of patients with ischemic stroke at hospital discharge (cryptogenic stroke). In rare cases, the pathophysiology of the ischemic infarct may not even be vascular. Examples include mitochondrial disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) in which the pathophysiology is a failure of the energy production system (mitochondria) rather than a problem with blood delivery. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 3/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate CEREBRAL AUTOREGULATION Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels, which is directly related to their diameter [3]. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. Cerebral autoregulation is the phenomenon by which cerebral blood flow is maintained at a relatively constant level despite moderate variations in perfusion pressure. The mechanism by which autoregulation occurs is not well understood and may involve multiple pathways. Evidence suggests that the smooth muscle in cerebral vessels can respond directly to changes in perfusion pressure, contracting when pressure increases and relaxing when pressure drops. Reductions in cerebral blood flow may also lead to dilation of blood vessels through the release of vasoactive substances, although the molecules responsible for this have not been identified. The endothelial release of nitric oxide also appears to play a role in autoregulation. Maintenance of cerebral blood flow by autoregulation typically occurs within a mean arterial pressure range of 60 to 150 mmHg. The upper and lower limits vary between individuals, however. Outside of this range, the brain is unable to compensate for changes in perfusion pressure, and the cerebral blood flow increases or decreases passively with corresponding changes in pressure, resulting in the risk of ischemia at low pressures and edema at high pressures ( figure 2). Cerebral autoregulation during stroke Cerebral autoregulation is impaired during some disease conditions, including ischemic stroke [3-5]. As cerebral perfusion pressure falls, cerebral blood vessels dilate to increase cerebral blood flow. A decrease in perfusion pressure beyond the ability of the brain to compensate results in a reduction in cerebral blood flow. Initially, the oxygen extraction fraction is increased in order to maintain levels of oxygen delivery to the brain. As the cerebral blood flow continues to fall, other mechanisms come into play ( figure 3). Inhibition of protein synthesis occurs at flow rates below 50 mL/100 g per minute. At 35 mL/100 g per minute, protein synthesis ceases completely, and glucose utilization is transiently increased. At 25 mL/100 g per minute, glucose utilization drops dramatically with the onset of anaerobic glycolysis, resulting in tissue acidosis from the accumulation of lactic acid. Neuronal electrical failure occurs at 16 to 18 mL/100 g per minute, and failure of membrane ion homeostasis occurs at 10 to 12 mL/100 g per minute. This level typically marks the threshold for the development of infarct ( figure 3). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 4/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate In hypertensive individuals, autoregulation has adapted to occur at higher arterial pressures. Reduction of blood pressure to normal levels could actually exacerbate the derangement to autoregulation that occurs during stroke and lead to a further decrease in cerebral blood flow ( figure 2). CONSEQUENCES OF REDUCTION IN BLOOD FLOW DURING STROKE The human brain is exquisitely sensitive and susceptible to even short durations of ischemia. The brain is responsible for a large part of the body's metabolism and receives approximately 20 percent of the cardiac output although it is only 2 percent of total body weight [3]. The brain contains little or no energy stores of its own, and therefore relies on the blood for their delivery. Even brief deprivation can lead to death of the affected brain tissue. During stroke, reduction of blood flow to a portion or all of the brain results in a deprivation of glucose and oxygen [2]. Most strokes are caused by focal ischemia, affecting only a portion of the brain, typically involving a single blood vessel and its downstream branches. The region directly surrounding the vessel is the most affected. Within this region, cells in a central core of tissue will be irreversibly damaged and die by necrosis if the duration of ischemia is long enough. At distances farther from the affected vessel, some cells may receive a small amount of oxygen and glucose by diffusion from collateral vessels. These cells do not die immediately and can recover if blood flow is restored in a timely manner. The central core of tissue destined to die, or containing tissue that is already dead, is called the infarct. The region of potentially salvageable tissue is known as the penumbra. Mechanisms of ischemic cell injury and death Brain ischemia initiates a cascade of events that eventually lead to cell death; including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes [2,6-8]. As a consequence of the electrical failure that occurs during ischemia, the release of the excitatory amino acid glutamate at neuronal synapses is increased [2]. This leads to the activation of glutamate receptors and the opening of ion channels that allow potassium ions to exit the cell and sodium and calcium ions to enter, which has a number of physiologic effects. The primary glutamate receptor subtype involved in ischemic damage is the N-methyl-D- aspartate (NMDA) receptor. In addition, the alpha-amino-3-hydroxy-5-methyl-4- isoxazoleproprionic acid (AMPA) and metabotropic glutamate receptors are thought to play a https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 5/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate role. Activation of these receptors leads to membrane depolarization and increased calcium influx. Numerous cellular signaling pathways respond to calcium levels, and the influx of calcium resulting from glutamate receptor stimulation leads to their activation. These pathways have both beneficial and detrimental effects. The influx of sodium ions is balanced by the influx of water into the cell, leading to edema. Sodium influx also causes reversal of the normal process of glutamate uptake by astrocyte glutamate transporters, resulting in increased glutamate release [9-12]. As a result of its increased release and decreased uptake, glutamate accumulates to excessive levels and leads to continuous stimulation. This condition is often referred to as excitotoxicity. Another effect of NMDA receptor activation is the production of nitric oxide [13]. The activity of nitric oxide synthase (NOS) and the total amount of nitric oxide present in the brain are increased following exposure to hypoxia [14]. Nitric oxide is an important signaling molecule within the body and can be beneficial at normal physiologic levels. As an example, endothelial nitric oxide synthase (eNOS) leads to the production of low levels of nitric oxide that cause vasodilation and increase blood flow [15]. However, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) result in larger amounts of nitric oxide that may lead to brain injury. Nitric oxide is a free radical and reacts directly with cellular components to damage them. Nitric oxide can also react with another free radical, superoxide, to produce the highly reactive peroxynitrite. Peroxynitrite causes single strand breaks in DNA [16]. This results in the activation of DNA repair enzymes, which consume vital energy needed for other processes. DNA damage also may activate the process of apoptosis, leading to cell death. The production of reactive oxygen species, a normal byproduct of oxidative metabolism, is also increased during ischemia. Like nitric oxide, they can react with and damage cellular components. Injury to the plasma membrane of a cell can lead to the inability to control ion flux, resulting in mitochondrial failure. Reactive oxygen species, as well as calcium influx and other factors, can also permeabilize the mitochondrial membrane [17]. This leads to metabolic failure as well as the release of initiators of apoptosis and DNA damage. Metabolic failure results in the depletion of cellular ATP levels. ATP is required for nuclear condensation and DNA degradation in the final stages of apoptosis [18]. In the absence of ATP, cell death occurs by necrosis rather than apoptosis. (See 'Necrosis and apoptosis' below.) The release of byproducts from cellular damage and death by necrosis activates components of the inflammatory pathway [19]. The role that inflammation plays during ischemia is mixed, https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 6/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate having both positive and negative effects [20]. On the one hand, inflammation results in an increase in blood flow to the ischemic region, which may deliver vital glucose and oxygen to cells. On the other hand, increased blood flow may also deliver more calcium to the area, resulting in increased tissue damage. Inflammation also results in the migration of activated leukocytes to damaged tissue [21,22]. Although these leukocytes may remove damaged and necrotic tissue, they also release cytokines to attract additional inflammatory cells. Under severe inflammatory conditions, these cytokines can accumulate to toxic levels. Necrosis and apoptosis Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. The process of necrosis is not well understood. In early stages, cellular chromatin becomes uniformly compacted, the endoplasmic reticulum is dilated, and ribosomes are dispersed [23]. In later stages, swelling of the cell and mitochondria is followed by rupture of the nuclear, organelle, and plasma membranes, leading to the release of cellular material into the surrounding environment. This release of material results in the stimulation of inflammatory processes within the brain. Apoptosis is highly regulated and has been studied in more detail than necrosis. As in necrosis, the chromatin begins to condense during early stages of apoptosis. Instead of cellular swelling, however, the contents of the cytoplasm also condense, and the mitochondria and other organelles remain intact. In later stages, the nucleus is broken into discrete fragments and the entire contents of the cell are divided into membrane bound bodies that are subsequently phagocytosed by macrophages. There are three known pathways by which apoptosis can be initiated [24]: Mitochondrial permeabilization Death receptor (Fas) pathway Endoplasmic reticulum stress The most well-known pathway involves permeabilization of the mitochondria and release of cytochrome c into the cytoplasm. Activation of membrane-bound Fas, the so called "death receptor," and the accumulation of misfolded proteins at the endoplasmic reticulum during stress, can also lead to apoptosis. These initiators all lead to the activation of caspases that cleave cellular proteins and eventually cause cell death. Caspase-independent mechanisms of apoptosis have also been proposed. The pattern of cell death after cerebral ischemia, as seen in animal models, depends on the nature of the insult to cerebral tissue [25]. In global cerebral ischemia, such as occurs after https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 7/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate cardiac arrest and resuscitation or transient severe systemic hypotension, the entire brain is exposed to ischemia. Formation of infarct is not immediate, but rather occurs after a delay of 12 hours to several days. Cell death is limited to those regions of the brain that are particularly susceptible to ischemic damage, such as the CA1 and CA4 regions of the hippocampus, the striatum, and cortical layers two and five. Cell death in these regions occurs primarily by apoptosis. Focal cerebral ischemia is a more common pattern than global ischemia in human stroke. In animal models of focal ischemia, changes in cell morphology are visible microscopically as early as two to three hours after the insult, and the infarct develops rapidly over a period of 6 to 24 hours. Cell death occurs by necrosis in the core, with apoptotic cells located on the periphery [6]. In addition to the type of insult, the duration of ischemia also affects the pattern by which cell death occurs. Longer ischemic insults produce greater damage to cerebral tissue, resulting in an increased proportion of necrosis and decreased proportion of apoptosis. There have been few studies of apoptosis in the brain following stroke in human patients. However, accumulating evidence suggests that apoptosis is involved [26-29], as illustrated by the following observations: In a neuropathology study that compared specimens from 27 patients who had cerebral infarction with specimens from rat brains subjected to experimental transient forebrain ischemia, the patterns of cell death were similar in human and animal brain tissue and included both morphologic and histochemical findings typical of apoptosis [26]. In the human stroke specimens, apoptosis was apparent during the subacute stage, but was not seen in acute or chronic stages. In another neuropathology report that compared 13 cases of fatal ischemic stroke with three patients who died of non-neurologic causes, histochemical and morphologic changes indicative of apoptosis were seen in cells throughout the brain of both patients and controls [29]. The morphologic changes were more advanced in the peri-infarct region and infarct core of the patients with stroke. Apoptotic cells were located primarily within the peri-infarct region, consisting of up to 26 percent of all cells. Increased ischemic damage and neuronal necrosis was associated with a decrease in the percentage of apoptotic cells. The deciding factor in determining whether cells undergo necrosis or apoptosis seems to be the level of energy available in the form of ATP, which is required for formation of the apoptosome. Apoptosis is unable to proceed in its absence. When energy levels are limiting, cell death therefore occurs by necrosis rather than apoptosis. The role of ATP in the mechanism of cell death has been investigated primarily using cell culture models. Cultured neurons depend on https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 8/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate the presence of serum in the culture medium for survival [24]. If the serum is removed, the cells die by necrosis. In serum-free media with added glucose, however, the cells die by apoptosis. Levels of ATP in the brain are decreased during stroke due to the lack of glucose and oxygen required for normal cellular metabolism. Glucose metabolism is decreased by approximately 50 percent in both global and focal ischemia models of stroke. As a consequence, ATP levels may fall to 10 percent of normal in global models or 25 percent in the infarct core in focal ischemia models. ATP levels in the penumbra, however, only drop to 50 percent to 70 percent of normal [30]. ATP levels in the brain may also be decreased by mitochondrial damage or failure; activity of DNA repair enzymes, such as poly ADP-ribose polymerase (PARP); and neuronal depolarization related to glutamate excitotoxicity. In stroke, therefore, low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the penumbra, ATP levels are sufficient enough that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased, with a decrease in the number of apoptotic cells. Loss of brain structural integrity Cerebral ischemia and infarction leads to loss of the structural integrity of the affected brain tissue and blood vessels [6]. This process of tissue destruction and neurovascular disruption is mediated in part by the release of various proteases, particularly the matrix metalloproteases (MMP) that degrade collagens and laminins in the basal lamina [7,31]. The loss of vascular integrity leads to a breakdown of the blood-brain- barrier and development of cerebral edema. Catastrophic failure of vascular integrity is postulated to cause hemorrhagic conversion of ischemic infarction by allowing extravasation of blood constituents into the brain parenchyma [32]. Cerebral edema Cerebral edema complicating stroke can cause secondary damage by several mechanisms, including increased intracranial pressure, which may decrease cerebral blood flow, and mass effect causing displacement of brain tissue from one compartment to another (ie, herniation), a process that can be life-threatening. Two types of cerebral edema can occur as a consequence of ischemic stroke [2,6,32,33]. Cytotoxic edema is caused by the failure of ATP-dependent transport of sodium and calcium ions across the cell membrane. The result is accumulation of water and swelling of the cellular elements of the brain, including neurons, glia, and endothelial cells. Vasogenic edema is caused by increased permeability or breakdown of the brain vascular endothelial cells that constitute the blood-brain barrier [34]. This allows proteins and other https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 9/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate macromolecules to enter the extracellular space, resulting in increased extracellular fluid volume. Roughly 10 percent of ischemic strokes are classified as malignant or massive because of the presence of space-occupying cerebral edema that is severe enough to produce elevated intracranial pressure and brain herniation. (See "Malignant cerebral hemispheric infarction with swelling and risk of herniation", section on 'Malignant hemispheric infarction'.) GENETICS OF STROKE Many of the known risk factors for stroke are variable traits influenced by multiple genes, making it difficult to sort out the genetics behind them. The study of stroke genetics is also impaired by interactions between different risk factors that modulate their effects. It is widely accepted, however, that there is a genetic component to stroke that can lead to increased or decreased risk. Outside of the monogenic disorders discussed below, it is probable that many alleles with small effect sizes contribute to the risk of ischemic stroke [35,36]. Much of the evidence for this comes from studies of twins and from families with a history of stroke [37]. Earlier studies of twins have been troubled by low sample numbers and poor classification of stroke type [37]. However, these studies indicate that stroke-related death in one sibling is associated with a higher risk of stroke-related death in the other sibling among monozygotic (identical) twins versus dizygotic (fraternal) twins. This observation suggests that genetic factors shared by the monozygotic twins played a role in their strokes. As an example, in one of the larger twin studies that evaluated 990 same-sex twin pairs, stroke death affecting both siblings was twice as likely among monozygotic twin pairs compared with dizygotic twin pairs (10 versus 5 percent), and the difference was statistically significant [38]. A family history of stroke is associated with an increased risk of stroke among the offspring [39]. This has been observed for offspring with maternal and paternal histories of stroke [37], and among individuals having a sibling with a prior stroke [40]. Additional insights into the relationship of genetic variants and the risk of ischemic stroke come from genome-wide association studies (GWAS): A 2012 meta-analysis of GWAS that analyzed data from over 12,000 subjects of European ancestry with ischemic stroke and 60,000 controls identified three loci (PITX2, ZFHX3, and HDAC9) with genome-wide significance for ischemic stroke [41]. Importantly, each locus was associated with a specific stroke subtype: https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 10/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate PITX2 and ZFHX3, previously identified as risk factors for atrial fibrillation [42-44], were associated with cardioembolic stroke [41] HDAC9 [44] was associated with large vessel ischemic stroke [41] Findings from a 2013 European GWAS of genetic factors related to coagulation suggested that ABO gene variants are associated with large vessel and cardioembolic stroke subtypes [45], and a systematic review and meta-analysis testing the association of APOE genotype with MRI markers of cerebrovascular disease found that APOE epsilon 2 carrier status was associated with an increased risk of ischemic stroke [46]. In accord with prior results, a 2016 meta-analysis of 12 GWAS with over 10,000 stroke cases and 19,000 controls found genome-wide significance for four loci [47]: PITX2 and ZFHX3 for cardioembolic stroke HDAC9 for large vessel disease ABO for all ischemic stroke Ethnic differences may also contribute to stroke risk. Although differences in lifestyle may be partly responsible for increased or decreased likelihood of stroke, genetic factors also play a role. As an example, individuals of Black African descent have a significantly higher rate of stroke than White populations, even after adjusting for differences in nongenetic risk factors [37,48]. This may or may not be related to the increased frequency among African populations of the sickle cell trait, which is a known cause of stroke due to the obstruction of small blood vessels by abnormal red blood cells. Even in monogenic disorders such as sickle cell disease, multiple genes may interact to modify risk. In a study of 1398 individuals with sickle cell anemia, 12 genes were found to interact with the mutated hemoglobin and modulate the risk of stroke [49]. Monogenic disorders A number of monogenic syndromes are associated with an increased risk of ischemic stroke, including the following [50]: Marfan syndrome and Ehlers-Danlos syndrome, which predispose to cervical artery dissection (see "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Associated conditions and risk factors' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders") Familial moyamoya disease (see "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Etiology and Pathogenesis') Fabry disease (see "Fabry disease: Neurologic manifestations") Pseudoxanthoma elasticum (see "Pseudoxanthoma elasticum") https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 11/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Homocystinuria (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders') Menkes disease (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders') Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)") Cerebral autosomal recessive arteriopathy with subcortical infarctions and leukoencephalopathy (CARASIL) [51-53] Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) [54,55] Sickle cell disease (see "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease") Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') It is important to note that all of these conditions together account for only a small percentage of ischemic strokes [56]. SUMMARY Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. (See 'Cerebral autoregulation' above.) The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. (See 'Consequences of reduction in blood flow during stroke' above.) Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes. (See 'Mechanisms of ischemic cell injury and death' above.). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 12/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased. (See 'Necrosis and apoptosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Daniel B Zemke, PhD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353. 4. Atkins ER, Brodie FG, Rafelt SE, et al. Dynamic cerebral autoregulation is compromised acutely following mild ischaemic stroke but not transient ischaemic attack. Cerebrovasc Dis 2010; 29:228. 5. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41:2697. 6. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 2010; 17:197. 7. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55:310. 8. Feske SK. Ischemic Stroke. Am J Med 2021; 134:1457. 9. Douen AG, Akiyama K, Hogan MJ, et al. Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 13/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 2000; 75:812. 10. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 1990; 348:443. 11. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 2000; 403:316. 12. Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 2008; 60:609. 13. Nandagopal K, Dawson TM, Dawson VL. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 2001; 297:474. 14. Lu GW, Liu HY. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol (1985) 2001; 91:1193. 15. Bola os JP, Almeida A. Roles of nitric oxide in brain hypoxia-ischemia. Biochim Biophys Acta 1999; 1411:415. 16. Love S. Oxidative stress in brain ischemia. Brain Pathol 1999; 9:119. 17. Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med 2003; 9:196. 18. Leist M, Single B, Castoldi AF, et al. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997; 185:1481. 19. Kamel H, Iadecola C. Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol 2012; 69:576. 20. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol 2001; 58:669. 21. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011; 10:471. 22. Kollikowski AM, Schuhmann MK, Nieswandt B, et al. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466. 23. Snider BJ, Gottron FJ, Choi DW. Apoptosis and necrosis in cerebrovascular disease. Ann N Y Acad Sci 1999; 893:243. 24. Ueda H, Fujita R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull 2004; 27:950. 25. Back T, Hemmen T, Sch ler OG. Lesion evolution in cerebral ischemia. J Neurol 2004; 251:388. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 14/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate 26. Guglielmo MA, Chan PT, Cortez S, et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis. Neurol Res 1998; 20:283. 27. Tarkowski E, Rosengren L, Blomstrand C, et al. Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999; 30:321. 28. Love S, Barber R, Wilcock GK. Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 2000; 26:55. 29. Sairanen T, Karjalainen-Lindsberg ML, Paetau A, et al. Apoptosis dominant in the periinfarct area of human ischaemic stroke a possible target of antiapoptotic treatments. Brain 2006; 129:189. 30. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999; 79:1431. 31. Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8:82. 32. Simard JM, Kent TA, Chen M, et al. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6:258. 33. Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol 1987; 72:236. 34. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. 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of ischemic strokes [56]. SUMMARY Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. (See 'Cerebral autoregulation' above.) The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. (See 'Consequences of reduction in blood flow during stroke' above.) Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes. (See 'Mechanisms of ischemic cell injury and death' above.). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 12/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased. (See 'Necrosis and apoptosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Daniel B Zemke, PhD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353. 4. Atkins ER, Brodie FG, Rafelt SE, et al. Dynamic cerebral autoregulation is compromised acutely following mild ischaemic stroke but not transient ischaemic attack. Cerebrovasc Dis 2010; 29:228. 5. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41:2697. 6. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 2010; 17:197. 7. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55:310. 8. Feske SK. Ischemic Stroke. Am J Med 2021; 134:1457. 9. Douen AG, Akiyama K, Hogan MJ, et al. Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 13/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 2000; 75:812. 10. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 1990; 348:443. 11. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 2000; 403:316. 12. Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 2008; 60:609. 13. Nandagopal K, Dawson TM, Dawson VL. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. 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Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011; 10:471. 22. Kollikowski AM, Schuhmann MK, Nieswandt B, et al. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466. 23. Snider BJ, Gottron FJ, Choi DW. Apoptosis and necrosis in cerebrovascular disease. Ann N Y Acad Sci 1999; 893:243. 24. Ueda H, Fujita R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull 2004; 27:950. 25. Back T, Hemmen T, Sch ler OG. Lesion evolution in cerebral ischemia. J Neurol 2004; 251:388. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 14/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate 26. Guglielmo MA, Chan PT, Cortez S, et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis. Neurol Res 1998; 20:283. 27. Tarkowski E, Rosengren L, Blomstrand C, et al. Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999; 30:321. 28. Love S, Barber R, Wilcock GK. Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 2000; 26:55. 29. Sairanen T, Karjalainen-Lindsberg ML, Paetau A, et al. Apoptosis dominant in the periinfarct area of human ischaemic stroke a possible target of antiapoptotic treatments. Brain 2006; 129:189. 30. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999; 79:1431. 31. Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8:82. 32. Simard JM, Kent TA, Chen M, et al. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6:258. 33. Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol 1987; 72:236. 34. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 2011; 42:3323. 35. Matarin M, Singleton A, Hardy J, Meschia J. The genetics of ischaemic stroke. J Intern Med 2010; 267:139. 36. Musunuru K, Hickey KT, Al-Khatib SM, et al. Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American Heart Association. Circ Cardiovasc Genet 2015; 8:216. 37. Carr FJ, McBride MW, Carswell HV, et al. Genetic aspects of stroke: human and experimental studies. J Cereb Blood Flow Metab 2002; 22:767. 38. Bak S, Gaist D, Sindrup SH, et al. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke 2002; 33:769. 39. Seshadri S, Beiser A, Pikula A, et al. Parental occurrence of stroke and risk of stroke in their children: the Framingham study. Circulation 2010; 121:1304. 40. Kasiman K, Lundholm C, Sandin S, et al. Familial effects on ischemic stroke: the role of sibling kinship, sex, and age of onset. Circ Cardiovasc Genet 2012; 5:226. 41. Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012; 11:951. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 15/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate 42. Damani SB, Topol EJ. Molecular genetics of atrial fibrillation. Genome Med 2009; 1:54. 43. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009; 41:876. 44. International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C, et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 2012; 44:328. 45. Williams FM, Carter AM, Hysi PG, et al. Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Ann Neurol 2013; 73:16. 46. Schilling S, DeStefano AL, Sachdev PS, et al. APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology 2013; 81:292. 47. Malik R, Traylor M, Pulit SL, et al. Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. Neurology 2016; 86:1217. 48. Rastenyte D, Tuomilehto J, Sarti C. Genetics of stroke a review. J Neurol Sci 1998; 153:132. 49. Sebastiani P, Ramoni MF, Nolan V, et al. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet 2005; 37:435. 50. Ballabio E, Bersano A, Bresolin N, Candelise L. Monogenic vessel diseases related to ischemic stroke: a clinical approach. J Cereb Blood Flow Metab 2007; 27:1649. 51. Onodera O, Nozaki H, Fukutake T. CARASIL. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK 32533/ (Accessed on May 03, 2011). 52. Nozaki H, Nishizawa M, Onodera O. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2014; 45:3447. 53. Nozaki H, Sekine Y, Fukutake T, et al. Characteristic features and progression of abnormalities on MRI for CARASIL. Neurology 2015; 85:459. 54. Jen J, Cohen AH, Yue Q, et al. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology 1997; 49:1322. 55. Ophoff RA, DeYoung J, Service SK, et al. Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet 2001; 69:447. 56. Lanktree MB, Dichgans M, Hegele RA. Advances in genomic analysis of stroke: what have we learned and where are we headed? Stroke 2010; 41:825. Topic 14085 Version 27.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 16/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate GRAPHICS TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 17/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate The progression of a dissection, thrombus development, and total vessel occlusion Courtesy of Dr. Mounzer Kassab. Graphic 57866 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 18/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Normal cerebral autoregulation and its disturbance during acute ischemic stroke Courtesy of Dr. Mounzer Kassab. Graphic 66923 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 19/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Effects of decreased cerebral blood flow on vital brain functions Courtesy of Dr. Mounzer Kassab. Graphic 77705 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 20/21 7/6/23, 12:10 PM Pathophysiology of ischemic stroke - UpToDate Contributor Disclosures Arshad Majid, MB, ChB, FRCP No relevant financial relationship(s) with ineligible companies to disclose. Mounzer Kassab, MD Speaker's Bureau: UCB Pharma [Anticonvulsant]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 21/21

7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke associated with patent foramen ovale (PFO): Evaluation : Steven R Mess , MD, Stephen JD Brecker, MD, FRCP, FESC, FACC : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 28, 2023. INTRODUCTION When embolic ischemic stroke occurs in an individual with a patent foramen ovale (PFO), the PFO may or may not be causally related to the stroke. This topic will review the approach to the evaluation of patients who have an ischemic stroke in the setting of a PFO. The management of PFO-associated stroke is reviewed elsewhere. (See "Stroke associated with patent foramen ovale (PFO): Management".) Cryptogenic stroke is reviewed in detail separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) The risk of stroke related to atrial septal abnormalities and indications for treating atrial septal defects in adults are also discussed elsewhere. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Management of atrial septal defects in adults".) COMPREHENSIVE EVALUATION Goals and approach Determining whether a PFO is incidental or pathogenic in relation to an ischemic stroke is essential to guide decisions about PFO management and secondary stroke prevention. The approach incorporates an evaluation for other possible causes of ischemic stroke, PFO features, and methods (ie, the Risk of Paradoxical Embolism [RoPE] score and PFO- https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 1/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate associated stroke causal likelihood [PASCAL] classification) that estimate the likelihood of paradoxical embolism through a PFO as the mechanism of the stroke. Clues from the history The history should include specific questions that define the circumstances immediately preceding the event. Was the patient doing something that might increase right-to-left shunt flow through a PFO, such as straining, coughing vigorously, or lifting or pushing a heavy object? Was there any risk for deep venous thrombosis (DVT), such as prolonged immobility (eg, postoperative status, sitting in a cramped airline seat with legs dependent and knees flexed), dehydration, or venous hypercoagulability? The presence of the above historical features raise concern for paradoxical embolism. However, absence of these features does not exclude paradoxical embolism. Is the stroke embolic? By definition, PFO-associated stroke is embolic. On evaluation, an embolic mechanism is especially likely when neuroimaging reveals infarcts in multiple vascular territories or a single wedge-shaped infarct involving cortex and the underlying subcortical white matter. With embolic stroke, the neurologic deficit is typically maximal from the onset, with a possibility of rapid improvement if there is spontaneous recanalization. (See "Overview of the evaluation of stroke", section on 'Determining a presumptive diagnosis of stroke subtype'.) Whether or not an embolic stroke is related to PFO or to another mechanism cannot be determined reliably based upon neuroimaging features alone. However, certain findings may be more suggestive of PFO. In an analysis of data from subjects with cryptogenic stroke and PFO (n = 1141) or no PFO (n = 1539) in the RoPE study database, characteristics associated with a significantly higher prevalence of PFO were a large index stroke (odds ratio [OR] 1.36), index stroke seen on imaging (OR 1.53), and superficial (ie, involving the cerebral or cerebellar cortex) stroke location (OR 1.54) [1]. The last of these characteristics is included in the RoPE score. Exclusion of other sources of ischemic stroke Patients with an ischemic stroke and a PFO should undergo a comprehensive evaluation by both a stroke neurologist and a cardiologist to ensure that other causes of ischemic stroke are excluded and that PFO-associated stroke (ie, paradoxical embolism through a PFO) is the most likely mechanism [2]. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Evaluation and diagnosis'.) PFO-associated stroke Patients with an embolic-appearing ischemic stroke who have a medium- or high-risk PFO (see 'PFO assessment' below) and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke [3]. Findings The evaluation of a PFO-associated stroke is characterized by the following findings [4]: https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 2/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate No large vessel stenosis ( 50 percent) or occlusion in the territory of the infarct. Intracranial and extracranial neurovascular imaging should be performed to exclude vascular causes of stroke, including large artery atherosclerosis, dissection, and other vasculopathy. (See "Neuroimaging of acute stroke".) No radiographic acute lacunar infarction (ie, a small [ 1.5 cm] deep perforator infarct) and no clinical lacunar stroke syndrome (ie, hemiparesis/plegia, hemianesthesia without cortical signs) if imaging shows no infarct. (See "Lacunar infarcts", section on 'Clinical features'.) No evidence of occult atrial fibrillation or other high-risk cardioembolic source ( table 1) on cardiac monitoring and echocardiography. Screening for atrial fibrillation should include a 12-lead electrocardiogram (ECG) and 24-hour cardiac monitoring (ambulatory or by telemetry). Adults over age 40 years with cryptogenic ischemic stroke or cryptogenic transient ischemic attack (TIA) with no atrial fibrillation detected on 12-lead ECG and 24-hour monitoring should undergo extended ambulatory monitoring, as discussed elsewhere. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Advanced evaluation'.) Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) not only enable identification and characterization of PFOs but also enable identification of relevant structural findings including atrial septal aneurysms and other potential embolic sources such as high-risk valve lesions (eg, mitral stenosis), cardiac tumors (eg, myxoma), intracardiac thrombus, fibroelastomas, and other valvular vegetations. Test selection is discussed below and reviewed separately. (See 'PFO assessment' below and "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) No hypercoagulable condition with a high risk for arterial thrombotic events, such as the antiphospholipid syndrome. (See "Clinical manifestations of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome" and "Management of antiphospholipid syndrome".) PFO assessment Methods to detect a right-to-left shunt associated with a PFO include TTE, TEE, and transcranial Doppler (TCD), in conjunction with agitated saline contrast (a "bubble study")Among these methods, TCD cannot confirm intracardiac shunting or relevant structural findings (e.g., atrial septal aneurysm), and generally only TEE enables visualization of the type https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 3/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate (eg, PFO, atrial septal defect [ASD]), site, and size of the shunt. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Cardiac and aortic evaluation'.) While cardiac CT and cardiovascular magnetic resonance (CMR) imaging have been used to identify PFO, they are less sensitive than TEE [5-7]. Identification of PFO The diagnostic evaluation of PFO is reviewed here briefly and discussed in detail separately. (See "Patent foramen ovale", section on 'Diagnosis and evaluation'.) TTE or TEE These tests are performed with intravenous injection of agitated saline contrast at rest, with Valsalva, and with cough; the study is considered positive if microbubbles (typically three or more) appear in the left heart within three cardiac cycles of bubbles filling the right atrium [8]. Multiple agitated saline contrast injections with provocative maneuvers may be required to enhance sensitivity for identification of a shunt via the PFO [9]. In some cases, intermittent flow through the PFO is also visualized by color Doppler. (See "Patent foramen ovale", section on 'Diagnosis and evaluation'.) TTE is often used as the initial study because it is better tolerated than TEE and is more widely available than TEE or TCD. Also, TTE provides a better assessment (with a microbubble ultrasound-enhancing agent) for left ventricular thrombus (particularly apical), which is an important component of the evaluation in patients who may have ischemic heart disease or cardiomyopathy. In addition, some patients are better able to perform the Valsalva maneuver and cough during TTE than during TEE (due to the effects of sedation and/or discomfort during TEE). Thus, in some cases, TTE may be more sensitive than TEE for PFO shunt detection [10]. However, TEE is the reference standard for the detection of PFO [9], is generally more sensitive than TTE [11], and better demonstrates its anatomic features. Therefore, patients who are candidates for PFO closure (ie, those 60 years of age with an embolic-appearing stroke or a TIA who have no evident source of stroke or TIA other than a PFO, despite a comprehensive evaluation) should undergo TEE as either the initial study or as a follow-up study to TTE or TCD, even when a preceding TTE is negative or nondiagnostic for PFO. (See "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) For patients who do not meet selection criteria for PFO closure, a follow-up TEE may still be indicated to identify a stroke etiology but is not required to assess for PFO. Note that all patients who are candidates for PFO closure should have preprocedural imaging with TEE, including those with features suggesting PFO detected by TTE or TCD. (See "Stroke https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 4/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate associated with patent foramen ovale (PFO): Management", section on 'Preprocedural imaging'.) TCD Insonating the middle cerebral artery through the temporal bone window, TCD is performed with intravenous injection of agitated saline contrast at rest, with Valsalva, and with cough; the study is considered positive for a right-to-left shunt if bubbles are detected in the middle cerebral artery. This approach is at least as sensitive as TEE to identify right- to-left shunt [12-15]; TCD also has advantages compared with TEE in being noninvasive and relatively easy to perform at the bedside. However, TCD cannot confirm the location of the shunt (which may be intracardiac or extracardiac), identify an atrial septal aneurysm, or rule out other cardioembolic sources. Thus, when TCD is positive, imaging (generally with TEE) is performed to identify shunt location [11]. PFO shunt size PFO size (small versus large) is a component of the PASCAL approach to risk classification. PFO size is generally inferred from the degree of right-to-left shunting apparent on echocardiography with agitated saline contrast, based on the number of microbubbles appearing in a single frame in the left atrium either spontaneously or after a provocative (Valsalva) maneuver within three cardiac cycles after opacification of the right atrium [16,17]. PFO size is categorized as small or large in the PASCAL classification described below. We use the following categories (based upon thresholds in four of six randomized trials in the meta-analysis discussed below [18]): Large: >20 microbubbles (which was the threshold used in four of the six included randomized trials) Small: 20 microbubbles Some trials have classified shunt size into small, moderate, and large categories [19]. In one small study, PFO measured ante mortem by assessment of jet size on color Doppler TEE and number of microbubbles on contrast TEE correlated well with autopsy finding; patients with a PFO >10 mm at autopsy had large shunts with >25 microbubbles on contrast TEE [20]. Among patients with an embolic stroke topography, a PFO, and no alternative cause, features associated with medium- to high-risk PFO include factors that increase right-to-left shunt flow (eg, large PFO size, chronic right atrial hypertension, or a Valsalva maneuver at onset of stroke) and concomitant pulmonary embolism or deep venous thrombosis preceding the ischemic stroke [3]. Individual patient characteristics (age and vascular risk factors) are also important in the assessment of PFO risk. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 5/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Atrial septal aneurysm An atrial septal aneurysm (ASA) is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic oscillation (intrusion) of at least 10 to 15 mm into the left or right atrium during the cardiorespiratory cycle and is most commonly identified on TEE (with lower sensitivity of detection by TTE). Although not a consistent finding across all studies, the risk of stroke is likely increased when a PFO is associated with an ASA. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'ASA' and "Patent foramen ovale", section on 'Atrial septal aneurysm'.) Straddling thrombus Thrombus trapped in a PFO is rarely encountered [21-24], but this finding confirms paradoxical embolus in transit via a very high-risk PFO, which may in some cases warrant surgical treatment to remove the clot and repair the PFO [3]. Search for venous thromboembolism We suggest performing a standard evaluation for DVT with D-dimer level and/or ultrasonography of the lower extremities for patients with a PFO- associated embolic infarct and no other evident source of stroke; additional investigations such as CT or MRI venography are generally not warranted. Details of the evaluation are discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".) Identification of DVT or other evidence of venous thromboembolism can help strengthen the clinical inference of paradoxical embolism and also has important implications for therapy (including identifying an indication for anticoagulation, which impacts the timing and need for PFO device closure). Ideally, the evaluation should be done within two to three days of stroke onset, before venous thrombosis develops secondary to stroke-related immobility [3]. Studies using radiograph venography or magnetic resonance venography to examine patients with ischemic cerebral events or other suspected embolic events have found variable rates of proximal leg or pelvic deep venous thrombosis (10 to 22 percent) [25-27]. Among those with documented DVT, most had no symptoms or signs of venous thrombosis. There are several potential explanations for the low rates of proximal DVT in patients with PFO-associated embolic infarct and no other evident source of stroke: Evaluation for DVT was incomplete in these studies since venography evaluated either the lower extremities or pelvic veins, but not both. The emboli consist of platelet fibrin particles that normally circulate in the systemic venous bed and are too small to be seen with conventional testing. These particles are removed by the efficient lytic system of the lungs; however, when shunted across a PFO or ASD, they may travel unlysed into the cerebral circulation [28]. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 6/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The clot forms in the heart at the edges or in the tunnel of the PFO, or in an ASA. The embolic source is in the systemic arterial circulation. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Left-sided sources'.) DVTs have resolved (lysed, completely embolized, or recanalized) during the delay between onset of the embolic event and venography. Proximal DVTs may be lysed in some patients treated with intravenous thrombolytic therapy [27]. Hypercoagulable evaluation Hematologic testing to exclude hypercoagulable states (eg, antiphospholipid syndrome and hyperhomocysteinemia) is indicated for patients with stroke being considered for PFO closure. (See "Diagnosis of antiphospholipid syndrome".) LIKELIHOOD OF A PFO-ASSOCIATED STROKE RoPE score The Risk of Paradoxical Embolism (RoPE) score, as shown in the table ( table 2) and calculator (calculator 1), estimates the probability that a PFO is incidental or pathogenic in a patient with a seemingly cryptogenic stroke [29]. The PFO-attributable fraction of stroke derived from the RoPE score ( table 3) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The RoPE score is a major component of the PFO-associated stroke causal likelihood (PASCAL) classification system, which provides additional discrimination, as described below. PASCAL classification The PASCAL classification system ( table 4) estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [3]. The classification is based upon the RoPE score combined with anatomic and clinical factors (see 'PFO assessment' above) including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism; PASCAL categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 4). Given the high prevalence of PFO in the general population and the low risk of stroke related to PFO, there is always some degree of uncertainty about the causal relationship between PFO and an embolic-appearing ischemic stroke with no other evident stroke mechanism despite a https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 7/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate comprehensive evaluation [30]. The possibility that the PFO is an "innocent bystander" and that another mechanism is responsible for the stroke is particularly applicable to older patients and to those with known risk factors for stroke (eg, hypertension, hypercholesterolemia, smoking) [31-33]. Causality can best be inferred in younger patients with no other apparent etiology for stroke [34], particularly if DVT is present (as a potential source for paradoxical emboli). MANAGEMENT The management of PFO-associated stroke, including selection of appropriate candidates for PFO closure ( algorithm 1), is reviewed separately. (See "Stroke associated with patent foramen ovale (PFO): Management".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 8/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Is the PFO incidental or pathogenic? Determining whether a patent foramen ovale (PFO) is incidental or pathogenic in relation to an ischemic stroke is essential to guide decisions about PFO management and secondary stroke prevention. This determination incorporates an evaluation for other possible causes of ischemic stroke, PFO features, and methods (ie, the Risk of Paradoxical Embolism [RoPE] score and PFO-associated stroke causal likelihood [PASCAL] classification) that estimate the likelihood of paradoxical embolism through a PFO as the mechanism of the stroke. (See 'Goals and approach' above.) Is the stroke embolic? By definition, PFO-associated stroke is embolic. Neuroimaging features that suggest embolism include infarcts in multiple vascular territories or a single wedge-shaped infarct involving cortex and the underlying subcortical white matter. (See 'Is the stroke embolic?' above.) Exclusion of other sources of ischemic stroke A PFO-associated embolic infarct requires that other causes of ischemic stroke are excluded by the following (see 'Exclusion of other sources of ischemic stroke' above): No large vessel stenosis in the territory of the infarct by neurovascular imaging No evidence of atrial fibrillation on telemetry and 30-day ambulatory cardiac monitoring A PFO but no other high-risk source of cardiogenic embolism identified on transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) No hypercoagulable condition with a high risk for arterial thrombotic events, such as the antiphospholipid syndrome PFO assessment The diagnostic evaluation of PFO should assess for the presence and size of a right-to-left shunting and other features suggestive of high risk for paradoxical embolism (eg, an atrial septal aneurysm or [rarely] a straddling thrombus). (See 'PFO assessment' above.) Evaluation for venous thromboembolism and hypercoagulable state We evaluate for these in all patients with a PFO-associated embolic infarct and no other evident source of stroke. (See 'Search for venous thromboembolism' above and 'Hypercoagulable evaluation' above.) Likelihood of a PFO-associated stroke The RoPE score ( table 2) and the PASCAL classification system ( table 4) are useful to estimate the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke ( algorithm 1). (See 'Likelihood of a PFO-associated stroke' above.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 9/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Naser M Ammash, MD, and Robert S Schwartz, MD, and Joseph K Perloff, MD who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Thaler DE, Ruthazer R, Di Angelantonio E, et al. Neuroimaging findings in cryptogenic stroke patients with and without patent foramen ovale. Stroke 2013; 44:675. 2. Farb A, Ibrahim NG, Zuckerman BD. Patent Foramen Ovale after Cryptogenic Stroke - Assessing the Evidence for Closure. N Engl J Med 2017; 377:1006. 3. Elgendy AY, Saver JL, Amin Z, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol 2020; 77:878. 4. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 5. Lou J, Bao Y, Lv T, Yang Y. Computed Tomography for Detecting Patent Foramen Ovale: A Meta-Analysis. Heart Surg Forum 2022; 25:E849. 6. Hamilton-Craig C, Sestito A, Natale L, et al. Contrast transoesophageal echocardiography remains superior to contrast-enhanced cardiac magnetic resonance imaging for the diagnosis of patent foramen ovale. Eur J Echocardiogr 2011; 12:222. 7. Zahuranec DB, Mueller GC, Bach DS, et al. Pilot study of cardiac magnetic resonance imaging for detection of embolic source after ischemic stroke. J Stroke Cerebrovasc Dis 2012; 21:794. 8. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010; 3:749. 9. Silvestry FE, Cohen MS, Armsby LB, et al. Guidelines for the Echocardiographic Assessment of Atrial Septal Defect and Patent Foramen Ovale: From the American Society of Echocardiography and Society for Cardiac Angiography and Interventions. J Am Soc Echocardiogr 2015; 28:910. 10. Rodrigues AC, Picard MH, Carbone A, et al. Importance of adequately performed Valsalva maneuver to detect patent foramen ovale during transesophageal echocardiography. J Am Soc Echocardiogr 2013; 26:1337. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 10/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate 11. Pristipino C, Sievert H, D'Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2019; 40:3182. 12. Park S, Oh JK, Song JK, et al. Transcranial Doppler as a Screening Tool for High-Risk Patent Foramen Ovale in Cryptogenic Stroke. J Neuroimaging 2021; 31:165. 13. Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovasc Dis 2000; 10:490. 14. Spencer MP, Moehring MA, Jesurum J, et al. Power m-mode transcranial Doppler for diagnosis of patent foramen ovale and assessing transcatheter closure. J Neuroimaging 2004; 14:342. 15. Palazzo P, Ingrand P, Agius P, et al. Transcranial Doppler to detect right-to-left shunt in cryptogenic acute ischemic stroke. Brain Behav 2019; 9:e01091. 16. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11. 17. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 18. Kent DM, Saver JL, Kasner SE, et al. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA 2021; 326:2277. 19. S ndergaard L, Kasner SE, Rhodes JF, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017; 377:1033. 20. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202. 21. Acikel S, Ertem AG, Kiziltepe U, et al. Double-edged sword in the heart: trapped deep venous thrombus in a patent foramen ovale. Blood Coagul Fibrinolysis 2012; 23:673. 22. Rajani R, Mirza F, Teoh Y, Gandhi S. Entrapment: thrombus within a patent foramen ovale. J Cardiovasc Med (Hagerstown) 2009; 10:576. 23. Ozdogru I, Kaya MG, Dogan A, et al. Thrombus crossing through a patent foramen ovale. Int J Cardiol 2009; 133:e55. 24. Mirode A, Tribouilloy C, Adam MC, et al. [Echocardiographic diagnosis of a thrombus trapped in a patent foramen ovale. Apropos of a case]. Arch Mal Coeur Vaiss 1993; 86:1065. 25. Lethen H, Flachskampf FA, Schneider R, et al. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 11/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate 1997; 80:1066. 26. St llberger C, Slany J, Schuster I, et al. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med 1993; 119:461. 27. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004; 35:46. 28. Meier B, Lock JE. Contemporary management of patent foramen ovale. Circulation 2003; 107:5. 29. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. 30. Kasner SE, Lattanzi S, Fonseca AC, Elgendy AY. Uncertainties and Controversies in the Management of Ischemic Stroke and Transient Ischemic Attack Patients With Patent Foramen Ovale. Stroke 2021; 52:e806. 31. Homma S, Di Tullio MR, Sacco RL, et al. Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke 1997; 28:2376. 32. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 33. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172. 34. Holmes DR Jr, Cabalka A. Was your mother right do we always need to close the door? Circulation 2002; 106:1034. Topic 1100 Version 51.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 12/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate GRAPHICS Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month Left atrial spontaneous echo contrast prior to stroke) ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 13/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 14/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 15/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 16/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 17/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri

Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 13/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 14/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 15/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 16/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 17/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri strategies including antithrombotic therapy, blood pressure control, low-density lipoprotein (LDL)-lowering th lifestyle modification, as appropriate. For details regarding the evaluation required for a comprehensive stroke evaluation, choice of antithromboti other factors that impact decision-making for PFO management, refer to appropriate UpToDate topics. PFO: patent foramen ovale; DVT: deep venous thrombosis; PE: pulmonary embolism; RoPE: Risk of Paradoxic PASCAL: PFO-associated stroke causal likelihood; ASA: atrial septal aneurysm. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 18/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate For most patients with an indication for anticoagulation >1 year, PFO closure is not performed, as benefit in uncertain. PFO closure may be an option for selected patients, such as those who experience recurrent embo other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Patients who undergo PFO closure (percutaneous or surgical) are treated with antiplatelet agents. We treat to 81 mg/day) plus clopidogrel (75 mg/day) for three months, followed by continued aspirin therapy. For the rare patient who has a concurrent indication for surgical valve intervention, surgical (rather than pe closure is appropriate. If percutaneous PFO closure is not feasible and there is no concurrent indication for c suggest against surgical PFO closure. For most patients >60 years old, PFO closure is not performed since such patients were excluded from tria and the benefit of closure in this setting is unproven. PFO closure may be an option for selected patients >60 as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Refer to UpToDate topic on cryptogenic stroke. Graphic 138535 Version 1.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 19/20 7/6/23, 12:11 PM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Stephen JD Brecker, MD, FRCP, FESC, FACC Grant/Research/Clinical Trial Support: Medtronic [Transcatheter valves]. Consultant/Advisory Boards: Aortic Innovations LLC [Transcatheter valves]; Medtronic [Transcatheter valves]. Speaker's Bureau: Medtronic [Transcatheter valves]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 20/20

7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke associated with patent foramen ovale (PFO): Management : Steven R Mess , MD, Stephen JD Brecker, MD, FRCP, FESC, FACC : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 27, 2023. INTRODUCTION This topic will review the approach to management of patients with an embolic-appearing ischemic stroke who have a patent foramen ovale (PFO) and no other apparent cause of stroke. The evaluation of patients with ischemic stroke and a PFO is reviewed elsewhere. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) The risk of stroke related to atrial septal abnormalities and indications for treating atrial septal defects in adults are discussed elsewhere. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Management of atrial septal defects in adults".) Despite a possible association of migraine with right-to-left cardiac shunts, PFO closure is not an effective treatment for migraine. This is reviewed elsewhere. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.) PATIENT SELECTION FOR PFO CLOSURE Role of RoPE and PASCAL in patient selection For patients with an embolic stroke without an evident cause, we use the PFO-associated stroke causal likelihood (PASCAL) classification system ( table 1), which incorporates the Risk of Paradoxical Embolism (RoPE) score ( table 2) (calculator 1), to classify the causal association of PFO with the stroke and to guide decision-making for PFO device closure. In the setting of a patient 60 years of age and no other https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 1/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate evident source of stroke despite a comprehensive evaluation, PFO closure is warranted if the RoPE score is >6 and/or there is a large shunt or atrial septal aneurysm. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification' and 'Benefit' below.) Given the high prevalence of PFO in the general population and the low risk of stroke related to PFO, there is always some degree of uncertainty about the causal relationship between PFO and an embolic-appearing ischemic stroke with no other evident stroke mechanism despite a comprehensive evaluation [1]. The possibility that the PFO is an "innocent bystander" and that another mechanism is responsible for the stroke is particularly applicable to older patients and to those with known risk factors for stroke (eg, hypertension, hypercholesterolemia, smoking) [2-4]. Causality can best be inferred in younger patients with no other apparent etiology for stroke [5], particularly if DVT is present (as a potential source for paradoxical emboli). Selection criteria PFO associated stroke Selected patients with PFO with all of the following characteristics are candidates for percutaneous PFO closure ( algorithm 1): Age 60 years Embolic stroke topography (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Is the stroke embolic?') No other evident source of stroke despite a comprehensive evaluation (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Exclusion of other sources of ischemic stroke') A possible, probable, or definite likelihood that the stroke was causally related to the PFO according to the PASCAL classification system ( table 1), which incorporates the RoPE score and high-risk features of the PFO on echocardiogram ( table 2) (calculator 1) No concurrent indication for anticoagulation (see 'Special considerations in anticoagulated patients' below) For most patients without a concurrent indication for anticoagulation who are 60 years of age with a possible, probable, or definite likelihood by PASCAL that the stroke was causally associated with the PFO, we suggest percutaneous PFO device closure in addition to antiplatelet therapy. (See 'Percutaneous PFO closure' below.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 2/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate For patients age >60 years with a PASCAL determination of possible, probable, or definite causal association, the safety and benefit of PFO device closure is unknown since these patients were excluded from the vast majority of randomized trials of PFO device closure (see 'Benefit' below). Furthermore, a patient-level meta-analysis demonstrated that risk of atrial fibrillation after PFO closure increases with age [6]. Thus, decisions about PFO closure for such patients should be based upon an individualized assessment of potential risks and benefits and patient preferences. PFO closure is not performed in most patients >60 years old in this setting but may be an option for selected patients such as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. Exceptions Among patients who otherwise meet criteria for percutaneous PFO closure, management may differ in the following clinical settings: Concurrent indication for anticoagulation If otherwise indicated, PFO device closure may be temporarily deferred for patients with a concurrent indication for short- term anticoagulation ( 1 year); the benefit of PFO device closure is uncertain for patients with a concurrent indication for long-term anticoagulation, as discussed below. (See 'Special considerations in anticoagulated patients' below.) Concurrent indication for cardiac surgery For rare patients aged 60 years who meet criteria for PFO device closure but have a concurrent indication for cardiac surgery (eg, for valve surgery), surgical closure of PFO for secondary stroke prevention is appropriate. (See 'Surgical PFO closure' below.) Percutaneous PFO closure not feasible For rare patients who have a PFO that is not amenable to percutaneous closure but meet PASCAL criteria for PFO causal association, the benefit of surgical closure is uncertain. In the absence of a concurrent indication for cardiac surgery, we suggest against surgical closure. PFO unlikely to be associated with stroke For patients who are unlikely to have a PFO- associated stroke by PASCAL classification ( table 1), we suggest against percutaneous PFO device closure. (See 'Benefit' below.) Note that the evidence from a 2021 meta-analysis [6] supporting the use of the PASCAL classification was published after the 2018 European position paper on the management of patients with PFO [7], the 2019 Clinical Commissioning Policy for PFO closure from the National Health Service in England [8], the 2020 American Academy of Neurology practice advisory [9], and the 2021 stroke prevention guideline from the American Heart Association/American Stroke Association [10]. Therefore, recommendations from these guidelines did not incorporate the PASCAL classification. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 3/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Special considerations in anticoagulated patients Patients with venous thromboembolism that is provoked by a known event or an identifiable transient risk factor are generally treated with anticoagulation for 3 to 12 months, and anticoagulation is generally the sole antithrombotic therapy required. In such cases, PFO device closure, if otherwise indicated, can be postponed until anticoagulation is stopped. For patients assigned to PFO closure in the RESPECT trial, the incidence of venous thromboembolism more than 30 days postprocedure was higher among those with a history of overt deep vein thrombosis than for those without such a history [11]. For patients with an embolic-appearing stroke who have an indication for chronic (>12 months) anticoagulation (eg, unprovoked or recurrent deep venous thrombosis), the benefit of PFO closure is uncertain. For such patients, we suggest individualized, multidisciplinary, shared decision-making that accounts for the risks of thrombosis, embolism, and intervention in determining whether to proceed with chronic anticoagulation alone or to also perform percutaneous PFO closure. For most patients with a concurrent indication for anticoagulation >1 year, PFO closure is not performed, given its uncertain benefit. PFO closure may be an option for selected patients such as those who experience recurrent embolic stroke without other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. Excepting venous thromboembolism, most common indications for anticoagulation are also potential higher-risk mechanisms for embolic stroke, such as atrial fibrillation and prosthetic heart valves. For patients with these conditions, cardiogenic embolism is the most likely cause of the stroke, and a PFO likely to be an incidental finding; in these settings, the presence of a PFO does not generally alter management. Informed decision-making Consideration of PFO closure, including benefits, risks, and alternative treatment options, must be discussed with the patient by the neurologist and cardiologist. The patient should understand the immediate and long-term potential benefits and risks of treatment options (including decreased risk of recurrent stroke and increased risk of atrial fibrillation with PFO percutaneous device closure) in order to make an appropriately informed decision that accounts for their own values and preferences. PERCUTANEOUS PFO CLOSURE Indications and exclusions Selection criteria for candidates for percutaneous PFO closure are discussed above. (See 'Patient selection for PFO closure' above.) Exclusions to percutaneous device closure include the presence of an inferior vena cava filter, elevated bleeding risk or coagulopathy, and vascular, cardiac, or PFO anatomy that is unsuitable https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 4/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate for device placement. Benefit The balance of evidence from randomized controlled trials suggests that percutaneous PFO closure is more effective for preventing recurrent ischemic stroke than antiplatelet therapy alone for highly selected patients who have an apparently embolic (seemingly cryptogenic) ischemic stroke and a PFO [11-14]. (See 'Percutaneous PFO closure' above.) Clinical trial evidence suggests that PFO percutaneous device closure is more effective than antiplatelet therapy alone for reducing the risk of recurrent stroke in select patients aged 60 years with an embolic-appearing ischemic stroke who have a PFO with a right-to-left interatrial shunt and who have no other identified stroke cause or mechanism. The risk of recurrent stroke with device closure is reduced by approximately 60 percent compared with medical therapy (eg, from approximately 5 to 2 percent during a three- to six-year period) [15]; the corresponding number needed to treat to prevent one recurrent stroke during this period is approximately 30. The patients most likely to benefit may be those with a large right-to-left interatrial shunt and/or an associated atrial septal aneurysm (ASA), characteristics that suggest an increased risk for paradoxical embolism. Almost all randomized controlled trials of percutaneous PFO closure have reported point estimates suggesting that PFO closure is more effective than medical therapy for reducing recurrent stroke rates. These results were not statistically significant by intention-to-treat analyses in the first three trials (CLOSURE I [16], PC [17], and RESPECT [18]), but were significant in later trials (RESPECT extended follow-up [11], REDUCE [14], and CLOSE [12]). The trials that found clear benefit for PFO device closure were likely positive because of several factors. First, these latter trials enrolled subjects when off-label PFO closure had waned to some extent, and thus it is possible that patients who were more likely to benefit were included in these studies. Furthermore, to varying degrees for the individual studies, they included a requirement for neuroimaging confirmation of stroke prior to enrollment, excluded lacunar infarcts, provided longer follow-up, and selected patients with PFO features (ie, large shunt size or presence of an associated ASA) that may portend an increased risk of paradoxical embolism. Meta-analyses of closure trials consistently show that patients in the PFO closure groups had increased rates of newly detected atrial fibrillation compared with the medical therapy groups [15,19]. (See 'Adverse effects' below.) Meta-analyses In a 2018 meta-analysis that included four trials (PC [17], RESPECT extended follow-up [11], REDUCE [14], and CLOSE [12]) with 2531 subjects and follow-up ranging from 3.2 to 5.9 years, PFO closure reduced the risk of recurrent stroke from 5.1 percent with medical therapy to 1.8 percent (absolute risk reduction [ARR] 3.3 percent, 95% https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 5/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate CI 6.2-0.4 percent) [15,20]. Based on these data, the number needed to treat with PFO device closure to prevent one recurrent stroke was approximately 30. Similarly, a separate 2018 meta-analysis that included the same trials, with follow-up ranging from 2.1 to 5.3 years, found that PFO closure reduced the risk of recurrent stroke from 4.1 percent with medical therapy to 1.2 percent (ARR 3.1 percent, 95% CI 5.1-1.0 percent) [19]. Both meta- analyses excluded the CLOSURE I trial because it used the STARFlex PFO closure device, which was associated with higher complication and lower procedural success rates than the PFO closure devices used in the other trials and is no longer available [15,19]. Other meta-analyses of PFO closure have generally reported similar findings [21-29]. A 2021 meta-analysis of individual patient data (n = 3740) from six randomized controlled trials, with a median follow-up of 57 months, found that PFO closure reduced the annualized incidence of stroke compared with medical therapy alone (0.47 versus 1.09 percent, adjusted hazard ratio [HR] 0.41, 95% CI 0.28-0.60) [6]. Importantly, the risk reduction for recurrent stroke with PFO closure varied among subgroups with different probabilities that the stroke was causally related to the PFO, as determined by the Risk of Paradoxical Embolism (RoPE) score ( table 2) and a modified PFO-associated stroke causal likelihood (PASCAL) classification ( table 1). For the risk of recurrent ischemic stroke with PFO closure compared with medical therapy alone, patients with high RoPE score (ie, higher risk PFO) had an HR of 0.21 (95% CI 0.11-0.42), while those with a low RoPE score (ie, lower risk PFO) had an HR of 0.61 (95% CI 0.37-1.00). However, patients categorized by the PASCAL classification as probable, possible, or unlikely to have a PFO- associated stroke had HRs of 0.10 (95% CI 0.03-0.35), 0.38 (95% CI 0.22-0.65), and 1.14 (95% CI 0.53-2.46), respectively. Thus, the PASCAL score provides greater discrimination of who is likely to benefit from closure and by what degree, compared with the RoPE score alone. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) Individual trials The individual trials used the broad term "cryptogenic" rather than "PFO-associated" stroke but aimed to enroll the latter, and reported the following results: In the CLOSURE I trial, 909 adult patients 60 years old with a PFO and cryptogenic stroke or transient ischemic attack (TIA) were randomly assigned either to PFO device closure (n = 447) or to medical therapy (n = 462) [16]. Patients in the device group were treated with the STARFlex PFO closure device and received aspirin plus clopidogrel for six months followed by aspirin alone; those in the medical therapy group were treated with aspirin or warfarin or both. The primary endpoint was a composite of stroke or TIA at two years plus 30-day mortality and neurologic mortality beyond 30 days. At two https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 6/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate years, by intention-to-treat analysis, there was no significant difference between device closure and medical therapy in the rates of the primary endpoint (5.5 versus 6.8 percent, hazard ratio [HR] 0.78, 95% CI 0.45-1.35), stroke (2.9 versus 3.1 percent), or TIA (3.1 versus 4.1 percent). Major vascular complications were significantly more frequent with device closure (3.2 versus 0 percent), as was atrial fibrillation (5.7 versus 0.7 percent), most of which was periprocedural. The PC trial randomly assigned 414 adults (<60 years of age) with PFO and ischemic stroke, TIA, or a peripheral embolic event to treatment with the Amplatzer PFO Occluder or medical therapy [17]. After a mean follow-up of four years, the composite primary endpoint of death, nonfatal stroke, TIA, or peripheral embolism for the intention-to- treat cohort occurred in 7 of 204 patients (3.4 percent) in the device closure group and 11 of 210 patients (5.2 percent) in the medical therapy group; the difference was not statistically significant (HR 0.63, 95% CI 0.24-1.62). Serious adverse events were slightly more frequent in the device closure group (21.1 percent versus 17.6 percent), including a nonsignificantly higher rate of new-onset atrial fibrillation in the device closure group (2.9 versus 1.0 percent). In the RESPECT trial, 980 patients (age 18 to 60 years) with a PFO and cryptogenic ischemic stroke were randomly assigned to receive treatment with the Amplatzer PFO Occluder or medical therapy [18]. The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The trial results were analyzed after reaching the target of 25 primary endpoint events; all 25 events were nonfatal ischemic strokes. The mean follow-up was approximately 2.6 years, and the primary endpoint for the intention-to-treat cohort occurred in 9 of 499 patients (1.8 percent) in the closure group and 16 of 481 patients (3.3 percent) in the medical therapy group, a difference that was not statistically significant (0.66 versus 1.38 events per 100 patient-years, HR 0.49, 95% CI 0.22-1.11). A later RESPECT publication reported outcomes at a median follow-up of 5.9 years [11]. By intention-to-treat analysis, recurrent ischemic stroke was less frequent in the closure group compared with the medical therapy group (18 versus 28 events, 0.58 versus 1.07 events per 100 patient-years, HR 0.55, 95% CI 0.31-0.99). However, the dropout rate was higher and treatment exposure lower in the medical therapy group, leading to an unequal exposure to the risk of outcome events among the two groups. The REDUCE trial randomly assigned 664 patients 18 to 59 years of age with cryptogenic embolic-appearing ischemic stroke and PFO with a right-to-left shunt demonstrated by means of transesophageal echocardiography [14,30]. Patients were randomly assigned https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 7/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate to PFO closure combined with antiplatelet therapy or treatment with antiplatelet therapy alone in a 2:1 ratio. During a median follow-up of 5 years, clinical ischemic stroke by intention-to-treat analysis occurred in fewer patients in the PFO closure group compared with the antiplatelet-only group (8 of 441 versus 12 of 223 patients, 1.8 versus 5.4 percent, HR 0.31, 95% CI 0.13-0.76). The CLOSE trial enrolled patients 16 to 60 years of age with recent cryptogenic stroke attributed to PFO who had an associated ASA or large interatrial shunt on echocardiography [12]. Patients were randomly assigned in a 1:1:1 ratio to PFO closure plus antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation, with the exception that patients with contraindications to PFO device closure or to anticoagulation were assigned to alternative noncontraindicated treatment or to antiplatelet therapy. The main arm of the trial (n = 473) compared PFO closure with antiplatelet therapy; at a mean follow-up of 5.3 years, there were no recurrent strokes among 238 patients in the PFO closure group compared with 14 strokes among 233 patients the antiplatelet-only group (HR 0.03, 95% CI 0.0-0.26). In the nonclosure arms of the trial, there was a nonsignificant trend toward fewer recurrent strokes in the anticoagulation group (3 among 187 patients) compared with the antiplatelet group (7 among 174 patients) (HR 0.44, 95% CI 0.11-1.48). Trial limitations There are important limitations of these trials that lower confidence in the results or result in important questions about generalizability. As examples: All of these trials utilized open-label endpoint ascertainment, which increases the risk of bias. However, objective neuroimaging support for the reduction in risk of recurrent stroke with PFO closure comes from the REDUCE trial, which required brain magnetic resonance imaging (MRI) at baseline and after a clinical neurologic event or at two years of follow-up for all subjects [31]. With clinical and imaging data available for approximately 90 percent of patients at two years, the rate of new infarcts (both symptomatic and silent) on MRI was lower for patients who had PFO closure compared with patients who had medical therapy alone (4.7 versus 10.7 percent, relative risk 0.44, 95% CI 0.24-0.81) [31]. The number of primary events was relatively low, with a total of 52 events in the CLOSURE I trial [16], 18 in the PC trial [17], 46 in the RESPECT trial [11], 18 clinical events in the REDUCE trial [14], and 14 events in the treatment groups comparing PFO closure with antiplatelet treatment in the CLOSE trial [12]. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 8/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate The duration of follow-up in the CLOSURE I trial (two years) and the primary analysis of the RESPECT trial (2.6 years) was not long enough to demonstrate benefit (eg, the trials of endarterectomy for asymptomatic carotid disease would not have demonstrated benefit at only two years). There was slow enrollment in most of these trials and suspicion that patients at high risk of recurrent embolism were disproportionately treated outside of the trials with PFO closure, particularly for the earlier trials. The trials primarily enrolled patients under 60 years of age, and the safety and efficacy of closure remains unclear in patients older than age 60, who are likely to be at increased risk of atrial fibrillation as a complication of PFO closure. An observational study that included 388 patients >60 years undergoing PFO closure found that the incidence of stroke, transient ischemic attack, or peripheral embolism events of 1.6 per 100 patient-years was lower than that expected according to the RoPE score (observed- to-expected ratio 0.31, 95% CI 0.11-0.91), although the event rate in these older patients was higher than in younger patients and postprocedural atrial fibrillation after the procedure was more frequent in older patients [32]. The trials mainly enrolled patients who had recent stroke (eg, within six months); therefore, the benefit of PFO closure for those with a more remote stroke attributed to PFO is less certain. However, given natural history data suggesting a relatively steady 1 to 1.5 percent annual risk of stroke on medical therapy [6], it is likely that the benefit of PFO closure extends beyond six months after stroke in carefully selected patients. Adverse effects New onset atrial fibrillation is the most common adverse effect of PFO device closure. Several meta-analyses have confirmed that PFO closure increases the risk of atrial fibrillation or atrial flutter [6,15,19,21-23,26,33], with a risk difference (ie, absolute risk increase) of 3.4 percent in one of the meta-analyses [19]. Of note, atrial fibrillation is a frequent complication of cardiac surgery, which is relevant for patients undergoing cardiac surgery with concomitant PFO closure. (See "Atrial fibrillation and flutter after cardiac surgery".) One concern about new onset atrial fibrillation is its potential long-term impact on the risk of stroke and other embolic events, but limited information is available on the clinical course of postprocedural atrial fibrillation. The management of new-onset atrial fibrillation after PFO closure (whether by device or surgery) is similar to that after cardiac surgery generally, as reviewed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery".) Other complications, all rare, include hematoma at the puncture site, device migration, device embolization, device erosion, and device thrombosis with possible and recurrent ischemic https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 9/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate stroke. (See 'Recurrent ischemic stroke' below.) Device erosion is rare (0.2 to 0.3 percent of cases) after device closure of atrial septal defects (ASDs), in most cases occurring during the first six months after implantation [34,35], and may be rarer with device closure of PFOs. Device erosion can lead to cardiac perforation with pericardial effusion, cardiac tamponade, and fistula formation or may rarely create an atrial septal defect [36,37]. Preprocedural imaging Patients with an embolic infarct and no other evident source of stroke who are being considered for PFO closure should undergo transesophageal echocardiography (TEE) to confirm that the intracardiac shunt is caused by a PFO, to define atrial septal anatomy (including thickness of rims around the PFO) and suitability for device closure, and to exclude other causes of embolic stroke (eg, intracardiac thrombus, mass or vegetation) or shunt [38]. The atrial septum is carefully examined to determine whether there are one or more concomitant ASDs and/or an atrial septal aneurysm (defined as a redundant mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm). The length of the PFO tunnel is also assessed. If a PFO is accompanied by one or more secundum- type ASDs, the location and size of these defects are examined to determine whether all the defects can be closed percutaneously by one or two devices and whether a surgical approach might be preferred. Procedure Percutaneous PFO closure should be performed using an approved PFO closure device. Access to the right atrium is established via the right femoral vein, and the PFO is crossed with a guidewire or catheter under fluoroscopic and echocardiographic (either TEE or intracardiac) guidance [34]. After the left atrium is accessed, an exchange-length stiff guidewire is advanced into a pulmonary vein. Balloon sizing may be used to determine the size of the device (typically twice the size of the balloon-stretched diameter of the defect). After the balloon is withdrawn, the delivery system is advanced into the left atrium over the guidewire. The device and the delivery system are flushed prior to insertion and the catheters aspirated to avoid air embolism. The left-sided occluder is opened in the left atrium and retracted against the interatrial septum before the right-sided occluder is opened. After device position is confirmed by echocardiography, the closure device is released from the delivery system. Echocardiography is performed after device release to assess for residual shunting and presence of any complications. The echocardiographic guidance is achieved by intracardiac echocardiography (ICE) or TEE. ICE, performed via a second venous access to the right atrium, is generally preferred, as it avoids the general anesthesia and intubation required for TEE [39]. When TEE is not used, the percutaneous closure procedure (with ICE) is generally performed with conscious sedation. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 10/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Antithrombotic therapy during the procedure Patients undergoing percutaneous device closure routinely receive antithrombotic therapy prior to, during, and following the procedure, though specific regimens vary. As an example, in the CLOSE trial, all patients undergoing percutaneous PFO closure received clopidogrel 300 mg, low molecular weight heparin, or continuation of their prior antiplatelet therapy before the procedure [12]. During the procedure, unfractionated heparin 100 international units/kg (up to 10,000 international units) was administered intravenously. SURGICAL PFO CLOSURE For rare patients aged 60 years with a PFO-associated stroke and no other evident source of stroke despite a comprehensive evaluation who have a concurrent indication for cardiac surgery (eg, an indication for valve surgery rather than a transcatheter procedure), surgical closure of PFO via standard or minimally invasive (including robotic) techniques for secondary stroke prevention after PFO-associated stroke is appropriate. The reported efficacy of surgical closure of a PFO in patients with prior cerebrovascular ischemic events has been variable [2,40-42], and randomized trials comparing surgical PFO closure with percutaneous closure or with medical therapy have not been performed. Rates of recurrent cerebrovascular events following surgical closure have ranged from 7 to 14 percent at one to two years [2,40]. Similar to findings from the randomized controlled trials for device closure of PFO, these events are likely due to mechanisms unrelated to paradoxical embolization, as illustrated by a report of 91 patients (mean age 44 years) with one or more cerebrovascular ischemic events who underwent surgical PFO closure [40]. The overall freedom from an ischemic episode at one and four years was 93 and 83 percent, respectively. The recurrent events were transient ischemic attacks (there were no cerebral infarctions), one of which was attributed to giant cell arteritis. Transesophageal echocardiography showed that the closures were intact in all patients, implying that paradoxical embolization was not the cause of the ischemic events. In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect who had cardiothoracic surgery [43]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 11/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limits confidence in the results of this study. GENERAL MANAGEMENT OF PFO-ASSOCIATED STROKE All patients with PFO and ischemic stroke require antithrombotic therapy, cardiovascular risk reduction measures, and other measures to reduce the risk of recurrent stroke and other adverse cardiovascular events. Antithrombotic therapy Agents Antithrombotic therapy is a key component of secondary prevention for all types of ischemic stroke. Patients without an indication for anticoagulation should be treated with antiplatelet therapy whether or not the PFO is successfully closed. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) After PFO closure For most patients who have undergone percutaneous or surgical PFO closure who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation. We treat with aspirin 75 to 81 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 to 81 mg/day). In the CLOSE trial, the antithrombotic regimen after percutaneous PFO closure was aspirin 75 mg/day plus clopidogrel 75 mg/day for three months [12]. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole. Without PFO closure For most patients with a PFO-associated embolic infarct and no other evident source of stroke who do not undergo PFO closure, we suggest antithrombotic therapy with antiplatelet agents rather than anticoagulation. However, anticoagulation therapy is used rather than antiplatelet agents for patients with high risk of venous thromboembolism, as discussed below. Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO-associated ischemic stroke or transient ischemic attack (TIA) is uncertain (see 'Comparative studies' below), high-quality data from randomized trials have established that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin'.) Concurrent indication for anticoagulation Anticoagulation is used for patients with a PFO-associated stroke who have a concurrent indication, such as acute deep venous https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 12/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate thrombosis, pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. Management of these conditions, including the duration of anticoagulation, is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow- up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".) Comparative studies The evidence comparing the benefit of antiplatelet therapy with anticoagulation for stroke prevention among patients with a PFO and ischemic stroke comes mainly from nonrandomized studies or randomized trials with important limitations, as illustrated by the following observations: In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [aHR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, aHR 0.75, 95% CI 0.44-1.27) [44]. In an updated meta-analysis of combined data from four trials (PICSS [45], CLOSE [12], NAVIGATE ESUS [46], and RESPECT ESUS [47]) that included patients with PFO and cryptogenic stroke who were randomly assigned to treatment with anticoagulant or antiplatelet therapy, the risk of recurrent ischemic stroke was similar for anticoagulation versus antiplatelet therapy (odds ratio 0.70, 95% CI 0.43-1.14) [47]. However, confidence in this result is limited by imprecision due to the small number of outcome events and wide confidence interval. Other cardiovascular risk reduction Patients with PFO who have an ischemic stroke or TIA should be treated with all appropriate cardiovascular risk reduction strategies (see above) including lifestyle modification (diet and exercise), blood pressure control, and statin therapy (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Additional preventive measures Certain general measures may be beneficial independent of the therapy chosen for the PFO. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for VTE, we suggest frequent ambulation and calf exercises, avoidance of dehydration or https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 13/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".) RECURRENT ISCHEMIC STROKE As with any stroke, patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients who have undergone PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [48-52]. Alternatively, thrombus may

the ischemic events. In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect who had cardiothoracic surgery [43]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 11/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limits confidence in the results of this study. GENERAL MANAGEMENT OF PFO-ASSOCIATED STROKE All patients with PFO and ischemic stroke require antithrombotic therapy, cardiovascular risk reduction measures, and other measures to reduce the risk of recurrent stroke and other adverse cardiovascular events. Antithrombotic therapy Agents Antithrombotic therapy is a key component of secondary prevention for all types of ischemic stroke. Patients without an indication for anticoagulation should be treated with antiplatelet therapy whether or not the PFO is successfully closed. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) After PFO closure For most patients who have undergone percutaneous or surgical PFO closure who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation. We treat with aspirin 75 to 81 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 to 81 mg/day). In the CLOSE trial, the antithrombotic regimen after percutaneous PFO closure was aspirin 75 mg/day plus clopidogrel 75 mg/day for three months [12]. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole. Without PFO closure For most patients with a PFO-associated embolic infarct and no other evident source of stroke who do not undergo PFO closure, we suggest antithrombotic therapy with antiplatelet agents rather than anticoagulation. However, anticoagulation therapy is used rather than antiplatelet agents for patients with high risk of venous thromboembolism, as discussed below. Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO-associated ischemic stroke or transient ischemic attack (TIA) is uncertain (see 'Comparative studies' below), high-quality data from randomized trials have established that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin'.) Concurrent indication for anticoagulation Anticoagulation is used for patients with a PFO-associated stroke who have a concurrent indication, such as acute deep venous https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 12/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate thrombosis, pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. Management of these conditions, including the duration of anticoagulation, is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow- up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".) Comparative studies The evidence comparing the benefit of antiplatelet therapy with anticoagulation for stroke prevention among patients with a PFO and ischemic stroke comes mainly from nonrandomized studies or randomized trials with important limitations, as illustrated by the following observations: In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [aHR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, aHR 0.75, 95% CI 0.44-1.27) [44]. In an updated meta-analysis of combined data from four trials (PICSS [45], CLOSE [12], NAVIGATE ESUS [46], and RESPECT ESUS [47]) that included patients with PFO and cryptogenic stroke who were randomly assigned to treatment with anticoagulant or antiplatelet therapy, the risk of recurrent ischemic stroke was similar for anticoagulation versus antiplatelet therapy (odds ratio 0.70, 95% CI 0.43-1.14) [47]. However, confidence in this result is limited by imprecision due to the small number of outcome events and wide confidence interval. Other cardiovascular risk reduction Patients with PFO who have an ischemic stroke or TIA should be treated with all appropriate cardiovascular risk reduction strategies (see above) including lifestyle modification (diet and exercise), blood pressure control, and statin therapy (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Additional preventive measures Certain general measures may be beneficial independent of the therapy chosen for the PFO. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for VTE, we suggest frequent ambulation and calf exercises, avoidance of dehydration or https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 13/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".) RECURRENT ISCHEMIC STROKE As with any stroke, patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients who have undergone PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [48-52]. Alternatively, thrombus may spontaneously form on or adjacent to the PFO device or in the left atrium due to stagnant blood flow [53], particularly given the possible increased risk of atrial arrhythmias (mainly atrial fibrillation) in patients with PFO and/or atrial septal aneurysm [54]. This risk may be augmented after PFO closure [16,17], especially in the first few weeks after device implantation. Recurrent stroke should be treated according to the underlying mechanism, if it can be identified: If the recurrence occurs in a patient who has not had their PFO closed, and the PFO still appears to be the most likely cause of stroke, we suggest PFO closure. (See 'Patient selection for PFO closure' above.) For patients on antiplatelet therapy who have a recurrent PFO-associated stroke (regardless of PFO closure status) and no atrial fibrillation on reevaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet regimen. For patients with recurrent embolic stroke of undetermined source (ESUS), switching to empiric anticoagulant therapy is also a reasonable option. These issues are discussed in detail elsewhere. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 14/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate In rare cases, thrombus formation on the PFO closure device should be treated with anticoagulant therapy; recurrent embolism in this setting may require surgical device removal with defect closure [55]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS Patient selection for PFO closure A causal association between a patent foramen ovale (PFO) and stroke (ie, a PFO-associated stroke) is thought likely in patients with PFO who meet all of the following criteria; patients with PFO who meet all of these criteria are candidates for percutaneous PFO closure: Age 60 years Embolic stroke topography (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Is the stroke embolic?') https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 15/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate No other evident source of stroke despite a comprehensive evaluation (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Exclusion of other sources of ischemic stroke') A possible, probable, or definite likelihood that the stroke was causally related to the PFO according to the PFO-associated stroke causal likelihood (PASCAL) classification system ( table 1), which incorporates the Risk of Paradoxical Embolism (RoPE) score and high-risk features of the PFO on echocardiogram ( table 2) (calculator 1) (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score') No concurrent indication for anticoagulation (see 'Special considerations in anticoagulated patients' above) Decision-making for PFO closure Our approach to management of a patient with an embolic appearing stroke, PFO, and no other identified cause is summarized in the algorithm ( algorithm 1). PFO-associated stroke For most patients without a concurrent indication for anticoagulation who are 60 years of age with a possible, probable, or definite likelihood by PASCAL ( table 1) that the PFO was causally associated with the stroke, we suggest percutaneous PFO device closure in addition to antiplatelet therapy (Grade 2B). For patients who are >60 years of age, we use an individualized treatment approach to PFO closure based upon patient preferences and other risk factors and comorbidities. If otherwise indicated, PFO device closure may be temporarily deferred for patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for patients with an indication for long-term anticoagulation; an individualized approach with shared decision-making is appropriate. (See 'Special considerations in anticoagulated patients' above.) For rare patients who have a concurrent indication for cardiac surgery (eg, valve surgery) and meet PASCAL criteria for PFO causal association, surgical PFO closure is appropriate. For rare patients who have a PFO that is not amenable to percutaneous closure but meet PASCAL criteria for PFO causal association, the benefit of surgical closure is https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 16/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate uncertain. In the absence of a concurrent indication for cardiac surgery, we suggest against surgical closure (Grade 2C). PFO unlikely to be associated with stroke For patients who do not meet criteria for a causal association of PFO with stroke (ie, association unlikely by PASCAL ( table 1)), we suggest against PFO closure (Grade 2C). Benefit of PFO closure PFO device closure is more effective than medical therapy alone for select patients aged 60 years with a PFO-associated stroke (ie, a nonlacunar ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation). Compared with medical therapy, PFO device closure reduces risk of recurrent stroke from approximately 5 to 2 percent over a three- to six-year period. (See 'Benefit' above.) For patients age >60 years, the benefit of PFO device closure is unknown, since these patients were generally excluded from randomized trials of PFO device closure. (See 'Benefit' above.) Choice of antithrombotic agent for PFO-associated stroke Following PFO closure For patients in this setting who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation (Grade 2C). Patients are treated with antiplatelet therapy whether or not the PFO is successfully closed. (See 'Antithrombotic therapy' above.) Without PFO closure For these patients, treatment with antiplatelet therapy is recommended, which is consistent with the recommendations for cryptogenic stroke. (See 'Antithrombotic therapy' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) Concurrent indication for anticoagulation In this setting (eg, usually venous thromboembolism), standard recommendations for anticoagulation apply, and anticoagulation is generally the sole antithrombotic therapy required. Recommendations are provided in separate topic reviews. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Recurrent ischemic stroke Patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 17/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. For patients with a previous PFO-associated stroke treated with antiplatelet therapy but not PFO closure who have a recurrent embolic-appearing stroke with no other identified cause, we suggest PFO closure in addition to antithrombotic therapy (Grade 2C). Switching to another antiplatelet agent or to anticoagulant therapy is a reasonable alternative. (See 'Recurrent ischemic stroke' above.) Use of UpToDate is subject to the Terms of Use. 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JACC Cardiovasc Imaging 2010; 3:749. 39. Rigatelli G, Pedon L, Zecchel R, et al. Long-Term Outcomes and Complications of Intracardiac Echocardiography-Assisted Patent Foramen Ovale Closure in 1,000 Consecutive Patients. J Interv Cardiol 2016; 29:530. 40. Dearani JA, Ugurlu BS, Danielson GK, et al. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100:II171. 41. Devuyst G, Bogousslavsky J, Ruchat P, et al. Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound. Neurology 1996; 47:1162. 42. Ruchat P, Bogousslavsky J, Hurni M, et al. Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study. Eur J Cardiothorac Surg 1997; 11:824. 43. Krasuski RA, Hart SA, Allen D, et al. Prevalence and repair of intraoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA 2009; 302:290. 44. Kent DM, Dahabreh IJ, Ruthazer R, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta- analysis. Eur Heart J 2015; 36:2381. 45. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 46. Kasner SE, Swaminathan B, Lavados P, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol 2018; 17:1053. 47. Diener HC, Chutinet A, Easton JD, et al. Dabigatran or Aspirin After Embolic Stroke of Undetermined Source in Patients With Patent Foramen Ovale: Results From RE-SPECT ESUS. Stroke 2021; 52:1065. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 21/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 48. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation 2000; 101:893. 49. Mart n F, S nchez PL, Doherty E, et al. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002; 106:1121. 50. Wahl A, Krumsdorf U, Meier B, et al. Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients. J Am Coll Cardiol 2005; 45:377. 51. Anzola GP, Morandi E, Casilli F, Onorato E. Does transcatheter closure of patent foramen ovale really "shut the door?" A prospective study with transcranial Doppler. Stroke 2004; 35:2140. 52. Deng W, Yin S, McMullin D, et al. Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence: A Prospective Cohort Study. Ann Intern Med 2020; 172:717. 53. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24:1865. 54. Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31:398. 55. Ciurus T, Piestrzeniewicz K, Maciejewski M, et al. Thrombus formation on the Amplatzer device: a need for critical attitude in percutaneous patent ovale closure decision-making. Eur Heart J 2015; 36:1195. Topic 138296 Version 4.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 22/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate GRAPHICS Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism or deep venous thrombosis preceding Probable Highly probable an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 23/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 24/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri strategies including antithrombotic therapy, blood pressure control, low-density lipoprotein (LDL)-lowering th lifestyle modification, as appropriate. For details regarding the evaluation required for a comprehensive stroke evaluation, choice of antithromboti other factors that impact decision-making for PFO management, refer to appropriate UpToDate topics. PFO: patent foramen ovale; DVT: deep venous thrombosis; PE: pulmonary embolism; RoPE: Risk of Paradoxic PASCAL: PFO-associated stroke causal likelihood; ASA: atrial septal aneurysm. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 25/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate For most patients with an indication for anticoagulation >1 year, PFO closure is not performed, as benefit in uncertain. PFO closure may be an option for selected patients, such as those who experience recurrent embo other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Patients who undergo PFO closure (percutaneous or surgical) are treated with antiplatelet agents. We treat to 81 mg/day) plus clopidogrel (75 mg/day) for three months, followed by continued aspirin therapy. For the rare patient who has a concurrent indication for surgical valve intervention, surgical (rather than pe closure is appropriate. If percutaneous PFO closure is not feasible and there is no concurrent indication for c suggest against surgical PFO closure. For most patients >60 years old, PFO closure is not performed since such patients were excluded from tria and the benefit of closure in this setting is unproven. PFO closure may be an option for selected patients >60 as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Refer to UpToDate topic on cryptogenic stroke. Graphic 138535 Version 1.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 26/27 7/6/23, 12:14 PM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Stephen JD Brecker, MD, FRCP, FESC, FACC Grant/Research/Clinical Trial Support: Medtronic [Transcatheter valves]. Consultant/Advisory Boards: Aortic Innovations LLC [Transcatheter valves]; Medtronic [Transcatheter valves]. Speaker's Bureau: Medtronic [Transcatheter valves]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 27/27

7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke in patients with atrial fibrillation : Warren J Manning, MD : Peter J Zimetbaum, MD, Scott E Kasner, MD : Nisha Parikh, MD, MPH, John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 18, 2023. INTRODUCTION An ischemic stroke may occur in patients with atrial fibrillation (AF) either as the initial presenting manifestation of AF or despite appropriate antithrombotic prophylaxis. In such patients, a cardiac embolus, most commonly a thrombus originating from the left atrial appendage (LAA), is the cause of the ischemic stroke. (See "Clinical diagnosis of stroke subtypes", section on 'Brain ischemia'.) Issues specific to stroke in patients with AF will be reviewed here. The risk of atheroembolism (including stroke), the role of anticoagulant prophylaxis (primary prevention) in patients with AF, and the general evaluation and management of the patient with stroke are presented elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Overview of the evaluation of stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) STROKE CHARACTERISTICS Strokes due to embolization of thrombus, most commonly from the left atrial appendage (LAA) in patients with AF, present with the characteristics of ischemic stroke. (See "Clinical diagnosis of stroke subtypes", section on 'Distinguishing stroke subtypes'.) Features suggestive of cardioembolic stroke https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 1/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Increased clinical severity AF is associated with more severe ischemic strokes and "longer" transient ischemic attacks (TIAs) than emboli from carotid disease, presumably due to embolization of larger thrombi with AF [1,2]. This relationship was illustrated in a report comparing ischemic brain events in patients with AF with those with carotid disease in two major trials. The ratio of hemispheric events to retinal events was 25:1 with AF compared with 2:1 with carotid disease [1]. As a result, patients with AF who suffer an ischemic stroke appear to have a worse outcome (more disability, greater mortality) than those who have an ischemic stroke in the absence of AF, even after adjustment for the advanced age of patients with AF-related stroke [3-5]. The "longer" TIAs typical in AF patients are more often associated with abnormal magnetic resonance diffusion imaging and would be classified as strokes by the revised American Heart Association definition [6]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack".) Radiologic patterns Cardioembolic stroke from AF may affect any vascular territory or multiple vascular territories of the brain with one or more wedge-shaped infarcts involving the cortex and the underlying subcortical white matter. Other patterns include striatocapsular infarction from a middle cerebral artery stem occlusion and/or borderzone infarcts [7]. Silent cerebral infarction In addition to causing symptomatic stroke with major deficits, AF is also associated with silent cerebral infarctions (SCIs) and TIA [8-13]. SCI is characterized by brain lesions that have a radiographic appearance consistent with cerebral infarction in the absence of clinical complaints or findings. In a 2014 systematic review and meta-analysis of 17 studies, the prevalence of SCI lesions on magnetic resonance imaging and computed tomography among patients with AF was 40 and 22 percent, respectively [12]. In this review, AF was associated with more than a twofold increased risk of SCI in patients with no history of symptomatic stroke (odds ratio 2.62, 95% CI 1.81-3.80) in 11 studies. However, most studies pooled in this meta- analysis were cross-sectional, making the causal link between AF and silent cerebral infarction uncertain. ACUTE ISCHEMIC STROKE The initial rapid evaluation of acute ischemic stroke for patients with known or suspected AF is similar to the approach for patients with other known or suspected causes of stroke. Is reperfusion therapy indicated? All patients with acute ischemic stroke should be evaluated for possible reperfusion therapy, including urgent brain and neurovascular imaging. The immediate goal of reperfusion therapy is to restore blood flow to the regions of brain that https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 2/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate are ischemic but not yet infarcted. (See "Approach to reperfusion therapy for acute ischemic stroke".) Intravenous thrombolysis (IVT) improves functional outcome at three to six months when given within 4.5 hours of ischemic stroke onset. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) However, contraindications to IVT may be relevant for patients with AF and acute ischemic stroke ( table 1): Current vitamin K antagonist (VKA) use (eg, warfarin) with evidence of anticoagulant effect (eg, an international normalized ratio [INR] >1.7 or prothrombin time >15 seconds). Direct-acting oral anticoagulant (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) use, unless the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function or laboratory tests such as partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal. In most cases, only the INR is readily available for clinical decision-making. Evidence of intracranial hemorrhage on neuroimaging. Mechanical thrombectomy is indicated for select patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who can be treated within 24 hours of the time last known to be well ( algorithm 1). (See "Mechanical thrombectomy for acute ischemic stroke".) Specific data on the effectiveness of thrombolytic therapy in ischemic stroke are limited for patients with AF, although such patients account for 20 to 30 percent of those participating in clinical trials [14,15]. As an example, the National Institute of Neurological Disorders and Stroke (NINDS) trial included 115 patients with AF (18 percent) [14]. No subgroup analysis of these patients has been reported, although there was no evidence of a treatment interaction between history of AF and benefit from alteplase. The large size and worse prognosis of AF-associated acute ischemic stroke accentuate both the risks and the benefits of fibrinolysis [15]. (See "Approach to reperfusion therapy for acute ischemic stroke".) Diagnostic approach Comprehensive evaluation Patients with AF who suffer an ischemic stroke are likely to have had a cardioembolic event. On the other hand, AF is common in older adults, who often are at https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 3/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate risk for other types of stroke. Thus, the presence of AF in a stroke patient does not always mean that there is a causal relationship [16]. As a result, all patients with a stroke, even in the setting of AF, need a complete evaluation for other causes of stroke, especially if they would result in different treatment. The evaluation is generally the same as the evaluation in other patients with acute stroke, including brain and neurovascular imaging, cardiac rhythm monitoring during the acute phase, and echocardiography. As for other patients with a suspected embolic stroke, transesophageal echocardiography (TEE) may be used to identify embolic sources (intracardiac or aortic), which may be particularly helpful for patients at increased risk for complications of anticoagulation. However, a TEE is not used to exclude AF as the cause of embolic stroke, since residual atrial thrombi may or may not be present. (See "Overview of the evaluation of stroke", section on 'Ischemia' and "Overview of the evaluation of stroke", section on 'Confirming the diagnosis'.) Source of embolism For those patients with AF in whom an embolic stroke seems likely, other sources than the left atrial appendage (LAA) need to be considered. Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. Embolic strokes may arise from a source in the heart, aorta, or large vessels ( table 2). (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism' and "Clinical diagnosis of stroke subtypes", section on 'Brain ischemia'.) Thromboembolism of aortic atheroma is discussed separately. (See "Thromboembolism from aortic plaque".) Brain and neurovascular imaging Neuroimaging should be obtained for all patients suspected of having acute ischemic stroke or transient ischemic attack (TIA). Brain and neurovascular imaging play an essential role in acute stroke by: Differentiating ischemia from hemorrhage Excluding stroke mimics, such as tumor Assessing the status of large cervical and intracranial arteries Estimating the volume of brain tissue that is irreversibly infarcted (ie, infarction "core") Estimating the extent of potentially salvageable brain tissue that is at risk for infarction (ie, ischemic "penumbra") Guiding acute interventions, including patient selection for reperfusion therapies (ie, intravenous thrombolysis and mechanical thrombectomy) Imaging of acute ischemic stroke is reviewed in detail elsewhere. (See "Neuroimaging of acute stroke".) https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 4/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Cardiac monitoring For patients in sinus rhythm without a history of AF, cardiac rhythm monitoring is recommended for at least the first 24 to 48 hours after the onset of ischemic stroke to identify AF or atrial flutter [17]. However, paroxysmal AF may not be detected on short- term cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. To increase the likelihood of detecting AF, ambulatory cardiac monitoring for several weeks is suggested for all adult patients with a cryptogenic ischemic stroke or cryptogenic TIA. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) Echocardiography Transthoracic echocardiographic (TTE) evaluation is recommended for most patients presenting with ischemic stroke, primarily to investigate the conditions associated with AF. Because chronic anticoagulation with warfarin or one of the DOACs is recommended in all eligible patients with AF and stroke, echocardiography often will not have a significant impact on anticoagulant management decisions. (See "Role of echocardiography in atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) The LAA and thus LAA thrombus are rarely seen on TTE but are easily visualized/detected by TEE. Approximately 45 percent of patients presenting with an acute embolic event in the setting of new-onset AF will have residual LAA thrombus [18,19]. Even when not seen on TEE, an intracardiac thrombus is presumed to have been present in all patients with AF who have had a recent thromboembolic event independent of anticoagulation status. This hypothesis is based in part upon the observations that microscopic thrombus can be identified in most patients with chronic sustained AF at autopsy [20] and that patients with a recent thromboembolism and newly recognized AF are significantly more likely to have spontaneous echocardiography contrast (a marker of stasis) than similar patients without a thromboembolic event (87 versus 48 percent) [19]. Thus, for patients with AF, diagnostic evaluation by TEE to search for a residual intraatrial thrombus is not essential since the absence of a thrombus will not alter the long-term clinical (anticoagulation) management. However, TEE to confirm absence of residual thrombus prior to cardioversion may be reasonable for those in whom a rhythm strategy is going to be pursued. (See "Role of echocardiography in atrial fibrillation" and "Management of atrial fibrillation: Rhythm control versus rate control".) Managing antithrombotic therapy acutely Stop anticoagulation temporarily For most patients on anticoagulant therapy at the time of stroke onset, anticoagulation is temporarily withheld during the acute phase of ischemic stroke due to the risk of hemorrhagic transformation of the brain infarction. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 5/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Acute antiplatelet therapy In patients with AF who experience an ischemic stroke, acute antiplatelet therapy ( algorithm 2) may be warranted to reduce both disability and the risk of early recurrent stroke, which is 3 to 5 percent in the first two weeks [21,22]. These benefits must be balanced against the risk of intracranial bleeding with antithrombotic therapy. Starting or resuming oral anticoagulation Once the stroke evaluation is complete, antithrombotic therapy may be modified according to the ischemic stroke mechanism ( algorithm 3). For patients with AF, long-term oral anticoagulation is started (or resumed) once the risk of hemorrhagic transformation has diminished, usually within the first days to two weeks after stroke onset, as guided mainly by the size of the ischemic infarct. (See 'Timing after acute ischemic stroke' below.) The management of acute antithrombotic therapy in patients with stroke is discussed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) RISK OF RECURRENT STROKE Patients who have had a prior embolic event already have the most potent risk factor for subsequent stroke. The risk of recurrent stroke in the first few weeks after the initial event is 3 to 5 percent based upon large numbers of patients observed in the control arms of randomized trials [21,22]. In addition, a risk of up to 12 percent per year has been reported in nonanticoagulated patients in the first two to three years after a stroke [23,24]. Due to the high risk of recurrent embolism, lifelong anticoagulation is recommended for secondary prevention (these patients have a minimum CHA DS -VASc score (calculator 1) of 2 for 2 2 which chronic anticoagulation is strongly recommended). LONG-TERM ANTICOAGULATION Indications For most patients with ischemic stroke and AF, chronic oral anticoagulation is recommended to reduce the risk of thromboembolism and recurrent ischemic stroke, independent of the cause of the stroke. Patients with a previous intracranial hemorrhage may be candidates for anticoagulation, depending upon their risk of recurrent ischemic stroke and intracranial bleeding. (See https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 6/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Anticoagulation'.) Benefit Randomized trials have shown that therapeutic oral anticoagulant with a vitamin K antagonist (VKA) or a direct-acting oral anticoagulant (DOAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo irrespective of baseline risk. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'General efficacy'.) DOACs Randomized trials have demonstrated that DOACs are either superior (apixaban and dabigatran) or noninferior (edoxaban or rivaroxaban) to VKAs for stroke prevention. Studies have also shown that DOACs have less bleeding side effects than VKAs among patients with AF and ischemic stroke or transient ischemic attack (TIA). DOACS are also preferred over VKAs for patients with AF and other indications for anticoagulation. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) In the ARISTOTLE trial, among 3436 participants with stroke or systemic embolism, apixaban was found to be superior to adjusted-dose warfarin in preventing recurrent stroke or systemic embolism (2.5 versus 3.2 percent; hazard ratio [HR] 0.79, 95% CI 0.66- 0.95) [25]. Apixaban also caused less major bleeding compared with warfarin (2.1 versus 3.1 percent; HR 0.69, 95% CI 0.60-0.80) and resulted in lower overall mortality (3.5 versus 3.9 percent). In a separate trial, among patients with prior stroke, dabigatran had a larger protective effect on stroke as compared with warfarin but had similar rates of major hemorrhage [26]. In other clinical trials of patients with prior stroke or TIA, both edoxaban [27] and rivaroxaban [28] were found to be noninferior to warfarin with respect to future stroke prevention. Warfarin Aspirin alone offers inadequate protection, with a stroke risk that averaged 10 percent per year in a pooled analysis of individual participants from six randomized trials [29]. Compared with aspirin, treatment with adjusted-dose warfarin (international normalized ratio 2 to 3) reduced this risk to 4 percent per year. In an analysis from the EAFT and SPAF III trials of 834 patients with prior nondisabling ischemic stroke or prior TIA at study entry, the long-term risk of recurrent stroke was lower in patients with a prior TIA than in those with a prior ischemic stroke [30]. However, the reduction in recurrent stroke risk with warfarin therapy was comparable in both groups: 3 versus 7 percent per year with aspirin in patients with a TIA and 4 versus 11 percent per year in those with ischemic stroke. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 7/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate In addition, anticoagulated patients with AF who experience ischemic stroke typically have smaller infarcts with a lower mortality rate compared with patients with AF and stroke who are not anticoagulated [31,32]. This is likely explained by a higher fraction of nonembolic strokes among anticoagulated AF patients and small size of embolic strokes. Anticoagulation greatly reduced the likelihood of large stroke due to left atrial emboli, so that the remaining strokes are from cerebral small artery disease or other mechanisms [31]. Risk The most feared complication of anticoagulant therapy is the risk of major bleeding, as reviewed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants".) The decision of whether to use chronic oral anticoagulants must take both benefit and risk into account through shared decision-making with the patient. However, the benefit of oral anticoagulants far outweighs the risk for nearly all patients with ischemic stroke and AF [33]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Choosing between direct-acting oral anticoagulants and warfarin For most patients with stroke or TIA and AF who do not have a specific indication for warfarin or another VKA, a DOAC is preferred to a VKA. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) Situations where a VKA is indicated (rather than a DOAC) include the following [33]: Moderate to severe mitral stenosis Mechanical heart valve in any location Warfarin is generally preferred for patients with severely impaired kidney function, since all DOACs are excreted by the kidney to some degree. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Dosing Dosing recommendations for DOACs ( table 3) are reviewed in detail elsewhere. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Note that there are legitimate reasons for DOAC dose reductions, which differ according to the specific agent. In general, clinical settings in which dose modification may be indicated include older age, low body weight, renal insufficiency, and/or concomitant use of interacting drugs. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 8/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate For patients with AF treated with a VKA (eg, warfarin), an INR between 2 and 3 is recommended, with an average annual time in the therapeutic range >70 percent. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Vitamin K antagonist'.) Timing after acute ischemic stroke For medically stable patients with AF and a small- or moderate-sized infarct with no intracranial bleeding, warfarin can be initiated soon (after 24 hours) after admission with minimal risk of transformation to hemorrhagic stroke. We prefer to wait 48 hours to start a DOAC in these patients, as DOACs have a more rapid anticoagulant effect. Withholding anticoagulation for one to two weeks is generally recommended for those with large ischemic stroke, symptomatic hemorrhagic transformation, or poorly controlled hypertension [34-38]. Patients may benefit from aspirin until therapeutic anticoagulation is achieved [39]. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke should generally be avoided, as studies have shown that such treatment causes more harm than good. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) Specific patient groups Patients with another potential stroke mechanism In some patients with ischemic stroke and AF, the work-up will identify a noncardioembolic stroke mechanism (eg, large artery atherosclerosis, small vessel disease, other determined etiology) as the potential cause of the stroke. Lacunar infarction The optimal therapy is not known for patients with AF who experience a small subcortical "lacunar" infarct deemed as likely to be due to cerebral small artery disease as opposed to a cardiac embolus [40]. Anticoagulation is recommended for these patients even though the stroke mechanism is uncertain. This is because in randomized trials, these patients would have been categorized as having a history of stroke; these trials have consistently shown that patients with a history of stroke benefit from VKA and DOACs. Large artery stenosis Some patients with AF have a significant ipsilateral stenosis of a large artery that supplies the territory of the acute ischemic stroke. In such cases, it is usually impossible to determine with certainty which mechanism was causative. Anticoagulation for AF is recommended, and the large artery stenosis should be treated https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 9/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate appropriately (eg, revascularization for cervical internal carotid artery stenosis) as a separate cause. Older age Older age is generally cited as a risk factor for bleeding; the risk increase with age is approximately linear. However, the risk of bleeding attributable to older age is often overestimated, and anticoagulants are underused in older individuals who are at the highest risk of stroke and may derive more benefit than younger individuals [33]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex'.) Fall risk Among patients with a history of falls or at high risk of falling, the risk of intracranial hemorrhage is increased among patients on anticoagulation, aspirin, or no antithrombotic therapy, but the absolute increased risk of intracranial hemorrhage related to anticoagulation is small. In particular, anticoagulation increases the risk of subdural hemorrhage (SDH), which is often due to falls, but the absolute risk with VKA therapy is approximately two additional SDHs per 1000 patients [41], which is much lower compared with the risk of cardioembolic stroke due to AF [33]. Nonrandomized studies suggest that for patients with AF and high risk of falls, the benefit of anticoagulation (ie, a reduced risk of ischemic stroke and consequent disability) outweighs the risk of intracranial bleeding from a fall. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding in specific sites'.) Anticoagulant-intolerant patients Left atrial appendage (LAA) occlusion or dual antiplatelet therapy may be reasonable alternatives to therapy with aspirin alone in high-risk patients with AF who cannot be treated with long-term warfarin or DOAC, or because of strong patient preference following careful consideration of the advantages of oral anticoagulation. LAA occlusion is discussed separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) ANTICOAGULATION FAILURE Determining the cause of recurrent stroke All patients with AF who have an ischemic stroke despite oral anticoagulation with a vitamin K antagonist (VKA) or a direct-acting oral anticoagulant (DOAC) should have a thorough evaluation to determine if the most likely stroke mechanism is cardioembolic due to AF or noncardioembolic due to large artery atherosclerosis, small vessel disease, or another cause of ischemic stroke. Note that patients with ischemic stroke and AF will still need chronic oral anticoagulation even if a competing stroke mechanism is found. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 10/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Transesophageal echocardiogram (TEE) is useful to assess for left atrial appendage (LAA) thrombus and other potential cardiac sources of embolism. (See "Overview of the evaluation of stroke", section on 'Ischemia' and "Overview of the evaluation of stroke", section on 'Confirming the diagnosis'.) Missed doses should be suspected in patients taking a DOAC, and subtherapeutic intensity of anticoagulation is a very common cause of treatment failure for patients taking a VKA [42-44]. For patients with stroke on DOACs with good compliance or while on warfarin anticoagulation with a therapeutic international normalized ratio (INR), a noncardioembolic stroke mechanism (eg, lacunar, large artery stenosis, malignancy) is often the cause, although cardioembolism may account for the majority [44,45]. In an analysis of patients with ischemic stroke despite oral anticoagulation, the stroke etiology for 1674 patients taking a DOAC was due to the following factors [44]: Cardioembolism - 49 percent Poor adherence or insufficient dose 23 percent A competing mechanism 28 percent For 1274 patients taking a VKA, the stroke etiology was due to the following factors [44]: Cardioembolism 37 percent Poor adherence or insufficient dose 43 percent A competing mechanism 20 percent Direct-acting oral anticoagulant treatment failure While data are limited, ischemic stroke that occurs during therapy with a DOAC (eg, apixaban, dabigatran, edoxaban, or rivaroxaban) for AF has been associated with several factors, including treatment at doses lower than recommended and/or poor adherence. LAA thrombus, if present, suggests the need to reassess dosing and compliance. One study compared 713 cases of ischemic stroke or transient ischemic attack (TIA) during DOAC treatment with unmatched controls (consecutive outpatients with AF) who did not have cerebrovascular events during DOAC treatment [46]. In multivariable analysis, ischemic cerebrovascular events were associated with off-label under-dosing of DOAC, atrial enlargement, hyperlipidemia, and higher CHA DS -VASc score. 2 2 It is important to verify that the correct DOAC dose was prescribed and that the patient was compliant. If a thrombus is present despite appropriate dosing and compliance, it is reasonable to change to another DOAC, but optimal treatment is uncertain, and no consensus exists. A retrospective study suggested that for patients with left ventricular thrombus, warfarin may be https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 11/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate superior to DOAC for reducing the risk of stroke or systemic embolism [47]. Analogous data for AF patients with LAA thrombi are not available. Regardless, resuming oral anticoagulation therapy for patients with AF is generally indicated after one to two weeks of temporary interruption with large infarcts or shorter interruption with small infarcts. Warfarin treatment failure In patients with AF who suffer ischemic stroke during warfarin anticoagulation, the intensity of anticoagulation is most often subtherapeutic (INR less than 2), and continuing warfarin after one to two weeks of temporary interruption for patients with large infarcts or shorter interruption with small infarcts with renewed efforts to keep the INR in the 2 to 3 therapeutic range or consideration of a change to a DOAC is advised. When ischemic stroke occurs with a therapeutic INR (2 to 3), we favor increasing the target INR to 2.5 to 3.5, or switching from warfarin to a DOAC rather than routine addition of antiplatelet therapy. The addition of antiplatelet therapy is known to increase major hemorrhage (and particularly brain hemorrhage), and the benefit is less well defined. HEMORRHAGIC STROKE For patients with AF on anticoagulation who develop a hemorrhagic stroke, anticoagulation and antiplatelet drugs should be discontinued, and medications to reverse the effects of anticoagulant drugs should be given immediately. These and other management issues are discussed separately.(See "Reversal of anticoagulation in intracranial hemorrhage" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) ADDITIONAL SECONDARY PREVENTION STRATEGIES Early rhythm control One trial suggested a benefit of early rhythm control among patients with AF who had a stroke [48]. In this study, 300 patients with AF and acute ischemic stroke were randomly assigned to early rhythm control or usual care. The rate of ischemic stroke was lower in the rhythm control group at 12 months (1.7 versus 6.3 percent); rates of mortality and hospitalizations did not differ. Rates of sustained AF were lower in the early rhythm control group compared with usual care (34 versus 63 percent) at 12 months. A potential limitation of this study was that it was non-blinded. Further randomized studies in other populations are needed before we can recommend the widespread use of early rhythm control in patients with stroke and AF. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 12/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Control of hypertension Blood pressure control is an important component of the management of patients with AF who have had a stroke. Antihypertensive therapy, preferably including an angiotensin-converting enzyme inhibitor, reduces the risk of vitamin K antagonist (VKA)-associated intracranial hemorrhage and may reduce the rate of recurrent stroke. (See "Reversal of anticoagulation in intracranial hemorrhage".) The latter benefit was suggested in a secondary analysis from the PROGRESS trial, which demonstrated the benefit of blood pressure lowering (using perindopril-indapamide) among both hypertensive and nonhypertensive patients who had a previous stroke or transient ischemic attack (TIA) [49]. (See "Antihypertensive therapy for secondary stroke prevention".) Among the subset of 476 patients with AF, perindopril-based therapy produced a mean 7.3/3.4 mmHg reduction in blood pressure compared with placebo and a 34 percent reduction in the incidence of recurrent stroke (13.6 versus 18.9 percent), a difference that was not statistically significant because of the small number of recurrent events [50]. However, there was a significant 38 percent reduction in all major vascular events (one major vascular event prevented in every 11 patients treated for five years), providing a strong rationale for blood pressure lowering. Revascularization for carotid artery stenosis About 10 percent of patients with AF with ischemic stroke or TIA have a cervical carotid stenosis of 50 percent or greater diameter, slightly more than half of which are ipsilateral to the neurological symptoms. Based on estimates of attributable risk, ipsilateral stenosis of at least 70 percent stenosis is equally likely to be the cause of cerebral ischemia as is cardiogenic embolism. Consequently, carotid revascularization with endarterectomy or stenting seems reasonable for AF patients with high-grade ipsilateral stenosis, followed by chronic anticoagulation and antiplatelet therapy, although this approach is empiric, without good supporting evidence, and the use of combined antiplatelet and anticoagulant therapy increases bleeding risk. The management of symptomatic carotid artery disease is discussed elsewhere. (See "Management of symptomatic carotid atherosclerotic disease".) Statin therapy For most patients with ischemic stroke, we start statin therapy. Statin therapy reduces the risk of recurrent ischemic stroke and cardiovascular events among patients with stroke of atherosclerotic origin, although the efficacy of statin therapy specifically for patients with ischemic stroke attributed to AF has not been well studied. However, a report of 6116 patients with ischemic stroke who were discharged on a statin found that outpatient adherence to statin therapy was associated with a reduced risk of recurrent ischemic stroke for patients with AF as well as those without AF, even after https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 13/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate adjustment for time in the therapeutic range of the international normalized ratio (INR) among patients with AF taking warfarin [51]. Many patients with AF have concomitant atherosclerotic disease, and statin therapy is recommended for patients with atherosclerotic cardiovascular disease (such as prior acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, ischemic stroke, TIA, or peripheral arterial disease) (see "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'). In addition, and in the absence of defined atherosclerotic cardiovascular disease, many patients are at high risk for a cardiovascular disease event due to age and the presence of hypertension. (See "Low- density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Age >75 years'.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease. These include smoking cessation, limited alcohol consumption, weight control, regular aerobic physical activity, salt restriction, and a Mediterranean diet. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) SUMMARY AND RECOMMENDATIONS Features suggestive of cardioembolic stroke Cardioembolic stroke from atrial fibrillation (AF) is generally associated with increased severity compared with embolic stroke from carotid disease. Cardioembolic stroke may affect single or multiple vascular territories of the brain and appear as wedge-shaped infarcts involving cortex and adjacent white matter. (See 'Features suggestive of cardioembolic stroke' above.) Evaluation for reperfusion therapy All patients with acute ischemic stroke should be assessed to see if they are eligible for reperfusion therapy. (See 'Is reperfusion therapy indicated?' above.) Comprehensive stroke evaluation All patients with acute stroke, even in the setting of AF, need a complete evaluation for other causes of stroke; the work-up should include brain and neurovascular imaging, cardiac rhythm monitoring, and echocardiography. Paroxysmal AF may not be detected on short-term cardiac monitoring; thus, ambulatory cardiac monitoring for several weeks is suggested for all adult patients with a cryptogenic ischemic stroke or cryptogenic transient ischemic attack (TIA). (See 'Diagnostic approach' above.) https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 14/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Antithrombotic therapy during the acute phase of stroke Anticoagulation is usually temporarily withheld immediately after ischemic stroke, due to the risk of hemorrhagic transformation, and restarted within the first days to two weeks, as guided mainly by the size of the ischemic infarct. (See 'Timing after acute ischemic stroke' above.) For patients with AF and large acute infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, we suggest withholding oral anticoagulation for one to two weeks (Grade 2C). (See 'Timing after acute ischemic stroke' above.) However, early acute antiplatelet therapy ( algorithm 2) may be warranted to reduce both disability and the risk of early recurrent stroke, which is 3 to 5 percent in the first two weeks. (See 'Managing antithrombotic therapy acutely' above.) Long-term anticoagulation For most patients with an ischemic stroke or TIA and AF, we recommend a direct-acting oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA) (Grade 1A). DOACs are more efficacious at preventing recurrent stroke and have lower rates of major hemorrhage. However, a VKA is indicated for patients with moderate to severe mitral stenosis or any mechanical heart valve and is generally preferred for patients with severely impaired kidney function. (See 'Long-term anticoagulation' above.) Anticoagulation treatment failure Determining the cause For patients with AF who develop an ischemic stroke while on anticoagulation, subtherapeutic intensity of anticoagulation (eg, inappropriate low-dose DOAC, missed DOAC doses, or low international normalized ratio [INR] on warfarin) at the time of stroke is the most common cause of treatment failure. Nevertheless, all such patients should have a thorough evaluation (including brain and neurovascular

randomized studies in other populations are needed before we can recommend the widespread use of early rhythm control in patients with stroke and AF. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 12/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Control of hypertension Blood pressure control is an important component of the management of patients with AF who have had a stroke. Antihypertensive therapy, preferably including an angiotensin-converting enzyme inhibitor, reduces the risk of vitamin K antagonist (VKA)-associated intracranial hemorrhage and may reduce the rate of recurrent stroke. (See "Reversal of anticoagulation in intracranial hemorrhage".) The latter benefit was suggested in a secondary analysis from the PROGRESS trial, which demonstrated the benefit of blood pressure lowering (using perindopril-indapamide) among both hypertensive and nonhypertensive patients who had a previous stroke or transient ischemic attack (TIA) [49]. (See "Antihypertensive therapy for secondary stroke prevention".) Among the subset of 476 patients with AF, perindopril-based therapy produced a mean 7.3/3.4 mmHg reduction in blood pressure compared with placebo and a 34 percent reduction in the incidence of recurrent stroke (13.6 versus 18.9 percent), a difference that was not statistically significant because of the small number of recurrent events [50]. However, there was a significant 38 percent reduction in all major vascular events (one major vascular event prevented in every 11 patients treated for five years), providing a strong rationale for blood pressure lowering. Revascularization for carotid artery stenosis About 10 percent of patients with AF with ischemic stroke or TIA have a cervical carotid stenosis of 50 percent or greater diameter, slightly more than half of which are ipsilateral to the neurological symptoms. Based on estimates of attributable risk, ipsilateral stenosis of at least 70 percent stenosis is equally likely to be the cause of cerebral ischemia as is cardiogenic embolism. Consequently, carotid revascularization with endarterectomy or stenting seems reasonable for AF patients with high-grade ipsilateral stenosis, followed by chronic anticoagulation and antiplatelet therapy, although this approach is empiric, without good supporting evidence, and the use of combined antiplatelet and anticoagulant therapy increases bleeding risk. The management of symptomatic carotid artery disease is discussed elsewhere. (See "Management of symptomatic carotid atherosclerotic disease".) Statin therapy For most patients with ischemic stroke, we start statin therapy. Statin therapy reduces the risk of recurrent ischemic stroke and cardiovascular events among patients with stroke of atherosclerotic origin, although the efficacy of statin therapy specifically for patients with ischemic stroke attributed to AF has not been well studied. However, a report of 6116 patients with ischemic stroke who were discharged on a statin found that outpatient adherence to statin therapy was associated with a reduced risk of recurrent ischemic stroke for patients with AF as well as those without AF, even after https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 13/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate adjustment for time in the therapeutic range of the international normalized ratio (INR) among patients with AF taking warfarin [51]. Many patients with AF have concomitant atherosclerotic disease, and statin therapy is recommended for patients with atherosclerotic cardiovascular disease (such as prior acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, ischemic stroke, TIA, or peripheral arterial disease) (see "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'). In addition, and in the absence of defined atherosclerotic cardiovascular disease, many patients are at high risk for a cardiovascular disease event due to age and the presence of hypertension. (See "Low- density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Age >75 years'.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease. These include smoking cessation, limited alcohol consumption, weight control, regular aerobic physical activity, salt restriction, and a Mediterranean diet. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) SUMMARY AND RECOMMENDATIONS Features suggestive of cardioembolic stroke Cardioembolic stroke from atrial fibrillation (AF) is generally associated with increased severity compared with embolic stroke from carotid disease. Cardioembolic stroke may affect single or multiple vascular territories of the brain and appear as wedge-shaped infarcts involving cortex and adjacent white matter. (See 'Features suggestive of cardioembolic stroke' above.) Evaluation for reperfusion therapy All patients with acute ischemic stroke should be assessed to see if they are eligible for reperfusion therapy. (See 'Is reperfusion therapy indicated?' above.) Comprehensive stroke evaluation All patients with acute stroke, even in the setting of AF, need a complete evaluation for other causes of stroke; the work-up should include brain and neurovascular imaging, cardiac rhythm monitoring, and echocardiography. Paroxysmal AF may not be detected on short-term cardiac monitoring; thus, ambulatory cardiac monitoring for several weeks is suggested for all adult patients with a cryptogenic ischemic stroke or cryptogenic transient ischemic attack (TIA). (See 'Diagnostic approach' above.) https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 14/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Antithrombotic therapy during the acute phase of stroke Anticoagulation is usually temporarily withheld immediately after ischemic stroke, due to the risk of hemorrhagic transformation, and restarted within the first days to two weeks, as guided mainly by the size of the ischemic infarct. (See 'Timing after acute ischemic stroke' above.) For patients with AF and large acute infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, we suggest withholding oral anticoagulation for one to two weeks (Grade 2C). (See 'Timing after acute ischemic stroke' above.) However, early acute antiplatelet therapy ( algorithm 2) may be warranted to reduce both disability and the risk of early recurrent stroke, which is 3 to 5 percent in the first two weeks. (See 'Managing antithrombotic therapy acutely' above.) Long-term anticoagulation For most patients with an ischemic stroke or TIA and AF, we recommend a direct-acting oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA) (Grade 1A). DOACs are more efficacious at preventing recurrent stroke and have lower rates of major hemorrhage. However, a VKA is indicated for patients with moderate to severe mitral stenosis or any mechanical heart valve and is generally preferred for patients with severely impaired kidney function. (See 'Long-term anticoagulation' above.) Anticoagulation treatment failure Determining the cause For patients with AF who develop an ischemic stroke while on anticoagulation, subtherapeutic intensity of anticoagulation (eg, inappropriate low-dose DOAC, missed DOAC doses, or low international normalized ratio [INR] on warfarin) at the time of stroke is the most common cause of treatment failure. Nevertheless, all such patients should have a thorough evaluation (including brain and neurovascular imaging, and echocardiography) to determine if the most likely cause of stroke is cardioembolic due to AF, or noncardioembolic due to another mechanism. (See 'Determining the cause of recurrent stroke' above.) DOAC treatment failure In this setting, it is important to verify that the correct DOAC dose is prescribed and that the patient is compliant. If a thrombus is present despite appropriate dosing and compliance, it is reasonable to change to another DOAC, but optimal treatment is uncertain. (See 'Direct-acting oral anticoagulant treatment failure' above.) Warfarin treatment failure In this setting, options include increasing the target INR to 2.5 to 3.5, switching to a DOAC, or considering LAA occlusion. For patients with a subtherapeutic INR at the time of the stroke, an attempt should be made to identify the https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 15/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate cause (eg, poor compliance, drug or food interaction) and to consider switching to a DOAC if the annual time in therapeutic range has been less than 70 percent. Hemorrhagic stroke on anticoagulation For patients on anticoagulation who develop a hemorrhagic stroke, anticoagulation and antiplatelet drugs should be discontinued, and medications to reverse the effects of anticoagulant drugs should be given immediately. These and other measures are reviewed separately. (See "Reversal of anticoagulation in intracranial hemorrhage" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Anderson DC, Kappelle LJ, Eliasziw M, et al. Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002; 33:1963. 2. Harrison MJ, Marshall J. Atrial fibrillation, TIAs and completed strokes. Stroke 1984; 15:441. 3. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27:1760. 4. J rgensen HS, Nakayama H, Reith J, et al. Acute stroke with atrial fibrillation. 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Eur Heart J 2016; 37:2893. 39. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31:1240. 40. Evans A, Perez I, Yu G, Kalra L. Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atrial fibrillation? Stroke 2001; 32:2828. 41. Connolly BJ, Pearce LA, Hart RG. Vitamin K antagonists and risk of subdural hematoma: meta-analysis of randomized clinical trials. Stroke 2014; 45:1672. 42. Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009; 40:235. 43. Yaghi S, Liberman AL, Henninger N, et al. Factors associated with therapeutic anticoagulation status in patients with ischemic stroke and atrial fibrillation. J Stroke Cerebrovasc Dis 2020; 29:104888. 44. Polymeris AA, Meinel TR, Oehler H, et al. Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation. J Neurol Neurosurg Psychiatry 2022; 93:588. 45. Freedman B, Martinez C, Katholing A, Rietbrock S. Residual Risk of Stroke and Death in Anticoagulant-Treated Patients With Atrial Fibrillation. JAMA Cardiol 2016; 1:366. 46. Paciaroni M, Agnelli G, Caso V, et al. Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention. Stroke 2019; 50:2168. 47. Robinson AA, Trankle CR, Eubanks G, et al. Off-label Use of Direct Oral Anticoagulants Compared With Warfarin for Left Ventricular Thrombi. JAMA Cardiol 2020; 5:685. 48. Park J, Shim J, Lee JM, et al. Risks and Benefits of Early Rhythm Control in Patients With Acute Strokes and Atrial Fibrillation: A Multicenter, Prospective, Randomized Study (the RAFAS Trial). J Am Heart Assoc 2022; 11:e023391. 49. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 19/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate 50. Arima H, Hart RG, Colman S, et al. Perindopril-based blood pressure-lowering reduces major vascular events in patients with atrial fibrillation and prior stroke or transient ischemic attack. Stroke 2005; 36:2164. 51. Flint AC, Conell C, Ren X, et al. Statin Adherence Is Associated With Reduced Recurrent Stroke Risk in Patients With or Without Atrial Fibrillation. Stroke 2017; 48:1788. Topic 1059 Version 46.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 20/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 21/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 22/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 23/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 24/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 25/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve Chronic myocardial infarction with ejection fraction <28 percent https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 26/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 27/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews. OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor). Refer to text and associated algorithm for details. Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 28/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable. Graphic 131697 Version 2.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 29/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 30/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 31/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Standard dosing of direct oral anticoagulants Nonvalvular AF - VTE primary Anticoagulant stroke VTE treatment prophylaxis prophylaxis* Dabigatran (Pradaxa) 150 mg twice daily Parenteral 110 mg for the first anticoagulation for 5 to day, then 220 mg once 10 days; then dabigatran 150 mg twice daily daily Apixaban (Eliquis) 5 mg twice daily 10 mg twice daily for one week, then 5 mg 2.5 mg twice daily twice daily Edoxaban (Savaysa, Lixiana) 60 mg once daily Parenteral anticoagulation for 5 to 10 days; then edoxaban 60 mg once daily Rivaroxaban (Xarelto) 20 mg once daily with the evening meal 15 mg twice daily with food for three weeks; then 20 mg once daily with food 10 mg once daily, with or without food This is a simplified table that lists the most common dosing in individuals with normal renal function, normal weight, and lack of concomitant interacting medications (eg, P-glycoprotein inhibitors or inducers). Refer to UpToDate topics on AF, VTE treatment, VTE prophylaxis, and DOAC dosing for possible changes based on impaired renal function or extremes of weight. Other factors may influence dosing in individual patients. AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Dosing may be reduced for certain drugs in certain settings (eg, use of dabigatran 110 mg twice daily for individuals who are at increased risk of bleeding; refer to UpToDate topic on anticoagulation for atrial fibrillation for other examples). Treatment for acute VTE typically refers to the first three to six months of administration; continued treatment beyond six months may be done with a lower dose for some anticoagulants (eg, apixaban, rivaroxaban); the dose is not lowered when therapy is continued using dabigatran or edoxaban. Refer to the latest prescribing information for each individual anticoagulant. Prophylaxis refers to primary prophylaxis in settings such as after knee or hip surgery. https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 32/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Graphic 112514 Version 5.0 https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 33/34 7/6/23, 12:15 PM Stroke in patients with atrial fibrillation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-in-patients-with-atrial-fibrillation/print 34/34

7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke: Etiology, classification, and epidemiology : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 15, 2022. INTRODUCTION The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite conditions: hemorrhage is characterized by too much blood within the closed cranial cavity, while ischemia is characterized by too little blood to supply an adequate amount of oxygen and nutrients to a part of the brain [1]. Each of these categories can be divided into subtypes that have somewhat different causes, clinical pictures, clinical courses, outcomes, and treatment strategies. As an example, intracranial hemorrhage can be caused by intracerebral hemorrhage (ICH, also called parenchymal hemorrhage), which involves bleeding directly into brain tissue, and subarachnoid hemorrhage (SAH), which involves bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord [1]. This topic will review the classification of stroke. The clinical diagnosis of stroke subtypes and an overview of stroke evaluation are discussed separately. (See "Clinical diagnosis of stroke subtypes" and "Overview of the evaluation of stroke".) DEFINITIONS Stroke is classified into two major types: Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 1/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) A stroke is the acute neurologic injury that occurs as a result of one of these pathologic processes. Approximately 80 percent of strokes are due to ischemic cerebral infarction and 20 percent to brain hemorrhage. (See 'Epidemiology' below.) An infarcted brain is pale initially. Within hours to days, the gray matter becomes congested with engorged, dilated blood vessels and minute petechial hemorrhages. When an embolus blocking a major vessel migrates, lyses, or disperses within minutes to days, recirculation into the infarcted area can cause a hemorrhagic infarction and may aggravate edema formation due to disruption of the blood-brain barrier. Transient ischemic attack (TIA) is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. The definition is changing with recognition that transient neurologic symptoms are frequently associated with permanent brain tissue injury. The definition of TIA is discussed in more detail separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) A primary ICH damages the brain directly at the site of the hemorrhage by compressing the surrounding tissue. Physicians must initially consider whether the patient with suspected cerebrovascular disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage. The great majority of ischemic strokes are caused by a diminished supply of arterial blood, which carries sugar and oxygen to brain tissue. Another cause of stroke that is difficult to classify is stroke due to occlusion of veins that drain the brain of blood. Venous occlusion causes a backup of fluid resulting in brain edema, and in addition it may cause both brain ischemia and hemorrhage into the brain. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) BRAIN ISCHEMIA There are three main subtypes of brain ischemia [2]: Thrombosis (see 'Thrombosis' below) generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 2/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Embolism (see 'Embolism' below) refers to particles of debris originating elsewhere that block arterial access to a particular brain region [3]. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Blood disorders (see 'Blood disorders' below) are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. Thrombosis Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to- artery embolism). Thrombotic strokes can be divided into either large or small vessel disease ( table 1). These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. Large vessel disease Large vessels include both the extracranial (common and internal carotids, vertebral) and intracranial arterial system (Circle of Willis and proximal branches) ( figure 1 and figure 2). Intrinsic lesions in large extracranial and intracranial arteries cause symptoms by reducing blood flow beyond obstructive lesions, and by serving as the source of intra-arterial emboli. At times a combination of mechanisms is operant. Severe stenosis promotes the formation of thrombi which can break off and embolize, and the reduced blood flow caused by the vascular obstruction makes the circulation less competent at washing out and clearing these emboli. Pathologies affecting large extracranial vessels include: Atherosclerosis Dissection Takayasu arteritis Giant cell arteritis Fibromuscular dysplasia Pathologies affecting large intracranial vessels include: Atherosclerosis https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 3/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Dissection Arteritis/vasculitis Noninflammatory vasculopathy Moyamoya syndrome Vasoconstriction Atherosclerosis is by far the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain. White platelet-fibrin and red erythrocyte-fibrin thrombi are often superimposed upon the atherosclerotic lesions, or they may develop without severe vascular disease in patients with hypercoagulable states. Vasoconstriction (eg, with migraine) is probably the next most common, followed in frequency by arterial dissection (a disorder much more common than previously recognized) and traumatic occlusion. Fibromuscular dysplasia is an uncommon arteriopathy, while arteritis is frequently mentioned in the differential diagnosis, but it is an extremely rare cause of thrombotic stroke. Aortic disease is really a form of proximal extracranial large vessel disease, but it is often considered together with cardioembolic sources because of anatomic proximity. (See 'Aortic atherosclerosis' below.) Identification of the specific focal vascular lesion, including its nature, severity, and localization, is important for treatment since local therapy may be effective (eg, surgery, angioplasty, intraarterial thrombolysis). It should be possible clinically in most patients to determine whether the local vascular disease is within the anterior (carotid) or posterior (vertebrobasilar) circulation and whether the disorder affects large or penetrating arteries. (See "Clinical diagnosis of stroke subtypes", section on 'Neurologic examination'.) Delivery of adequate blood through a blocked or partially blocked artery depends upon many factors, including blood pressure, blood viscosity, and collateral flow. Local vascular lesions also may throw off emboli, which can cause transient symptoms. In patients with thrombosis, the neurologic symptoms often fluctuate, remit, or progress in a stuttering fashion ( figure 3). (See "Clinical diagnosis of stroke subtypes", section on 'Clinical course of symptoms and signs' and "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Mechanisms and clinical manifestations'.) Small vessel disease Small vessel disease affects the intracerebral arterial system, specifically penetrating arteries that arise from the distal vertebral artery, the basilar artery, the middle cerebral artery stem, and the arteries of the circle of Willis. These arteries thrombose due to: https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 4/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension) and fibrinoid degeneration Atheroma formation at their origin or in the parent large artery The most common cause of obstruction of the smaller arteries and arterioles that penetrate at right angles to supply the deeper structures within the brain (eg, basal ganglia, internal capsule, thalamus, pons) is lipohyalinosis (ie, blockage of an artery by medial hypertrophy and lipid admixed with fibrinoid material in the hypertrophied arterial wall). A stroke due to obstruction of these vessels is referred to as a lacunar stroke (see "Lacunar infarcts"). Lipohyalinosis is most often related to hypertension, but aging may play a role. Microatheromas can also block these small penetrating arteries, as can plaques within the larger arteries that block or extend into the orifices of the branches (called atheromatous branch disease) [1]. Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days ( figure 4), compared with large artery-related brain ischemia, which can evolve over a longer period. Embolism Embolic strokes are divided into four categories ( table 1) [3]. Those with a known source that is cardiac Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings Those with an arterial source (artery to artery embolism) Those with a truly unknown source in which tests for embolic sources are negative The symptoms depend upon the region of brain rendered ischemic [4,5]. The embolus suddenly blocks the recipient site so that the onset of symptoms is abrupt and usually maximal at the start ( figure 5). Unlike thrombosis, multiple sites within different vascular territories may be affected when the source is the heart (eg, left atrial appendage or left ventricular thrombus) or aorta. Treatment will depend upon the source and composition of the embolus. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Cardioembolic strokes usually occur abruptly, although they occasionally present with stuttering, fluctuating symptoms. The symptoms may clear entirely since emboli can migrate and lyse, particularly those composed of thrombus. When this occurs, infarction generally also occurs but is silent; the area of infarction is smaller than the area of ischemia that gave rise to the https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 5/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate symptoms. This process is often referred to as a TIA due to embolism, although it is more correctly termed an embolic infarction or stroke in which the symptoms clear within 24 hours. High-risk cardiac source The diagnosis of embolic strokes with a known cardiac source is generally agreed upon by physicians ( table 2) [6,7]; included in this category are those due to: Atrial fibrillation and paroxysmal atrial fibrillation Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valves Atrial or ventricular thrombus Sinus node dysfunction Sustained atrial flutter Recent myocardial infarction (within one month) Chronic myocardial infarction together with ejection fraction <28 percent Symptomatic congestive heart failure with ejection fraction <30 percent Dilated cardiomyopathy Fibrous nonbacterial endocarditis as found in patients with systemic lupus (ie, Libman- Sacks endocarditis), antiphospholipid syndrome, and cancer (marantic endocarditis) Infective endocarditis Papillary fibroelastoma Left atrial myxoma Coronary artery bypass graft (CABG) surgery With CABG, for example, the incidence of postoperative neurologic sequelae is approximately 2 to 6 percent, most of which is due to stroke [8]. Atheroemboli associated with ascending aortic atherosclerosis is probably the most common cause. (See "Neurologic complications of cardiac surgery".) Potential cardiac source Embolic strokes considered to have a potential cardiac source ( table 2) are ones in which a possible source is detected (usually) by echocardiographic methods [6,7,9], including: Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Atrial cardiopathy (large or malfunctioning left atrium) Left ventricular aneurysm without thrombus Isolated left atrial smoke on echocardiography (no mitral stenosis or atrial fibrillation) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 6/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Complex atheroma in the ascending aorta or proximal arch (see 'Aortic atherosclerosis' below) In this group, the association of the cardiac or aortic lesion and the rate of embolism is often uncertain, since some of these lesions do not have a high frequency of embolism and are often incidental findings unrelated to the stroke event [10]. Thus, they are considered potential sources of embolism. A truly unknown source represents embolic strokes in which no clinical evidence of heart disease is present ( table 1). Aortic atherosclerosis In longitudinal population studies with nonselected patients, complex aortic atherosclerosis does not appear to be associated with any increased primary ischemic stroke risk [11-13]. However, most studies evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [14-17]. The range of findings is illustrated by the following studies: A prospective case-control study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [15]. Atherosclerotic plaques 4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques 4 mm were much more common in patients with brain infarcts of unknown cause (relative risk 4.7). In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, sex, and other clinical risk factors [12]. However, there was an association between complex aortic plaque and noncryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 7/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate In the author's opinion, there is no question that large protruding plaques in the ascending aorta and arch, particularly mobile plaques, are an important cause of stroke [18]. (See "Thromboembolism from aortic plaque".) Systemic hypoperfusion Reduced blood flow is more global in patients with systemic hypoperfusion and does not affect isolated regions. The reduced perfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain. Symptoms of brain dysfunction typically are diffuse and nonfocal in contrast to the other two categories of ischemia. Most affected patients have other evidence of circulatory compromise and hypotension such as pallor, sweating, tachycardia or severe bradycardia, and low blood pressure. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting asymmetrical craniocerebral vascular occlusive disease. The most severe ischemia may occur in border zone (watershed) regions between the major cerebral supply arteries since these areas are most vulnerable to systemic hypoperfusion. The signs that may occur with borderzone infarction include cortical blindness, or at least bilateral visual loss; stupor; and weakness of the shoulders and thighs with sparing of the face, hands, and feet (a pattern likened to a "man-in-a-barrel"). Blood disorders Blood and coagulation disorders are an uncommon primary cause of stroke and TIA, but they should be considered in patients younger than age 45, patients with a history of clotting dysfunction, and in patients with a history of cryptogenic stroke [10]. The blood disorders associated with arterial cerebral infarction include: Sickle cell anemia Polycythemia vera Essential thrombocytosis Heparin induced thrombocytopenia Protein C or S deficiency, acquired or congenital Prothrombin gene mutation Factor V Leiden (resistance to activated protein C) Antithrombin III deficiency Antiphospholipid syndrome Hyperhomocysteinemia Thrombotic thrombocytopenic purpura (TTP) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 8/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Factor V Leiden mutation and prothrombin 20210 mutations are associated mostly with venous rather than arterial thrombosis. They can result in cerebral venous thrombosis or deep venous thrombosis with paradoxical emboli. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) Infectious and inflammatory disease such as pneumonia, urinary tract infections, Crohn disease, ulcerative colitis, HIV/AIDS, and cancers result in a rise in acute phase reactants such as fibrinogen, C-reactive protein, and coagulation factors VII and VIII. In the presence of an endothelial cardiac or vascular lesion, this increase can promote active thrombosis and embolism. CLASSIFICATION SYSTEMS FOR ISCHEMIC STROKE TOAST classification The TOAST classification scheme for ischemic stroke is widely used and has good interobserver agreement [19]. The TOAST system ( table 3) attempts to classify ischemic strokes according to the major pathophysiologic mechanisms that are recognized as the cause of most ischemic strokes ( table 1). It assigns ischemic strokes to five subtypes based upon clinical features and the results of ancillary studies including brain imaging, neurovascular evaluations, cardiac tests, and laboratory evaluations for a prothrombotic state. The five TOAST subtypes of ischemic stroke are: Large artery atherosclerosis Cardioembolism Small vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology The last subtype, stroke of undetermined etiology, involves cases where the cause of a stroke cannot be determined with any degree of confidence, and by definition includes those with two or more potential causes identified, those with a negative evaluation, and those with an incomplete evaluation. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) SSS-TOAST and CCS classification Since the original TOAST classification scheme was developed in the early 1990s, advances in stroke evaluation and diagnostic imaging have allowed more frequent identification of potential vascular and cardiac causes of stroke [6]. These advances could cause an increasing proportion of ischemic strokes to be classified as https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 9/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate "undetermined" if the strict definition of this category (cases with two or more potential causes) is applied. As a result, an evidenced-based modification of the TOAST criteria called SSS-TOAST was developed [6]. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic evidence as determined by predefined clinical and imaging criteria. In a further refinement, an automated version of the SSS-TOAST called the Causative Classification System (CCS) was devised ( table 4) to improve its usefulness and accuracy for stroke subtyping [20]. The CCS is a computerized algorithm that consists of questionnaire-style classification scheme. The CCS appears to have good inter-rater reliability among multiple centers [21]. It is available online at https://ccs.mgh.harvard.edu/ccs_title.php. The overall agreement between the original TOAST and CCS classification systems appears to be moderate at best, suggesting that two methods often classify stroke cases into different categories despite having categories with similar names [22]. BRAIN HEMORRHAGE There are two main subtypes of brain hemorrhage [2]: Intracerebral hemorrhage (ICH) refers to bleeding directly into the brain parenchyma Subarachnoid hemorrhage (SAH) refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain Intracerebral hemorrhage Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma that spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The hematoma continues to grow until the pressure surrounding it increases enough to limit its spread or until the hemorrhage decompresses itself by emptying into the ventricular system or into the cerebrospinal fluid (CSF) on the pial surface of the brain [23,24]. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations [23,24] (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis"). Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 10/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate The earliest symptoms of ICH relate to dysfunction of the portion of the brain that contains the hemorrhage [23,24]. As examples: Bleeding into the right putamen and internal capsule region causes left limb motor and/or sensory signs Bleeding into the cerebellum causes difficulty walking Bleeding into the left temporal lobe presents as aphasia The neurologic symptoms usually increase gradually over minutes or a few hours. In contrast to brain embolism and SAH, the neurologic symptoms related to ICH may not begin abruptly and are not maximal at onset ( figure 6) (and see below). Headache, vomiting, and a decreased level of consciousness develop if the hematoma becomes large enough to increase intracranial pressure or cause shifts in intracranial contents ( figure 7) [23,24]. These symptoms are absent with small hemorrhages; the clinical presentation in this setting is that of a gradually progressing stroke. ICH destroys brain tissue as it enlarges. The pressure created by blood and surrounding brain edema is life threatening; large hematomas have a high mortality and morbidity. The goal of treatment is to contain and limit the bleeding. Recurrences are unusual if the causative disorder is controlled (eg, hypertension or bleeding diathesis). Subarachnoid hemorrhage The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Rupture of an aneurysm releases blood directly into the CSF under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is very common. With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly in contrast to the more gradual onset of ICH. The sudden increase in pressure causes a cessation of activity (eg, loss of memory or focus or knees buckling). Headache is an invariable symptom and is typically instantly severe and widespread; the pain may radiate into the neck or even down the back into the legs. Vomiting occurs soon after onset. There are usually no important focal neurologic signs unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). Onset headache is more common than in ICH, and the combination of onset headache and vomiting is infrequent in https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 11/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate ischemic stroke ( figure 7) [25]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Approximately 30 percent of patients have a minor hemorrhage manifested only by sudden and severe headache (the so-called sentinel headache) that precedes a major SAH ( figure 7) [25]. The complaint of the sudden onset of severe headache is sufficiently characteristic that SAH should always be considered. In a prospective study of 148 patients presenting with sudden and severe headache, for example, SAH was present in 25 percent overall and 12 percent in patients in whom headache was the only symptom [26]. EPIDEMIOLOGY Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries [27,28]. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively [29]. The lifetime risk of stroke for adult men and women (25 years of age and older) is approximately 25 percent [30]. The highest risk of stroke is found in East Asia, Central Europe, and Eastern Europe. Worldwide, stroke is the second most common cause of mortality and the second most common cause of disability [31]. In China, which has the greatest burden of stroke in the world, the age-standardized prevalence, incidence, and mortality rates are estimated to be 1115, 247, and 115 per 100,000 person-years, respectively [32]. These data suggest that the stroke prevalence in China is relatively low compared with the prevalence in high-income countries, but the stroke incidence and mortality rates in China are among the highest in the world. While the incidence of stroke is decreasing in high-income countries, including the United States [33-35], the incidence is increasing in low-income countries [36]. The overall rate of stroke-related mortality is decreasing in high and low income countries, but the absolute number of people with stroke, stroke survivors, stroke-related deaths, and the global burden of stroke-related disability is high and increasing [37]. In the United States, the annual incidence of new or recurrent stroke is about 795,000, of which about 610,000 are first-ever strokes, and 185,000 are recurrent strokes [29]. There is a higher regional incidence and prevalence of stroke and a higher stroke mortality rate in the southeastern United States (sometimes referred to as the "stroke belt") than in the rest of the country [38-42]. The lifetime risk of stroke is higher for females compared with males [29]. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 12/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Black and Hispanic Americans have an increased risk of stroke compared with White Americans, as illustrated by the following observations: The Northern Manhattan Study reported that the age-adjusted incidence of first ischemic stroke among White, Hispanic, and Black Americans was 88, 149, and 191 per 100,000 respectively [43]. Among Black compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.85, 3.18, 3.09, and 1.58 respectively. Among Hispanic compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.00, 1.71, 2.32, and 1.42. The Greater Cincinnati/Northern Kentucky Stroke Study showed that small vessel strokes and strokes of undetermined origin were nearly twice as common, and large vessel strokes were 40 percent more common, among Black compared with White patients [44]. The incidence of cardioembolic strokes was not significantly different. An increased incidence of stroke has also been found among Mexican Americans compared with non-Hispanic White Americans [45]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic

th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 20. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 21. Arsava EM, Ballabio E, Benner T, et al. The Causative Classification of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 16/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate 22. McArdle PF, Kittner SJ, Ay H, et al. Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study. Neurology 2014; 83:1653. 23. Caplan LR. Intracerebral haemorrhage. Lancet 1992; 339:656. 24. Kase CS, Caplan LR. Intracerebral Hemorrhage, Butterworth-Heinemann, Boston 1996. 25. Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. 26. Linn FH, Wijdicks EF, van der Graaf Y, et al. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994; 344:590. 27. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1:e259. 28. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20:795. 29. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation 2022; 145:e153. 30. GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. N Engl J Med 2018; 379:2429. 31. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:459. 32. Wang W, Jiang B, Sun H, et al. Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480 687 Adults. Circulation 2017; 135:759. 33. Koton S, Schneider AL, Rosamond WD, et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA 2014; 312:259. 34. Vangen-L nne AM, Wilsgaard T, Johnsen SH, et al. Declining Incidence of Ischemic Stroke: What Is the Impact of Changing Risk Factors? The Troms Study 1995 to 2012. Stroke 2017; 48:544. 35. Madsen TE, Khoury JC, Leppert M, et al. Temporal Trends in Stroke Incidence Over Time by Sex and Age in the GCNKSS. Stroke 2020; 51:1070. 36. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383:245. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 17/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate 37. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:439. 38. Lanska DJ. Geographic distribution of stroke mortality in the United States: 1939-1941 to 1979-1981. Neurology 1993; 43:1839. 39. Casper ML, Wing S, Anda RF, et al. The shifting stroke belt. Changes in the geographic pattern of stroke mortality in the United States, 1962 to 1988. Stroke 1995; 26:755. 40. Centers for Disease Control and Prevention (CDC). Disparities in deaths from stroke among persons aged <75 years United States, 2002. MMWR Morb Mortal Wkly Rep 2005; 54:477. 41. Rich DQ, Gaziano JM, Kurth T. Geographic patterns in overall and specific cardiovascular disease incidence in apparently healthy men in the United States. Stroke 2007; 38:2221. 42. Glymour MM, Kosheleva A, Boden-Albala B. Birth and adult residence in the Stroke Belt independently predict stroke mortality. Neurology 2009; 73:1858. 43. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005; 111:1327. 44. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 45. Morgenstern LB, Smith MA, Lisabeth LD, et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the Brain Attack Surveillance in Corpus Christi Project. Am J Epidemiol 2004; 160:376. Topic 1089 Version 33.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 18/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate GRAPHICS Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 19/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Chronic myocardial infarction with ejection fraction <28 percent Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 20/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 21/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 22/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Stuttering time course of thrombotic stroke The course of weakness of the right limb in a patient with a thrombotic stroke reveals fluctuating symptoms, varying between normal and abnormal, progressing in a stepwise or stuttering fashion with some periods of improvement. Graphic 64107 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 23/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 24/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of embolic stroke Embolic stroke occurs suddenly, with symptoms maximal at onset. This patient had multiple embolic events with different clinical symptoms (initially weakness, followed by paresthesias). Graphic 73261 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 25/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for ischemic stroke Sources with low or uncertain primary risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an akinesia, dyskinesia) other than apical akinesia ejection fraction of <40% or fractional shortening of <25%) Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 26/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 27/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 28/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Causative Classification System (CCS) of ischemic stroke etiology Stroke Level of Criteria mechanism confidence 1. Either occlusive or stenotic ( 50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or Large artery Evident atherosclerosis thrombosis) vascular disease judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries, and 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery 1. History of 1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month, or Probable 2. Evidence of near-occlusive stenosis or nonchronic complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries), or 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible 1. The presence of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of 2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis, at least one event within the last month, or 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 29/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardio-aortic embolism Evident The presence of a high-risk cardiac source of cerebral embolism Probable 1. Evidence of systemic embolism, or 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and hemostatic or hemodynamic disturbances must not be present. Possible 1. The presence of a cardiac condition with low or uncertain primary risk of cerebral embolism, or 2. Evidence for evident cardio-aortic embolism in the absence of complete diagnostic investigation for other mechanisms Small artery Evident Imaging evidence of a single and clinically relevant acute infarction occlusion <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc) Probable 1. The presence of stereotypic lacunar transient ischemic attacks within the past week, or 2. The presence of a classical lacunar syndrome Possible 1. Presenting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions, or 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms Other causes Evident The presence of a specific disease process that involves clinically appropriate brain arteries Probable A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions Possible Evidence for an evident other cause in the absence of complete diagnostic investigation for mechanisms listed above https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 30/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Undetermined Unknown (no Cryptogenic embolism: causes evident, probable, or 1. Angiographic evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial arteries, or possible criteria for 2. Imaging evidence of complete recanalization of previously the causes occluded artery, or above) 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels Other cryptogenic: Those not fulfilling the criteria for cryptogenic embolism Incomplete evaluation: The absence of diagnostic tests that, under the examiner's judgment, would have been essential to uncover the underlying etiology Unclassified The presence of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 31/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 32/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 33/34 7/6/23, 12:16 PM Stroke: Etiology, classification, and epidemiology - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 34/34

7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Use and utility of stroke scales and grading systems : Larry B Goldstein, MD, FAAN, FANA, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 09, 2023. INTRODUCTION This topic will review stroke scales and grading systems that are used for ischemic and hemorrhagic stroke. Grading systems used to classify patients with subarachnoid hemorrhage are reviewed separately. (See "Subarachnoid hemorrhage grading scales".) Categorization systems used in the classification and etiology of stroke are also discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification' and "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'.) ROLE OF SCALES IN STROKE ASSESSMENT In addition to their importance for assessing the impact of therapeutic interventions in clinical trials, stroke scales are useful in the routine clinical setting as aids to improve diagnostic accuracy, help determine the appropriateness of specific treatments, monitor a patient's neurologic deficits through the continuum of care, and predict and gauge outcomes. Not only are different types of scales needed for these different purposes, but no single scale is suitable for capturing all of the effects of stroke. A plethora of stroke scales have been developed for each of these purposes as discussed in the sections that follow. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 1/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Dimensions of disease The International Classification of Functioning, Disability and Health, developed by the World Health Organization, categorizes the impact of disease into three dimensions [1]: Body Dimension, referring to the structure and function of body systems Activities Dimension, referring to the complete range of activities performed by an individual Participation Dimension, classifying areas of life in which an individual is involved, has access, has societal opportunities or barriers These three general dimensions correspond to what clinicians might describe as neurologic impairments (ie, deficits such as a hemianopsia, aphasia, limb paresis, gait imbalance, or sensory loss), disabilities (ie, loss of the ability to perform daily tasks, such as eating, dressing, and bathing, resulting from physiological deficits), and handicaps (ie, the impact of deficits and disabilities on social participation such as employment) [2]. Additionally, it is becoming increasingly important to assess the effects of disease and treatment on quality of life. Measuring the impact of stroke Although the impact of stroke as reflected by these different dimensions (body, activity, participation) is generally consistent, it is important to measure each dimension, as focusing on any one alone could be misleading. As an example, consider a patient with a paralyzed hand. This deficit would be measured in the Body Dimension as a motor impairment. With compensatory strategies such as the use of the unimpaired hand or prosthetics, that same patient might have no disability (ie, able to eat, dress, bathe). If the patient was a truck driver, they might be able to return to work by driving a modified vehicle (no handicap), whereas if they were a watchmaker, they might be unable to return to their previous employment (ie, a social handicap). Thus, the impact of a neurologic impairment on quality of life can be quite different depending on individual circumstances. In addition, a stroke considered to be mild based upon a measure of one dimension may be severe when measured on a different dimension [3]. A homonymous inferior quadrantanopia might represent a minimal impairment and result in no disability, but could be an important handicap and have a large impact on quality of life because driving a motor vehicle is precluded. Therefore, when choosing a stroke scale, one must first consider why it is being used and what it is measuring. STROKE DIAGNOSIS https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 2/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Because of poor recognition and the nonspecific nature of many stroke symptoms, stroke scales and grading systems have been developed both to aid the general public, emergency responders, and emergency physicians in the identification of persons with acute stroke, and to hasten transport of stroke victims to appropriate medical facilities. These tools must be simple and rapidly applicable. Selected diagnostic scales The best-studied scales for general stroke recognition and diagnosis are the Face Arm Speech Test (FAST), the Cincinnati Prehospital Stroke Scale (CPSS), the Los Angeles Prehospital Stroke Screen (LAPSS), and the Recognition of Stroke in the Emergency Room (ROSIER). FAST and CPSS are simple and easy to use, which makes them most appropriate for the general public and nonmedical first responders [4]. Each evaluates the presence or absence of facial weakness, arm weakness, and speech difficulty. The main difference between the two is that FAST incorporates assessment of language function during normal conversation, whereas CPSS tests language by asking the patient to repeat a short sentence. Both the American Stroke Association and the United States Centers for Disease Control and Prevention promote FAST as a tool to increase public awareness of stroke signs and symptoms [5,6]. LAPSS and ROSIER are more complex and may be more appropriate for use by trained emergency responders and emergency physicians [4]. The LAPSS and ROSIER scales incorporate additional items to help exclude stroke mimics and to increase specificity with a potential disadvantage of reduced sensitivity [7]. FAST The Face Arm Speech Test (FAST; the "T" is a reminder of the importance of time and the need to reach a hospital immediately) evaluates patients with suspected stroke by assessing them for the presence of facial weakness, arm weakness, and speech impairment ( figure 1) [8]. FAST is considered positive if at least one item is abnormal. A prospective study found good agreement for the detection of the acute stroke signs between emergency medical responders using the FAST system and stroke physicians [9]. The scale is insensitive to isolated stroke-related visual or sensory impairments, vertigo, and gait disturbances. BE-FAST The BE-FAST test is a modification of FAST that accounts for imbalance or leg weakness (B for balance) and visual symptoms (E for eyes), as these potentially debilitating symptoms are not otherwise captured by either screening tool [10]. The BE-FAST test may reduce the likelihood of a stroke diagnosis missed using the FAST test but requires field validation in a prospective study. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 3/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate CPSS The CPSS focuses on the assessment facial paresis, arm drift, and abnormal speech ( table 1) [11]. In a prospective report evaluating the CPSS, the diagnostic accuracy for emergency department physicians compared with non-physician emergency medical personnel was similar with high correlation for total score between these groups [12]. The presence of an abnormality on any one of the three stroke scale items was associated with a marked increase in the likelihood of stroke [13]. It has the same limitations as FAST for certain stroke-related deficits that can occur in isolation. LAPSS The LAPSS assesses for unilateral arm drift, handgrip weakness, and facial paresis ( form 1) [14]. The criteria for an "in-the-field" stroke diagnosis are met when the patient age is >45 years, seizure/epilepsy history is absent, symptom duration is <24 hours, the patient is not a full-time wheelchair user or bedridden at baseline, the blood glucose is between 60 and 400 mg/dL, and a unilateral deficit is present in one of the three items (arm, handgrip, or face). The LAPSS was evaluated in an observer-blind prospective study of all non-comatose, non-trauma patients with neurologic complaints compatible with stroke who were transported by emergency medical technicians to a single hospital [14]. Compared with the final diagnosis, a prehospital stroke diagnosis made by paramedics with LAPSS had a sensitivity of 91 percent (95% CI 76-98 percent) and specificity of 97 percent (95% CI 93-99 percent). ROSIER The ROSIER scale was developed to facilitate rapid stroke patient identification and triage by emergency department clinicians [15]. The ROSIER scale incorporates the Glasgow Coma Scale ( table 2) and measurement of blood pressure and blood glucose along with assessment of a seven-item stroke-recognition scale. The first two items inquire about clinical history to exclude stroke mimics [15]: Loss of consciousness or syncope (yes = -1; no = 0) Seizure activity (yes = -1; no = 0) The next five items inquire about specific neurologic deficits of new acute onset (or present since awakening from sleep): Asymmetric facial weakness (yes = +1; no = 0) Asymmetric arm weakness (yes = +1; no = 0) Asymmetric leg weakness (yes = +1; no = 0) Speech disturbance (yes = +1; no = 0) Visual field defect (yes = +1; no = 0) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 4/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The total score range is -2 to +5. Stroke is unlikely, but not completely excluded, if total score is 0 [15]. When prospectively validated at a cut-off score of >0 in the original publication, the scale had a sensitivity of 93 percent (95% CI 89-97 percent) and specificity of 83 percent (95% CI 77-89 percent) [15]. A 2020 systematic review and meta-analysis identified 15 datasets that evaluated the ROSIER scale and found that the combined sensitivity and specificity were 88 and 66 percent, respectively [16]. Utility of stroke diagnostic scales In a 2019 systematic review of studies evaluating the accuracy of stroke recognition scales used in the prehospital setting or emergency department, the CPSS had the highest sensitivity in prehospital settings, while the ROSIER had the highest sensitivity in emergency department settings [4]. LARGE VESSEL OCCLUSION TRIAGE Selected triage scales The advent of proven therapies for the treatment of patients with large-vessel distribution ischemic stroke requires the triage of patients to centers capable of rapid endovascular clot retrieval [17]. Scales that have been evaluated as stroke triage aids to detect patients with large vessel occlusion include the Rapid Arterial oCclusion Evaluation (RACE) scale ( table 3), the Los Angeles Motor Scale (LAMS) ( table 4), the Cincinnati Stroke Triage Assessment Tool (C-STAT) ( table 5), and the Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale ( table 6). As reviewed below, none of the available scales predict stroke due to large vessel occlusion with both high sensitivity and specificity. With this limitation in mind, our EMS providers generally use RACE. (See 'Utility of stroke triage scales' below.) RACE The RACE scale is based on the items of National Institutes of Health Stroke Scale (NIHSS) that had the highest predictive value for large artery occlusion, as determined in a retrospective study of 654 patients with acute ischemic stroke of the anterior circulation [18]. The RACE scale assesses facial palsy, limb motor function, head and gaze deviation, and aphasia or agnosia, as shown in the table ( table 3). The RACE score ranges from a normal of 0 to a maximum of 9 points. For detecting large vessel occlusion, a RACE scale score 5 had sensitivity and specificity of 85 and 68 percent, respectively [18]. LAMS The LAMS ( table 4) employs a three-item motor score derived from the LAPSS and assesses facial droop, arm drift, and grip strength, with the total score ranging from 0 to 5 points [19]. In a retrospective study of 119 patients with anterior circulation ischemic stroke evaluated within 12 hours of time last known well, a LAMS score of 4 predicted a large vessel occlusion with a sensitivity and specificity of 81 and 89 percent, respectively [20]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 5/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate C-STAT The C-STAT ( table 5) is a three-item score that assigns two points for conjugate gaze deviation, one point if the patient answers incorrectly on one of two level of consciousness questions and does not follow one of two commands from the NIHSS, and one point for arm weakness; the total score ranges from 0 to 4 points [21,22]. In a prospective study of prehospital evaluation with complete data for 58 patients who had a positive FAST score among 158 screened for suspicion for stroke or TIA, a C-STAT score 2 had a sensitivity of 71 percent (95% CI 29-96) and specificity of 70 percent (95% CI 55-83) for the diagnosis of large vessel stroke [22]. FAST-ED The FAST-ED scale ( table 6) assigns points for facial palsy, arm weakness, speech changes, eye deviation, and denial or neglect; the total score ranges from 0 to 9 [23]. In a retrospective study of 727 patients suspected of having acute stroke within 24 hours of symptom onset, large vessel occlusion was detected in 240. For prediction of large vessel occlusion, a FAST-ED score 4 had a sensitivity of 61 percent and a specificity of 89 percent [23]. Utility of stroke triage scales Although detection of ischemic stroke caused by a large artery occlusion is important to help identify patients who may benefit from mechanical thrombectomy, none of the available scales predicts this type of stroke with optimal accuracy. Triage decisions based on the use of these scales will miss some patients with large vessel occlusion who have milder stroke impairments [24]. This limitation needs to be understood if these scales are used to help triage patients for mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke".) In a 2018 systematic review of prediction scales for large vessel occlusion, the sensitivities of these scales ranged from 47 to 73 percent, and the specificities ranged from 78 to 90 percent; no single scale could predict a large vessel occlusion with high sensitivity and specificity [24]. A prospective cohort study of 2007 patients conducted in the Netherlands comparing seven stroke prediction scales found that sensitivities for large vessel occlusion ranged from 38 to 62 percent and specificities ranged from 80 to 93 percent, with LAMS and RACE having the highest accuracy [25]. Another prospective cohort study from the Netherlands of over 1000 patients with suspected stroke found that the RACE was the best performing scale for detecting large vessel occlusion [26]. Another cohort study found similar calibrations for RACE, LAMS C-STAT, and FAST- ED [27]. None had an AUC (area under the receiver operating curve) >0.8, a threshold generally considered for clinical usefulness. STROKE IMPAIRMENT AND SEVERITY https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 6/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The main stroke impairment scales are the National Institutes of Health Stroke Scale (NIHSS), the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), the European Stroke Scale, and the Canadian Neurologic Scale (CNS). The Scandinavian Stroke Scale has also been used in clinical trials. Although these scales are useful to assess the severity of neurologic impairment due to stroke, they are not useful for making the diagnosis of stroke. Stroke severity and prognosis Stroke severity is assessed with an impairment-level scale, such as the NIHSS. Stroke prognosis is largely determined by the severity of the patient's initial impairments. The association of neurologic impairment, stroke severity, and outcome after ischemic stroke is reviewed separately. (See "Overview of ischemic stroke prognosis in adults", section on 'Neurologic severity'.) NIHSS The NIHSS is both reliable and valid, and has become a standard stroke impairment scale for use in both clinical trials and as part of clinical care in the United States in many other countries [28-32]. As examples, the NIHSS score is part of the assessment that helps determine whether a patient is a candidate for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke"). In addition, the baseline NIHSS score is predictive of long-term outcome after acute stroke, as noted above. The NIHSS can also be assessed remotely and may be useful in telemedicine programs [33]. The NIHSS measures neurologic impairment using a 15 item scale ( table 7) [28]. A printable version of the NIHSS is available online at https://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf. An NIHSS calculator (calculator 1) is best used by a certified NIHSS examiner in conjunction with a copy of the full NIHSS. Both physician and nurse stroke providers can be trained to use the scale with similar levels of accuracy [34]. Reliability can be further improved through the use of standardized video training [35,36]. However, the value of routine retraining is uncertain [37]. The NIHSS has been validated for retrospective use based upon information available in the patient's medical record over a range of severities [38-41]. An important limitation of the NIHSS is that it does not capture all stroke-related impairments, particularly with infarction involving the vertebrobasilar circulation [42,43]. This is also true for modified, shortened versions of the scale [44,45]. Modified NIHSS The modified NIHSS (mNIHSS) is a shortened version of the NIHSS that omits level of consciousness (item 1a), facial weakness (item 4), limb ataxia (item 7), and dysarthria (item 10) from the original NIHSS and condenses the sensory test (item 8) choices from three to two responses ( table 8) [46]. In the original derivation study and subsequent prospective https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 7/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate validation, the validity and reliability of the mNIHSS was nearly identical to the original NIHSS [44,46]. The use of the "Cookie Theft" picture for language assessment as part of the NIHSS may be culturally biased [47]. An alternative has not yet been adopted. Pediatric NIHSS The Pediatric National Institutes of Health Stroke Scale (PedNIHSS) was developed by modifying the adult NIHSS so that examination items and testing materials are age-appropriate ( table 9 and figure 2 and figure 3 and figure 4) [48]. In a multicenter, prospective cohort study of children with acute arterial ischemic stroke, the PedNIHSS showed good interrater reliability when employed by trained pediatric neurologists. Other impairment scales European Stroke Scale The European Stroke Scale was designed to evaluate patients with stroke involving the territory of the middle cerebral artery. It is similar to the NIHSS and is also reliable and partially validated [49]. Canadian Neurological Scale The Canadian Neurological Scale (CNS) is simpler and more rapidly performed than the NIHSS, but does not capture many stroke-related impairments ( table 10) [50,51]. Like the NIHSS, the CNS has been validated for use retrospectively based on information available in the patient's medical record over a range of severities [40,52]. Scandinavian Stroke Scale The Scandinavian Stroke Scale assesses consciousness, gaze palsy, arm and leg weakness, dysphasia, orientation, facial palsy, and gait [53]. The scale has good to excellent reliability. It can be reliably scored based on data routinely recorded in the medical record and has been validated for retrospective use [54]. Specific neurologic deficits Scales to measure specific types of deficits have been developed and validated in patients with stroke: Motor impairments (eg, Fugl-Meyer Assessment [55,56], Motor Assessment Scale [57], and Motricity Index [58,59]) Balance (eg, Berg Balance Scale [60]) Arm/hand function (eg, Research Action Arm Test [61-64]) Mobility (eg, Rivermead Mobility Index [65]) Aphasia (eg, Frenchay Aphasia Screening Test [66,67] and Porch Index of Communicative Ability [68]) Cognition (eg, Montreal Cognitive Assessment [MoCA] [69,70]) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 8/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate These scales are most useful for research studies targeting specific types of deficits. One exception is the MoCA, which is a widely used clinical screening test for cognitive impairment. The MoCA includes assessments of executive functions that are commonly affected by stroke. (See "Mental status scales to evaluate cognition", section on 'Montreal Cognitive Assessment (MoCA)'.) In addition, depression commonly complicates the recovery of stroke patients, and several instruments are available to aid in its diagnosis and measurement, including the following: Beck Depression Inventory (BDI) [71] Center for Epidemiological Studies of Depression (CES-D) [72] Hamilton Depression Scale [73] Personal Health Questionnaire (PHQ-9) [74] Of these, aphasic patients and older adults may have difficulty with the BDI, CES-D, and the PHQ- 9. The Hamilton Depression Scale is observer- rather than patient-rated, but its inter-observer reliability may be limited. These depression rating scales have been used primarily in research settings. The PHQ-9 has been validated for use as a depression screening tool in general practice settings. A simple two-question screen for depression has been used in primary care settings, but its use in stroke populations has not been assessed [75]. DISABILITY The two most frequently used stroke disability scales are the Barthel Index (BI) and the Functional Independence Measure (FIM). Both were similarly responsive to change in disability in one study [76], whereas another report found that the FIM was more sensitive to change [77]. Instrumental activities of daily living (IADL) scales attempt to bridge the gap between disability and handicap. Combining basic scales such as the BI or FIM with IADL assessments may provide more comprehensive information than can be gleaned from either type of scale alone and can be a useful strategy for both clinical and research applications in stroke patients [78]. Barthel Index The BI measures 10 basic aspects of self-care and physical dependency ( table 11) [79-81]. A normal score is 100, and lower scores indicate increasing disability; a BI >60 corresponds to assisted independence, and a BI <40 corresponds to severe dependency [80]. A systematic review and meta-analysis concluded that the interrater reliability of the BI is excellent [82]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 9/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Although not specifically designed as a stroke scale, the BI correlates moderately well with radiologic infarct size [83-86]. In addition, the BI is frequently used as an outcome measure for stroke trials [81], and limited evidence suggests that the BI can predict outcome after stroke [83,87,88]. However, the predictive capacity of the BI for outcome is reduced in the setting of acute stroke, particularly within the first 72 hours [42,89]. In addition, the BI has significant limitations related to floor and ceiling effects, meaning that the BI is relatively insensitive to change in function at the extreme ends of the scale [3,77,81]. FIM The FIM is a proprietary instrument that assesses patient disability in 13 aspects of motor function and five aspects of cognitive function [90-92]. The FIM is widely used for monitoring functional improvement through the course of rehabilitation therapy [93,94]. It can be assessed by telephone as well as in person [95]. A systematic review concluded that the FIM may have some utility for predicting outcome after stroke, though high-quality evidence was limited [91]. IADL As noted above, IADL scales attempt to bridge the gap between disability and handicap [96]. They are intended to capture the patient's ability to live independently in the home and assess a variety of activities (cooking, home management, recreation, etc). Several IADL scales are available, but the Frenchay Activities Index was specifically developed for use with stroke patients and is reliable [97-99]. HANDICAP The main stroke handicap scales are the Rankin Scale and its derivatives, the modified Rankin Scale (mRS), the Rankin Focused Assessment, and the Oxford Handicap Scale [100-104]. Of these, the mRS is the most widely used. The Craig Handicap Assessment and Reporting Technique (CHART) was specifically designed to assess handicap [105,106], but has not been used as extensively as the mRS in the assessment of patients with stroke. Modified Rankin Scale The mRS measures functional independence on a seven grade scale ( table 12) [100,101]. The mRS has been used as a measure of stroke-related handicap in many interventional trials and is frequently used as a global measure of the functional impact of stroke [31,107,108]. In addition, the mRS score at 90 days after intravenous thrombolysis or endovascular interventions for acute ischemic stroke is a proposed "core metric" of comprehensive stroke centers in the United States [31]. A systematic review published in 2007 concluded that interrater reliability of the mRS was moderate and was improved with structured interview [109], although a subsequent study found no significant difference between standard and structured mRS [110]. A systematic review https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 10/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate published in 2009 found that the overall interrater reliability of the mRS was moderate but varied widely among included studies; the effect of structured interview was inconsistent [111]. The mRS score shows moderate correlation with the volume of cerebral infarction [85,86,112]. The mRS ( table 12) places particular emphasis on the patient's ability to walk. Because it is weighted towards physical function [107], the results of the mRS correlate closely with scores on the Barthel Index [113-115] and therefore do not fully reflect the impact of stroke on social participation. There has been some debate regarding cutoffs and the analysis of mRS data in the setting of clinical trials. Different trials have used dichotomous cutoff scores of 1, 2, or 3 to identify those with favorable compared with unfavorable outcomes. Another approach is using a so- called "shift" analysis, in which the entire range of possible scores is considered rather than dichotomous outcomes [116]. Some trials that were negative using prespecified dichotomous cutoffs might have been positive if a shift analysis had been used [117]. QUALITY OF LIFE Health-related quality of life (HRQOL) reflects the physical, emotional, and social aspects of life that can be affected by acute or chronic disease [118]. These types of assessments are generally used for research and not clinical purposes. Generic scales Several generic scales have been used for the assessment of HRQOL in patients with stroke, including the following: Sickness Impact Profile [119,120] Short Form 36 [121] Health Utilities Index [122-125] EuroQol [126-128] The use of these HRQOL scales in patients with stroke is particularly challenging because the scales are generally lengthy, and because the disease itself can affect the patient's ability to respond, often necessitating obtaining responses from proxies [129]. The physical subscore of the Sickness Impact Profile correlates with stroke-related impairments as measured with the National Institutes of Health Stroke Scale (NIHSS) and Canadian Neurologic Scale (CNS) [114]. Disability scores measured with the Barthel Index and handicap scores measured with the Rankin Scale explain only 33 percent of the variance in Sickness Impact Profile scores [130]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 11/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Stroke-specific scales One response to the difficulty of assessing quality of life in stroke patients with generic scales has been the development of stroke-specific HRQOL instruments, such as the following: Stroke Impact Scale (SIS) [131] Stroke-Specific Quality of Life Scale [132,133] Stroke-adapted version of the Sickness Impact Profile [134] The SIS was designed to measure changes in hand function, activities of daily living, mobility, emotion, communication, memory, thinking, and participation after stroke [131]. The SIS is reliable, valid, and sensitive to change [131,135]. A briefer version focused on physical functioning has also been developed [136]. In addition, the SIS has been evaluated for postal administration [137]. As with other HRQOL scales, a major limitation of the SIS is that assessment is made by self-report of the patient, posing an obstacle to its use in patients with aphasia or other cognitive impairments [42]. This limitation can be partially addressed by use of a proxy [138]. ADDITIONAL STROKE SCALES A number of stroke scales specific to transient ischemic attack (TIA), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage are discussed in separate topic reviews. These include: 2 TIA The ABCD score ( table 13) is intended to estimate the risk of ischemic stroke in the first days after a TIA. Intracerebral hemorrhage The ICH score is intended to predict mortality after intracerebral hemorrhage. Subarachnoid hemorrhage Grading systems used to classify patients with subarachnoid hemorrhage include the Glasgow Coma Scale, the Hunt and Hess grading system, the World Federation of Neurological Surgeons scale, the Fisher scale, the modified Fisher scale, and the Ogilvy and Carter grading system. (See "Subarachnoid hemorrhage grading scales".) SUMMARY AND RECOMMENDATIONS Stroke scales are useful for clinical and research purposes as aids to improve diagnostic accuracy, determine the suitability of specific treatments, monitor change in neurologic https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 12/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. Effect of Known Atrial Fibrillation and Anticoagulation Status on the Prehospital Identification of Large Vessel Occlusion. J Stroke Cerebrovasc Dis 2019; 28:104404. 28. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864. 29. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660. 30. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994; 25:362. 31. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:849. 32. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 15/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344.

impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. 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Stroke 2002; 33:2593. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 22/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Topic 14084 Version 16.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 23/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate GRAPHICS Face Arm Speech Test Reproduced with permission from: Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance sta using the face arm speech test. Stroke 2003; 34:71. Copyright 2003 Lippincott Williams & Wilkins. Graphic 54134 Version 7.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 24/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Prehospital Stroke Scale (CPSS) The CPSS evaluates for facial palsy, arm weakness, and speech abnormalities. Items are scored as either normal or abnormal. Facial droop The patient shows teeth or smiles Normal: Both sides of face move equally. Abnormal: One side of face does not move as well as the other. Arm drift The patient closes their eyes and extends both arms straight out for 10 seconds Normal: Both arms move the same, or both arms do not move at all. Abnormal: One arm either does not move, or one arm drifts down compared to the other. Speech The patient repeats "The sky is blue in Cincinnati" Normal: The patient says correct words with no slurring of words. Abnormal: The patient slurs words, says the wrong words, or is unable to speak. Reproduced from: Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 62856 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 25/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Los Angeles Prehospital Stroke Screen Reproduced with permission from: Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the eld. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. Copyright 2000 Lippincott Williams & Wilkins. Graphic 78128 Version 10.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 26/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 27/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Rapid Arterial oCclusion Evaluation (RACE) scale RACE NIHSS score Item score equivalence Facial palsy Absent 0 0 Mild 1 1 Moderate to severe 2 2 to 3 Arm motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Leg motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Head and gaze deviation Absent 0 0 Present 1 1 to 2 Aphasia* (if right hemiparesis) Performs both tasks correctly 0 0 Performs 1 task correctly 1 1 Performs neither tasks 2 2 Agnosia (if left hemiparesis) Patient recognizes their arm and the impairment 0 0 Does not recognize their arm or the impairment 1 1 Does not recognize their arm nor the impairment 2 2 Score total 0 to 9 Aphasia: Ask the patient to (1) "close your eyes"; (2) "make a fist" and evaluate if the patient obeys. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 28/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Agnosia: Ask the patient: (1) while showing their the paretic arm: "Whose arm is this" and evaluate if the patient recognizes their own arm. (2) "Can you lift both arms and clap" and evaluate if the patient recognizes their functional impairment. From: P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. DOI: 10.1161/STROKEAHA.113.003071. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130953 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 29/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or

29/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). raise eyebrows and close eyes. Score symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- paralysis of lower face). comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 35/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 for full 10 seconds. 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not degrees (if supine). Drift is scored if the arm falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, degrees, drifts down to bed, but has some effort against gravity. beginning with the non-paretic arm. Only in the case of amputation or joint fusion at the _____ shoulder, the examiner should record the score as untestable (UN), and clearly write 3 = No effort against gravity; limb falls. 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the 0 = No drift; leg holds 30-degree position appropriate position: hold the leg at 30 degrees (always tested supine). Drift is for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. against gravity. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and 4 = No movement. clearly write the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, are performed on both sides, and ataxia is scored only if present out of proportion to explain:________________ weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 36/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is affected side; or there is a loss of superficial pain with pinprick, but patient is aware of scored as abnormal and the examiner should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," not aware of being touched in the face, arm, and leg. should only be given when a severe or total loss of sensation can be clearly _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obtained during the preceding sections of obvious loss of fluency or facility of comprehension, without significant the examination. For this scale item, the patient is asked to describe what is limitation on ideas expressed or form of expression. Reduction of speech and/or happening in the attached picture, to name the items on the attached naming sheet and comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, examiner can identify picture or naming the preceding general neurological exam. If visual loss interferes with the tests, ask the card content from patient's response. patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. for inference, questioning, and guessing by The patient in a coma (item 1a=3) will automatically score 3 on this item. The the listener. Range of information that can be exchanged is limited; listener carries examiner must choose a score for the patient with stupor or limited cooperation, burden of communication. Examiner cannot but a score of 3 should be used only if the https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 37/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be obtained by asking patient to read or repeat words from the attached list. If the be understood with some difficulty. patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence _____ rated. Only if the patient is intubated or has of or out of proportion to any dysphasia, or other physical barriers to producing speech, the examiner should record the score as is mute/anarthric. untestable (UN), and clearly write an explanation for this choice. Do not tell the UN = Intubated or other physical barrier, explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous bilateral simultaneous stimulation in one of the sensory modalities. stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient 2 = Profound hemi-inattention or extinction to more than one modality; _____ has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 38/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The Modified National Institutes of Health Stroke Scale (mNIHSS) scoring sheet Patient score Item number Item name Scoring guide 1b LOC questions 0 = Answers both correctly 1 = Answers one correctly _____ 2 = Answers neither correctly 1c LOC commands 0 = Performs both tasks correctly 1 = Performs one task _____ correctly 2 = Performs neither task 2 Gaze 0 = Normal 1 = Partial gaze palsy _____ 2 = Total gaze palsy 3 Visual fields 0 = No visual loss 1 = Partial hemianopsia _____ 2 = Complete hemianopsia 3 = Bilateral hemianopsia 5a Left arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 39/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 5b Right arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement 6a Left leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 6b Right leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 8 Sensory 0 = Normal _____ 1 = Abnormal 9 Language 0 = Normal 1 = Mild aphasia _____ 2 = Severe aphasia 3 = Mute or global aphasia 11 Neglect 0 = Normal 1 = Mild _____ 2 = Severe Score (out of 31): _____ The item numbers correspond to the NIHSS scale. The scale is shorter, having only 11 total items (versus 15 items on the NIHSS). LOC: level of consciousness. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 40/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate From: Meyer BC, Hemmen TM, Jackson CM, Lyden PD. Modi ed National Institutes of Health Stroke Scale for use in stroke clinical trials: prospective reliability and validity. Stroke 2002; 33:1261. DOI: 10.1161/01.str.0000015625.87603.a7. Copyright 2002 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130998 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 41/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Pediatric National Institutes of Health Stroke Scale (PedNIHSS) PedNIHSS INSTRUCTIONS: Administer stroke scale items in the order listed. Follow directions provided for each exam item. Scores should reflect what the patient does, not what the clinician thinks the patient can do. MODIFICATIONS FOR CHILDREN: Modi cations to testing instructions from the adult version for use in children are shown in bold italic with each item where appropriate. Items with no modi cations should be administered and scored with children in the same manner as for adults. Scale definition and Item# and instructions scoring guide 1a. Level of consciousness: The investigator must choose a response, even if a full evaluation 0 = Alert; keenly responsive. is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the 1 = Not alert, but arousable by minor stimulation to obey, answer, or respond. patient makes no movement (other than reflexive posturing) in response to noxious stimulation. 2 = Not alert, requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, areflexic. 1b. LOC questions: The patient is asked the month and his/her age. The answer must 0 = Answers both questions be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will correctly. 1 = Answers one question correctly. score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, 2 = Answers neither question language barrier or any other problem not secondary to aphasia correctly. are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non- verbal cues. Modi ed for children, age 2 years and up. A familiar Family Member must be present for this item: Ask the child "how old are you?" Or "How many years old are you?" for question number one. Give credit if the child states the correct age, or shows the correct number of ngers for his/her age. For the second question, ask the child "where is XX?", XX referring to the name of the parent or other familiar family member present. Use the name for that person which the child typically uses, eg, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 42/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate "mommy". Give credit if the child correctly points to or gazes purposefully in the direction of the family member. 1c. LOC commands: The patient is asked to open and close the eyes and then to grip 0 = Performs both tasks and release the non-paretic hand. For children one may substitute the command to grip the hand with the command "show me your correctly. 1 = Performs one task correctly. nose" or "touch your nose". Substitute another one step command if the hands cannot be used. Credit is given if an 2 = Performs neither task unequivocal attempt is made but not completed due to weakness. correctly. If the patient does not respond to command, the task should be demonstrated to them (pantomime) and score the result (ie, follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored but caloric 0 = Normal. 1 = Partial gaze palsy. This score is given when gaze is testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the abnormal in one or both eyes, but where forced deviation or score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI) score a 1. Gaze is testable in all aphasic total gaze paresis are not present. patients. Patients with ocular trauma, bandages, pre-existing blindness or other disorder of visual acuity or fields should be tested with reflexive movements and a choice made by the 2 = Forced deviation, or total gaze paresis not overcome by investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a the oculocephalic maneuver. partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting (for children >6 years) or 0 = No visual loss. 1 = Partial hemianopia. visual threat (for children age 2 to 6 years) as appropriate. Patient must be encouraged, but if they look at the side of the moving 2 = Complete hemianopia. fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining 3 = Bilateral hemianopia (blind including cortical blindness). eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia is found. If patient is blind from any cause score 3. Double simultaneous stimulation is performed at this point. If there is extinction patient receives a 1 and the results are used to answer question 11. 4. Facial palsy: Ask, or use pantomime to encourage the patient to show teeth or 0 = Normal symmetrical raise eyebrows and close eyes. Score symmetry of grimace in movement. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 43/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate response to noxious stimuli in the poorly responsive or non- 1 = Minor paralysis (flattened comprehending patient. If facial trauma/bandages, orotracheal tube, tape or other physical barrier obscures the face, these nasolabial fold, asymmetry on smiling). should be removed to the extent possible. 2 = Partial paralysis (total or near total paralysis of lower face). 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). 5 & 6. Motor arm and leg: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 44/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate The limb is placed in the appropriate position: extend the arms 5a. Left arm (palms down) 90 degrees (if sitting) or 45 degrees (if supine) and the leg 30 degrees (always tested supine). Drift is scored if the arm 5b. Right arm 0 = No drift, limb holds 90 (or 45) degrees for full 10 falls before 10 seconds or the leg before 5 seconds. For children too immature to follow precise directions or uncooperative for seconds. any reason, power in each limb should be graded by observation of spontaneous or elicited movement according to the same 1 = Drift, limb holds 90 (or 45) degrees, but drifts down grading scheme, excluding the time limits. The aphasic patient is before full 10 seconds; does encouraged using urgency in the voice and pantomime but not noxious stimulation. Each limb is tested in turn, beginning with not hit bed or other support. the non-paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip, or immobilization by an IV board, may the 2 = Some effort against gravity, limb cannot get to or score be "9" and the examiner must clearly write the explanation maintain (if cued) 90 (or 45) degrees, drifts down to bed, for scoring as a "9". Score each limb separately. but has some effort against gravity. 3 = No effort against gravity, limb falls. 4 = No movement. 9 = Amputation, joint fusion explain. 6a. Left leg 6b. Right leg 0 = No drift, leg holds 30 degrees position for full 5 seconds. 1 = Drift, leg falls by the end of the 5 second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. 3 = No effort against gravity, leg falls to bed immediately. 4 = No movement. 9 = Amputation, joint fusion explain. 7. Limb ataxia: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 45/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate This item is aimed at finding evidence of a unilateral cerebellar 0 = Absent. lesion. Test with eyes open. In case of visual defect, insure testing 1 = Present in one limb. is done in intact visual field. The finger-nose-finger and heel-shin 2 = Present in two limbs. tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. In children, substitute this task with reaching for a toy for the upper extremity, and kicking a toy or the examiner's hand, in children too young (<5 years) or otherwise uncooperative for the standard exam item. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion may the item be scored "9", and the examiner must clearly write the explanation for not scoring. In case of blindness test by touching nose from extended arm position. 8. Sensory: Sensation or grimace to pin prick when tested, or withdrawal from 0 = Normal; no sensory loss. noxious stimulus in the obtunded or aphasic patient. For children 1 = Mild to moderate sensory too young or otherwise uncooperative for reporting gradations of loss; patient feels pinprick is sensory loss, observe for any behavioral response to pin prick, less sharp or is dull on the affected side; or there is a loss and score it according to the same scoring scheme as a "normal" response, "mildly diminished" or "severely diminished" response. of superficial pain with Only sensory loss attributed to stroke is scored as abnormal and pinprick but patient is aware the examiner should test as many body areas [arms (not hands), he/she is being touched. legs, trunk, face] as needed to accurately check for hemisensory 2 = Severe to total sensory loss. A score of 2, "severe or total," should only be given when a severe or total loss of sensation can be clearly demonstrated. loss; patient is not aware of being touched in the face, Stuporous and aphasic patients will therefore probably score 1 or arm, and leg. 0. 9. Best language: A great deal of information about comprehension will be obtained 0 = No aphasia, normal. during the preceding sections of the examination. For children age 6 years and up with normal language development before 1 = Mild to moderate aphasia; some obvious loss of fluency onset of stroke: The patient is asked to describe what is or facility of comprehension, happening in the attached picture, to name the items on the without significant limitation on ideas expressed or form of attached naming sheet, to repeat words from the attached list, and to read from the attached list of sentences (see Table expression. Reduction of S1 "Language testing items" below, and see separate gures speech and/or for Cookie theft picture, Picture naming for PedNIHSS, and comprehension, however, Reading for PedNIHSS). Comprehension is judged from responses makes conversation about provided material difficult or here as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the impossible. For example in patient to identify objects placed in the hand, repeat, and produce conversation about provided speech. The intubated patient should be asked to write. The materials examiner can patient in coma (question 1a = 3) will arbitrarily score 3 on this identify picture or naming card from patient's response. item. The examiner must choose a score in the patient with stupor https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 46/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back)

or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 54/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason The need for supervision renders the patient not independent Patient performance should be established using the best available evidence provided by the patient, family, friends and caregivers; direct observation and common sense are also important, but direct testing is not needed Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will be relevant Middle categories imply that the patient supplies over 50 percent of the effort Use of aids to be independent is allowed ADL: activities of daily living. References: 1. Mahoney FI, Barthel D. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:56. Used with permission. 2. Loewen SC, Anderson BA. Predictors of stroke outcome using objective measurement scales. Stroke 1990; 21:78. 3. Gresham GE, Phillips TF, Labi ML. ADL status in stroke: Relative merits of three standard indexes. Arch Phys Med Rehabil 1980; 61:355. 4. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: A reliability study. Int Disability Study 1988; 10:61. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 55/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 77371 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 56/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 57/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 58/59 7/6/23, 12:19 PM Use and utility of stroke scales and grading systems - UpToDate Contributor Disclosures Larry B Goldstein, MD, FAAN, FANA, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 59/59

7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease : Alex George, MD, PhD, Lori Jordan, MD, PhD : Douglas R Nordli, Jr, MD, Michael R DeBaun, MD, MPH : Jennifer S Tirnauer, MD, John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 16, 2023. INTRODUCTION Stroke is a common and devastating manifestation of sickle cell disease (SCD) that can affect children and adults. This topic discusses assessment and treatment of acute stroke in children and adults with SCD. Risk stratification and stroke prevention are presented separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) PRESENTATION Stroke subtypes Ischemic stroke Central nervous system ischemia is defined as brain, spinal cord, or retinal cell death attributable to ischemia; ischemic stroke is defined as brain infarction accompanied by sudden onset of overt stroke symptoms. Hemorrhagic stroke Represents one-third of acute neurologic events in patients with SCD. ICH Intracerebral hemorrhage (ICH) involves bleeding directly into the brain parenchyma and formation of hematoma. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 1/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate IVH Intraventricular hemorrhage (IVH) involves bleeding into the ventricles, excluding IVH in preterm infants. SAH Subarachnoid hemorrhage (SAH) involves bleeding that occurs directly into the subarachnoid space under arterial pressure. The blood spreads quickly within the cerebrospinal fluid (CSF), leading to a rapid increase in intracranial pressure. When to suspect Acute ischemic stroke due to vaso-occlusion in cerebral vessels is the first consideration in a patient with SCD who presents with new neurologic findings or severe headache. However, it is important not to overlook other potential causes of neurologic deterioration. (See 'Differential diagnoses' below.) Presenting features may suggest certain stroke subtypes or stroke mimics, though no clinical features are pathognomonic for distinguishing among types of stroke: Ischemic stroke Infants may present with focal weakness but are more likely than older children to present with seizures and altered mental status. Older children usually have hemiparesis or other focal neurologic signs such as aphasia, or visual disturbance; other symptoms may include seizures, headache, and lethargy. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Overview of the evaluation of stroke".) The most common locations for an acute ischemic stroke in patients with SCD include large vessel territories and borderzone regions ( figure 1). Hemorrhagic transformation of infarcts can occur in these sites [1]. Transient ischemic attack (TIA) Stroke symptoms or signs lasting <24 hours have been historically defined as a TIA. However, when appropriate neuroimaging is completed, up to 33 percent of patients with stroke symptoms lasting <24 hours are found to have an infarct [2]. In a small study in children with TIA, 16 percent had infarcts on follow-up magnetic resonance imaging (MRI) [3]. This has led to a tissue-based definition of TIA as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction on neuroimaging [4]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack".) During a TIA or acute ischemic infarct, blood transfusion may hasten recovery to baseline. The traditional threshold for distinguishing stroke from TIA is therefore somewhat arbitrary. Cerebral venous thrombosis Cerebral venous thrombosis (CVT; also called cerebral venous sinus thrombosis [CVST]) has a highly variable presentation, since there may be https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 2/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate associated brain swelling, edema, venous infarction, or hemorrhagic venous infarction caused by venous occlusion. The onset can be acute, subacute, or chronic. Headache (of gradual, acute, or thunderclap onset) is the most frequent symptom and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, papilledema, and encephalopathy with altered mental status or coma. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) ICH The presentation of ICH depends primarily on the size of the hematoma, anatomic location, and whether the hemorrhage extends into the ventricles. Typical findings include rapid onset of neurologic dysfunction and signs of increased intracranial pressure such as headache, vomiting, and decreased level of consciousness. For patients with large volume hemorrhage, stupor or coma is typical. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) SAH The primary symptom of aneurysmal SAH is a sudden, severe headache, which may or may not be associated with a brief loss of consciousness, nausea or vomiting, and meningismus. Restricted SAH may manifest with transient motor or sensory symptoms that suggest epileptic phenomena and/or frank seizures. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".) Age may be somewhat helpful for predicting the ultimate diagnosis. Ischemic stroke is more common than hemorrhagic stroke in children and adolescents with SCD. Hemorrhagic stroke is more common than ischemic stroke in adults with SCD [1]. TIA is rare in children. However, individuals of all ages with SCD may have any of these diagnoses. The epidemiology of stroke in SCD, which may differ according to the age of the patient, is discussed separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence'.) Differential diagnoses The following alternative diagnoses warrant consideration [1]: Infection, including acute meningitis, brain abscess, meningoencephalitis, or cerebral malaria (in endemic areas) Seizure, particularly when associated with prolonged postictal paralysis (Todd paralysis) Migraine (especially hemiplegic migraine) Tumors and other structural brain lesions https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 3/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Alternating hemiplegia of childhood Posterior reversible leukoencephalopathy syndrome (PRES) Metabolic derangements Demyelinating conditions such as acute disseminated encephalomyelitis (ADEM) Idiopathic intracranial hypertension Drug toxicity, including opioid overdose for patients on chronic opioid therapy Musculoskeletal conditions Psychogenic conditions Distinguishing characteristics and laboratory findings are discussed separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis' and "Differential diagnosis of transient ischemic attack and acute stroke".) IMMEDIATE EVALUATION AND MANAGEMENT Evaluation and treatment proceed in parallel Initial stabilization with a rapid clinical assessment should occur simultaneously with prompt simple transfusion and neuroimaging to differentiate ischemia from hemorrhage and to exclude stroke mimics. In practice, this means that labs required for transfusion are sent while rapid neuroimaging is requested ( algorithm 1). Initial stabilization All patients with SCD and possible stroke should have [1,5]: Immediate assessment by clinicians with expertise in stroke and SCD management, typically from the neurology and hematology services. Monitoring of oxygen saturation. Supplemental oxygen to maintain saturation >95 percent. Airway protection from aspiration. Baseline laboratory testing. (See 'Laboratory and other testing' below.) Urgent simple transfusion to reduce the percent sickle hemoglobin and to raise the hemoglobin to approximately 10 g/dL, but not higher. (See 'Simple transfusion for all patients' below and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".) Brain imaging. (See 'Neuroimaging' below.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 4/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Precautions to minimize crying and hyperventilation (treat pain, minimize the number of medical personnel in the room, have a parent or caregiver keep the patient calm). In some patients, crying and hyperventilation can lower the PaCO and thereby induce or worsen 2 cerebral ischemia by causing vasoconstriction. Avoidance of hypotension, hypovolemia, hyperthermia, hyperglycemia, and hypocarbia. Intravenous hydration with isotonic fluids, typically at the normal maintenance rate, holding fluids during transfusion. Volume depletion should be avoided, but fluid overload can contribute to hypertension and pulmonary edema. Blood pressure control. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Identification and treatment of concurrent infection, with antipyretics if fever is present. Management of seizures if present. Intensive monitoring and care in a dedicated stroke unit when possible. Management of acute stroke in SCD requires specialized expertise in exchange transfusion. Transfer to another facility may be required if needed to provide access to exchange transfusion. (See 'Exchange transfusion' below.) Oxygenation and treatment of infection can reduce sickling, which could further worsen cerebral ischemia and other vaso-occlusive complications. Maximizing cerebral perfusion, ventilation, and normoglycemia is also critical. Hydration with normal saline rather than hypotonic saline will avoid the potential worsening of cerebral edema; excessive fluids should be avoided. (See "Initial assessment and management of acute stroke" and "Ischemic stroke in children: Management and prognosis", section on 'Initial management'.) Patients with fever Fever can occur with infection (meningitis, acute chest syndrome, sepsis) or with stroke in the absence of infection. Distinguishing between these is critical. Individuals with SCD are immunocompromised due to functional asplenia and are at high risk of sepsis from encapsulated organisms. Prompt institution of broad-spectrum antibiotics may be lifesaving. All patients with SCD who present with fever and acute neurologic findings should be treated presumptively for a bacterial infection until this possibility is eliminated, unless there is a good rationale not to do so. (See "Evaluation and management of fever in children and adults with sickle cell disease".) Laboratory and other testing Laboratory testing should include [1]: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 5/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Complete blood count (CBC) Reticulocyte count Type and crossmatch for transfusion Percent hemoglobin S, to facilitate exchange transfusion Prothrombin time (PT) and activated partial thromboplastin time (aPTT) Basic metabolic profile with electrolytes, urea nitrogen, creatinine, and glucose Blood cultures if fever is present The role of these studies is discussed in more detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".) Simple transfusion for all patients Red blood cell (RBC) transfusion is the cornerstone of treatment for acute ischemic stroke because it treats anemia and lowers the percent sickle hemoglobin. The role in acute hemorrhagic stroke is less clear; however, simple transfusion is recommended for all patients. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.) Simple transfusion is a temporizing measure until exchange transfusion can be performed. Exchange transfusion is much more effective at lowering the percent hemoglobin S while avoiding hyperviscosity. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Risk of hyperviscosity syndrome from simple transfusion'.) If clinical suspicion for an acute stroke is high and the patient's hemoglobin level is 8.5 g/dL, a simple transfusion should be given rapidly, within two hours of clinical presentation. Raising the hemoglobin to 10 g/dL also facilitates sedation for neuroimaging and central venous catheter placement if necessary. Overtransfusion (to hemoglobin >10 g/dL) is avoided since it may cause hyperviscosity, which decreases oxygen delivery. If the hemoglobin level is <5 g/dL, it can be raised to 10 g/dL with sequential simple transfusions of 5 to 10 mL/kg, and the hemoglobin S concentration can then be determined to assess the need for exchange transfusion. Neuroimaging Neuroimaging (brain and neurovascular) is critical for all patients with suspected stroke in order to: Differentiate ischemia from hemorrhage Exclude stroke mimics, such as tumor Assess the status of large cervical and intracranial arteries The major management implication of the distinction between ischemia and hemorrhage is in helping to decide whether urgent exchange transfusion is appropriate. Urgent exchange https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 6/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate transfusion is indicated for patients with acute ischemic stroke, TIA, and/or hemorrhagic transformation of an acute ischemic stroke. The role of exchange transfusion in the management of hemorrhagic stroke is less clear. Imaging methods are reviewed here briefly and presented separately. (See "Neuroimaging of acute stroke".) MRI versus CT Brain magnetic resonance imaging (MRI) is preferred if it can be obtained rapidly. Brain MRI is more sensitive for acute ischemia than computed tomography (CT), particularly with diffusion-weighted imaging (DWI) in the hyperacute time period. Brain MRI provides better visualization of the posterior fossa and detects intracerebral hemorrhage (ICH) with good sensitivity using high susceptibility sequences. Limitations of MRI include availability and cost. Young children and other individuals who cannot cooperate with lying still may require sedation for MRI, which carries additional risks and costs. Head CT typically takes <5 minutes and thus is easier to obtain, and unenhanced CT has a high sensitivity for hemorrhage. However, CT is a source of radiation exposure. Children Head CT is generally not considered adequate to diagnose ischemic stroke; MRI may be required to reliably exclude stroke mimics. CT should be used if MRI is not rapidly available or if a child is not stable for (or cannot tolerate) MRI. If CT is unrevealing, MRI can be obtained once the patient is stabilized [1]. Adults Either CT or MRI may be used as the initial study. Brain MRI with DWI is typically preferred if available because it is more sensitive for acute ischemic stroke. For older adults with risk factors for embolic stroke such as atrial fibrillation, head CT with CT angiography (CTA) of the head and neck will rapidly diagnose large vessel occlusion. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Brain imaging' and "Neuroimaging of acute stroke".) Given these considerations, the imaging approach and local institutional practices may vary. MRA and CTA Magnetic resonance angiography (MRA) or CTA should be obtained in all adults and children with acute stroke to evaluate large vessel arteriopathy (large vessel stenosis, dissection, moyamoya, atherosclerosis) and to exclude aneurysm. In a patient whose clinical picture is not concerning for arterial dissection or aneurysm, vascular imaging can be deferred until after the patient has been stabilized. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 7/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate MRV Brain MRI with magnetic resonance venography (MRV) is the most sensitive technique for demonstrating cerebral venous sinus thrombosis (CVST). Some experts recommend obtaining MRV with the initial MRI to reduce the likelihood of missing a cerebral venous thrombosis (CVT), particularly those with altered mental status and headache [1]. Clinical features and evaluation for CVST are presented separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Neuroimaging'.) Lack of access to imaging A large portion of the world's SCD population may not have immediate access to neuroimaging. For these individuals, it is necessary to make a presumptive diagnosis of stroke based on clinical features alone, as discussed separately. (See "Sickle cell disease in sub-Saharan Africa", section on 'Stroke'.) Supportive care Venous thromboembolism (VTE) prophylaxis Prophylaxis for deep venous thrombosis and pulmonary embolism is indicated for patients with acute stroke who have restricted mobility or other risk factors for VTE, such as an indwelling central venous catheter, significant inflammation, or high body mass index. VTE prophylaxis in younger children is determined on a case-by-case basis; sequential compression devices may be preferred to anticoagulation in some children. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Swallowing assessment Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. Swallowing function should be assessed prior to administering oral medications or food. Nothing should be administered orally until swallowing function is evaluated. (See "Complications of stroke: An overview", section on 'Dysphagia'.) TIA AND ISCHEMIC STROKE MANAGEMENT Transfusion For patients with SCD who have a clinically and/or radiologically confirmed acute ischemic stroke or TIA, we suggest exchange transfusion ( algorithm 1). Goals The goals of transfusion in ischemic stroke are: Lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically 15 to 20 percent). https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 8/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Aim for a total hemoglobin of approximately 10 g/dL. This is best achieved using exchange transfusion. However, it takes time to mobilize resources and possibly transfer to another facility for exchange transfusion. When exchange transfusion is not available within two hours of presentation and the hemoglobin is 8.5 g/dL, simple transfusion can be performed, with careful estimation of the transfusion volume so as not to raise the post-transfusion hemoglobin above 10 g/dL, often while awaiting the results of the clinical assessment and neuroimaging and possibly the placement of an apheresis catheter. (See 'Immediate evaluation and management' above.) Exchange transfusion Rationale We use exchange transfusion rather than simple transfusion alone or other interventions for children and adults with SCD who have confirmed ischemic stroke or TIA. The rationale is that reducing the percentage of hemoglobin S decreases vaso-occlusion and further ischemia, and that children who have early exchange transfusion have a lower rate of recurrent stroke compared with those who receive only simple transfusion [6]. A high percentage of adults with TIA have an ischemic stroke within seven days, and exchange transfusion is protective [7]. Simple transfusion cannot provide a sufficient volume of allogeneic red blood cells (RBCs) to lower the percentage of hemoglobin S sufficiently without causing hyperviscosity or transfusion-associated circulatory overload. Procedure Exchange transfusion involves a type of apheresis (erythrocytapheresis) in which blood removed from the patient is depleted of RBCs, reconstituted with donor RBCs, and retransfused in a continuous circuit. This procedure typically requires placement of a double-lumen apheresis catheter. If equipment for automated exchange is not available, manual exchange can be performed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.) A single exchange transfusion is usually sufficient to lower the hemoglobin S concentration to the desired level. The apheresis catheter can be removed after the exchange transfusion is completed unless it is absolutely required for venous access. Total hemoglobin and percent hemoglobin S are monitored during the exchange. The usual post-transfusion targets are: Total hemoglobin approximately 10 g/dL (not higher) Hemoglobin S <30 percent of total hemoglobin (target, 15 to 20 percent) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 9/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate This should maintain the hemoglobin S concentration <30 percent of total hemoglobin for two to four weeks until another transfusion is needed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.) Supporting evidence There are no randomized trials comparing exchange transfusion with simple transfusion or other interventions for acute stroke in SCD. Evidence for the benefit of transfusion in patients with SCD and acute stroke includes our clinical experience and studies revealing improved cerebral perfusion with transfusion [8,9]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Mechanisms'.) Evidence for the superiority of exchange transfusion in secondary prevention (reducing the risk of stroke recurrence) includes a 2006 retrospective study of 137 children with SCD and acute stroke [6]. For the 52 patients who presented within 24 hours of onset of initial stroke symptom for whom treatment information was available, second strokes were more likely in those who received simple transfusions (8 of 14 patients [57 percent]) compared with those who were treated with exchange transfusions (8 of 38 patients [21 percent]; RR 5.0, 95% CI 1.3-18.6), despite similar baseline risk factors. Our approach is consistent with a 2014 consensus report on SCD management from the National Heart, Lung, and Blood Institute (NHLBI) in the United States [10,11], and with 2020 guidelines from the American Society of Hematology [5]. Additional information on risks and benefits of simple versus exchange transfusion are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".) Reperfusion therapy Reperfusion therapy (intravenous thrombolysis with tissue plasminogen activator [tPA] and/or mechanical thrombectomy) for acute ischemic stroke associated with SCD is controversial, and data are sparse. For adults with a high likelihood of a non-SCD-related cause of ischemic stroke, such as embolism in the setting of atrial fibrillation or large artery stenosis or occlusion, it is logical to consider reperfusion therapies unless there is a strong reason not to do so ( algorithm 1). Patients most likely to benefit are older adults with conventional stroke risk factors such as hypertension, diabetes, hyperlipidemia, and/or atrial fibrillation [12]. Intravenous thrombolysis Adults with SCD presenting with symptoms of acute ischemic stroke should be considered for intravenous tPA [5]. They should meet typical criteria: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 10/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Age 18 years No hemorrhage on brain imaging Within 4.5 hours of stroke symptom onset No contraindications for thrombolysis Full inclusion and exclusion criteria are listed in the table ( table 1). For children <18 years with SCD, intravenous tPA is not recommended [5]. There is a concern that the use of thrombolytic agents could precipitate intracranial hemorrhage (ICH) at a higher rate in individuals with SCD. However, the risk of ICH in SCD appears to be due to an increased prevalence of aneurysm rather than increased bleeding tendency specific to SCD. Thus, SCD is not an exclusion criterion for tPA treatment of adults with ischemic stroke. An observational study using administrative data to compare 832 adults with stroke and SCD versus 3328 adults with stroke who did not have SCD found no difference in the percentage treated with thrombolytic therapy (8.2 versus 9.4 percent) or in the incidence of symptomatic ICH complicating thrombolysis (4.9 versus 3.2 percent) [13]. Thrombolysis was felt to be safe; however, the effect on functional outcomes was not reported. Administration of tPA should not replace or delay typical SCD-related acute stroke care, specifically simple blood transfusion [5]. Since tPA guidelines require the placement of two intravenous lines, tPA infusion and transfusion could be concurrent. Importantly, the apheresis catheter for exchange transfusion must be placed before tPA is administered. Older adults with typical stroke risk factors such as atrial fibrillation, diabetes, hypertension, or hyperlipidemia may be viewed as more likely to benefit from tPA than younger adults without these risk factors [5,12]. Moyamoya disease is a relative contraindication to tPA. (See 'Moyamoya syndrome' below.) Mechanical thrombectomy (MT) MT is not well-studied for the treatment of stroke in patients with SCD [5]. In the general population, mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be at their neurologic baseline (last time known well), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) Patient selection for MT is reviewed in the figure ( algorithm 2) and discussed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 11/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Patients and their families/caregivers must be counseled about the limited evidence for reperfusion therapies in SCD [5,12,14]. These therapies should only be used in centers with significant experience and in consultation with the appropriate specialists from neurology, hematology, and interventional radiology. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Evaluation for the cause Additional evaluation for causes of ischemic stroke and TIA other than vaso-occlusive vasculopathy may be appropriate in select cases, particularly in adults with typical stroke risk factors. (see "Overview of the evaluation of stroke") These may include: Cardioembolic sources such as atrial fibrillation or patent foramen ovale (PFO) Vasospasm in association with drug use (eg, from cocaine or amphetamines) Vascular disease associated with hypercholesterolemia or diabetes Appropriate history, brain and blood vessel imaging, cardiac monitoring, echocardiography, and laboratory testing (fasting lipids, hemoglobin A1c) are essential for the evaluation for these risk factors In principle, any of these conditions could affect patients of any age. However, their likelihood is age-dependent. Additional information on possible etiologies and evaluation in children is presented separately. Newborns (see "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis") Children (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis") Other rare stroke mimics must be considered if the initial evaluation and imaging do not reveal a cause. (See 'Differential diagnoses' above and "Differential diagnosis of transient ischemic attack and acute stroke".) Treatment for specific causes Moyamoya syndrome For patients with moyamoya syndrome (bilateral or unilateral internal carotid artery stenosis with prominent collateral vessels) and acute stroke, acute treatment is mainly symptomatic and directed towards improving cerebral blood flow with fluids and https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 12/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate transfusion and controlling seizures. In moyamoya disease, tPA should not be used due to the increased risk of bleeding. Some clinicians start antiplatelet therapy for children and adults with moyamoya syndrome; however, evidence is lacking for prevention of infarct recurrence. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) Cerebral venous thrombosis The main treatment for symptomatic cerebral venous thrombosis (CVT, also called central venous sinus thrombosis [CVST]) is anticoagulation with heparin (unfractionated or low molecular weight [LMW] heparin). Hemorrhagic venous infarction, intracerebral hemorrhage (ICH), or isolated subarachnoid hemorrhage (SAH) are not contraindications to anticoagulation in CVT, including in patients with SCD [1]. (See "Cerebral venous thrombosis: Treatment and prognosis".) Testing for hypercoagulable conditions and COVID-19 is appropriate when CVT is found. (See "Overview of the causes of venous thrombosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".) Other causes Other defined traditional stroke mechanisms may be present in patients with SCD. Management is reviewed separately: Small vessel disease (see "Lacunar infarcts") Large vessel atherosclerosis (see "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis") Cardiogenic embolism (see "Stroke in patients with atrial fibrillation") Role of antiplatelet agents and anticoagulation Antiplatelet agents The efficacy of antiplatelet agents has not been studied for acute treatment or secondary prevention of SCD-associated TIA or ischemic stroke in children or adults [15]. In the general population, aspirin or short-term dual antiplatelet therapy (DAPT) are indicated for most adults with acute TIA or acute ischemic stroke, and antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors, especially intracranial atherosclerosis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 13/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Antiplatelet therapy may also be appropriate for secondary stroke prevention in adults with SCD who have traditional stroke risk factors, similar to the general population [16]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Anticoagulation We generally do not use anticoagulation for ischemic stroke in patients with SCD. However, SCD is a hypercoagulable state, and prophylactic dose anticoagulation may be appropriate for venous thromboembolism (VTE) prophylaxis in those admitted with an acute medical illness, especially adults and those with decreased mobility. (See 'Supportive care' above and "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Anticoagulation may be appropriate for: CVT (see "Cerebral venous thrombosis: Treatment and prognosis") Increased probability of thromboembolic disease, after the immediate risk of hemorrhagic conversion has receded (see "Stroke in patients with atrial fibrillation" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome") Administration and adverse events are discussed separately. (see "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management") INTRACRANIAL HEMORRHAGE MANAGEMENT Intracranial hemorrhage (ICH), also called hemorrhagic stroke, accounts for approximately one- third of cerebrovascular events in patients with SCD and is more common in older individuals [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Hemorrhagic stroke'.) Urgent interventions In addition to acute stabilization of the patient as described above (see 'Immediate evaluation and management' above), the following should be done immediately ( algorithm 1): Discontinue all anticoagulants and antiplatelet agents, unless the benefits of continuing are thought to outweigh their risks for that patient, such as in the setting of CVST and hemorrhagic venous infarction or a prosthetic heart valve where anticoagulation might be held briefly for stabilization and then restarted. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 14/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate For patients receiving an anticoagulant, decide whether a reversal agent is needed. For those who have received a short-acting anticoagulant for which several half-lives have passed, reversal may not be required. For patients with thrombocytopenia, administer platelet transfusions as necessary to maintain the platelet count 100,000/microL. Obtain neurosurgical consultation if a procedure may be required to reduce intracranial pressure or to treat a bleeding aneurysm. Obtain imaging such as CT- or MR-angiography to guide further therapy in most cases. Management of ICH and subarachnoid hemorrhage (SAH) in the general population is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage".) Additional therapy according to type of bleed Hemorrhagic transformation of arterial ischemic stroke Hemorrhagic transformation of an ischemic stroke should be managed as with other causes of hemorrhagic stroke, including stopping and reversing any anticoagulation, correcting any coagulopathy, and transfusing platelets as needed. Transfusion is appropriate. (See 'Transfusion' above.) Cerebral venous sinus thrombosis (CVST) Management is similar to individuals without SCD. (See "Cerebral venous thrombosis: Treatment and prognosis".) SAH from aneurysmal bleeding Initial treatment of SAH includes intensive care monitoring, analgesia, and close attention to blood pressure control; as well as ventriculostomy for those with increased intracranial pressure. Aneurysm repair should be attempted if possible. Details are presented separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of cerebral aneurysms" and "Nonaneurysmal subarachnoid hemorrhage".) Patients with SAH who are undergoing surgery should have exchange transfusion if possible prior to surgery, to reduce sickle hemoglobin to <30 percent of total hemoglobin; ideally surgery is performed within a week of exchange transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 15/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Intraventricular hemorrhage (IVH) IVH may occur when subarachnoid or intraparenchymal hemorrhage extends into the ventricles [18]. Patients with prior ischemic stroke may be at risk for IVH and intraparenchymal hemorrhage, even months to years later [19]. Hemorrhage into the third ventricle or cerebral aqueduct confers a high risk for late deterioration. Patients may be awake and alert immediately following the bleed and become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation. Emergency ventricular drainage may be necessary [20]. Management is discussed separately. (See "Intraventricular hemorrhage".) Despite these interventions, mortality from ICH in SCD is as high as 24 to 30 percent [14,17]. Deaths generally occur within the first two weeks, many on the first day [17]. Some individuals have moderate to severe residual disability [21]. FOLLOW-UP AFTER THE ACUTE EVENT Repeat imaging If the initial magnetic resonance imaging (MRI) study does not show ischemic injury and clinically the patient seemed to have a stroke or transient ischemic attack (TIA), we perform a repeat MRI of the brain two to four weeks after the initial presentation, since diffusion weighted images of the brain may rarely be negative upon presentation and may still demonstrate very small areas of ischemic injury upon

"Overview of the causes of venous thrombosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".) Other causes Other defined traditional stroke mechanisms may be present in patients with SCD. Management is reviewed separately: Small vessel disease (see "Lacunar infarcts") Large vessel atherosclerosis (see "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis") Cardiogenic embolism (see "Stroke in patients with atrial fibrillation") Role of antiplatelet agents and anticoagulation Antiplatelet agents The efficacy of antiplatelet agents has not been studied for acute treatment or secondary prevention of SCD-associated TIA or ischemic stroke in children or adults [15]. In the general population, aspirin or short-term dual antiplatelet therapy (DAPT) are indicated for most adults with acute TIA or acute ischemic stroke, and antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors, especially intracranial atherosclerosis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 13/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Antiplatelet therapy may also be appropriate for secondary stroke prevention in adults with SCD who have traditional stroke risk factors, similar to the general population [16]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Anticoagulation We generally do not use anticoagulation for ischemic stroke in patients with SCD. However, SCD is a hypercoagulable state, and prophylactic dose anticoagulation may be appropriate for venous thromboembolism (VTE) prophylaxis in those admitted with an acute medical illness, especially adults and those with decreased mobility. (See 'Supportive care' above and "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Anticoagulation may be appropriate for: CVT (see "Cerebral venous thrombosis: Treatment and prognosis") Increased probability of thromboembolic disease, after the immediate risk of hemorrhagic conversion has receded (see "Stroke in patients with atrial fibrillation" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome") Administration and adverse events are discussed separately. (see "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management") INTRACRANIAL HEMORRHAGE MANAGEMENT Intracranial hemorrhage (ICH), also called hemorrhagic stroke, accounts for approximately one- third of cerebrovascular events in patients with SCD and is more common in older individuals [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Hemorrhagic stroke'.) Urgent interventions In addition to acute stabilization of the patient as described above (see 'Immediate evaluation and management' above), the following should be done immediately ( algorithm 1): Discontinue all anticoagulants and antiplatelet agents, unless the benefits of continuing are thought to outweigh their risks for that patient, such as in the setting of CVST and hemorrhagic venous infarction or a prosthetic heart valve where anticoagulation might be held briefly for stabilization and then restarted. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 14/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate For patients receiving an anticoagulant, decide whether a reversal agent is needed. For those who have received a short-acting anticoagulant for which several half-lives have passed, reversal may not be required. For patients with thrombocytopenia, administer platelet transfusions as necessary to maintain the platelet count 100,000/microL. Obtain neurosurgical consultation if a procedure may be required to reduce intracranial pressure or to treat a bleeding aneurysm. Obtain imaging such as CT- or MR-angiography to guide further therapy in most cases. Management of ICH and subarachnoid hemorrhage (SAH) in the general population is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage".) Additional therapy according to type of bleed Hemorrhagic transformation of arterial ischemic stroke Hemorrhagic transformation of an ischemic stroke should be managed as with other causes of hemorrhagic stroke, including stopping and reversing any anticoagulation, correcting any coagulopathy, and transfusing platelets as needed. Transfusion is appropriate. (See 'Transfusion' above.) Cerebral venous sinus thrombosis (CVST) Management is similar to individuals without SCD. (See "Cerebral venous thrombosis: Treatment and prognosis".) SAH from aneurysmal bleeding Initial treatment of SAH includes intensive care monitoring, analgesia, and close attention to blood pressure control; as well as ventriculostomy for those with increased intracranial pressure. Aneurysm repair should be attempted if possible. Details are presented separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of cerebral aneurysms" and "Nonaneurysmal subarachnoid hemorrhage".) Patients with SAH who are undergoing surgery should have exchange transfusion if possible prior to surgery, to reduce sickle hemoglobin to <30 percent of total hemoglobin; ideally surgery is performed within a week of exchange transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 15/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Intraventricular hemorrhage (IVH) IVH may occur when subarachnoid or intraparenchymal hemorrhage extends into the ventricles [18]. Patients with prior ischemic stroke may be at risk for IVH and intraparenchymal hemorrhage, even months to years later [19]. Hemorrhage into the third ventricle or cerebral aqueduct confers a high risk for late deterioration. Patients may be awake and alert immediately following the bleed and become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation. Emergency ventricular drainage may be necessary [20]. Management is discussed separately. (See "Intraventricular hemorrhage".) Despite these interventions, mortality from ICH in SCD is as high as 24 to 30 percent [14,17]. Deaths generally occur within the first two weeks, many on the first day [17]. Some individuals have moderate to severe residual disability [21]. FOLLOW-UP AFTER THE ACUTE EVENT Repeat imaging If the initial magnetic resonance imaging (MRI) study does not show ischemic injury and clinically the patient seemed to have a stroke or transient ischemic attack (TIA), we perform a repeat MRI of the brain two to four weeks after the initial presentation, since diffusion weighted images of the brain may rarely be negative upon presentation and may still demonstrate very small areas of ischemic injury upon subsequent imaging [22]. Secondary stroke prevention Secondary stroke prevention is critical, typically involving chronic transfusions. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of hemorrhagic strokes'.) Cognitive or behavioral dysfunction (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Management of cognitive and behavioral dysfunction'.) Motor deficits (See "Overview of geriatric rehabilitation: Patient assessment and common indications for rehabilitation", section on 'Stroke' and "Overview of ischemic stroke prognosis in adults", section on 'Interventions that improve outcomes'.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 16/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: Stroke in children".) PATIENT PERSPECTIVE TOPIC Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".) SUMMARY AND RECOMMENDATIONS Presentation Acute ischemic stroke due to cerebral vaso-occlusion is the first consideration in patients with sickle cell disease (SCD) who present with new neurologic findings or severe headache. Hemorrhagic stroke accounts for one-third of events. It is important not to overlook other potential causes of neurologic deterioration, including transient ischemic attack (TIA), cerebral venous thrombosis (CVT), seizure, infection, and other stroke mimics. (See 'Presentation' above.) Immediate measures Management involves initial stabilization by clinicians with expertise in stroke and SCD, supplemental oxygen to maintain saturation >95 percent, rapid clinical assessment and baseline laboratory testing, and simple transfusion, followed by neuroimaging ( algorithm 1). Patients with fever should receive empiric broad- spectrum antibiotics and antipyretics. (See 'Immediate evaluation and management' above.) Neuroimaging Brain and neurovascular imaging is essential to differentiate ischemia from hemorrhage, exclude stroke mimics, and assess large cervical and intracranial arteries. Magnetic resonance imaging (MRI) is generally preferred. (See 'Neuroimaging' above.) Transfusion For patients with SCD who have a suspected or confirmed stroke (ischemic or hemorrhagic) or TIA, we suggest exchange transfusion (Grade 2C). The goal is to lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically to 15 to 20 percent) without raising the total hemoglobin >10 g/dL and causing hyperviscosity. Simple transfusion is used as a temporizing measure until exchange transfusion can be instituted. (See 'Transfusion' above.) https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 17/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Reperfusion Adults with SCD and acute ischemic stroke should be evaluated for intravenous thrombolysis and mechanical thrombectomy. (See 'Reperfusion therapy' above.) Mechanism-specific treatment The following is appropriate in addition to immediate assessment, stabilization, and other standard acute stroke management ( algorithm 1): Ischemic stroke or TIA Antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors. (See 'Role of antiplatelet agents and anticoagulation' above.) Intracranial hemorrhage Neurosurgical evaluation and angiography to guide therapy. Additional interventions for specific types of hemorrhagic stroke are discussed above. (See 'Intracranial hemorrhage management' above.) Moyamoya syndrome Some clinicians start antiplatelet therapy. (See 'Moyamoya syndrome' above.) CVT Heparin anticoagulation, even if hemorrhagic transformation occurs. (See 'Cerebral venous thrombosis' above.) Follow-up Secondary stroke prevention is critical. Repeat imaging, cognitive assistance, and rehabilitation services may be appropriate. (See 'Follow-up after the acute event' above.) ACKNOWLEDGMENTS UpToDate acknowledges ZoAnn Dreyer, MD, who contributed to earlier versions of this topic review. The UpToDate editorial staff also acknowledge the extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kassim AA, Galadanci NA, Pruthi S, DeBaun MR. How I treat and manage strokes in sickle cell disease. Blood 2015; 125:3401. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 18/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 2. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue- based definition of transient ischemic attack. Stroke 2003; 34:919. 3. Lehman LL, Watson CG, Kapur K, et al. Predictors of Stroke After Transient Ischemic Attack in Children. Stroke 2016; 47:88. 4. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009; 40:2276. 5. DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv 2020; 4:1554. 6. Hulbert ML, Scothorn DJ, Panepinto JA, et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. J Pediatr 2006; 149:710. 7. Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 2007; 6:1063. 8. Guilliams KP, Fields ME, Ragan DK, et al. Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood 2018; 131:1012. 9. Juttukonda MR, Lee CA, Patel NJ, et al. Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia. J Magn Reson Imaging 2019; 49:466. 10. https://www.nhlbi.nih.gov/sites/default/files/media/docs/Evd-Bsd_SickleCellDis_Rep2014.pd f (Accessed on July 20, 2018). 11. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033. 12. Alakbarzade V, Maduakor C, Khan U, et al. Cerebrovascular disease in sickle cell disease. Pract Neurol 2023; 23:131. 13. Adams RJ, Cox M, Ozark SD, et al. Coexistent Sickle Cell Disease Has No Impact on the Safety or Outcome of Lytic Therapy in Acute Ischemic Stroke: Findings From Get With The Guidelines-Stroke. Stroke 2017; 48:686. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 19/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 14. Strouse JJ, Lanzkron S, Urrutia V. The epidemiology, evaluation and treatment of stroke in adults with sickle cell disease. Expert Rev Hematol 2011; 4:597. 15. Guilliams KP, Kirkham FJ, Holzhauer S, et al. Arteriopathy Influences Pediatric Ischemic Stroke Presentation, but Sickle Cell Disease Influences Stroke Management. Stroke 2019; 50:1089. 16. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 17. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288. 18. Adams RJ, Nichols FT. Sickle cell anemia, sickle cell trait and thalassemia. In: Handbook of Cli nical Neurology, Vascular Disease Part III, Vinken PJ, Bruyn GW, Klawans HL (Eds), Elsevier, A msterdam 1989. p.503. 19. Powars D, Adams RJ, Nichols FT, et al. Delayed intracranial hemorrhage following cerebral infarction in sickle cell anemia. J Assoc Acad Minor Phys 1990; 1:79. 20. Adams RJ. Neurologic complications. In: Sickle Cell Disease: Basic Principles and Clinical Prac tice, Embury SH, Robert P, Hebbel RP, et al (Eds), Raven Press, Ltd, New York 1994. p.599. 21. Oyesiku NM, Barrow DL, Eckman JR, et al. Intracranial aneurysms in sickle-cell anemia: clinical features and pathogenesis. J Neurosurg 1991; 75:356. 22. Makin SD, Doubal FN, Dennis MS, Wardlaw JM. Clinically Confirmed Stroke With Negative Diffusion-Weighted Imaging Magnetic Resonance Imaging: Longitudinal Study of Clinical Outcomes, Stroke Recurrence, and Systematic Review. Stroke 2015; 46:3142. Topic 5926 Version 52.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 20/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate GRAPHICS Cerebrovascular complications with their locations in sickle cell disease Cerebrovascular complications of the large and small vessels of the brain and their corresponding territories are shown. The most common complications are cerebral infarcts in major vessels and "borderzone" infarctions. Borderzone infarctions are most common in the areas between the middle and anterior cerebral arteries, and between the middle and posterior cerebral arteries. Fat embolism and venous side abnormalities are the least common lesions. Small white matter lesions visualized on magnetic resonance imaging can be seen in asymptomatic patients. Multiple cerebral aneurysms can be present within the branches of the circle of Willis. ICA: internal carotid artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; MRI: magnetic resonance imaging; BA: basilar artery. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 21/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Modi ed from: Adams RJ. Neurologic complications. In: Sickle Cell Disease: Basic Principles and Clinical Practice, Embury SH, Robert P, Hebbel RP, et al (Eds), Raven Press, New York 1994. Graphic 50288 Version 4.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 22/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Management of acute stroke in sickle cell disease SCD: sickle cell disease; IV: intravenous; Hb: hemoglobin; RBC: red blood cell; TIA: transient ischemic attack; I magnetic resonance angiography; CTA: CT angiography; CBC: complete blood count; PT: prothrombin time; a DBP: diastolic blood pressure; ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; MAP: mean a resonance venography; CT: computed tomography. Initial stabilization with a rapid clinical assessment should occur simultaneously with prompt RBC transfusi transfusion are sent while rapid neuroimaging is ordered. https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 23/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate IVT can proceed concurrently with RBC transfusion but should not replace or delay transfusion. Importantl IVT is administered. Graphic 140156 Version 1.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 24/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 25/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 26/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 27/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 28/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 29/30 7/6/23, 12:22 PM Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease - UpToDate Contributor Disclosures Alex George, MD, PhD Grant/Research/Clinical Trial Support: Forma Pharmaceuticals [Sickle cell disease]. Consultant/Advisory Boards: Agios Pharmaceuticals [Sickle cell disease]; Chiesi USA [Transfusional iron overload]; GBT Pharmaceuticals [Sickle cell disease]. Speaker's Bureau: GBT Pharmaceuticals [Sickle cell disease]. All of the relevant financial relationships listed have been mitigated. Lori Jordan, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael R DeBaun, MD, MPH Consultant/Advisory Boards: Forma therapeutics [Sickle cell disease]; Global Blood Therapeutics [Sickle cell disease]; Novartis [Priapism in sickle cell disease]; Vertex/CRISPR Therapeutics [Sickle cell disease, beta thalassemia]. All of the relevant financial relationships listed have been mitigated. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/acute-stroke-ischemic-and-hemorrhagic-in-children-and-adults-with-sickle-cell-disease/print 30/30

7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral and cervical artery dissection: Clinical features and diagnosis : David S Liebeskind, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 13, 2023. INTRODUCTION Arterial dissections are a common cause of stroke in the young but may occur at any age. Dissection occurs when structural integrity of the arterial wall is compromised, allowing blood to collect between layers as an intramural hematoma. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. This topic will review the pathophysiology, etiology, clinical features, and diagnosis of cerebral and cervical artery dissection. The treatment and prognosis of cervicocephalic dissection is reviewed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Other mechanisms of ischemic stroke and subarachnoid hemorrhage are discussed elsewhere. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Stroke: Etiology, classification, and epidemiology" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".) ANATOMY AND PATHOLOGY Separation of the arterial wall layers results in dissection. A false lumen arises in the space where blood seeps into the vessel wall ( figure 1). Hemorrhage may be due to an intimal tear https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 1/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate or result from rupture or other pathology in the vasa vasorum [1,2]. Subintimal dissections cause luminal stenosis or occlusion, whereas subadventitial dissections largely result in dissecting aneurysm formation ( figure 2). False lumen extension back into the true lumen can form a double channel for blood flow in the artery. [3,4] Extracranial carotid dissections typically occur 2 cm or more beyond the carotid bifurcation, near or adjacent to the level of the skull base [3]. Intracranial carotid dissections are most frequent in the supraclinoid segment [4]. Vertebral artery dissection most often occurs in the cervical transverse processes of C6 to C2 (V2 segment) or the extracranial segment between the transverse process of C2 and the foramen magnum at the base of the skull (V3 segment) ( figure 3) [5]. Multiple simultaneous cervicocephalic dissections are found in 13 to 22 percent of cases [6-9] and may occur more often in females than males [7,8,10]. Three or more dissections occur in approximately 2 percent of cases [10]. Although evidence is limited to observations in small numbers of patients, multiple simultaneous dissections are not typically associated with a known underlying predisposition to dissection [10]. Rather, most cases may be due to a transient vasculopathy following minor trauma or infection. Ischemia may manifest in only one of the downstream arterial territories, if at all. Histopathologic specimens of dissected arteries are rarely obtained; when done, examination may reveal intramural hemorrhage, disruption of the subintimal plane, and less frequently separation of the media and adventitia ( picture 1) [11]. In a case-control study, superficial temporal artery specimens obtained by biopsy or autopsy from 14 patients with cervical artery dissection showed pathologic changes involving mainly the adventitial and medial layers, with vacuolar degeneration and fissuring, along with capillary neoangiogenesis and microscopic erythrocyte extravasation into connective tissue [2]. In contrast, only one of nine control arteries obtained from accident victims showed pathologic changes in the outer arterial walls. There is a high prevalence of ultrastructural connective tissue abnormalities in patients with apparently sporadic cervicocephalic artery dissection [12-14]. These abnormalities consist primarily of composite fibrils within collagen bundles and fragmented elastic fibers. PATHOPHYSIOLOGY The development of intramural hematoma with subintimal dissections causes luminal stenosis or occlusion. This may result in cerebral ischemia due to thromboembolism, hypoperfusion, or a https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 2/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate combination of both. Thromboembolism rather than hypoperfusion is considered the major cause of ischemic symptoms [15,16]. (See 'Ischemic stroke or TIA' below.) Subadventitial dissections with aneurysm or hematoma formation and vessel dilatation ( figure 2) may cause local symptoms from compression of adjacent nerves and their feeding vessels, resulting in pain, partial oculosympathetic paresis (Horner syndrome), lower cranial neuropathies, or cervical nerve root involvement. (See 'Local symptoms' below.) In a minority of cases, dissection of intracranial arteries, which lack an external elastic lamina and have only a thin adventitial layer, can lead to vessel rupture with subarachnoid hemorrhage. (See 'Subarachnoid hemorrhage' below.) Head, neck, or facial pain is thought to be caused by activation of nociceptors from distension of the vessel wall due to the intimal tear and/or intramural hematoma formation [17,18]. ETIOLOGY Arterial dissections are generally caused by various degrees of trauma or triggering events, with or without an underlying predisposition. While major head and neck trauma can cause dissection, most dissections occur after a mechanical trigger, which may not always be remembered [19]. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. Minor trauma and other triggers Observational data suggest that trauma, typically mild or trivial in nature, or other mechanical events are triggers for cervical artery dissection in up to 40 percent of cases [20]. The list of physical activities associated with dissection is long and includes the following: Basketball [21] Childbirth [22] Cervical manipulation therapy [23-28] Coughing or sneezing [29] Dancing [30,31] Minor sports injuries [32,33] Roller coaster or amusement park rides [34-39] Scuba diving [40,41] Sexual intercourse [42] Skating [43] https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 3/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Swimming [44] Tennis [45,46] Trampoline use [47] Vigorous exercise [29] Volleyball [48] Weightlifting [49] Yoga [29] While cervical manipulation therapy may trigger dissection, causality is difficult to establish, and the absolute incidence of dissection caused by spinal manipulation is unknown [28,50-52]. Associated conditions and risk factors Connective tissue disorders, vascular abnormalities, and other conditions have been associated with dissection. Connective tissue or vascular disorders The proportion of patients with cervical artery dissection who are affected by a known connective tissue or vascular disorder is low [53- 56]. Nevertheless, various connective tissue and vascular disorders have been associated with dissection, including the following [13,57,58]: Fibromuscular dysplasia [59-63] Ehlers-Danlos syndrome type IV (vascular Ehlers-Danlos) Marfan syndrome Osteogenesis imperfecta [64] Cystic medial necrosis [65] Reticular fiber deficiency [66] Homocystinuria [67] Autosomal dominant polycystic kidney disease [68] Alpha-1 antitrypsin deficiency [69] Segmental mediolytic arteriopathy [70] Reversible cerebral vasoconstriction syndromes [71] Aortic root diameter >34 mm [72] Carotid artery redundancy [73] Cervical artery tortuosity [74] Cerebral aneurysms [75] The most common association is with fibromuscular dysplasia, a nonspecific arteriopathy, which accounts for 15 to 40 percent of cases of cervicocephalic dissection in some reports [61,63,76]. Ehlers-Danlos syndrome type IV is found in <2 percent of all cases of cervical or cerebral artery dissection [53,54]. The prevalence of dissection among all patients with https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 4/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Ehlers-Danlos is similarly infrequent. In one cohort of over 400 patients with Ehlers Danlos type IV, carotid artery dissection was observed in 2 percent [77]. For the remaining connective tissue and vascular disorders listed above, all of which are rare diseases, it remains uncertain whether the association with dissection is greater than would be expected by chance alone [58]. As an example, a series of 1934 patients with cervical artery dissection identified only 6 (<1 percent) with an inherited connective tissue disease [55]. There were two patients with genetically confirmed vascular Ehlers-Danlos and one patient each (diagnosed by clinical criteria) with Marfan syndrome, classic Ehlers- Danlos, hypermobile Ehlers-Danlos, and osteogenesis imperfecta. Although Marfan syndrome is a known cause of aortic dissection, only a few cases of isolated cervicocephalic dissection have been reported in patients with Marfan syndrome [78,79], and several large series of patients with Marfan syndrome have reported no occurrences of cervicocephalic dissection [80,81]. In contrast to the rare association of connective tissue disease with cervicocephalic artery dissection, one case-control study involving 84 patients with cervical artery dissection compared with 84 matched controls who had ischemic stroke without dissection found that the individuals with cervical artery dissection were significantly more likely to have clinical signs suggestive of connective tissue abnormalities [56]. These signs involved mainly skeletal (eg, scoliosis, pectus excavatum), skin (eg, mild skin hyperextension), and ocular abnormalities as well as craniofacial dysmorphisms. However, none of the patients with cervical artery dissection had an established hereditary connective tissue disease. Other conditions A number of other conditions have been associated with cervicocephalic dissection, including: Recent infection [58,72,82-84] Hypertension [85,86] Migraine [72,87-91] Elevated homocysteine levels [58,72,92] Oral contraceptive use [63,93] Smoking [87] Higher body height and lower body weight [94] Elongated styloid process compressing the cervical internal carotid artery (sometimes referred to as the stylocarotid artery syndrome or the vascular variant of the Eagle syndrome) [95,96] Pregnancy, mainly in the postpartum period [97] https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 5/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Genetics There are no established genetic markers for cervicocephalic dissection. Studies using whole exome sequencing of candidate genes associated with arterial dissection or aneurysm have identified probable pathogenic variants in genes associated with connective tissue disorders, including Marfan syndrome, vascular Ehlers-Danlos syndrome, classic Ehlers Danlos syndrome, digenic Alport syndrome, and hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome [98,99]. In addition, a genome-wide association study suggested that the rs9349379[G] allele of the PHACTR1 gene was associated with a lower risk of cervical artery dissection [100]. However, further confirmation in larger studies is needed to confirm these findings. In addition to the monogenic connective tissue disorders, polygenetic factors may be involved in the etiology and pathophysiology of dissection as part a multifactorial predisposition [53]. In theory, such factors could cause an inherited weakness of the vessel wall, thereby increasing susceptibility to dissection from minor trauma, inflammation, thrombosis, or other environmental triggers. Despite the paucity of evidence, there are valid reasons to suspect that genetic factors are related to the pathophysiology of cervicocephalic dissection. As an example, patients with a family history of arterial dissections involving cervicocephalic arteries, renal arteries or the aorta appear to be at increased risk for recurrent arterial dissection [101,102]. Furthermore, patients with apparently sporadic cervicocephalic artery dissection have a high prevalence of ultrastructural connective tissue abnormalities (see 'Anatomy and pathology' above) that are not associated with any defined collagen vascular disease. In some families, these connective tissue alterations appear to be transmitted in an autosomal dominant pattern [103,104]. EPIDEMIOLOGY Dissection is a common cause of stroke, particularly in young adults (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Extracranial dissection'). In studies from North America and Europe, the mean age of individuals affected by dissection was 44 to 53 years [6-8,105]. While the prevalence of dissection as a cause of ischemic stroke is higher in younger adults, evidence from national registry data in the United States indicates that the prevalence of hospitalization for dissection-related stroke is evident across the lifespan [105]. A population-based study from Minnesota reported that the average annual incidence rate for internal carotid artery dissection was 1.72 per 100,000 individuals, while that for vertebral artery dissection was 0.97 per 100,000; the combined annual incidence of dissection was 2.6 per https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 6/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate 100,000 [6]. The true incidence is probably even higher, since many cases of dissection may escape detection because they have minor or no clinical signs [58]. There is no clear sex or ethnic predilection [6-8,58,106,107]. Dissection may be more common in winter, although the cause of seasonal variation remains unclear [108]. Extracranial dissection is far more frequent than intracranial dissection in reports from North America and Europe. However, evidence from several case series suggests that intracranial dissection is more common in Asian populations and in children [109,110]. CLINICAL MANIFESTATIONS Evidence from population- and hospital-based reports suggests that dissection most often results in ischemic stroke or transient ischemic attack, usually associated with local symptoms such as neck pain or headache [6-8,111]. However, these studies may underestimate the proportion of cases that are asymptomatic or associated with local symptoms only [58]. For patients without ischemia at the time of diagnosis, retrospective data suggest that the risk of ischemic stroke is highest in the first two weeks after the diagnosis of cervical artery dissection [112]. Local symptoms Local symptoms caused by cervical or cerebral artery dissection can include pain, Horner syndrome, cranial and cervical neuropathies, and pulsatile tinnitus. Head and neck pain The most frequent initial symptom of cervicocephalic dissection is head and/or neck pain, found in 57 to 90 percent of cases [6,111,113-116]. The pain is often severe, continuous, and of recent onset; in a study of 49 patients with cervical artery dissection, patients with head or neck pain presented within one to five days after the onset of pain [116]. Neck pain may be more frequent with vertebral artery dissection compared with carotid artery dissection [111]. The headache is typically ipsilateral to the dissection and often localizes to the temple, eye, cheek, or teeth with carotid artery dissection, and to the occipital region with vertebral artery dissection [117]. Headaches from dissection may also mimic migraine or cluster headache [118], or have a sudden and severe ("thunderclap") onset [119]. (See "Overview of thunderclap headache".) Isolated orbital or monocular pain is a rare presentation of carotid artery dissection [120,121] Horner syndrome Horner syndrome ( figure 4) occurs in approximately 25 percent of cases [6] and is due most often to distension of sympathetic fibers spanning the external surface https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 7/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate of the internal carotid artery [6,122,123]. The Horner syndrome seen with internal carotid artery dissection is usually partial, involving ptosis and miosis but not anhidrosis. This occurs because the sympathetic fibers responsible for facial sweating and vasodilation branch off at the superior cervical ganglion from the remainder of the oculosympathetic pathway and travel with the external carotid artery. (See "Horner syndrome", section on 'Third-order syndrome'.) Cranial or cervical neuropathies Carotid dissection may cause single or multiple compressive cranial neuropathies in up to 12 percent of cases [7,124,125]. Cranial nerve XII is most commonly affected ( figure 5), followed by IX; involvement of cranial nerves III, V, and VI is less common [124-127]. Cervical nerve root involvement is a rare complication of vertebral artery dissection [128-131]. Cranial or cervical neuropathies due to arterial dissection may occur without associated ischemia. Pulsatile tinnitus Pulsatile tinnitus can occur in isolation or in combination with other manifestations of cervical artery dissection [132-134]. In the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study of 778 patients with cervical artery dissection, pulsatile tinnitus was present in 8 percent [134]. Ischemic stroke or TIA Ischemic symptoms are a common manifestation of cerebral and cervical artery dissection. In a population-based report of 48 patients with dissection of the internal carotid and vertebral arteries, cerebral ischemia was noted in 67 percent, with transient ischemic attack (TIA) and cerebral infarction in 23 and 56 percent, respectively [6]. Neurologic symptoms and signs of ischemic stroke or TIA due to carotid or vertebral artery dissection are not specific to dissection but are related to the different vascular territories involved. Carotid artery dissection may cause anterior circulation stroke syndrome, transient monocular blindness, retinal artery occlusion, or ischemic optic neuropathy [7,111,135,136]. Vertebral artery dissection may lead to lateral medullary infarction (Wallenberg syndrome), other posterior circulation stroke syndromes, or cervical spinal cord ischemia [128]. In a 2012 systematic review of 75 studies that described over 1900 patients with vertebral artery dissection, dizziness/vertigo was the most common symptom, although it is not certain that ischemia was the cause [137]. Subarachnoid hemorrhage Intracranial artery dissection may result in subarachnoid hemorrhage. In a 2015 systematic review of retrospective case series, subarachnoid https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 8/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate hemorrhage was associated with intracranial artery dissection in 8 to 69 percent of cases [110]. In rare cases, subarachnoid hemorrhage is found in combination with ischemic stroke [5]. EVALUATION AND DIAGNOSIS When to suspect dissection The diagnosis of cervical or intracranial artery dissection should be suspected in patients presenting with acute or subacute headache, neck pain, and/or stroke symptoms, particularly in following settings [138]: History of recent potential triggering events: Trauma, even if minor or trivial Participation in sports or physical activities Intense sneezing or coughing Peripartum Valsalva Personal or family history of connective tissue or vascular disorders or migraine Acute or subacute symptoms: Neurologic symptoms suggestive of ischemic stroke involving the anterior or posterior circulation stroke or suggestive of subarachnoid hemorrhage Horner syndrome Cranial or cervical neuropathies Pulsatile tinnitus Tooth pain without a dental cause Headache or neck pain at or prior to stroke onset may suggest underlying dissection, especially as a cause of stroke in the young. The acute onset of Horner syndrome in association with neck pain and an ischemic stroke or transient ischemic attack (TIA) in the territory of the ipsilateral internal carotid artery is suggestive of carotid artery dissection [58]. However, patients age 60 years with cervical artery dissection may be less likely to present with neck pain, headache, preceding trauma, or a mechanical triggering event [139]. Therefore, the possibility of dissection should not be disregarded when these features are absent in older individuals with unexplained TIA or acute ischemic stroke. Confirming the diagnosis We obtain urgent noninvasive multimodal imaging with brain and neck magnetic resonance imaging (MRI) and head and neck magnetic resonance angiography (MRA), or head computed tomography (CT) and computed tomography angiography (CTA) of the head and neck to confirm an initial diagnosis of cervicocephalic dissection and to guide serial https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 9/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate treatment decisions. While clinical features may raise suspicion for dissection, the diagnosis is confirmed by neuroimaging findings, particularly the demonstration of a long tapered arterial stenosis, a tapered occlusion, a dissecting aneurysm (pseudoaneurysm), an intimal flap, a double lumen, or an intramural hematoma. (See 'Choice of neuroimaging study' below.) Choice of neuroimaging study MRI should be ordered with standard axial T1-weighted, T2- weighted, fluid attenuation inversion recovery (FLAIR), and diffusion-weighted sequences. Cervical and cranial T1 fat-saturation imaging is useful for identifying small intramural hemorrhages [140]. MRA of the head and neck should be obtained with contrast-enhanced and time-of-flight MRA. Alternatively, a noncontrast head CT with CTA (which requires injection of contrast media) of the head and neck can be ordered. Axial source images and three- dimensional reconstructions are useful for detecting dissection, intimal tears, and medial or subendothelial hemorrhage [140]. The choice between these modalities is based primarily on availability and experience at local hospitals. There is no "gold standard," and the diagnosis often requires complementary imaging modalities, which may need repeating over time. These imaging studies should be performed urgently as part of a comprehensive stroke evaluation for patients who present with a clinical diagnosis of acute ischemic or hemorrhagic stroke, particularly for patients with ischemic stroke who may be candidates for reperfusion therapy using intravenous thrombolysis or mechanical thrombectomy. In addition, we obtain multimodal MRI/MRA or CT/CTA if dissection is suspected on the basis of local symptoms in the absence of ischemic stroke or subarachnoid hemorrhage. We reserve the use of conventional angiography for younger patients when clinical suspicion for dissection remains high despite negative noninvasive imaging. There is no need for conventional angiography if the diagnosis of cerebral or cervical artery dissection is clear using CTA or MRA. In most centers, conventional angiography has been supplanted by noninvasive approaches, particularly brain MRI with MRA and cranial CT with CTA [141-143]. A systematic review published in 2009 found that the sensitivity and specificity of MR techniques and CTA for the diagnosis of cervicocephalic arterial dissection were relatively similar [141]. Carotid duplex and transcranial Doppler ultrasonography (TCD) may be used to screen for suspected dissection, or to monitor therapy [144-147]. However, carotid duplex detects abnormalities in only 68 to 95 percent of cases [144,148]. Duplex and transcranial Doppler have a suboptimal yield for identifying arterial dissection near the skull base and vertebral artery dissection within the transverse foramina [58,143]. In addition, ultrasound is unreliable for detecting carotid artery dissection in patients with an isolated Horner syndrome [149]. Therefore, confirmation with MRA or CTA should be pursued in ultrasound-negative cases when the clinical history is suggestive of dissection [150]. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 10/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Characteristic imaging findings Angiographic findings of dissection include: String sign ( image 1) Tapered stenosis or occlusion or flame-shaped occlusion ( image 2) Intimal flap ( image 3) Dissecting aneurysm ( image 4) Intramural hematoma crescent sign ( image 5) Distal pouch In a population-based study of 48 consecutive patients with cervical artery dissection, the diagnostic neuroimaging patterns were an elongated tapered stenosis, a tapered occlusion, and a dissecting aneurysm in 48, 35, and 17 percent, respectively [6]. In a prospective European study of patients with vertebral artery dissection, the most frequent diagnostic neuroimaging finding on MRI was intramural hematoma, which was observed in 91 percent of 157 vertebral artery dissections [5]. The pathognomonic crescent sign of intramural hematoma is formed by an eccentric rim of hyperintensity surrounding a hypointense arterial lumen on MRI ( image 5). This crescent sign has traditionally been described on T1-weighted fat-saturation MRI sequences but may be apparent on other sequences such as diffusion-weighted imaging [151] or CTA. The degree of MRI hyperintensity and the methemoglobin content of the intramural hematoma varies with age of the lesion. Dissections of the horizontal vertebral artery segment may be difficult to diagnose as the classic crescent may be missing due to orientation of the vessel and the vertebral venous plexus may also appear hyperintense. The orientation of the vertebral artery may also limit delineation of a crescent, as the lumen may be patent yet surrounded by a more irregular "suboccipital rind" sign [152]. Assessment of multimodal CT or MRI source images is crucial to define vessel wall abnormalities. The pattern of brain ischemia on diffusion-weighted MRI may be influenced by the patency of the dissected artery, with territorial rather than borderzone infarcts apparent when there is complete occlusion of the vessel [153]. The advent of high-resolution 3 Tesla MRI has made it possible to detail interval recanalization, degree of stenosis, formation of dissecting aneurysms and the appearance of new dissections as part of serial imaging evaluations [154]. Periarterial inflammation associated with dissection may also be visualized with such high-resolution MRI techniques [155]. Evaluation for connective tissue disorders As noted previously (see 'Associated conditions and risk factors' above), the proportion of patients with dissection who are affected by a known connective tissue or vascular disorder is low. Therefore, we generally do not pursue additional https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 11/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate testing for such disorders unless there is heightened clinical suspicion because of suggestive symptoms, signs or family history (eg, joint hypermobility, multiple joint dislocations, translucent skin, poor wound healing, easy bruising, and unusual scars consistent with Ehlers-Danlos syndrome). (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".) The diagnosis of fibromuscular dysplasia (FMD) is made from angiography, so typically no additional testing is needed if extracranial arteries show no signs of FMD on MRA or CTA. An exception might be patients with clinical manifestations suggestive of renal FMD, where evaluation of renal arteries could prove diagnostic. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) DIFFERENTIAL DIAGNOSIS The differential diagnosis of cervicocephalic dissection is broad, given that the manifestations may include local symptoms (primarily head and neck pain, Horner syndrome, lower cranial nerve palsy), brain ischemia, or subarachnoid hemorrhage, either in isolation or in combination. (See 'Clinical manifestations' above.) Head and neck pain Entities to be considered in the differential diagnosis of head and neck pain include various types of headache, particularly those with unilateral head pain and those accompanied by autonomic symptoms such as ptosis and miosis. The list includes migraine, cluster headache and other trigeminal autonomic cephalalgias (eg, paroxysmal hemicrania and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing [SUNCT] syndrome), and Raeder paratrigeminal neuralgia [114]. Migraine should be suspected when there is a characteristic march of transient neurological deficits, although this pattern has been reported as well in rare patients with internal carotid artery dissection [156]. Cluster headache typically occurs without focal deficits. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults" and "Pathophysiology, clinical features, and diagnosis of migraine in children" and "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Paroxysmal hemicrania: Clinical features and diagnosis" and "Overview of craniofacial pain", section on 'Paratrigeminal oculosympathetic syndrome'.) Thunderclap headache Thunderclap headache, a severe headache of sudden onset, occurs in a minority of patients with cervicocephalic dissection. In addition, thunderclap headache is characteristic of the pain associated with the onset of subarachnoid hemorrhage and can be associated with multiple other causes as listed in the table ( table 1). (See "Overview of thunderclap headache".) https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 12/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Ischemic stroke and TIA The differential diagnosis for the cause of brain ischemia includes cardiogenic embolism, large artery atherosclerosis, small vessel disease, and a host of less common mechanisms such as a vasculopathy other than dissection. Intracranial vertebral artery occlusive disease due to atherosclerosis is a more common cause of lateral medullary ischemia than is vertebral dissection. (See "Differential diagnosis of transient ischemic attack and acute stroke" and "Stroke: Etiology, classification, and epidemiology" and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Posterior circulation cerebrovascular syndromes", section on 'Lateral medullary infarction'.) Subarachnoid hemorrhage The differential diagnosis of subarachnoid hemorrhage includes saccular aneurysm rupture, bleeding from a vascular malformation, perimesencephalic nonaneurysmal subarachnoid hemorrhage, and a number of less common causes. Angiography is the key to determining whether subarachnoid hemorrhage is caused by intracranial dissection or another vascular abnormality. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage" and "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children" and "Society guideline links: Fibromuscular dysplasia".) SUMMARY AND RECOMMENDATIONS Location Extracranial carotid dissections typically occur 2 cm or more beyond the carotid bifurcation, near or adjacent to the level of the skull base. Intracranial carotid dissections are most frequent in the supraclinoid segment. Vertebral artery dissection most often occurs in the cervical transverse processes of C6 to C2 (V2 segment) or the extracranial segment between the transverse process of C2 and the foramen magnum at the base of the skull (V3 segment) ( figure 3). (See 'Anatomy and pathology' above.) Pathophysiology Separation of the arterial wall layers results in dissection. A false lumen arises in the space where blood seeps into the vessel wall ( figure 1). Hemorrhage may https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate be due to an intimal tear or result from rupture or other pathology in the vasa vasorum. Subintimal dissections cause luminal stenosis or occlusion whereas subadventitial dissections largely result in dissecting aneurysm formation ( figure 2). (See 'Pathophysiology' above.) Etiology Dissection may result from a combination of intrinsic deficiencies of vessel wall integrity and extrinsic factors, including minor trauma. Numerous proposed risk factors and inciting activities have been associated with dissection. (See 'Etiology' above.) Epidemiology Dissection of the cervical and cerebral arteries occurs in about 3 cases per 100,000 individuals across all ages yet accounts for up to one quarter of all strokes in the young. (See 'Epidemiology' above.) Clinical manifestations Evidence from population and hospital-based reports suggests that dissection most often results in ischemic stroke or transient ischemic attack, usually preceded or accompanied by local symptoms such as neck pain, headache, Horner syndrome ( figure 4), and/or cranial neuropathies ( figure 5). However, these studies may underestimate the proportion of cases that are asymptomatic or associated with local symptoms only. Uncommonly, intracranial dissection results in subarachnoid hemorrhage. (See 'Clinical manifestations' above.) Evaluation and diagnosis We obtain urgent noninvasive multimodal imaging with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head and neck, or computed tomography (CT) and computed tomography angiography (CTA) of the head and neck to confirm an initial diagnosis of cervicocephalic dissection and to guide serial treatment decisions. While clinical features may raise suspicion for dissection, the diagnosis is confirmed by neuroimaging findings, particularly the demonstration of a long tapered arterial stenosis, a tapered occlusion, a dissecting aneurysm (pseudoaneurysm), an intimal flap, a double lumen, or an intramural hematoma. (See 'Evaluation and diagnosis' above.) Treatment and prognosis The treatment and prognosis of cervicocephalic dissection is reviewed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 14/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate 1. Pannone A, Lucchetti G, Stazi G, et al. Internal carotid artery dissection in a patient with Beh et's syndrome. Ann Vasc Surg 1998; 12:463. 2. V lker W, Dittrich R, Grewe S, et al. The outer arterial wall layers are primarily affected in spontaneous cervical artery dissection. Neurology 2011; 76:1463. 3. Downer J, Nadarajah M, Briggs E, et al. The location of origin of spontaneous extracranial internal carotid artery dissection is adjacent to the skull base. J Med Imaging Radiat Oncol 2014; 58:408. 4. Chaves C, Estol C, Esnaola MM, et al. Spontaneous intracranial internal carotid artery dissection: report of 10 patients. Arch Neurol 2002; 59:977. 5. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006; 37:2499. 6. Lee VH, Brown RD Jr, Mandrekar JN, Mokri B. Incidence and outcome of cervical artery dissection: a population-based study. Neurology 2006; 67:1809. 7. Arnold M, Kappeler L, Georgiadis D, et al. Gender differences in spontaneous cervical artery dissection. Neurology 2006; 67:1050. 8. Touz E, Gauvrit JY, Moulin T, et al. Risk of stroke and recurrent dissection after a cervical artery dissection: a multicenter study. Neurology 2003; 61:1347. 9. Hassan AE, Zacharatos H, Mohammad YM, et al. Comparison of single versus multiple spontaneous extra- and/or intracranial arterial dissection. J Stroke Cerebrovasc Dis 2013; 22:42. 10. Arnold M, De Marchis GM, Stapf C, et al. Triple and quadruple spontaneous cervical artery dissection: presenting characteristics and long-term outcome. J Neurol Neurosurg Psychiatry 2009; 80:171. 11. Besselmann M, Vennemann B, Lowens S, et al. Internal carotid artery dissection. Neurology 2000; 54:442. 12. Ulbricht D, Diederich NJ, Hermanns-L T, et al. Cervical artery dissection: An atypical presentation with Ehlers-Danlos-like collagen pathology? Neurology 2004; 63:1708. 13. Brandt T, Morcher M, Hausser I. Association of cervical artery dissection with connective tissue abnormalities in skin and arteries. Front Neurol Neurosci 2005; 20:16. 14. Brandt T, Orberk E, Weber R, et al. Pathogenesis of cervical artery dissections: association with connective tissue abnormalities. Neurology 2001; 57:24. 15. Lucas C, Moulin T, Deplanque D, et al. Stroke patterns of internal carotid artery dissection in 40 patients. Stroke 1998; 29:2646. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 15/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate 16. Morel A, Naggara O, Touz E, et al. Mechanism of ischemic infarct in spontaneous cervical artery dissection. Stroke 2012; 43:1354. 17. Arnold M, Cumurciuc R, Stapf C, et al. Pain as the only symptom of cervical artery dissection. J Neurol Neurosurg Psychiatry 2006; 77:1021.

includes cardiogenic embolism, large artery atherosclerosis, small vessel disease, and a host of less common mechanisms such as a vasculopathy other than dissection. Intracranial vertebral artery occlusive disease due to atherosclerosis is a more common cause of lateral medullary ischemia than is vertebral dissection. (See "Differential diagnosis of transient ischemic attack and acute stroke" and "Stroke: Etiology, classification, and epidemiology" and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Posterior circulation cerebrovascular syndromes", section on 'Lateral medullary infarction'.) Subarachnoid hemorrhage The differential diagnosis of subarachnoid hemorrhage includes saccular aneurysm rupture, bleeding from a vascular malformation, perimesencephalic nonaneurysmal subarachnoid hemorrhage, and a number of less common causes. Angiography is the key to determining whether subarachnoid hemorrhage is caused by intracranial dissection or another vascular abnormality. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage" and "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children" and "Society guideline links: Fibromuscular dysplasia".) SUMMARY AND RECOMMENDATIONS Location Extracranial carotid dissections typically occur 2 cm or more beyond the carotid bifurcation, near or adjacent to the level of the skull base. Intracranial carotid dissections are most frequent in the supraclinoid segment. Vertebral artery dissection most often occurs in the cervical transverse processes of C6 to C2 (V2 segment) or the extracranial segment between the transverse process of C2 and the foramen magnum at the base of the skull (V3 segment) ( figure 3). (See 'Anatomy and pathology' above.) Pathophysiology Separation of the arterial wall layers results in dissection. A false lumen arises in the space where blood seeps into the vessel wall ( figure 1). Hemorrhage may https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate be due to an intimal tear or result from rupture or other pathology in the vasa vasorum. Subintimal dissections cause luminal stenosis or occlusion whereas subadventitial dissections largely result in dissecting aneurysm formation ( figure 2). (See 'Pathophysiology' above.) Etiology Dissection may result from a combination of intrinsic deficiencies of vessel wall integrity and extrinsic factors, including minor trauma. Numerous proposed risk factors and inciting activities have been associated with dissection. (See 'Etiology' above.) Epidemiology Dissection of the cervical and cerebral arteries occurs in about 3 cases per 100,000 individuals across all ages yet accounts for up to one quarter of all strokes in the young. (See 'Epidemiology' above.) Clinical manifestations Evidence from population and hospital-based reports suggests that dissection most often results in ischemic stroke or transient ischemic attack, usually preceded or accompanied by local symptoms such as neck pain, headache, Horner syndrome ( figure 4), and/or cranial neuropathies ( figure 5). However, these studies may underestimate the proportion of cases that are asymptomatic or associated with local symptoms only. Uncommonly, intracranial dissection results in subarachnoid hemorrhage. (See 'Clinical manifestations' above.) Evaluation and diagnosis We obtain urgent noninvasive multimodal imaging with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head and neck, or computed tomography (CT) and computed tomography angiography (CTA) of the head and neck to confirm an initial diagnosis of cervicocephalic dissection and to guide serial treatment decisions. While clinical features may raise suspicion for dissection, the diagnosis is confirmed by neuroimaging findings, particularly the demonstration of a long tapered arterial stenosis, a tapered occlusion, a dissecting aneurysm (pseudoaneurysm), an intimal flap, a double lumen, or an intramural hematoma. (See 'Evaluation and diagnosis' above.) Treatment and prognosis The treatment and prognosis of cervicocephalic dissection is reviewed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. 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AJNR Am J Neuroradiol 2008; 29:1753. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 23/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate 143. Provenzale JM. MRI and MRA for evaluation of dissection of craniocerebral arteries: lessons from the medical literature. Emerg Radiol 2009; 16:185. 144. Benninger DH, Baumgartner RW. Ultrasound diagnosis of cervical artery dissection. Front Neurol Neurosci 2006; 21:70. 145. Imray CH, Pattinson KT. Potential role for TCD-directed antiplatelet agents in symptomatic carotid artery dissection. Stroke 2006; 37:767. 146. Sengelhoff C, Nebelsieck J, Nassenstein I, et al. Neurosonographical follow-up in patients with spontaneous cervical artery dissection. Neurol Res 2008; 30:687. 147. Wessels T, Mosso M, Krings T, et al. Extracranial and intracranial vertebral artery dissection: long-term clinical and duplex sonographic follow-up. J Clin Ultrasound 2008; 36:472. 148. Nebelsieck J, Sengelhoff C, Nassenstein I, et al. Sensitivity of neurovascular ultrasound for the detection of spontaneous cervical artery dissection. J Clin Neurosci 2009; 16:79. 149. Arnold M, Baumgartner RW, Stapf C, et al. Ultrasound diagnosis of spontaneous carotid dissection with isolated Horner syndrome. Stroke 2008; 39:82. 150. Dittrich R, Dziewas R, Ritter MA, et al. Negative ultrasound findings in patients with cervical artery dissection. Negative ultrasound in CAD. J Neurol 2006; 253:424. 151. Choi KD, Jo JW, Park KP, et al. Diffusion-weighted imaging of intramural hematoma in vertebral artery dissection. J Neurol Sci 2007; 253:81. 152. Lum C, Chakraborty S, Schlossmacher M, et al. Vertebral artery dissection with a normal- appearing lumen at multisection CT angiography: the importance of identifying wall hematoma. AJNR Am J Neuroradiol 2009; 30:787. 153. Bonati LH, Wetzel SG, Gandjour J, et al. Diffusion-weighted imaging in stroke attributable to internal carotid artery dissection: the significance of vessel patency. Stroke 2008; 39:483. 154. Bachmann R, Nassenstein I, Kooijman H, et al. High-resolution magnetic resonance imaging (MRI) at 3.0 Tesla in the short-term follow-up of patients with proven cervical artery dissection. Invest Radiol 2007; 42:460. 155. Naggara O, Touz E, Marsico R, et al. High-resolution MR imaging of periarterial edema associated with biological inflammation in spontaneous carotid dissection. Eur Radiol 2009; 19:2255. 156. Silverman IE, Wityk RJ. Transient migraine-like symptoms with internal carotid artery dissection. Clin Neurol Neurosurg 1998; 100:116. Topic 14082 Version 37.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 24/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate GRAPHICS The progression of a dissection, thrombus development, and total vessel occlusion Courtesy of Dr. Mounzer Kassab. Graphic 57866 Version 2.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 25/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Mechanism of dissecting aneurysm formation Lateral and cross-sectional schematic view of the carotid artery. (A) Aneurysmal dilatation of the vessel related to a hemorrhage between the media and the adventitia (subadventitial dissection). (B) Communication between the arterial lumen and the dissection cavity or disappearance of the hematoma may lead to the formation of an extraluminal pouch or a fusiform dilatation. Reproduced with permission from: Guillon B, Brunereau L, Biousse V, et al. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology 1999; 53:117. Copyright 1999 Lippincott Williams & Wilkins. Graphic 57174 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Segments of the vertebral artery The vertebral artery is divided into four anatomic segments: V1 Origin of the vessel to the foramina of the sixth cervical (C6) transverse process. V2 Intraforaminal segment from the sixth to the second cervical vertebral body (C6 to C2). V3 From the second cervical (C2) foramina to the base of the skull. V4 Intracerebral segment of the vertebral artery. The vertebral arteries merge to form the basilar artery and are intradural. Graphic 56466 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Pathology of internal carotid artery dissection Elastica van Gieson stain of specimens from a 61-year-old man with internal carotid artery dissection and fibromuscular dysplasia. (A) Postmortem exposition of intramural hematoma of the right internal carotid artery above the bifurcation (arrow). (B) Cross-section of the dissected artery shows subintimal and intramedial hematoma (small arrows). (C) Longitudinal section with zipper-like separation within the arterial wall (large arrow) corresponding to the false lumen and myxoid degeneration of the media (small arrows). Asterisk: true lumen; Scale bar: 0.25 mm. Reproduced with permission from: Besselmann M, Vennemann B, Lowens S, et al. Internal carotid artery dissection. Neurology 2000; 54:442. Copyright 2000 Lippincott Williams & Wilkins. Graphic 73102 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Horner syndrome due to internal carotid artery dissection (A) Horner syndrome (miosis and ptosis). (B) Multiple left frontoparietal acute ischemic lesions on diffusion- weighted MRI. (C) Carotid angiography with evidence of left extracranial internal carotid artery occlusion. (D) Internal carotid artery mural hematoma due to dissection evident on MRI scan. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate (E) Intimal flap (arrows) appearance on Duplex scan, a pathognomonic sign of dissection. Reproduced with permission from: Mazzucco S, Rizzuto N. Teaching NeuroImage: Horner syndrome due to internal carotid artery dissection. Neurology 2006; 66:E19. Copyright 2006 Lippincott Williams & Wilkins. Graphic 80623 Version 5.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Isolated hypoglossal nerve palsy due to internal carotid artery dissection (A) The patient's tongue deviated to the left. (B) T1-weighted MRI demonstrates narrowing of the lumen and intramural hematoma in the left internal carotid artery. (C) True fast MRI with steady-state precession reveals the anatomic juxtaposition of the hypoglossal nerve (arrowhead) and the dissected internal carotid artery (arrow). Reproduced with permission from: Okunomiya T, Kageyama T, Suenaga T. Teaching NeuroImages: Isolated hypoglossal nerve palsy due to internal carotid artery dissection. Neurology 2012; 79:e37. Copyright 2012 Lippincott Williams & Wilkins. Graphic 86467 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate String sign on MR angiography Left internal carotid artery dissection in a 43-year-old man. A hemorrhagic crescent on axial T1 cervical MRI (A) and the string sign on follow-up neck MR angiography (B) are consistent with dissection. MRI: magnetic resonance imaging; MR: magnetic resonance. Reproduced with permission from: Pary LF, Rodnitzky RL. Traumatic internal carotid artery dissection associated with taekwondo. Neurology 2003; 60:1392. Copyright 2003 Lippincott Williams & Wilkins. Graphic 65212 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Flame-shaped occlusion of internal carotid artery from dissection Digital subtraction angiogram (lateral projection) shows an internal carotid artery occlusion secondary to dissection, as indicated by the typical flame- shaped appearance and location of the occlusion distal to the carotid bifurcation. Reproduced with permission from: Koch S, Lorenzo D, Rabinstein AA, Lam B. Ischemic optic neuropathy and carotid dissection. Neurology 2005; 64:827. Copyright 2005 Lippincott Williams & Wilkins. Graphic 61851 Version 5.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Intracranial dissection with intimal flap (A, B) Diffusion-weighted sequence of MRI of the brain shows acute infarction in the right MCA territory. (C, D) Catheter angiography showed irregularities of the right supraclinoid internal carotid artery, extending into the M1 segment of the right MCA. An intimal flap (arrow) indicates dissection. MRI: magnetic resonance imaging; MCA: middle cerebral artery. Reproduced with permission from: Suter B, El-Hakam LM. Child neurology: stroke due to nontraumatic intracranial dissection in a child. Neurology 2009; 72:e100. Copyright 2009 Lippincott Williams & Wilkins. Graphic 55635 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:24 PM

associated with biological inflammation in spontaneous carotid dissection. Eur Radiol 2009; 19:2255. 156. Silverman IE, Wityk RJ. Transient migraine-like symptoms with internal carotid artery dissection. Clin Neurol Neurosurg 1998; 100:116. Topic 14082 Version 37.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 24/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate GRAPHICS The progression of a dissection, thrombus development, and total vessel occlusion Courtesy of Dr. Mounzer Kassab. Graphic 57866 Version 2.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 25/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Mechanism of dissecting aneurysm formation Lateral and cross-sectional schematic view of the carotid artery. (A) Aneurysmal dilatation of the vessel related to a hemorrhage between the media and the adventitia (subadventitial dissection). (B) Communication between the arterial lumen and the dissection cavity or disappearance of the hematoma may lead to the formation of an extraluminal pouch or a fusiform dilatation. Reproduced with permission from: Guillon B, Brunereau L, Biousse V, et al. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology 1999; 53:117. Copyright 1999 Lippincott Williams & Wilkins. Graphic 57174 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Segments of the vertebral artery The vertebral artery is divided into four anatomic segments: V1 Origin of the vessel to the foramina of the sixth cervical (C6) transverse process. V2 Intraforaminal segment from the sixth to the second cervical vertebral body (C6 to C2). V3 From the second cervical (C2) foramina to the base of the skull. V4 Intracerebral segment of the vertebral artery. The vertebral arteries merge to form the basilar artery and are intradural. Graphic 56466 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Pathology of internal carotid artery dissection Elastica van Gieson stain of specimens from a 61-year-old man with internal carotid artery dissection and fibromuscular dysplasia. (A) Postmortem exposition of intramural hematoma of the right internal carotid artery above the bifurcation (arrow). (B) Cross-section of the dissected artery shows subintimal and intramedial hematoma (small arrows). (C) Longitudinal section with zipper-like separation within the arterial wall (large arrow) corresponding to the false lumen and myxoid degeneration of the media (small arrows). Asterisk: true lumen; Scale bar: 0.25 mm. Reproduced with permission from: Besselmann M, Vennemann B, Lowens S, et al. Internal carotid artery dissection. Neurology 2000; 54:442. Copyright 2000 Lippincott Williams & Wilkins. Graphic 73102 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Horner syndrome due to internal carotid artery dissection (A) Horner syndrome (miosis and ptosis). (B) Multiple left frontoparietal acute ischemic lesions on diffusion- weighted MRI. (C) Carotid angiography with evidence of left extracranial internal carotid artery occlusion. (D) Internal carotid artery mural hematoma due to dissection evident on MRI scan. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate (E) Intimal flap (arrows) appearance on Duplex scan, a pathognomonic sign of dissection. Reproduced with permission from: Mazzucco S, Rizzuto N. Teaching NeuroImage: Horner syndrome due to internal carotid artery dissection. Neurology 2006; 66:E19. Copyright 2006 Lippincott Williams & Wilkins. Graphic 80623 Version 5.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Isolated hypoglossal nerve palsy due to internal carotid artery dissection (A) The patient's tongue deviated to the left. (B) T1-weighted MRI demonstrates narrowing of the lumen and intramural hematoma in the left internal carotid artery. (C) True fast MRI with steady-state precession reveals the anatomic juxtaposition of the hypoglossal nerve (arrowhead) and the dissected internal carotid artery (arrow). Reproduced with permission from: Okunomiya T, Kageyama T, Suenaga T. Teaching NeuroImages: Isolated hypoglossal nerve palsy due to internal carotid artery dissection. Neurology 2012; 79:e37. Copyright 2012 Lippincott Williams & Wilkins. Graphic 86467 Version 4.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate String sign on MR angiography Left internal carotid artery dissection in a 43-year-old man. A hemorrhagic crescent on axial T1 cervical MRI (A) and the string sign on follow-up neck MR angiography (B) are consistent with dissection. MRI: magnetic resonance imaging; MR: magnetic resonance. Reproduced with permission from: Pary LF, Rodnitzky RL. Traumatic internal carotid artery dissection associated with taekwondo. Neurology 2003; 60:1392. Copyright 2003 Lippincott Williams & Wilkins. Graphic 65212 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Flame-shaped occlusion of internal carotid artery from dissection Digital subtraction angiogram (lateral projection) shows an internal carotid artery occlusion secondary to dissection, as indicated by the typical flame- shaped appearance and location of the occlusion distal to the carotid bifurcation. Reproduced with permission from: Koch S, Lorenzo D, Rabinstein AA, Lam B. Ischemic optic neuropathy and carotid dissection. Neurology 2005; 64:827. Copyright 2005 Lippincott Williams & Wilkins. Graphic 61851 Version 5.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Intracranial dissection with intimal flap (A, B) Diffusion-weighted sequence of MRI of the brain shows acute infarction in the right MCA territory. (C, D) Catheter angiography showed irregularities of the right supraclinoid internal carotid artery, extending into the M1 segment of the right MCA. An intimal flap (arrow) indicates dissection. MRI: magnetic resonance imaging; MCA: middle cerebral artery. Reproduced with permission from: Suter B, El-Hakam LM. Child neurology: stroke due to nontraumatic intracranial dissection in a child. Neurology 2009; 72:e100. Copyright 2009 Lippincott Williams & Wilkins. Graphic 55635 Version 6.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Extracranial aneurysm of the internal carotid artery Arteriography of an extracranial aneurysm of the internal carotid artery at the skull base resulting from carotid dissection in a 34-year-old man. Reproduced with permission from: Meairs S, Hennerici M. Long-term follow-up of aneurysms developed during extracranial internal carotid artery dissection. Neurology 2000; 54:2190. Copyright 2000 Lippincott Williams & Wilkins. Graphic 80873 Version 5.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 35/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate MRI of ICA dissection Axial T1-weighted MRI showing a right internal carotid artery dissection as a crescent-shaped hypersignal within the internal carotid artery wall. MRI: magnetic resonance imaging; ICA: internal carotid artery. Graphic 59392 Version 3.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 36/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 37/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 38/39 7/6/23, 12:24 PM Cerebral and cervical artery dissection: Clinical features and diagnosis - UpToDate Contributor Disclosures David S Liebeskind, MD Consultant/Advisory Boards: Cerenovus [Stroke]; Genentech [Stroke]; Medtronic [Stroke]; Stryker [Stroke]. Speaker's Bureau: Astra-Zeneca [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-clinical-features-and-diagnosis/print 39/39

7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral and cervical artery dissection: Treatment and prognosis : David S Liebeskind, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2022. INTRODUCTION Arterial dissections are a common cause of stroke in the young but may occur at any age. Dissection occurs when structural integrity of the arterial wall is compromised, allowing blood to collect between layers as an intramural hematoma. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. The optimal treatment of dissection remains a challenge due to limitations in rapidly establishing a definitive diagnosis, the overall low incidence, low recurrence rate, and marked variation in patient characteristics [1]. This topic will review the treatment and prognosis of cerebral and cervical artery dissection. Other aspects of this disorder are reviewed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".) ACUTE ISCHEMIC STROKE OR TIA DUE TO DISSECTION General management For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to management should be rigorously followed including blood pressure regulation, fluid administration, control of hyperglycemia and other metabolic derangements, and airway management. These issues are discussed in detail separately. (See "Initial assessment and management of acute stroke" https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 1/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see 'Reperfusion therapy for eligible patients' below). Reperfusion therapy for eligible patients The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis with alteplase or tenecteplase, and mechanical thrombectomy. Since the ischemic stroke mechanism is often unknown or unconfirmed at the time of decision-making for intravenous thrombolysis, and since cervical or cerebral artery dissection is not a contraindication, patients with suspected cervical or intracranial dissection should receive intravenous thrombolysis if otherwise eligible. Intravenous thrombolysis Intravenous thrombolysis with alteplase (tPA) or tenecteplase is indicated for eligible patients ( table 1) with acute ischemic stroke, including those with isolated extracranial or intracranial cervical artery dissection. Extension of aortic dissection, however, is a known complication of thrombolysis. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) The major randomized trials of intravenous thrombolysis for acute ischemic stroke did not exclude patients with cervicocephalic arterial dissection. While thrombolysis in the setting of dissection may theoretically cause enlargement of the intramural hematoma, accumulating evidence suggests that the effectiveness and safety of thrombolysis for patients with ischemic stroke related to cervical artery dissection are similar to its effectiveness and safety for patients with ischemic stroke from other causes [2-7]. Perhaps the strongest evidence, although indirect, comes from a 2011 meta-analysis of individual patient data from 14 retrospective series and 22 case reports involving 180 patients with cervical artery dissection who were treated with thrombolysis and followed for a median of three months [4]. When these patients were compared with matched historic controls from the observational SITS-ISTR registry of patients treated with intravenous alteplase for acute ischemic stroke, there were no major differences between groups for rates of symptomatic intracranial hemorrhage, mortality, excellent outcome, or favorable outcome. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 2/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate There is controversy regarding the use of thrombolysis for ischemic symptoms in patients with isolated intracranial dissection alone or intracranial extension of extracranial dissection because of a presumed increased risk of subarachnoid or symptomatic intracranial hemorrhage. Limited observational data suggest this risk is minimal, but efficacy and safety are still uncertain [8]. Mechanical thrombectomy For select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, early treatment with mechanical thrombectomy is indicated when performed at stroke centers with appropriate expertise, whether or not the patient received treatment with intravenous thrombolysis. This includes patients with extracranial carotid dissection who have a tandem proximal intracranial artery occlusion amenable to mechanical thrombectomy [9-13]. The efficacy of mechanical thrombectomy for vertebral and basilar artery occlusions is unproven. (See "Mechanical thrombectomy for acute ischemic stroke".) Emergency stenting In addition to mechanical thrombectomy, angioplasty and stenting of arterial dissection may be treatment options for acute stroke at expert centers [14-17]. Choosing between antiplatelet and anticoagulation therapy Antithrombotic therapy is often used for the prevention of new or recurrent ischemic symptoms caused by arterial dissection, but the approach may differ for extracranial versus intracranial dissection. Extracranial dissection For patients with extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended [18-24]. However, there is no clear consensus about which of these is optimal. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy [25], while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by shared decision making that incorporates patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests, but does not establish, that there is no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection. In an open-label, assessor-blind pilot trial (CADISS), 250 subjects with extracranial carotid and vertebral dissection were randomly assigned to antiplatelet or anticoagulant treatment for three months [26]. At the end of this period, there was no significant difference between the two treatment groups; ipsilateral ischemic stroke occurred in 3 of 126 (2 percent) in the antiplatelet group and 1 of 124 (1 percent) in the anticoagulant group (odds https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 3/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate ratio 0.34, 95% CI 0.01-4.23). There were no deaths in either group. There was one major bleeding event, a subarachnoid hemorrhage, in a patient assigned to the anticoagulation group who had a vertebral artery dissection with intracranial extension. At 12 months of follow-up, the rate of recurrent stroke remained low (approximately 2.5 percent) in both treatment groups with no difference between groups for any outcome, including no difference in the angiographic recanalization rate among patients with confirmed dissection [27]. Because of the low stroke rate and rarity of outcome events, the CADISS trial was unable to establish which treatment is superior or safer when used to treat cervical artery dissection [1]. The investigators estimated that a definitive trial would require approximately 10,000 participants, making such a trial unfeasible given the slow enrollment rate of the CADISS trial. However, it is highly likely that anticoagulation is associated with a higher risk of hemorrhagic events, since anticoagulation is a known risk factor for bleeding. (See "Risks and prevention of bleeding with oral anticoagulants".) The subsequent TREAT-CAD trial was an open-label, assessor-blind trial that enrolled 194 adult patients who presented with symptomatic extracranial dissection within two weeks of enrollment and were randomly assigned to aspirin monotherapy (300 mg daily) or to anticoagulation with a vitamin K antagonist (target INR 2.0 to 3.0) for 90 days [28]. The trial was designed to test the noninferiority of aspirin compared with vitamin K antagonist anticoagulants. The trialists chose a composite primary endpoint of clinical events (stroke, major hemorrhage, or death) and magnetic resonance imaging findings (new silent ischemic or hemorrhagic brain lesions) in order to achieve sufficient power, and performed a per-protocol analysis of 173 patients who received the allocated treatment and completed the assessment period. The composite endpoint occurred more often in the aspirin group compared with the vitamin K antagonist group (23 versus 15 percent, absolute difference 8 percent, 95% CI -4 to 21 percent); while the difference was not statistically significant, aspirin failed to meet noninferiority criteria because the upper limit of the 95% CI (21 percent) exceeded the predefined noninferiority margin of 12 percent. Ischemic stroke was also more frequent in the aspirin group (8 versus 0 percent), and all ischemic stroke occurred within seven days of trial enrollment. There were no deaths in either group. There was one major extracranial hemorrhage (a gastrointestinal bleed) in a patient from the vitamin K antagonist group and none in the aspirin group. The risk of ischemic stroke in the TREAT-CAD aspirin group (8 percent) was greater than that in the CADISS antiplatelet group (2 percent); one possible explanation for the difference is that TREAT-CAD used aspirin monotherapy, whereas CADISS permitted the use of other antiplatelet agents and dual antiplatelet therapy [29]. However, this is speculative, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 4/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate as indirect cross-trial comparisons may be confounded by various issues and lead to erroneous conclusions. A 2012 meta-analysis of nonrandomized studies with over 1600 patients with cervical artery dissection reported no significant difference in recurrent stroke risk or mortality comparing anticoagulation with antiplatelet agents [30]. Similarly, a 2015 meta-analysis of nonrandomized studies with over 1300 patients who had acute carotid artery dissection found no differences in outcome or complication rates comparing anticoagulation with antiplatelet therapy [31]. Intracranial dissection For patients who have ischemic neurologic symptoms caused by intracranial arterial dissection, we suggest antiplatelet therapy rather than anticoagulation [24]. Anticoagulation is generally avoided in the setting of intracranial dissection due to the risk of subarachnoid hemorrhage, although limited evidence suggests that anticoagulation can be used safely for some patients who have intracranial dissection without subarachnoid hemorrhage [32]. Starting antiplatelet therapy For patients selected for antiplatelet therapy (rather than anticoagulation), initiation should be delayed for 24 hours after infusion of intravenous thrombolytic therapy. Otherwise, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) 2 For patients with a low-risk TIA, defined by an ABCD score <4 ( table 2), or moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3), we start treatment with aspirin (162 to 325 mg daily) alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4 ( table 2), or minor ischemic stroke, defined by a NIHSS score 5 ( table 3), we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Most reports of antiplatelet therapy for acute cervical artery dissection have employed daily aspirin at various doses; there are few data regarding other antiplatelet agents such as clopidogrel, dipyridamole, or combinations of these agents. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 5/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Starting anticoagulation therapy For patients selected for anticoagulation rather than antiplatelet therapy, the initiation of therapy is affected by a number of factors. For medically stable patients with a small- or moderate-sized infarct, anticoagulation using heparin or low molecular weight heparin (as a bridge to warfarin) can be started as soon as 24 hours after symptom onset, or at least 24 hours after infusion of thrombolytic therapy, with minimal risk of transformation to hemorrhagic stroke; anticoagulation with a direct oral anticoagulant (DOAC) can be started as soon as 48 hours after stroke onset, as DOACs have a more rapid anticoagulant effect. However, the role of DOACs for treating dissection is uncertain and data are limited [21]. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended. In such cases, we start aspirin if there are no significant bleeding complications; anticoagulation can be started (and aspirin stopped) after one to two weeks if the patient is stable. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of long-term anticoagulation'.) Anticoagulation can be started immediately for patients with a TIA due to dissection. Acute anticoagulation may be achieved with either subcutaneous low molecular weight heparin such as enoxaparin (1 mg/kg twice daily) or dalteparin (100 units/kg twice daily) or with intravenous unfractionated heparin (dose-adjusted to achieve a goal activated partial thromboplastin time of 1.5 to 2 times control). Transition to warfarin (dose adjusted for a goal international normalized ratio [INR] of 2.5 with an acceptable range of 2 to 3) can be pursued in the subacute period for clinically stable patients. Vessel monitoring and repeat imaging After three to six months from symptom onset or diagnosis of dissection, repeat neurovascular imaging is suggested to assess the status of artery or arteries affected by dissection and guide the need for ongoing treatment, particularly if the patient is being treated with anticoagulation. We use transcranial Doppler, carotid duplex, computed tomography angiography (CTA), and/or magnetic resonance angiography (MRA) to help us decide the status of the arterial system prior to discontinuing anticoagulation therapy. Further treatment is tailored to imaging findings. (See 'Duration of antithrombotic therapy' below.) In most cases, arteries with stenosis or luminal irregularities caused by dissection undergo recanalization and healing in the first months after the initial event. In a report of 61 patients with acute vertebral artery dissection who presented with symptoms of vertebrobasilar territory ischemia, complete recanalization of the vertebral artery was observed at six months in 62 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 6/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate percent [33]. In another study that followed 76 patients with cervical artery dissection involving 105 vessels with a mean follow-up of 58 months, complete recanalization was noted in 51 percent of vessels, nearly all occurring within the first nine months, and hemodynamically significant recanalization in 20 percent [34]. Data from the prospective CADISS study suggest that dissecting aneurysms are inconstant and can either resolve or develop for the first time in the months following the clinical diagnosis of extracranial cervical artery dissection [35]. Residual headache may indicate persistent vascular abnormalities [36]. Duration of antithrombotic therapy For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed on repeat imaging at three to six months. For patients with persistent vascular luminal stenosis, irregularity, or dissecting aneurysm, it is reasonable to continue anticoagulation. For patients treated with antiplatelet therapy in the acute phase, long-term antiplatelet therapy is recommended using aspirin, clopidogrel, aspirin-extended-release dipyridamole, or cilostazol for secondary prevention of stroke. However, there are no concrete data regarding optimal duration of antithrombotic therapy. The time course of healing of the vessel wall or resolution of vascular abnormalities may be used to guide duration of initial treatment. Most arterial abnormalities stabilize in appearance or resolve by three months, and vessels that fail to reconstitute a normal lumen by six months are highly unlikely to recover at later time points [37]. Recurrent ischemia Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes with a history and examination, brain and vessel imaging, and cardiac and laboratory testing. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Neuroimaging of acute stroke".) Due to dissection In various reports, the rate of recurrent ischemic symptoms (stroke and transient ischemic attack) after dissection ranges from 0 to 13 percent [38,39], but it is likely that the actual rate of recurrent ischemic stroke caused by dissection is at the lower end of this range. The prospective CADISS trial found that the rate of recurrent ischemic stroke at three months was approximately 2 percent, and all recurrences were within 10 days of randomization, suggesting that the risk beyond the first two weeks is extremely low https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 7/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate [26]. Prospective data from the CADISS study also suggest that extracranial cervical dissecting aneurysms have a benign prognosis, with a low rate (1 of 48, or approximately 2 percent) of ischemic stroke during 12 months of follow-up, similar to the rate observed in dissections without aneurysm formation [35]. Another study evaluated 432 surviving patients with carotid or vertebral dissection who were followed for a mean time of 31 months [40]. Recurrent ischemic stroke due to initial or recurrent dissection was observed in four patients (0.9 percent), giving an annual incidence of 0.3 percent. Transient ischemic attack was observed in eight patients (1.8 percent), for an annual incidence of 0.6 percent. Endovascular and surgical repair for dissection Endovascular techniques or surgical repair have been used to treat dissection, mainly for patients who have recurrent ischemia despite antithrombotic therapy [23]. Endovascular techniques for the treatment of dissection and dissecting aneurysm include angioplasty, stent placement, embolization with various materials, and combinations of such approaches [23,41]. Angioplasty and stenting may occlude the false lumen and restore true arterial lumen patency. However, data regarding endovascular treatment of dissection is limited to case reports and case series [41-48]. There are no randomized trial data comparing endovascular techniques with medical therapies, and the long-term safety and durability of these methods are unknown. In isolated cases, accessible lesions may be treated by surgical vessel reconstruction or bypass around a dissecting aneurysm [49,50]. Other surgical revascularization procedures include extracranial-intracranial bypass, endarterectomy, thrombectomy, and proximal vessel ligation. SUBARACHNOID HEMORRHAGE DUE TO INTRACRANIAL DISSECTION Subarachnoid hemorrhage is an uncommon complication of intracranial dissection. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Intracranial arterial dissection'.) It is managed according to the same principles as subarachnoid hemorrhage caused by rupture of a saccular aneurysm (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis"), with the exception that the surgical or endovascular treatment of dissecting aneurysm itself may differ from that of a saccular aneurysm because of morphologic differences between the two types of aneurysms. The risk of rebleeding from an intracranial dissecting https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 8/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate aneurysm is as high as 40 percent in the first week or so after the event [51-54]. Thus, early repair is typically recommended [51]. The morphology of most dissecting aneurysms limits standard surgical clipping. Management is individualized according to location and other anatomic features, and can include proximal occlusion of the artery, trapping or wrapping of the pseudoaneurysm, bypass, embolization, or stenting [52,54]. These are complicated procedures that can incur additional morbidity. NONISCHEMIC LOCAL SYMPTOMS For patients with nonischemic symptoms caused by extracranial or intracranial carotid or vertebral artery dissection, we suggest antiplatelet therapy for prevention of ischemic stroke. Headache and neck pain associated with dissection can usually be managed with simple analgesics such as acetaminophen. Anecdotally, gabapentin may be helpful. Nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen sodium, ibuprofen) are generally avoided in patients receiving anticoagulation because of the increased risk of bleeding. There is no specific treatment for other local symptoms of dissection such as Horner syndrome, lower cranial nerve palsy, audible bruit, or tinnitus, but these may improve with time and vessel healing. MEASURES TO REDUCE RISK OF DISSECTION There are no proven methods that reduce the risk of recurrent cervicocephalic arterial dissection. Nevertheless, some experts suggest that patients with dissection should avoid contact sports, chiropractic neck manipulation, and any activity that involves abrupt rotation and flexion-extension of the neck [55,56]. In addition, estrogen-containing compounds should be discontinued, as estrogen may induce proliferation of intimal and fibromuscular arterial tissue. All vascular risk factors including hypertension should be addressed. (See "Overview of secondary prevention of ischemic stroke".) PROGNOSIS Neurologic outcome The prognosis of cerebral and cervical artery dissection is related primarily to the severity of associated ischemic stroke or subarachnoid hemorrhage. Morbidity and mortality of acute cervicocephalic arterial dissection varies according to the specific arteries involved and location of the lesion. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 9/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate In the CADISP study of 982 patients with extracranial cervical artery dissection, an unfavorable outcome at three months among patients with ischemic stroke, defined as a modified Rankin Scale ( table 4) score >2, was more likely with stroke due to internal carotid artery dissection compared with stroke due to vertebral artery dissection (25 versus 8 percent) [57]. This result was largely driven by stroke severity at onset, which was greater for patients with internal carotid dissection compared with those who had vertebral dissection by mean National Institutes of Health Stroke Scale (NIHSS) score on admission (8 versus 3). Only limited systematic data are available regarding long-term outcomes of dissection. Complete or excellent recovery occurs in 70 to 85 percent of patients with extracranial dissection, with major disabling deficits in 10 to 25 percent, and death in 5 to 10 percent of cases [38,58]. In observational studies, factors associated with poor functional outcome after cervical artery dissection include a high NIHSS score at onset, arterial occlusion, and older age [58-61]. Quality of life may be impaired in almost half of long-term survivors after dissection [62]. Recurrence of dissection The recurrence rate of cervical and intracranial artery dissection, with or without symptoms, is uncertain, and available data are inconsistent. In the CADISP study, which retrospectively and prospectively recruited 982 patients with cervical artery dissection, the recurrence rate for extracranial cervical dissection at three months was 2 percent [57]. Even higher rates were reported by a single-center study of 232 patients with cervical artery dissection who were followed clinically and with serial imaging for at least one year. Over the course of the study, there were 46 new dissections affecting 39 patients (16 percent). Recurrent dissection was detected within one month of the initial event in 9 percent, and beyond one month until up to eight years after the initial event in another 7 percent [63]. Most initial dissections were linked to ischemic stroke, but the majority of recurrent dissections were either asymptomatic or associated with purely local symptoms. Recurrent dissection may affect several vessels at once, even when preceded by initial dissection isolated to one artery [63,64]. Although data are limited, rare patients with familial dissection tend to be young (mean age 36 years) and are probably at high risk for recurrent or multiple dissection [65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 10/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute management of TIA or ischemic stroke For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to stroke management should be rigorously followed. All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. (See 'General management' above and 'Reperfusion therapy for eligible patients' above and "Approach to reperfusion therapy for acute ischemic stroke".) Choice of antithrombotic therapy for secondary ischemic stroke prevention Beyond the hyperacute period of acute stroke, antithrombotic therapy with either anticoagulation or antiplatelet drugs is accepted treatment for prevention of new or recurrent ischemic symptoms due to extracranial artery dissection, although there is controversy regarding the choice between the two. (See 'Choosing between antiplatelet and anticoagulation therapy' above.) Ischemia due to extracranial dissection For patients with acute ischemic stroke or TIA caused by extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy, while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests (but does not establish) that there no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection, although it is likely that anticoagulation is associated with a higher risk of hemorrhagic events. (See 'Extracranial dissection' above.) Nonischemic local symptoms due to extracranial dissection For patients with nonischemic local symptoms caused by extracranial cervical dissection, we suggest antiplatelet therapy for prevention of ischemic stroke (Grade 2C). (See 'Nonischemic local symptoms' above.) Ischemia due to intracranial dissection For patients who have ischemic stroke or TIA caused by intracranial dissection, we suggest antiplatelet therapy rather than https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 11/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate anticoagulation (Grade 2C). (See 'Intracranial dissection' above.) Initiating therapy The timing and suggested dosing for starting antiplatelet or anticoagulant therapy is detailed in the sections above. (See 'Starting antiplatelet therapy' above and 'Starting anticoagulation therapy' above.) Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361.

Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361. 27. Markus HS, Levi C, King A, et al. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results. JAMA Neurol 2019; 76:657. 28. Engelter ST, Traenka C, Gensicke H, et al. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol 2021; 20:341. 29. Kasner SE. Antithrombotic therapy for cervical arterial dissection. Lancet Neurol 2021; 20:328. 30. Kennedy F, Lanfranconi S, Hicks C, et al. Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. Neurology 2012; 79:686. 31. Chowdhury MM, Sabbagh CN, Jackson D, et al. Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. Eur J Vasc Endovasc Surg 2015; 50:148. 32. Metso TM, Metso AJ, Helenius J, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke 2007; 38:1837. 33. Arauz A, M rquez JM, Artigas C, et al. Recanalization of vertebral artery dissection. Stroke 2010; 41:717. 34. Baracchini C, Tonello S, Meneghetti G, Ballotta E. Neurosonographic monitoring of 105 spontaneous cervical artery dissections: a prospective study. Neurology 2010; 75:1864. 35. Larsson SC, King A, Madigan J, et al. Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review. Neurology 2017; 88:646. 36. Manabe H, Yonezawa K, Kato T, et al. Incidence of intracranial arterial dissection in non- emergency outpatients complaining of headache: preliminary investigation with MRI/MRA examinations. Acta Neurochir Suppl 2010; 107:41. 37. Nedeltchev K, Bickel S, Arnold M, et al. R2-recanalization of spontaneous carotid artery dissection. Stroke 2009; 40:499. 38. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009; 8:668. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 15/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 39. Arauz A, Hoyos L, Espinoza C, et al. Dissection of cervical arteries: Long-term follow-up study of 130 consecutive cases. Cerebrovasc Dis 2006; 22:150. 40. Touz E, Gauvrit JY, Moulin T, et al. Risk of stroke and recurrent dissection after a cervical artery dissection: a multicenter study. Neurology 2003; 61:1347. 41. Donas KP, Mayer D, Guber I, et al. Endovascular repair of extracranial carotid artery dissection: current status and level of evidence. J Vasc Interv Radiol 2008; 19:1693. 42. Ansari SA, Thompson BG, Gemmete JJ, Gandhi D. Endovascular treatment of distal cervical and intracranial dissections with the neuroform stent. Neurosurgery 2008; 62:636. 43. Ecker RD, Levy EI, Hopkins LN. Acute neuroform stenting of a symptomatic petrous dissection. J Invasive Cardiol 2007; 19:E137. 44. Cohen JE, Leker RR, Gotkine M, et al. Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making. Stroke 2003; 34:e254. 45. Biondi A, Katz JM, Vallabh J, et al. Progressive symptomatic carotid dissection treated with multiple stents. Stroke 2005; 36:e80. 46. Kadkhodayan Y, Jeck DT, Moran CJ, et al. Angioplasty and stenting in carotid dissection with or without associated pseudoaneurysm. AJNR Am J Neuroradiol 2005; 26:2328. 47. Edgell RC, Abou-Chebl A, Yadav JS. Endovascular management of spontaneous carotid artery dissection. J Vasc Surg 2005; 42:854. 48. Kim BM, Shin YS, Kim SH, et al. Incidence and risk factors of recurrence after endovascular treatment of intracranial vertebrobasilar dissecting aneurysms. Stroke 2011; 42:2425. 49. M ller BT, Luther B, Hort W, et al. Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980. 50. Chiche L, Praquin B, Koskas F, Kieffer E. Spontaneous dissection of the extracranial vertebral artery: indications and long-term outcome of surgical treatment. Ann Vasc Surg 2005; 19:5. 51. Ono H, Nakatomi H, Tsutsumi K, et al. Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation. Stroke 2013; 44:126. 52. Debette S, Compter A, Labeyrie MA, et al. Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection. Lancet Neurol 2015; 14:640. 53. Mizutani T, Aruga T, Kirino T, et al. Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 1995; 36:905. 54. Bond KM, Krings T, Lanzino G, Brinjikji W. Intracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history. J Neuroradiol 2021; 48:176. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 16/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 55. Paciaroni M, Bogousslavsky J. Cerebrovascular complications of neck manipulation. Eur Neurol 2009; 61:112. 56. Reuter U, H mling M, Kavuk I, et al. Vertebral artery dissections after chiropractic neck manipulation in Germany over three years. J Neurol 2006; 253:724. 57. Debette S, Grond-Ginsbach C, Bodenant M, et al. Differential features of carotid and vertebral artery dissections: the CADISP study. Neurology 2011; 77:1174. 58. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006; 37:2499. 59. Milhaud D, de Freitas GR, van Melle G, Bogousslavsky J. Occlusion due to carotid artery dissection: a more severe disease than previously suggested. Arch Neurol 2002; 59:557. 60. Dziewas R, Konrad C, Dr ger B, et al. Cervical artery dissection clinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003; 250:1179. 61. Traenka C, Grond-Ginsbach C, Goeggel Simonetti B, et al. Artery occlusion independently predicts unfavorable outcome in cervical artery dissection. Neurology 2020; 94:e170. 62. Fischer U, Ledermann I, Nedeltchev K, et al. Quality of life in survivors after cervical artery dissection. J Neurol 2009; 256:443. 63. Kloss M, Grond-Ginsbach C, Ringleb P, et al. Recurrence of cervical artery dissection: An underestimated risk. Neurology 2018; 90:e1372. 64. Dittrich R, Nassenstein I, Bachmann R, et al. Polyarterial clustered recurrence of cervical artery dissection seems to be the rule. Neurology 2007; 69:180. 65. Martin JJ, Hausser I, Lyrer P, et al. Familial cervical artery dissections: clinical, morphologic, and genetic studies. Stroke 2006; 37:2924. Topic 16649 Version 30.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 17/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 18/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 19/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 20/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 21/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial _____ answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes and then to grip and release the non-paretic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. 2 = Performs neither task correctly. made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 22/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. maneuver. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or raise eyebrows and close eyes. Score 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 23/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice 2 = Some effort against gravity; limb and pantomime, but not noxious cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency period but does not hit bed. 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is UN = Amputation or joint fusion, explain:________________ scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 24/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. Comprehension is judged from responses conversation about provided materials difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is hand, repeat, and produce speech. The through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 25/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so articulation of spontaneous speech can be _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify 1 = Visual, tactile, auditory, spatial, or neglect may be obtained during the prior testing. If the patient has a severe visual loss personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; does not recognize own hand or orients to has aphasia but does appear to attend to both sides, the score is normal. The only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 26/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 27/28 7/6/23, 12:25 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Contributor Disclosures David S Liebeskind, MD Consultant/Advisory Boards: Cerenovus [Stroke]; Genentech [Stroke]; Medtronic [Stroke]; Stryker [Stroke]. Speaker's Bureau: Astra-Zeneca [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 28/28

7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral venous thrombosis: Etiology, clinical features, and diagnosis : Jos M Ferro, MD, PhD, Patr cia Canh o, MD, PhD : Scott E Kasner, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 02, 2023. INTRODUCTION Cerebral vein and dural sinus thrombosis (CVT) is less common than most other types of stroke but can be more challenging to diagnose. Due to the widespread use of magnetic resonance imaging (MRI) and rising clinical awareness, CVT is recognized with increasing frequency. In addition, it is now known to have a more varied clinical spectrum than previously realized. Because of its myriad causes and presentations, CVT is a disease that may be encountered not only by neurologists and neurosurgeons but also by emergency clinicians, internists, oncologists, hematologists, obstetricians, pediatricians, and family practitioners. This topic will review the epidemiology, pathogenesis, clinical features, and diagnosis of CVT. Treatment and prognosis are discussed separately. (See "Cerebral venous thrombosis: Treatment and prognosis".) CVT in newborns is also reviewed elsewhere. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Cerebral sinovenous thrombosis'.) EPIDEMIOLOGY The available data suggest that CVT is uncommon [1]. The annual incidence ranges from 1.16 to 2.02 per 100,000 [2-4] and is more common in females than males, with a female-to-male ratio https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 1/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate of 3:1 [5,6]. The imbalance may be due to the increased risk of CVT associated with pregnancy and puerperium and with oral contraceptives [7]. (See 'Acquired risk factors' below.) In adults, CVT affects patients who are younger on average than those with arterial types of stroke. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), the median age of patients with CVT was 37 years [5], and only 8 percent of the patients were older than 65 [8]. Compared with males, females were significantly younger (median age 34 years, versus 42 years for men) [6]. There is a low risk of recurrent CVT and venous thromboembolism after a first CVT, as reviewed separately. (See "Cerebral venous thrombosis: Treatment and prognosis", section on 'Recurrence'.) PATHOGENESIS The pathogenesis of CVT remains incompletely understood because of the high variability in the anatomy of the venous system and the paucity of experiments in animal models of CVT. However, there are at least two different mechanisms that may contribute to the clinical features of CVT ( figure 1) [9]: Thrombosis of cerebral veins or dural sinus obstructs blood drainage from brain tissue, leading to cerebral parenchymal lesions (eg, stroke) or dysfunction and to increased venous and capillary pressure with disruption of the blood-brain barrier. Occlusion of dural sinus resulting in decreased cerebrospinal fluid (CSF) absorption and elevated intracranial pressure. Obstruction of the venous structures ( figure 2) results in increased venous pressure, decreased capillary perfusion pressure, and increased cerebral blood volume. Dilatation of cerebral veins and recruitment of collateral pathways play an important role in the early phases of CVT and may initially compensate for changes in pressure. The increase in venous and capillary pressure leads to blood-brain barrier disruption, causing vasogenic edema, with leakage of blood plasma into the interstitial space. As intravenous pressure continues to increase, localized cerebral edema and venous hemorrhage may occur due to venous or capillary rupture. The increased intravenous pressure may lead to an increase in intravascular pressure and a lowering of cerebral perfusion pressure, resulting in decreased cerebral blood flow (CBF) and failure of energy metabolism. In turn, this allows intracellular entry https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 2/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate of water from failure of the Na+/K+ ATPase pump and consequent cytotoxic edema [10]. Venous infarction and hemorrhage may be confluent (ie, venous hemorrhagic infarction). Advances in understanding the pathophysiology of venous occlusion have been aided by the use of MRI, mainly diffusion-weighted MRI and perfusion-weighted MRI [11-14]. These techniques have demonstrated the coexistence of both cytotoxic and vasogenic edema in patients with CVT [11,13-15]. The other effect of venous thrombosis is impairment of CSF absorption. Normally, CSF absorption occurs in the arachnoid granulations and glymphatic system, which drain CSF into the venous system. Thrombosis of the dural sinuses leads to increased venous pressure, impaired CSF absorption, and consequently elevated intracranial pressure. Elevated intracranial pressure is more frequent if superior sagittal sinus thrombosis is present, but it may also occur with thrombosis of the jugular vein or the lateral sinus. Note that the lateral sinus consists of two segments; the proximal segment is termed the transverse sinus, and the distal segment is termed the sigmoid sinus ( figure 2). RISK FACTORS AND ASSOCIATED CONDITIONS Many conditions are associated with CVT. The major risk factors for CVT in adults can be grouped as transient or permanent ( table 1). The most frequent risk factors for CVT are [1,5]: Prothrombotic conditions, either genetic or acquired Obesity Oral contraceptives Pregnancy and the puerperium Malignancy Infection Head injury and mechanical precipitants In more than 85 percent of adult patients, at least one risk factor for CVT can be identified, most often an inherited or acquired prothrombotic condition [5]. In the Canadian pediatric ischemic stroke registry, a risk factor was identified in 98 percent of the children [16]. A prothrombotic state was found in 41 percent. In infants older than four weeks of age and in children, head and neck disorders, mostly infections and chronic systemic diseases (eg, connective tissue disease, hematologic disorder, and cancer) were common. The most common risk factors in those 65 years old are genetic or acquired thrombophilia, malignancy, and hematologic disorders such as polycythemia [8,17]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 3/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Acquired risk factors The most common acquired risk factors are pregnancy and the puerperium, the use of oral contraceptives, malignancy, and obesity [18,19]. (See "Cerebrovascular disorders complicating pregnancy" and "Combined estrogen-progestin contraception: Side effects and health concerns" and "Risk and prevention of venous thromboembolism in adults with cancer".) In the prospective International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort of 624 adults with CVT, females comprised 75 percent [6]. Furthermore, a sex-specific risk factor (ie, oral contraceptives, pregnancy, puerperium, and hormone replacement therapy) was identified in 65 percent of females. Estrogen receptor modulators, such as tamoxifen, and hormone replacement therapy have been associated with CVT in case reports [20-23]. In an earlier report of the ISCVT cohort, a prothrombotic condition was found in 34 percent of all patients, and a genetic prothrombotic condition was found in 22 percent of all patients [5]. Oral contraceptives The most frequent risk factor for CVT in younger female patients is the use of oral contraceptives [24,25]. Furthermore, the risk for CVT in females using oral contraceptives is increased in the presence of a prothrombotic defect and obesity [25,26]. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.) Chemotherapeutic agents Several medications used to treat cancer (eg, L-asparaginase, all-trans retinoic acid, and cisplatin) may increase the risk of venous thromboembolism including CVT through procoagulant effects. (See "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors'.) Obesity is a risk factor for CVT and other forms of venous thromboembolism. In an observational study of 186 patients with CVT and matched controls, obesity was associated with an elevated risk of CVT for females (adjusted odds ratio [aOR] 3.5, 95% CI 2.0-6.1) but not males (aOR 1.2, 95% CI 0.3-5.3) [26]. The risk was highest for females with obesity using oral contraceptive medications (aOR 29.3, 95% CI 13.5-63.6). (See "Overview of the causes of venous thrombosis", section on 'Obesity'.) Genetic thrombophilia The risk for CVT is influenced by the individual's genetic background [27]. In the presence of some prothrombotic conditions, patients are at an increased risk of developing a CVT when exposed to a precipitant such as head trauma, lumbar puncture, jugular catheter placement, pregnancy, surgery, infection, and drugs. These prothrombotic conditions include the following: Antithrombin deficiency [28,29] Protein C deficiency or protein S deficiency [16,30,31] https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 4/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Factor V Leiden pathologic variant [24,32,33] G20210 A prothrombin gene pathologic variant [24,33-35] Hyperhomocysteinemia [36] In a meta-analysis of case-control studies, with over 200 neonatal and pediatric cases of sinovenous thrombosis (ie, CVT) and 1200 control subjects, the prevalence of factor V Leiden (FVL) variant among cases and controls was 12.8 and 3.6 percent, respectively, and carriers of the FVL variant were significantly more likely to develop CVT (odds ratio [OR] 3.1, 95% CI 1.8-5.5) [37]. Similarly, the prevalence of the prothrombin gene variant among cases and controls was 5.2 and 2.5 percent, respectively, and carriers were significantly more likely to develop CVT (OR 3.1, 95% CI 1.4-6.8). The association of CVT with hyperhomocysteinemia due to genetic variants in methylene tetrahydrofolate reductase (MTHFR) is controversial [27,38,39]. A 2010 meta-analysis of case-control studies found that the frequency of the MTHFR 677C>T polymorphism in adults was similar for 382 patients with CVT compared with 1217 controls (15.7 versus 14.6 percent; OR 1.12, 95% CI 0.8-1.58), suggesting that the MTHFR 677C>T polymorphism is not a risk factor for CVT [40]. In contrast, a 2011 meta-analysis, after controlling for heterogeneity among studies, found that the MTHFR 677C>T polymorphism was associated with CVT (OR 2.30, 95% CI 1.20-4.42) [27]. There is no association of CVT with PAI-1 or protein Z polymorphisms. COVID-19 infection and COVID-19 vaccine-associated thrombosis Several cases of CVT have been observed in the setting of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection, the majority of which occurred in patient without other predisposing risk factors [41]. In a review of 34,331 patients hospitalized with SARS-CoV-2 infection, the frequency of CVT was 0.08 percent (95% CI 0.01-0.5) [41]. The in-hospital mortality was 40 percent. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.) Multiple reports describe thromboembolism including CVT associated with thrombocytopenia among patients immunized with the adenovirus-vector AstraZeneca (ChAdOx1 nCov-19) COVID- 19 and Janssen/Johnson & Johnson (Ad26.COV2.S) COVID-19 vaccines [42-48]. In cohort studies, those with vaccine-induced thrombotic thrombocytopenia (VITT) have been typically younger and less likely to have other thromboembolic risk factors than those with CVT not attributed to VITT [47,49,50]. However, patients with VITT have a higher burden of both intracranial and extracranial venous thromboses [49]. In addition, the clinical presentation is more severe and mortality is higher for those with CVT associated with VITT than other causes of CVT, ranging https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 5/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate from 22 to 47 percent in studies, compared with 3 to 5 percent among those with other causes of CVT [46,47,49-51]. Cases of CVT associated with VITT have typically occurred in patients who are between 5 and 30 days post-vaccination [42-44,52,53]. Some cases occurring after the second dose of the AstraZeneca COVID-19 vaccine have also been reported [54]. The evaluation and management of patients with VITT is discussed in greater detail separately. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".) Other conditions Although infectious causes of CVT were frequently reported in the past, they are responsible for only 6 to 12 percent of cases in modern-era studies of adults with CVT [5,18]. Local infections (eg, involving the ears, sinuses, mouth, face, or neck) are typically responsible, although systemic infection is sometimes the only cause. Head injury and mechanical precipitants are less common causes of CVT [55-57]. Inflammatory diseases are also risk factors for CVT, including systemic lupus erythematosus, Beh et disease, granulomatosis with polyangiitis, thromboangiitis obliterans, inflammatory bowel disease, and sarcoidosis. As with venous thrombosis in other parts of the body, multiple risk factors may be found in about half of adult patients with CVT [5]. In light of this, a thorough search for additional causes should be carried out even when a specific risk factor is identified in a given patient. (See "Overview of the causes of venous thrombosis".) Cryptogenic CVT No underlying etiology or risk factor for CVT is found in a minority of children ( 10 percent) and adults (13 percent) with CVT [8,16,58]. In older adult CVT patients, the proportion of cases without identified risk factors is higher (37 percent) than it is in adults under age 65 (10 percent) [8]. CLINICAL ASPECTS Cerebral vein and dural sinus thrombosis has a highly variable clinical presentation [59,60]. The onset can be acute, subacute, or chronic. CVT most often presents with new headache or as a syndrome of isolated intracranial hypertension. Additional manifestations include focal neurologic deficits, seizures, and/or encephalopathy. Symptoms and signs Symptoms and signs of CVT can be grouped into three major syndromes: https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 6/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Isolated intracranial hypertension syndrome (headache with or without vomiting, papilledema, and visual problems) [61] Focal syndrome (focal deficits, seizures, or both) Encephalopathy (multifocal signs, mental status changes, stupor, or coma) [59,62] Less common presentations include cavernous sinus syndrome, subarachnoid hemorrhage, and multiple cranial nerve palsies. A case of CVT mimicking a transient ischemic attack has also been reported [63]. The clinical symptoms and signs in CVT depend upon several factors, including patient age and sex, the site and number of occluded sinuses and veins, the presence of parenchymal brain lesions, and the interval from CVT onset to presentation. In children, signs of diffuse brain injury, coma, and seizures are the main clinical manifestations, especially in neonates [16]. In older children, the manifestations of CVT resemble those in adults, with headache and hemiparesis [64]. Females are more likely than males to have a headache on presentation and less likely to have a chronic onset of symptoms [6]. Older adults may also have a distinctive presentation; depressed consciousness and mental status changes are more common, while headaches and isolated intracranial hypertension are less frequent than in younger patients [8]. Cerebral edema, venous infarction, and hemorrhagic venous infarction are associated with a more severe syndrome; patients are more likely to be comatose or to have motor deficits, aphasia, and seizures and less likely to present with isolated headache. Headache Headache is the most frequent symptom of CVT. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) cohort, headache was present in 89 percent of patients [5]. Headaches associated with CVT are more frequent in females and young patients than in males or older adults [65]. Headache is usually the first symptom of CVT and can be the only symptom [66] or can precede other symptoms and signs by days or weeks [67]. The features of CVT-related headache are quite variable. Head pain may be localized or diffuse [67]. Headache caused by intracranial hypertension from CVT is typically characterized by severe head pain that worsens with Valsalva maneuvers and with recumbency. The site of the headache has no relationship with the localization of the occluded sinus or the parenchymal lesions [68,69]. Headache onset with CVT is usually gradual, increasing over several days [7]. However, some patients with CVT have sudden explosive onset of severe head pain (ie, thunderclap headache) that mimics subarachnoid hemorrhage [70,71]. (See "Overview of thunderclap headache" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 7/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Headache due to CVT may also resemble migraine with aura [72-74]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults" and "Pathophysiology, clinical features, and diagnosis of migraine in children".) CVT must be included as a possible cause of persisting headache following lumbar puncture, because lumbar puncture can rarely precipitate a CVT. (See "Post dural puncture headache".) Isolated intracranial hypertension syndrome Isolated intracranial hypertension syndrome (ie, headache associated with papilledema or visual problems) accounts for a significant proportion of CVT cases [61]. Visual obscurations may occur, coinciding with bouts of increased headache intensity. Isolated intracranial hypertension is more frequent in patients with a chronic presentation than in those who present acutely [75]. In addition, patients with chronic course or delayed clinical presentation may show papilledema on fundoscopy, a finding that is less frequent in acute cases. (See "Overview and differential diagnosis of papilledema".) Seizures Focal or generalized seizures, including status epilepticus, are more frequent in CVT than in other cerebrovascular disorders. In the ISCVT cohort of 624 patients, seizures at presentation occurred in 39 percent, and seizures after the diagnosis of CVT occurred in 7 percent [76]. In a retrospective cohort of 70 children (including 25 neonates) with CVT, seizures at presentation occurred in 20 of 45 non-neonates (44 percent) [77]. Variables associated with seizures include supratentorial parenchymal brain lesions, sagittal sinus and cortical vein thrombosis, and motor deficits [76]. Encephalopathy Severe cases of CVT can cause disturbances of consciousness and cognitive dysfunction, such as delirium, apathy, a dysexecutive syndrome, multifocal deficits, or seizures. Focal syndrome Weakness with monoparesis or hemiparesis, sometimes bilateral, is the most frequent focal deficit associated with CVT. In the ISCVT cohort, motor weakness was present in 37 percent of patients [5]. Aphasia, in particular of the fluent type, may follow sinus thrombosis, especially when the left lateral sinus is affected. Sensory deficits and visual field defects are less common. Syndromes associated with isolated sinus or vein thrombosis Isolated thrombosis of the different sinuses and veins produces diverse clinical pictures. In cavernous sinus thrombosis, ocular signs dominate the clinical picture with orbital pain, chemosis, proptosis, and oculomotor palsies [78-81]. Isolated cortical vein occlusion produces motor/sensory deficits and seizures [82-84]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 8/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate With sagittal sinus occlusion, motor deficits, bilateral deficits, and seizures are frequent, while presentation as an isolated intracranial hypertension syndrome is infrequent. Patients with isolated lateral sinus thrombosis frequently present with isolated headache or isolated intracranial hypertension [85]. Less often, they may also present with focal deficits or seizures. Aphasia often follows if the left transverse sinus is occluded. Jugular vein or lateral sinus thrombosis may present as isolated pulsating tinnitus [86,87]. Multiple cranial nerve palsies may occur in thrombosis of the lateral sinus, jugular, or posterior fossa veins [88]. When the deep cerebral venous system (ie, the straight sinus and its branches) is occluded, the signs and symptoms of CVT are generally severe, with coma or other alterations in mental status and motor deficits, often bilateral [89-91]. However, more limited thrombosis of the deep venous system can produce relatively mild symptoms [92]. Neuroimaging The neuroimaging features of CVT can include focal areas of edema or venous infarction, hemorrhagic venous infarction, diffuse brain edema, or (rarely) isolated subarachnoid hemorrhage [1]. In patients with CVT, the proportion who present with intracerebral hemorrhage is 30 to 40 percent [93,94]. Small nontraumatic juxtacortical hemorrhages ( image 1), which are located just below the cortex in the white matter and have a diameter of <2 cm, account for up to one-fourth of intracerebral hemorrhages in patients with CVT and are associated with superior sagittal sinus occlusion [95]. In a minority of cases, computed tomography (CT) may demonstrate direct signs of CVT, which include the dense triangle sign, the empty delta sign, and the cord sign, described below (see 'CT' below). Brain MRI in combination with magnetic resonance venography is the most informative technique for demonstrating the presence of dural thrombus, cortical vein thrombosis, and extent of brain injury. The imaging findings of CVT are discussed in greater detail below. (See 'Urgent imaging' below.) DIAGNOSIS In patients with clinically suspected CVT (eg, presenting with new headache, isolated intracranial hypertension syndrome, focal neurologic deficits, seizures, and/or encephalopathy), urgent neuroimaging is necessary as the first step in the diagnostic evaluation. Aside from neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 9/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Diagnostic approach The diagnosis of CVT should be suspected in patients who present with one or more of the following: New-onset headache Headache with features that differ from the usual pattern (eg, progression or change in attack frequency, severity, or clinical features) in patients with a previous primary headache Symptoms or signs of intracranial hypertension Encephalopathy Focal neurologic symptoms and signs, especially those not fitting a specific vascular distribution or those involving multiple vascular territories Seizures In addition, the diagnosis of CVT should be suspected in patients who have atypical neuroimaging features on routine CT or MRI at presentation, such as cerebral infarction that crosses typical arterial boundaries, hemorrhagic infarction, or lobar intracerebral hemorrhage of otherwise unclear origin [1]. In any of these scenarios, suspicion for CVT should be particularly high for patients with known risk factors, including prothrombotic conditions, oral contraceptive use, pregnancy and the puerperium, malignancy, infection, and head injury, even if the initial neuroimaging study (most often a CT) is normal. Urgent imaging For patients with any presentation raising concern for CVT, we recommend urgent neuroimaging with brain MRI and magnetic resonance (MR) venography or with cranial CT with CT venography if MRI is not an option [1]. The clear demonstration of absence of flow and intraluminal venous thrombus by CT or MRI is the most important finding for confirming the diagnosis. However, these findings are not always evident, and the diagnosis may rest on imaging features demonstrated by MR venography or CT venography showing only absence of flow in a venous sinus or cortical vein. A number of normal anatomic variants may mimic sinus thrombosis, including sinus atresia, sinus hypoplasia, asymmetric sinus drainage, and normal sinus filling defects associated with arachnoid granulations or intrasinus septa [1]. For example, a study of 100 subjects (without CVT) with normal brain MRI found artifactual transverse sinus flow gaps on MR venography (in nondominant or codominant but not in dominant transverse sinuses) in 31 percent [96]. Another report of 100 subjects without venous pathology found asymmetric lateral sinuses in 49 percent and partial or total absence of one lateral sinus in 20 percent [97]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 10/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate CT Head CT is normal in up to 30 percent of CVT cases, and most of the findings are nonspecific [59]. However, CT is often the first investigation to be performed in clinical practice, and it is useful to rule out other acute or subacute cerebral disorders. In about one-third of cases, CT demonstrates direct signs of CVT, including the following ( image 2 and image 3) [59,98-100]: The cord sign is a curvilinear or linear hyperdensity from a thrombosed cortical vein typically found over the cerebral cortex. The dense triangle sign is a triangular or round hyperdensity reflecting a thrombosed sinus on a cross-section view. The empty delta sign (also called the empty triangle or negative delta sign) is a triangular pattern of contrast enhancement surrounding a central region without contrast enhancement found in the posterior part of the superior sagittal sinus on head CT performed with contrast. Indirect signs of CVT on head CT are more frequent. These can include intense contrast enhancement of falx and tentorium, dilated transcerebral veins, small ventricles, and parenchyma abnormalities. In addition, associated brain lesions may be depicted in 60 to 80 percent of patients with CVT. These may be hemorrhagic or nonhemorrhagic: Hemorrhagic lesions include intracerebral hemorrhage, hemorrhagic infarcts, or rarely (<1 percent) subarachnoid hemorrhage usually limited to the convexity [101-103]. Nonhemorrhagic lesions include focal areas of hypodensity caused by vasogenic edema or venous infarction, usually not respecting the arterial boundaries, as well as diffuse brain edema. With serial imaging, some lesions may disappear ("vanishing infarcts"), and new lesions may appear. CT venography Head CT is often normal in patients with CVT, and MRI techniques for confirming the diagnosis are not readily available in some hospitals and geographic locations. In this situation, we suggest CT venography as a useful alternative to MR venography or digital subtraction angiography for the diagnosis of CVT, in agreement with guidelines from the United States and Europe [1,104]. The overall accuracy of head CT combined with CT venography is 90 to 100 percent, depending on the occlusion site [105]. Compared with digital subtraction intra- arterial angiography, the combination of head CT and CT venography has a sensitivity and specificity of 95 and 91 percent [106]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 11/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate CT venography gives a good visualization of the major dural sinuses [107,108], is readily available, and is quicker than MRI. It can be used for patients who have contraindications to MRI [1]. When combined with head CT, it may demonstrate filling defects, sinus wall enhancement, and increased collateral venous drainage ( image 4) [106,109,110]. CT venography is often particularly helpful in subacute or chronic CVT because it can demonstrate heterogeneous density in thrombosed venous sinuses. However, its use may be limited because of low resolution of the deep venous system and cortical veins, the risk of contrast reactions, and radiation exposure [105,111,112]. MRI MRI using gradient echo T2* susceptibility-weighted sequences in combination with MR venography is the most sensitive imaging method for demonstrating the thrombus and the occluded dural sinus or vein ( image 4 and image 5) [15,111,113-116]. The characteristics of the MRI signal depend on the age of the thrombus [117,118]: In the first five days, the thrombosed sinuses appear isointense on T1-weighted images and hypointense on T2-weighted images. Beyond five days, venous thrombus becomes more apparent because signal is increased on both T1- and T2-weighted images. After the first month, thrombosed sinuses exhibit a variable pattern of signal, which may appear isointense. On T2*-weighted gradient echo and T2* susceptibility-weighted MRI sequences, the acute thrombus can be directly visualized as an area of hypointensity in the engorged sinus or cortical vein ( image 5) [84,113,119,120]. In addition, a chronically thrombosed sinus may also demonstrate low signal on these sequences. Limited data from a series of 28 patients with CVT suggest that the presence of hyperintensities in the veins or sinuses on diffusion-weighted MRI sequences predicts a low recanalization rate [121]. Parenchymal brain lesions secondary to venous occlusion, including brain swelling, vasogenic edema, or venous infarction, are hypointense or isointense on T1-weighted MRI and hyperintense on T2-weighted MRI ( image 6). Venous congestion may show reversible reduced diffusivity on diffusion-weighted MRI sequences. Agreement among observers for the diagnosis of CVT with MRI varies with the location of sinus or vein thrombosis. It is good or very good for most of the occluded sinus and veins, moderate to very good for the left lateral sinus and straight sinus, and poor to good for the cortical veins [122]. The diagnosis of isolated cortical vein thrombosis can be difficult, but the use of T2* https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 12/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate susceptibility-weighted MRI may enable a diagnosis of isolated cortical vein thrombosis by demonstrating thrombus as an area of hypointensity [84,113,119]. MR venography MR venography, usually performed using the time-of-flight (TOF) technique, is useful for demonstrating absence of flow in cerebral venous sinuses, though interpretation can be confounded by normal anatomic variants such as sinus hypoplasia and asymmetric flow [1]. Other MR techniques may be useful to distinguish these variants from venous thrombosis. Contrast-enhanced MR venography can provide better visualization of cerebral venous channels, and gradient echo or susceptibility-weighted sequences will show normal signal in a hypoplastic sinus and abnormally low signal in the presence of thrombus. A chronically thrombosed hypoplastic sinus will show absence of flow on two-dimensional TOF MR venography and enhancement on contrast-enhanced MRI and MR venography. Conventional angiography Cerebral digital subtraction angiography is typically reserved for cases when the clinical suspicion for CVT is high but CT venography or MR venography are inconclusive [1]. Angiography may be helpful for making this diagnosis by showing the sudden termination of a cortical vein surrounded by dilated and tortuous collateral "corkscrew veins" or by the filling of a cortical vein that was not apparent on an earlier angiographic study during the acute phase of CVT. Other typical signs of CVT on angiography are nonvisualization of all or part of a venous sinus, delayed venous emptying with pathologically increased collaterals, and reversal of venous flow. As with MR and CT venography, conventional cerebral angiography may be limited by potential pitfalls. Anatomic variations, such as variability of number and location of cortical veins, hypoplasia of the anterior part of the superior sagittal sinus, duplication of the superior sagittal sinus, and hypoplasia or aplasia of the transverse sinuses, may make the diagnosis of CVT by all types of angiography difficult [59]. While the interobserver agreement for a diagnosis of CVT is not perfect, the combination of conventional contrast angiography plus brain MRI has a higher interobserver agreement than angiography alone (94 versus 62 percent) [123]. Laboratory tests Aside from neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. We suggest routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time for patients with suspected CVT, in agreement with guidelines from the American Heart Association/American Stroke Association [1]. The findings from these tests may suggest the presence of conditions that contribute to the development of CVT such as an underlying hypercoagulable state, infection, or inflammatory process. The guidelines recommend screening for these and other potential prothrombotic conditions that may predispose to CVT, including use of contraceptives, at the initial clinical presentation. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 13/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The utility of D-dimer testing and lumbar puncture is reviewed in the following sections. D-dimer An elevated plasma D-dimer level supports the diagnosis of CVT, but a normal D- dimer does not exclude the diagnosis in patients with suggestive symptoms and predisposing factors. The potential utility of D-dimer for the diagnosis of CVT is illustrated by the following observations: A 2012 meta-analysis included 14 studies that evaluated D-dimer in 1134 patients for the diagnosis of suspected or confirmed CVT [124]. In seven studies that evaluated patients with suspected CVT, D-dimer was elevated in 145 of 155 patients in whom CVT was confirmed and was normal in 692 of 771 patients in whom CVT was ruled out, yielding a sensitivity and specificity of 94 and 90 percent, respectively. D-dimer performed less well in seven studies that enrolled subjects with already-confirmed CVT; the sensitivity and specificity were 89 and 83 percent, respectively. The sensitivity of D-dimer for CVT was also lower in patients with isolated headache as the presenting symptom (82 percent), in those with subacute or chronic clinical presentations of CVT (83 percent), and in those with a single affected venous sinus (84 percent). In a subsequent study of 233 patients with suspected CVT and symptom onset of less than seven days, D-dimer demonstrated a sensitivity and specificity of 94 and 98 percent, respectively, for predicting CVT [125]. Thus, D-dimer measurement may have some value as a diagnostic screening tool for the assessment of patients with possible CVT. However, a normal D-dimer value cannot exclude CVT, especially in patients with isolated headache or with thrombosis of a single sinus. Individual assays used to measure D-dimer vary, but it is reasonable to use the same threshold levels as used in diagnostic protocols for deep venous thrombosis (eg, D-dimer >500 ng/mL of fibrinogen equivalent units). (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'D-dimer'.) Lumbar puncture Lumbar puncture may be useful to exclude meningitis in patients with CVT who present with isolated intracranial hypertension, a syndrome that may account for up to 25 percent of all patients with CVT [5]. In addition, lumbar puncture is valuable in such patients to measure and decrease cerebrospinal fluid (CSF) pressure when vision is threatened. However, in the absence of suspicion for meningitis, CSF analysis is usually not helpful diagnostically for patients with focal neurologic findings and neuroimaging confirmation of CVT [1]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 14/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The CSF abnormalities in CVT are nonspecific and may include a lymphocytic pleocytosis, elevated red blood cell count, and elevated protein; these abnormalities are present in 30 to 50 percent of patients with CVT [60,61]. Performing a lumbar puncture is not harmful in patients with CVT, as suggested by the findings of a study that analyzed 624 patients with CVT and identified 224 who had lumbar puncture [126]. The groups with and without lumbar puncture did not differ on any of the outcome measures, which were neurologic worsening within 30 days of CVT onset, acute death, complete recovery at six months, or death or dependency at six months. Nevertheless, lumbar puncture is contraindicated in patients with large brain lesions because they have an increased risk of herniation. Evaluation for thrombophilic state Searching for a thrombophilic state, either genetic or acquired, should be done for patients with CVT who have a high pretest probability of severe thrombophilia, a category that includes those with a personal and/or family history of venous thrombosis, CVT at a young age, and CVT in the absence of a transient or permanent risk factor ( table 1) [104]. When appropriate, screening should include: Antithrombin Protein C Protein S Factor V Leiden

to very good for the left lateral sinus and straight sinus, and poor to good for the cortical veins [122]. The diagnosis of isolated cortical vein thrombosis can be difficult, but the use of T2* https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 12/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate susceptibility-weighted MRI may enable a diagnosis of isolated cortical vein thrombosis by demonstrating thrombus as an area of hypointensity [84,113,119]. MR venography MR venography, usually performed using the time-of-flight (TOF) technique, is useful for demonstrating absence of flow in cerebral venous sinuses, though interpretation can be confounded by normal anatomic variants such as sinus hypoplasia and asymmetric flow [1]. Other MR techniques may be useful to distinguish these variants from venous thrombosis. Contrast-enhanced MR venography can provide better visualization of cerebral venous channels, and gradient echo or susceptibility-weighted sequences will show normal signal in a hypoplastic sinus and abnormally low signal in the presence of thrombus. A chronically thrombosed hypoplastic sinus will show absence of flow on two-dimensional TOF MR venography and enhancement on contrast-enhanced MRI and MR venography. Conventional angiography Cerebral digital subtraction angiography is typically reserved for cases when the clinical suspicion for CVT is high but CT venography or MR venography are inconclusive [1]. Angiography may be helpful for making this diagnosis by showing the sudden termination of a cortical vein surrounded by dilated and tortuous collateral "corkscrew veins" or by the filling of a cortical vein that was not apparent on an earlier angiographic study during the acute phase of CVT. Other typical signs of CVT on angiography are nonvisualization of all or part of a venous sinus, delayed venous emptying with pathologically increased collaterals, and reversal of venous flow. As with MR and CT venography, conventional cerebral angiography may be limited by potential pitfalls. Anatomic variations, such as variability of number and location of cortical veins, hypoplasia of the anterior part of the superior sagittal sinus, duplication of the superior sagittal sinus, and hypoplasia or aplasia of the transverse sinuses, may make the diagnosis of CVT by all types of angiography difficult [59]. While the interobserver agreement for a diagnosis of CVT is not perfect, the combination of conventional contrast angiography plus brain MRI has a higher interobserver agreement than angiography alone (94 versus 62 percent) [123]. Laboratory tests Aside from neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. We suggest routine blood studies consisting of a complete blood count, chemistry panel, prothrombin time, and activated partial thromboplastin time for patients with suspected CVT, in agreement with guidelines from the American Heart Association/American Stroke Association [1]. The findings from these tests may suggest the presence of conditions that contribute to the development of CVT such as an underlying hypercoagulable state, infection, or inflammatory process. The guidelines recommend screening for these and other potential prothrombotic conditions that may predispose to CVT, including use of contraceptives, at the initial clinical presentation. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 13/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The utility of D-dimer testing and lumbar puncture is reviewed in the following sections. D-dimer An elevated plasma D-dimer level supports the diagnosis of CVT, but a normal D- dimer does not exclude the diagnosis in patients with suggestive symptoms and predisposing factors. The potential utility of D-dimer for the diagnosis of CVT is illustrated by the following observations: A 2012 meta-analysis included 14 studies that evaluated D-dimer in 1134 patients for the diagnosis of suspected or confirmed CVT [124]. In seven studies that evaluated patients with suspected CVT, D-dimer was elevated in 145 of 155 patients in whom CVT was confirmed and was normal in 692 of 771 patients in whom CVT was ruled out, yielding a sensitivity and specificity of 94 and 90 percent, respectively. D-dimer performed less well in seven studies that enrolled subjects with already-confirmed CVT; the sensitivity and specificity were 89 and 83 percent, respectively. The sensitivity of D-dimer for CVT was also lower in patients with isolated headache as the presenting symptom (82 percent), in those with subacute or chronic clinical presentations of CVT (83 percent), and in those with a single affected venous sinus (84 percent). In a subsequent study of 233 patients with suspected CVT and symptom onset of less than seven days, D-dimer demonstrated a sensitivity and specificity of 94 and 98 percent, respectively, for predicting CVT [125]. Thus, D-dimer measurement may have some value as a diagnostic screening tool for the assessment of patients with possible CVT. However, a normal D-dimer value cannot exclude CVT, especially in patients with isolated headache or with thrombosis of a single sinus. Individual assays used to measure D-dimer vary, but it is reasonable to use the same threshold levels as used in diagnostic protocols for deep venous thrombosis (eg, D-dimer >500 ng/mL of fibrinogen equivalent units). (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity", section on 'D-dimer'.) Lumbar puncture Lumbar puncture may be useful to exclude meningitis in patients with CVT who present with isolated intracranial hypertension, a syndrome that may account for up to 25 percent of all patients with CVT [5]. In addition, lumbar puncture is valuable in such patients to measure and decrease cerebrospinal fluid (CSF) pressure when vision is threatened. However, in the absence of suspicion for meningitis, CSF analysis is usually not helpful diagnostically for patients with focal neurologic findings and neuroimaging confirmation of CVT [1]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 14/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The CSF abnormalities in CVT are nonspecific and may include a lymphocytic pleocytosis, elevated red blood cell count, and elevated protein; these abnormalities are present in 30 to 50 percent of patients with CVT [60,61]. Performing a lumbar puncture is not harmful in patients with CVT, as suggested by the findings of a study that analyzed 624 patients with CVT and identified 224 who had lumbar puncture [126]. The groups with and without lumbar puncture did not differ on any of the outcome measures, which were neurologic worsening within 30 days of CVT onset, acute death, complete recovery at six months, or death or dependency at six months. Nevertheless, lumbar puncture is contraindicated in patients with large brain lesions because they have an increased risk of herniation. Evaluation for thrombophilic state Searching for a thrombophilic state, either genetic or acquired, should be done for patients with CVT who have a high pretest probability of severe thrombophilia, a category that includes those with a personal and/or family history of venous thrombosis, CVT at a young age, and CVT in the absence of a transient or permanent risk factor ( table 1) [104]. When appropriate, screening should include: Antithrombin Protein C Protein S Factor V Leiden Prothrombin G20210A pathologic variant Lupus anticoagulant, anticardiolipin, and anti-beta2 glycoprotein-I antibodies Homocysteine Acute thrombosis can transiently reduce levels of antithrombin, protein C, and protein S, so the utility of testing for these disorders in the acute phase of CVT is limited. In practice, it is preferable to test for protein C, protein S, and antithrombin at least two weeks after oral anticoagulation has been discontinued, since warfarin therapy reduces measurements of protein C and protein S and may raise plasma antithrombin concentrations into the normal range in patients with hereditary antithrombin deficiency. It is possible to test for protein C and protein S levels while receiving heparin therapy, which does not alter plasma protein C or protein S concentrations. However, testing for antithrombin should be performed when off heparin, which can lower antithrombin levels. (See "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency".) No underlying etiology or risk factor for CVT is found in approximately 13 percent of adult patients. However, it is important to continue searching for a cause even after the acute phase of https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 15/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate CVT, as some patients may have a condition such as the antiphospholipid syndrome, polycythemia, thrombocythemia, malignancy, or inflammatory bowel disease that is discovered weeks or months after the acute phase. (See 'Risk factors and associated conditions' above.) If abnormal results are found in assays for lupus anticoagulant, anticardiolipin, or anti-beta2 glycoprotein-I antibodies, testing should be repeated at least 12 weeks later, as the diagnosis of antiphospholipid syndrome requires two positive determinations of these biomarkers. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.) An evaluation for paroxysmal nocturnal hemoglobinuria should be pursued if the complete blood count shows unexplained hemolytic anemia, iron deficiency, or pancytopenia. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.) In patients older than 40 years without identified etiology, we suggest searching for an occult malignancy. In patients with sepsis or with fever and no obvious cause of infection, we recommend performing a lumbar puncture. DIFFERENTIAL DIAGNOSIS The clinical presentation of CVT can be nonspecific (eg, headache, seizure, encephalopathy) and the cause may not be apparent on initial routine neuroimaging studies. For patients presenting with symptoms and signs of isolated intracranial hypertension syndrome (headache with or without vomiting, papilledema, and visual problems), the main considerations in the differential are idiopathic intracranial hypertension (pseudotumor cerebri) and meningitis. Other conditions associated with elevated intracranial pressure (eg, intracranial mass lesions from tumor or abscess) are usually apparent on neuroimaging with CT or MRI. If neuroimaging reveals no structural intracranial lesion responsible for intracranial hypertension, a lumbar puncture is indicated with measurement of opening pressure and cerebrospinal fluid for analysis. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".) For patients presenting with a focal neurologic syndrome (eg, focal deficits, seizures, or both) the differential is broad and includes other vascular etiologies (eg, intracerebral hemorrhage from a variety of other causes, subdural hemorrhage, ischemic stroke), infection (eg, meningitis, abscess), and tumor. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 16/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate For patients presenting with encephalopathy (eg, multifocal signs, mental status changes, stupor, or coma), the differential includes infection (eg, bacterial and viral meningoencephalitis), inflammation (eg, paraneoplastic and autoimmune encephalitis), demyelination (eg, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorders), and toxic and metabolic disturbances. For patients presenting with thunderclap headache, which is rare in CVT, the differential ( table 2) includes subarachnoid hemorrhage, other types of intracranial hemorrhage, reversible cerebral vasoconstriction syndromes (RCVS), cervical artery dissection, viral and bacterial meningitis, acute complicated sinusitis, spontaneous intracranial hypotension, ischemic stroke, acute hypertensive crisis, third ventricular colloid cyst, and pituitary apoplexy. If initial neuroimaging is nondiagnostic, patients with thunderclap headache should have lumbar puncture with measurement of opening pressure and cerebrospinal fluid analysis to exclude subarachnoid hemorrhage and meningitis ( algorithm 1). If lumbar puncture is also nondiagnostic, imaging of the cerebral circulation is necessary, preferably with magnetic resonance angiography/venography. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Reversible cerebral vasoconstriction syndrome" and "Overview of thunderclap headache".) For patients during pregnancy or puerperium, preeclampsia or eclampsia are diagnostic considerations with any of the presentations listed above or otherwise when presenting with ischemic stroke or intracerebral hemorrhage. (See "Cerebrovascular disorders complicating pregnancy".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Epidemiology and risk factors Cerebral venous thrombosis (CVT) is uncommon, with an estimated incidence of <2.5 per 100,000 annually. Among young adults, CVT is more common in females than males. The mean age of onset is 39 years old. (See 'Epidemiology' above.) https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 17/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The major risk factors for CVT in adults ( table 1) are prothrombotic (hypercoagulable) conditions, oral contraceptives, pregnancy and the puerperium, malignancy, obesity, infection, head injury, and mechanical precipitants. (See 'Risk factors and associated conditions' above.) Clinical features The clinical presentation of CVT is highly variable. The onset can be acute, subacute, or chronic. Headache (of gradual, acute, or thunderclap onset) is the most frequent symptom, occurring in almost 90 percent of patients, and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, and encephalopathy with altered mental status or coma. (See 'Clinical aspects' above.) Neuroimaging features Parenchymal brain lesions, including brain swelling, edema, venous infarction, or hemorrhagic venous infarction, may occur secondary to venous occlusion. (See 'Neuroimaging' above.) Head CT scan is normal in up to 30 percent of CVT cases, and most of the findings with CVT are nonspecific. However, in about one-third of patients, CT demonstrates direct signs of CVT, which include the cord sign, the dense triangle sign, and the empty delta sign ( image 2 and image 3). CT venography may demonstrate filling defects, sinus wall enhancement, and increased collateral venous drainage and is an alternative to magnetic resonance (MR) venography ( image 4 and image 2). (See 'CT' above and 'CT venography' above.) Brain MRI along with MR venography is the most informative technique for demonstrating the presence of dural thrombus, cortical vein thrombosis, and the extent of brain injury ( image 6 and image 5). (See 'MRI' above and 'MR venography' above.) Diagnosis The combination of an abnormal signal in a venous sinus on brain MRI and the corresponding absence of flow on MR venography confirms the diagnosis of CVT. However, these findings are not always evident, and the diagnosis may rest on imaging features showing only absence of flow in a venous sinus or cortical vein. Other than neuroimaging, there is no simple confirmatory laboratory test that can confidently rule out CVT in the acute phase of the disease. (See 'Diagnosis' above.) Evaluation for underlying thrombophilia Screening for thrombophilia should be done for patients with CVT who have a high pretest probability for severe thrombophilia, a https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 18/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate category that includes those with a personal and/or family history of venous thrombosis, CVT at a young age, and CVT in the absence of a transient or permanent risk factor ( table 1). (See 'Evaluation for thrombophilic state' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Saposnik G, Barinagarrementeria F, Brown RD Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:1158. 2. Coutinho JM, Zuurbier SM, Aramideh M, Stam J. 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AJNR Am J Neuroradiol 2007; 28:946. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 25/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate 106. Wetzel SG, Kirsch E, Stock KW, et al. Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. AJNR Am J Neuroradiol 1999; 20:249. 107. Ozsvath RR, Casey SO, Lustrin ES, et al. Cerebral venography: comparison of CT and MR projection venography. AJR Am J Roentgenol 1997; 169:1699. 108. Khandelwal N, Agarwal A, Kochhar R, et al. Comparison of CT venography with MR venography in cerebral sinovenous thrombosis. AJR Am J Roentgenol 2006; 187:1637. 109. Casey SO, Alberico RA, Patel M, et al. Cerebral CT venography. Radiology 1996; 198:163. 110. Majoie CB, van Straten M, Venema HW, den Heeten GJ. Multisection CT venography of the dural sinuses and cerebral veins by using matched mask bone elimination. AJNR Am J Neuroradiol 2004; 25:787. 111. Leach JL, Fortuna RB, Jones BV, Gaskill-Shipley MF. Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. Radiographics 2006; 26 Suppl 1:S19. 112. Rodallec MH, Krainik A, Feydy A, et al. Cerebral venous thrombosis and multidetector CT angiography: tips and tricks. Radiographics 2006; 26 Suppl 1:S5. 113. Selim M, Fink J, Linfante I, et al. Diagnosis of cerebral venous thrombosis with echo-planar T2*-weighted magnetic resonance imaging. Arch Neurol 2002; 59:1021. 114. Meckel S, Reisinger C, Bremerich J, et al. Cerebral venous thrombosis: diagnostic accuracy of combined, dynamic and static, contrast-enhanced 4D MR venography. AJNR Am J Neuroradiol 2010; 31:527. 115. Rizzo L, Crasto SG, Rud R, et al. Cerebral venous thrombosis: role of CT, MRI and MRA in the emergency setting. 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Stroke 2004; 35:99. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 26/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate 122. Ferro JM, Morgado C, Sousa R, Canh o P. Interobserver agreement in the magnetic resonance location of cerebral vein and dural sinus thrombosis. Eur J Neurol 2007; 14:353. 123. de Bruijn SF, Majoie CB, Koster PA, et al. Interobserver agreement for MR-imaging and conv entional angiography in the diagnosis of cerebral venous thrombosis. In: Cerebral venous si nus thrombosis. Clinical and epidemiological studies, de Bruijn SF (Ed), Thesis, Amsterdam 1 998. p.23. 124. Dentali F, Squizzato A, Marchesi C, et al. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2012; 10:582. 125. Meng R, Wang X, Hussain M, et al. Evaluation of plasma D-dimer plus fibrinogen in predicting acute CVST. Int J Stroke 2014; 9:166. 126. Canh o P, Abreu LF, Ferro JM, et al. Safety of lumbar puncture in patients with cerebral venous thrombosis. Eur J Neurol 2013; 20:1075. Topic 1103 Version 40.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 27/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS Mechanisms of cerebral venous thrombosis CSF: cerebrospinal fluid. Graphic 80911 Version 3.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 28/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Major cerebral veins and sinuses Graphic 72961 Version 2.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 29/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis

patients. J Neurol 1998; 245:137. 88. Kuehnen J, Schwartz A, Neff W, Hennerici M. Cranial nerve syndrome in thrombosis of the transverse/sigmoid sinuses. Brain 1998; 121 ( Pt 2):381. 89. Crawford SC, Digre KB, Palmer CA, et al. Thrombosis of the deep venous drainage of the brain in adults. Analysis of seven cases with review of the literature. Arch Neurol 1995; 52:1101. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 24/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate 90. Lafitte F, Boukobza M, Guichard JP, et al. Deep cerebral venous thrombosis: imaging in eight cases. Neuroradiology 1999; 41:410. 91. Lacour JC, Ducrocq X, Anxionnat R, et al. [Thrombosis of deep cerebral veins in form adults: clinical features and diagnostic approach]. Rev Neurol (Paris) 2000; 156:851. 92. van den Bergh WM, van der Schaaf I, van Gijn J. The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. Neurology 2005; 65:192. 93. Wasay M, Bakshi R, Bobustuc G, et al. Cerebral venous thrombosis: analysis of a multicenter cohort from the United States. J Stroke Cerebrovasc Dis 2008; 17:49. 94. Girot M, Ferro JM, Canh o P, et al. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke 2007; 38:337. 95. Coutinho JM, van den Berg R, Zuurbier SM, et al. Small juxtacortical hemorrhages in cerebral venous thrombosis. Ann Neurol 2014; 75:908. 96. Ayanzen RH, Bird CR, Keller PJ, et al. Cerebral MR venography: normal anatomy and potential diagnostic pitfalls. AJNR Am J Neuroradiol 2000; 21:74. 97. Zouaoui A, Hidden G. Cerebral venous sinuses: anatomical variants or thrombosis? Acta Anat (Basel) 1988; 133:318. 98. Virapongse C, Cazenave C, Quisling R, et al. The empty delta sign: frequency and significance in 76 cases of dural sinus thrombosis. Radiology 1987; 162:779. 99. Lee EJ. The empty delta sign. Radiology 2002; 224:788. 100. Boukobza M, Crassard I, Bousser MG. When the "dense triangle" in dural sinus thrombosis is round. Neurology 2007; 69:808. 101. Sztajzel R, Coeytaux A, Dehdashti AR, et al. Subarachnoid hemorrhage: a rare presentation of cerebral venous thrombosis. Headache 2001; 41:889. 102. Oppenheim C, Domigo V, Gauvrit JY, et al. Subarachnoid hemorrhage as the initial presentation of dural sinus thrombosis. AJNR Am J Neuroradiol 2005; 26:614. 103. Spitzer C, Mull M, Rohde V, Kosinski CM. Non-traumatic cortical subarachnoid haemorrhage: diagnostic work-up and aetiological background. Neuroradiology 2005; 47:525. 104. Ferro JM, Bousser MG, Canh o P, et al. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology. Eur J Neurol 2017; 24:1203. 105. Linn J, Ertl-Wagner B, Seelos KC, et al. Diagnostic value of multidetector-row CT angiography in the evaluation of thrombosis of the cerebral venous sinuses. AJNR Am J Neuroradiol 2007; 28:946. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 25/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate 106. Wetzel SG, Kirsch E, Stock KW, et al. Cerebral veins: comparative study of CT venography with intraarterial digital subtraction angiography. AJNR Am J Neuroradiol 1999; 20:249. 107. Ozsvath RR, Casey SO, Lustrin ES, et al. Cerebral venography: comparison of CT and MR projection venography. AJR Am J Roentgenol 1997; 169:1699. 108. Khandelwal N, Agarwal A, Kochhar R, et al. Comparison of CT venography with MR venography in cerebral sinovenous thrombosis. AJR Am J Roentgenol 2006; 187:1637. 109. Casey SO, Alberico RA, Patel M, et al. Cerebral CT venography. Radiology 1996; 198:163. 110. Majoie CB, van Straten M, Venema HW, den Heeten GJ. Multisection CT venography of the dural sinuses and cerebral veins by using matched mask bone elimination. AJNR Am J Neuroradiol 2004; 25:787. 111. Leach JL, Fortuna RB, Jones BV, Gaskill-Shipley MF. Imaging of cerebral venous thrombosis: current techniques, spectrum of findings, and diagnostic pitfalls. Radiographics 2006; 26 Suppl 1:S19. 112. Rodallec MH, Krainik A, Feydy A, et al. Cerebral venous thrombosis and multidetector CT angiography: tips and tricks. Radiographics 2006; 26 Suppl 1:S5. 113. Selim M, Fink J, Linfante I, et al. Diagnosis of cerebral venous thrombosis with echo-planar T2*-weighted magnetic resonance imaging. Arch Neurol 2002; 59:1021. 114. Meckel S, Reisinger C, Bremerich J, et al. Cerebral venous thrombosis: diagnostic accuracy of combined, dynamic and static, contrast-enhanced 4D MR venography. AJNR Am J Neuroradiol 2010; 31:527. 115. Rizzo L, Crasto SG, Rud R, et al. Cerebral venous thrombosis: role of CT, MRI and MRA in the emergency setting. Radiol Med 2010; 115:313. 116. Boukobza M, Crassard I, Bousser MG, Chabriat H. MR imaging features of isolated cortical vein thrombosis: diagnosis and follow-up. AJNR Am J Neuroradiol 2009; 30:344. 117. Dormont D, Anxionnat R, Evrard S, et al. MRI in cerebral venous thrombosis. J Neuroradiol 1994; 21:81. 118. Isensee C, Reul J, Thron A. Magnetic resonance imaging of thrombosed dural sinuses. Stroke 1994; 25:29. 119. Fellner FA, Fellner C, Aichner FT, M lzer G. Importance of T2*-weighted gradient-echo MRI for diagnosis of cortical vein thrombosis. Eur J Radiol 2005; 56:235. 120. Idbaih A, Boukobza M, Crassard I, et al. MRI of clot in cerebral venous thrombosis: high diagnostic value of susceptibility-weighted images. Stroke 2006; 37:991. 121. Favrole P, Guichard JP, Crassard I, et al. Diffusion-weighted imaging of intravascular clots in cerebral venous thrombosis. Stroke 2004; 35:99. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 26/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate 122. Ferro JM, Morgado C, Sousa R, Canh o P. Interobserver agreement in the magnetic resonance location of cerebral vein and dural sinus thrombosis. Eur J Neurol 2007; 14:353. 123. de Bruijn SF, Majoie CB, Koster PA, et al. Interobserver agreement for MR-imaging and conv entional angiography in the diagnosis of cerebral venous thrombosis. In: Cerebral venous si nus thrombosis. Clinical and epidemiological studies, de Bruijn SF (Ed), Thesis, Amsterdam 1 998. p.23. 124. Dentali F, Squizzato A, Marchesi C, et al. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. J Thromb Haemost 2012; 10:582. 125. Meng R, Wang X, Hussain M, et al. Evaluation of plasma D-dimer plus fibrinogen in predicting acute CVST. Int J Stroke 2014; 9:166. 126. Canh o P, Abreu LF, Ferro JM, et al. Safety of lumbar puncture in patients with cerebral venous thrombosis. Eur J Neurol 2013; 20:1075. Topic 1103 Version 40.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 27/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS Mechanisms of cerebral venous thrombosis CSF: cerebrospinal fluid. Graphic 80911 Version 3.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 28/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Major cerebral veins and sinuses Graphic 72961 Version 2.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 29/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis Transient risk factors Infection Central nervous system Ear, sinus, mouth, face, and neck Systemic infectious disease Pregnancy and puerperium Dehydration Mechanical precipitants Head injury Lumbar puncture Neurosurgical procedures Jugular catheter occlusion Drugs Oral contraceptives Hormone replacement therapy Androgens Asparaginase Tamoxifen Glucocorticoids Permanent risk factors Inflammatory diseases Systemic lupus erythematosus Beh et disease Granulomatosis with polyangiitis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Malignancy Central nervous system https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 30/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Solid tumour outside central nervous system Hematologic Hematologic condition Prothrombotic states, genetic or acquired Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V Leiden mutation G20210A prothrombin gene mutation Antiphospholipid syndrome Myeloproliferative neoplasms Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Hyperhomocysteinemia Polycythemia, thrombocythemia Severe anemia, including paroxysmal nocturnal hemoglobinuria Central nervous system disorders Dural fistulae Other disorders Congenital heart disease Thyroid disease Graphic 65303 Version 10.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 31/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Small nontraumatic juxtacortical hemorrhage associated with cerebral venous thrombosis A noncontrast head CT scan shows a small juxtacortical hemorrhage, which is a characteristic feature of CVT, particularly with thrombosis of the superior sagittal sinus. CT: computed tomography; CVT: cerebral venous thrombosis. Patr cia Canh o, MD, PhD. Graphic 115378 Version 1.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 32/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Cerebral venous thrombosis on CT imaging (A) Axial head CT image shows hyperdensity in superior sagittal sinus (thick arrow) and adjacent superficial co vein (arrow) consistent with "cord" sign. (B) Coronal head CT image shows dense superior sagittal sinus (thick arrow) consistent with "dense triangle" (C) Sagittal image on CT venography shows long-filling defect (arrows) in superior sagittal sinus. (D) Coronal image on CT venography and magnified inset show "empty-delta" sign (circle). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 33/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Graphic 138275 Version 1.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 34/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Signs of cerebral venous thrombosis on head CT scan (A) Noncontrast head CT shows a hyperdense thrombosed cortical vein (arrow). (B) Noncontrast head CT shows a hyperdensity in the torcula (small arrowhead) and the straight sinus (large arrowhead), a direct sign of dural sinus thrombosis (the dense triangle sign). (C) Head CT shows non-filling of the confluent sinus after contrast injection (the empty delta sign). CT: computed tomography. Graphic 59194 Version 4.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 35/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage due to cerebral sinus thrombosis Noncontrast head CT showing left frontal ICH (arrow) and vasogenic edema (arrowhead) (A). Mid-sagittal plane on CT angiography (B) and MRV (C) showing filling defect (thick arrows) in superior sagittal sinus (B). Subsequent brain MRI with FLAIR (D) and T2* gradient recall echo (E) imaging showing larger ICH (arrows) and associated edema (arrowheads). ICH: intracerebral hemorrhage; CT: computed tomography; MRV: magnetic resonance venography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Courtesy of Glenn A Tung, MD, FACR. Graphic 132274 Version 1.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 36/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Cerebral venous thrombosis on magnetic resonance imaging (A) Axial post-contrast T1-weighted MRI sequence shows filling defect consistent with acute thrombus in superior sagittal sinus (thick arrow) and superior cerebral veins (arrows). (B) Time-of-flight sequence on MR venogram shows absent venous flow in superior sagittal sinus (arrows). (C) Axial susceptibility-weighted MRI sequence shows thick and hypointense thrombus in superior sagittal sinus (thick arrows) and superior cerebral veins (arrows). (D) Follow-up axial susceptibility-weighted MRI sequence 10 months later shows venous recanalization. MRI: magnetic resonance imaging; MR: magnetic resonance. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 37/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Courtesy of Glenn A Tung, MD, FACR. Graphic 138276 Version 1.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 38/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Parenchymal brain lesions associated with cerebral venous thrombosis (A) Bilateral thalamic edema in a case of deep cerebral venous system thrombosis, identified in a T2-weighted FLAIR MRI. (B) T2-weighted FLAIR MRI (coronal view) showing left temporal hemorrhagic infarct due to a thrombosis of left lateral sinus (arrow). FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging. Graphic 82376 Version 4.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 39/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 40/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 41/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Evaluation of thunderclap headache (TCH) https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 42/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 43/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate The evaluation of patients with TCH involves assessing for acute subarachnoid hemorrhage as well as other intracranial and cerebrovascular conditions that may present with these symptoms. TCH: thunderclap headache; CT: computed tomography; SAH: subarachnoid hemorrhage; CTA: computed tomography angiography; MRA: magnetic resonance angiography; RCVS: reversible cerebral vasoconstriction syndrome; ICH: intracerebral hemorrhage; SDH: subdural hematoma; MRV: magnetic resonance venography; CVT: cerebral venous thrombosis; CSF: cerebrospinal fluid; MRI: magnetic resonance imaging; RPLS: reversible posterior leukoencephalopathy syndrome. The sensitivity of head CT to detect SAH is reduced when imaging is obtained >6 hours from onset of TCH, when volume of bleeding is small, and with spinal sources of SAH. In addition to SAH, other causes of TCH that may be identified on neuroimaging include ICH, SDH, ischemic stroke, CVT, spontaneous intracranial hypotension, RPLS, and tumors. Vascular imaging in RCVS may be normal within the first two weeks after symptom onset. Evaluation to exclude other entities and/or repeat imaging may be warranted. Refer to UpToDate topic for additional details. Contraindications to lumbar puncture include cerebral edema/mass effect on head CT, coagulopathy, or suspected epidural spinal abscess. When lumbar pucture is contraindicated, neuroimaging with brain MRI as well as MRA and MRV of the head may be performed as the next step. Refer to UpToDate topics for additional information. If MRI is unavailable or contraindicated, head CT with contrast as well as CTA head/neck and CTV of the head may be performed as alternatives. Graphic 114084 Version 2.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 44/45 7/6/23, 12:26 PM Cerebral venous thrombosis: Etiology, clinical features, and diagnosis - UpToDate Contributor Disclosures Jos M Ferro, MD, PhD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Daiichi-Sankyo [Stroke]. All of the relevant financial relationships listed have been mitigated. Patr cia Canh o, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-venous-thrombosis-etiology-clinical-features-and-diagnosis/print 45/45

7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral venous thrombosis: Treatment and prognosis : Jos M Ferro, MD, PhD, Patr cia Canh o, MD, PhD : Scott E Kasner, MD, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 05, 2022. INTRODUCTION Cerebral venous thrombosis (CVT) is an uncommon but serious disorder. Clinical manifestations can include headache, papilledema, visual loss, focal or generalized seizures, focal neurologic deficits, confusion, altered consciousness, and coma. Many cases have been linked to inherited and acquired thrombophilias, pregnancy, puerperium, infection, and malignancy. Infarctions due to CVT are often hemorrhagic and associated with vasogenic edema. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) Treatment, which is started as soon as the diagnosis is confirmed, consists of reversing the underlying cause when known, control of seizures and intracranial hypertension, and antithrombotic therapy. Anticoagulation is the mainstay of acute and subacute treatment for CVT. This topic will review the prognosis and treatment of CVT. Other aspects of this disorder are discussed separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) ACUTE ANTITHROMBOTIC MANAGEMENT While the overall aim of treatment for CVT is to improve outcome, the immediate goals treatment for CVT are [1-4]: https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 1/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate To recanalize the occluded sinus/vein To prevent the propagation of the thrombus, namely to the bridging cerebral veins To treat the underlying prothrombotic state, in order to prevent venous thrombosis in other parts of the body, particularly pulmonary embolism, and to prevent the recurrence of CVT The main treatment option to achieve these goals is anticoagulation, most commonly using either heparin or low molecular weight heparin (LMWH), as discussed in the next section. Initial anticoagulation Management for most patients For most patients with CVT, we recommend anticoagulation with subcutaneous LMWH or intravenous heparin for adults with symptomatic CVT who have no contraindication. The presence of hemorrhagic venous infarction, intracerebral hemorrhage, or isolated subarachnoid hemorrhage are not contraindications for anticoagulant treatment in CVT. The evidence summarized below (see 'Efficacy' below) suggests that subcutaneous LMWH is more effective than unfractionated heparin (UFH) and is at least as safe. Therefore, we prefer subcutaneous LMWH unless the patient is clinically unstable or invasive interventions such as lumbar puncture or surgery are planned or there is a contraindication to LMWH, such as kidney failure. Treatment for children during the acute phase of CVT is similar to that for adults, but the evidence is weaker since there are no large randomized trials in this age group [5]. Treatment regimens for patients with CVT and heparin-induced thrombocytopenia (HIT) are discussed separately. (See "Management of heparin-induced thrombocytopenia".) The duration of antithrombotic treatment is reviewed below. (See 'Long-term anticoagulation' below.) Management for patients with COVID-19 vaccine-associated thrombosis Case series have described instances of CVT associated with thrombocytopenia in patients who are between 5 and 30 days post-vaccination with an adenovirus-vector ChAdOx1 nCov-19 (AstraZeneca COVID-19) or Ad26.COV2.S (Janssen COVID-19) vaccine [6-11]. These events are due to vaccine-induced autoantibodies against a PF4 platelet antigen, similar to those found in patients with HIT [7]. Treatment for most patients includes anticoagulation (eg, a direct oral anticoagulant, fondaparinux, argatroban) and intravenous immune globulin [12]. Platelet transfusions are typically reserved for cases of clinical relevant bleeding or https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 2/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate preoperatively for procedures associated with a high bleeding risk (eg, neurosurgery) [13,14]. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Management'.) Efficacy Although definitive evidence of effectiveness is lacking, there is a general consensus that anticoagulation with UFH or LMWH is appropriate treatment for acute CVT, based on available data on efficacy as well as rapid onset of effect and reversibility [3]. As an example, more than 80 percent of the patients in the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) were treated with anticoagulation [15]. Two randomized controlled trials of anticoagulation in acute CVT ( table 1) have been published [1,16]. Both have methodologic problems, most importantly their modest sample size. The Berlin trial of intravenous heparin versus placebo was stopped prematurely because of excess mortality in the placebo arm [16]. Patients randomized to the heparin arm had significantly better outcomes on a nonvalidated composite CVT severity scale than those in the placebo group. The average length from onset of symptoms to anticoagulation treatment, four weeks, was exceptionally long. The Dutch trial of subcutaneous nadroparin versus placebo enrolled 60 patients but excluded those who needed lumbar punctures for the relief of increased intracranial pressure [1]. More patients treated with LMWH followed by oral anticoagulation had a favorable outcome than controls, but the difference between the groups was not statistically significant ( table 1). Despite randomization, an imbalance at baseline may have favored the placebo group, as there were more cases with isolated intracranial hypertension in the placebo group and more patients with infarcts in the nadroparin group. A meta-analysis of these two trials found that anticoagulant treatment compared with placebo was associated with a pooled relative risk of death of 0.33 (95% CI 0.08-1.21) and a risk of death or dependency of 0.46 (95% CI 0.16-1.31) [17]. While these data suggest that anticoagulant treatment for CVT may be associated with a reduced risk of death or dependency, the results did not achieve statistical significance. Limited data suggest that LMWH is more effective than UFH and at least as safe for the treatment of CVT: In an open-label trial, 66 adults with CVT were randomly assigned to treatment with LMWH or UFH [18]. In-hospital mortality was significantly lower in the LMWH group (0 versus 19 percent). At three months, the proportion of patients with complete recovery was greater https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 3/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate for the LMWH group (88 versus 63 percent), but the difference was not statistically significant. Small numbers limit the strength of these findings. In a nonrandomized case-control study, a greater proportion of adult patients treated with LMWH (n = 119) compared with UFH (n = 302) were independent at six months (92 versus 84 percent; adjusted odds ratio 2.4, 95% CI 1.0-5.7) [19]. Treatment with LMWH was also associated with slightly lower rates of mortality (6 versus 8 percent) and new intracranial hemorrhage (10 versus 16 percent), but these outcomes were not statistically significant. In a single-center double-blind trial conducted in Iran, 52 cases of CVT were randomly assigned to treatment with LMWH or UFH. There was no difference between the treatment groups in neurological deficits, disability, and mortality [20]. Risk of new intracranial hemorrhage Anticoagulants appear to be safe to use in adult patients with CVT who have associated intracranial hemorrhage, either intracerebral (such as hemorrhagic venous infarction) or subarachnoid [21]. In the Berlin and Dutch trials, 34 of 79 patients (43 percent) had an intracerebral hemorrhage at baseline [1,16]. None of the patients randomized to heparin developed a new intracerebral hemorrhage. In contrast, a new intracerebral hemorrhage developed in three patients randomized to placebo. Case series have also reported relatively low risks of intracranial hemorrhage (<5 percent) and systemic hemorrhage (<2 percent), and such hemorrhages did not influence outcome [22-25]. These findings are in accordance with the hypothesis that hemorrhage in CVT is caused by the probable mechanism of venous outflow blockage and very high intradural and intravenous pressure, leading to both rupture of venules and to hemorrhagic transformation of venous infarctions. Similarly, observational data from case series and subgroup analyses of controlled trials suggest that anticoagulant therapy is safe in children with CVT [5,26-32]. Endovascular treatment For selected adults and children with CVT who develop progressive neurologic worsening despite adequate anticoagulation with subcutaneous LMWH or intravenous heparin, endovascular thrombolysis or mechanical thrombectomy may be a treatment option at centers experienced with these methods. The potential utility of endovascular treatment was described in a 2015 systematic review that identified 42 studies and 185 patients with CVT who were treated with mechanical thrombectomy [33]. Many of the patients were severely ill; pretreatment intracerebral hemorrhage was present in 60 percent and stupor or coma in 47 percent. A variety of devices were used, including the AngioJet rheolytic catheter, balloon angioplasty, stents, and microsnares; concurrent local thrombolysis was used in 71 percent. Overall, a good outcome https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 4/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate was reported for 84 percent of patients; mortality was 12 percent. New or worsened intracerebral hemorrhage affected 10 percent. A high recanalization rate (95 percent; 21 percent partial) was achieved. However, a randomized controlled trial (TO-ACT) [34] failed to show benefit of endovascular treatment (thrombectomy with or without chemical thrombolysis) over anticoagulation in patients with acute CVT and at least one risk factor for clinical deterioration (coma, mental status disturbance, CVT involving the deep venous system, intracerebral hemorrhage). However, as the trial had a modest sample size and was prematurely stopped for futility, the possibility of a small treatment effect in some patients cannot be excluded. Among nearly 50,000 patients with CVT from the United States Nationwide Inpatient Sample 2004 to 2014, mortality was higher for patients with CVT treated with endovascular approaches than medical therapy with anticoagulation, even after adjusting for age, severity of symptoms, and the burden of complications (eg, intracranial hemorrhage, venous infarction, and cerebral edema; odds ratio 1.96, 95% CI 1.6-3.3) [35]. In addition, a 2010 systematic review of 15 studies including 156 patients revealed that despite endovascular treatment, there is a death rate of 9 percent and that local thrombolysis is complicated by a non-negligible rate of major bleeding (10 percent), including 8 percent intracranial hemorrhages, 58 percent of which were fatal [36]. Guideline recommendations Consensus guidelines support the use of anticoagulation for the acute treatment of CVT in adults and children. Guidelines for acute treatment in adults include: The 2017 European Stroke Organization guidelines for the diagnosis and treatment of cerebral venous thrombosis, endorsed by the European Academy of Neurology, recommend heparin at therapeutic dosage to treat adult patients with acute CVT, including those with an intracerebral hemorrhage at baseline [37]. The guidelines suggest using LMWH instead of UFH. No recommendation is made regarding thrombolysis for acute CVT, except that patients who have a pretreatment low risk of poor outcome (eg, absence of coma, mental status disturbance, thrombosis of the deep venous system, intracranial hemorrhage, and malignancy) should not be exposed to aggressive treatments such as thrombolysis. The 2014 American Heart Association (AHA)/American Stroke Association (ASA) guidelines for the prevention of stroke state that anticoagulation is reasonable for patients with acute CVT, even in selected patients with intracranial hemorrhage [38]. The 2011 AHA/ASA guidelines for the diagnosis and management of CVT conclude that initial anticoagulation with adjusted-dose UFH or weight-based LMWH in full anticoagulant doses is reasonable, https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 5/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate followed by vitamin K antagonists, regardless of the presence of intracerebral hemorrhage [39]. Guidelines for acute treatment in children include: The 2012 American Academy of Chest Physicians (ACCP) guidelines recommends initial anticoagulation with UFH or LMWH, followed by LMWH or vitamin K antagonist treatment (ie, warfarin) for a minimum of three months for children with CVT but without significant intracerebral hemorrhage [40]. Anticoagulation for an additional three months is suggested if there is still cerebral sinovenous occlusion or ongoing symptoms (the latter presumably meaning new venous infarcts or increased intracranial pressure) after three months of therapy. For children with CVT who have significant intracerebral hemorrhage, the ACCP suggests either initial anticoagulation as for children without hemorrhage or radiologic monitoring of the thrombosis at five to seven days and anticoagulation if thrombus extension is noted at that time [40]. The ACCP suggests thrombolysis, thrombectomy, or surgical decompression only in children with severe CVT in whom there is no improvement with initial anticoagulation therapy. The 2019 AHA/ASA scientific statement for the management of stroke in neonates and children endorses anticoagulation for children with CVT [41]. Antithrombotic selection should be individualized, guided by patient circumstances, and informed by a multidisciplinary consensus approach particularly when CVT is associated with hemorrhagic infarction, otitis media/mastoiditis, head trauma, or cranial surgery. Surveillance vascular neuroimaging is recommended to guide the duration of anticoagulation. Endovascular intervention is an option for rare circumstances when there is sudden clinical deterioration or a high risk of mortality. For neonatal patients with CVT, anticoagulation with LMWH or heparin may be considered, particularly those with clinical deterioration or evidence of thrombus extension on serial imaging [41]. Serial imaging at five to seven days should be considered to exclude propagation when a decision is made not to be anticoagulated. OTHER ACUTE MANAGEMENT ISSUES Major problems that may require intervention in the acute phase of CVT include elevated intracranial pressure, brain swelling, and seizures. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 6/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Elevated intracranial pressure and herniation In the acute phase, elevated intracranial pressure (ICP) may arise from single or multiple large hemorrhagic lesions, infarcts, or brain edema. Elevated ICP or space-occupying lesions may cause transtentorial herniation and death. General recommendations to control acutely elevated ICP should be followed, including elevating the head of the bed, intensive care unit admission, mild sedation as needed, administering osmotic therapy (mannitol or hypertonic saline), hyperventilation to a target partial pressure of carbon dioxide (PaCO ) of 30 to 35 mmHg, and ICP monitoring [21,42]. 2 (See "Evaluation and management of elevated intracranial pressure in adults" and "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis".) In patients with impending herniation due to unilateral hemispheric lesion, hemicraniectomy can be lifesaving. Retrospective data from a registry and systematic reviews suggest that death can be prevented and a good functional outcome can be achieved [43,44]. There is no good evidence to support ventricular shunting as a treatment for acute hydrocephalus or impending brain herniation in the acute phase of CVT [45]. In patients with sustained ICP elevation, successful treatment of intracranial hypertension can prevent visual failure and resolve headache. A prospective study in 59 patients with CVT presenting with isolated intracranial hypertension noted a complete recovery in over 90 percent [46]; patients had a variety of interventions, and most had a therapeutic lumbar puncture (LP). However, there are no studies specifically evaluating therapeutic LP for elevated ICP or isolated intracranial hypertension in patients with CVT. Data from the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) did not show differences in the outcomes in patients who had diagnostic LP [15]. European guidelines state that therapeutic LP may be considered in patients with CVT and signs of intracranial hypertension, because of a potential beneficial effect on visual loss and/or headache, whenever its safety profile is acceptable [37]. Although glucocorticoids, in particular intravenous dexamethasone, are prescribed in many centers, they are not recommended for treating CVT in the absence of an underlying inflammatory disorder such as Beh et disease or systemic lupus erythematosus [37,47-49]. No randomized clinical trials have been performed to evaluate their efficacy for CVT, but available evidence suggests they are ineffective. This conclusion is supported by a study that analyzed data from the observational ISCVT cohort of 642 patients with CVT (including 150 patients treated with glucocorticoids) using case-control methods that failed to demonstrate any benefit of glucocorticoids, even for patients with parenchymal lesions [50]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 7/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Seizures For patients with CVT who have both seizures and focal cerebral supratentorial lesions such as edema or infarction on admission head computed tomography (CT) or brain magnetic resonance imaging (MRI) lesions, we recommend seizure prophylaxis with antiseizure medication. In patients with CVT, recurrent seizures are more likely to develop in those who present with seizures and in those with supratentorial brain lesions (focal edema or ischemic or hemorrhagic infarcts) on admission brain imaging [51]. The risk of developing seizures after CVT diagnosis is very low in patients who do not have these risk factors. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Seizures'.) Data are limited regarding the effectiveness of seizure prophylaxis with antiseizure medications in patients with CVT [21,52]. In the ISCVT cohort, early seizures (those occurring within two weeks after CVT diagnosis) were observed in the following patient subgroups, comparing those not treated with antiseizure medication versus those treated with antiseizure medication [51]: In patients with no supratentorial lesion and no seizure at presentation, early seizure occurred in 5 of 197 (2.5 percent) not on antiseizure medications versus 0 of 11 (0 percent) on antiseizure medications. In those with no supratentorial lesion who presented with seizure, early seizures occurred in 1 of 14 (7 percent) not on antiseizure medications and 0 of 35 (0 percent) on antiseizure medications. In patients with a supratentorial lesion but no seizure at presentation, early seizures occurred in 11 of 134 (8 percent) not on antiseizure medications and 1 of 35 (3 percent) on antiseizure medications (odds ratio [OR] 0.3, 95% CI 0.04-2.6). In patients with a supratentorial lesion who presented with seizure, early seizures occurred in 24 of 47 (51 percent) not on antiseizure medications and 1 of 148 (<1 percent) on antiseizure medications (OR 0.006, 95% CI 0.001-0.05). Thus, antiseizure medications prophylaxis appears to be associated with a reduced risk of early seizures in patients with CVT. The risk reduction was statistically significant for patients in the highest risk group (those with a supratentorial lesion and seizure at presentation) [51]. The strength of this study is limited by its observational and retrospective design, but it represents the largest experience in the literature. Based upon these data, we recommend seizure prophylaxis only for patients with both seizures at presentation and supratentorial lesions such as edema, infarction, or hemorrhage on admission head CT or brain MRI. Prophylaxis is not clearly required for a single early https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 8/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate symptomatic seizure with CVT in the absence of supratentorial lesion, as there is often no seizure recurrence. Furthermore, seizure prophylaxis is not recommended for patients who have focal cerebral lesions without seizures [37,39]. When antiseizure medication prophylaxis is used, valproate or levetiracetam is preferable to phenytoin because they have fewer pharmacologic interactions with oral vitamin K antagonist anticoagulants (eg, warfarin) [53]. General recommendations for the selection of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) The duration of antiseizure medication therapy is discussed separately (See 'Seizure prevention' below.) Infection and inflammation Antibiotic treatment is mandatory whenever there is meningitis or other intracranial infection or an infection of a neighboring structure, such as otitis or mastoiditis. For associated inflammatory diseases such as Beh et disease, lupus, or vasculitis, treatment with glucocorticoids may be necessary. MANAGEMENT AFTER THE ACUTE PHASE The subacute phase of CVT often involves decisions regarding the duration of anticoagulation and antiseizure medication use. In addition, there may be long-term complications including headaches, visual loss, cognitive impairment, and psychiatric disturbances. Long-term anticoagulation The aim of continuing anticoagulation after the acute phase is to prevent CVT recurrence, which affects 2 to 7 percent of patients, and to prevent extracerebral venous thrombosis, which occurs in up to 5 percent of patients with CVT, mainly from deep venous thrombosis of the limbs or pelvis, and/or pulmonary embolism [15]. (See 'Recurrence' below.) Selection of anticoagulant For most adults with CVT, we suggest anticoagulation with warfarin or a direct oral anticoagulant after the acute phase. Direct oral anticoagulants may be preferable for most patients, based upon the lower burden of blood monitoring and dose adjustments, fewer drug interactions, and lack of dietary restrictions when compared with warfarin. When warfarin is used, the dose should be adjusted to an international normalized ratio (INR) target of 2.5 (acceptable range: 2 to 3). https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 9/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Although high-quality evidence is limited, either warfarin or a direct oral anticoagulant appears to be safe and effective to prevent recurrent CVT and other forms of venous thromboembolism (VTE) in patients with CVT. A systematic review of 19 studies that included nearly 2000 patients with CVT found rates of recurrent thromboembolism and intracranial hemorrhage were similar for patients treated with vitamin K antagonists or direct oral anticoagulants [54]. However, certainty of the data is limited by the observational nature of many of the included studies, risk of selection and treatment biases, as well as varied outcome parameters. In the open-label RE- SPECT CVT trial, 120 patients with CVT of mild to moderate severity were randomly assigned to dabigatran (150 mg twice daily) or warfarin (titrated to a target INR of 2 to 3) for a period of 24 weeks [55]. Patients with coma, major trauma, central nervous system infections, or active cancer were excluded. During the study period, there were no recurrent venous thromboembolic events in either treatment group. Major bleeding was limited to intestinal bleeding in one patient assigned to dabigatran and subdural hemorrhages in two patients assigned to warfarin. European guidelines, which were published in 2017 prior to the RE-SPECT CVT trial, do not recommend using direct oral anticoagulants for the prevention of recurrent venous thrombosis after CVT [37]. In the retrospective ACTION-CVT observational study that included 845 anticoagulated patients with CVT of mild to moderate severity, clinical and radiographic outcomes were assessed at a median follow-up of 345 days for patients treated with warfarin (52 percent), a direct oral anticoagulant (33 percent), or both at different times (15 percent) [56]. Patients with CVT associated with pregnancy, antiphospholipid syndrome, and cancer were excluded. Compared with warfarin, treatment with a direct oral anticoagulant was associated with similar risks of recurrent venous thrombosis and death, as well as similar rates of recanalization on follow-up imaging. In addition, treatment with a direct oral anticoagulant was associated with a lower risk of major hemorrhage (adjusted hazard ratio 0.35, 95% CI 0.15-0.82). Special populations of patients with CVT require a different approach: Malignancy For patients with malignancy who require long-term anticoagulation and who do not have chronic kidney failure (creatinine clearance <30 mL/minute), low molecular weight heparin (LMWH) is generally preferred rather than warfarin or direct oral anticoagulants, but oral anticoagulation is preferred over no therapy. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) Antiphospholipid syndrome For patients with an antiphospholipid antibody syndrome and CVT, clinical efficacy and safety data suggest warfarin is preferred over direct oral anticoagulants. (See "Management of antiphospholipid syndrome".) https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 10/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Kidney failure Patients with severe chronic kidney failure should not receive direct oral anticoagulants; vitamin K antagonists (eg, warfarin) are preferred for oral therapy. Pregnancy For most patients who require long-term anticoagulation during pregnancy (with the exception of patients with mechanical heart valves), heparins are safer than other anticoagulants. Warfarin and direct oral anticoagulants are contraindicated. (See "Use of anticoagulants during pregnancy and postpartum".) Children Several anticoagulants have been used for children with CVT including vitamin K antagonists, unfractionated heparin, or LMWH [5]. Rivaroxaban or dabigatran can also be used to prevent recurrent venous thrombotic events after acute CVT, depending on patient and parent preferences and drug and dietary interactions. Rivaroxaban was compared with standard anticoagulation (LMWH or vitamin K antagonist) in children with CVT in an exploratory substudy [57] of the open-label EINSTEIN-Jr trial [58], which assigned patients with VTE to bodyweight-adjusted rivaroxaban 20 mg equivalent dose or standard anticoagulation for a period of three months. Partial or complete recanalization rates were similar in both groups and occurred in roughly 75 percent. There was one recurrent VTE (in a child assigned to standard anticoagulation). One subdural hematoma occurred among children assigned to standard anticoagulation (n = 41) and five clinically relevant (nonmajor extracranial) bleeding events in those who received rivaroxaban (n = 73). A subgroup analysis of the EINSTEIN-Jr trial, including children with CVT and an associated head or neck infection administered therapeutic anticoagulants, showed that generally they had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation [59]. In a subgroup analysis of the DIVERSITY trial, a single-arm trial of dabigatran in children with VTE, few children with CVT developed recurrent VTE or experienced major or clinically relevant nonmajor bleeding when receiving prophylaxis with dabigatran [60]. Duration of anticoagulation After the acute phase of CVT, we suggest continuing anticoagulation for a minimum period of three months and up to 12 months. However, there is no definitive evidence regarding the optimal duration of anticoagulant therapy specifically for reducing the risk of recurrent CVT [37]. A reasonable approach may be to stratify the duration of anticoagulant therapy according to the individual prothrombotic risk as follows [39,61]: For patients with a provoked CVT associated with a transient risk factor ( table 2), anticoagulation is continued for three to six months. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 11/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate For patients with an unprovoked CVT, anticoagulation is continued for 6 to 12 months. For patients with recurrent CVT, VTE after CVT, or a first CVT with a severe thrombophilia (ie, homozygous prothrombin gene G20210A variant, homozygous factor V Leiden genetic variant, deficiencies of protein C, protein S, or antithrombin, combined thrombophilia defects, or antiphospholipid syndrome), anticoagulation may be continued indefinitely. Aspirin We generally do not use aspirin or other antiplatelet medications for long-term management of patients after CVT, unless a separate indication for therapy is present. The benefit of aspirin or other antiplatelet agents after CVT has not been established in controlled trials or observational studies, and current guidelines make no recommendation about aspirin in this setting [37,39]. Seizure prevention Patients who experience a seizure after a hemispheric CVT are typically started on antiseizure medication treatment, while patients who do not are generally not started on antiseizure medication prophylaxis. (See 'Seizures' above.) The optimal duration of antiseizure medication treatment after CVT is unknown. For patients with CVT and associated parenchymal brain lesions who present with one or more seizures in the acute phase, antiseizure medications should be continued until seizure-free for a defined duration (eg, one year). The risk of epilepsy after CVT ranges from 5 to 11 percent of patients [15,62-64]. The risk is higher in those with seizures in the acute phase, with hemorrhagic parenchymal lesions, and who survived a decompressive hemicraniectomy [63,64]. Late-onset seizures indicate an even higher risk of epilepsy. In one study of 123 CVT patients with late seizures (occurring more than seven days after CVT diagnosis), 70 percent had a recurrent seizure during a mean two-year follow-up [64]. General recommendations for the selection and withdrawal of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) Headaches Chronic headaches have been reported to occur in more than half of patients with prior CVT [65]. Headaches severe enough to require bed rest or hospital admission afflict 14 percent of patients with CVT [15]. Repeated brain MRI and magnetic resonance venography (MRV) are necessary to exclude the rare case of recurrent CVT. MRV may depict stenosis of a previously occluded sinus [66,67]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 12/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Lumbar puncture may be necessary to exclude chronically elevated intracranial pressure (ICP) if headache persists and brain MRI and MRV are normal. In such cases, therapeutic options to treat elevated ICP include acetazolamide (500 mg twice daily) or topiramate (for patients who cannot tolerate acetazolamide), but efficacy is unproven [39]. Additional options if severe headache associated with increased intracranial hypertension persists include repeated lumbar punctures, a lumboperitoneal shunt, or stenting of sinus stenosis [68-70], but efficacy after CVT is also unproven. Visual loss Severe visual loss due to CVT is fortunately a rare event [71-73]. Nevertheless, elevated intracranial pressure must be rapidly ruled out and managed accordingly if visual acuity decreases during follow-up and is not explained by ocular causes. Fenestration of the optic nerve sheath has also been used to relieve pressure and prevent optic nerve atrophy, but efficacy is not established [39,74]. Because of the potential for visual loss caused by severe or long-standing elevation of intracranial pressure, serial assessment of visual fields and visual acuity is recommended for children with CVT during follow-up, particularly during the first year [39,42]. It is reasonable to do the same for adults with visual complaints, chronic headaches, or papilledema. Cognitive and psychiatric complications Despite the apparent general good recovery in most patients with CVT, approximately one-half of the survivors feel depressed or anxious, and minor cognitive or language deficits may preclude them from resuming their previous jobs [75,76]. Patients should be reassured of the very low level of risk of recurrence of CVT and be encouraged to return to previous occupations and hobbies. In some cases, antidepressants may be necessary. Subsequent pregnancy We suggest prophylaxis with LMWH during pregnancy and puerperium for those with a previous history of CVT to reduce the risk of recurrent CVT and other venous thromboembolic events, in accord with guidelines from the European Stroke Organization and the American Heart Association/American Stroke Association [37,39,77]. For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) Pregnancy and the puerperium are known risk factors for CVT (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Risk factors and associated conditions'). The absolute risk of complications during subsequent pregnancy among those who have a history of CVT appears to be low, although the relative risks of recurrent CVT and noncerebral VTE are quite elevated compared with the general population. Supporting evidence comes from https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 13/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate a 2016 systematic review of 13 observational studies evaluating the frequency of CVT or noncerebral VTE associated with pregnancy and the puerperium in those with a history of previous CVT [78]. The following observations were reported: Recurrent CVT occurred in 2 of 217 pregnancies (9 per 1000 pregnancies, 95% CI 3-33 per 1000), a rate that was more than 80-fold higher than the previously reported incidence in the general population. Noncerebral VTE occurred in 5 of 186 pregnancies (27 per 1000, 95% CI 12-61 per 1000), a rate that was approximately 16-fold higher than the incidence previously described in the general population. Spontaneous abortion occurred in 33 of 186 pregnancies (18 percent, 95% CI 13-24 percent), a rate similar to the estimated rate in the general population. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology", section on 'Incidence'.) There was no significant difference in the rate of spontaneous abortion for patients treated or not treated with antithrombotic therapy (11 versus 19 percent). Thus, based upon the available evidence, a history of CVT, including pregnancy- or puerperium- related CVT, is not a contraindication for future pregnancy. Patients should be advised not to become pregnant while on warfarin because of its teratogenic effects and increased risk of fetal bleeding. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Already taking warfarin'.) Oral contraceptives Because it is a risk factor for CVT, female patients with prior CVT should be informed about the risks of combined estrogen-progestin hormonal contraception and advised against its use [37,42]. Risk is associated with the dose of ethinyl estradiol (less risk with doses <50 mcg). The type of progestin is also associated with VTE risk; in general, the lowest risk is seen with combined oral contraceptives that contain a second-generation progestin such as levonorgestrel. These risks are discussed in greater detail separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.) PROGNOSIS CVT can result in death or permanent disability but usually has a favorable prognosis. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 14/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Early deterioration and death Approximately 5 percent of patients die in the acute phase of the disorder [79,80]. Most of the early deaths are a consequence of CVT. A systematic review found that mortality rates among patients with CVT declined since the 1960s; increased detection of less severe cases with advances in neuroimaging along with improved hospital care may have accounted for some or all of the decreased mortality [81]. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) that evaluated 624 patients (age >15 years) with CVT, 27 patients (4.3 percent) died during hospitalization for

with CVT and associated parenchymal brain lesions who present with one or more seizures in the acute phase, antiseizure medications should be continued until seizure-free for a defined duration (eg, one year). The risk of epilepsy after CVT ranges from 5 to 11 percent of patients [15,62-64]. The risk is higher in those with seizures in the acute phase, with hemorrhagic parenchymal lesions, and who survived a decompressive hemicraniectomy [63,64]. Late-onset seizures indicate an even higher risk of epilepsy. In one study of 123 CVT patients with late seizures (occurring more than seven days after CVT diagnosis), 70 percent had a recurrent seizure during a mean two-year follow-up [64]. General recommendations for the selection and withdrawal of antiseizure medications are discussed separately. (See "Overview of the management of epilepsy in adults", section on 'Antiseizure medication therapy' and "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Selection of an antiseizure medication'.) Headaches Chronic headaches have been reported to occur in more than half of patients with prior CVT [65]. Headaches severe enough to require bed rest or hospital admission afflict 14 percent of patients with CVT [15]. Repeated brain MRI and magnetic resonance venography (MRV) are necessary to exclude the rare case of recurrent CVT. MRV may depict stenosis of a previously occluded sinus [66,67]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 12/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Lumbar puncture may be necessary to exclude chronically elevated intracranial pressure (ICP) if headache persists and brain MRI and MRV are normal. In such cases, therapeutic options to treat elevated ICP include acetazolamide (500 mg twice daily) or topiramate (for patients who cannot tolerate acetazolamide), but efficacy is unproven [39]. Additional options if severe headache associated with increased intracranial hypertension persists include repeated lumbar punctures, a lumboperitoneal shunt, or stenting of sinus stenosis [68-70], but efficacy after CVT is also unproven. Visual loss Severe visual loss due to CVT is fortunately a rare event [71-73]. Nevertheless, elevated intracranial pressure must be rapidly ruled out and managed accordingly if visual acuity decreases during follow-up and is not explained by ocular causes. Fenestration of the optic nerve sheath has also been used to relieve pressure and prevent optic nerve atrophy, but efficacy is not established [39,74]. Because of the potential for visual loss caused by severe or long-standing elevation of intracranial pressure, serial assessment of visual fields and visual acuity is recommended for children with CVT during follow-up, particularly during the first year [39,42]. It is reasonable to do the same for adults with visual complaints, chronic headaches, or papilledema. Cognitive and psychiatric complications Despite the apparent general good recovery in most patients with CVT, approximately one-half of the survivors feel depressed or anxious, and minor cognitive or language deficits may preclude them from resuming their previous jobs [75,76]. Patients should be reassured of the very low level of risk of recurrence of CVT and be encouraged to return to previous occupations and hobbies. In some cases, antidepressants may be necessary. Subsequent pregnancy We suggest prophylaxis with LMWH during pregnancy and puerperium for those with a previous history of CVT to reduce the risk of recurrent CVT and other venous thromboembolic events, in accord with guidelines from the European Stroke Organization and the American Heart Association/American Stroke Association [37,39,77]. For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) Pregnancy and the puerperium are known risk factors for CVT (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Risk factors and associated conditions'). The absolute risk of complications during subsequent pregnancy among those who have a history of CVT appears to be low, although the relative risks of recurrent CVT and noncerebral VTE are quite elevated compared with the general population. Supporting evidence comes from https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 13/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate a 2016 systematic review of 13 observational studies evaluating the frequency of CVT or noncerebral VTE associated with pregnancy and the puerperium in those with a history of previous CVT [78]. The following observations were reported: Recurrent CVT occurred in 2 of 217 pregnancies (9 per 1000 pregnancies, 95% CI 3-33 per 1000), a rate that was more than 80-fold higher than the previously reported incidence in the general population. Noncerebral VTE occurred in 5 of 186 pregnancies (27 per 1000, 95% CI 12-61 per 1000), a rate that was approximately 16-fold higher than the incidence previously described in the general population. Spontaneous abortion occurred in 33 of 186 pregnancies (18 percent, 95% CI 13-24 percent), a rate similar to the estimated rate in the general population. (See "Pregnancy loss (miscarriage): Terminology, risk factors, and etiology", section on 'Incidence'.) There was no significant difference in the rate of spontaneous abortion for patients treated or not treated with antithrombotic therapy (11 versus 19 percent). Thus, based upon the available evidence, a history of CVT, including pregnancy- or puerperium- related CVT, is not a contraindication for future pregnancy. Patients should be advised not to become pregnant while on warfarin because of its teratogenic effects and increased risk of fetal bleeding. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Already taking warfarin'.) Oral contraceptives Because it is a risk factor for CVT, female patients with prior CVT should be informed about the risks of combined estrogen-progestin hormonal contraception and advised against its use [37,42]. Risk is associated with the dose of ethinyl estradiol (less risk with doses <50 mcg). The type of progestin is also associated with VTE risk; in general, the lowest risk is seen with combined oral contraceptives that contain a second-generation progestin such as levonorgestrel. These risks are discussed in greater detail separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.) PROGNOSIS CVT can result in death or permanent disability but usually has a favorable prognosis. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 14/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Early deterioration and death Approximately 5 percent of patients die in the acute phase of the disorder [79,80]. Most of the early deaths are a consequence of CVT. A systematic review found that mortality rates among patients with CVT declined since the 1960s; increased detection of less severe cases with advances in neuroimaging along with improved hospital care may have accounted for some or all of the decreased mortality [81]. In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) that evaluated 624 patients (age >15 years) with CVT, 27 patients (4.3 percent) died during hospitalization for the acute phase, including 21 patients (3.4 percent) who died within 30 days from symptom onset [79]. Predictors of mortality at 30 days in the ISCVT were as follows [79]: Depressed consciousness Altered mental status Thrombosis of the deep venous system Right hemisphere hemorrhage Posterior fossa lesions Early mortality in children with CVT is similar to that in adults. In a European cohort of 396 children with CVT (median age 5.2 years), death in the first two weeks after presentation occurred in 12 patients (3 percent) [82]. The main cause of acute death with CVT is transtentorial herniation secondary to a large hemorrhagic lesion [79]. Other causes of early death include herniation due to multiple lesions or to diffuse brain edema, status epilepticus, medical complications, and pulmonary embolism [2]. Long-term outcome Mortality after the acute phase of CVT is predominantly related to underlying conditions. The main ISCVT report [15] performed a meta-analysis of seven prospective series and found that acute CVT was associated with a 15 percent overall death or dependency rate at the end of follow-up, which varied from 3 to 78 months. In the ISCVT study, complete recovery at the end of follow-up (median 16 months) was noted in 79 percent of the entire cohort of patients, while death was the outcome in 8 percent [15]. Predictors of poor long-term prognosis in the ISCVT were as follows [15]: Central nervous system infection Any malignancy Thrombosis of the deep venous system https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 15/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Hemorrhage on head CT or MRI Glasgow coma scale score <9 on admission ( table 3) Mental status abnormality Age >37 years Male sex The CVT risk score was designed to estimate the functional prognosis at six months after CVT onset; the score was derived using data from the original ISCVT cohort of 624 patients and validated in two smaller cohorts [83]. The score is tallied as follows: Presence of malignancy 2 points Coma on admission 2 points Thrombosis involving the deep venous system 2 points Mental status disturbance on admission 1 point Male sex 1 point Intracranial hemorrhage on admission 1 point A CVT risk score 3 was associated with a poor outcome, defined as a modified Rankin Scale ( table 4) score of >2 (dependency or death), with a high sensitivity but poor specificity (96 and 14 percent, respectively) [83]. In the ISCVT, complete recovery at six months was significantly more common for female than male patients (81 versus 71 percent), while dependency or death was less likely for females than males (12 versus 20 percent) [84]. These differences were driven entirely by the more favorable outcome for the subgroup of females who had sex-specific risk factors (mainly oral contraceptives, pregnancy, or puerperium) for CVT. Females without sex-specific risk factors had outcomes similar to males. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Epidemiology'.) Intracerebral hemorrhage present at the time of CVT diagnosis was identified in 245 patients (39 percent) of the ISCVT cohort [85]. In this subgroup with early intracerebral hemorrhage, predictors of poor prognosis at six months were older age, male sex, thrombosis of the deep cerebral venous system or of the right lateral sinus, and a motor deficit [85]. By contrast, several studies have found that a good outcome after CVT is predicted when symptoms of intracranial hypertension are the only manifestations of CVT at the time of diagnosis [46,86]. In patients with CVT presenting with isolated intracranial hypertension, a subgroup analysis of the ISCVT cohort found that poor outcome was associated with a longer diagnostic delay [87]. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 16/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Recurrence The risk of recurrent CVT is approximately 2 to 4 percent, while the risk of recurrent venous thromboembolism (VTE) in other locations after CVT ranges from 4 to 7 percent. In the ISCVT study, which evaluated 624 patients with CVT over a median 16 months of follow-up, 14 (2 percent) had a recurrent CVT and 27 (4 percent) had other thrombotic events during follow-up [15]. The risks of recurrent CVT or any venous thrombosis were 1.5 and 4.1 per 100 person-years, respectively [88]. Observational data also suggest longer-term CVT recurrence rates appear to be lower than rates of recurrent VTE. In a retrospective cohort study of 706 patients with a first CVT who were followed for 6 to 297 months (median 40 months), CVT recurred in 31 patients (4 percent), and VTE in a different site occurred in 46 patients (7 percent) [89]. In another study that prospectively followed 145 patients with CVT for a median of six years after discontinuation of anticoagulant therapy, a recurrent CVT developed in five patients (3 percent), and other types of VTE developed in another 10 patients (6 percent) [90]. The risks of recurrent CVT or other types of VTE were 0.5 and 2.0 per 100 person-years, respectively. Risk factors for CVT recurrence in adults include the following [88-91]: History of prior VTE Polycythemia/thrombocythemia Clinical history or laboratory evidence of thrombophilia Male sex Black race Data on CVT recurrence and risk factors in children are limited. In the European cohort of 396 children with CVT (median age five years) followed for a median of 36 months, recurrent venous thrombosis occurred in 22 children at a median of six months, including CVT in 13 children (3 percent) [82]. There were no recurrences of CVT among children younger than 25 months. Factors independently associated with recurrent cerebral and systemic venous thrombosis in children were nonadministration of anticoagulant therapy before relapse (hazard ratio [HR] 11.2, 95% CI 3.4-37.0), persistent occlusion on repeat venous imaging (HR 4.1, 95% CI 1.1-14.8), and heterozygosity for the prothrombin (factor II) G20210A variant (HR 4.3, 95% CI 1.1-16.2) [82]. Recanalization Most patients with CVT achieve some degree of cerebral vein and sinus recanalization. A 2018 systematic review and meta-analysis identified 19 studies, mostly retrospective, that reported recanalization rates for adult patients with CVT who were treated with anticoagulation [92]. The overall recanalization rate was 85 percent among 818 patients who received follow-up imaging, with partial recanalization achieved by 35 percent and complete recanalization by 49 percent of patients. In the few studies with available data, the https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 17/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate recanalization rate increased with time, and approximately three-quarters of patients had achieved recanalization at three months. Positive predictors of recanalization were thrombosis of the superior sagittal sinus and female sex; negative predictors of recanalization were multiple thromboses, hormonal therapy, older age, and lack of identified risk factors for CVT. The meta-analysis also found that recanalization was associated with functional recovery [92]. A favorable outcome, defined as a modified Rankin Scale score ( table 4) of 0 (no symptoms) or 1 (no significant disability despite symptoms), was achieved in 319 of 357 (89 percent) patients with recanalization and in 42 of 59 (71 percent) patients without recanalization; the pooled odds ratio for a favorable outcome with recanalization was 3.3 (95% CI 1.2-8.9). In subsequent prospective cohort study of 68 patients with newly diagnosed CVT treated with anticoagulation and followed with MRI and magnetic resonance venography, early venous recanalization (confirmed by imaging on day 8 after starting anticoagulation) was associated with both regression and a reduced risk of enlargement of nonhemorrhagic lesions, including those with venous infarction [93]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute anticoagulation For adults with symptomatic cerebral venous thrombosis (CVT), with or without hemorrhagic venous infarction, we recommend initial anticoagulation therapy with subcutaneous low molecular weight heparin (LMWH) or intravenous heparin (Grade 1C). For children with CVT, with or without significant secondary hemorrhage, we suggest initial anticoagulation therapy with subcutaneous LMWH or intravenous heparin (Grade 2C). (See 'Initial anticoagulation' above.) Management of acute complications Complications that require intervention during the acute phase of CVT include elevated intracranial pressure, brain swelling, seizures, and infection. (See 'Other acute management issues' above.) Measures to control acutely increased intracranial pressure and impending herniation, including decompressive surgery, may be required in patients with CVT. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 18/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate For patients with CVT who have both seizures at presentation and focal cerebral supratentorial lesions (eg, edema, infarction, or hemorrhage on admission computed tomography or magnetic resonance imaging), we recommend seizure prophylaxis with an antiseizure medication (Grade 1B). For patients with a single early symptomatic seizure due to CVT in the absence of a supratentorial cerebral lesion, the benefit of seizure prophylaxis is uncertain due to low likelihood of recurrence. Seizure prophylaxis is avoided for those who have focal cerebral lesions without seizures. (See 'Seizures' above.) Antibiotic treatment is mandatory whenever there is meningitis or other intracranial infection or an infection of a neighboring structure, such as otitis or mastoiditis. Selection and duration of anticoagulation After the acute phase of CVT, we suggest anticoagulation for most patients with either a direct oral anticoagulant or warfarin for 3 to 12 months (Grade 2C). Exceptions include patients with comorbid malignancy (for whom LMWH is preferred), antiphospholipid syndrome or chronic kidney disease (for whom warfarin is preferred), and those who are pregnant (for whom heparins are preferred). (See 'Long-term anticoagulation' above and 'Selection of anticoagulant' above.) It is reasonable to continue anticoagulation for three to 6 months for patients with a provoked CVT associated with a transient risk factor ( table 2) and for 6 to 12 months for patients with an unprovoked CVT. Indefinite oral anticoagulation is reserved for patients with recurrent CVT, extracerebral venous thromboembolism after CVT, or those with an associated severe thrombophilia. (See 'Duration of anticoagulation' above.) Managing the risk of recurrence For pregnant patients with a history of CVT, we suggest temporary prophylactic anticoagulation with subcutaneous LMWH throughout pregnancy and continuing up to eight weeks postpartum (Grade 2C). For adolescent and adult females with a history of CVT, we advise not using combined oral contraceptives. Prognosis CVT is associated with a good outcome in close to 80 percent of patients. Approximately 5 percent of patients die in the acute phase of the disorder, and longer-term mortality is nearly 10 percent. The main cause of acute death with CVT is neurologic, most often from brain herniation. After the acute phase, most deaths are related to underlying disorders such as cancer. (See 'Prognosis' above.) 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Early Recanalization in Patients With Cerebral Venous Thrombosis Treated With Anticoagulation. Stroke 2020; 51:1174. Topic 1109 Version 45.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 26/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate GRAPHICS Placebo-controlled randomized trials of anticoagulants in acute cerebral venous thrombosis Einh upl et al 1991, intravenous heparin versus placebo Heparin versus placebo Outcome at three months Heparin group (n = 10) Total recovery 8 patients Residual motor deficit 2 patients Placebo group (n = 10) Total recovery 1 patient Minor residual deficit 6 patients Deaths 3 patients De Bruijn and Stam 1999, subcutaneous nadroparin versus placebo Outcome difference Nadroparin (n = 30) Placebo (n = 29) Risk difference At three weeks Deaths 2 4 BI score <15 4 3 Death or BI <15 6 (20 percent) 7 (24 percent) 4 percent (95% CI, 25 to 17 percent) At 12 weeks Deaths 2 4 Dependent (OHS 2 2 3 to 5) Death or dependent 4 (13 percent) 6 (21 percent) 7 percent (95% CI, 26 to 12 percent) BI: Barthel Index; OHS: Oxford Handicap Score. Data from: 1. Einh upl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597. 2. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484. Graphic 69484 Version 7.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 27/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis Transient risk factors Infection Central nervous system Ear, sinus, mouth, face, and neck Systemic infectious disease Pregnancy and puerperium Dehydration Mechanical precipitants Head injury Lumbar puncture Neurosurgical procedures Jugular catheter occlusion Drugs Oral contraceptives Hormone replacement therapy Androgens Asparaginase Tamoxifen Glucocorticoids Permanent risk factors Inflammatory diseases Systemic lupus erythematosus Beh et disease Granulomatosis with polyangiitis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Malignancy Central nervous system

61. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 62. Preter M, Tzourio C, Ameri A, Bousser MG. Long-term prognosis in cerebral venous thrombosis. Follow-up of 77 patients. Stroke 1996; 27:243. 63. Ferro JM, Correia M, Rosas MJ, et al. Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis 2003; 15:78. 64. S nchez van Kammen M, Lindgren E, Silvis SM, et al. Late seizures in cerebral venous thrombosis. Neurology 2020; 95:e1716. 65. Bossoni AS, Peres MFP, Leite CDC, et al. Headache at the chronic stage of cerebral venous thrombosis. Cephalalgia 2022; 42:1476. 66. Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology 2003; 60:1418. 67. Higgins JN, Gillard JH, Owler BK, et al. MR venography in idiopathic intracranial hypertension: unappreciated and misunderstood. J Neurol Neurosurg Psychiatry 2004; 75:621. 68. Higgins JN, Owler BK, Cousins C, Pickard JD. Venous sinus stenting for refractory benign intracranial hypertension. Lancet 2002; 359:228. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 24/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate 69. Owler BK, Parker G, Halmagyi GM, et al. Pseudotumor cerebri syndrome: venous sinus obstruction and its treatment with stent placement. J Neurosurg 2003; 98:1045. 70. Tsumoto T, Miyamoto T, Shimizu M, et al. Restenosis of the sigmoid sinus after stenting for treatment of intracranial venous hypertension: case report. Neuroradiology 2003; 45:911. 71. Ferro JM, Lopes MG, Rosas MJ, et al. Long-term prognosis of cerebral vein and dural sinus thrombosis. results of the VENOPORT study. Cerebrovasc Dis 2002; 13:272. 72. Ferro JM, Canh o P, Bousser MG, et al. Cerebral vein and dural sinus thrombosis in elderly patients. Stroke 2005; 36:1927. 73. Purvin VA, Trobe JD, Kosmorsky G. Neuro-ophthalmic features of cerebral venous obstruction. Arch Neurol 1995; 52:880. 74. Acheson JF. Optic nerve disorders: role of canal and nerve sheath decompression surgery. Eye (Lond) 2004; 18:1169. 75. de Bruijn SF, Budde M, Teunisse S, et al. Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis. Neurology 2000; 54:1687. 76. Hiltunen S, Putaala J, Haapaniemi E, Tatlisumak T. Long-term outcome after cerebral venous thrombosis: analysis of functional and vocational outcome, residual symptoms, and adverse events in 161 patients. J Neurol 2016; 263:477. 77. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. 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Cerebrovasc Dis 2009; 28:39. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 25/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate 84. Coutinho JM, Ferro JM, Canh o P, et al. Cerebral venous and sinus thrombosis in women. Stroke 2009; 40:2356. 85. Girot M, Ferro JM, Canh o P, et al. Predictors of outcome in patients with cerebral venous thrombosis and intracerebral hemorrhage. Stroke 2007; 38:337. 86. Gameiro J, Ferro JM, Canh o P, et al. Prognosis of cerebral vein thrombosis presenting as isolated headache: early vs. late diagnosis. Cephalalgia 2012; 32:407. 87. Ferro JM, Canh o P, Stam J, et al. Delay in the diagnosis of cerebral vein and dural sinus thrombosis: influence on outcome. Stroke 2009; 40:3133. 88. Miranda B, Ferro JM, Canh o P, et al. Venous thromboembolic events after cerebral vein thrombosis. Stroke 2010; 41:1901. 89. Dentali F, Poli D, Scoditti U, et al. Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study. J Thromb Haemost 2012; 10:1297. 90. Martinelli I, Bucciarelli P, Passamonti SM, et al. Long-term evaluation of the risk of recurrence after cerebral sinus-venous thrombosis. Circulation 2010; 121:2740. 91. Shu L, Bakradze E, Omran SS, et al. Predictors of Recurrent Venous Thrombosis After Cerebral Venous Thrombosis: Analysis of the ACTION-CVT Study. Neurology 2022; 99:e2368. 92. Aguiar de Sousa D, Lucas Neto L, Canh o P, Ferro JM. Recanalization in Cerebral Venous Thrombosis. Stroke 2018; 49:1828. 93. Aguiar de Sousa D, Lucas Neto L, Arauz A, et al. Early Recanalization in Patients With Cerebral Venous Thrombosis Treated With Anticoagulation. Stroke 2020; 51:1174. Topic 1109 Version 45.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 26/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate GRAPHICS Placebo-controlled randomized trials of anticoagulants in acute cerebral venous thrombosis Einh upl et al 1991, intravenous heparin versus placebo Heparin versus placebo Outcome at three months Heparin group (n = 10) Total recovery 8 patients Residual motor deficit 2 patients Placebo group (n = 10) Total recovery 1 patient Minor residual deficit 6 patients Deaths 3 patients De Bruijn and Stam 1999, subcutaneous nadroparin versus placebo Outcome difference Nadroparin (n = 30) Placebo (n = 29) Risk difference At three weeks Deaths 2 4 BI score <15 4 3 Death or BI <15 6 (20 percent) 7 (24 percent) 4 percent (95% CI, 25 to 17 percent) At 12 weeks Deaths 2 4 Dependent (OHS 2 2 3 to 5) Death or dependent 4 (13 percent) 6 (21 percent) 7 percent (95% CI, 26 to 12 percent) BI: Barthel Index; OHS: Oxford Handicap Score. Data from: 1. Einh upl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991; 338:597. 2. de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke 1999; 30:484. Graphic 69484 Version 7.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 27/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Systemic and local conditions increasing the risk of cerebral venous thrombosis Transient risk factors Infection Central nervous system Ear, sinus, mouth, face, and neck Systemic infectious disease Pregnancy and puerperium Dehydration Mechanical precipitants Head injury Lumbar puncture Neurosurgical procedures Jugular catheter occlusion Drugs Oral contraceptives Hormone replacement therapy Androgens Asparaginase Tamoxifen Glucocorticoids Permanent risk factors Inflammatory diseases Systemic lupus erythematosus Beh et disease Granulomatosis with polyangiitis Thromboangiitis obliterans Inflammatory bowel disease Sarcoidosis Malignancy Central nervous system https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 28/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Solid tumour outside central nervous system Hematologic Hematologic condition Prothrombotic states, genetic or acquired Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V Leiden mutation G20210A prothrombin gene mutation Antiphospholipid syndrome Myeloproliferative neoplasms Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Hyperhomocysteinemia Polycythemia, thrombocythemia Severe anemia, including paroxysmal nocturnal hemoglobinuria Central nervous system disorders Dural fistulae Other disorders Congenital heart disease Thyroid disease Graphic 65303 Version 10.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 29/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Glasgow Coma Scale and Pediatric Glasgow Coma Scale Glasgow Coma [2] Sign Pediatric Glasgow Coma Scale Score [1] Scale Eye opening Spontaneous Spontaneous 4 To command To sound 3 To pain To pain 2 None None 1 Verbal Oriented Age-appropriate vocalization, smile, or orientation to 5 response sound; interacts (coos, babbles); follows objects Confused, disoriented Cries, irritable 4 Inappropriate words Cries to pain 3 Incomprehensible sounds Moans to pain 2 None None 1 Motor Obeys commands Spontaneous movements (obeys verbal command) 6 response Localizes pain Withdraws to touch (localizes pain) 5 Withdraws Withdraws to pain 4 Abnormal flexion to Abnormal flexion to pain (decorticate posture) 3 pain Abnormal extension to pain Abnormal extension to pain (decerebrate posture) 2 None None 1 Best total score 15 The Glasgow Coma Scale (GCS) is scored between 3 and 15, with 3 being the worst and 15 the best. It is composed of 3 parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. The Pediatric Glasgow Coma Scale (PGCS) was validated in children 2 years of age or younger. Data from: 1. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81. 2. Holmes JF, Palchak MJ, MacFarlane T, Kuppermann N. Performance of the pediatric Glasgow coma scale in children with blunt head trauma. Acad Emerg Med 2005; 12:814. https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 30/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Graphic 59662 Version 14.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 31/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 32/33 7/6/23, 12:28 PM Cerebral venous thrombosis: Treatment and prognosis - UpToDate Contributor Disclosures Jos M Ferro, MD, PhD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Daiichi-Sankyo [Stroke]. All of the relevant financial relationships listed have been mitigated. Patr cia Canh o, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-venous-thrombosis-treatment-and-prognosis/print 33/33

7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cryptogenic stroke and embolic stroke of undetermined source (ESUS) : Shyam Prabhakaran, MD, MS, Chinwe Ibeh, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 19, 2023. INTRODUCTION The majority of ischemic strokes are due to cardioembolism, large vessel atherothromboembolism, small vessel occlusive disease, or other unusual mechanisms. However, many ischemic strokes occur without a well-defined etiology and are labeled as cryptogenic. This topic will provide an overview of cryptogenic stroke. A discussion of stroke classification and the clinical diagnosis of stroke subtypes is found separately. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) CLASSIFICATION Cryptogenic stroke The cryptogenic stroke category was devised first, for research purposes, in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank [1,2] and later modified in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) trial [3]. Classification along these lines has become increasingly used in clinical practice, as optimal management relates to the underlying mechanism. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification'.) By the TOAST classification ( table 1), which is the one most commonly used in clinical practice, cryptogenic stroke (or stroke of undetermined etiology in TOAST terminology) is defined as brain https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 1/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a standard vascular, cardiac, and serologic evaluation. The category of stroke of undetermined etiology in the TOAST classification includes patients with less well-established potential causes of cardiac embolism, such as patent foramen ovale (PFO), aortic arch atheroma, and mitral valve strands. A limitation of the TOAST classification, however, is that stroke of undetermined etiology also includes patients with two or more equally plausible identified causes of stroke and patients in whom a diagnostic evaluation has not been performed [3]. In its most useful clinical sense, the term cryptogenic stroke designates the category of ischemic stroke for which no probable cause is found despite a thorough diagnostic evaluation [4]. In addition to TOAST, there are several other ischemic stroke classification systems that include a category for stroke of undetermined cause, as discussed in detail separately (see "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'). Among these, the Causative Classification System (CCS) was designed to determine the most likely cause of stroke even when multiple possible mechanisms are present ( table 2) [5,6]. Embolic stroke of undetermined source Embolic stroke of undetermined source (ESUS) represents a subset of cryptogenic stroke and emphasizes the likelihood that most strokes of unexplained etiology are probably embolic from an unestablished source [4,7,8]. ESUS is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources [7]. The concept of ESUS, moreover, implies that a full standard evaluation was done, whereas the TOAST equivalent of cryptogenic stroke did not require a full evaluation, as noted above. The criteria for ESUS are: Stroke detected by computed tomography (CT) or magnetic resonance imaging (MRI) that is not lacunar (lacunar is defined as a subcortical infarct in the distribution of the small, penetrating cerebral arteries whose largest dimension is 1.5 cm on CT or 2.0 cm on MRI diffusion images) Absence of extracranial or intracranial atherosclerosis causing 50 percent luminal stenosis of the artery supplying the area of ischemia No major-risk cardioembolic source of embolism (ie, no permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (within four weeks) myocardial infarction, left ventricular ejection fraction <30 percent, valvular vegetations, or infective endocarditis) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 2/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate No other specific cause of stroke identified (eg, arteritis, dissection, migraine, vasospasm, drug abuse) POSSIBLE MECHANISMS Numerous mechanisms for cryptogenic stroke have been proposed. Details regarding the various mechanisms of embolic stroke of undetermined source (ESUS) are described below and broadly include: Cardiac embolism secondary to occult paroxysmal atrial fibrillation (AF), aortic atheromatous disease, or other cardiac sources Paradoxical embolism, which originates in the systemic venous circulation and enters the systemic arterial circulation through a patent foramen ovale (PFO), atrial septal defect, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation Undefined thrombophilia (ie, hypercoagulable states including those related to antiphospholipid antibodies or to occult cancer with hypercoagulability of malignancy) Substenotic cerebrovascular disease (ie, intracranial and extracranial atherosclerotic disease causing less than 50 percent stenosis) and other vasculopathies (eg, dissection) In a single-center analysis using a machine-learning classifier to distinguish between cardioembolic and noncardioembolic subtypes of stroke, the classifier predicted that 44 percent of ESUS was due to occult cardioembolic sources [9]. In an analysis of the NAVIGATE-ESUS trial, which enrolled 7213 patients, the most commonly identified potential sources of embolism were atrial cardiopathy (37 percent), left ventricular disease (36 percent), and arterial atherosclerotic disease (29 percent) [10]. In studies of thrombi extracted from cerebral vessels in the setting of large vessel occlusions, the histologic composition of thrombi from patients with cryptogenic stroke is similar to that of those with cardioembolic stroke, providing further indirect evidence that most cryptogenic strokes are due to emboli from undetermined cardiac causes [11]. It is also likely that important but unidentified mechanisms exist, awaiting discovery. Embolism from occult sources in the heart or aorta The embolic appearance of most cryptogenic strokes implies that the cause is embolism from an occult source in the heart, aorta, or large artery. Cardioaortic conditions with a low or uncertain risk for embolic stroke include difficult to diagnose ("occult") or subclinical atrial fibrillation and related atrial cardiopathies, atrial septal abnormalities, complex aortic atheroma, and others listed in the table ( table 3). https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 3/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Occult atrial fibrillation Occult paroxysmal AF refers to asymptomatic paroxysmal AF in a patient without a prior history of AF, which is detected only by monitoring techniques. Evidence linking occult AF and cryptogenic stroke comes from the prospective ASSERT study of 2580 subjects, age 65 years, with hypertension and no history of AF who had recent implantation of a pacemaker or defibrillator [12]. At three months, subclinical atrial tachyarrhythmias detected by the implanted devices had occurred in 10 percent of patients and were associated with an increased risk (at a mean of 2.5 years) for clinical AF (hazard ratio [HR] 5.6, 95% CI 3.8-8.2) and for the combined endpoint of ischemic stroke or systemic embolism (HR 2.5, 95% CI 1.3-4.9). Among subjects with at least three months of continuous monitoring who experienced ischemic stroke or systemic embolism (n = 51), subclinical AF was detected overall in 26 (51 percent) [13]. However, subclinical AF occurring 30 days before ischemic stroke or systemic embolism was detected in only 4 subjects (8 percent). Thus, while subclinical AF was associated with an increased risk of embolic events, there was no definite temporal relationship of subclinical AF with stroke in most subjects. Atrial septal abnormalities Atrial septal abnormalities, including PFO, atrial septal aneurysm, and atrial septal defect, have been associated with cryptogenic stroke. There is an increased prevalence of PFO and atrial septal aneurysm in patients who have had an otherwise unexplained stroke. In addition, there is high-quality evidence that PFO closure reduces the risk of recurrence in patients age 60 years with an embolic-appearing ischemic stroke who have a medium- to high-risk PFO and no other evident source of stroke despite a comprehensive evaluation. In this setting. it is reasonable to conclude that paradoxical embolism through a PFO is the most likely stroke mechanism. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke' and "Stroke associated with patent foramen ovale (PFO): Evaluation".) Atrial cardiopathies Structural and functional changes in the atria may increase the risk of thrombus formation and embolization. Markers of left atrial cardiopathy include left atrial enlargement, atrial fibrosis, elevated pro-brain natriuretic peptide (proBNP), increased P wave terminal force velocity in lead V1 (PWTFV1), and atrial fibrillation. Even in the absence of diagnosed atrial fibrillation, biomarkers of atrial dysfunction are associated with an increased risk of ischemic stroke [14-16]. For example, serum troponin and proBNP are associated with both AF and stroke. Similarly, PWTFV1, a measure of atrial contraction that can be measured on the electrocardiogram, is associated with stroke risk even in the absence of AF [17]. Although cardioembolism is presumed to be the most likely mechanism of stroke in patients with elevated proBNP or PWTFV1, it is difficult to establish a cause-and-effect relationship between these elevated cardiac biomarkers and occult cardioembolism; the association is confounded because https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 4/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate cardiac disease and elevated cardiac biomarkers are also markers of systemic atherosclerosis. In addition, these biomarkers are not widely available in clinical practice and their utility for management is still uncertain. However, biomarkers have the advantage of being measurable at the time of stroke without the need for long-term monitoring, and thus provide the potential to detect a high risk of cardioembolism. Further prospective study, including clinical trials, is needed to confirm that any of these biomarkers reliably predict a cardioembolic stroke mechanism and response to anticoagulant therapy in secondary stroke prevention. Aortic embolism Thoracic aortic atherosclerotic plaques are an important potential source of systemic emboli, leading to stroke, transient ischemic attack, and embolization to other arterial beds. The risk of thromboembolism in patients with aortic atherosclerosis is increased when there is complex plaque, which is defined as thickness >4 mm or ulceration. (See "Thromboembolism from aortic plaque", section on 'Complex aortic plaque'.) Besides proximal aortic atheromas, distal aortic sources of embolism have been proposed as a potential cause for cryptogenic stroke. One study using cardiac MRI suggested that complex atheromas in the descending aortic arch could lead to stroke via retrograde flow [18]. During diastole, retrograde flow in the descending aorta reached the great vessels supplying the brain in up to 24 percent of patients with cryptogenic stroke. This finding suggests that embolic material in the descending aortic arch could enter the cerebral vasculature during retrograde flow and cause ischemic stroke. Other potential causes of stroke include coarctation of the aorta and aortic dissection. The relationship of aortic embolism and stroke is reviewed in detail separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Aortic atherosclerosis' and "Thromboembolism from aortic plaque".) Pulmonary shunts Based on limited evidence, intrapulmonary right-to-left shunts due to pulmonary arteriovenous malformations or arteriovenous fistulas have been associated with cryptogenic stroke in several small studies [19-23]. This association does not prove causation; further studies are needed to define the relationship between intrapulmonary shunt and cryptogenic stroke. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.) Substenotic atherosclerotic disease Some cases of cryptogenic stroke may be caused by undetected large vessel disease, including occult atherosclerosis and nonstenosing, unstable plaques [24-28]. Imaging features of substenotic (<50 percent) carotid disease that have been https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 5/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate associated with increased stroke risk include plaque ulceration, plaque thickness >3 mm, intraplaque hemorrhage, fibrous cap rupture, lipid-rich core, and plaque echolucency [26]. In a Canadian cohort of 138 patients with ESUS, nonstenotic carotid plaques (<50 percent stenosis) were present in 39 percent of patients and were more frequently ipsilateral to the side of the stroke compared with contralateral (61 versus 39 percent, adjusted odds ratio 1.83, 95% CI 1.05-3.18) [27]. In another report of 579 patients who had anterior circulation stroke and were studied with brain magnetic resonance imaging (MRI) and neck magnetic resonance angiography (MRA) intraplaque hemorrhage on neck MRA was more common ipsilateral to brain infarction in cryptogenic stroke compared with contralateral (relative risk 2.1, 95% CI 1.4-3.1) [25]. Among 197 patients with ESUS, the presence of intraplaque hemorrhage ipsilateral to brain infarction allowed 41 patients (21 percent) to be reclassified from ESUS to large artery atherosclerosis. Data from autopsy studies suggest that ischemic stroke can be associated with lesser degrees of extracranial and intracranial large vessel stenosis (eg, 30 to 70 percent) or with vulnerable plaques without appreciable luminal compromise. In a case-control study that included 259 patients with fatal ischemic stroke, intracranial atherosclerotic plaques (with or without stenosis) were noted in 62 percent [29]. Furthermore, plaques with superimposed thrombi and stenosis of 30 to 70 percent were considered responsible for infarcts in four cases (1.5 percent), a group that would have been classified as cryptogenic in nonautopsy studies. In a subsequent study from the same investigators, plaques and stenoses involving the origin or proximal vertebral artery were present in more than twice as many patients with infarcts in posterior circulation as compared with anterior circulation infarcts (adjusted odds ratio 2.10, 95% CI 1.01-4.38) [30]. These lesions may be responsible for a larger proportion of strokes in the brainstem and posterior circulation than previously appreciated. Other causes Infection and associated thrombophilia may be a cause of unexplained stroke in young, otherwise healthy patients. As an example, coronavirus disease 2019 (COVID-19) may be a cause of otherwise unexplained strokes. In addition to traditional stroke mechanisms, potential mechanisms of ischemic stroke related to COVID-19 include thromboinflammation, severe inflammation, renin-angiotensin-aldosterone system dysfunction, cardiac dysfunction, and the consequences of severe respiratory illness [31]. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Cerebrovascular disease'.) Furthermore, subtle or undetected abnormalities of the large arteries, coagulation system, and genetic factors may be missed during the initial evaluation. These conditions include: https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 6/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Nonatherosclerotic vasculopathies, such as dissection, fibromuscular dysplasia, reversible cerebral vasoconstriction syndromes (RCVS), and vasculitis. Occult hypercoagulable states, such as the antiphospholipid syndrome, genetic thrombophilia, and hypercoagulable state associated with malignancy. Rare genetic conditions may present with stroke in the young; monogenic syndromes associated with an increased risk of ischemic stroke include Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), sickle cell disease, and hereditary thrombotic thrombocytopenic purpura (TTP). However, detection of any of the above conditions would generally alter the diagnostic classification of stroke from cryptogenic stroke to stroke of other determined cause. In practice, an initial diagnosis of cryptogenic stroke may thus yield over time to a later diagnosis of a specific cause. Therefore, a diagnosis of cryptogenic stroke can be regarded as provisional until diagnostic testing is completed. EPIDEMIOLOGY AND RISK FACTORS Large epidemiologic studies have consistently reported that cryptogenic stroke accounts for 25 to 40 percent of ischemic stroke [32-40]. The incidence and prevalence of stroke subtypes among these studies may vary based upon the demographics of the study population, diagnostic definitions, extent of diagnostic evaluation, and methodology. Thus, it is conceivable that some strokes of other determined cause (eg, migraine, dissection, vasculitis) were misclassified in the undetermined category (ie, as cryptogenic) due to inadequate work-up or the limitations of diagnostic detection. However, given the rarity of these other causes in most registries (usually representing less than 5 percent of all strokes), this would not account for all cryptogenic strokes. Demographic factors The risk of cryptogenic stroke may vary by demographics, with higher incidence rates in Black and Hispanic populations compared with White populations, but no clear association has been found for age or sex. With the exception of the strokes classified in TOAST as "other determined etiology" (which includes dissection), all stroke subtypes are rare in the young, and incidence rates rise dramatically with increasing age. A few studies have reported that cryptogenic stroke disproportionately affects younger individuals, but the evidence is inconsistent. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 7/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate In the Northern Manhattan Stroke Study (NOMASS, 1993 to 1996), 55 percent of strokes in the young (age <45 years) were cryptogenic versus 42 percent in the older (age >45 years) group [41]. In a 2003 meta-analysis, young age (defined as <50 years) was inversely associated with cryptogenic stroke with a total odds ratio of 0.6 (95% CI 0.4-1.0, p = 0.05) [34]. Other stroke registries found lower rates (23 to 34 percent) in younger age groups, which were similar to those in older age groups [42-44]. The incidence of cryptogenic stroke may be higher in Black Americans and Hispanic Americans than in White Americans. In NOMASS, incidence rates of all ischemic stroke subtypes, including cryptogenic stroke, were higher in Black Americans and Hispanic Americans than in White Americans [45]. In the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS), Black Americans had twice the annual incidence rate of cryptogenic stroke as White Americans (125 versus 65 per 100,000 persons), a result not confounded by differential testing patterns among Black American versus White American patients [46]. In San Diego, an increased prevalence (nearly 46 percent) of cryptogenic stroke was seen in Mexican American patients, a statistic again that was not explained by differences in diagnostic testing [47]. The higher rates of cryptogenic stroke in Black and Hispanic Americans may be due to several dynamics affecting these populations, including higher rates of all ischemic stroke subtypes, possible underdetection of cardioembolic and large vessel stroke, and/or other unidentified factors [45,48]. Other risk factors Although risk factors often help unravel stroke mechanisms and may overlap with mechanisms, stroke risk factors and mechanisms are conceptually distinct. Thus, the presence of hypertension (ie, a risk factor) does not preclude the etiologic classification (ie, mechanism) of cryptogenic stroke. While it is possible to compare risk factors for cryptogenic stroke versus other stroke subtypes, the comparison is hindered in large part by definitional constraints. As an example, atrial fibrillation will be rare in cryptogenic stroke because of the way in which the subtypes are defined. In addition, risk factors that are associated with large artery ischemic stroke (eg, hypertension, hyperlipidemia, peripheral vascular disease, and diabetes mellitus) and cardioembolic stroke (eg, acute coronary events) are underrepresented in patients with cryptogenic stroke [37]. Several studies have documented that hypertension is less common in cryptogenic stroke compared with other stroke subtypes [34,35,37,38,46,49]. However, patients with cryptogenic stroke may have an increased prevalence of hypertension compared with stroke-free controls, https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 8/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate and one case-control study found that hypertension was associated with cryptogenic stroke (odds ratio 4.5, 95% CI 1.5-13.2) [50]. The prevalence of cardiac disease among patients with cryptogenic stroke varies from 10 to 30 percent. In Rochester, coronary artery disease was less common in the undetermined (ie, cryptogenic) subtype than in the large artery atherosclerosis subtype [32]. Studies assessing the prevalence of prothrombotic states and genetic polymorphisms predisposing individuals to thrombosis have not yielded convincing evidence that these are more common in patients with cryptogenic stroke than nonstroke controls [51-54]. Nevertheless, the available reports are small and not definitive. CLINICAL FEATURES Like patients with embolic stroke, patients with cryptogenic stroke typically present with sudden onset of focal neurologic deficits; most will have a superficial hemispheric ("embolic") infarct topography on brain imaging. They may also present with syndromes indicative of cortical involvement, such as aphasia, or faciobrachial motor syndromes rather than syndromes involving the entire hemibody. In one study of patients with cryptogenic stroke, cortical signs were present in 27 percent, and abrupt onset occurred in 59 percent [55]. Lacunar syndromes are rare, accounting for usually less than 5 percent [56,57]. The severity of the initial presentation varies but, on average, tends to be milder than cardioembolic strokes and worse than lacunar strokes [38,55,57-59]. Superficial hemispheric infarction is present in 62 to 84 percent of patients [56,57]. Forty percent of cryptogenic strokes in the Stroke Data Bank were found to have cortical infarcts [56]. Among 314 patients with cryptogenic stroke in the PFO-ASA study, 56 percent had superficial infarcts [55]. The German Stroke Study found that parenchymal hemorrhagic transformation occurred in approximately 2 percent of patients with stroke of unknown etiology in the first seven days, comparable to the percentage among cardioembolic stroke, suggesting an embolic mechanism [38]. Large subcortical strokes (>15 mm) also tend to be either cryptogenic or cardioembolic in origin. In a nationwide study of registry data from the United States, patients with cryptogenic stroke had milder presentations based on the National Institutes of Health Stroke Scale (NIHSS) score than patients with cardioembolic stroke (median NIHSS 3 versus 5) [60]. While cryptogenic stroke is often associated with cortical syndromes and milder deficits, stroke subtypes cannot be distinguished on the basis of clinical symptoms alone. In patients with cryptogenic stroke, the most frequently found abnormalities with echocardiography are patent foramen ovale (PFO), atrial septal aneurysm (ASA), and aortic https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 9/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate atheromas [61,62]. The timing of transesophageal echocardiography (<72 hours versus >72 hours) in relation to the index stroke does not appear to alter sensitivity [63]. The clinical significance of many of these findings is still unclear, with conflicting studies on the relative risks and appropriate management. EVALUATION AND DIAGNOSIS In its most useful clinical role, cryptogenic stroke is a diagnosis of exclusion based upon a thorough investigation for potential stroke etiologies. The diagnosis of cryptogenic stroke is made when a standard evaluation (see 'Standard evaluation' below) reveals no probable cause; there is no definite evidence of cardioembolism, large artery atherosclerosis (stenosis >50 percent) in the vessel supplying the area of infarction, small artery disease, or other determined etiology, and no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) or on 24-hour cardiac monitoring. Patient age influences the relative likelihood of possible ischemic stroke mechanisms [4]. Cervicocephalic artery dissection is the most common cause in young adults (variably defined as <45 years of age); other considerations include congenital cardiac defects, recent pregnancy, hypercoagulable states, illicit drug use, metabolic disorders, and migraine. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Etiologies and risk factors in young adults'.) Premature atherosclerosis and acquired cardiac disease are increasingly prevalent in adults older than 30 years of age, and occult atrial fibrillation is increasingly discovered in patients older than 60 years of age [4]. Standard evaluation The standard evaluation of patients with acute ischemic stroke includes a history and physical examination, brain imaging to determine the location and topography of the lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. Additional studies can be pursued if the standard evaluation fails to determine the probable cause. (See "Initial assessment and management of acute stroke" and "Overview of the evaluation of stroke".) Brain imaging Urgent brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory in all patients with sudden neurologic deterioration or https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 10/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate acute stroke (see "Neuroimaging of acute stroke"). Brain MRI with diffusion-weighted imaging is superior to noncontrast CT for the detection of acute ischemia, small infarcts, and infarcts located in the brainstem. The localization, topography, and distribution of ischemic brain lesions on MRI and CT can suggest a specific stroke mechanism [4,64]: Isolated superficial cerebral or cerebellar infarction suggests an embolic mechanism from a large artery, heart, or aorta Cortical or large subcortical infarcts in multiple vascular territories suggest a proximal source of embolism from the heart or aorta Infarcts of varying age in a single vascular territory suggest a large artery source of embolism Infarcts along the boundary regions between the major cerebral arteries (ie, border zone or watershed regions) suggest the stroke mechanism is low flow (hypoperfusion) or multiple small emboli Small subcortical infarcts suggest lacunar infarction from small vessel disease The diagnosis of small vessel disease as the cause of ischemic stroke is generally confirmed by neuroimaging when the location of a small noncortical infarct on CT or MRI correlates with the clinical features of a lacunar stroke syndrome. However, a small deep infarct may be considered cryptogenic when found in a patient <50 years of age with no standard vascular risk factors and no white matter hyperintensities or prior small deep infarcts [4,65]. Vessel imaging Vessel imaging to identify the lesion (eg, atherosclerotic stenosis or occlusion, dissection) responsible for stroke can be done with magnetic resonance angiography (MRA), computed tomography angiography (CTA), carotid duplex ultrasonography and transcranial Doppler ultrasonography, or conventional angiography (see "Neuroimaging of acute stroke"). Neurovascular imaging should assess the extracranial (internal carotid and vertebral) and intracranial (internal carotid, vertebral, basilar, and Circle of Willis) large vessels. Noninvasive methods are generally used unless urgent endovascular therapy is planned. MRA or CTA is preferred, while the combination of ultrasound methods (duplex and transcranial Doppler) can be used if CTA and MRA are unavailable or contraindicated. Availability and expertise at individual centers are major factors in the choice of the initial noninvasive neurovascular studies. Various neuroimaging modalities may be used to confirm a diagnosis of dissection, but fat- saturated T1 MRI is capable of revealing the intramural hematoma caused by dissection in vessels that otherwise have a normal appearance on MRA and CTA. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 11/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Conventional angiography is usually reserved for situations where acute intraarterial intervention is being considered and for follow-up when noninvasive studies are inconclusive. Cardiac and aortic evaluation The basic cardiac evaluation of acute ischemic stroke includes an electrocardiogram, cardiac monitoring for at least the first 24 hours after stroke onset to look for occult atrial fibrillation (AF), and echocardiography. (See "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are effective diagnostic tests for the evaluation of suspected cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE may be especially helpful to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve or suspected infectious or marantic endocarditis Patients with suspected aortic pathology For patients 60 years of age with an embolic-appearing cryptogenic stroke or TIA, particularly those who lack cardiovascular risk factors, we suggest TEE when TTE is nondiagnostic. The TEE https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 12/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate should be performed with color Doppler study and agitated saline contrast injection at rest, with cough, and Valsalva maneuver. Although data are limited, a prospective study of 61 patients with embolic stroke of undetermined source (ESUS) found that abnormalities on TEE changed the therapeutic strategy in 16 percent [66]. Another prospective study enrolled patients with ischemic stroke, TIA, or retinal infarction of undetermined cause prior to cardiac imaging (and therefore not selected by criteria for ESUS); for 453 patients evaluated with both TTE and TEE, the treatment was changed after TEE in approximately 3 percent, and the classification of the cause of stroke was changed in 11.5 percent [67]. Transcranial Doppler with agitated saline may also be used to identify patent foramen ovale (PFO), atrial septal defect, and intrapulmonary shunting, and appears to be more sensitive than echocardiography to identify and quantify right-to-left intracardiac shunting [68]. TEE may provide greater morphological detail of the atrial septal wall, however. (See "Patent foramen ovale", section on 'Diagnosis and evaluation' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) Evaluation for PFO-associated stroke The diagnosis of stroke or TIA due to paradoxical embolism through a PFO or atrial septal defect has traditionally been one of exclusion; a PFO or atrial septal defect has been considered a potential cause of cryptogenic embolic stroke or TIA in patients who are 60 years of age with no other identifiable cause. However, it is now recognized that patients with an embolic stroke who have a medium- or high-risk PFO and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke. Stroke risk classification of PFO is based on anatomic and clinical factors including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism and is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) A relatively simple scoring system incorporating age of the patient, traditional stroke risk factors, and prior history of stroke can be used to estimate the likelihood that an otherwise unexplained stroke could be attributed to a PFO. The Risk of Paradoxical Embolism (RoPE) score ( table 4) estimates the probability that a PFO is incidental or pathogenic in a patient with an otherwise-cryptogenic stroke. The PFO-attributable fraction of stroke derived from the RoPE score ( table 5) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The score can thus be used to help neurologists and cardiologists decide which patients should undergo PFO closure. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 13/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The PFO-associated stroke causal likelihood (PASCAL) classification system estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [69]. The classification uses the RoPE score combined with anatomic and clinical factors and categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 6). (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) In presence of a PFO or atrial septal defect, it is reasonable to search for a source of thrombus in the leg veins with Doppler of the lower extremities as standard test and obtain a hypercoagulable panel in those <45 years of age. Pelvic magnetic resonance venography is of limited utility but could be used in specific scenarios (eg, recent pelvic surgery or mass) [70,71]. Advanced evaluation Additional testing, particularly further cardiac monitoring for atrial fibrillation, is warranted for patients with ischemic stroke when the cause is undetermined despite a standard evaluation described above. However, there is no consensus or strong evidence base regarding the use of more advanced or specialized investigations for rare causes of ischemic stroke [72]. Prolonged cardiac monitoring We suggest ambulatory cardiac monitoring for several weeks (eg, 30 days) for adult patients with a cryptogenic ischemic stroke or cryptogenic TIA (ie, no atrial fibrillation on initial monitoring) who have any of the following [73-76]: Age 50 years or older Abnormal P wave morphology on ECG Frequent ectopy or paroxysmal tachycardia on ECG or short-term monitoring/telemetry Atrial enlargement by echocardiography Elevated cardiac biomarkers such as N-terminal pro-brain natriuretic peptide (NT- proBNP) or troponin T Family history of atrial fibrillation The rationale is that paroxysmal atrial fibrillation, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous

Cardiac and aortic evaluation The basic cardiac evaluation of acute ischemic stroke includes an electrocardiogram, cardiac monitoring for at least the first 24 hours after stroke onset to look for occult atrial fibrillation (AF), and echocardiography. (See "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) Both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are effective diagnostic tests for the evaluation of suspected cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE may be especially helpful to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve or suspected infectious or marantic endocarditis Patients with suspected aortic pathology For patients 60 years of age with an embolic-appearing cryptogenic stroke or TIA, particularly those who lack cardiovascular risk factors, we suggest TEE when TTE is nondiagnostic. The TEE https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 12/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate should be performed with color Doppler study and agitated saline contrast injection at rest, with cough, and Valsalva maneuver. Although data are limited, a prospective study of 61 patients with embolic stroke of undetermined source (ESUS) found that abnormalities on TEE changed the therapeutic strategy in 16 percent [66]. Another prospective study enrolled patients with ischemic stroke, TIA, or retinal infarction of undetermined cause prior to cardiac imaging (and therefore not selected by criteria for ESUS); for 453 patients evaluated with both TTE and TEE, the treatment was changed after TEE in approximately 3 percent, and the classification of the cause of stroke was changed in 11.5 percent [67]. Transcranial Doppler with agitated saline may also be used to identify patent foramen ovale (PFO), atrial septal defect, and intrapulmonary shunting, and appears to be more sensitive than echocardiography to identify and quantify right-to-left intracardiac shunting [68]. TEE may provide greater morphological detail of the atrial septal wall, however. (See "Patent foramen ovale", section on 'Diagnosis and evaluation' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) Evaluation for PFO-associated stroke The diagnosis of stroke or TIA due to paradoxical embolism through a PFO or atrial septal defect has traditionally been one of exclusion; a PFO or atrial septal defect has been considered a potential cause of cryptogenic embolic stroke or TIA in patients who are 60 years of age with no other identifiable cause. However, it is now recognized that patients with an embolic stroke who have a medium- or high-risk PFO and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke. Stroke risk classification of PFO is based on anatomic and clinical factors including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism and is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PFO assessment'.) A relatively simple scoring system incorporating age of the patient, traditional stroke risk factors, and prior history of stroke can be used to estimate the likelihood that an otherwise unexplained stroke could be attributed to a PFO. The Risk of Paradoxical Embolism (RoPE) score ( table 4) estimates the probability that a PFO is incidental or pathogenic in a patient with an otherwise-cryptogenic stroke. The PFO-attributable fraction of stroke derived from the RoPE score ( table 5) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The score can thus be used to help neurologists and cardiologists decide which patients should undergo PFO closure. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 13/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The PFO-associated stroke causal likelihood (PASCAL) classification system estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [69]. The classification uses the RoPE score combined with anatomic and clinical factors and categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 6). (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) In presence of a PFO or atrial septal defect, it is reasonable to search for a source of thrombus in the leg veins with Doppler of the lower extremities as standard test and obtain a hypercoagulable panel in those <45 years of age. Pelvic magnetic resonance venography is of limited utility but could be used in specific scenarios (eg, recent pelvic surgery or mass) [70,71]. Advanced evaluation Additional testing, particularly further cardiac monitoring for atrial fibrillation, is warranted for patients with ischemic stroke when the cause is undetermined despite a standard evaluation described above. However, there is no consensus or strong evidence base regarding the use of more advanced or specialized investigations for rare causes of ischemic stroke [72]. Prolonged cardiac monitoring We suggest ambulatory cardiac monitoring for several weeks (eg, 30 days) for adult patients with a cryptogenic ischemic stroke or cryptogenic TIA (ie, no atrial fibrillation on initial monitoring) who have any of the following [73-76]: Age 50 years or older Abnormal P wave morphology on ECG Frequent ectopy or paroxysmal tachycardia on ECG or short-term monitoring/telemetry Atrial enlargement by echocardiography Elevated cardiac biomarkers such as N-terminal pro-brain natriuretic peptide (NT- proBNP) or troponin T Family history of atrial fibrillation The rationale is that paroxysmal atrial fibrillation, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. The optimal monitoring method (ie, continuous telemetry, ambulatory electrocardiography, serial ECG, transtelephonic ECG monitoring, or insertable cardiac monitor, also sometimes referred to as implantable cardiac monitor or implantable loop recorder) is uncertain, though longer durations of monitoring are likely to obtain the highest diagnostic yield. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 14/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Advanced cardiac imaging Cardiac structural imaging with MRI can be helpful for identifying potential sources of embolism that may be missed by echocardiography, including left ventricular thrombi, isolated left ventricular noncompaction, and complex aortic atheroma [64,77]. (See "Clinical utility of cardiovascular magnetic resonance imaging" and "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Thromboembolism from aortic plaque".) Cardiac CT and CT angiography may also be useful for the detection of cardiac thrombi and to assess left ventricular morphology [78-83]. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".) Vascular studies Advanced vascular imaging can be useful for demonstrating lesions that escape detection on standard MRA and CTA. These are considered in specific scenarios such as small vessel vasculitis or vasculopathy (eg, catheter angiography) or subclinical atherosclerotic plaques (eg, high-resolution MRA). Conventional angiography is superior to standard noninvasive methods (MRA, CTA, and ultrasonography) for visualizing small and medium sized arteries. Digital subtraction angiography, the most widely used method of conventional catheter-based angiography, remains the gold standard for determining the degree of arterial stenosis and for identifying some nonatherosclerotic vasculopathies (see "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'). The yield of catheter angiography may be highest in the first hours after stroke onset, since vascular abnormalities may resolve in the acute phase [4]. Monitoring with transcranial Doppler (TCD) ultrasonography for 30 to 60 minutes may be useful to detect asymptomatic microemboli arising from the heart, aorta, or large arteries, and thereby point to the possible embolic source of the cryptogenic stroke. (See "Management of asymptomatic extracranial carotid atherosclerotic disease", section on 'Asymptomatic embolism'.) Advanced, high-resolution MRI techniques allow direct visualization of the vessel wall, rather than just luminal narrowing as detected by conventional imaging [84]. These methods show promise for the evaluation of intracranial arterial pathology, such as differentiating atherosclerotic, vasospastic, and inflammatory vasculopathies, demonstrating nonstenotic plaques that occlude penetrating arteries, and identifying features that suggest plaque vulnerability, including in substenotic plaques (see 'Substenotic atherosclerotic disease' above) [85-89]. However, high-resolution MRI has https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 15/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate limited availability and requires further study to establish reliability and to determine how well imaging findings correlate with vessel pathology [84]. Hematologic testing Hematologic testing for arterial hypercoagulable states (eg, antiphospholipid syndrome and hyperhomocysteinemia) is indicated for many patients with cryptogenic stroke, particularly for patients who are young, have a history of lupus or symptoms compatible with lupus, or have features suggestive of antiphospholipid syndrome such as unexplained venous or arterial thrombotic events, miscarriages, or unexplained thrombocytopenia [90]. (See "Clinical manifestations of antiphospholipid syndrome" and "Overview of homocysteine", section on 'Vascular disease'.) In addition to testing for the antiphospholipid syndrome, additional testing for hypercoagulable states associated with venous thrombosis (eg, Factor V Leiden mutation, prothrombin gene mutation, protein S deficiency, protein C deficiency, and antithrombin deficiency) is suggested by some experts for patients with evidence of a cardiac or pulmonary right-to-left shunt [4]. For patients with cryptogenic stroke and systemic or constitutional symptoms suggestive of vasculitis, screening tests include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum cryoglobulins, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and complement levels. (See "Overview of and approach to the vasculitides in adults".) Another consideration is testing ADAMTS13 activity, particularly in patients with low platelet counts; in rare cases, ischemic stroke may be the presenting finding or occur during remission in individuals with thrombotic thrombocytopenic purpura (TTP), which is caused by deficient activity of the ADAMTS13 protease [91-93]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.) Specialized evaluation In some patients with recurrent cryptogenic stroke in whom standard and advanced evaluations are nondiagnostic, a search for other rare causes may be indicated [4]. Specialized testing may include the following investigations: Testing for occult malignancy with mammography, stool Hemoccult, and CT of the chest, abdomen, and pelvis. A lumbar puncture with cerebrospinal fluid analysis for patients with symptoms suggestive of primary angiitis of the central nervous system (PACNS), such as unexplained TIA or https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 16/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate stroke (often multiple strokes in different vascular territories), headache, spinal cord dysfunction, or cognitive impairment. (See "Primary angiitis of the central nervous system in adults".) A brain biopsy, which is required to diagnose patients with suspected vasculitis, intravascular lymphoma, or certain infectious causes. Studies to detect a pulmonary arteriovenous malformation, a rare cause of ischemic stroke, which may be suspected in patients who have features such as a nodule on chest radiography, stigmata of a right-to-left shunt (eg, cyanosis, clubbing, history of ischemic stroke or brain abscess), unexplained hemoptysis, hypoxemia or dyspnea, and patients with suspected or known hereditary hemorrhagic telangiectasia. A delayed right-to-left shunt is often detected on transthoracic echocardiography with contrast (ie, bubble study) and the diagnosis can be confirmed with chest CT or pulmonary angiography. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) TREATMENT Acute therapy for patients with cryptogenic stroke is no different from other types of ischemic stroke (see 'Acute therapy' below). The choice of antithrombotic therapy for secondary prevention is challenging because no clear treatment target can be identified. (See 'Secondary prevention' below.) Acute therapy Intravenous thrombolysis with tPA (alteplase) is beneficial for eligible patients with ischemic stroke who can be treated within 4.5 hours of stroke onset, and mechanical thrombectomy using a second-generation stent retriever device is beneficial for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation. Acute management for patients with cryptogenic stroke who are not eligible for these interventions is also similar to patients with other ischemic stroke subtypes. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Secondary prevention For secondary prevention, most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies. Currently viable strategies include blood pressure reduction, antithrombotic therapy, statin therapy, and lifestyle modification. (See "Overview of secondary prevention of ischemic stroke".) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 17/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antiplatelet therapy Antiplatelet therapy is recommended for most patients with noncardioembolic stroke, including cryptogenic TIA and stroke, as outlined in the algorithms ( algorithm 1 and algorithm 2) [94,95]. However, the choice of antithrombotic therapy for secondary stroke prevention after cryptogenic TIA or stroke is challenging because no clear treatment target can be identified, with the exception of a patent foramen ovale (PFO) with right- to-left shunt (see 'Presence of a PFO' below). (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) There is a high degree of uncertainty regarding the optimal management of patients with cryptogenic stroke who have an isolated atrial septal aneurysm (ASA), or atheromatous aortic disease. The optimal management of specific coagulation disorders is also unclear at the moment. Therefore, antiplatelet therapy is usually recommended for patients with cryptogenic stroke who have these conditions [94,95]. Lack of benefit with anticoagulation There is no proven benefit of anticoagulation compared with antiplatelet therapy for preventing recurrent ischemic stroke in patients with cryptogenic stroke, including those with embolic stroke of undetermined source (ESUS). Direct oral anticoagulants (DOACs) such as rivaroxaban and dabigatran should not be used as empiric treatment for patients with cryptogenic stroke, including ESUS. The NAVIGATE- ESUS trial randomly assigned over 7200 patients with ESUS to treatment with rivaroxaban or aspirin [96]. The trial was stopped early for futility after an interim analysis showed no benefit of rivaroxaban on the rate of stroke or systemic embolism but an increase in major bleeding in the rivaroxaban arm. Likewise, the RE-SPECT ESUS trial, with over 5300 patients with ESUS, found that rate of stroke (of any type) at 19 months was similar in the groups assigned to dabigatran or aspirin (4.1 and 4.8 percent per year, respectively) [97]. In the multicenter, double-blind COMPASS trial, over 27,000 patients with stable atherosclerotic vascular disease were randomly assigned to rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). A secondary analysis of ischemic stroke subtypes identified 291 patients who had an ischemic stroke during follow-up; among this group, criteria for ESUS were met in 42 (14 percent) [98]. ESUS was less likely in the rivaroxaban-plus-aspirin group compared with the aspirin-only group (HR 0.30, 95% CI 0.12-0.74). In addition to inherent limitations as a secondary analysis, this trial was not conducted among those with history of cryptogenic stroke and so cannot be used to determine optimal therapy for those with cryptogenic stroke. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 18/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate The Warfarin-Aspirin Recurrent Stroke Study (WARSS) compared aspirin with warfarin in the prevention of recurrent ischemic stroke among noncardioembolic stroke patients and found no superiority of warfarin over aspirin [99]. Among patients with cryptogenic stroke, the event rate (recurrent stroke or death) at two years was not significantly different for the warfarin-treated group compared with the aspirin-treated group (15.0 versus 16.5 percent, respectively). A post hoc analysis of WARSS data showed that warfarin therapy was associated with significantly fewer recurrent strokes or deaths at two years compared with aspirin in selected subgroups of patients with cryptogenic stroke: those with mild stroke severity (National Institutes of Health Stroke Scale score 5), those with posterior circulation infarcts sparing the brainstem, and those with no hypertension at baseline [100]. In the subgroup of patients with cryptogenic stroke who had an infarct topography consistent with an embolic mechanism, the event rate was lower with warfarin compared with aspirin (12 versus 18 percent, HR 0.66, 95% CI 0.37-1.15), but this difference did not achieve statistical significance. In another post-hoc analysis of WARSS data, there was a significant reduction in the composite end point of stroke or death favoring warfarin over aspirin treatment among patients with highly elevated levels of N-terminal pro-brain natriuretic peptide (NT- proBNP), a marker associated with atrial fibrillation and cardiac dysfunction [101]. Since these results come from post-hoc analyses based on relatively small numbers of patients, they must be interpreted with great caution, and further prospective studies are needed to determine if warfarin is beneficial in specific subgroups of patients with cryptogenic stroke. Pending long-term cardiac monitoring As above, we recommend antiplatelet therapy while awaiting the results of long-term cardiac monitoring to detect atrial fibrillation in patients with a first cryptogenic stroke and continuing antiplatelet therapy if no atrial fibrillation is detected on long-term monitoring. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Some stroke experts use anticoagulation when there is a high suspicion for a cardiac source of embolism despite the lack of evidence from randomized trials to support such an approach. For example, while awaiting the results of long-term cardiac monitoring, some experts would start empiric oral anticoagulation at hospital discharge for patients with acute embolic stroke that is cryptogenic after standard evaluation if there are multiple risk factors for occult atrial fibrillation [4]. These include higher CHA DS -VASc score ( table 7), the presence of cortical or large 2 2 subcortical infarcts in multiple vascular territories, and evidence of left atrial cardiopathy (eg, left atrial dilatation, strain, reduced emptying fraction, left atrial appendage size and single lobe morphology, increased P wave dispersion on electrocardiogram [ECG], and frequent premature atrial complex [PAC; also referred to a premature atrial beat, premature supraventricular https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 19/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate complex, or premature supraventricular beat]) [4]. Further antithrombotic treatment is directed by the presence or absence of atrial fibrillation detected on 30-day cardiac monitoring. Occult or subclinical atrial fibrillation on monitoring We suggest anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC) for patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke. Most experts agree that occult or subclinical atrial fibrillation found on long-term monitoring should be treated with anticoagulants [95]. However, there is no consensus regarding the use of anticoagulant treatment for patients when monitoring detects only very brief (eg, 30 seconds) or rare episodes of paroxysmal atrial fibrillation. Presence of a PFO Patients with an embolic stroke who have a medium- or high-risk PFO are now classified as having a PFO-associated stroke [69]. Percutaneous PFO closure in addition to antiplatelet therapy is suggested for most patients age 60 years with an embolic-appearing ischemic stroke who have a PFO, no other evident source of stroke despite a comprehensive evaluation, and a possible, probable, or definite likelihood by the PASCAL classification ( table 6) that the PFO was causally associated with the stroke. PFO closure is reviewed in greater detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Recurrent cryptogenic stroke For patients on antiplatelet therapy who have a recurrent cryptogenic stroke and no atrial fibrillation on re-evaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet agent; for patients with recurrent embolic stroke of undetermined source (see 'Embolic stroke of undetermined source' above), switching to empiric anticoagulant therapy is also a reasonable option. PROGNOSIS Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis at three months, six months, and one year. Approximately 50 to 60 percent of patients score <2 on the modified Rankin Scale ( table 8) at follow-up [38,58,59,102]. Mortality rates are lower than those for cardioembolic stroke but higher than those for small artery disease. Overall, the short-term risk of recurrent stroke after cryptogenic stroke is intermediate between the high early risk after large artery atherosclerosis stroke and low risk after small artery disease stroke. In the Oxford meta-analysis of four large population-based studies, the risk of recurrent stroke after cryptogenic stroke was 1.6 percent at seven days, 4.2 percent at one month, and 5.6 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 20/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate percent at three months [103]. In the NINDS Stroke Data Bank, 3 percent of patients with cryptogenic stroke had recurrent events at one month [104]. In the NOMASS study at three months, the risk of recurrence for the cryptogenic group was 3.7 percent [105], slightly lower than those found in the Oxford meta-analysis [103]. At two years, recurrence risk ranges from 14 to 20 percent [33,99,102]. In the Stroke Data Bank, cryptogenic stroke had the lowest two-year recurrence risk and was an independent predictor of low recurrence risk [106]. At five years, the long-term recurrence risk was 33.2 percent in Rochester, not significantly different from the other subtypes [102]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Classification Cryptogenic stroke is defined as brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a thorough vascular, cardiac, and serologic evaluation. Embolic stroke of undetermined source (ESUS) is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources. ESUS represents a subset of cryptogenic stroke. (See 'Classification' above.) Cause The pathophysiology of cryptogenic stroke is likely heterogeneous. Proposed mechanisms include cardiac embolism secondary to occult paroxysmal atrial fibrillation, aortic atheromatous disease or other cardiac sources, paradoxical embolism from atrial septal abnormalities such as patent foramen ovale (PFO), hypercoagulable states, and preclinical or subclinical cerebrovascular disease. (See 'Possible mechanisms' above.) Epidemiology Cryptogenic stroke accounts for 25 to 40 percent of ischemic stroke. (See 'Epidemiology and risk factors' above.) Presentation Cryptogenic stroke presents with superficial hemispheric infarction in the majority of patients, and a significant proportion of cryptogenic strokes adhere to embolic infarct topography on brain imaging. (See 'Clinical features' above.) https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 21/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Diagnosis Cryptogenic stroke is a diagnosis of exclusion. The diagnosis is made when a standard evaluation reveals no definite evidence of cardioembolism, large artery atherosclerosis, small artery disease, or other determined etiology, and no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) and on 24-hour cardiac monitoring. Additional studies can be pursued if the standard evaluation fails to determine the probable cause. We suggest prolonged (eg, 30 days) ambulatory cardiac monitoring for select patients with a cryptogenic ischemic stroke or cryptogenic transient ischemic stroke (TIA) who are age 50 years or have abnormal P wave morphology, ectopy, paroxysmal tachycardia, atrial enlargement, elevated cardiac biomarkers, or a family history of atrial fibrillation. (See 'Evaluation and diagnosis' above.) Management The acute management of cryptogenic stroke is similar to that of other ischemic stroke subtypes. For secondary prevention, most patients with an ischemic stroke or TIA should be treated with blood pressure reduction, antithrombotic therapy, statin therapy, and lifestyle modification. However, the optimal antithrombotic therapy of patients with cryptogenic stroke who have atrial septal aneurysm, atheromatous aortic disease, or coagulation disorders is uncertain. (See 'Treatment' above.) For patients with a first cryptogenic stroke, we recommend antiplatelet therapy rather than anticoagulant therapy while awaiting the results of long-term cardiac monitoring (Grade 1B). (See 'Pending long-term cardiac monitoring' above.) For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, we suggest anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC) rather than antiplatelet therapy (Grade 2C). (See 'Occult or subclinical atrial fibrillation on monitoring' above.) Percutaneous PFO closure in addition to antiplatelet therapy is suggested for most patients age 60 years with an embolic-appearing ischemic stroke who have a PFO, no other evident source of stroke despite a comprehensive evaluation, and a possible, probable, or definite likelihood by the PASCAL classification ( table 6) that the PFO was causally associated with the stroke. PFO closure is reviewed in greater detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) For patients on antiplatelet therapy who have a recurrent cryptogenic stroke and no atrial fibrillation on re-evaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet agent; for https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 22/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate patients with recurrent ESUS, switching to empiric anticoagulant therapy is also a reasonable option. (See 'Recurrent cryptogenic stroke' above.) Outcomes Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis and lower long-term risk of recurrence. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Mitchell SV Elkind, MD, MS, FAAN, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984; 15:740. 2. Foulkes MA, Wolf PA, Price TR, et al. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 1988; 19:547. 3. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 4. Saver JL. CLINICAL PRACTICE. Cryptogenic Stroke. N Engl J Med 2016; 374:2065. 5. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 6. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 7. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 8. Kamel H, Merkler AE, Iadecola C, et al. Tailoring the Approach to Embolic Stroke of Undetermined Source: A Review. JAMA Neurol 2019; 76:855. 9. Kamel H, Navi BB, Parikh NS, et al. Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source. Stroke 2020; 51:e203. 10. Ntaios G, Pearce LA, Veltkamp R, et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke 2020; 51:1797. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 23/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 11. Boeckh-Behrens T, Kleine JF, Zimmer C, et al. Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke. Stroke 2016; 47:1864. 12. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 13. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129:2094. 14. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 15. Fonseca AC, Alves P, In cio N, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke 2018; 49:734. 16. Kamel H, Okin PM, Longstreth WT Jr, et al. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11:323. 17. He J, Tse G, Korantzopoulos P, et al. P-Wave Indices and Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. Stroke 2017; 48:2066. 18. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 19. Abushora MY, Bhatia N, Alnabki Z, et al. Intrapulmonary shunt is a potentially unrecognized cause of ischemic stroke and transient ischemic attack. J Am Soc Echocardiogr 2013; 26:683. 20. Ahn KT, Choi JH, Park SW. Pulmonary arteriovenous fistula in a patient with cryptogenic stroke. Heart 2011; 97:2093. 21. Alhazzaa M, Sharma M, Stotts G. A case report of an isolated pulmonary arteriovenous malformation causing stroke. Can J Neurol Sci 2011; 38:158. 22. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 23. Cottin V, Chinet T, Lavol A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore) 2007; 86:1. 24. Komatsu T, Iguchi Y, Arai A, et al. Large but Nonstenotic Carotid Artery Plaque in Patients With a History of Embolic Stroke of Undetermined Source. Stroke 2018; 49:3054. 25. Kamel H, Navi BB, Merkler AE, et al. Reclassification of Ischemic Stroke Etiological Subtypes on the Basis of High-Risk Nonstenosing Carotid Plaque. Stroke 2020; 51:504. 26. Goyal M, Singh N, Marko M, et al. Embolic Stroke of Undetermined Source and Symptomatic Nonstenotic Carotid Disease. Stroke 2020; 51:1321. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 24/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 27. Ospel JM, Singh N, Marko M, et al. Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source. Stroke 2020; 51:1743. 28. Fakih R, Roa JA, Bathla G, et al. Detection and Quantification of Symptomatic Atherosclerotic Plaques With High-Resolution Imaging in Cryptogenic Stroke. Stroke 2020; 51:3623. 29. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke 2008; 39:1142. 30. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke. Stroke 2009; 40:713. 31. Bonaventura A, Vecchi A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21:319. 32. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 33. Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32:2735. 34. Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003; 34:2050. 35. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 36. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. Cerebrovasc Dis 2001; 12:145. 37. Li L, Yiin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol 2015; 14:903. 38. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32:2559. 39. Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke 2009; 40:1195. 40. Ornello R, Degan D, Tiseo C, et al. Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis. Stroke 2018; 49:814. 41. Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the northern Manhattan stroke study. Stroke 2002; 33:2789. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 25/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 42. Adams HP Jr, Kappelle LJ, Biller J, et al. Ischemic stroke in young adults. Experience in 329

reasonable option. (See 'Recurrent cryptogenic stroke' above.) Outcomes Compared with other stroke subtypes, cryptogenic stroke tends to have a better prognosis and lower long-term risk of recurrence. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Mitchell SV Elkind, MD, MS, FAAN, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kunitz SC, Gross CR, Heyman A, et al. The pilot Stroke Data Bank: definition, design, and data. Stroke 1984; 15:740. 2. Foulkes MA, Wolf PA, Price TR, et al. The Stroke Data Bank: design, methods, and baseline characteristics. Stroke 1988; 19:547. 3. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 4. Saver JL. CLINICAL PRACTICE. Cryptogenic Stroke. N Engl J Med 2016; 374:2065. 5. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 6. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 7. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 8. Kamel H, Merkler AE, Iadecola C, et al. Tailoring the Approach to Embolic Stroke of Undetermined Source: A Review. JAMA Neurol 2019; 76:855. 9. Kamel H, Navi BB, Parikh NS, et al. Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source. Stroke 2020; 51:e203. 10. Ntaios G, Pearce LA, Veltkamp R, et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke 2020; 51:1797. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 23/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 11. Boeckh-Behrens T, Kleine JF, Zimmer C, et al. Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke. Stroke 2016; 47:1864. 12. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 13. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129:2094. 14. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 15. Fonseca AC, Alves P, In cio N, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke 2018; 49:734. 16. Kamel H, Okin PM, Longstreth WT Jr, et al. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11:323. 17. He J, Tse G, Korantzopoulos P, et al. P-Wave Indices and Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. Stroke 2017; 48:2066. 18. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 19. Abushora MY, Bhatia N, Alnabki Z, et al. Intrapulmonary shunt is a potentially unrecognized cause of ischemic stroke and transient ischemic attack. J Am Soc Echocardiogr 2013; 26:683. 20. Ahn KT, Choi JH, Park SW. Pulmonary arteriovenous fistula in a patient with cryptogenic stroke. Heart 2011; 97:2093. 21. Alhazzaa M, Sharma M, Stotts G. A case report of an isolated pulmonary arteriovenous malformation causing stroke. Can J Neurol Sci 2011; 38:158. 22. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259. 23. Cottin V, Chinet T, Lavol A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: a series of 126 patients. Medicine (Baltimore) 2007; 86:1. 24. Komatsu T, Iguchi Y, Arai A, et al. Large but Nonstenotic Carotid Artery Plaque in Patients With a History of Embolic Stroke of Undetermined Source. Stroke 2018; 49:3054. 25. Kamel H, Navi BB, Merkler AE, et al. Reclassification of Ischemic Stroke Etiological Subtypes on the Basis of High-Risk Nonstenosing Carotid Plaque. Stroke 2020; 51:504. 26. Goyal M, Singh N, Marko M, et al. Embolic Stroke of Undetermined Source and Symptomatic Nonstenotic Carotid Disease. Stroke 2020; 51:1321. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 24/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 27. Ospel JM, Singh N, Marko M, et al. Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source. Stroke 2020; 51:1743. 28. Fakih R, Roa JA, Bathla G, et al. Detection and Quantification of Symptomatic Atherosclerotic Plaques With High-Resolution Imaging in Cryptogenic Stroke. Stroke 2020; 51:3623. 29. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke 2008; 39:1142. 30. Mazighi M, Labreuche J, Gongora-Rivera F, et al. Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke. Stroke 2009; 40:713. 31. Bonaventura A, Vecchi A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol 2021; 21:319. 32. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 33. Kolominsky-Rabas PL, Weber M, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32:2735. 34. Schulz UG, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003; 34:2050. 35. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 36. Lee BI, Nam HS, Heo JH, et al. Yonsei Stroke Registry. Analysis of 1,000 patients with acute cerebral infarctions. 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Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004; 35:46. 72. McMahon NE, Bangee M, Benedetto V, et al. Etiologic Workup in Cases of Cryptogenic Stroke: A Systematic Review of International Clinical Practice Guidelines. Stroke 2020; 51:1419. 73. Marks D, Ho R, Then R, et al. Real-world experience with implantable loop recorder monitoring to detect subclinical atrial fibrillation in patients with cryptogenic stroke: The value of p wave dispersion in predicting arrhythmia occurrence. Int J Cardiol 2021; 327:86. 74. Favilla CG, Ingala E, Jara J, et al. Predictors of finding occult atrial fibrillation after cryptogenic stroke. Stroke 2015; 46:1210. 75. Diederichsen SZ, Haugan KJ, Brandes A, et al. Incidence and predictors of atrial fibrillation episodes as detected by implantable loop recorder in patients at risk: From the LOOP study. Am Heart J 2020; 219:117. 76. Suzuki S, Sagara K, Otsuka T, et al. Usefulness of frequent supraventricular extrasystoles and a high CHADS2 score to predict first-time appearance of atrial fibrillation. Am J Cardiol 2013; 111:1602. 77. Takasugi J, Yamagami H, Noguchi T, et al. Detection of Left Ventricular Thrombus by Cardiac Magnetic Resonance in Embolic Stroke of Undetermined Source. Stroke 2017; 48:2434. 78. Boussel L, Cakmak S, Wintermark M, et al. Ischemic stroke: etiologic work-up with multidetector CT of heart and extra- and intracranial arteries. Radiology 2011; 258:206. 79. Hur J, Kim YJ, Lee HJ, et al. Cardiac computed tomographic angiography for detection of cardiac sources of embolism in stroke patients. Stroke 2009; 40:2073. 80. Sipola P, Hedman M, Onatsu J, et al. Computed tomography and echocardiography together reveal more high-risk findings than echocardiography alone in the diagnostics of stroke etiology. Cerebrovasc Dis 2013; 35:521. 81. Groeneveld NS, Guglielmi V, Leeflang MMG, et al. CT angiography vs echocardiography for detection of cardiac thrombi in ischemic stroke: a systematic review and meta-analysis. J Neurol 2020; 267:1793. 82. Aimo A, Kollia E, Ntritsos G, et al. Echocardiography versus computed tomography and cardiac magnetic resonance for the detection of left heart thrombosis: a systematic review and meta-analysis. Clin Res Cardiol 2021; 110:1697. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 28/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 83. Kauw F, Velthuis BK, Takx RAP, et al. Detection of Cardioembolic Sources With Nongated Cardiac Computed Tomography Angiography in Acute Stroke: Results From the ENCLOSE Study. Stroke 2023; 54:821. 84. Bodle JD, Feldmann E, Swartz RH, et al. High-resolution magnetic resonance imaging: an emerging tool for evaluating intracranial arterial disease. Stroke 2013; 44:287. 85. Klein IF, Lavall e PC, Touboul PJ, et al. In vivo middle cerebral artery plaque imaging by high- resolution MRI. Neurology 2006; 67:327. 86. Ryu CW, Jahng GH, Kim EJ, et al. High resolution wall and lumen MRI of the middle cerebral arteries at 3 tesla. Cerebrovasc Dis 2009; 27:433. 87. Swartz RH, Bhuta SS, Farb RI, et al. Intracranial arterial wall imaging using high-resolution 3- tesla contrast-enhanced MRI. Neurology 2009; 72:627. 88. Mandell DM, Matouk CC, Farb RI, et al. Vessel wall MRI to differentiate between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis: preliminary results. Stroke 2012; 43:860. 89. Klein IF, Lavall e PC, Mazighi M, et al. Basilar artery atherosclerotic plaques in paramedian and lacunar pontine infarctions: a high-resolution MRI study. Stroke 2010; 41:1405. 90. Salehi Omran S, Hartman A, Zakai NA, Navi BB. Thrombophilia Testing After Ischemic Stroke: Why, When, and What? Stroke 2021; 52:1874. 91. Badugu P, Idowu M. Atypical Thrombotic Thrombocytopenic Purpura Presenting as Stroke. Case Rep Hematol 2019; 2019:7425320. 92. Albo Z, Mathew C, Catton R, et al. Thrombotic Thrombocytopenic Purpura (ADAMTS13 [a Disintegrin and Metalloproteinase With a Thrombospondin Type 1 Motif, Member 13] Deficiency) as Cause of Recurrent Multiterritory Ischemic Strokes. Stroke 2022; 53:e237. 93. Upreti H, Kasmani J, Dane K, et al. Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors. Blood 2019; 134:1037. 94. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 95. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 96. Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med 2018; 378:2191. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 29/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate 97. Diener HC, Sacco RL, Easton JD, et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N Engl J Med 2019; 380:1906. 98. Perera KS, Ng KKH, Nayar S, et al. Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes: A Secondary Analysis of the COMPASS Trial. JAMA Neurol 2020; 77:43. 99. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345:1444. 100. Sacco RL, Prabhakaran S, Thompson JL, et al. Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis 2006; 22:4. 101. Longstreth WT Jr, Kronmal RA, Thompson JL, et al. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke 2013; 44:714. 102. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. Stroke 2000; 31:1062. 103. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62:569. 104. Sacco RL, Foulkes MA, Mohr JP, et al. Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke 1989; 20:983. 105. Moroney JT, Bagiella E, Paik MC, et al. Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke 1998; 29:2118. 106. Hier DB, Foulkes MA, Swiontoniowski M, et al. Stroke recurrence within 2 years after ischemic infarction. Stroke 1991; 22:155. Topic 1090 Version 45.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 30/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate GRAPHICS TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 31/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Causative Classification System (CCS) of ischemic stroke etiology Stroke Level of Criteria mechanism confidence 1. Either occlusive or stenotic ( 50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or thrombosis) vascular disease judged to be caused by Large artery Evident atherosclerosis atherosclerosis in the clinically relevant extracranial or intracranial arteries, and 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery 1. History of 1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month, or Probable 2. Evidence of near-occlusive stenosis or nonchronic complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries), or 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible 1. The presence of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of 2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis, at least one event within the last month, or 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 32/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Cardio-aortic embolism Evident The presence of a high-risk cardiac source of cerebral embolism Probable 1. Evidence of systemic embolism, or 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and hemostatic or hemodynamic disturbances must not be present. Possible 1. The presence of a cardiac condition with low or uncertain primary risk of cerebral embolism, or 2. Evidence for evident cardio-aortic embolism in the absence of complete diagnostic investigation for other mechanisms Small artery occlusion Evident Imaging evidence of a single and clinically relevant acute infarction <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc) Probable 1. The presence of stereotypic lacunar transient ischemic attacks within the past week, or 2. The presence of a classical lacunar syndrome Possible 1. Presenting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions, or 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms Other causes Evident The presence of a specific disease process that involves clinically appropriate brain arteries Probable A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions Possible Evidence for an evident other cause in the absence of complete diagnostic investigation for mechanisms listed above https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 33/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Undetermined causes Unknown (no evident, Cryptogenic embolism: 1. Angiographic evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial probable, or possible arteries, or criteria for the causes 2. Imaging evidence of complete recanalization of previously occluded artery, or above) 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels Other cryptogenic: Those not fulfilling the criteria for cryptogenic embolism Incomplete evaluation: The absence of diagnostic tests that, under the examiner's judgment, would have been essential to uncover the underlying etiology Unclassified The presence of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 4.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 34/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low Apical akinesia ejection fraction (<28%) Dilated cardiomyopathy (prior established diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) Wall motion abnormalities (hypokinesia, akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 35/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 36/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 37/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 38/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 39/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 40/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 41/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 42/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 43/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results

150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 38/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 39/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 40/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 41/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 42/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 43/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 44/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 45/46 7/6/23, 12:29 PM Cryptogenic stroke and embolic stroke of undetermined source (ESUS) - UpToDate Contributor Disclosures Shyam Prabhakaran, MD, MS Grant/Research/Clinical Trial Support: Agency for Healthcare Research and Quality [Diagnostic error, prehospital care]; National Institutes of Health (NIH) [Stroke]. All of the relevant financial relationships listed have been mitigated. Chinwe Ibeh, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cryptogenic-stroke-and-embolic-stroke-of-undetermined-source-esus/print 46/46

7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Migraine-associated stroke: risk factors, diagnosis, and prevention : Muhammad Ramzan, MD, Sandhya Mehla, MD : Jerry W Swanson, MD, MHPE, Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA, Kristen Eckler, MD, FACOG All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 05, 2023. INTRODUCTION Migraine is a common headache disorder characterized by symptoms that typically occur over several hours to a few days. Migraine-associated stroke (also known as migrainous infarction or migraine-induced stroke) is an uncommon complication of migraine identified by ischemic stroke on neuroimaging that corresponds to prolonged aura symptoms in a patient with migraine. This topic will discuss migraine-associated stroke and stroke prevention for patients with migraine. The general approach to the diagnosis and evaluation of migraine is discussed elsewhere. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".) Other risk factors and preventive treatment for ischemic stroke are discussed separately. (See "Overview of secondary prevention of ischemic stroke".) MIGRAINE-ASSOCIATED ISCHEMIC STROKE Epidemiology Migraine and ischemic stroke are both common conditions. The epidemiology of the intersection of migraine and stroke can be examined by the prevalence of migraine in stroke patients and the incidence of stroke in patients with migraine. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 1/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Prevalence Data on the prevalence of migraine in stroke patients vary in different retrospective studies. A small case-control study of 145 patients in France reported that the prevalence of migraine among patients with ischemic stroke was double that of controls (60 versus 30 percent) [1]. In a European World Health Organization (WHO) collaborative study, the prevalence of migraine in patients with all types of stroke compared with controls was 25 versus 13 percent [2]. However, this study has been criticized on several grounds, including the high proportion of migraine with aura patients compared with those without aura and the high incidence of migrainous stroke (between 20 to 40 percent) among the study participants, a finding that does not concur with clinical experience [3]. Among younger adults with a history of stroke, migraine prevalence rates range between 27 and 34 percent. The Collaborative Group for the Study of Stroke in Young Women found that the prevalence of migraine in females with stroke, other hospitalized patients, and controls was 34, 33, and 24 percent, respectively [4]. In a case-control study of 1668 adults <45 years old with cryptogenic stroke, the prevalence of migraine was 27 percent, compared with 17 percent for matched controls [5]. The applicability of these data to older patients is uncertain. Younger patients have higher baseline prevalence of migraine and lower burden of stroke risks than older patients. Incidence The reported incidence of stroke due to migraine (migrainous infarction) ranges from 0.8 to 3.4 per 100,000 per year [6,7]. However, the true incidence is unknown due to reporting bias and varied criteria used to identify patients with migraine. In a Taiwanese case-control study involving nearly 240,000 patients, the risk of ischemic stroke over a median of 3.6-year interval was higher for patients with a history of migraine than those without (adjusted hazard ratio [aHR] 1.24, 95% CI, 1.1-1.4) [8]. A meta-analysis of nine observational studies found the pooled relative risk (RR) for ischemic stroke among subjects with any type of migraine was 1.73 (95% CI 1.31-2.29) [9]. The strength of this meta-analysis is limited mainly by the case-control nature of many of the studies, with their inherent susceptibility to recall bias. In addition, the included studies were heterogeneous with regard to subject characteristics and cardiovascular disease definitions. Case series and stroke registries have reported migrainous infarction accounts for an estimated 0.2 to 0.8 percent of all ischemic strokes [6,10-13]. However, migraine-induced stroke accounted for 13.7 percent of infarcts in young adults in a study that used a strict definition of migrainous infarction [10]. The epidemiology of ischemic stroke and of migraine are reviewed separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Epidemiology' and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Epidemiology'.) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 2/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Modifiers of risk Among patients with migraine, the risk of ischemic stroke is elevated in those with specific factors including migraine aura, female sex, smoking, and exposure to hormonal contraception [9]. Similar clinical factors have been reported in other studies [8,14]. In a study of nearly 120,000 patients in Taiwan that compared patients with migraine and a propensity score-matched comparison cohort, migraine was associated with an increased risk of ischemic stroke (aHR 1.2, 95% CI 1.1-1.4) with the highest risk among females aged 45 years who had migraine with aura (aHR 4.6, 95% CI 2.5-8.6) [8]. While migraine may confer a risk for stroke, the presence of active migraine headaches may attenuate this risk and indicate a healthy vascular system. In an analysis of patients from the Women s Health Study stratifying patients by present versus past history of migraine, females age 45 years old with an elevated risk of future cardiovascular disease were likelier to have a history of migraine than those with a low risk of future cardiovascular disease but less likely to have an active history of migraine (odds ratio [OR] 0.64, 95% CI 0.5-0.8) [15]. Migraine aura The increased risk of stroke in patients with migraine appears to be driven largely from subjects who have migraine with aura [9,16-18]. In one meta-analysis of 16 cohort studies involving more than 1.1 million patients, migraine was associated with an elevated risk of stroke (aHR 1.4, 95% CI 1.3-1.6) [18]. When stratified by migraine subtype, the risk was elevated for patients with migraine with aura (aHR 1.6, 95% CI 1.3-1.9) but not those with migraine without aura (aHR 1.1, 95% CI 0.9-1.3). In an analysis of more than 27,000 female health professionals from the Women s Health Study cohort, the adjusted incidence rate of major cardiovascular events was 3.36 per 1000 person-years (95% CI 2.72-3.99) for those with migraine with aura and 2.11 per 1000 person-years (95% CI 1.98-2.24) for those with migraine without aura or no migraine history [19]. In addition, migraine appears to be associated with an elevated perioperative stroke risk, driven largely migraine with aura. In a prospective hospital registry of nearly 125,000 surgical patients, the risk of perioperative ischemic stroke was elevated for patients with and without aura but higher for patients with a history of migraine with aura (adjusted OR [aOR] 2.61, 95% CI 1.6-4.3) than those with migraine without aura (aOR 1.6, 95% CI 1.3-2.1) [20]. Female sex There is evidence that females with migraine are at an increased risk of ischemic stroke [9,19,21], but the absolute increase in risk of stroke remains low in the absence of other stroke risk factors [16,22,23]. In the Women s Health Study, patients with migraine experienced four additional ischemic stroke events per 10,000 females each year [22]. However, on a population level, the small increase in absolute risk remains important as the prevalence of females with migraine with aura is over 4 percent [24]. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 3/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Impact of age Baseline thrombotic stroke incidence per 100,000 females increases with increasing age: 3 for ages 15 to 19 years, 11 for ages 15 to 45 years, and 64 for ages 45 to 49 years [25,26]. Impact of aura Meta-analyses have reported the stroke risk to be 2.0 to 2.5 times greater among females with migraine with aura compared with no aura [9,16]. There is some evidence that increased frequency of migraine with aura is related to increased burden of ischemic stroke risk factors [27]. (See 'Migraine aura' above.) Impact of cardiovascular risk factors Stroke risk among females is further increased with hypertension, diabetes, and ischemic heart disease [9,26,28,29]. (See 'Modifiers of risk' above.) Discussions of stroke risk related to estrogen-containing contraception are discussed below. (See 'Estrogen-containing contraception' below.) Estrogen-containing contraception The use of estrogen-containing contraception is associated with an increased relative risk of ischemic stroke in patients with migraine [30]. The absolute risk of stroke remains low for most patients who use estrogen-containing contraception, excluding those with migraine with aura. Studies have estimated a 2- to 16-fold relative risk elevation in this population [30-32]. However, significant limitations of studies of contraception, migraine, and stroke include that they generally combine a wide range of estrogen doses (including doses no longer in typical use), differing progestin components (which may also impact stroke risk), multiple routes of administration (oral pill, vaginal ring, transdermal patch), and different types of migraine (without versus with aura), which other reports have identified as important factors related to stroke risk [33]. Estrogen dose Increasing estrogen dose appears to increase stroke risk. In a large, population-based cohort study in Denmark, the RR of ischemic stroke increased with increasing doses of ethinyl estradiol (20 mcg dose: adjusted RR 0.88-1.53; 30 to 40 mcg doses: adjusted RR 1.40-2.20) [25]. Compared with those with neither migraine nor combination hormonal contraceptive use, the OR of ischemic stroke was highest among those with migraine with aura using combination hormonal therapy (OR 6.1, 95% CI 3.1- 12.1). Aura The presence of aura appears to increase the risk of future stroke among patients taking estrogen-containing contraception. In a systematic review of 15 studies, the risk of stroke for individuals using estrogen-containing contraceptives was higher for patients https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 4/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate with aura compared with without (with aura: aORs of 6.1, 95% CI 31-12.1 versus without aura: OR 1.8, 95% CI 1.1-2.9) [31]. The authors concluded that the review demonstrated "a lack of good quality studies assessing risk of stroke associated with low-dose estrogen use in women with migraine. Further study in this area is needed." These and other impacts of estrogen-containing contraceptives are discussed in greater detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".) Other factors Smoking Smoking is a risk factor for stroke and also modifies the risk of stroke among patients with migraine. In a meta-analysis of studies assessing the association between migraine and cardiovascular risk factors that evaluated the role of smoking, the risk of ischemic stroke was significantly elevated among patients with migraine who smoke (pooled RR 9, 95% CI 4.2-19.3) [9]. Age The risk of stroke among patients with migraine appears to be higher for patients age <45 years compared with older patients [9]. This observation may reflect the higher prevalence of migraine among younger patients and/or the increased burden of other vascular risk factors in older patients. (See 'Epidemiology' above.) Mechanisms The pathophysiology underlying migraine as a risk factor or cause for stroke is not clear. Prolonged or severe changes in cerebral blood flow have been frequently postulated as the cause of migrainous infarction. However, this assumption has been challenged by the limited supportive data and competing nonvascular causes to migraine that may cause or contribute to the risk of stroke. Multiple cerebral, vascular, hematologic, and cardiac mechanisms have been suggested, including the following: Cerebral and neuronal factors Prolongation of cortical spreading depression (CSD) and aura [17] Neuronal glutamatergic hyperexcitability resulting in enhanced susceptibility to ischemic depolarizations [34,35] Dysregulated activity of serotonergic raphe cells causing excitotoxicity [36] Vascular factors Vasospasm and changes in cerebral blood flow [3,37-41] Release of prothrombotic factors or vasoactive peptides [42-47] Endothelial dysfunction [35,48] https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 5/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Prothrombotic factors Increased platelet aggregability [49-51] Elevated von Willebrand factor [46] Higher prevalence of hypercoagulable states [52] Prothrombotic genetic polymorphisms (eg, the methylenetetrahydrofolate reductase C677T variant) [53] (see "Overview of homocysteine", section on 'Disease associations') Cardiac factors Atrial fibrillation attributed to the autonomic dysfunction associated with migraine [54,55] Myocardial infarction associated with migraine leading to cardioembolism [23,56-59] None of the postulated mechanisms have been confirmed as a pathophysiological explanation linking stroke and migraine. However, posterior circulation border zone infarcts in migraine have been most frequently attributed to a combination of low flow (hypoperfusion) and local thromboembolism [60,61]. Shared risk factors In addition, migraine has been associated with other known or putative risk factors for stroke, including: Patent foramen ovale (PFO) [62] (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Right-to-left cardiac shunt' and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults") Cervical artery dissection [63] (see "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Associated conditions and risk factors') Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [64] (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Migraine with aura') Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) [65] (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') Antiphospholipid antibodies and lupus [66-69] (see "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement') Livedo reticularis and Sneddon syndrome [70-73] https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 6/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Sickle cell disease [74] (see "Overview of the clinical manifestations of sickle cell disease", section on 'Neurologic complications') Cardiovascular disease including myocardial infarction [23,56-59] The pathophysiology of migraine is discussed in greater detail separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Pathophysiology'.) Clinical and imaging findings The clinical features of migraine-associated stroke vary according to the criteria used. Data on clinical features of patients who have had acute migrainous infarction and a complete stroke evaluation are limited. The largest study with modern neuroimaging is a case series of 11 patients with migrainous infarction according to strict criteria who were identified from a stroke database of 8137 patients [75]. All patients reported symptoms at onset similar to previous migraine aura without new or atypical symptoms. However, the previously transient aura symptoms persisted. On diffusion-weighted brain magnetic resonance imaging (MRI) sequences, 4 of the 11 patients had multiple foci of acute infarction, mainly in the posterior circulation, while four had a single area of acute infarction in the posterior circulation territory, and three had isolated infarcts in the middle cerebral artery territory ( image 1). Evaluation and diagnosis of migrainous stroke It can be difficult to determine migraine as the cause of stroke; there are no diagnostic findings specific to migraine-induced stroke and experts vary in defining migraine-associated stroke [3,37,76-80]. Patients who develop a stroke during a migraine headache should have a comprehensive evaluation to exclude other possible causes. The diagnosis and evaluation of ischemic stroke are discussed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Diagnostic criteria rd Migrainous infarction The International Classification of Headache Disorders, 3 edition (ICHD-3) defines migrainous infarction by the following features [80]: (A) A migraine attack fulfilling criteria B and C (B) Occurring in a patient with migraine with aura and typical of previous attacks except that one or more aura symptoms persists for >60 minutes (C) Neuroimaging demonstrates ischemic infarction in a relevant area https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 7/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate (D) Not better accounted for by another diagnosis Migrainous infarction also may be called migraine-induced stroke [3]. Migraine-related stroke Some experts have used the term migraine-related stroke for patients whose symptoms do not fulfill all diagnostic criteria for migrainous infarction and also to allow inclusion of patients who have migraine without aura [37]. Since the 1990s, when migraine was thought to have only vascular pathophysiology, several reports have noted the occurrence of migrainous infarction associated with attacks of migraine without aura [76-78]. However, most studies have found no association of migraine without aura and ischemic stroke [80,81]. (See 'Migraine aura' above.) Other experts use migraine-related stroke for cases when additional stroke mechanisms coexist with migraine [79]. Differential diagnosis Both cerebrovascular events and migraine attacks can present as acute transient neurologic events with similar symptoms ( table 1). In addition, acute neurologic symptoms that are persistent may also be caused by either migraine or stroke. Forms of migraine with aura Migraine with aura occurs in about 15 to 20 percent or more of patients with migraine and may mimic stroke [82]. Neuroimaging may be performed for patients with atypical migraine features to exclude stroke. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Diagnostic testing'.) Typical aura Typical migraine aura symptoms develop gradually over 5 to 20 minutes and last less than one hour per symptom; the most common types involve homonymous visual disturbances. Other common types of migraine aura may manifest as sensory, motor, brainstem, or language disturbances. There is usually little clinical difficulty recognizing these aura symptoms as manifestations of migraine when the auras are brief and precede headaches. In addition, migraine aura is typically characterized by positive symptoms (eg, presence of bright lights or visual aberrations) while stroke symptoms typically involve loss of function or negative symptoms (eg, vision loss). (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'.) Other forms of migraine Some forms of migraine present with motor or brainstem symptoms that may mimic transient ischemic attack (TIA) or acute stroke. These include: Sporadic and familial hemiplegic migraine (see "Hemiplegic migraine") Migraine with brainstem aura (see "Migraine with brainstem aura") https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 8/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Retinal or ocular migraine (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Retinal migraine') Hemiplegic and brainstem auras may also be prolonged, requiring neuroimaging evaluation to distinguish from acute stroke. Migraine aura without headache Migraine aura that occurs without headache may be difficult to distinguish from stroke symptoms. This form of migraine was previously known as acephalgic migraine and migraine with acute-onset aura. These symptoms are more common in patients over age 50 years and may also be called late-life migraine accompaniments [83]. Imaging may be required to exclude stroke as cause to these symptoms. Persistent aura without infarction Prolonged symptoms may last for the entire headache, for several days or weeks, or in some cases leave a permanent neurologic deficit. Many such patients have neuroimaging evidence of acute stroke, indicating migrainous infarction. However, some patients have persistent aura without infarction if the aura lasts one week or longer with no evidence of infarction. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Complications of migraine'.) The general approach to the differential diagnosis of migraine is reviewed separately. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Differential diagnosis'.) Other causes of stroke presenting with headache Some patients with ischemic or hemorrhagic cerebrovascular conditions may present neurologic symptoms and headache or with isolated headache without associated focal neurologic impairment, such as weakness, numbness, aphasia, or visual dysfunction [3]. Specific stroke symptoms vary according to the brain regions impacted and some small cerebrovascular lesions may not produce neurologic deficits. Headache may occur due to activation of nociceptors in vascular walls from acute thrombosis or those in dural membranes from local mass effect of bleeding or edema. Cerebrovascular conditions that may commonly present with isolated headache include: Intracranial hemorrhage Subarachnoid hemorrhage Aneurysmal subarachnoid hemorrhage (SAH) frequently presents with acute onset (thunderclap) severe headache [84]. Other patients may present with a prodrome or less severe headaches, frequently called "sentinel https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 9/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate headaches" up to several days prior to overt SAH [85]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation'.) Subdural and epidural hematomas Acute intracranial bleeding in the potential spaces adjacent to the nociceptor-containing dural membranes can present with acute or chronic headaches. Epidural hematomas may present with headache due to bleeding between the dura and inner table of the skull, but additional neurologic deficits from mass effect on the underlying brain tissue are common, such as hemiparesis or impaired consciousness. Similarly, subdural hematomas (SDH), due to bleeding between the dura and arachnoid membranes, can present with headache with or without other neurologic deficits. Patients with chronic SDH are likelier to present with nonfocal symptoms such as isolated headache, but symptoms may be progressive if the bleeding expands. (See "Intracranial epidural hematoma in adults" and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) Intracerebral hemorrhage For patients with intracerebral hemorrhage (ICH), headache may occur acutely at stroke onset or may occur within hours of onset as the hematoma gradually expands and begins to compress pain sensitive intracranial structures such as larger arteries and the meninges. Large volume intracerebral hemorrhages may present with headache that is typically associated with nausea and/or vomiting and a decreased level of consciousness due to mass effect of the bleeding and brain compression. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'.) Ischemic stroke Headache can occasionally occur with TIA or ischemic stroke due to acute arterial thromboembolism. For patients with ischemic stroke of large vessel origin, headache may occur prior to, during, or after stroke onset [86]. In one prospective study of 284 patients with acute ischemic stroke, concomitant headache during the early phase of stroke was reported by 38 percent [87]. Although the cause is often unclear, several plausible mechanisms have been postulated, including vascular dilation as a homeostatic response to ischemia and direct arterial irritation by thrombus, embolism, or dissection [88]. (See "Clinical diagnosis of stroke subtypes", section on 'Associated symptoms'.) Headache may be common with specific ischemic stroke presentations and causes, including the following: Cervical internal carotid artery dissection Cervical internal carotid artery dissection may occasionally present with isolated headache or as a migraine mimic with visual scintillating scotomata [89,90]. One study of 161 patients found that nearly 70 percent https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 10/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate of cervical carotid and vertebral dissections were associated with headache, and headache was the initial symptom in 33 to 47 percent [91]. Another study found that 19 of 21 patients with angiographically documented carotid dissection had ipsilateral head pain in one or more regions such as the orbit, frontal region, and side of the head [92]. The head pain was typically acute and severe, and neck pain occurred as well in 12 patients. Approximately three quarters of the 21 patients had ischemic events related to the dissection, with the headache preceding the ischemic symptoms in about half. The relationship of dissection with headache is further complicated because approximately half of patients with cervical artery dissection also have a prior history of migraine. (See 'Mechanisms' above.) Insular cortex infarction Ischemic stroke involving the insula may present with headache [93]. One study using MRI lesion mapping found that infarctions in the insular cortex were significantly associated with headache, perhaps related to the role of this region in pain processing [94]. Headache is uncommon in subcortical small vessel stroke syndromes. (See "Clinical diagnosis of stroke subtypes" and "Overview of the evaluation of stroke".) Posterior circulation infarction Multiple observational studies have reported an association between headache and acute ischemic stroke involving the posterior arterial circulation [93,95-97]. A meta-analysis of observational studies of adults with ischemic stroke found that the prevalence of headache in patients with posterior circulation stroke was nearly twice that of patients with anterior circulation stroke (OR 1.9, 95% CI 1.4-2.6) [98]. Migraine has also been associated with the presence of asymptomatic stroke-like lesions in the posterior circulation on brain MRI in patients without a clinical history of stroke. (See 'Subclinical brain lesions' below.) Malignant hemispheric infarction Headache due to cerebral edema may develop in patients with large ischemic strokes but is typically associated with additional neurologic deficits. (See "Malignant cerebral hemispheric infarction with swelling and risk of herniation".) Cerebral venous thrombosis Headache is the most common clinical feature of cerebral venous thrombosis (CVT) being present in nearly 90 percent of patients [99]. Headache characteristics in CVT may be focal or diffuse and can mimic migraine but are frequently gradually progressive. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Headache'.) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 11/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Reversible cerebral vasoconstriction syndromes Reversible cerebral vasoconstriction syndrome (RCVS) is a group of conditions characterized by reversible narrowing of the cerebral arteries. The clinical presentation of RCVS is usually dramatic with sudden, severe "thunderclap" headaches that simulate aneurysmal SAH; however, in patients with RCVS, thunderclap headaches often recur over a span of one to four weeks. The etiology of RCVS is unknown, though the reversible nature of the vasoconstriction suggests an abnormality in the control of cerebrovascular tone. Recurrence of an episode of RCVS is rare, but some patients develop chronic headaches after RCVS, which are usually migrainous in nature. RCVS is discussed in greater detail separately. (See "Reversible cerebral vasoconstriction syndrome".) Others Headache may also be a presenting feature of other cerebrovascular conditions. These conditions share a common pathophysiology involving failure of cerebral blood flow autoregulation or endothelial dysfunction [100]. Reversible posterior leukoencephalopathy syndrome [101] (see "Reversible posterior leukoencephalopathy syndrome") Hypertensive encephalopathy [100,102] (see "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults") Cerebral hyperperfusion syndrome [103] (see "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome') Stroke-like migraine attacks after radiation therapy (SMART) [104] (see "Delayed complications of cranial irradiation", section on 'Migraine-like headache (SMART) syndrome') Cerebral arteriovenous malformation (AVM) [105,106] (see "Brain arteriovenous malformations", section on 'Clinical presentation') Moyamoya disease and syndrome [107] (see "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Other manifestations') Vasculitis involving the central nervous system (both primary and systemic) [108-111] (see "Primary angiitis of the central nervous system in adults" and "Overview of and approach to the vasculitides in adults") https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 12/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate CADASIL [112,113] (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Migraine with aura') Some of these conditions may present with headaches that have migrainous features. Patients with cerebral AVMs may present with migraine-like attacks that lateralize to the same cerebral hemisphere [105,106,114]. Migraine-like headaches are a frequent and early manifestation of both SMART syndrome and CADASIL and may be the sole symptom in some patients. Other conditions in the differential diagnosis of stroke are reviewed elsewhere. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Migraine coincidental with stroke Migraine or other headache may occur coincidentally with stroke since both are common conditions. With advancing age, the prevalence of migraine decreases, while that of stroke increases. In addition, stroke risk factors such as hypertension, diabetes, and heart disease are more common in older age groups. Migraine and stroke may occur together as presenting features of or covariables for other conditions such as antiphospholipid antibody syndrome and CADASIL. (See 'Mechanisms' above.) Management The general approach to the acute stroke treatment of patients with migraine is similar to other patients without migraine. Acute stroke management is discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Ischemic stroke management'.) Treatment aimed at primary or secondary stroke prevention in patients with migraine or nonspecific headache is not well studied, but an approach combining stroke risk factor control with migraine prophylaxis seems most reasonable. Patients with additional stroke risk factors such as hypertension, tobacco use, or high-estrogen-containing oral contraception should be informed about the increased stroke risk, and efforts should be taken to minimize risks. Education Patients with migraine should be taught to recognize the early warning signs of stroke to prevent confusion between migraine aura and TIA ( table 1) and to seek appropriate intervention. Similarly, clinicians should be aware of the potentially increased risk of stroke in the migraine population and should not dismiss focal symptoms in their evaluation of these patients. (See "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Distinguishing transient attacks'.) Managing medications Specific medication management strategies for patients with stroke and migraine are discussed below. (See 'Managing medications that impact stroke risk' below.) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 13/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate General preventive therapy for stroke and treatment of migraine are discussed in greater detail separately. (See "Overview of primary prevention of cardiovascular disease".) (See "Overview of secondary prevention of ischemic stroke".) (See "Acute treatment of migraine in adults".) (See "Preventive treatment of episodic migraine in adults".) OTHER MIGRAINE-ASSOCIATED CEREBROVASCULAR MANIFESTATIONS Intracerebral hemorrhage Most studies have reported on the association between migraine and ischemic stroke. However, migraine has been identified as a possible risk factor for other cerebrovascular conditions, including intracerebral hemorrhage [23]. The relationship of migraine with intracerebral hemorrhage is supported by a meta-analysis of eight studies (four case-control and four cohort), which found that the overall pooled effect estimate of hemorrhagic stroke was 1.48 (95% CI 1.16-1.88) for subjects with any migraine [115]. Subclinical brain lesions Several prospective population-based studies have found an association between migraine with aura and silent infarct-like lesions on brain MRI [11,60,116- 118]. However, the etiology, nature, and clinical significance of the MRI lesions reported in these studies remains unclear [118,119]. Two patterns of brain lesions have been associated with migraine with aura: Infarct-like lesions in the posterior circulation territory In a population-based study of 4689 subjects from Iceland, subjects were evaluated at a mean age of 51 years and then reevaluated at a mean age of 76 years by interview and brain MRI. Those subjects who reported migraine with aura at the initial evaluation had an increased risk of infarct-like lesions 25 years later (adjusted odds ratio [aOR] 1.4, 95% CI 1.1-1.8) [117]. This result was driven mainly by an increased risk of cerebellar infarct-like lesions in the subgroup of females who had migraine with aura (odds ratio [OR] 1.9, 95% CI 1.4-2.6). Migraine with (but not without) aura was also associated with an increased risk for subclinical posterior circulation territory infarct-like lesions in a cross-sectional study of Dutch adults aged 30 to 60 years [116]. Most lesions were in the cerebellum. In another study report, patients with migraine had a significantly increased prevalence of small infratentorial hyperintense lesions, most located in the mid-pons [120]. White matter lesions - A 2013 systematic review and meta-analysis of four clinic-based case-control studies found that white matter lesions were more common in subjects with https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 14/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate migraine compared with controls [118]. The association was significant for migraine with aura (OR 1.68, 95% CI 1.07-2.65) but not for migraine without aura (OR 1.34, 95% CI 0.96- 1.87). By contrast, a subsequent population-based study found that severe white matter disease was associated with migraine without aura (OR 1.87, 95% CI 1.04-3.37) but not with migraine with aura (OR 0.55, 95% CI 0.17-1.83) [121]. In this study, a history of migraine was not associated with white matter lesion progression over time [121]. MANAGING MEDICATIONS THAT IMPACT STROKE RISK Indications for antithrombotic therapy The indications for antithrombotic therapy are not impacted by migraine, either with or without aura. Primary prevention Primary prevention of stroke with aspirin or other antiplatelet therapy is not warranted for patients with migraine with or without aura in the absence of cardiovascular risk factors. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Assessing benefits and risks'.) Secondary prevention Secondary stroke prevention with antiplatelet or anticoagulant medications is warranted for patients with and without migraine who have a history of transient ischemic attack (TIA) or stroke. (See "Overview of secondary prevention of ischemic stroke", section on 'Antithrombotic therapy'.) Use of estrogen-containing therapies While estrogen-containing therapies are associated with an increased risk of venous thromboembolism and ischemic stroke, these medications can be used safely in many patients with migraine depending on the migraine characteristics (no aura), estrogen indication (contraception or therapy for menopause symptoms), dose, delivery (oral, transdermal), and relative benefits compared with risks. However, estrogen-containing medications are typically avoided in patients with migraine with aura who have a history of stroke or are at elevated risk for cardiovascular disease, including stroke. The cardiovascular impact of estrogen-containing contraceptives is reviewed separately. (See "Combined estrogen-

12/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate CADASIL [112,113] (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)", section on 'Migraine with aura') Some of these conditions may present with headaches that have migrainous features. Patients with cerebral AVMs may present with migraine-like attacks that lateralize to the same cerebral hemisphere [105,106,114]. Migraine-like headaches are a frequent and early manifestation of both SMART syndrome and CADASIL and may be the sole symptom in some patients. Other conditions in the differential diagnosis of stroke are reviewed elsewhere. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Migraine coincidental with stroke Migraine or other headache may occur coincidentally with stroke since both are common conditions. With advancing age, the prevalence of migraine decreases, while that of stroke increases. In addition, stroke risk factors such as hypertension, diabetes, and heart disease are more common in older age groups. Migraine and stroke may occur together as presenting features of or covariables for other conditions such as antiphospholipid antibody syndrome and CADASIL. (See 'Mechanisms' above.) Management The general approach to the acute stroke treatment of patients with migraine is similar to other patients without migraine. Acute stroke management is discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Ischemic stroke management'.) Treatment aimed at primary or secondary stroke prevention in patients with migraine or nonspecific headache is not well studied, but an approach combining stroke risk factor control with migraine prophylaxis seems most reasonable. Patients with additional stroke risk factors such as hypertension, tobacco use, or high-estrogen-containing oral contraception should be informed about the increased stroke risk, and efforts should be taken to minimize risks. Education Patients with migraine should be taught to recognize the early warning signs of stroke to prevent confusion between migraine aura and TIA ( table 1) and to seek appropriate intervention. Similarly, clinicians should be aware of the potentially increased risk of stroke in the migraine population and should not dismiss focal symptoms in their evaluation of these patients. (See "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Distinguishing transient attacks'.) Managing medications Specific medication management strategies for patients with stroke and migraine are discussed below. (See 'Managing medications that impact stroke risk' below.) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 13/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate General preventive therapy for stroke and treatment of migraine are discussed in greater detail separately. (See "Overview of primary prevention of cardiovascular disease".) (See "Overview of secondary prevention of ischemic stroke".) (See "Acute treatment of migraine in adults".) (See "Preventive treatment of episodic migraine in adults".) OTHER MIGRAINE-ASSOCIATED CEREBROVASCULAR MANIFESTATIONS Intracerebral hemorrhage Most studies have reported on the association between migraine and ischemic stroke. However, migraine has been identified as a possible risk factor for other cerebrovascular conditions, including intracerebral hemorrhage [23]. The relationship of migraine with intracerebral hemorrhage is supported by a meta-analysis of eight studies (four case-control and four cohort), which found that the overall pooled effect estimate of hemorrhagic stroke was 1.48 (95% CI 1.16-1.88) for subjects with any migraine [115]. Subclinical brain lesions Several prospective population-based studies have found an association between migraine with aura and silent infarct-like lesions on brain MRI [11,60,116- 118]. However, the etiology, nature, and clinical significance of the MRI lesions reported in these studies remains unclear [118,119]. Two patterns of brain lesions have been associated with migraine with aura: Infarct-like lesions in the posterior circulation territory In a population-based study of 4689 subjects from Iceland, subjects were evaluated at a mean age of 51 years and then reevaluated at a mean age of 76 years by interview and brain MRI. Those subjects who reported migraine with aura at the initial evaluation had an increased risk of infarct-like lesions 25 years later (adjusted odds ratio [aOR] 1.4, 95% CI 1.1-1.8) [117]. This result was driven mainly by an increased risk of cerebellar infarct-like lesions in the subgroup of females who had migraine with aura (odds ratio [OR] 1.9, 95% CI 1.4-2.6). Migraine with (but not without) aura was also associated with an increased risk for subclinical posterior circulation territory infarct-like lesions in a cross-sectional study of Dutch adults aged 30 to 60 years [116]. Most lesions were in the cerebellum. In another study report, patients with migraine had a significantly increased prevalence of small infratentorial hyperintense lesions, most located in the mid-pons [120]. White matter lesions - A 2013 systematic review and meta-analysis of four clinic-based case-control studies found that white matter lesions were more common in subjects with https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 14/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate migraine compared with controls [118]. The association was significant for migraine with aura (OR 1.68, 95% CI 1.07-2.65) but not for migraine without aura (OR 1.34, 95% CI 0.96- 1.87). By contrast, a subsequent population-based study found that severe white matter disease was associated with migraine without aura (OR 1.87, 95% CI 1.04-3.37) but not with migraine with aura (OR 0.55, 95% CI 0.17-1.83) [121]. In this study, a history of migraine was not associated with white matter lesion progression over time [121]. MANAGING MEDICATIONS THAT IMPACT STROKE RISK Indications for antithrombotic therapy The indications for antithrombotic therapy are not impacted by migraine, either with or without aura. Primary prevention Primary prevention of stroke with aspirin or other antiplatelet therapy is not warranted for patients with migraine with or without aura in the absence of cardiovascular risk factors. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Assessing benefits and risks'.) Secondary prevention Secondary stroke prevention with antiplatelet or anticoagulant medications is warranted for patients with and without migraine who have a history of transient ischemic attack (TIA) or stroke. (See "Overview of secondary prevention of ischemic stroke", section on 'Antithrombotic therapy'.) Use of estrogen-containing therapies While estrogen-containing therapies are associated with an increased risk of venous thromboembolism and ischemic stroke, these medications can be used safely in many patients with migraine depending on the migraine characteristics (no aura), estrogen indication (contraception or therapy for menopause symptoms), dose, delivery (oral, transdermal), and relative benefits compared with risks. However, estrogen-containing medications are typically avoided in patients with migraine with aura who have a history of stroke or are at elevated risk for cardiovascular disease, including stroke. The cardiovascular impact of estrogen-containing contraceptives is reviewed separately. (See "Combined estrogen- progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.) Hormonal contraception The decision to start or continue estrogen-containing contraceptive therapy in patients with migraine involves shared decision making after discussing individual risks and benefits of therapy and alternative options. Estrogen-containing contraceptives include oral pills, transdermal patches, and vaginal rings ( figure 1). (See "Contraception: Counseling and selection".) https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 15/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Without aura Patients experiencing migraine without aura who are otherwise candidates for estrogen-containing contraception can safely use estrogen-containing contraceptives, including oral pills, transdermal patches, and vaginal rings [122-124]. If contraceptive pills are selected, formulations containing 35 mcg of ethinyl estradiol, or the equivalent, are preferred ( table 2). Patients who elect estrogen-containing contraceptives should be younger than 35 years if they are smokers and do not have other cardiovascular, thromboembolism, or stroke risk factors [122-124]. Detailed discussions, including supporting data, on candidates and risks related to estrogen-containing contraception are presented separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.) (See "Combined estrogen-progestin contraception: Side effects and health concerns".) With aura Individuals with aura are generally not candidates for estrogen-containing contraceptives [28,122-125]. However, high-quality studies specific to low-dose estrogen products are lacking [31]. Therefore, the use of estrogen-containing contraception in patients with aura should be individualized. For those with a clear indication for estrogen- containing contraceptives, such as endometriosis or those who desire this method after a clear discussion of the risks, their use may be reasonable. Presentation of the data regarding candidates for estrogen-containing contraception, contraindications, and risks associated with use are discussed separately. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".) (See "Combined estrogen-progestin contraception: Side effects and health concerns".) Consideration of other medical conditions We and other experts use comprehensive tables of medical conditions and personal characteristics from the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to counsel patients regarding safe use of the various hormonal methods of contraception [122,123]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Candidates'.) Menopausal hormone therapy Concerns have been raised that estrogen-containing hormone therapy for symptoms of menopause may increase stroke risk. However, available data conflict, in part because of variables such as patient age and medical comorbidities as well as https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 16/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate estrogen dose and route of administration. These issues are reviewed in detail in related content. (See "Menopausal hormone therapy and cardiovascular risk".) The safety of menopausal hormone therapy, either estrogen alone or estrogen plus progestin, in patients with migraine varies by migraine type and the patient s thromboembolic risk. Patients who should avoid estrogen We avoid estrogen-containing menopausal hormone therapy for patients with migraine with aura and a history of stroke or those at high risk (eg, >10 percent 10-year risk) for cardiovascular disease including stroke (calculator 1). For these patients, we use nonhormonal options that are not associated with an elevated risk of thromboembolic complications. (See "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'.) Estrogen use acceptable Menopausal estrogen therapy is acceptable for patients with migraine with or without aura and otherwise at low risk of cardiovascular disease (ie, 10 percent 10-year risk). The rationale is that the estrogen therapy for menopausal symptoms is not a supraphysiologic dose (as it is with estrogen-containing contraceptives). (See "Menopausal hormone therapy: Benefits and risks".) (See "Treatment of menopausal symptoms with hormone therapy".) Additional discussion on use of estrogen therapy in peri- and postmenopausal patients with migraine is discussed separately. (See "Estrogen-associated migraine headache, including menstrual migraine", section on 'Peri- and postmenopause'.) Medications to avoid Some medications are avoided in those who have migraine with aura and a history of stroke, TIA, or cardiovascular disease due the risk of cerebral ischemia. These include vasoconstrictive medications: Triptans Ergotamine derivatives Serotonin antagonists (eg, pizotifen and methysergide) In a case-control study of patients prescribed ergotamine or triptans, 188 patients hospitalized with ischemic events were age and sex-matched with 689 controls. Ergotamine overuse was a risk factor for ischemic complications (odds ratio [OR] 2.55, 95% CI 1.22-5.36); but triptan overuse was not [126]. However, cases of cardiac arrest, cerebral infarcts, and spinal cord infarcts have been reported in the setting of triptan use [127-131]. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 17/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate We also avoid long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) in older patients and in patients with other uncontrolled risk factors for stroke due to the elevated risk of thrombotic cardiovascular events [132]. (See "NSAIDs: Adverse cardiovascular effects", section on 'NSAIDs and cardiovascular events'.) We suggest that beta blockers should not be used as initial therapy for migraine prophylaxis in patients over age 60 years and in patients who smoke. Compared with other antihypertensive drugs in the primary treatment of hypertension, beta blockers may be associated with a higher rate of stroke and other cardiovascular events. (See "Choice of drug therapy in primary (essential) hypertension".) The safety of calcitonin gene-related peptide antagonists has not been established for patients with a migraine with aura and a history of or uncontrolled risk factors for stroke [133,134]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Migraines in adults (The Basics)") https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 18/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Beyond the Basics topics (see "Patient education: Migraines in adults (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)"). SUMMARY AND RECOMMENDATIONS Migraine-associated ischemic stroke Epidemiology The reported incidence of stroke due to migraine (migrainous stroke) ranges from 0.8 to 3.4 per 100,000 per year. Clinical factors associated with an elevated risk of stroke in patients with migraine include (see 'Modifiers of risk' above): - - - - Patients with migraine with aura Female patients Patients who smoke Patients who take estrogen-containing contraception Patients age <45 years Clinical and imaging findings Clinical symptoms of migraine-associated stroke are typically similar to previous migraine aura without new or atypical symptoms. However, the previously transient aura symptoms persist for longer duration. Infarction is frequently located in the posterior circulation and may be multifocal. (See 'Clinical and imaging findings' above.) Diagnosis Migrainous infarction occurs in a patient with migraine with aura that is typical of previous attacks except that one or more aura symptoms persists for >60 minutes. Neuroimaging demonstrates ischemic infarction in a relevant area. (See 'Diagnostic criteria' above.) Differential diagnosis Both cerebrovascular events and migraine attacks can present as acute transient neurologic events with similar symptoms ( table 1). In addition, acute neurologic symptoms that are persistent may also be caused by either migraine or stroke. Management The general approach to the acute stroke treatment of patients with migraine is similar to other patients without migraine. Treatment aimed at primary or secondary stroke prevention in patients with migraine involves combining stroke risk factor control with migraine prophylaxis. Patients should be taught to recognize the https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 19/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate early warning signs of stroke to prevent confusion between migraine aura and transient ischemic attack (TIA) ( table 1) and to seek appropriate intervention. (See 'Management' above.) Migraine and other stroke subtypes Migraine has been identified as a possible risk factor for other cerebrovascular conditions, including intracerebral hemorrhage and silent infarct-like lesions on brain MRI. (See 'Other migraine-associated cerebrovascular manifestations' above.) Managing medications that impact stroke risk Antithrombotic therapy Primary prevention of stroke with aspirin is not warranted for patients with migraine with or without aura in the absence of cardiovascular risk factors. Secondary stroke prevention with antiplatelet or anticoagulant medications is warranted for patients with and without migraine who have a history of TIA or stroke. (See 'Indications for antithrombotic therapy' above.) Estrogen-containing therapies While estrogen-containing therapies are associated with an increased risk of thromboembolism, these medications can be used safely in select patients with migraine depending on the migraine characteristics (no aura), estrogen dose, and relative benefits compared with risks. (See 'Use of estrogen- containing therapies' above.) Hormonal contraception We suggest that patients with migraine with aura avoid estrogen-containing contraceptives (Grade 2C). We give similar guidance to patients with other forms of migraine and an additional risk factor for stroke. Patients who are nonsmokers <35 years, without aura, and have no additional thromboembolic risk factors may consider estrogen-containing contraceptives. If oral contraceptives are selected, we prefer formulations containing 35 mcg or less of estrogen. (See 'Hormonal contraception' above.) Menopausal hormone therapy We suggest that patients with migraine with aura and a history of stroke or at high risk for future cardiovascular disease (calculator 1) avoid estrogen-containing menopausal hormone therapy (Grade 2C). Menopausal estrogen therapy is acceptable for patients with migraine with or without aura who are at low risk of cardiovascular disease, including stroke (ie, 10 percent 10-year risk). (See 'Menopausal hormone therapy' above.) Migraine medications to avoid We avoid triptans, ergotamine derivatives, serotonin antagonists, and long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) for https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 20/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate patients with migraine with aura and a history of stroke or cardiovascular disease. We do not use beta blockers for patients over age 60 years and those who smoke. (See 'Medications to avoid' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Marc Fisher, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Tzourio C, Tehindrazanarivelo A, Igl sias S, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995; 310:830. 2. Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999; 318:13. 3. Diener HC, Welch KMA, Mohr JP. Migraine and stroke. In: Stroke: pathophysiology, diagnosi s, and management, Mohr JP, Choi DW, Grotta JC, et al. (Eds), Churchill Livingstone, Philadel phia 2004. p.629. 4. Oral contraceptives and stroke in young women. Associated risk factors. JAMA 1975; 231:718. 5. Mazzoleni V, Grassi M, Lodigiani C, et al. Migraine and Cryptogenic Ischemic Stroke. 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ACOG Practice Bulletin No. 206: Use of Hormonal Contraception in Women With Coexisting Medical Conditions: Correction. Obstet Gynecol 2019; 133:1288. 125. Sacco S, Merki-Feld GS, gidius KL, et al. Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain 2017; 18:108. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 28/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate 126. Wammes-van der Heijden EA, Rahimtoola H, Leufkens HG, et al. Risk of ischemic complications related to the intensity of triptan and ergotamine use. Neurology 2006; 67:1128. 127. Main ML, Ramaswamy K, Andrews TC. Cardiac arrest and myocardial infarction immediately after sumatriptan injection. Ann Intern Med 1998; 128:874. 128. Kato Y, Hayashi T, Mizuno S, et al. Triptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review. Intern Med 2016; 55:3525. 129. Jayamaha JE, Street MK. Fatal cerebellar infarction in a migraine sufferer whilst receiving sumatriptan. Intensive Care Med 1995; 21:82. 130. Vijayan N, Peacock JH. Spinal cord infarction during use of zolmitriptan: a case report. Headache 2000; 40:57. 131. Aboul Nour H, Miller DJ, Danoun OA. Naratriptan-Associated Spinal Artery Infarction. Am J Ther 2021; 28:e734. 132. Kang DO, An H, Park GU, et al. Cardiovascular and Bleeding Risks Associated With Nonsteroidal Anti-Inflammatory Drugs After Myocardial Infarction. J Am Coll Cardiol 2020; 76:518. 133. Chua AL, Mehla S, Orlova YY. Drug Safety in Episodic Migraine Management in Adults. Part 2: Preventive Treatments. Curr Pain Headache Rep 2022; 26:493. 134. Orlova YY, Mehla S, Chua AL. Drug Safety in Episodic Migraine Management in Adults Part 1: Acute Treatments. Curr Pain Headache Rep 2022; 26:481. Topic 3344 Version 43.0 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 29/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate GRAPHICS Brain MRI migrainous infarction Diffusion-weighted imaging lesion patterns of 11 patients with migrainous infarction. Patients 1 through 4 have multiple small lesions, patients 5 through 8 have isolated lesions in the posterior circulation territory, and patients 9 through 11 have isolated lesions in the middle cerebral artery territory. MRI: magnetic resonance imaging. Reproduced with permission from: Wolf ME, Szabo K, Griebe M, et al. Clinical and MRI characteristics of acute migrainous infarction. Neurology 2011; 76:1911. Copyright 2011 Lippincott Williams & Wilkins. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 30/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Graphic 57203 Version 9.0 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 31/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Clinical features of seizures, syncope, and other paroxysmal neurologic events in adults Clinical Recall of the Diagnostic Duration features event tools Focal seizure Initial symptoms depend on Usually <2 minutes; can be Variable depending on EEG may show interictal spikes location in brain; difficult to whether (poor sensitivity); motor and visual symptoms usually distinguish ictal from postictal consciousness is impaired ambulatory EEG if episodes are "positive" (eg, phase frequent enough; shaking, jerking, flashing lights, or visual distortion); MRI may show structural lesion may have anatomic "march" over seconds; some progress rapidly to GTC Generalized seizure Sudden alteration or loss of consciousness without warning; <5 minutes (for GTC); <1 minute for absence Complete amnesia; patient may recall initial focal symptoms EEG may show generalized spike- and-wave characteristic of some have myoclonic jerks or staring; tongue- biting and urinary incontinence may occur (for GTC) specific syndrome; MRI usually normal for generalized epilepsy syndromes, may show structural lesion if focal onset Psychogenic nonepileptic Fluctuating, asynchronous Rarely <1 minute; often prolonged Variable Video-EEG monitoring seizure motor activity, often with eye (>30 minutes) closure, side-to- side head or body movements, pelvic thrusting; most occur in front of a witness; fully or partially https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 32/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate alert despite bilateral motor activity; tongue- biting is rare Syncope Transient loss of 1 to 2 minutes Patient can recall ECG; consciousness resulting in loss of prodromal symptoms, if echocardiography if structural postural tone; present; lack of cardiac disease is prodrome of lightheadedness, warning may suggest cardiac suspected; ambulatory ECG warm or cold feeing, sweating, source monitoring if arrhythmia is palpitations, pallor; myoclonic suspected; orthostatic blood jerks or tonic pressure posturing may occur, especially if patient is kept measurements upright; no or minimal post- event confusion Transient ischemic attack (TIA) Rapid loss of neurologic function due to interrupted blood flow; symptoms depend on Several minutes to a few hours Usually complete unless language areas involved MRI/MRA, CTA, vascular risk factors vascular territory but are typically "negative" (eg, weakness, numbness, aphasia, visual loss); intensity is usually maximal at onset; consciousness usually preserved Migraine aura Positive and/or negative Up to 1 hour Complete Personal or family history of neurologic symptoms, most migraine often visual and sensory, evolving gradually over 5 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 33/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate minutes (slower onset than TIA or focal seizure); slow spread of positive followed by negative symptoms, if present, is very characteristic; usually followed by headache Panic attack Palpitations, Minutes to hours Complete History of anxiety dyspnea, chest pain, or depressive symptoms, lightheadedness, triggering events sense of impending doom; associated or stressors hyperventilation may result in perioral and distal limb paresthesias Transient global amnesia Prominent anterograde amnesia (inability to form new memories) and 1 to 10 hours (mean 6 hours) Complete amnesia for the main episode; retrograde amnesia resolves Clinical diagnosis; negative MRI and toxicology screens variable retrograde amnesia; patient is disoriented in time, asking within 24 hours repetitive questions; other cognitive and motor functions spared; rare in adults younger than 50 years GTC: generalized tonic-clonic; EEG: electroencephalography; MRI: magnetic resonance imaging; ECG: electrocardiogram; MRA: magnetic resonance angiography; CTA: computed tomography angiography. Graphic 111740 Version 3.0 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 34/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Comparison of effectiveness of contraceptive methods Other methods of contraception: Lactational amenorrhea method LAM is a highly effective, temporary method of contraception Emergency contraception Emergency contraceptive pills or an IUD (copper or LNG) after unprotected intercourse substantially reduces risk of pregnancy LNG: levonorgestrel. Adapted from: U.S. Selected Practice Recommendations for Contraceptive Use, 2013: Adapted from the World Health Organization Selected Practice Recommendations for Contraceptive Use, 2nd Edition. MMWR Morb Mortal Wkly Rep 2013; 62:1. Additional information from: https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 35/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate 1. Trussell J, Aiken ARA, Mickes E, Guthrie K. E cacy, Safety, and Personal Considerations. In: Contraceptive Technology, 21st ed, Hatcher RA, Nelson AL, Trussell J, et al (Eds), Ayer Company Publishers, Inc., New York 2018. Graphic 57795 Version 10.0 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 36/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Selected hormonal contraceptives: Oral contraceptives (birth control pills) and other delivery methods Estrogen United States Progestin (mg)* Notes (micrograms) brand name Monophasic combinations Drospirenone (3) Ethinyl estradiol Also approved for acne and Beyaz (20) premenstrual dysphoric disorder. Jasmiel Lo- In patients with conditions requiring Zumandimine chronic therapy with medications that may increase potassium, monitor serum potassium during the first treatment cycle and periodically Loryna Nikki Vestura thereafter if patient begins medication or develops a condition Yaz that increases risk for hyperkalemia. Packaged as active tablets for 24 days and placebo for 4 days; except Beyaz, which contains 451 mcg of levomefolate per tablet (24 active tablets and 4 levomefolate tablets). Levonorgestrel (0.09) Ethinyl estradiol (20) Amethyst Dolishale Levonorgestrel (0.1) Ethinyl estradiol (20) Packaged as active tablets for 21 days and placebo for 7 days. Afirmelle Aubra EQ Aviane Balcoltra Delyla Falmina Lessina Lutera Sronyx Tyblume Vienva https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 37/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Norethindrone acetate (1) Ethinyl estradiol (20) Packaged as active pills for 24 days and ferrous fumarate for 4 days. Aurovela 24 FE Blisovi 24 Fe Charlotte 24 Fe chewable tablets Finzala chewable tablets Gemmily capsules Hailey 24 Fe Junel Fe 24 Larin 24 Fe Merzee capsules Mibelas 24 Fe chewable tablets Microgestin 24 Fe Minastrin 24 Fe chewable tablets Tarina 24 Fe Taysofy capsules Taytulla capsules https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 38/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Packaged as active tablets for 21 days and ferrous fumarate for 7 days. Aurovela FE 1/20 Blisovi FE 1/20 Hailey FE 1/20 Junel FE 1/20 Larin Fe 1/20 Loestrin Fe 1/20 Microgestin FE 1/20 Tarina FE 1/20 EQ Packaged as active tablets for 21 Aurovela 1/20 days (does not contain iron). Junel 1/20 Larin 1/20 Loestrin 1/20 Microgestin 1/20 Norethindrone (0.8) Ethinyl estradiol (25) Packaged as active tablets for 24 days and ferrous fumarate for 4 days. Generess FE chewable tablets Kaitlib Fe chewable tablets Layolis FE chewable tablets Desogestrel (0.15) Ethinyl estradiol (30) Packaged as active tablets for 21 days and placebo for 7 days. Apri Cyred Cyred EQ Enskyce Isibloom Juleber Kalliga Reclipsen Drospirenone (3) Ethinyl estradiol (30) In patients with conditions requiring chronic therapy with medications Ocella Safyral that may increase potassium, monitor serum potassium during the Syeda Tydemy first treatment cycle and periodically Yasmin thereafter if patient begins https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 39/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Zumandimine medication or develops a condition that increases risk for hyperkalemia. Packaged as active tablets for 21 days and placebo for 7 days; except Safyral and Tydemy, which contain 451 mcg of levomefolate per tablet (21 active tablets and 7 levomefolate tablets). Levonorgestrel Ethinyl estradiol Packaged as active tablets for 21 Altavera (0.15) (30) days and placebo for 7 days. Ayuna Chateal EQ Kurvelo Levora 0.15/30 Marlissa Portia-28 Norethindrone acetate (1.5) Ethinyl estradiol (30) Packaged as active tablets for 21 days and ferrous fumarate for 7 days. Aurovela Fe 1.5/30 Blisovi Fe 1.5/30 Junel FE 1.5/30 Hailey FE 1.5/30 Larin Fe 1.5/30 Loestrin Fe 1.5/30 Microgestin FE 1.5/30 Packaged as active tablets for 21 days (does not contain iron). Aurovela 1.5/30 Junel 1.5/30 Hailey 1.5/30 Larin 1.5/30 Loestrin 1.5/30 Microgestin 1.5/30 Norgestrel (0.3) Ethinyl estradiol Packaged as active tablets for 21 Cryselle-28 (30) days and placebo for 7 days. Elinest Low-Ogestrel Ethynodiol diacetate (1) Ethinyl estradiol (35) Packaged as active tablets for 21 days and placebo for 7 days. Kelnor 1/35 Zovia 1/35 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 40/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Norethindrone (0.4) Ethinyl estradiol (35) Packaged as active tablets for 21 days and placebo for 7 days. Balziva Briellyn Philith Vyfemla Packaged as active tablets for 21 days and ferrous fumarate for 7 days. Wymzya Fe chewable tablets Norethindrone Ethinyl estradiol Packaged as active tablets for 21 Necon 0.5/35 (28) (0.5) (35) days and placebo for 7 days. Nortrel 0.5/35 (28) Wera Norethindrone (1) Ethinyl estradiol (35) Packaged as active tablets for 21 days and placebo for 7 days. Alyacen 1/35 Dasetta 1/35 Nortrel 1/35 (28) Nortrel 1/35 is also available as a 21- day regimen (packaged without placebo). Nylia 1/35 Pirmella 1/35 Norgestimate (0.25) Ethinyl estradiol (35) Packaged as active tablets for 21 days and placebo for 7 days. Estarylla Femynor Mili Mono-Linyah Nymyo Sprintec 28 VyLibra Cyproterone (2) Ethinyl estradiol (35) Labeled approval in Canada is for treatment of acne; provides reliable contraception if taken as Cleo-35 Cyestra-35 Diane-35 recommended for treatment of acne. Packaged as active tablets for 21 days. Not available in the United States; Canadian product shown. Ethynodiol diacetate (1) Ethinyl estradiol (50) Packaged as active tablets for 21 days and placebo for 7 days. Kelnor 1/50 NOTE: Pills containing 50 mcg of ethinyl estradiol are not indicated for routine contraceptive use because of increased risk of https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 41/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate cardiovascular events compared with lower-dose oral contraceptive pills. Drospirenone (3) Estetrol (14.2) Packaged as active tablets for 24 days and placebo for 4 days. Nextstellis NOTE: Estetrol strength listed in In patients with conditions requiring milligrams (mg) chronic therapy with medications that may increase potassium, monitor serum potassium during the first treatment cycle and periodically thereafter if patient begins medication or develops a condition that increases risk for hyperkalemia. Nomegestrol Estradiol (as Packaged as active tablets for 24 Zoely acetate (2.5) hemihydrate) (1.5) days and placebo for 4 days. NOTE: Estradiol strength listed in milligrams (mg) Not available in the United States; United Kingdom and European Union product shown. Multiphasic combinations Dienogest (0,2,3,0) Estradiol valerate (3,2,2,1) Packaged as active tablets for 26 days and placebo for 2 days. Natazia NOTE: Estradiol strength listed in milligrams (mg) Norethindrone acetate (1,0) Ethinyl estradiol (10,10) Packaged as active tablets for 26 days and ferrous fumarate for 2 days. Lo Loestrin Fe Desogestrel Ethinyl estradiol Packaged as active tablets for 26 Azurette (0.15,0,0) (20,0,10) days and placebo for 2 days. Kariva Mircette Pimtrea Simliya Viorele Volnea Norethindrone acetate (1,1,1) Ethinyl estradiol (20,30,35) Also approved for acne. Tilia Fe Tri-Legest Fe Packaged as active tablets for 21 days and ferrous fumarate for 7 days. Norgestimate Ethinyl estradiol Packaged as active tablets for 21 Tri-Lo-Estarylla (0.18,0.215,0.25) (25,25,25) days and placebo for 7 days. Tri-Lo-Marzia Tri-Lo-Mili https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 42/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Tri-Lo-Sprintec Tri-Vylibra Lo Desogestrel (0.1,0.125,0.15) Ethinyl estradiol (25,25,25) Packaged as active tablets for 21 days and placebo for 7 days. Velivet Levonorgestrel (0.05,0.075,0.125) Ethinyl estradiol (30,40,30) Packaged as active tablets for 21 days and placebo for 7 days. Enpresse-28 Levonest Trivora (28) Norgestimate Ethinyl estradiol Also approved for acne. Tri-Estarylla (0.18,0.215,0.25) (35,35,35) Tri-Linyah Packaged as active tablets for 21 Tri-Mili days and placebo for 7 days. Tri-Nymyo Tri-Sprintec Tri-VyLibra Norethindrone (0.5,0.75,1) Ethinyl estradiol (35,35,35) Packaged as active tablets for 21 days and placebo for 7 days. Alyacen 7/7/7 Dasetta 7/7/7 Nortrel 7/7/7 Nylia 7/7/7 Pirmella 7/7/7 Norethindrone (0.5,1,0.5) Ethinyl estradiol (35,35,35) Packaged as active tablets for 21 days and placebo for 7 days. Aranelle Leena Extended combinations (91-day regimens) Levonorgestrel (0.1,0) Ethinyl estradiol (20,10) Packaged as a 91-day regimen: 84 days of the combination and 7 days Camrese Lo LoJaimiess of 10 mcg ethinyl estradiol only. LoSeasonique Levonorgestrel (0.15,0.15,0.15,0) Ethinyl estradiol (20,25,30,10) Packaged as a 91-day regimen: 84 days of the combination and 7 days Fayosim Quartette of 10 mcg ethinyl estradiol only. Rivelsa Levonorgestrel (0.15,0) Ethinyl estradiol (30,10) Packaged as a 91-day regimen: 84 days of the combination and 7 days Amethia Ashlyna of 10 mcg ethinyl estradiol only. Camrese Daysee Jaimiess Seasonique Simpesse Levonorgestrel (0.15) Ethinyl estradiol (30) Packaged as a 91-day regimen: active tablets for 84 days and placebo for 7 Introvale Iclevia days. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 43/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Jolessa Setlakin Continuous combinations May use any monophasic 21/7 combination (eg, Amethyst [levonorgestrel 0.09 mcg-ethinyl estradiol 20 mcg]) by taking active hormone pills for 28 or more days continuously. Any progestin may be used, and higher doses of ethinyl estradiol may be used in some women. Refer to UpToDate topic. Progestin-only Norethindrone (0.35) None Packaged as active tablets for 28 days. Camila Deblitane Errin Heather Incassia Jencycla Lyleq Lyza Nora-BE Norlyroc Sharobel Drospirenone (4) None Packaged as active tablets for 24 days and placebo for 4 days. Slynd In patients with conditions requiring chronic therapy with medications that may increase potassium, monitor serum potassium during the first treatment cycle and periodically thereafter if patient begins medication or develops a condition that increases risk for hyperkalemia. Norgestrel None Packaged as active tablets for 28 Opill (0.075) days. Not in production globally but in review for over-the-counter use in the United States. Desogestrel (0.075) None Packaged as active tablets for 28 days. Cerazette Cerelle Hana Not available in the United States or Canada; United Kingdom product Lovima shown. Zelleta Transdermal patch, weekly https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 44/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Norelgestromin (releases 0.15 Ethinyl estradiol (releases 35 May have diminished efficacy in women 90 kg. Xulane Zafemy mg/day) mcg/day) A new patch is applied every 7 days for 3 weeks followed by a patch-free week. These products are therapeutically equivalent to Ortho Evra patch, which is no longer available in the United States. Levonorgestrel Ethinyl estradiol Contraindicated in women with BMI 30 kg/m due to decreased efficacy and increased risk of VTE. Diminished Twirla 2 (releases 0.12 mg/day) (releases 30 mcg/day) efficacy was observed in women with 2 BMI 25 kg/m . A new patch is applied every 7 days for 3 weeks followed by a patch-free week. Vaginal ring, monthly Etonogestrel (releases 0.12 mg/day) Ethinyl estradiol (releases 15 mcg/day) Ring is inserted for 3 weeks followed by 1 week without ring in place. A new ring is inserted 7 days after the last was removed. NuvaRing EluRyng Haloette Segesterone (releases 0.15 Ethinyl estradiol (releases 13 Ring is inserted for 3 weeks followed by 1 week without ring in place. The Annovera mg/day) mcg/day) ring is then reinserted for the first 21 days of subsequent 28-day cycles. One system provides contraception for 13 28-day cycles (1 year). Not yet adequately evaluated in women with 2 BMI >29 kg/m . Oral and IUD emergency contraceptive options are listed in a table that is available separately in UpToDate. Generic (non-branded) products are also available for most combination oral contraceptives in the United States. Descriptions are for US-available products unless noted otherwise. Consult local product information before use. Fe: contains iron; BMI: body mass index; VTE: venous thromboembolism; IUD: intrauterine device. Different progestins are not equivalent on a milligram basis. Refer to the UpToDate overview of combined hormonal contraceptives for guidance on selection. https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 45/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate The progestin norgestrel contains two isomers; only levonorgestrel is bioactive. The amount of norgestrel in each tablet is twice the amount of levonorgestrel. Adapted from: 1. The Medical Letter on Drugs and Therapeutics, October 8, 2018; Vol. 60 (1557): 161-168. 2. The Medical Letter on Drugs and Therapeutics, May 15, 2023; Vol. 65 (1676): 73-82. 3. Lexicomp online. Copyright 1978-2023 by Lexicomp, Inc. All rights reserved. Graphic 69223 Version 49.0 https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 46/47 7/6/23, 12:30 PM Migraine-associated stroke: risk factors, diagnosis, and prevention - UpToDate Contributor Disclosures Muhammad Ramzan, MD No relevant financial relationship(s) with ineligible companies to disclose. Sandhya Mehla, MD No relevant financial relationship(s) with ineligible companies to disclose. Jerry W Swanson, MD, MHPE Other Financial Interest: Elsevier [Honorarium as editor of texts about migraine]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Kristen Eckler, MD, FACOG No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/migraine-associated-stroke-risk-factors-diagnosis-and-prevention/print 47/47

7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis : Nijasri Charnnarong Suwanwela, MD : Jos Biller, MD, FACP, FAAN, FAHA, Douglas R Nordli, Jr, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 08, 2022. INTRODUCTION Moyamoya is an uncommon cerebrovascular condition characterized by progressive narrowing of large intracranial arteries and the secondary development of prominent small-vessel collaterals. These collateral vessels produce a characteristic smoky appearance on angiography, which was first called "moyamoya," a Japanese word meaning puffy, obscure, or hazy like a puff of smoke in the air. Moyamoya is a progressive disorder that may lead to ischemic stroke or intracranial hemorrhage in children and adults. This topic will review the etiologies, clinical features, and diagnosis of moyamoya. The prognosis and treatment of moyamoya are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) CLASSIFICATION AND TERMINOLOGY The term "moyamoya" describes the specific angiographic findings of unilateral or bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation ( image 1). https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 1/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no associated conditions. This may also be called primary or idiopathic moyamoya disease as well as the descriptive "spontaneous occlusion of the circle of Willis" [1,2]. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition as described below. (See 'Associated conditions' below.) These secondary forms of the condition have been termed "moyamoya phenomenon," "angiographic moyamoya," or "quasi-moyamoya disease" [1,3-5]. ETIOLOGY AND PATHOGENESIS The etiology of MMD is unknown, but genetic associations have been identified. MMS has been associated with multiple conditions, which may implicate diverse pathophysiologic processes leading to the characteristic vascular abnormalities. Genetic associations The high incidence among the Japanese population, together with a familial occurrence of approximately 10 to 15 percent of cases, strongly suggests a genetic etiology. Accumulating evidence suggests that the RNF213 gene on chromosome 17q25.3 is an important susceptibility factor for MMD in populations in several East Asian countries [6-14]. Several reports have also linked familial MMD to chromosomes 3p24.2, p26, 6q25, 8q23, and 12p12 [15-17]. Although the mode of inheritance is not established, one study suggested that familial moyamoya is an autosomal dominant disease with incomplete penetrance [18]. The authors proposed that genomic imprinting and epigenetic modification may account for the predominantly maternal transmission and elevated female-to-male incidence ratio. (See 'Epidemiology' below and "Inheritance patterns of monogenic disorders (Mendelian and non- Mendelian)", section on 'Parent-of-origin effects (imprinting)'.) A later genome-wide association study confirmed the relationship of MMD and a previously reported locus on chromosome 17q25 [19]. The study also identified 10 novel risk loci, including the genes regulating homocysteine metabolism, loci related to large vessel disease, and loci that are highly expressed in the immune system. Associated conditions There are many conditions associated with MMS. They may be causative or syndromic. Some of the conditions reported to be associated with MMS include: Disease affecting arteries around the circle of Willis https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 2/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Atherosclerosis [20] Radiation therapy to the base of the brain [21] (see "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects') Cranial trauma [22] Brain tumors [23-25] Meningitis [26] Other viral or bacterial infection (eg, Cutibacterium acnes, leptospirosis, human immunodeficiency virus [HIV]) [27-29] Hematologic conditions Sickle cell disease [30-32] Beta thalassemia [33] Fanconi anemia [34] Hereditary spherocytosis [35] Homocystinuria and hyperhomocysteinemia [36] Factor XII deficiency [37] Essential thrombocythemia [38] Protein S deficiency [39-41] Pyruvate kinase deficiency [42] Vasculitis and autoimmune and multisystem diseases Systemic lupus erythematosus [43] Polyarteritis nodosa and postinfectious vasculopathy [44] Graves disease and thyroiditis [45-48] Sneddon syndrome and the antiphospholipid antibody syndrome [49,50] Anti-Ro and anti-La antibodies [51] Type 1 diabetes mellitus [48] Pulmonary sarcoidosis [52,53] Genetic and developmental disorders Alagille syndrome [54,55] Down syndrome [56,57] Hypomelanosis of Ito [58] Marfan syndrome [59] Microcephalic osteodysplastic primordial dwarfism type 2 [60] Multisystem disorder with short stature, hypergonadotropic hypogonadism, and dysmorphism [61,62] https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 3/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurofibromatosis type 1 [63-66] Noonan syndrome [67-69] Phakomatosis pigmentovascularis type IIIb [70] Prader-Willi syndrome [71] Pseudoxanthoma elasticum [72] Sturge-Weber syndrome [73] Tuberous sclerosis [74] Turner syndrome [75] Williams syndrome [76] Morning glory optic disc anomaly ( image 2), usually in conjunction with other craniofacial abnormalities [77-79] (see "Congenital and acquired abnormalities of the optic nerve", section on 'Morning glory disc') Other vasculopathies and extracranial cardiovascular diseases Coarctation of the aorta [80] Congenital heart disease [81] Fibromuscular dysplasia [82] Renal artery stenosis [83] Metabolic diseases Type I glycogenosis [84,85] Hyperphosphatasia [86] Primary oxalosis [87] Renal disorders Polycystic kidney disease [88-90] Wilms tumor [83,91-103] Pathogenesis The pathophysiologic processes leading to arterial stenosis and small vessel collateralization involve vessel wall thickening and angiogenesis. A genetic susceptibility may be implicated in MMD, while underlying associated conditions trigger the development of MMS. Vascular changes in moyamoya may be related to impaired response to inflammation or defects in cellular repair mechanisms [104]. Such changes have been associated with evidence of increased angiogenesis-related factors, including endothelial colony-forming cells, various cytokines, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) [105-107]. High levels of fibroblast growth factor, which may stimulate arterial growth, have been found in the vascular intima, media, and smooth muscle as well as cerebrospinal fluid https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 4/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate among patients with moyamoya [108,109]. Transforming growth factor beta-1 (TGFB1), which mediates neovascularization, may also contribute to the pathogenesis [110,111]. High levels of hepatocyte growth factor (a strong inducer of angiogenesis) have been detected in the carotid fork and cerebrospinal fluid in patients with moyamoya [112]. Pathologic findings Tissue analysis in patients with moyamoya shows evidence of arterial vessel narrowing and secondary vascular proliferation characteristic of the disease as well as tissue damage related to the vascular abnormalities. Stroke Brain tissue of patients with moyamoya usually reveals evidence of prior ischemic or hemorrhagic stroke. Multiple areas of cerebral infarction and focal cortical atrophy are commonly found. Although large-vessel stenosis and occlusion are the hallmark of this disease, extensive territorial infarction is uncommon. The brain infarcts are generally small and located in the basal ganglia, internal capsule, thalamus, and subcortical regions [113]. However, the cause of death in most autopsy cases is intracerebral hemorrhage [93]. The hemorrhage is commonly found in the basal ganglia, thalamus, hypothalamus, midbrain, and/or periventricular region. Bleeding into the intraventricular space is frequently observed. Vascular stenosis Pathologic vascular lesions appear in the large vessels of the circle of Willis and in the small collateral vessels [94]. The terminal portions of the internal carotid arteries as well as the proximal middle and anterior cerebral arteries are most commonly involved [114]. Some patients may have unilateral stenosis at presentation, although progression to bilateral involvement may occur [115,116]. Less frequently, the posterior circulation is affected, especially the posterior cerebral artery. In the affected large arteries, variable stenosis or occlusion is associated with intimal fibrocellular thickening, tortuosity or duplication of the internal elastic lamina, and attenuation of the media [91,117-119]. Collateral vessels One of the hallmarks of moyamoya is the presence of a collateral meshwork of overgrown and dilated small arteries, the moyamoya vessels, that branch from the circle of Willis ( image 3). The pathology of the smaller perforating vessels in moyamoya is variable. Morphometric analysis suggests that some are dilated with relatively thin walls, while others are stenotic with thick walls [117]. Dilated vessels, more common in younger patients than in adults, tend to show fibrosis with attenuation of the media and microaneurysm formation. Histologic study from autopsy specimens of aneurysms showed disappearance of internal https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 5/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate elastic lamina and media [92]. These findings are similar to those of the berry aneurysms commonly observed in primary subarachnoid hemorrhage. Leptomeningeal vessels are another source of collaterals in moyamoya. As a result of intracranial internal carotid artery stenosis, leptomeningeal anastomoses may develop from the three main cerebral arteries (middle, anterior, and posterior). These collaterals result from dilatation of preexisting arteries and veins. In addition, transdural anastomoses, termed vault moyamoya, may develop from extracranial arteries such as the middle meningeal and superficial temporal arteries [95]. Aneurysms Cerebral aneurysms have been associated with moyamoya in a number of reports [96-100]. Aneurysms can develop at vessel branching points in the circle of Willis or along collateral vessels [101,120]. In a review of 111 moyamoya patients with cerebral aneurysm, most presented with intracranial hemorrhage and were found to have a single aneurysm in 86 percent of cases. Aneurysms along the circle of Willis were found in 56 percent, of which almost 60 percent were in the posterior circulation [120]. Aneurysms can also arise from the small collateral moyamoya vessels, choroidal arteries, or other peripheral collateral arteries [101]. These small-vessel aneurysms are the major cause of parenchymal (intracerebral) hemorrhage in moyamoya. Extracranial involvement In patients with moyamoya, stenosis due to fibrocellular intimal thickening may also affect the extracranial and systemic arteries, including the cervical carotid, renal, pulmonary, and coronary vessels [91,102]. Involvement of the renal arteries has been most frequently reported. In one study of 86 patients with MMD, six had renal artery stenosis, two had associated renovascular hypertension, and one had a renal artery aneurysm [83]. Similarly, in a later study of 73 consecutive patients with MMD, four had renal artery stenosis [121]. EPIDEMIOLOGY Incidence and prevalence The relative prevalence of MMD and MMS vary geographically. MMD is more common in East Asian countries than elsewhere, with the highest prevalence found in Japan, China, and Korea [114,122,123]. In epidemiologic surveys conducted in Japan, the following observations have been made [124- 127]: The annual incidence of moyamoya is 0.35 to 0.94 per 100,000 population. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 6/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate The prevalence of moyamoya is 3.2 to 10.5 per 100,000 population. There is a female predominance, with a female-to-male ratio of 1.9. A family history of MMD is present in 10 to 12 percent of patients. Using hospital admissions data, a United States study found an incidence of 0.57 per 100,000 persons/year [128]. Among ethnic groups in California, the moyamoya incidence rate for Asian Americans was 0.28 per 100,000, similar to that in Japan. The incidence rates were lower for African American, White American, and Hispanic populations (0.13, 0.06, and 0.03 per 100,000, respectively). The incidence of MMS in Japan is approximately 10 times lower than MMD [129,130]. Age distribution MMD and MMS both occur in children and adults; presentation in infancy is uncommon [131,132]. Data from a nationwide registry in Japan, with 2545 cases of MMD, showed a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second broader peak at approximately 40 years of age [127]. A cohort study of 802 patients with MMD from China also demonstrated a bimodal age distribution, with a major peak at five to nine years of age and another peak at 35 to 39 years of age [133]. CLINICAL PRESENTATIONS Moyamoya has varying clinical presentations; the expression of disease and the age at presentation are influenced by regional and ethnic differences. Ischemic stroke and transient ischemic attack The most common initial presentation of moyamoya is ischemic stroke [134-138]. Transient ischemic attack (TIA) is also a frequent initial presentation and may be recurrent [134,138]. In one retrospective series from the United States, 61 percent of 31 adults with MMD or MMS presented with ischemic symptoms; in those with stroke, the predominant pattern was a border- zone pattern of infarction [137]. In another retrospective study, 21 German patients with MMD all presented with ischemic events, including 16 who were adults at symptom onset [136]. In children, symptomatic episodes of ischemia in the anterior and middle cerebral artery vascular territories may commonly be triggered by exercise, crying, coughing, straining, fever, or hyperventilation [104,139,140]. In the International Pediatric Stroke Study involving 174 children with moyamoya, ischemic stroke was the initial presentation in 90 percent of children and TIA in 7.5 percent [134]. Ischemic symptoms of hemiparesis or speech impairment predominated, reflecting the predilection for stenosis of the anterior cerebral circulation (anterior and middle https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 7/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate cerebral artery territories). In this series, 20 percent of children had recurrent symptoms in the median 13-month follow-up interval. Multiple recurrent events are common in other studies as well, likely reflecting the fixed stenosis susceptible to recurrent hypoperfusion. In one study from Korea of 88 children and adults who were followed for 6 to 216 months, multiple cerebrovascular events occurred in 55 percent [141]. Recurrences were most commonly ischemic. Intracerebral, intraventricular, and subarachnoid hemorrhage While ischemic symptoms may be more common at presentation, hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage (ICH), represent a significant clinical burden. ICH is more common in adults than children [138,142]. In the International Pediatric Stroke Study, ICH was the presenting syndrome in 2.5 percent [134], while, in a series of adult patients, 10 percent of patients presented with intracranial hematoma [137]. In a systematic review, intracerebral hemorrhage at initial presentation was more frequent for patients in China and Taiwan than in the United States [135]. Intraventricular hemorrhage with or without ICH was a common presentation of MMD, according to one report from Korea [143]. In adults who presented with ICH or intraventricular hemorrhage, small aneurysms in the periventricular area have been reported ( image 4). Patients may also present with subarachnoid hemorrhage [144]. Seizures Patients with moyamoya present infrequently with seizures, often secondary to ischemic damage [145]. The rate of epilepsy may be more frequent in children than in adults [142]. Other manifestations Headache Headache is common in patients with moyamoya [146]. Migraine is the most common headache phenotype, but tension-type headache and cluster headache have also been reported [147,148]. Other neurologic symptoms There are case reports of patients with moyamoya who develop dystonia, chorea, or dyskinesia, but these appear to be uncommon manifestations [149-151]. Asymptomatic disease Moyamoya can be found incidentally in asymptomatic patients undergoing screening imaging for other conditions or because of family history [152,153]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 8/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate A nationwide study in Japan using a questionnaire in 1994 identified 33 asymptomatic cases (1.5 percent) out of a total of 2193 patients [154]. INITIAL TEST FINDINGS Because patients with MMD or MMS may present with signs and symptoms of acute cerebrovascular disease, initial testing typically includes neuroimaging. Electroencephalography is often performed in patients with seizures and sometimes in those with transient ischemic attack (TIA). Specific findings on these tests may suggest moyamoya. Neuroimaging Cerebral infarction may involve cortical and subcortical regions ( image 5). Ischemic injury distal to the stenotic or occluded moyamoya vessel is common in superficial and deep border-zone regions most susceptible to hypoperfusion [155]. Patterns of infarction may be suggestive of moyamoya, but these features are not specific for this condition. In a retrospective series of 32 adults with first-ever ischemic stroke, patients with early-stage MMD had ischemic lesions involving only deep subcortical structures, while those with advanced stage had predominantly cortical lesions [156]. In patients with intracerebral hemorrhage (ICH), bleeding occurs in deep structures such as the basal ganglia, thalamus, and/or ventricular system. Bleeding in the cortical and subcortical regions has been reported with lower frequency [157,158]. Asymptomatic cerebral microbleeds were present on T2*-weighted gradient-echo magnetic resonance imaging (MRI) in 30 percent or more of adult patients with MMD [159-161]. One study of 50 patients with moyamoya found that the presence of multiple microbleeds was an independent risk factor for subsequent intracerebral hemorrhage (hazard ratio [HR] 2.89, 95% CI 1.001-13.24) [160]. Additional MRI findings have been implicated in identifying vascular changes consistent with moyamoya: Dilated collateral vessels in the basal ganglia or thalamus can be demonstrated as multiple punctate flow voids, a finding that is considered virtually diagnostic of moyamoya ( image 6) [162]. The "ivy sign" refers to focal, tubular, or serpentine hyperintensities on fluid-attenuated inversion recovery (FLAIR) or contrast-enhanced T1 images in the subarachnoid spaces that represent slow, retrograde collateral flow through engorged pial vessels via leptomeningeal anastomoses ( image 7) [163-165]. Observational data of 48 patients with ischemic symptoms and MMD showed the extent of the ivy sign was associated with a reduction in cerebral vascular reserve assessed by single-photon emission computed https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 9/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate tomography (SPECT) [166]. This sign is not specific for MMS/MMD and has been reported in association with large-vessel stenosis or occlusions, where it is referred to as FLAIR vascular hyperintensities or the hyperintense vessel sign [167]. The "brush sign" refers to prominent hypointensity in medullary veins draining areas of impaired cerebral perfusion on susceptibility-weighted imaging (SWI), a high-spatial- resolution 3D gradient-echo MRI technique that accentuates paramagnetic properties of blood products such as deoxyhemoglobin. In a group of 33 patients, the brush sign was identified more often in moyamoya patients with TIA and infarction than in asymptomatic patients. This sign was also more prominent in those with impaired cerebrovascular reserve ( image 8) [168]. Like the ivy sign, the "brush sign" is not specific for moyamoya and has been identified in patients with subacute stroke from many causes [169]. Post-contrast enhancement within the arterial wall may be seen using high-resolution MRI [170]. One study of 24 patients with moyamoya who underwent high-resolution vessel wall imaging protocol with 3-tesla MRI showed that patients with MMD demonstrated concentric enhancement of the distal internal carotid arteries, whereas patients with intracranial atherosclerotic disease generally had focal and eccentric enhancement of the symptomatic arterial segment [171]. In addition, at six-month follow-up, vessel wall enhancement was found in eight of the nine patients (odds ratio [OR] 36.2, 95% CI 2.8- 475.0), while absence of enhancement was associated with nonprogressive stenosis. This technique may be helpful if angiographic findings on other more routine testing are not diagnostic but may not be readily available in many centers. Electroencephalographic findings Children with MMD often exhibit abnormalities on electroencephalography (EEG). Hyperventilation, performed as a part of EEG protocol, induces generalized high-voltage slow waves (the "build-up" phenomenon) that resolve after hyperventilation stops. The reappearance of generalized or localized high-voltage slow waves on EEG 20 to 60 seconds after the end of hyperventilation (the "rebuild-up" phenomenon) is considered pathognomonic for moyamoya and occurs in approximately two-thirds of affected children [172,173]. Asymmetric posterior alpha activity and centrotemporal slowing have also been described in children with moyamoya. Background abnormalities in children and adults with MMD include nonspecific generalized, asymmetric, or localized slow-wave activity [173,174]. Of note, hyperventilation should be minimized in patients with a diagnosis of moyamoya since it may induce reflex cerebral vasoconstriction [175]. While EEG with hyperventilation was reported https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 10/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate to be safe in one series of 127 children [173], rare reports link hyperventilation to limb-shaking TIA and episodes of chorea and dystonia [176-178]. DIAGNOSIS The diagnosis of moyamoya is made by identifying the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries (or other proximal circle of Willis vessels) along with the presence of prominent collateral vessels ( image 5). MMS is diagnosed by identifying characteristic angiographic features in the setting of an associated condition. MMD is diagnosed in patients with a genetic susceptibility or family history of moyamoya after associated conditions have been excluded. (See 'Associated conditions' above.) Indications for vascular imaging The possibility of MMD disease should be considered in: Children or young adults with repeated symptoms of ischemic attacks resulting from low perfusion in the same arterial territory. Patients who lack common factors for primary intracerebral hemorrhage (ICH) but present with intracerebral hemorrhage in brain regions supplied by small vessels that branch from the circle of Willis (eg, caudate, thalamus, or intraventricular hemorrhage within the lateral ventricles) ( image 9). Children or young adults with ischemic or hemorrhagic stroke who may lack common cerebrovascular risk factors. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis'.) Patients who undergo MRI, particularly in the context of evaluation for cerebral ischemia, that shows associated findings such as dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," the "brush sign," or enhancement of the arterial wall. (See 'Neuroimaging' above.) Diagnostic criteria Definitive diagnosis of moyamoya requires neurovascular imaging. Diagnostic criteria proposed by a Japanese research committee include the following major requirements [4]: Stenosis or occlusion at the terminal portion of the internal carotid artery and at the proximal portion of the anterior and middle cerebral arteries. Abnormal vascular networks in the basal ganglia; these networks can also be diagnosed by the presence of multiple flow voids on brain MRI. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 11/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Angiographic findings are present bilaterally; cases with unilateral angiographic findings are considered probable. For the diagnosis of MMD, underlying associated conditions (suggestive instead of MMS) are excluded. (See 'Further evaluation' below.) Angiography Stenotic distal internal carotid or proximal circle of Willis arteries and prominent collateral vessels can be identified by angiogram, computed tomography angiogram (CTA), or magnetic resonance angiography (MRA). Conventional digital subtraction angiography (DSA) is the gold standard for the diagnosis of MMD. Additionally, DSA is typically required for treatment planning. Characteristic angiographic findings include stenosis or occlusion at the distal internal carotid artery and the origin of the anterior cerebral and middle cerebral arteries on both sides, as well as abnormal vascular networks at the basal ganglia or moyamoya vessels ( image 1). Noninvasive imaging (CTA and MRA) can demonstrate stenotic or occlusive lesions in the distal internal carotid arteries ( image 10) and the arteries around the circle of Willis [179-181]. Although less sensitive than DSA for smaller vessels, noninvasive testing can also visualize the collateral "moyamoya vessels" in the basal ganglia ( image 11). Nevertheless, due to its high diagnostic yield and noninvasive nature, CTA and MRA have supplanted conventional DSA in many centers as the initial imaging modality to evaluate moyamoya [162,181]. Because the vascular changes and associated risks of ischemia or hemorrhage sequelae in MMD and MMS are often progressive, characterizing the degree of vascular abnormality is important. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) Angiographic severity staging systems can provide insight and guidance. Suzuki followed patients with MMD and classified the angiographic progression [182,183]. Further evaluation In the absence of a known genetic predisposition to MMD or known diagnosis associated with MMS (eg, sickle cell anemia), patients should be further evaluated for underlying conditions in order to institute the most appropriate secondary prevention strategy. Evaluation for vasculitis and other metabolic conditions may be indicated when suggestive features of clinical presentation are present. In general, work-up for atherosclerotic risk factors such as diabetes, dyslipidemia, hyperhomocysteinemia, and alternative sources to large-vessel vasculopathy should be performed. (See "Primary angiitis of the central nervous system in adults", section on 'When to suspect the diagnosis' and "Intracranial large artery atherosclerosis: https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 12/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Epidemiology, clinical manifestations, and diagnosis", section on 'Identifying other causes of intracranial stenosis'.) Hemodynamic studies are useful both pre- and postoperatively to help determine cerebrovascular reserve and to assess disease severity and risk of ischemic morbidity. These topics are discussed elsewhere. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Neuroimaging'.) SCREENING IMAGING In general, we do not screen asymptomatic individuals for moyamoya; however, screening with a noninvasive angiographic modality may be reasonable in those with a family history of MMD, particularly individuals from or with families from Eastern Asia. The 2008 American Heart Association Stroke Council guidelines state that there is insufficient evidence to justify screening studies in asymptomatic individuals or in relatives of patients with MMS in the absence of a strong family history of MMD or medical conditions that predispose to MMS [162]. Even in individuals with a strong family history of MMD or those with medical conditions that predispose to MMS, the utility of angiographic screening is unclear, particularly since available medical and surgical treatment of asymptomatic MMD is of uncertain benefit. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification and terminology Moyamoya describes chronic progressive cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. J https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 14/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Neurosurg Pediatr 2012; 9:353. 2. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). 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Liu W, Morito D, Takashima S, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011; 6:e22542. 8. Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 2012; 78:803. 9. Yamauchi T, Tada M, Houkin K, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000; 31:930. 10. Mineharu Y, Liu W, Inoue K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology 2008; 70:2357. 11. Miyawaki S, Imai H, Takayanagi S, et al. Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion. Stroke 2012; 43:3371. 12. Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One 2012; 7:e48179. 13. Bang OY, Ryoo S, Kim SJ, et al. 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Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 2006; 77:1025. 19. Duan L, Wei L, Tian Y, et al. Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study. Stroke 2018; 49:11. 20. Lee SJ, Ahn JY. Stenosis of the proximal external carotid artery in an adult with moyamoya disease: moyamoya or atherosclerotic change? Neurol Med Chir (Tokyo) 2007; 47:356. 21. Ullrich NJ, Robertson R, Kinnamon DD, et al. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology 2007; 68:932. 22. Fernandez-Alvarez E, Pineda M, Royo C, Manzanares R. "Moya-moya' disease caused by cranial trauma. Brain Dev 1979; 1:133. 23. Kitano S, Sakamoto H, Fujitani K, Kobayashi Y. Moyamoya disease associated with a brain stem glioma. Childs Nerv Syst 2000; 16:251. 24. Arita K, Uozumi T, Oki S, et al. Moyamoya disease associated with pituitary adenoma report of two cases. 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cerebrovascular diseases typically characterized by bilateral stenosis or occlusion of the arteries around the circle of Willis with prominent arterial collateral circulation. (See 'Classification and terminology' above.) Moyamoya disease (MMD) refers to patients with moyamoya angiographic findings who may have genetic susceptibilities but no underlying risk factors. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 13/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See 'Classification and terminology' above and 'Associated conditions' above.) Epidemiology MMD and MMS are rare. MMD is more common in East Asian countries than elsewhere. There is a bimodal distribution in the age of onset, with one peak at approximately 10 years of age and a second, broader peak at approximately 40 years of age. (See 'Incidence and prevalence' above.) Clinical presentations Ischemic stroke and transient ischemic attack (TIA) affecting the anterior circulation are the most common clinical presentations. (See 'Ischemic stroke and transient ischemic attack' above and 'Neuroimaging' above.) Intracranial hemorrhage is less common and is rare in children. Hemorrhage usually affects deep structures such as the basal ganglia or thalamus but may also be intraventricular or subarachnoid. (See 'Intracerebral, intraventricular, and subarachnoid hemorrhage' above and 'Neuroimaging' above.) Clinical and imaging findings suggestive of underlying moyamoya pathology MRI findings that suggest the diagnosis of moyamoya include dilated collateral vessels in the basal ganglia or thalamus, the "ivy sign," or the "brush sign." (See 'Neuroimaging' above.) The diagnosis of moyamoya is most often considered in those with suggestive MRI findings in the context of evaluation for ischemic stroke. Other settings in which the diagnosis should be considered include repeated episodes of ischemia in the same arterial territory, deep intracerebral hemorrhage in the absence of hypertension or other known cause, and ischemic or hemorrhagic stroke in children or young adults who lack cerebrovascular risk factors. (See 'Indications for vascular imaging' above.) Diagnosis The diagnosis of moyamoya is made by angiographic demonstration of bilateral stenoses affecting the distal internal carotid arteries or proximal circle of Willis vessels along with the presence of prominent basal collateral vessels. (See 'Diagnosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya summary with proposed evidence-based practice guidelines. A review. 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Clinical and neuroradiological findings of moyamoya disease in Italy. Clin Neurol Neurosurg 1997; 99 Suppl 2:S54. 141. Choi JU, Kim DS, Kim EY, Lee KC. Natural history of moyamoya disease: comparison of activity of daily living in surgery and non surgery groups. Clin Neurol Neurosurg 1997; 99 Suppl 2:S11. 142. Kitamura K, Fukui M, Oka K. Moyamoya disease. In: Handbook of Clinical Neurology, Elsevie r, Amsterdam, 1989. Vol 2, p.293. 143. Nah HW, Kwon SU, Kang DW, et al. Moyamoya disease-related versus primary intracerebral hemorrhage: [corrected] location and outcomes are different. Stroke 2012; 43:1947. 144. Wan M, Han C, Xian P, et al. Moyamoya disease presenting with subarachnoid hemorrhage: Clinical features and neuroimaging of a case series. Br J Neurosurg 2015; 29:804. 145. Kim JS. Moyamoya Disease: Epidemiology, Clinical Features, and Diagnosis. J Stroke 2016; 18:2. 146. Seol HJ, Wang KC, Kim SK, et al. Headache in pediatric moyamoya disease: review of 204 consecutive cases. 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Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 2007; 38:1430. 154. Yamada M, Fujii K, Fukui M. [Clinical features and outcomes in patients with asymptomatic moyamoya disease from the results of nation-wide questionnaire survey]. No Shinkei Geka 2005; 33:337. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 24/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 155. Rafay MF, Armstrong D, Dirks P, et al. Patterns of cerebral ischemia in children with moyamoya. Pediatr Neurol 2015; 52:65. 156. Kim JM, Lee SH, Roh JK. Changing ischaemic lesion patterns in adult moyamoya disease. J Neurol Neurosurg Psychiatry 2009; 80:36. 157. Takahashi M, Miyauchi T, Kowada M. 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Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 2008; 39:2644. 163. Ohta T, Tanaka H, Kuroiwa T. Diffuse leptomeningeal enhancement, "ivy sign," in magnetic resonance images of moyamoya disease in childhood: case report. Neurosurgery 1995; 37:1009. 164. Maeda M, Tsuchida C. "Ivy sign" on fluid-attenuated inversion-recovery images in childhood moyamoya disease. AJNR Am J Neuroradiol 1999; 20:1836. 165. Chung PW, Park KY. Leptomeningeal enhancement in petients with moyamoya disease: correlation with perfusion imaging. Neurology 2009; 72:1872. 166. Mori N, Mugikura S, Higano S, et al. The leptomeningeal "ivy sign" on fluid-attenuated inversion recovery MR imaging in Moyamoya disease: a sign of decreased cerebral vascular reserve? AJNR Am J Neuroradiol 2009; 30:930. 167. Azizyan A, Sanossian N, Mogensen MA, Liebeskind DS. Fluid-attenuated inversion recovery vascular hyperintensities: an important imaging marker for cerebrovascular disease. AJNR Am J Neuroradiol 2011; 32:1771. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 25/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 168. Horie N, Morikawa M, Nozaki A, et al. "Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. AJNR Am J Neuroradiol 2011; 32:1697. 169. Yu X, Yuan L, Jackson A, et al. Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AJNR Am J Neuroradiol 2016; 37:423. 170. Muraoka S, Araki Y, Taoka T, et al. Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy: Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging. World Neurosurg 2018; 116:e1114. 171. Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke 2014; 45:2457. 172. Kodama N, Aoki Y, Hiraga H, et al. Electroencephalographic findings in children with moyamoya disease. Arch Neurol 1979; 36:16. 173. Cho A, Chae JH, Kim HM, et al. Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. Childs Nerv Syst 2014; 30:449. 174. Frechette ES, Bell-Stephens TE, Steinberg GK, Fisher RS. Electroencephalographic features of moyamoya in adults. Clin Neurophysiol 2015; 126:481. 175. Smith ER. Moyamoya arteriopathy. Curr Treat Options Neurol 2012; 14:549. 176. Kim HY, Chung CS, Lee J, et al. Hyperventilation-induced limb shaking TIA in Moyamoya disease. Neurology 2003; 60:137. 177. Spengos K, Tsivgoulis G, Toulas P, et al. Hyperventilation-enhanced chorea as a transient ischaemic phenomenon in a patient with moyamoya disease. Eur Neurol 2004; 51:172. 178. Bakdash T, Cohen AR, Hempel JM, et al. Moyamoya, dystonia during hyperventilation, and antiphospholipid antibodies. Pediatr Neurol 2002; 26:157. 179. Tsuchiya K, Makita K, Furui S. Moyamoya disease: diagnosis with three-dimensional CT angiography. Neuroradiology 1994; 36:432. 180. Hasuo K, Mihara F, Matsushima T. MRI and MR angiography in moyamoya disease. J Magn Reson Imaging 1998; 8:762. 181. Yamada I, Nakagawa T, Matsushima Y, Shibuya H. High-resolution turbo magnetic resonance angiography for diagnosis of Moyamoya disease. Stroke 2001; 32:1825. 182. Suzuki J, Kodama N. Moyamoya disease a review. Stroke 1983; 14:104. 183. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net- like vessels in base of brain. Arch Neurol 1969; 20:288. Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome

25/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 168. Horie N, Morikawa M, Nozaki A, et al. "Brush Sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. AJNR Am J Neuroradiol 2011; 32:1697. 169. Yu X, Yuan L, Jackson A, et al. Prominence of Medullary Veins on Susceptibility-Weighted Images Provides Prognostic Information in Patients with Subacute Stroke. AJNR Am J Neuroradiol 2016; 37:423. 170. Muraoka S, Araki Y, Taoka T, et al. Prediction of Intracranial Arterial Stenosis Progression in Patients with Moyamoya Vasculopathy: Contrast-Enhanced High-Resolution Magnetic Resonance Vessel Wall Imaging. World Neurosurg 2018; 116:e1114. 171. Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of Moyamoya disease. Stroke 2014; 45:2457. 172. Kodama N, Aoki Y, Hiraga H, et al. Electroencephalographic findings in children with moyamoya disease. Arch Neurol 1979; 36:16. 173. Cho A, Chae JH, Kim HM, et al. Electroencephalography in pediatric moyamoya disease: reappraisal of clinical value. Childs Nerv Syst 2014; 30:449. 174. Frechette ES, Bell-Stephens TE, Steinberg GK, Fisher RS. Electroencephalographic features of moyamoya in adults. Clin Neurophysiol 2015; 126:481. 175. Smith ER. Moyamoya arteriopathy. Curr Treat Options Neurol 2012; 14:549. 176. Kim HY, Chung CS, Lee J, et al. Hyperventilation-induced limb shaking TIA in Moyamoya disease. Neurology 2003; 60:137. 177. Spengos K, Tsivgoulis G, Toulas P, et al. Hyperventilation-enhanced chorea as a transient ischaemic phenomenon in a patient with moyamoya disease. Eur Neurol 2004; 51:172. 178. Bakdash T, Cohen AR, Hempel JM, et al. Moyamoya, dystonia during hyperventilation, and antiphospholipid antibodies. Pediatr Neurol 2002; 26:157. 179. Tsuchiya K, Makita K, Furui S. Moyamoya disease: diagnosis with three-dimensional CT angiography. Neuroradiology 1994; 36:432. 180. Hasuo K, Mihara F, Matsushima T. MRI and MR angiography in moyamoya disease. J Magn Reson Imaging 1998; 8:762. 181. Yamada I, Nakagawa T, Matsushima Y, Shibuya H. High-resolution turbo magnetic resonance angiography for diagnosis of Moyamoya disease. Stroke 2001; 32:1825. 182. Suzuki J, Kodama N. Moyamoya disease a review. Stroke 1983; 14:104. 183. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net- like vessels in base of brain. Arch Neurol 1969; 20:288. Topic 1131 Version 41.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 26/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS 40-year-old with moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid carotid, proximal middle cerebral artery a artery (oval), and lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129102 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 27/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Morning glory disc anomaly The disc is large and there is a central, white tuft of glial tissue. The retinal vessels proceed radially from the disc. Courtesy of Karl C Golnik, MD. Graphic 55325 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 28/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old with unilateral moyamoya disease Digital subtraction angiogram shows stenosis of right supraclinoid and proximal middle cerebral arteries (cir lenticulostriate moyamoya collateral vessels (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129103 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 29/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Aneurysm in moyamoya disease Cerebral angiogram showing aneurysm (arrow) in patient with moyamoya disease. Courtesy of Nijasri Suwanwela, MD. Graphic 64850 Version 4.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 30/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 9-year-old male with moyamoya disease who presented with repeated episodes of transient left hemiparesis (A) Noncontrast head CT scan shows low-density area of infarction in the right basal ganglia (arrow). (B) MRI FLAIR image depicting a high-signal-intensity area in the right basal ganglia and multiple small hyperintense areas in both basal ganglia consistent with infarction. (C, D) Selective intra-arterial DSA (anteroposterior projection) shows severe stenoses of the distal right and left internal carotid arteries. Abnormal network of blood vessels (puff of smoke or moyamoya vessels) in the vicinity of the stenotic areas were noted (arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DSA: digital subtraction angiogram. Courtesy of Nijasri Suwanwela, MD. Graphic 74421 Version 8.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 31/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 54-year-old with moyamoya disease T2-weighted sequence on magnetic resonance imaging shows lenticulostriate moyamoya collateral vessels on right (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129104 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 32/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 40-year-old with moyamoya disease "ivy sign" Fluid-attenuated inversion recovery sequence magnetic resonance imaging shows linear and curvilinear hyperintensities in the cerebral sulci consistent with "ivy sign" (arrows). Courtesy of Glenn A Tung, MD, FACR. Graphic 129105 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 33/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Moyamoya disease "brush sign" The conspicuity of multiple deep medullary veins on susceptibility- weighted imaging sequence (oval) from reduced oxygen supply relative to tissue demand resulting in an increase in the concentration of deoxyhemoglobin in venous blood. Republished with permission of the American Society of Neuroradiology, from: Horie N, Morikawa M, Nozaki A, et al. "Brush sign" on susceptibility-weighted MR imaging indicates the severity of moyamoya disease. Am J Neurorad 2011; 32:1697; permission conveyed through Copyright Clearance Center, Inc. Copyright 2011. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 34/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Graphic 129106 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 35/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 36/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Magnetic resonance angiography (MRA) of a patient with moyamoya disease A) There is severe narrowing of the distal part of the both carotid arteries (arrows). In addition, there is markedly reduced flow in the left middle cerebral artery and absence of both anterior cerebral arteries. B) Lateral projection MRA demonstrates severe narrowing of the distal internal carotid artery (arrow). Courtesy of Nijasri Suwanwela, MD. Graphic 51947 Version 2.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 37/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate 12-year-old with moyamoya syndrome secondary to neurofibromatosis type 1 Magnetic resonance angiogram shows occlusion of left supraclinoid internal carotid artery (circles) and lentic collateral vessels (arrow). Courtesy of Glenn A Tung, MD, FACR. Graphic 129107 Version 3.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 38/39 7/6/23, 12:31 PM Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis - UpToDate Contributor Disclosures Nijasri Charnnarong Suwanwela, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-etiology-clinical-features-and-diagnosis/print 39/39

7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Moyamoya disease and moyamoya syndrome: Treatment and prognosis : Nijasri Charnnarong Suwanwela, MD : Jos Biller, MD, FACP, FAAN, FAHA, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2023. INTRODUCTION AND TERMINOLOGY Moyamoya is an uncommon cerebrovascular condition characterized by progressive narrowing of large intracranial arteries and the secondary development of prominent small vessel collaterals. These collateral vessels produce a characteristic smoky appearance on angiography, which was first called "moyamoya," a Japanese word meaning puffy, obscure, or hazy like a puff of smoke in the air. Moyamoya, or moyamoya vasculopathy, refers to the characteristic vascular findings. The term moyamoya disease (MMD) is used when the condition is idiopathic and not associated with another disease or due to a genetic susceptibility; moyamoya syndrome (MMS) is used when vascular findings occur in the presence of an associated condition, such as sickle cell disease. MMD or MMS may lead to ischemic stroke or intracranial hemorrhage in children and adults. This topic will review the treatment and prognosis of moyamoya. The etiologies, clinical features, and diagnosis of MMD and MMS are discussed separately. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) SUPPORTIVE MANAGEMENT FOR ALL PATIENTS Moyamoya is a progressive intracranial vasculopathy that can lead to neurologic complications due to impaired cerebral circulation, including ischemic stroke and intracranial hemorrhage. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 1/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate There is no curative treatment for moyamoya. However, supportive management may reduce the risk of complications, and imaging surveillance can help to identify patients who are at highest risk for future ischemic and hemorrhagic complications and would benefit from surgical revascularization. Identify patients with an indication for surgical referral Surgical revascularization for moyamoya is typically indicated both for patients who are symptomatic and for asymptomatic patients with neuroimaging findings suggestive of severe impairment of resting blood flow or impaired hemodynamic perfusion reserve ( algorithm 1). These patients are at high risk for future complications, and surgical revascularization may reduce the risk of subsequent morbidity [1-3]. However, the final decision to pursue surgical revascularization for moyamoya depends on individual risks and benefits with surgery and patient values and preferences. (See 'Preoperative evaluation' below.) Medical management with follow-up surveillance imaging is continued for other patients who are asymptomatic and have preserved cerebral blood flow. (See 'Management of antithrombotic medications' below and 'Additional management for specific groups' below and 'Follow-up surveillance' below.) Symptomatic presentations We suggest surgical revascularization for children and adults with moyamoya who develop symptoms related to cerebral ischemia (including transient ischemic attack [TIA], ischemic stroke, or cognitive decline) or hemorrhage and who have no contraindication to surgery, in agreement with guidelines from the American College of Chest Physicians (ACCP) and the American Heart Association (AHA) [4-6]. Surgical referral may also be appropriate for patients with less common clinical symptoms associated with moyamoya such as dystonia or seizures. The clinical features of moyamoya are discussed in greater detail separately. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Hemodynamic compromise on blood flow studies We also suggest surgical revascularization for asymptomatic children and adults with decreased regional cerebral blood flow or inadequate hemodynamic perfusion reserve as measured by cerebral blood flow studies, in agreement with ACCP and AHA guidelines [4-6]. Similarly, guidelines from Japan and others support surgical revascularization for patients with progressive ischemic symptoms or evidence of reduced cerebral perfusion reserve or inadequate cerebral blood flow [7-9]. Imaging studies to assess cerebral blood flow for patients with moyamoya include transcranial Doppler (TCD) ultrasound, perfusion computed tomography (CT) or magnetic resonance imaging https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 2/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate (MRI), positron emission tomography (PET), and single-photon emission CT (SPECT). Indirect information on the status of cerebral blood flow may be attained with vascular studies including multiphase CT angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography. (See 'Neuroimaging' below.) Management of antithrombotic medications The use of antithrombotic medications in moyamoya is complex because the vasculopathy is associated with the risk of both ischemic and hemorrhagic cerebrovascular complications. Use of antiplatelet therapy We suggest long-term aspirin for children (2 to 5 mg/kg daily) and adults (50 to 100 mg daily) with asymptomatic or symptomatic ischemic-type moyamoya. Cilostazol may be used as an alternative. For most patients who present with hemorrhagic-type moyamoya, we avoid antiplatelet therapy acutely and during recovery. We typically start antiplatelet therapy postoperatively for patients with ischemic or hemorrhagic moyamoya who undergo surgical revascularization to help maintain bypass graft patency. Antiplatelet agents are used to reduce the risk of ischemic symptoms in moyamoya [5,6]. Ischemic events in patients with moyamoya are most frequently due to hypoperfusion, but thromboembolism may also occur [10]. In a retrospective study of patients undergoing revascularization surgery, there was a trend toward fewer postoperative major strokes in patients who took aspirin compared with those who did not (1 of 59 versus 9 of 138 patients) [11]. The rate of hemorrhagic complications was similar for both groups. In another observational study, aspirin use was associated with a lower rate of postoperative hemorrhage complications, possibly due to improved hemodynamic parameters or reduced risk of infarction with hemorrhagic transformation [12]. Guidelines from the ACCP also recommend aspirin over no treatment as initial therapy for children with acute arterial ischemic stroke secondary to moyamoya [4]. Another antiplatelet option is cilostazol, a phosphodiesterase inhibitor that has been associated with improved imaging parameters in small studies of patients with moyamoya. An observational study from Japan found that adults with moyamoya treated with cilostazol (if <50 years of age) had an improvement in cerebral blood flow on a two-year follow-up PET scan while other patients treated with clopidogrel (if 50 years of age) showed no change [13]. Moreover, neuropsychologic testing suggested that patients in the cilostazol group, but not the clopidogrel group, had improved cognition [14]. An obvious limitation of these findings is that the benefits associated with cilostazol could also be attributed to the younger age of those in the cilostazol group. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 3/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Avoidance of anticoagulation Long-term anticoagulation is generally contraindicated for children or adults with moyamoya. High-quality data to suggest benefit of anticoagulation in moyamoya are unavailable. Long-term oral anticoagulation in children is associated with the risk of hemorrhage due to incidental trauma and difficulty maintaining therapeutic levels [15]. In adults, long-term anticoagulation is also avoided because hemorrhage is the predominant manifestation of moyamoya. The safety of short-term anticoagulation (eg, treatment of deep venous thrombosis) has not been established in moyamoya. The decision to use short-term anticoagulation for patients with a transient thromboembolic risk when alternative options are unavailable should be individualized. Additional management for specific groups Patients with moyamoya syndrome Some patients with moyamoya vasculopathy due to an underlying associated condition (MMS) may also require treatment for the underlying condition. As an example, patients with sickle cell disease who develop MMS typically require transfusion therapy both for primary and secondary stroke prevention. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".) The treatment of underlying causes for MMS is generally the same as the treatment for such patients without MMS. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Associated conditions'.) Pregnant patients Pregnant patients with moyamoya should be instructed to maintain adequate oral hydration. Low-dose aspirin is typically used for patients with moyamoya for primary or secondary stroke prevention. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Aspirin (low dose)'.) Plans for childbirth for patients with moyamoya should be made by assessment of the individual risks and benefits of birthing options in consultation with the patient's obstetrician. Cesarean delivery is commonly selected for pregnant patients with moyamoya to reduce the risk of morbidity associated with cerebral ischemia due to hypocapnia from hyperventilation [16]. However, Cesarean delivery may expose patients to additional risks of cerebral ischemia due to blood loss or perioperative blood pressure fluctuations. A 2018 systematic review of available case series and reports of pregnant patients with moyamoya failed to find an outcome benefit with Cesarean delivery [17]. In a single-center review of 27 pregnancies of patients with moyamoya, 20 patients had good outcomes with vaginal delivery and epidural anesthesia [18]. For patients with moyamoya undergoing Cesarean delivery, anesthesia management is geared to minimizing ischemic risks as well as pain. Some observational reports have found patients https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 4/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate with moyamoya given spinal anesthesia during Cesarean delivery had better blood pressure control and less postoperative pain compared with those managed with general anesthesia [19]. Surgical revascularization for selected patients is typically delayed until after delivery and recovery. (See 'Preoperative evaluation' below.) Follow-up surveillance Asymptomatic patients with moyamoya with favorable hemodynamic imaging who are not referred for surgical revascularization should undergo serial surveillance testing to evaluate for evidence of disease progression ( algorithm 1). Patients with clinical symptoms or progression on imaging are typically referred for surgical revascularization. (See 'Surgical revascularization' below.) Clinical examination We monitor patients with periodic clinical examinations to assess for the development of symptoms or neurologic examination findings attributable to vascular stenosis in moyamoya. We assess for abnormalities on neurologic examination and the presence of TIA or stroke symptoms or other symptoms including transient episodes of weakness that may be provoked by crying, laughing, or hyperventilating. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Neuroimaging We perform surveillance imaging studies for patients with moyamoya because progressive changes in stenosis or impairment of cerebral perfusion may precede clinical symptoms. Asymptomatic patients are typically referred for surgical revascularization if surveillance imaging shows evidence of impaired resting blood flow or hemodynamic compromise. (See 'Surgical revascularization' below.) An imaging study may be performed yearly for asymptomatic patients, but the timing of imaging studies varies by the severity of baseline and subsequent surveillance imaging findings. As examples, a shorter follow-up study at six months may be performed for a patient who has not yet had follow-up surveillance imaging when severe stenosis was found at initial diagnosis. The interval for follow-up imaging may be extended to every other year or longer for other asymptomatic adult patients with less severe vascular findings and follow-up surveillance imaging that has been stable for at least three years. The selection of neuroimaging modality varies by availability and institutional practice. Our practice is as follows: Vascular imaging We perform noninvasive vascular studies to monitor all patients for progressive stenosis or occlusion. Vascular studies may also provide indirect evidence of the status of cerebral blood flow. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 5/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate For most patients, we prefer surveillance MRA of the brain to minimize exposure to radiation and intravenous contrast and because MRA has comparable resolution to CTA. CTA of the head may be used as an alternative study or for patients unable to obtain MRA. Digital subtraction angiography is typically reserved for instances when noninvasive testing is nondiagnostic or for presurgical planning. (See 'Preoperative evaluation' below.) TCD ultrasonography is a noninvasive study that may be performed at the bedside to evaluate intracranial hemodynamics by measuring blood flow velocity in large intracranial vessels at the circle of Willis [5]. Since the velocity of blood flow is inversely related to arterial diameter, TCD can detect arterial occlusive disease; a focal increase in velocity usually suggests large artery stenosis. Diagnostic evaluation with TCD avoids exposure to radiation or the use of contrast. However, the study is unable to assess stenosis in smaller arteries, the adequacy of tissue perfusion, or the status of collaterals. Results can be operator dependent, so it should be performed by an experienced operator, but poor acoustic windows still preclude effective insonation in up to 15 percent of patients. Cerebral blood flow imaging For patients with moderate to severe stenosis on vascular imaging, we also use hemodynamic studies to assess for impaired baseline blood flow or hemodynamic perfusion reserve within the tissue distal to the area of stenosis. Regional hypoperfusion may be found on hemodynamic studies before progressive stenosis becomes apparent on vascular studies. Hemodynamic studies may also be performed to evaluate cerebrovascular reserve before and after induced vasodilation using acetazolamide or CO . Provocative testing using vasodilation may increase diagnostic 2 sensitivity to detect impairment of perfusion. Several modalities may be used to determine the extent of inadequate resting blood flow or cerebral perfusion reserve in patients with moyamoya. We typically use perfusion CT or perfusion-weighted MRI. Other methods include Xenon-enhanced CT, MRI with arterial spin labeling techniques, PET, and SPECT [5,20-25]. The selection of modality depends on institutional availability and experience. Other brain imaging Brain MRI can be obtained to identify evidence of ischemia when clinical signs or symptoms are of uncertain relationship to moyamoya. Head CT may be performed as a less sensitive alternative imaging test. SURGICAL REVASCULARIZATION Surgical revascularization for moyamoya is the treatment used to improve cerebral blood flow and perfusion reserve, and to reduce the risk of cerebrovascular complications. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 6/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Revascularization is based on the principle that ischemic and hemorrhagic cerebrovascular complications can be prevented by augmenting cerebral blood flow to the ischemic hemisphere and secondarily reducing pressure in the moyamoya collaterals [26]. Surgery involves one of several techniques typically using a craniotomy to permit connecting a branch of the external carotid artery to the ischemic hemisphere. Preoperative evaluation The selection of patients who may benefit from surgical revascularization is guided by a preoperative evaluation that includes clinical examination and imaging testing. Clinical evaluation The benefits of surgery to prevent neurologic damage may be diminished for patients with moyamoya who have chronic neurologic deficits and tissue loss following ischemic stroke or intracerebral hemorrhage. Some patients with severe, irreversible deficits may not benefit from surgery; however, others with milder deficits may pursue surgery after recovery. Adults with moyamoya and cardiovascular risk factors should undergo a cardiac evaluation prior to surgery to manage and mitigate these risks. (See "Evaluation of cardiac risk prior to noncardiac surgery".) Angiographic evaluation Preoperative cerebral angiography with bilateral injections of the internal and external carotid arteries and vertebral arteries is generally recommended to evaluate the sites of stenosis or occlusion, the status of the collateral circulation, and the identification of donor vessels. At select centers, high-resolution 3-Tesla MRI with magnetic resonance angiography (MRA) has been used for preoperative planning to identify the recipient artery. Patients with recent neurologic symptoms should be evaluated with brain MRI to identify ischemic and hemorrhagic brain lesions and to assess the overall stroke burden. Head CT is a less sensitive alternative test for patients unable to undergo brain MRI. Patients with recent or acute stroke have an elevated risk of perioperative stroke and hyperperfusion syndrome. Timing of surgery For patients who present with ischemic stroke or intracerebral hemorrhage, revascularization surgery is typically delayed until recovery both to reduce the risk of surgical complications and to permit optimal recovery from the cerebrovascular event. The specific timing varies by the severity of cerebrovascular injury and the duration of recovery, as well as assessment of risks associated with the selected surgical technique and patient-level factors. However, patients with moyamoya who present with intracerebral hemorrhage or subarachnoid hemorrhage due to an associated ruptured aneurysm are https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 7/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate typically referred for urgent aneurysm treatment, similar to other patients with a ruptured cerebral aneurysm. (See "Treatment of cerebral aneurysms", section on 'Timing and choice of therapy'.) For asymptomatic patients, revascularization surgery is typically performed when imaging studies show hemodynamic compromise or progressive vascular changes. However, earlier referral for surgery may be appropriate for selected asymptomatic patients with an expected high risk of future progression, such as for some patients with sickle cell disease [27]. By contrast, surgery may be delayed for other patients such as those who are pregnant and for patients without severe imaging findings who smoke tobacco products to allow time to quit. Surgical techniques Surgical techniques for moyamoya can be divided into direct and indirect revascularization procedures and their combinations [2,5,28,29]. The use of specific revascularization procedures for moyamoya varies by institutional protocol and surgical training and experience. There are no convincing data that one method of revascularization surgery is more effective than another. However, indirect revascularization is generally preferred in younger children [5]. (See 'Efficacy of surgery' below.) Direct techniques Direct revascularization refers to procedures where the superficial temporal artery (or middle meningeal artery, occipital artery, or other donor branch) from the external carotid artery is directly connected to a cortical artery within the ischemic hemisphere [30]. Retrograde and anterograde blood flow from the bypass graft improves perfusion to the ischemic territory. Direct revascularization has been associated with improved long-term prognosis in patients with moyamoya [20,31]. Direct revascularization is used by many centers, most commonly in adult patients. Direct methods are technically difficult to perform in children because of the small size of donor and/or recipient vessels. Indirect techniques Indirect revascularization refers to one of the several procedures where tissue perfused by a branch of the external carotid artery is applied to the surface of the ischemic hemisphere to encourage revascularization with underlying cortical vessels over time. The tissue may include dura, muscle, branch of an artery, or omentum. Indirect revascularization is frequently used for children with moyamoya. In addition, it may be selected when a suitable recipient artery is not available for anastomosis [1]. In general, indirect revascularization requires less operation time and may have lower procedure-related complications than direct revascularization. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 8/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Encephaloduroarteriosynangiosis Artery and dura Encephaloarteriosynangiosis Artery Pial synangiosis Artery applied to the pial surface Encephalomyosynangiosis Temporalis muscle Encephaloduroarteriomyosynangiosis Artery, dura, and muscle Encephalodurogaleosynangiosis Dura and galeal tissue Encephaloperiocranialsynangiosis Pericranium Other indirect techniques include [32,33]: Craniotomy with inversion of the dura Revascularization occurs from repositioned dura. Multiple burr holes without vessel synangiosis Revascularization into burr hole sites develops from the overlying scalp. Omentum transplantation Highly vascularized omental tissue is applied to the cortical surface. Other procedures Combined revascularization involves direct revascularization (to augment cerebral blood flow rapidly) plus indirect revascularization (to promote improved cerebral blood flow over time) [9,34,35]. This procedure is a more complex surgery than either direct or indirect procedures alone as it requires a suitable donor and recipient vessel for direct revascularization as well as placement of perfused tissue along the surface of the ischemic hemisphere for indirect revascularization. However, combination procedures may promote both rapid and delayed revascularization. In one small study, the use of a combination revascularization procedure was also associated with regression of dilated lenticulostriate vessels, a major source of hemorrhagic morbidity in moyamoya [36]. Endovascular embolization has been evaluated in small uncontrolled studies to obliterate ruptured intracranial aneurysms or pseudoaneurysms associated with moyamoya disease [37,38]. Efficacy of surgery Limited data support the effectiveness of surgical treatment for moyamoya. Two meta-analyses compared data of patients who had surgical revascularization with those who received conservative treatment [39,40]. Overall, patients in the surgical group had a reduced risk of stroke compared with the conservative group. In a meta-analysis of 10 studies that included nearly 2500 patients with MMD, the subsequent stroke rate over a mean follow-up of 2.2 to 7.1 years was lower for patients treated with surgery than those who received conservative management (14 versus 30 percent) [39]. In addition, surgery was associated with a https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 9/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate reduced rate of hemorrhage during follow-up (5 versus 19 percent) and a trend toward reduction in the rate of ischemic stroke (10 versus 14 percent; pooled odds ratio [OR] 0.71, 95% CI 0.5-1.1). In a separate meta-analysis of nearly 2300 patients from 20 studies of patients who presented with symptomatic MMD, those who underwent surgery had a lower risk of future stroke than patients managed conservatively (OR 0.26, 95% CI 0.2-0.3) [40]. Additionally, the risk of death due to bleeding was lower in the five studies (624 patients) reporting hemorrhagic complications for those treated with surgery (OR 0.27, 95% CI 0.1-0.7). However, the conclusions of these analyses are limited by differences in baseline characteristics, selection and publication bias, and potential variability of outcome measures. MMD versus MMS Most studies reporting the efficacy of surgery included patients with MMD. MMS is also regarded to be a progressive condition, similar to MMD, and is also associated with the risk of cerebrovascular complications due to shared underlying moyamoya vasculopathy, but data to support these similarities are limited [1]. The rate of vascular progression in MMS may vary according to the underlying etiology and epidemiologic differences. In an observational study that included 881 patients with MMD and 292 patients with MMS attributed to atherosclerosis, the incidence of cerebrovascular events was higher over a mean follow-up of 46 months for those with MMD than MMS (14 versus 7 percent) [41]. MMD is more common than MMS in several East Asian countries than elsewhere and frequently presents in children, where the course can be aggressive [42,43]. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Epidemiology'.) Observational data show that revascularization surgery for MMS appears to be effective. A systematic review of 13 case reports and series for patients with MMS attributed to sickle cell disease found that direct surgical revascularization was feasible and associated with a lower risk of subsequent stroke compared with natural history [27]. In an Irish cohort study of 21 patients with moyamoya including 5 patients with MMS, postoperative complications were uncommon (median follow-up of 52 months) and only one patient had a stroke [44]. Successful surgical revascularization with a stable postoperative course has also been reported in case reports and series of patients with MMS from other conditions such as thyroiditis, neurofibromatosis, and Down syndrome [45-47]. Direct versus indirect techniques The selection of surgical procedure is based on several factors, including size and availability of suitable donor and recipient arterial vessels, as well as local protocol and experience. Direct procedures are typically more complex surgeries sometimes requiring a larger operative field, longer surgical time to perform a direct anastomosis, and longer hospitalization and recovery [29]. Indirect https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 10/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate revascularization surgery is frequently performed for children who have smaller vessels, less suitable to direct anastomosis [1,29]. Direct procedures provide more immediate revascularization for patients with suitable donor and recipient vasculature. In a 2022 pooled analysis of 143 studies involving more than 11,000 adults undergoing surgery for moyamoya, favorable outcome rates were higher for those undergoing direct or combined bypass versus indirect bypass surgery (93 and 94 percent versus 81 percent, respectively) [48]. A 2019 meta-analysis of 15 studies that included patients treated with surgery for moyamoya similarly reported that stroke prevention appeared to be more effective in patients treated with direct surgery (OR 2.0, 95% CI 1.3-3.1) [40]. These results may be driven by lower rates of late (>30 days after surgery) ischemic or hemorrhage stroke in patients treated with direct techniques [48]. However, these data are mostly from observational studies and are limited by differences in baseline characteristics, potential for selection bias, and limited follow-up. Hemorrhagic presentations The use of surgery for hemorrhagic moyamoya has been controversial because of concern that revascularization might increase the risk of recurrent hemorrhage by increasing cerebral perfusion pressure in dilated collateral vessels [49,50]. However, the available data suggest that revascularization surgery reduces the risk of recurrent hemorrhage, at least for adults [51-53]. In a network meta-analysis of nine studies evaluating hemorrhagic moyamoya, with data for 557 patients treated with surgery and 493 patients managed conservatively, surgical revascularization was associated with a lower rate of total recurrent stroke, ischemic stroke, and hemorrhagic stroke [52]. The Japan adult moyamoya trial evaluated 88 patients who presented with intracranial hemorrhage who were assigned to bilateral direct surgery or conservative care [53]. By five-year follow-up, patients in the surgery group had numerically fewer events for the combined end point of recurrent bleeding or stroke (14 versus 34 percent for conservative care; hazard ratio [HR] 0.39, 95% CI 0.15-1.03), a finding that just missed statistical significance. The difference between the surgery and conservative groups for the annual event rate of recurrent bleeding or stroke (8.2 versus 3.2 percent) just achieved statistical significance (p = 0.048). Pediatric surgery Limited indirect evidence suggests that revascularization surgery is more effective in children than in adults [26]. In addition, children who present at a very young age may have a higher stroke rate and a more aggressive course than older children. In a cohort of 204 children with moyamoya treated with indirect surgery, the rate of ischemic stroke at initial presentation was higher for children <3 years old than those 3 to 6 years old and those >6 years old (87 versus 58 versus 46 percent) [54]. In addition, https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 11/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate after presentation, the subsequent preoperative stroke rate was also highest in the youngest age group (39 versus 6 versus 1 percent). The rate of stroke attributed to surgery was similar between groups. A systematic review published in 2005 identified 55 studies with data for 1156 children (mainly from Japan) who had surgical revascularization for moyamoya [2]. Most patients were treated with indirect surgical techniques or a combination of direct and indirect methods. The perioperative stroke rate was 4.4 percent. Over a mean postoperative follow- up of 58 months, symptomatic benefit, defined as complete disappearance or reduction in symptomatic cerebral ischemia, was reported in 1003 children (87 percent). In detail, outcomes were asymptomatic, improved, unchanged, or worse in 51, 36, 11, and 3 percent of patients, respectively. Longer-term outcomes in children also appear to be favorable. In a series from the United States of 143 children with symptomatic moyamoya who were treated with pial synangiosis, perioperative stroke occurred in 11 (8 percent) [55]. Among 126 patients followed for more than one year, late-onset stroke occurred in four (3 percent). In 46 patients who were followed for more than five years, late-onset stroke occurred in two patients (4 percent). Complications of surgery Perioperative stroke Peri- and postoperative stroke is a major complication of surgical revascularization for moyamoya. Ischemic stroke may occur due to baseline impairment of cerebral blood flow and perioperative hypoperfusion or thrombosis. Improved cerebral blood flow with surgery may also expose patients to the risk of postoperative intracerebral hemorrhage or edema from hyperperfusion. Additionally, other sites of intracranial hemorrhage, including subdural hematoma, may occur following revascularization. Efforts to maintain optimal cerebral perfusion during the perioperative period are important to minimize the risk of complications. Relative hypoperfusion can occur as a result of competing blood flow from the preexisting collateral circulation and the new anastomosis in the setting of impaired cerebral autoregulation [56]. In a single-center series of 1250 pediatric and adult revascularizations performed from 1991 to 2014, the 30- day postoperative rate of major stroke was 6.8 percent [57]. In a meta-analysis of eight studies with over 1600 adult patients with moyamoya disease who had surgery, independent risk factors for postoperative stroke were operative ischemic events, posterior cerebral artery involvement, and diabetes [58]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 12/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Maintaining normocapnia is recommended during and after perioperative period to prevent ischemic complications. Both hypercapnia and hypocapnia can alter the regional cerebral blood flow through the mechanisms of vasoconstriction and steal phenomenon via vasodilation [59]. Delayed transient neurologic deficits Delayed transient neurologic deficits can occur typically 12 to 24 hours after revascularization surgery. Symptoms may include aphasia, oro-bulbar apraxia, motor weakness, or sensory abnormalities. Imaging shows no evidence of ischemic stroke, hemorrhage, or edema in these cases, and the symptoms usually resolve within several days to weeks. While the pathophysiology of this syndrome is uncertain, it may be due to either hyperperfusion or hypoperfusion [56,60,61]. Hyperperfusion syndrome Cerebral hyperperfusion syndrome may occur after surgical revascularization due to abrupt changes in perfusion to the ischemic hemisphere [5,62,63]. Changes in cerebral autoregulation induced by chronic cerebral hemodynamic insufficiency lead to compensatory vasodilation of cerebral vessels. After revascularization, blood flow is restored to a normal or elevated perfusion pressure within the previously hypoperfused hemisphere. The chronically dilated cerebral vessels are unable to vasoconstrict quickly enough to protect the capillary bed because of impaired cerebral blood flow autoregulation. Breakthrough perfusion pressure then causes the clinical manifestations that may include headache, seizures, focal neurologic deficits, cerebral edema, and rarely intracerebral hemorrhage. The reported incidence of clinically symptomatic cerebral hyperperfusion syndrome following bypass surgery for moyamoya disease ranges from 15 to 47 percent [62,64-66]. In a 2020 meta-analysis that included 2225 patients from 27 cohort studies, the incidence of postoperative hyperperfusion for adults was 20 percent but only 4 percent for children [63]. In nearly all cases, complete resolution occurs over several days to weeks. However, some patients with hyperperfusion syndrome can have persistent deficits when associated with intracerebral hemorrhage. Prophylactic postoperative blood pressure control may prevent or ameliorate symptomatic cerebral hyperperfusion. In a cohort of 108 adults with moyamoya, immediate postoperative blood pressure control to a target systolic blood pressure of <130 mmHg was associated a lower risk of hyperperfusion complications than expectant management (25 versus 7 percent) [67]. Hyperperfusion syndrome is discussed in greater detail separately. (See "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome'.) https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 13/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Other complications Infection and surgical site bleeding are other uncommon complications of moyamoya surgery [5]. MANAGEMENT OF COMPLICATIONS OF MOYAMOYA Patients may present with complications due to moyamoya vasculopathy, including ischemic stroke or intracerebral hemorrhage. Management of the presenting complication involves minimizing the risk of further brain injury associated with cerebral stenosis from moyamoya. Transient ischemic attack and ischemic stroke For children and adults with moyamoya and ischemic stroke, acute treatment is mainly supportive, directed toward minimizing ischemic injury, reducing cerebral edema, and controlling secondary complications such as seizures [68]. Acute treatment measures During hospitalization for acute stroke or surgery, specific management issues should be addressed to minimize ischemic injury, especially in children with moyamoya [5]: Precautions to minimize hyperventilation Hyperventilation occurring with pain, excitement, or crying can lower the carbon dioxide levels in the blood and induce or worsen cerebral ischemia by causing vasoconstriction [5,69]. Strategies to provide a comfortable and calm setting and control pain are recommended. Pain control may help reduce the risk of hyperventilation and also reduce the risk of stroke and the length of hospitalization [70]. Specific methods include appropriate periprocedural sedation, painless wound-handling techniques (eg, Steri-Strip closure, use of paraffin gauze, avoidance of adhesive tapes), and protocolized pain management. Maintaining euvolemia Oral and intravenous fluids should be given to reduce the risk of cerebral ischemia from hypotension and hypovolemia [55,69]. Intravenous hydration with isotonic fluids may be administered at 1.25 to 1.5 times the normal maintenance rate [1,70]. Other experts keep blood pressure slightly elevated in the acute setting [70]. However, cerebral hyperperfusion syndrome may occur with significant elevations in blood pressure; blood pressure treatment may be helpful to prevent this complication. Thrombolysis The safety of intravenous thrombolytic therapy for acute ischemic stroke in moyamoya patients has not been established. Its use may be considered on an individual basis for selected patients with disabling stroke symptoms and no history of

was similar between groups. A systematic review published in 2005 identified 55 studies with data for 1156 children (mainly from Japan) who had surgical revascularization for moyamoya [2]. Most patients were treated with indirect surgical techniques or a combination of direct and indirect methods. The perioperative stroke rate was 4.4 percent. Over a mean postoperative follow- up of 58 months, symptomatic benefit, defined as complete disappearance or reduction in symptomatic cerebral ischemia, was reported in 1003 children (87 percent). In detail, outcomes were asymptomatic, improved, unchanged, or worse in 51, 36, 11, and 3 percent of patients, respectively. Longer-term outcomes in children also appear to be favorable. In a series from the United States of 143 children with symptomatic moyamoya who were treated with pial synangiosis, perioperative stroke occurred in 11 (8 percent) [55]. Among 126 patients followed for more than one year, late-onset stroke occurred in four (3 percent). In 46 patients who were followed for more than five years, late-onset stroke occurred in two patients (4 percent). Complications of surgery Perioperative stroke Peri- and postoperative stroke is a major complication of surgical revascularization for moyamoya. Ischemic stroke may occur due to baseline impairment of cerebral blood flow and perioperative hypoperfusion or thrombosis. Improved cerebral blood flow with surgery may also expose patients to the risk of postoperative intracerebral hemorrhage or edema from hyperperfusion. Additionally, other sites of intracranial hemorrhage, including subdural hematoma, may occur following revascularization. Efforts to maintain optimal cerebral perfusion during the perioperative period are important to minimize the risk of complications. Relative hypoperfusion can occur as a result of competing blood flow from the preexisting collateral circulation and the new anastomosis in the setting of impaired cerebral autoregulation [56]. In a single-center series of 1250 pediatric and adult revascularizations performed from 1991 to 2014, the 30- day postoperative rate of major stroke was 6.8 percent [57]. In a meta-analysis of eight studies with over 1600 adult patients with moyamoya disease who had surgery, independent risk factors for postoperative stroke were operative ischemic events, posterior cerebral artery involvement, and diabetes [58]. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 12/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Maintaining normocapnia is recommended during and after perioperative period to prevent ischemic complications. Both hypercapnia and hypocapnia can alter the regional cerebral blood flow through the mechanisms of vasoconstriction and steal phenomenon via vasodilation [59]. Delayed transient neurologic deficits Delayed transient neurologic deficits can occur typically 12 to 24 hours after revascularization surgery. Symptoms may include aphasia, oro-bulbar apraxia, motor weakness, or sensory abnormalities. Imaging shows no evidence of ischemic stroke, hemorrhage, or edema in these cases, and the symptoms usually resolve within several days to weeks. While the pathophysiology of this syndrome is uncertain, it may be due to either hyperperfusion or hypoperfusion [56,60,61]. Hyperperfusion syndrome Cerebral hyperperfusion syndrome may occur after surgical revascularization due to abrupt changes in perfusion to the ischemic hemisphere [5,62,63]. Changes in cerebral autoregulation induced by chronic cerebral hemodynamic insufficiency lead to compensatory vasodilation of cerebral vessels. After revascularization, blood flow is restored to a normal or elevated perfusion pressure within the previously hypoperfused hemisphere. The chronically dilated cerebral vessels are unable to vasoconstrict quickly enough to protect the capillary bed because of impaired cerebral blood flow autoregulation. Breakthrough perfusion pressure then causes the clinical manifestations that may include headache, seizures, focal neurologic deficits, cerebral edema, and rarely intracerebral hemorrhage. The reported incidence of clinically symptomatic cerebral hyperperfusion syndrome following bypass surgery for moyamoya disease ranges from 15 to 47 percent [62,64-66]. In a 2020 meta-analysis that included 2225 patients from 27 cohort studies, the incidence of postoperative hyperperfusion for adults was 20 percent but only 4 percent for children [63]. In nearly all cases, complete resolution occurs over several days to weeks. However, some patients with hyperperfusion syndrome can have persistent deficits when associated with intracerebral hemorrhage. Prophylactic postoperative blood pressure control may prevent or ameliorate symptomatic cerebral hyperperfusion. In a cohort of 108 adults with moyamoya, immediate postoperative blood pressure control to a target systolic blood pressure of <130 mmHg was associated a lower risk of hyperperfusion complications than expectant management (25 versus 7 percent) [67]. Hyperperfusion syndrome is discussed in greater detail separately. (See "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome'.) https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 13/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Other complications Infection and surgical site bleeding are other uncommon complications of moyamoya surgery [5]. MANAGEMENT OF COMPLICATIONS OF MOYAMOYA Patients may present with complications due to moyamoya vasculopathy, including ischemic stroke or intracerebral hemorrhage. Management of the presenting complication involves minimizing the risk of further brain injury associated with cerebral stenosis from moyamoya. Transient ischemic attack and ischemic stroke For children and adults with moyamoya and ischemic stroke, acute treatment is mainly supportive, directed toward minimizing ischemic injury, reducing cerebral edema, and controlling secondary complications such as seizures [68]. Acute treatment measures During hospitalization for acute stroke or surgery, specific management issues should be addressed to minimize ischemic injury, especially in children with moyamoya [5]: Precautions to minimize hyperventilation Hyperventilation occurring with pain, excitement, or crying can lower the carbon dioxide levels in the blood and induce or worsen cerebral ischemia by causing vasoconstriction [5,69]. Strategies to provide a comfortable and calm setting and control pain are recommended. Pain control may help reduce the risk of hyperventilation and also reduce the risk of stroke and the length of hospitalization [70]. Specific methods include appropriate periprocedural sedation, painless wound-handling techniques (eg, Steri-Strip closure, use of paraffin gauze, avoidance of adhesive tapes), and protocolized pain management. Maintaining euvolemia Oral and intravenous fluids should be given to reduce the risk of cerebral ischemia from hypotension and hypovolemia [55,69]. Intravenous hydration with isotonic fluids may be administered at 1.25 to 1.5 times the normal maintenance rate [1,70]. Other experts keep blood pressure slightly elevated in the acute setting [70]. However, cerebral hyperperfusion syndrome may occur with significant elevations in blood pressure; blood pressure treatment may be helpful to prevent this complication. Thrombolysis The safety of intravenous thrombolytic therapy for acute ischemic stroke in moyamoya patients has not been established. Its use may be considered on an individual basis for selected patients with disabling stroke symptoms and no history of https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 14/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate brain hemorrhage after discussing risks and benefits. Because of the risk of hemorrhage in areas of extensive moyamoya collateral vessels, many experts are reluctant to use thrombolytic therapy to treat acute ischemic stroke in patients with moyamoya [71]. Secondary preventive therapy Antiplatelet medications are typically prescribed for patients with ischemic stroke due to moyamoya. Antithrombotic therapy is discussed in greater detail separately. (See 'Management of antithrombotic medications' above.) Patients with moyamoya may have hypertension, and treatment is indicated to reduce the risk of future ischemic and hemorrhagic complications. However, hypotension and hypovolemia should be avoided to minimize the risk of ischemia. Additional details on the general approach to the evaluation and management of acute ischemic stroke is reviewed separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Initial assessment and management of acute stroke".) Intracranial hemorrhage The treatment of acute intracranial hemorrhage is similar for patients with or without moyamoya. Ventricular drainage and/or hematoma removal may be required for some patients with intracerebral hemorrhage. Vascular repair of ruptured aneurysm may be required for patients presenting with subarachnoid hemorrhage. The acute treatment of forms of intracranial hemorrhage are presented separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Subdural hematoma in adults: Management and prognosis".) Other complications Patients with moyamoya may also present with other neurologic symptoms such as seizures and headaches. Other neurologic presentations are uncommon. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Neuroimaging evaluation should be performed to assess for evidence of associated cerebral ischemia. In some cases, neurologic symptoms such as seizures or movement disorders may be attributed to moyamoya in patients without clinical or radiographic ischemia. The decision to pursue surgery for these symptomatic patients should be individualized, based on severity of symptoms, effectiveness of medical therapy, and patient preferences after clinical and imaging evaluation. (See 'Identify patients with an indication for surgical referral' above and 'Follow-up surveillance' above.) https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 15/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Symptomatic management of these conditions is typically the same for patients with or without moyamoya. (See "Evaluation and management of the first seizure in adults" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Evaluation of headache in adults" and "Headache in children: Approach to evaluation and general management strategies".) PROGNOSIS The natural history of moyamoya tends to be progressive in children and adults [72-74]. In studies with long-term follow-up of untreated patients, progressive neurologic deficits and poor outcome were reported in 50 to 66 percent [75-77]. Radiographic progression within five years of diagnosis was reported in 36 percent of a cohort of children with moyamoya [78]. The vascular pathology usually worsens with extensive intracranial large artery occlusion and collateral circulation. Patients often suffer cognitive and neurologic decline due to repeated ischemic stroke or hemorrhage [74]. However, the rate and extent of progression varies substantially between populations. Moyamoya may have a more rapid progression and a worse prognosis in younger rather than in older children, as evidenced by a single-center observational study of 204 patients from Korea who had surgical treatment for moyamoya [54]. Ischemic stroke was more frequent at initial presentation in children 6 years old compared with children >6 years old, as were subsequent preoperative infarctions. The median interval between the onset of symptoms and preoperative infarction was three months (range 1 to 14). The rate of favorable clinical outcomes was significantly lower in children less than three years old compared with those who were three to six or older than six years, mainly because of preoperative infarctions. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Identify patients with an indication for surgical referral For patients with symptomatic moyamoya as well as those with impaired resting blood flow or hypoperfusion on neuroimaging, we suggest surgical revascularization ( algorithm 1) (Grade 2C). Antiplatelet management with follow-up surveillance imaging is continued for https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 16/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate other patients who are asymptomatic and have preserved cerebral blood flow. (See 'Identify patients with an indication for surgical referral' above.) Antithrombotic therapy Antiplatelets For patients with asymptomatic or symptomatic ischemic-type moyamoya, we suggest long-term aspirin for children (2 to 5 mg/kg daily) and adults (50 to 100 mg daily) rather than no therapy (Grade 2C). Cilostazol may be used as an alternative. (See 'Management of antithrombotic medications' above.) For most patients who present with hemorrhagic-type moyamoya, we avoid antiplatelet therapy acutely and during recovery. We typically start antiplatelet therapy postoperatively for patients with ischemic or hemorrhagic moyamoya who undergo surgical revascularization. Anticoagulation Long-term anticoagulation is generally contraindicated for patients with moyamoya. (See 'Management of antithrombotic medications' above.) Follow-up surveillance Patients with moyamoya who are not referred for surgical revascularization should undergo serial surveillance testing to evaluate for evidence of disease progression ( algorithm 1). (See 'Follow-up surveillance' above.) Clinical examination We monitor patients with periodic clinical examinations to assess for the development of symptoms or neurologic examination findings attributable to vascular stenosis in moyamoya including transient episodes of weakness that may be provoked by crying, laughing, or hyperventilating. (See 'Clinical examination' above.) Neuroimaging We perform surveillance imaging studies for patients with moyamoya because progressive changes in stenosis or impairment of cerebral perfusion may precede clinical symptoms. The timing of imaging studies varies by the severity of baseline and subsequent surveillance imaging findings. (See 'Neuroimaging' above.) Patients who develop symptoms or progression on imaging are typically referred for surgical revascularization. Surgical management Surgery for moyamoya involves one of several techniques using a craniotomy to permit connecting a branch of the external carotid artery to the ischemic hemisphere. (See 'Surgical revascularization' above.) https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 17/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Preoperative evaluation The selection of patients who may benefit from surgical revascularization is guided by a preoperative evaluation that includes clinical examination and imaging testing. (See 'Preoperative evaluation' above.) Techniques Direct revascularization refers to procedures where a branch of the external carotid artery is directly connected to a cortical artery within the ischemic hemisphere. Indirect revascularization refers to procedures where tissue perfused by a branch of the external carotid artery is applied to the surface of the ischemic hemisphere to encourage revascularization with underlying cortical vessels over time. (See 'Surgical techniques' above.) The use of specific revascularization procedures for moyamoya varies by institutional protocol and surgical training and experience. However, indirect revascularization is generally preferred in younger children because of the small size of donor and/or recipient vessels. (See 'Efficacy of surgery' above.) Management of complications of moyamoya For children and adults with moyamoya and acute stroke, acute treatment is mainly supportive, directed toward minimizing brain injury, limiting cerebral edema, and controlling secondary complications such as seizures. Efforts to minimize cerebral ischemic injury include avoiding or controlling hyperventilation, preventing pain or agitation, and avoiding hypovolemia. (See 'Management of complications of moyamoya' above.) Prognosis The natural history of moyamoya tends to be progressive. However, the rate and extent of progression varies substantially between populations. (See 'Prognosis' above.) Use of UpToDate is subject to the Terms of Use. 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Moyamoya disease among young patients: its aggressive clinical course and the role of active surgical treatment. Neurosurgery 2004; 54:840. 55. Scott RM, Smith JL, Robertson RL, et al. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg 2004; 100:142. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 22/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate 56. Mukerji N, Cook DJ, Steinberg GK. Is local hypoperfusion the reason for transient neurological deficits after STA-MCA bypass for moyamoya disease? J Neurosurg 2015; 122:90. 57. Teo M, Abhinav K, Bell-Stephens TE, et al. Short- and long-term outcomes of moyamoya patients post-revascularization. J Neurosurg 2023; 138:1374. 58. Wei W, Chen X, Yu J, Li XQ. Risk factors for postoperative stroke in adults patients with moyamoya disease: a systematic review with meta-analysis. BMC Neurol 2019; 19:98. 59. Iwama T, Hashimoto N, Yonekawa Y. The relevance of hemodynamic factors to perioperative ischemic complications in childhood moyamoya disease. Neurosurgery 1996; 38:1120. 60. Fujimura M, Kaneta T, Mugikura S, et al. Temporary neurologic deterioration due to cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya disease. Surg Neurol 2007; 67:273. 61. Fujimura M, Kaneta T, Shimizu H, Tominaga T. Symptomatic hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in a child with moyamoya disease. Childs Nerv Syst 2007; 23:1195. 62. Uchino H, Kuroda S, Hirata K, et al. Predictors and clinical features of postoperative hyperperfusion after surgical revascularization for moyamoya disease: a serial single photon emission CT/positron emission tomography study. Stroke 2012; 43:2610. 63. Yu J, Zhang J, Li J, et al. Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-Analysis. World Neurosurg 2020; 135:357. 64. Fujimura M, Mugikura S, Kaneta T, et al. Incidence and risk factors for symptomatic cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease. Surg Neurol 2009; 71:442. 65. Hayashi K, Horie N, Suyama K, Nagata I. Incidence and clinical features of symptomatic cerebral hyperperfusion syndrome after vascular reconstruction. World Neurosurg 2012; 78:447. 66. Hwang JW, Yang HM, Lee H, et al. Predictive factors of symptomatic cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in adult patients with moyamoya disease. Br J Anaesth 2013; 110:773. 67. Fujimura M, Inoue T, Shimizu H, et al. Efficacy of prophylactic blood pressure lowering according to a standardized postoperative management protocol to prevent symptomatic cerebral hyperperfusion after direct revascularization surgery for moyamoya disease. Cerebrovasc Dis 2012; 33:436. https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 23/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate 68. Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis ('moyamoya' disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 1997; 99 Suppl 2:S238. 69. Parray T, Martin TW, Siddiqui S. Moyamoya disease: a review of the disease and anesthetic management. J Neurosurg Anesthesiol 2011; 23:100. 70. Nomura S, Kashiwagi S, Uetsuka S, et al. Perioperative management protocols for children with moyamoya disease. Childs Nerv Syst 2001; 17:270. 71. Pollak L. Moyamoya disease and moyamoya syndrome. N Engl J Med 2009; 361:98; author reply 98. 72. Kuroda S, Ishikawa T, Houkin K, et al. Incidence and clinical features of disease progression in adult moyamoya disease. Stroke 2005; 36:2148. 73. Hallemeier CL, Rich KM, Grubb RL Jr, et al. Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke 2006; 37:1490. 74. Morioka M, Hamada J, Todaka T, et al. High-risk age for rebleeding in patients with hemorrhagic moyamoya disease: long-term follow-up study. Neurosurgery 2003; 52:1049. 75. Choi JU, Kim DS, Kim EY, Lee KC. Natural history of moyamoya disease: comparison of activity of daily living in surgery and non surgery groups. Clin Neurol Neurosurg 1997; 99 Suppl 2:S11. 76. Kurokawa T, Tomita S, Ueda K, et al. Prognosis of occlusive disease of the circle of Willis (moyamoya disease) in children. Pediatr Neurol 1985; 1:274. 77. Ezura M, Yoshimoto T, Fujiwara S, et al. Clinical and angiographic follow-up of childhood- onset moyamoya disease. Childs Nerv Syst 1995; 11:591. 78. Gatti JR, Sun LR. Nonischemic Presentations of Pediatric Moyamoya Arteriopathy: A Natural History Study. Stroke 2022; 53:e219. Topic 1112 Version 31.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 24/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate GRAPHICS Evaluation and management of moyamoya disease and moyamoya syndrome https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 25/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 26/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Moyamoya is generally regarded as a progressive cerebrovascular entity, but the extent and rate of progression varies among patients. Treatment for patients with impaired blood flow is surgical, but other patients with milder findings may be managed with conservative therapy and surveillance imaging. ICA: internal carotid artery; MCA: middle cerebral artery; MMD: moyamoya disease; MMS: moyamoya syndrome; TIA: transient ischemic attack; MRA: magnetic resonance angiography; CTA: computed tomography angiography; DSA: digital subtraction angiography; TCD: transcranial Doppler; CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography; SPECT: single photon emission computed tomography. Moyamoya vasculopathy is most frequently bilateral but may be asymmetric or initially unilateral. Vascular changes may also be found infrequently in the posterior circulation (eg, posterior cerebral arteries). MMS may be caused by several underlying conditions. Refer to the UpToDate topic for additional details on associated conditions. Evaluations for clinical or imaging progression may be performed every 12 months for asymptomatic patients. Less frequent evaluations may be appropriate for adult patients who remain stable for at least three years. Refer to the UpToDate topic for additional details. Graphic 139077 Version 1.0 https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 27/28 7/6/23, 12:32 PM Moyamoya disease and moyamoya syndrome: Treatment and prognosis - UpToDate Contributor Disclosures Nijasri Charnnarong Suwanwela, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/moyamoya-disease-and-moyamoya-syndrome-treatment-and-prognosis/print 28/28

7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pathophysiology of ischemic stroke : Arshad Majid, MB, ChB, FRCP, Mounzer Kassab, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 23, 2022. INTRODUCTION The term ischemic stroke is used to describe a variety of conditions in which blood flow to part or all of the brain is reduced, resulting in tissue damage. Although in some cases this may be a chronic condition, most strokes occur acutely. Research over the last four decades has resulted in a significant expansion of our knowledge and understanding of the molecular and cellular processes that underlie ischemia-induced cellular injury. The goal of this review is to provide an overview of the underlying factors, such as the hemodynamic changes and molecular and cellular pathways, which are involved in stroke- related brain injury. A better understanding of these processes may help in the development of new therapies that are needed to treat this devastating disease. STROKE SUBTYPES The etiology and clinical classification of ischemic stroke subtypes is reviewed here briefly and discussed in greater detail separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Brain ischemia' and "Clinical diagnosis of stroke subtypes".) Acute ischemic stroke subtypes are often classified in clinical studies using a system developed by investigators of the TOAST trial, based upon the underlying cause ( table 1) [1]. Under this system, strokes are classified into the following categories: Large artery atherosclerosis https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 1/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Cardioembolism Small vessel occlusion Stroke of other, unusual, determined etiology Stroke of undetermined etiology Ischemic strokes are due to a reduction or complete blockage of blood flow [2]. This reduction can be due to decreased systemic perfusion, severe stenosis, or occlusion of a blood vessel. Decreased systemic perfusion can be the result of low blood pressure, heart failure, or loss of blood. Determination of the type of stroke can influence treatment to be used. The main causes of ischemia are thrombosis, embolization, and lacunar infarction from small vessel disease. Ischemic strokes represent approximately 80 percent of all strokes. (See "Stroke: Etiology, classification, and epidemiology", section on 'Epidemiology'.) Thrombosis refers to obstruction of a blood vessel due to a localized occlusive process within a blood vessel [2]. The obstruction may occur acutely or gradually. In many cases, underlying pathology such as atherosclerosis may cause narrowing of the diseased vessel. This may lead to restriction of blood flow gradually, or in some cases, platelets may adhere to the atherosclerotic plaque forming a clot leading to acute occlusion of the vessel. Atherosclerosis usually affects larger extracranial and intracranial vessels. In some cases, acute occlusion of a vessel unaffected by atherosclerosis may occur because of a hypercoagulable state. (See "Stroke: Etiology, classification, and epidemiology", section on 'Thrombosis'.) Embolism refers to clot or other material formed elsewhere within the vascular system that travels from the site of formation and lodges in distal vessels causing blockage of those vessel and ischemia [2]. The heart is a common source of this material, although other arteries may also be sources of this embolic material (artery to artery embolism). In the heart, clots may form on valves or chambers. Tumors, venous clots, septic emboli, air, and fat can also embolize and cause stroke. Embolic strokes tend to be cortical and are more likely to undergo hemorrhagic transformation, probably due to vessel damage caused by the embolus. Emboli from venous sources such as a deep venous thrombosis (DVT) can also cause stroke if the emboli are able to migrate to the arterial system through a patent foramen ovale (PFO) or an arteriovenous (AV) shunt such as pulmonary AV fistulae. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) Lacunar infarction occurs as a result of small vessel disease. Smaller penetrating vessels are more commonly affected by chronic hypertension leading to hyperplasia of the tunica media of these vessels and deposition of fibrinoid material leading to lumen narrowing and occlusion [2]. Lacunar strokes can occur anywhere in the brain but are typically seen in https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 2/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate subcortical areas. Atheroma can also encroach on the orifices of smaller vessels leading to occlusion and stroke. (See "Lacunar infarcts".) Nonatherosclerotic abnormalities of the cerebral vasculature, whether inherited or acquired, predispose to ischemic stroke at all ages, but particularly in younger adults and children. These can be divided into noninflammatory and inflammatory etiologies. The following list, though not exhaustive, highlights the major nonatherosclerotic vasculopathies associated with ischemic stroke: Arterial dissection ( figure 1) Fibromuscular dysplasia (see "Clinical manifestations and diagnosis of fibromuscular dysplasia") Vasculitis (see "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Incidence and classification") Moyamoya disease (see "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis") Sickle cell disease arteriopathy (see "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease") Focal cerebral arteriopathy of childhood (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Focal cerebral arteriopathy') Decreased systemic perfusion due to systemic hypotension may produce generalized ischemia to the brain [2]. This is most critical in the borderzone (or watershed) areas, which are territories that occupy the boundary region of two adjacent arterial supply zones. The ischemia caused by hypotension may be asymmetric due to preexisting vascular lesions. Areas of the brain commonly affected include the hippocampal pyramidal cells, cerebellar Purkinje cells, and cortical laminar cells discussed below. (See "Stroke: Etiology, classification, and epidemiology", section on 'Systemic hypoperfusion'.) Despite extensive testing to identify the etiology of the stroke, no clear cause is found in approximately 25 percent of patients with ischemic stroke at hospital discharge (cryptogenic stroke). In rare cases, the pathophysiology of the ischemic infarct may not even be vascular. Examples include mitochondrial disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) in which the pathophysiology is a failure of the energy production system (mitochondria) rather than a problem with blood delivery. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 3/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate CEREBRAL AUTOREGULATION Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels, which is directly related to their diameter [3]. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. Cerebral autoregulation is the phenomenon by which cerebral blood flow is maintained at a relatively constant level despite moderate variations in perfusion pressure. The mechanism by which autoregulation occurs is not well understood and may involve multiple pathways. Evidence suggests that the smooth muscle in cerebral vessels can respond directly to changes in perfusion pressure, contracting when pressure increases and relaxing when pressure drops. Reductions in cerebral blood flow may also lead to dilation of blood vessels through the release of vasoactive substances, although the molecules responsible for this have not been identified. The endothelial release of nitric oxide also appears to play a role in autoregulation. Maintenance of cerebral blood flow by autoregulation typically occurs within a mean arterial pressure range of 60 to 150 mmHg. The upper and lower limits vary between individuals, however. Outside of this range, the brain is unable to compensate for changes in perfusion pressure, and the cerebral blood flow increases or decreases passively with corresponding changes in pressure, resulting in the risk of ischemia at low pressures and edema at high pressures ( figure 2). Cerebral autoregulation during stroke Cerebral autoregulation is impaired during some disease conditions, including ischemic stroke [3-5]. As cerebral perfusion pressure falls, cerebral blood vessels dilate to increase cerebral blood flow. A decrease in perfusion pressure beyond the ability of the brain to compensate results in a reduction in cerebral blood flow. Initially, the oxygen extraction fraction is increased in order to maintain levels of oxygen delivery to the brain. As the cerebral blood flow continues to fall, other mechanisms come into play ( figure 3). Inhibition of protein synthesis occurs at flow rates below 50 mL/100 g per minute. At 35 mL/100 g per minute, protein synthesis ceases completely, and glucose utilization is transiently increased. At 25 mL/100 g per minute, glucose utilization drops dramatically with the onset of anaerobic glycolysis, resulting in tissue acidosis from the accumulation of lactic acid. Neuronal electrical failure occurs at 16 to 18 mL/100 g per minute, and failure of membrane ion homeostasis occurs at 10 to 12 mL/100 g per minute. This level typically marks the threshold for the development of infarct ( figure 3). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 4/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate In hypertensive individuals, autoregulation has adapted to occur at higher arterial pressures. Reduction of blood pressure to normal levels could actually exacerbate the derangement to autoregulation that occurs during stroke and lead to a further decrease in cerebral blood flow ( figure 2). CONSEQUENCES OF REDUCTION IN BLOOD FLOW DURING STROKE The human brain is exquisitely sensitive and susceptible to even short durations of ischemia. The brain is responsible for a large part of the body's metabolism and receives approximately 20 percent of the cardiac output although it is only 2 percent of total body weight [3]. The brain contains little or no energy stores of its own, and therefore relies on the blood for their delivery. Even brief deprivation can lead to death of the affected brain tissue. During stroke, reduction of blood flow to a portion or all of the brain results in a deprivation of glucose and oxygen [2]. Most strokes are caused by focal ischemia, affecting only a portion of the brain, typically involving a single blood vessel and its downstream branches. The region directly surrounding the vessel is the most affected. Within this region, cells in a central core of tissue will be irreversibly damaged and die by necrosis if the duration of ischemia is long enough. At distances farther from the affected vessel, some cells may receive a small amount of oxygen and glucose by diffusion from collateral vessels. These cells do not die immediately and can recover if blood flow is restored in a timely manner. The central core of tissue destined to die, or containing tissue that is already dead, is called the infarct. The region of potentially salvageable tissue is known as the penumbra. Mechanisms of ischemic cell injury and death Brain ischemia initiates a cascade of events that eventually lead to cell death; including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes [2,6-8]. As a consequence of the electrical failure that occurs during ischemia, the release of the excitatory amino acid glutamate at neuronal synapses is increased [2]. This leads to the activation of glutamate receptors and the opening of ion channels that allow potassium ions to exit the cell and sodium and calcium ions to enter, which has a number of physiologic effects. The primary glutamate receptor subtype involved in ischemic damage is the N-methyl-D- aspartate (NMDA) receptor. In addition, the alpha-amino-3-hydroxy-5-methyl-4- isoxazoleproprionic acid (AMPA) and metabotropic glutamate receptors are thought to play a https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 5/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate role. Activation of these receptors leads to membrane depolarization and increased calcium influx. Numerous cellular signaling pathways respond to calcium levels, and the influx of calcium resulting from glutamate receptor stimulation leads to their activation. These pathways have both beneficial and detrimental effects. The influx of sodium ions is balanced by the influx of water into the cell, leading to edema. Sodium influx also causes reversal of the normal process of glutamate uptake by astrocyte glutamate transporters, resulting in increased glutamate release [9-12]. As a result of its increased release and decreased uptake, glutamate accumulates to excessive levels and leads to continuous stimulation. This condition is often referred to as excitotoxicity. Another effect of NMDA receptor activation is the production of nitric oxide [13]. The activity of nitric oxide synthase (NOS) and the total amount of nitric oxide present in the brain are increased following exposure to hypoxia [14]. Nitric oxide is an important signaling molecule within the body and can be beneficial at normal physiologic levels. As an example, endothelial nitric oxide synthase (eNOS) leads to the production of low levels of nitric oxide that cause vasodilation and increase blood flow [15]. However, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) result in larger amounts of nitric oxide that may lead to brain injury. Nitric oxide is a free radical and reacts directly with cellular components to damage them. Nitric oxide can also react with another free radical, superoxide, to produce the highly reactive peroxynitrite. Peroxynitrite causes single strand breaks in DNA [16]. This results in the activation of DNA repair enzymes, which consume vital energy needed for other processes. DNA damage also may activate the process of apoptosis, leading to cell death. The production of reactive oxygen species, a normal byproduct of oxidative metabolism, is also increased during ischemia. Like nitric oxide, they can react with and damage cellular components. Injury to the plasma membrane of a cell can lead to the inability to control ion flux, resulting in mitochondrial failure. Reactive oxygen species, as well as calcium influx and other factors, can also permeabilize the mitochondrial membrane [17]. This leads to metabolic failure as well as the release of initiators of apoptosis and DNA damage. Metabolic failure results in the depletion of cellular ATP levels. ATP is required for nuclear condensation and DNA degradation in the final stages of apoptosis [18]. In the absence of ATP, cell death occurs by necrosis rather than apoptosis. (See 'Necrosis and apoptosis' below.) The release of byproducts from cellular damage and death by necrosis activates components of the inflammatory pathway [19]. The role that inflammation plays during ischemia is mixed, https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 6/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate having both positive and negative effects [20]. On the one hand, inflammation results in an increase in blood flow to the ischemic region, which may deliver vital glucose and oxygen to cells. On the other hand, increased blood flow may also deliver more calcium to the area, resulting in increased tissue damage. Inflammation also results in the migration of activated leukocytes to damaged tissue [21,22]. Although these leukocytes may remove damaged and necrotic tissue, they also release cytokines to attract additional inflammatory cells. Under severe inflammatory conditions, these cytokines can accumulate to toxic levels. Necrosis and apoptosis Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. The process of necrosis is not well understood. In early stages, cellular chromatin becomes uniformly compacted, the endoplasmic reticulum is dilated, and ribosomes are dispersed [23]. In later stages, swelling of the cell and mitochondria is followed by rupture of the nuclear, organelle, and plasma membranes, leading to the release of cellular material into the surrounding environment. This release of material results in the stimulation of inflammatory processes within the brain. Apoptosis is highly regulated and has been studied in more detail than necrosis. As in necrosis, the chromatin begins to condense during early stages of apoptosis. Instead of cellular swelling, however, the contents of the cytoplasm also condense, and the mitochondria and other organelles remain intact. In later stages, the nucleus is broken into discrete fragments and the entire contents of the cell are divided into membrane bound bodies that are subsequently phagocytosed by macrophages. There are three known pathways by which apoptosis can be initiated [24]: Mitochondrial permeabilization Death receptor (Fas) pathway Endoplasmic reticulum stress The most well-known pathway involves permeabilization of the mitochondria and release of cytochrome c into the cytoplasm. Activation of membrane-bound Fas, the so called "death receptor," and the accumulation of misfolded proteins at the endoplasmic reticulum during stress, can also lead to apoptosis. These initiators all lead to the activation of caspases that cleave cellular proteins and eventually cause cell death. Caspase-independent mechanisms of apoptosis have also been proposed. The pattern of cell death after cerebral ischemia, as seen in animal models, depends on the nature of the insult to cerebral tissue [25]. In global cerebral ischemia, such as occurs after https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 7/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate cardiac arrest and resuscitation or transient severe systemic hypotension, the entire brain is exposed to ischemia. Formation of infarct is not immediate, but rather occurs after a delay of 12 hours to several days. Cell death is limited to those regions of the brain that are particularly susceptible to ischemic damage, such as the CA1 and CA4 regions of the hippocampus, the striatum, and cortical layers two and five. Cell death in these regions occurs primarily by apoptosis. Focal cerebral ischemia is a more common pattern than global ischemia in human stroke. In animal models of focal ischemia, changes in cell morphology are visible microscopically as early as two to three hours after the insult, and the infarct develops rapidly over a period of 6 to 24 hours. Cell death occurs by necrosis in the core, with apoptotic cells located on the periphery [6]. In addition to the type of insult, the duration of ischemia also affects the pattern by which cell death occurs. Longer ischemic insults produce greater damage to cerebral tissue, resulting in an increased proportion of necrosis and decreased proportion of apoptosis. There have been few studies of apoptosis in the brain following stroke in human patients. However, accumulating evidence suggests that apoptosis is involved [26-29], as illustrated by the following observations: In a neuropathology study that compared specimens from 27 patients who had cerebral infarction with specimens from rat brains subjected to experimental transient forebrain ischemia, the patterns of cell death were similar in human and animal brain tissue and included both morphologic and histochemical findings typical of apoptosis [26]. In the human stroke specimens, apoptosis was apparent during the subacute stage, but was not seen in acute or chronic stages. In another neuropathology report that compared 13 cases of fatal ischemic stroke with three patients who died of non-neurologic causes, histochemical and morphologic changes indicative of apoptosis were seen in cells throughout the brain of both patients and controls [29]. The morphologic changes were more advanced in the peri-infarct region and infarct core of the patients with stroke. Apoptotic cells were located primarily within the peri-infarct region, consisting of up to 26 percent of all cells. Increased ischemic damage and neuronal necrosis was associated with a decrease in the percentage of apoptotic cells. The deciding factor in determining whether cells undergo necrosis or apoptosis seems to be the level of energy available in the form of ATP, which is required for formation of the apoptosome. Apoptosis is unable to proceed in its absence. When energy levels are limiting, cell death therefore occurs by necrosis rather than apoptosis. The role of ATP in the mechanism of cell death has been investigated primarily using cell culture models. Cultured neurons depend on https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 8/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate the presence of serum in the culture medium for survival [24]. If the serum is removed, the cells die by necrosis. In serum-free media with added glucose, however, the cells die by apoptosis. Levels of ATP in the brain are decreased during stroke due to the lack of glucose and oxygen required for normal cellular metabolism. Glucose metabolism is decreased by approximately 50 percent in both global and focal ischemia models of stroke. As a consequence, ATP levels may fall to 10 percent of normal in global models or 25 percent in the infarct core in focal ischemia models. ATP levels in the penumbra, however, only drop to 50 percent to 70 percent of normal [30]. ATP levels in the brain may also be decreased by mitochondrial damage or failure; activity of DNA repair enzymes, such as poly ADP-ribose polymerase (PARP); and neuronal depolarization related to glutamate excitotoxicity. In stroke, therefore, low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the penumbra, ATP levels are sufficient enough that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased, with a decrease in the number of apoptotic cells. Loss of brain structural integrity Cerebral ischemia and infarction leads to loss of the structural integrity of the affected brain tissue and blood vessels [6]. This process of tissue destruction and neurovascular disruption is mediated in part by the release of various proteases, particularly the matrix metalloproteases (MMP) that degrade collagens and laminins in the basal lamina [7,31]. The loss of vascular integrity leads to a breakdown of the blood-brain- barrier and development of cerebral edema. Catastrophic failure of vascular integrity is postulated to cause hemorrhagic conversion of ischemic infarction by allowing extravasation of blood constituents into the brain parenchyma [32]. Cerebral edema Cerebral edema complicating stroke can cause secondary damage by several mechanisms, including increased intracranial pressure, which may decrease cerebral blood flow, and mass effect causing displacement of brain tissue from one compartment to another (ie, herniation), a process that can be life-threatening. Two types of cerebral edema can occur as a consequence of ischemic stroke [2,6,32,33]. Cytotoxic edema is caused by the failure of ATP-dependent transport of sodium and calcium ions across the cell membrane. The result is accumulation of water and swelling of the cellular elements of the brain, including neurons, glia, and endothelial cells. Vasogenic edema is caused by increased permeability or breakdown of the brain vascular endothelial cells that constitute the blood-brain barrier [34]. This allows proteins and other https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 9/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate macromolecules to enter the extracellular space, resulting in increased extracellular fluid volume. Roughly 10 percent of ischemic strokes are classified as malignant or massive because of the presence of space-occupying cerebral edema that is severe enough to produce elevated intracranial pressure and brain herniation. (See "Malignant cerebral hemispheric infarction with swelling and risk of herniation", section on 'Malignant hemispheric infarction'.) GENETICS OF STROKE Many of the known risk factors for stroke are variable traits influenced by multiple genes, making it difficult to sort out the genetics behind them. The study of stroke genetics is also impaired by interactions between different risk factors that modulate their effects. It is widely accepted, however, that there is a genetic component to stroke that can lead to increased or decreased risk. Outside of the monogenic disorders discussed below, it is probable that many alleles with small effect sizes contribute to the risk of ischemic stroke [35,36]. Much of the evidence for this comes from studies of twins and from families with a history of stroke [37]. Earlier studies of twins have been troubled by low sample numbers and poor classification of stroke type [37]. However, these studies indicate that stroke-related death in one sibling is associated with a higher risk of stroke-related death in the other sibling among monozygotic (identical) twins versus dizygotic (fraternal) twins. This observation suggests that genetic factors shared by the monozygotic twins played a role in their strokes. As an example, in one of the larger twin studies that evaluated 990 same-sex twin pairs, stroke death affecting both siblings was twice as likely among monozygotic twin pairs compared with dizygotic twin pairs (10 versus 5 percent), and the difference was statistically significant [38]. A family history of stroke is associated with an increased risk of stroke among the offspring [39]. This has been observed for offspring with maternal and paternal histories of stroke [37], and among individuals having a sibling with a prior stroke [40]. Additional insights into the relationship of genetic variants and the risk of ischemic stroke come from genome-wide association studies (GWAS): A 2012 meta-analysis of GWAS that analyzed data from over 12,000 subjects of European ancestry with ischemic stroke and 60,000 controls identified three loci (PITX2, ZFHX3, and HDAC9) with genome-wide significance for ischemic stroke [41]. Importantly, each locus was associated with a specific stroke subtype: https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 10/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate PITX2 and ZFHX3, previously identified as risk factors for atrial fibrillation [42-44], were associated with cardioembolic stroke [41] HDAC9 [44] was associated with large vessel ischemic stroke [41] Findings from a 2013 European GWAS of genetic factors related to coagulation suggested that ABO gene variants are associated with large vessel and cardioembolic stroke subtypes [45], and a systematic review and meta-analysis testing the association of APOE genotype with MRI markers of cerebrovascular disease found that APOE epsilon 2 carrier status was associated with an increased risk of ischemic stroke [46]. In accord with prior results, a 2016 meta-analysis of 12 GWAS with over 10,000 stroke cases and 19,000 controls found genome-wide significance for four loci [47]: PITX2 and ZFHX3 for cardioembolic stroke HDAC9 for large vessel disease ABO for all ischemic stroke Ethnic differences may also contribute to stroke risk. Although differences in lifestyle may be partly responsible for increased or decreased likelihood of stroke, genetic factors also play a role. As an example, individuals of Black African descent have a significantly higher rate of stroke than White populations, even after adjusting for differences in nongenetic risk factors [37,48]. This may or may not be related to the increased frequency among African populations of the sickle cell trait, which is a known cause of stroke due to the obstruction of small blood vessels by abnormal red blood cells. Even in monogenic disorders such as sickle cell disease, multiple genes may interact to modify risk. In a study of 1398 individuals with sickle cell anemia, 12 genes were found to interact with the mutated hemoglobin and modulate the risk of stroke [49]. Monogenic disorders A number of monogenic syndromes are associated with an increased risk of ischemic stroke, including the following [50]: Marfan syndrome and Ehlers-Danlos syndrome, which predispose to cervical artery dissection (see "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Associated conditions and risk factors' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders") Familial moyamoya disease (see "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Etiology and Pathogenesis') Fabry disease (see "Fabry disease: Neurologic manifestations") Pseudoxanthoma elasticum (see "Pseudoxanthoma elasticum") https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 11/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Homocystinuria (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders') Menkes disease (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders') Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)") Cerebral autosomal recessive arteriopathy with subcortical infarctions and leukoencephalopathy (CARASIL) [51-53] Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) [54,55] Sickle cell disease (see "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease") Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') It is important to note that all of these conditions together account for only a small percentage of ischemic strokes [56]. SUMMARY Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. (See 'Cerebral autoregulation' above.) The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. (See 'Consequences of reduction in blood flow during stroke' above.) Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes. (See 'Mechanisms of ischemic cell injury and death' above.). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 12/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased. (See 'Necrosis and apoptosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Daniel B Zemke, PhD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353. 4. Atkins ER, Brodie FG, Rafelt SE, et al. Dynamic cerebral autoregulation is compromised acutely following mild ischaemic stroke but not transient ischaemic attack. Cerebrovasc Dis 2010; 29:228. 5. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41:2697. 6. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 2010; 17:197. 7. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55:310. 8. Feske SK. Ischemic Stroke. Am J Med 2021; 134:1457. 9. Douen AG, Akiyama K, Hogan MJ, et al. Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 13/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 2000; 75:812. 10. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 1990; 348:443. 11. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 2000; 403:316. 12. Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 2008; 60:609. 13. Nandagopal K, Dawson TM, Dawson VL. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 2001; 297:474. 14. Lu GW, Liu HY. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol (1985) 2001; 91:1193. 15. Bola os JP, Almeida A. Roles of nitric oxide in brain hypoxia-ischemia. Biochim Biophys Acta 1999; 1411:415. 16. Love S. Oxidative stress in brain ischemia. Brain Pathol 1999; 9:119. 17. Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med 2003; 9:196. 18. Leist M, Single B, Castoldi AF, et al. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997; 185:1481. 19. Kamel H, Iadecola C. Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol 2012; 69:576. 20. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol 2001; 58:669. 21. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011; 10:471. 22. Kollikowski AM, Schuhmann MK, Nieswandt B, et al. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466. 23. Snider BJ, Gottron FJ, Choi DW. Apoptosis and necrosis in cerebrovascular disease. Ann N Y Acad Sci 1999; 893:243. 24. Ueda H, Fujita R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull 2004; 27:950. 25. Back T, Hemmen T, Sch ler OG. Lesion evolution in cerebral ischemia. J Neurol 2004; 251:388. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 14/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate 26. Guglielmo MA, Chan PT, Cortez S, et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis. Neurol Res 1998; 20:283. 27. Tarkowski E, Rosengren L, Blomstrand C, et al. Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999; 30:321. 28. Love S, Barber R, Wilcock GK. Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 2000; 26:55. 29. Sairanen T, Karjalainen-Lindsberg ML, Paetau A, et al. Apoptosis dominant in the periinfarct area of human ischaemic stroke a possible target of antiapoptotic treatments. Brain 2006; 129:189. 30. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999; 79:1431. 31. Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8:82. 32. Simard JM, Kent TA, Chen M, et al. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6:258. 33. Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol 1987; 72:236. 34. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 2011; 42:3323. 35. Matarin M, Singleton A, Hardy J, Meschia J. The genetics of ischaemic stroke. J Intern Med 2010; 267:139. 36. Musunuru K, Hickey KT, Al-Khatib SM, et al. Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American Heart Association. Circ Cardiovasc Genet 2015; 8:216. 37. Carr FJ, McBride MW, Carswell HV, et al. Genetic aspects of stroke: human and experimental studies. J Cereb Blood Flow Metab 2002; 22:767. 38. Bak S, Gaist D, Sindrup SH, et al. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke 2002; 33:769. 39. Seshadri S, Beiser A, Pikula A, et al. Parental occurrence of stroke and risk of stroke in their

of ischemic strokes [56]. SUMMARY Under normal conditions, the rate of cerebral blood flow is primarily determined by the amount of resistance within cerebral blood vessels. Dilation of vessels leads to an increased volume of blood in the brain and increased cerebral blood flow, whereas constriction of vessels has the opposite effect. Cerebral blood flow is also determined by variation in the cerebral perfusion pressure. (See 'Cerebral autoregulation' above.) The brain is exquisitely sensitive to even short durations of ischemia. Multiple mechanisms are involved in tissue damage that results from brain ischemia. (See 'Consequences of reduction in blood flow during stroke' above.) Brain ischemia initiates a cascade of events that eventually lead to cell death, including depletion of adenosine triphosphate (ATP); changes in ionic concentrations of sodium, potassium, and calcium; increased lactate; acidosis; accumulation of oxygen free radicals; intracellular accumulation of water; and activation of proteolytic processes. (See 'Mechanisms of ischemic cell injury and death' above.). https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 12/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Cell death following cerebral ischemia or stroke can occur by either necrosis or by apoptosis. Low levels of ATP within the core infarct are insufficient to support apoptosis, and cell death occurs by necrosis. In the ischemic penumbra, ATP levels are sufficiently high that cell death by apoptosis can occur. As the duration of ischemia increases, however, ATP levels are eventually depleted and the proportion of cells that undergo necrosis is increased. (See 'Necrosis and apoptosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Daniel B Zemke, PhD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004; 75:353. 4. Atkins ER, Brodie FG, Rafelt SE, et al. Dynamic cerebral autoregulation is compromised acutely following mild ischaemic stroke but not transient ischaemic attack. Cerebrovasc Dis 2010; 29:228. 5. Aries MJ, Elting JW, De Keyser J, et al. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke 2010; 41:2697. 6. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 2010; 17:197. 7. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55:310. 8. Feske SK. Ischemic Stroke. Am J Med 2021; 134:1457. 9. Douen AG, Akiyama K, Hogan MJ, et al. Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 13/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. J Neurochem 2000; 75:812. 10. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 1990; 348:443. 11. Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 2000; 403:316. 12. Grewer C, Gameiro A, Zhang Z, et al. Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 2008; 60:609. 13. Nandagopal K, Dawson TM, Dawson VL. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 2001; 297:474. 14. Lu GW, Liu HY. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol (1985) 2001; 91:1193. 15. Bola os JP, Almeida A. Roles of nitric oxide in brain hypoxia-ischemia. Biochim Biophys Acta 1999; 1411:415. 16. Love S. Oxidative stress in brain ischemia. Brain Pathol 1999; 9:119. 17. Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol Med 2003; 9:196. 18. Leist M, Single B, Castoldi AF, et al. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997; 185:1481. 19. Kamel H, Iadecola C. Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol 2012; 69:576. 20. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol 2001; 58:669. 21. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011; 10:471. 22. Kollikowski AM, Schuhmann MK, Nieswandt B, et al. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466. 23. Snider BJ, Gottron FJ, Choi DW. Apoptosis and necrosis in cerebrovascular disease. Ann N Y Acad Sci 1999; 893:243. 24. Ueda H, Fujita R. Cell death mode switch from necrosis to apoptosis in brain. Biol Pharm Bull 2004; 27:950. 25. Back T, Hemmen T, Sch ler OG. Lesion evolution in cerebral ischemia. J Neurol 2004; 251:388. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 14/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate 26. Guglielmo MA, Chan PT, Cortez S, et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis. Neurol Res 1998; 20:283. 27. Tarkowski E, Rosengren L, Blomstrand C, et al. Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999; 30:321. 28. Love S, Barber R, Wilcock GK. Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 2000; 26:55. 29. Sairanen T, Karjalainen-Lindsberg ML, Paetau A, et al. Apoptosis dominant in the periinfarct area of human ischaemic stroke a possible target of antiapoptotic treatments. Brain 2006; 129:189. 30. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999; 79:1431. 31. Rosell A, Lo EH. Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 2008; 8:82. 32. Simard JM, Kent TA, Chen M, et al. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6:258. 33. Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol 1987; 72:236. 34. Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 2011; 42:3323. 35. Matarin M, Singleton A, Hardy J, Meschia J. The genetics of ischaemic stroke. J Intern Med 2010; 267:139. 36. Musunuru K, Hickey KT, Al-Khatib SM, et al. Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American Heart Association. Circ Cardiovasc Genet 2015; 8:216. 37. Carr FJ, McBride MW, Carswell HV, et al. Genetic aspects of stroke: human and experimental studies. J Cereb Blood Flow Metab 2002; 22:767. 38. Bak S, Gaist D, Sindrup SH, et al. Genetic liability in stroke: a long-term follow-up study of Danish twins. Stroke 2002; 33:769. 39. Seshadri S, Beiser A, Pikula A, et al. Parental occurrence of stroke and risk of stroke in their children: the Framingham study. Circulation 2010; 121:1304. 40. Kasiman K, Lundholm C, Sandin S, et al. Familial effects on ischemic stroke: the role of sibling kinship, sex, and age of onset. Circ Cardiovasc Genet 2012; 5:226. 41. Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 2012; 11:951. https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 15/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate 42. Damani SB, Topol EJ. Molecular genetics of atrial fibrillation. Genome Med 2009; 1:54. 43. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009; 41:876. 44. International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), Bellenguez C, et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 2012; 44:328. 45. Williams FM, Carter AM, Hysi PG, et al. Ischemic stroke is associated with the ABO locus: the EuroCLOT study. Ann Neurol 2013; 73:16. 46. Schilling S, DeStefano AL, Sachdev PS, et al. APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology 2013; 81:292. 47. Malik R, Traylor M, Pulit SL, et al. Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. Neurology 2016; 86:1217. 48. Rastenyte D, Tuomilehto J, Sarti C. Genetics of stroke a review. J Neurol Sci 1998; 153:132. 49. Sebastiani P, Ramoni MF, Nolan V, et al. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet 2005; 37:435. 50. Ballabio E, Bersano A, Bresolin N, Candelise L. Monogenic vessel diseases related to ischemic stroke: a clinical approach. J Cereb Blood Flow Metab 2007; 27:1649. 51. Onodera O, Nozaki H, Fukutake T. CARASIL. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK 32533/ (Accessed on May 03, 2011). 52. Nozaki H, Nishizawa M, Onodera O. Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2014; 45:3447. 53. Nozaki H, Sekine Y, Fukutake T, et al. Characteristic features and progression of abnormalities on MRI for CARASIL. Neurology 2015; 85:459. 54. Jen J, Cohen AH, Yue Q, et al. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Neurology 1997; 49:1322. 55. Ophoff RA, DeYoung J, Service SK, et al. Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3. Am J Hum Genet 2001; 69:447. 56. Lanktree MB, Dichgans M, Hegele RA. Advances in genomic analysis of stroke: what have we learned and where are we headed? Stroke 2010; 41:825. Topic 14085 Version 27.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 16/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate GRAPHICS TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 17/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate The progression of a dissection, thrombus development, and total vessel occlusion Courtesy of Dr. Mounzer Kassab. Graphic 57866 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 18/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Normal cerebral autoregulation and its disturbance during acute ischemic stroke Courtesy of Dr. Mounzer Kassab. Graphic 66923 Version 1.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 19/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Effects of decreased cerebral blood flow on vital brain functions Courtesy of Dr. Mounzer Kassab. Graphic 77705 Version 2.0 https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 20/21 7/6/23, 12:34 PM Pathophysiology of ischemic stroke - UpToDate Contributor Disclosures Arshad Majid, MB, ChB, FRCP No relevant financial relationship(s) with ineligible companies to disclose. Mounzer Kassab, MD Speaker's Bureau: UCB Pharma [Anticonvulsant]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pathophysiology-of-ischemic-stroke/print 21/21

7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Reversible cerebral vasoconstriction syndrome : Aneesh Singhal, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 01, 2022. INTRODUCTION Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing of the cerebral arteries with clinical manifestations that typically include thunderclap headache and sometimes include neurologic deficits related to brain edema, stroke, or seizure. The clinical outcome is usually benign, although major strokes can result in severe disability or death in a minority. This topic will review RCVS. Other conditions associated with thunderclap headache are discussed separately. (See "Overview of thunderclap headache" and "Primary cough headache" and "Exercise (exertional) headache" and "Primary headache associated with sexual activity".) TERMINOLOGY RCVS has been reported using variable terminology, including the following: Migrainous vasospasm or migraine angiitis [1,2] Call-Fleming syndrome (or Call syndrome) [3,4] Thunderclap headache-associated vasospasm [5-7] Drug-induced cerebral arteritis [8] Postpartum cerebral angiopathy [9] Benign angiopathy of the central nervous system [10] Central nervous system pseudovasculitis [11] https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 1/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate These conditions are characterized by clinical manifestations that typically include thunderclap headache and, less commonly, focal neurologic deficits related to brain edema, stroke, or seizure and angiographic reversible multifocal narrowing of the cerebral arteries. It is now apparent that patients with reversible cerebral arterial narrowing have nearly identical clinical, laboratory, imaging, and prognostic features regardless of the associated condition [12-14]. The descriptive term "reversible cerebral vasoconstriction syndrome" has been proposed to facilitate the recognition and management of this group of disorders [15]. The adoption of the broad term RCVS, along with its main clinical and imaging features, has encouraged relatively large retrospective and prospective studies that have helped characterize the syndrome [15-23]. PATHOPHYSIOLOGY The pathophysiology of the abrupt-onset headache and of the prolonged but reversible vasoconstriction is not known. Reversible angiographic narrowing suggests an abnormality in the control of cerebrovascular tone [24]. It remains unclear whether the angiographic abnormalities trigger the headaches or result from severe headache, but there certainly is a close relationship [25,26]. The anatomic basis to explain both the vasoconstriction and headaches is the innervation of cerebral blood vessels with sensory afferents from the trigeminal nerve (V1) and dorsal root of C2. Cerebral vasoconstriction, when severe or progressive, may result in ischemic stroke and in some cases brain hemorrhages that probably reflect postischemic reperfusion injury due to the dynamic and reversible nature of the arterial narrowing. Some patients develop convexal subarachnoid hemorrhages, presumably from the rupture of small surface arteries undergoing dynamic vasoconstriction-vasodilation. The pathophysiologies of RCVS and reversible posterior leukoencephalopathy syndrome (RPLS) may overlap as both entities can present with reversible brain lesions, including transient brain edema in patients with RCVS and transient cerebral angiographic abnormalities in patients with RPLS [27-34]. (See "Reversible posterior leukoencephalopathy syndrome".) EPIDEMIOLOGY The true incidence of RCVS is unknown. In a study using administrative claims data from 2016 in the United States, the incidence of RCVS hospitalizations was approximately three per one million adults [35]. Clinical experience suggests the true incidence of RCVS is likely much higher [36]. RCVS is being reported with increasing frequency, presumably due to greater awareness of the syndrome, higher detection rates due to the widespread use of relatively noninvasive imaging tests such as computed tomography angiography (CTA) and magnetic resonance https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 2/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate angiography (MRA), and perhaps the escalating use of illicit drugs and vasoconstrictive medications [37]. In adults, RCVS predominantly affects females, with female to male ratios ranging from 2:1 to 10:1, depending on the case series [35,36,38,39]. In contrast, a 2017 review of pediatric RCVS found that most cases affected males (11 of 13) [40]. The mean age of affected individuals across published studies is 42 to 48 years, with an age range of 4 months to 65 years [16,22,36,39-42]. RCVS occurs worldwide in individuals of all races. RISK FACTORS AND ASSOCIATED CONDITIONS RCVS has been associated with a variety of conditions including pregnancy [8,43], migraine [1,2,44], use of vasoconstrictive drugs [8,36,45,46] and other medications [29,47], neurosurgical procedures [48], hypercalcemia [49], unruptured saccular aneurysms [5,50], cervical artery dissection [50,51], cerebral venous thrombosis [52,53], and others [41,54-57]. The individual risk factors, triggers, and conditions associated with RCVS ( table 1) appear unrelated (ie, without a common pathophysiological theme) and may simply reflect the biases of investigators in attributing risk. Indeed, the variable nosology previously used by different physician groups (eg, stroke neurologists, headache specialists, obstetricians, internists, and rheumatologists) to report this clinical-angiographic syndrome reflects uncertainties concerning the pathogenesis and clinical approach. Authors have implicated the listed conditions, including commonly used medications such as serotonergic antidepressants, based on their known vasoconstrictive effects or the temporal relationship with the onset headaches [4]. However, epidemiologic evidence to support a causal relationship is lacking. Some authors have speculated that the vasoconstriction is related to transient vasculitis, but there is no evidence to support a role for inflammation. Cerebrospinal fluid examination and extensive serological tests are normal, and pathological studies of the brain and temporal arteries have shown no abnormality [58]. CLINICAL PRESENTATION AND COURSE Thunderclap headaches The clinical presentation of RCVS is usually dramatic, with sudden, excruciating headaches that reach peak intensity within seconds, meeting the definition for "thunderclap headache" [59,60]. The thunderclap headaches tend to recur over a span of days to weeks. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 3/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate The onset headaches are usually diffuse or located in the occipital region or vertex. They are often accompanied with nausea and photosensitivity. The character of these headaches is usually different from the patient's prior migraine headaches, if any. Most patients experience moderate pain relief within a few minutes to hours, only to be followed by sudden, severe exacerbations that can recur for days. In one study, patients reported an average of four recurrences [16]. Less than 10 percent of patients with RCVS present with subacute or less severe headaches; the absence of headache at onset is exceptional [16,22,61,62]. Triggering factors Many patients have triggering factors, such as orgasm, physical exertion, acute stressful or emotional situations, Valsalva maneuvers (eg, straining, coughing, sneezing), bathing, and swimming [22,63]. Blood pressure The initial blood pressure can be elevated with RCVS due to severe headache pain, the disease itself, or the associated condition (eg, eclampsia, cocaine exposure). Neurologic involvement Headache remains the only symptom in many patients with RCVS; others develop focal deficits from underlying ischemic stroke, intracerebral hemorrhage, or reversible cerebral edema [15,16,22]. In published series, the frequency of focal neurologic deficits ranged from 9 to 63 percent, being higher in inpatient case series. In one report of 139 patients with RCVS, a majority (81 percent) eventually developed brain lesions including ischemic infarction (39 percent), brain edema (38 percent), convexity subarachnoid hemorrhage (33 percent), and lobar hemorrhage (20 percent) [22]. Generalized tonic-clonic seizures are reported in 0 to 21 percent of patients at the time of presentation; however, recurrent seizures are rare. Hemiplegia, tremor, hyperreflexia, ataxia, and aphasia can develop. Visual deficits, including scotomas, blurring, hemianopia, and cortical blindness, are common, and these patients typically have concomitant reversible posterior leukoencephalopathy syndrome [62]. Many patients show features of Balint syndrome, which is made up of the triad of simultanagnosia (the inability to integrate a visual scene despite adequate acuity to resolve individual elements), optic ataxia (the inability to reach accurately under visual guidance), and ocular apraxia (the inability to direct gaze accurately to a new target, frequently leading to difficulty reading) [22,64]. Neuroimaging Brain imaging is often normal early in the course of RCVS. Typical abnormalities include vasogenic edema and/or fluid-attenuated inversion recovery (FLAIR) sulcal hyperintensities (dot sign) on magnetic resonance imaging (MRI). Infarcts, if present, https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 4/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate are usually symmetric and distributed along border zones of arterial territories. Intraparenchymal hemorrhage and/or nonaneurysmal convexity subarachnoid hemorrhage may be present in some cases of RCVS. Multifocal segmental cerebral artery vasoconstriction on cerebral angiography is the hallmark of RCVS. These findings are discussed in detail below. (See 'Brain imaging' below and 'Neurovascular imaging' below.) Time course The resolution of the different components of RCVS, including thunderclap headaches, focal deficits, and angiographic narrowing, usually occurs over days to weeks but does not always follow the same time course. (See 'Clinical course and prognosis' below.) EVALUATION Urgent evaluation Nearly all patients with RCVS present with one or more thunderclap headaches. Thunderclap headache must be evaluated and treated as a medical emergency, beginning with an evaluation for potentially serious secondary causes such as a ruptured brain aneurysm, brain hemorrhage, cervical artery dissection, and other conditions listed in the table ( table 2). Urgent brain and cerebral vascular imaging with a cranial computed tomography (CT) or brain magnetic resonance imaging (MRI) and head and neck CT angiography (CTA) or magnetic resonance angiography (MRA) is appropriate. If initial imaging is normal, lumbar puncture with measurement of opening pressure and cerebrospinal fluid examination for cell counts, glucose and protein levels, and xanthochromia should be pursued to exclude subarachnoid hemorrhage and infectious causes of thunderclap headache. The past medical history should inquire specifically about associated conditions and possible triggering factors for RCVS, such as those listed in the table ( table 1) and discussed above. (See 'Risk factors and associated conditions' above and 'Clinical presentation and course' above.) The systemic examination of patients with RCVS is usually unrevealing, although the initial blood pressure can be elevated due to either severe headache pain, the disease itself, or an associated condition (eg, eclampsia, cocaine exposure). Brain imaging Between 30 and 70 percent of patients with RCVS have no abnormality on initial neuroimaging studies with cranial CT or MRI, despite having (eventually) widespread cerebral vasoconstriction [16,22,26,36,65,66]. However, approximately 75 percent of admitted patients eventually develop parenchymal lesions ( image 1 and image 2). The most frequent lesions are ischemic stroke and cortical surface (convexity) nonaneurysmal subarachnoid hemorrhage, followed by reversible vasogenic brain edema and parenchymal hemorrhage [16,22,36]. Any combination of lesions can be present. CT and MRI remain normal https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 5/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate in approximately 25 percent of cases reported from in-hospital settings; this number is much higher in emergency department case series. Infarcts are often bilateral and symmetrical, located in arterial border-zone (ie, watershed) regions of the cerebral hemispheres or in the cortical-subcortical junction. Larger infarcts are often wedge shaped. Perfusion-weighted MRI may show areas of hypoperfusion in border-zone regions. Cortical surface (convexity) subarachnoid hemorrhage is typically minor, restricted to a few sulcal spaces [27,67,68]. Several studies have shown that RCVS is the most frequent cause of cortical surface (convexity) subarachnoid hemorrhage ( image 3 and image 1) in individuals below age 60 years [69-71]. Single as well as multiple lobar hemorrhages can occur, and brain hemorrhages can develop a few days after onset, which again suggests a mechanistic role for reperfusion injury. Subdural hemorrhage has been reported [38]. Fluid-attenuated inversion recovery (FLAIR) MRI often shows indirect signs of RCVS in the form of dot (ie, the dot sign) or linear hyperintensities within sulcal spaces, which are believed to represent slow flow within dilated surface vessels [72,73]. Intravascular hyperdensities can be hard to distinguish from convexity subarachnoid hemorrhage ( image 1). Neurovascular imaging Abnormal cerebral angiography is the primary diagnostic feature of RCVS. Cerebral angiographic abnormalities are dynamic, progressing over time from distal to proximal vessels, and appear as intermittent areas of focal narrowing ("sausage on a string" appearance) of the circle of Willis arteries and their branches. Smooth, tapered narrowing followed by abnormal dilated segments of second- and third-order branches of the cerebral arteries ( image 1) is the most characteristic abnormality. Study selection CTA or MRA are preferred initial modalities to document the segmental cerebral arterial narrowing and vasodilatation ( image 1 and image 4). Digital subtraction catheter angiography (DSA) is typically reserved for cases when CTA or MRA are nondiagnostic or in atypical cases to exclude other entities in the differential diagnosis. DSA is more sensitive than either CTA or MRA for identifying abnormalities in smaller vessels (ie, lumen diameter <2 mm) ( image 5) but is invasive and carries a higher risk than the noninvasive vascular studies. The diagnosis of RCVS can be made with accuracy based on history and the results of initial brain and noninvasive vascular imaging alone [36,62]. Transcranial Doppler ultrasound has been used for diagnosis; however, normal results do not exclude this diagnosis [9]. This noninvasive bedside tool has utility in monitoring the progression of vasoconstriction [17]. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 6/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Timing of imaging Initial CTA or MRA can be normal because the condition starts distally in small vessels that are not well visualized; one study found that 21 percent had normal findings on initial MRA and 9 percent had normal findings on both MRA and transcranial Doppler ultrasonography [16]. Vasoconstriction may not become evident for more than one week after clinical onset, peaks at two to three weeks, and is typically reversible within three months ( image 4). For patients with a high degree of clinical suspicion for RCVS, a follow-up CTA or MRA should be done after three to five days. Vascular imaging may reveal concomitant cervicocephalic arterial dissection or unruptured aneurysms [5,51,74,75]. In some patients, the extracranial internal carotid or vertebral artery can be affected by RCVS. Systemic arteries are rarely involved [76,77]. Other tests Serum and urine toxicology screens should be routinely performed to investigate for exposure to vasoconstrictive drugs such as cannabinoids and cocaine. Laboratory evaluation should also include urine vanillylmandelic acid and 5-hydroxyindoleacetic levels to evaluate for vasoactive tumors (eg, pheochromocytoma, carcinoid) that are associated with RCVS, and a serum calcium level to exclude hypercalcemia as a cause of RCVS, if there is clinical suspicion for these conditions based on symptoms or signs. Serum magnesium should be obtained if there is local preference to treat vasoconstriction with intravenous magnesium. When there is uncertainty about the cause of cerebral arteriopathy, we obtain complete blood count, electrolytes, liver and renal function tests, and tests for inflammation (eg, erythrocyte sedimentation rate, rheumatoid factor, and antinuclear cytoplasmic antibodies), all of which are typically normal in patients with RCVS. However, these tests are not necessary if the diagnosis of RCVS is highly likely, based upon the presence of recurrent thunderclap headaches ( table 3) or RCVS2 score ( table 4 and table 5). (See 'Diagnosis' below and 'Angiographic differential' below.) Lumbar puncture Although lumbar puncture is required in patients presenting with thunderclap headache to exclude secondary causes such as a ruptured cerebral aneurysm or meningitis, it could be avoided in patients with multiple thunderclap headaches, since three or more recurrent thunderclap headaches are diagnostic for RCVS [36,62]. In patients with a single thunderclap headache, lumbar puncture may be needed to exclude secondary causes unless there is clear evidence for RCVS on CTA or MRA with multifocal segmental narrowing of the cerebral arteries [36,62]. Patients with RCVS typically have normal cerebrospinal fluid findings (ie, protein level <60 3 mg/dL, 5 white blood cells per mm ). In one series, with cerebrospinal fluid examination performed in over 100 patients with RCVS, results were normal in approximately 85 percent https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 7/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate [22]. Minor abnormalities can result from ischemic or hemorrhagic strokes. The classic lumbar puncture findings of aneurysmal subarachnoid hemorrhage (ie, an elevated opening pressure, an elevated red blood cell count that does not diminish from tube 1 to tube 4, and xanthochromia) are absent in RCVS. Biopsy There is generally no role for brain biopsy or temporal artery biopsy unless the diagnosis remains unclear despite a thorough evaluation and there is at least moderate suspicion for cerebral vasculitis. DIAGNOSIS The diagnosis of RCVS is based upon the characteristic clinical, brain imaging, and angiographic features. Key components of the diagnosis ( table 3 and table 6 and table 4 and table 5) are single or recurrent thunderclap headaches, absence of aneurysmal subarachnoid hemorrhage, and typical brain imaging findings ( image 2) (eg, normal, or variable presence of vasogenic edema, fluid-attenuated inversion recovery sulcal hyperintensities [dot sign] on magnetic resonance imaging, symmetric border-zone infarcts, intraparenchymal hemorrhage, and/or nonaneurysmal convexity subarachnoid hemorrhage), combined with multifocal segmental cerebral artery vasoconstriction on angiography, which usually develops within a week of symptom onset [15,36,62]. The presence of multiple thunderclap headaches recurring over a few days has nearly 100 percent sensitivity and specificity for the diagnosis of RCVS [36,62]. The sensitivity and specificity of variables useful to diagnose RCVS and to distinguish it from primary angiitis of the central nervous system (a historic mimic of RCVS) is shown in the table ( table 6). In patients with a newly detected cerebral arteriopathy, the RCVS score ( table 4 and table 5) has excellent 2 sensitivity and specificity for diagnosing RCVS and distinguishing it from a variety of other cerebral arteriopathies. DIFFERENTIAL DIAGNOSIS To the experienced clinician, RCVS is an instantly recognizable entity based on certain features (see 'Clinical presentation and course' above). Most patients report severe thunderclap headaches and characteristic brain imaging features and vascular abnormalities that resolve over a few weeks. The syndrome is known to occur in certain clinical settings ( table 1). Individually, however, the clinical and imaging features carry a wide range of differential diagnoses. In the past, patients with RCVS have been misinterpreted as having primary angiitis https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 8/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate of the central nervous system (PACNS) or aneurysmal subarachnoid hemorrhage due to overlapping features such as headache, stroke, and cerebral angiographic narrowing. Headache differential Aneurysmal subarachnoid hemorrhage is a major consideration in the differential of RCVS because of the presence of thunderclap headaches, subarachnoid blood, and cerebral artery narrowing [19,67,68]. However, the recurrent nature of thunderclap headaches related to RCVS, the superficial location and small quantity of subarachnoid blood, and the widespread, symmetric vasoconstriction distinguish RCVS from aneurysmal bleeds [19]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Other causes of thunderclap headache should be considered. The presence of recurrent thunderclap headaches over the span of a few days is pathognomonic for RCVS [36,62]. Nevertheless, isolated thunderclap headache can signify a variety of ominous conditions, including cerebral artery dissection, cerebral venous sinus thrombosis, ischemic stroke, intracranial infection, spontaneous intracranial hypotension, reversible posterior leukoencephalopathy syndrome, pituitary apoplexy, and colloid cyst of the third ventricle ( table 2 and table 7). These conditions are differentiated with appropriate evaluation and imaging. The clinical features, imaging characteristics, and cerebrospinal fluid findings of the more common causes of thunderclap headache are summarized in the table ( table 8). (See "Overview of thunderclap headache" and "Overview of thunderclap headache", section on 'Diagnostic evaluation' and "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) If secondary causes of thunderclap headache are excluded, the differential diagnosis narrows to include RCVS, primary thunderclap headache, and associated primary headaches (ie, primary cough headache, primary exercise headache, and primary headache associated with sexual activity). These conditions are closely related [26]. The segmental angiographic abnormalities that accompany RCVS may be absent in the early stages of the condition; hence, the patient initially may be misdiagnosed as having a primary thunderclap headache. In such cases, a follow-up cranial computed tomography angiography (CTA) or magnetic resonance angiography (MRA) after approximately one week should be performed to investigate for RCVS. In one study, 39 percent of patients presenting with thunderclap headache and normal brain magnetic resonance imaging (MRI) findings proved to have vasoconstriction on MRA, and those with and without vasoconstriction had similar clinical features, suggesting that RCVS and primary https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 9/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate thunderclap headache belong to the same spectrum of disorders [26]. (See "Overview of thunderclap headache", section on 'Primary TCH' and "Primary cough headache" and "Exercise (exertional) headache" and "Primary headache associated with sexual activity".) Migraine is another consideration in the differential diagnosis of RCVS, and the misdiagnosis of migraine can lead to inappropriate treatment with antimigraine agents such as triptans, which can exacerbate vasoconstriction and stroke risk [4,78]. Although there may be some overlap, RCVS appears distinct from migraine because, unlike migraine, RCVS rarely recurs, the sudden-onset headaches of RCVS are quite different from migraine headaches, the brain and vascular imaging abnormalities are inconsistent with migraine, and the angiographic abnormalities of RCVS persist for several weeks. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults" and "Pathophysiology, clinical features, and diagnosis of migraine in children".) Angiographic differential Intracranial arteriopathies The angiographic abnormalities of RCVS can raise concern for intracranial atherosclerosis, infectious arteritis, vasculitis, moyamoya disease, fibromuscular dysplasia, and other cerebral arteriopathies. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Clinical manifestations and diagnosis of fibromuscular dysplasia".) A number of features on initial evaluation help to distinguish RCVS from other intracranial arteriopathies that affect large and medium-sized vessels. In a retrospective study of consecutive patients with RCVS (n = 30) or non-RCVS arteriopathy (n = 80), recurrent or single thunderclap headache, vasoconstrictive trigger, female sex, and convexity subarachnoid hemorrhage were predictors of RCVS; luminal irregularities of the intracranial carotid artery was a negative predictor, being more frequently present in non- RCVS (mainly moyamoya disease) compared with RCVS (58 versus 20 percent) [62]. These features were incorporated into the RCVS score ( table 4): 2 Recurrent or single thunderclap headache: present 5, absent 0 Carotid artery (intracranial segment) narrowing: affected -2, not affected 0 Vasoconstrictive trigger: present 3, absent 0 Sex: female 1, male 0 Subarachnoid hemorrhage: present 1, absent 0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 10/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate The RCVS score can now be used for diagnosis shortly after admission, even before 2 angiographic reversal occurs, with high accuracy [62]. In the derivation cohort, RCVS 2 scores 5 had a high specificity and sensitivity (99 and 90 percent, respectively) for diagnosing RCVS, while scores 2 had a high specificity and sensitivity (100 and 85) percent for excluding RCVS; intermediate scores of 3 to 4 had a lower specificity and sensitivity (86 and 10 percent) for diagnosing RCVS ( table 5) [62]. Performance was similar in the validation cohort of 156 patients with RCVS and 47 with PACNS. Among patients in the derivation and validation cohorts with RCVS scores of 3 or 4, clinical features of recurrent 2 thunderclap headaches, vasoactive triggers, and normal brain imaging or the presence of convexity subarachnoid hemorrhage correctly identified 25 of 37 patients with RCVS. Primary angiitis of the central nervous system Historically, it was considered difficult to exclude PACNS from RCVS because features such as headache, focal deficits, stroke, seizures, and angiographic irregularities are common to both conditions. (See "Primary angiitis of the central nervous system in adults".) While there is overlap, the nature of the headaches and imaging abnormalities are quite different [15,16,22,36,61,79,80]. Patients with PACNS usually have an insidious progressive clinical course with chronic headaches and rarely have thunderclap headache that is typical of RCVS. The characteristic vasoconstriction of RCVS usually manifests as smooth, tapered narrowing followed by abnormal dilated segments of second- and third-order branches of the cerebral arteries. This angiographic appearance distinguishes RCVS from PACNS, where the arterial narrowing is much more irregular. Brain imaging in RCVS can be normal or show watershed infarcts or lobar hemorrhages, whereas PACNS is usually associated with accumulating T2-hyperintense brain lesions, leptomeningeal enhancement, and scattered deep infarcts [36]. In a retrospective report that compared 159 patients with RCVS and 47 patients with PACNS, several features had 98 to 100 percent specificity for the diagnosis of RCVS and a similarly high positive predictive value (ie, the likelihood that a patient with a positive finding has the disease) ( table 6) [36]. These were (1) recurrent thunderclap headache or (2) single thunderclap headache combined with normal neuroimaging, border zone infarcts, or vasogenic edema, or (3) no thunderclap headache but abnormal angiography and no brain lesions on neuroimaging. Note that the absence of brain lesions virtually rules out PACNS. These criteria were independently validated in a study comparing cohorts of 173 patients with RCVS and 110 patients with PACNS [81]. They can be used for bedside diagnosis at the https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 11/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate time of admission, even without cerebral angiography or documentation of vasoconstriction reversal on follow-up imaging. There have been rare reports of cases with severe and prolonged vasoconstriction associated with irreversible angiographic changes, making the distinction between vasculitis and vasoconstriction extremely difficult [82]. In challenging cases, 3D contrast- enhanced vessel wall imaging may help to identify arterial wall enhancement that has been associated with cases of cerebral vasculitis but not in cases of RCVS ( image 6) [83]. However, the utility of this test remains to be confirmed [84]. MANAGEMENT Supportive care There is no proven or established therapy for RCVS. While most patients fully recover with time, up to one-third can develop transient symptoms in the initial few days, and rare cases can develop a progressive clinical course [18]. Therefore, it is reasonable to admit patients for observation, pain control, and supportive care for the first few days after symptom onset. Blood pressure Patients with severe angiographic abnormalities are often admitted to the intensive care unit for neurologic monitoring and blood pressure management. The goals of blood pressure control are controversial. While there is no consensus, we generally allow a broad range of systolic blood pressure, from 90 to 180 mmHg. We treat hypotension (systolic <90 mmHg) with intravenous fluids, although the threshold of 90 mmHg may be too low if vasoconstriction is severe. High blood pressure (systolic >180 mmHg) can be treated with labetalol or nicardipine. Theoretically, pharmacologically induced hypertension can induce further cerebral vasoconstriction or result in brain hemorrhage and, in the setting of cerebral vasoconstriction, even mild hypotension can trigger ischemic stroke [85]. Pain The pain of RCVS-associated headache is extreme and frequently warrants the use of opioid analgesics in addition to nonsteroidal anti-inflammatory drugs (NSAIDs). In our experience, oral treatment with hydromorphone or acetaminophen-codeine is usually sufficient to manage pain. Thunderclap headaches typically decrease in intensity and frequency over a span of days to weeks. Triptans and the ergot derivatives are contraindicated because of their vasoconstrictive actions [4,78]. Seizures Acute seizures warrant treatment with antiseizure medications, though seizures are usually present only upon presentation and do not recur. Therefore, long-term seizure prophylaxis is probably unnecessary. No seizure prophylaxis is needed for patients who do https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 12/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate not have a seizure. (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic seizures' and "Evaluation and management of the first seizure in adults", section on 'When to start antiseizure medication therapy'.) Avoid empiric glucocorticoids We suggest not using empiric glucocorticoid therapy for possible primary angiitis of the central nervous system (PACNS) when RCVS is suspected. However, glucocorticoids are often administered to minimize the risk of delaying treatment in patients who may actually have PACNS, a condition that shares certain features with RCVS (see 'Differential diagnosis' above) and is believed to be progressive and potentially fatal without prompt immunosuppressive therapy. Unfortunately, many patients remain on glucocorticoids for prolonged durations and incur the risk of serious steroid-related adverse effects. There are several reasons to avoid glucocorticoid therapy: Distinguishing RCVS and PACNS in the acute setting is generally straightforward ( table 6 and table 4 and table 5). (See 'Angiographic differential' above.) There is little evidence that a therapeutic delay of a few days would increase the risk for worse outcome in PACNS; even with diagnostically challenging cases, the diagnosis usually becomes apparent after a brief period of observation. Glucocorticoids are associated with worse outcome in RCVS [22,86]. Bedside efforts should focus on distinguishing RCVS from PACNS on the basis of the initial clinical and imaging features and reserve empiric glucocorticoid therapy for the rare patient with a rapidly worsening clinical course while the diagnosis remains uncertain. Vasoconstriction Because clinical and angiographic resolution occur spontaneously without any medical intervention in approximately 90 percent of patients with RCVS, we generally do not use any agent to treat vasoconstriction. In the absence of controlled trials, management of vasoconstriction is guided by observational data and expert opinion. Empiric therapy is not justified for patients who present with thunderclap headache but have not yet undergone vascular imaging. Even when cerebral vasoconstriction has been documented, specific treatment remains undefined. While the literature is replete with various treatment approaches associated with good outcome, these reports probably reflect publication bias. Pharmacologic treatment Calcium channel blockers such as nimodipine and verapamil [87] and brief courses of magnesium sulfate [27,88], serotonin antagonists, and dantrolene https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 13/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate [89] have been administered in an effort to relieve the vasoconstriction. Data from two prospective case series suggest that nimodipine does not affect the time course of cerebral vasoconstriction [16,17]. However, nimodipine might relieve the number and intensity of headaches and has documented effects on the smaller vasculature not easily imaged by angiography. Calcium channel blockers can be discontinued after resolution of symptoms or angiographic abnormalities if they are used. Intra-arterial vasodilation We reserve intra-arterial measures for patients exhibiting clear signs of clinical progression, particularly since over 90 to 95 percent of RCVS patients have a benign, self-limited syndrome despite the presence of severe angiographic vasoconstriction and ischemic or hemorrhagic brain lesions. Unfortunately, no known clinical or imaging features reliably predict disease progression. Balloon angioplasty and direct intra-arterial administration of nicardipine, papaverine, milrinone, and nimodipine have been used with variable success [90-92]. In patients with RCVS, intra-arterial infusion of vasodilators into a single constricted artery can promptly reverse vasoconstriction in that artery and often in multiple brain arteries, including the contralateral arteries. A similar but milder response has rarely been observed in RCVS mimics such as PACNS and intracranial atherosclerosis. On this basis, the demonstration of arterial dilatation using intra-arterial vasodilator infusions has been proposed as a "diagnostic test" for RCVS [93]. However, intra-arterial interventions carry a risk for reperfusion injury. Prevention and counseling In the acute setting, it is logical to avoid further exposure to any potential precipitating factors, such as marijuana, cocaine, exercise stimulants, amphetamines and triptans, serotonergic antidepressants, or other vasoconstrictive medications that can worsen the clinical course. Patients should avoid physical exertion, sexual activity, the Valsalva maneuver, and other known triggers of recurrent headaches for a few weeks. Laxatives and stool softeners should be used to avoid constipation (which can trigger the Valsalva maneuver), especially in patients receiving opioids for head pain. The risk of recurrent RCVS is low; hence, reexposure to the potential precipitating factor (eg, antidepressants) can be considered if clinically necessary and after other therapeutic options are exhausted. Usual secondary stroke preventive medications, such as antiplatelet agents, anticoagulants, and cholesterol-lowering agents, are probably not indicated. There are no known genetic implications of RCVS. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 14/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate CLINICAL COURSE AND PROGNOSIS The resolution of the different components of RCVS, including headaches, focal deficits, and angiographic narrowing, does not always follow the same time course. The thunderclap headaches typically resolve over days to weeks. Similarly, most patients show resolution of visual and other focal neurologic signs and symptoms within days to weeks. Less than 15 to 20 percent are left with residual deficits from stroke, and in most cases the deficits are relatively minor or moderate (ie, 90 to 95 percent have a modified Rankin scale score ( table 9) of 0 to 2 at discharge) [94]. Progressive cerebral arterial vasoconstriction culminating in massive strokes, brain edema, severe morbidity, or death occurs in less than five percent of cases, and these fulminant cases

allow a broad range of systolic blood pressure, from 90 to 180 mmHg. We treat hypotension (systolic <90 mmHg) with intravenous fluids, although the threshold of 90 mmHg may be too low if vasoconstriction is severe. High blood pressure (systolic >180 mmHg) can be treated with labetalol or nicardipine. Theoretically, pharmacologically induced hypertension can induce further cerebral vasoconstriction or result in brain hemorrhage and, in the setting of cerebral vasoconstriction, even mild hypotension can trigger ischemic stroke [85]. Pain The pain of RCVS-associated headache is extreme and frequently warrants the use of opioid analgesics in addition to nonsteroidal anti-inflammatory drugs (NSAIDs). In our experience, oral treatment with hydromorphone or acetaminophen-codeine is usually sufficient to manage pain. Thunderclap headaches typically decrease in intensity and frequency over a span of days to weeks. Triptans and the ergot derivatives are contraindicated because of their vasoconstrictive actions [4,78]. Seizures Acute seizures warrant treatment with antiseizure medications, though seizures are usually present only upon presentation and do not recur. Therefore, long-term seizure prophylaxis is probably unnecessary. No seizure prophylaxis is needed for patients who do https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 12/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate not have a seizure. (See "Evaluation and management of the first seizure in adults", section on 'Acute symptomatic seizures' and "Evaluation and management of the first seizure in adults", section on 'When to start antiseizure medication therapy'.) Avoid empiric glucocorticoids We suggest not using empiric glucocorticoid therapy for possible primary angiitis of the central nervous system (PACNS) when RCVS is suspected. However, glucocorticoids are often administered to minimize the risk of delaying treatment in patients who may actually have PACNS, a condition that shares certain features with RCVS (see 'Differential diagnosis' above) and is believed to be progressive and potentially fatal without prompt immunosuppressive therapy. Unfortunately, many patients remain on glucocorticoids for prolonged durations and incur the risk of serious steroid-related adverse effects. There are several reasons to avoid glucocorticoid therapy: Distinguishing RCVS and PACNS in the acute setting is generally straightforward ( table 6 and table 4 and table 5). (See 'Angiographic differential' above.) There is little evidence that a therapeutic delay of a few days would increase the risk for worse outcome in PACNS; even with diagnostically challenging cases, the diagnosis usually becomes apparent after a brief period of observation. Glucocorticoids are associated with worse outcome in RCVS [22,86]. Bedside efforts should focus on distinguishing RCVS from PACNS on the basis of the initial clinical and imaging features and reserve empiric glucocorticoid therapy for the rare patient with a rapidly worsening clinical course while the diagnosis remains uncertain. Vasoconstriction Because clinical and angiographic resolution occur spontaneously without any medical intervention in approximately 90 percent of patients with RCVS, we generally do not use any agent to treat vasoconstriction. In the absence of controlled trials, management of vasoconstriction is guided by observational data and expert opinion. Empiric therapy is not justified for patients who present with thunderclap headache but have not yet undergone vascular imaging. Even when cerebral vasoconstriction has been documented, specific treatment remains undefined. While the literature is replete with various treatment approaches associated with good outcome, these reports probably reflect publication bias. Pharmacologic treatment Calcium channel blockers such as nimodipine and verapamil [87] and brief courses of magnesium sulfate [27,88], serotonin antagonists, and dantrolene https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 13/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate [89] have been administered in an effort to relieve the vasoconstriction. Data from two prospective case series suggest that nimodipine does not affect the time course of cerebral vasoconstriction [16,17]. However, nimodipine might relieve the number and intensity of headaches and has documented effects on the smaller vasculature not easily imaged by angiography. Calcium channel blockers can be discontinued after resolution of symptoms or angiographic abnormalities if they are used. Intra-arterial vasodilation We reserve intra-arterial measures for patients exhibiting clear signs of clinical progression, particularly since over 90 to 95 percent of RCVS patients have a benign, self-limited syndrome despite the presence of severe angiographic vasoconstriction and ischemic or hemorrhagic brain lesions. Unfortunately, no known clinical or imaging features reliably predict disease progression. Balloon angioplasty and direct intra-arterial administration of nicardipine, papaverine, milrinone, and nimodipine have been used with variable success [90-92]. In patients with RCVS, intra-arterial infusion of vasodilators into a single constricted artery can promptly reverse vasoconstriction in that artery and often in multiple brain arteries, including the contralateral arteries. A similar but milder response has rarely been observed in RCVS mimics such as PACNS and intracranial atherosclerosis. On this basis, the demonstration of arterial dilatation using intra-arterial vasodilator infusions has been proposed as a "diagnostic test" for RCVS [93]. However, intra-arterial interventions carry a risk for reperfusion injury. Prevention and counseling In the acute setting, it is logical to avoid further exposure to any potential precipitating factors, such as marijuana, cocaine, exercise stimulants, amphetamines and triptans, serotonergic antidepressants, or other vasoconstrictive medications that can worsen the clinical course. Patients should avoid physical exertion, sexual activity, the Valsalva maneuver, and other known triggers of recurrent headaches for a few weeks. Laxatives and stool softeners should be used to avoid constipation (which can trigger the Valsalva maneuver), especially in patients receiving opioids for head pain. The risk of recurrent RCVS is low; hence, reexposure to the potential precipitating factor (eg, antidepressants) can be considered if clinically necessary and after other therapeutic options are exhausted. Usual secondary stroke preventive medications, such as antiplatelet agents, anticoagulants, and cholesterol-lowering agents, are probably not indicated. There are no known genetic implications of RCVS. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 14/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate CLINICAL COURSE AND PROGNOSIS The resolution of the different components of RCVS, including headaches, focal deficits, and angiographic narrowing, does not always follow the same time course. The thunderclap headaches typically resolve over days to weeks. Similarly, most patients show resolution of visual and other focal neurologic signs and symptoms within days to weeks. Less than 15 to 20 percent are left with residual deficits from stroke, and in most cases the deficits are relatively minor or moderate (ie, 90 to 95 percent have a modified Rankin scale score ( table 9) of 0 to 2 at discharge) [94]. Progressive cerebral arterial vasoconstriction culminating in massive strokes, brain edema, severe morbidity, or death occurs in less than five percent of cases, and these fulminant cases have been more commonly reported in postpartum patients [58,95-97]. Predictors of poor outcome in retrospective studies include baseline clinical factors (advanced age, comorbid medical conditions), severe imaging findings (infarction, intracerebral hemorrhage, cerebral edema), and exposure to glucocorticoid therapy [39,86]. Some patients go on to have intractable chronic migraine-like headaches or depression [94]. The time course of vasoconstriction is variable, but most patients show resolution within three months. Note that "reversible" in the term RCVS refers to the dynamic and reversible nature of vasoconstriction; clinical deficits from brain damage might persist, and the vasoconstriction (particularly if severe and prolonged) may not fully reverse in rare cases. Recurrence of an episode of RCVS after resolution of the initial symptomatic period is uncommon, approximately 5 to 6 percent in two studies [98,99], and usually manifests as an isolated thunderclap headache without complications such as stroke [98,100]. SUMMARY AND RECOMMENDATIONS Definition and epidemiology Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions (including Call-Fleming syndrome, benign angiopathy of the central nervous system, and postpartum angiopathy) characterized by reversible narrowing and dilatation of the cerebral arteries. The mean age of onset of RCVS is approximately 42 years. In adults, RCVS affects females more often than males. (See 'Terminology' above and 'Epidemiology' above.) Clinical presentation and risk factors The clinical presentation of RCVS is usually dramatic with sudden, severe thunderclap headaches that often recur over a span of days https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 15/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate to weeks. Some patients develop seizures or focal neurologic deficits. (See 'Clinical presentation and course' above.) Many patients have triggering factors, such as orgasm, physical exertion, acute stressful or emotional situations, Valsalva maneuvers, bathing, or swimming. A variety of conditions have been associated with RCVS including exposure to vasoconstrictive drugs and medications, other headache disorders, and recent pregnancy ( table 1). (See 'Risk factors and associated conditions' above.) Neuroimaging features Cerebral angiographic abnormalities of RCVS are dynamic and progress proximally, resulting in a "sausage on a string" appearance of the circle of Willis arteries and their branches. These abnormalities resolve spontaneously over a few weeks. (See 'Neurovascular imaging' above.) Magnetic resonance imaging (MRI) of the brain is normal in over 50 percent of patients with RCVS. In the ensuing days, many patients may develop complications such as ischemic stroke, convexity (nonaneurysmal) subarachnoid hemorrhage, lobar hemorrhage, and reversible brain edema, alone or in combination. (See 'Brain imaging' above.) Diagnostic evaluation Patients who present with thunderclap headache must be evaluated as a medical emergency, beginning with cranial computed tomography (CT) or brain MRI and head and neck CT angiography (CTA) or magnetic resonance angiography (MRA). If imaging is normal, lumbar puncture and cerebrospinal fluid analysis is appropriate to exclude other causes such as subarachnoid hemorrhage. (See 'Urgent evaluation' above.) The diagnosis of RCVS is based upon the characteristic clinical, brain imaging, and angiographic features, as summarized in the tables ( table 3 and table 6 and table 4 and table 5). (See 'Diagnosis' above.) Differential diagnosis The individual clinical and imaging features if RCVS carry a wide range of differential diagnoses, particularly aneurysmal subarachnoid hemorrhage, other conditions associated with thunderclap headache, and intracranial arteriopathies including intracranial atherosclerosis, primary angiitis of the central nervous system, moyamoya disease, and fibromuscular dysplasia. (See 'Differential diagnosis' above.) Management There is no proven therapy for RCVS. Supportive care is directed toward managing blood pressure, severe headaches, and other complications such as seizures. We generally do not use calcium channel blockers or other agents to treat vasoconstriction, as https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 16/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate evidence for this strategy is lacking. Intra-arterial vasodilator therapy has been attempted in fulminant cases with variable success. (See 'Management' above.) Prognosis The clinical outcome is benign in 90 to 95 percent of patients. Rare patients develop severe irreversible deficits or death from progressive strokes or cerebral edema. Recurrence of an episode of RCVS is rare. (See 'Clinical course and prognosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Serdaru M, Chiras J, Cujas M, Lhermitte F. Isolated benign cerebral vasculitis or migrainous vasospasm? J Neurol Neurosurg Psychiatry 1984; 47:73. 2. Jackson M, Lennox G, Jaspan T, Jefferson D. 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Topic 14075 Version 19.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 23/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate GRAPHICS Risk factors, triggers, and other conditions associated with reversible cerebral vasoconstriction syndrome Changes in estrogen-progesterone levels Pregnancy Eclampsia-preeclampsia Ovarian stimulation Oral contraceptive medications Headache disorders Primary thunderclap headache Primary cough headache Primary headache associated with sexual activity Exercise (exertional) headache Migraine Vasoconstrictive agents Antimigraine agents (triptans, isometheptene, ergotamine tartrate) Blood products (red blood cell transfusions, erythropoietin) Cough and cold suppressants (phenylpropanolamine, pseudoephedrine) Diet pills and energy-enhancing agents (amphetamine derivatives, Hydroxycut) Antidepressants (selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors) Adrenergic agents (epinephrine, bromocriptine, lisuride) Illicit drugs (cocaine, ecstasy, marijuana, lysergic acid diethylamide) Chemotherapeutic agents (tacrolimus, cyclophosphamide) Other (indomethacin, interferon alpha, intravenous immune globulin, licorice, ma huang [ephedra], methylergonovine, nicotine patches) Tumors Carcinoid, carotid paraganglioma, pheochromocytoma Metabolic Hypercalcemia, porphyria https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 24/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Environmental exposure or trauma High altitude Cold water exposure Swimming Head trauma Vascular Cerebral venous thrombosis Cervical artery dissection Postcarotid endarterectomy Posterior reversible encephalopathy syndrome (PRES) Neurosurgical manipulation of intracerebral arteries Spinal subdural hematoma Unruptured saccular cerebral aneurysm Adapted from: Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 3:91. Graphic 101277 Version 4.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 25/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 26/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 27/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Typical neuroimaging features of reversible cerebral vasoconstriction syndrome (A) Head CT angiogram: sagittal, maximum-intensity projection image showing the classic "sausage on a string" appearance of both anterior cerebral arteries. (B) Head CT: axial image showing subarachnoid hemorrhage overlying the right frontal lobe (arrow). (C) Brain MRI: axial FLAIR image in the same patient showing the right frontal subarachnoid hemorrhage (arrow) as well as multiple dot-shaped hyperintensities (arrowhead) within the sulci of both hemispheres, suggesting the presence of dilated cortical surface arteries. (D) Brain MRI: axial FLAIR image showing the posterior-predominant crescentic hyperintense signal in the cortical-subcortical regions (dashed arrow). Corresponding DWI and SWI (not shown) were normal. These findings suggest the presence of brain edema as described in the posterior reversible leukoencephalopathy syndrome. (E) Brain MRI: axial DWI showing ischemic lesions (short arrows) in the bilateral "watershed" regions of the middle and posterior cerebral arteries. (F) Head CT scan: axial image showing a left frontal parenchymal hemorrhage. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 28/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS: reversible cerebral vasoconstriction syndrome; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted image; SWI: susceptibility-weighted image. Reproduced with permission from: Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: Analysis of 139 cases. Arch Neurol 2011; 68:1005. Copyright 2011 American Medical Association. All rights reserved. Graphic 101799 Version 9.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 29/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Brain lesions in reversible cerebral vasoconstriction syndrome Representative brain images from patients with RCVS are shown to highlight different lesion patterns. The numbers in parenthesis show the percentages of the lesion patterns; totals exceed 100% due to lesion combinations. (A) No acute parenchymal lesion (24%). Normal axial DWI, GRE, and FLAIR images are shown. The hyperintense dot sign is present on FLAIR (far right, arrow). (B) Border zone/watershed infarcts (25%). On the far left, DWI shows typical symmetric, posterior infarcts that spare the cortical ribbon. In https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 30/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate the middle and on the far right, DWI shows widespread watershed infarcts. (C) Vasogenic edema (28%). Subcortical crescent-shaped T2- hyperintense lesions consistent with the posterior reversible encephalopathy syndrome are seen on FLAIR. (D) Hemorrhagic lesions (42%). The two images on the left (axial GRE) show simultaneous lobar and deep intraparenchymal hemorrhages. The two images on the right show convexal subarachnoid hemorrhages on CT and axial GRE. (E) Lesion combinations (28%). The two images on the left show bilateral watershed infarcts on DWI and the two images on the right show lobar as well as convexal subarachnoid hemorrhages on axial FLAIR and CT, all in the same patient. RCVS: reversible cerebral vasoconstriction syndrome; DWI: diffusion- weighted images; GRE: gradient-echo; FLAIR: fluid-attenuated inversion recovery; CT: computed tomography. From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109962 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 31/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Convexal subarachnoid hemorrhage in a patient with reversible cerebral vasoconstriction syndrome (A) CT scan of a 56-year-old man with severe headaches showing presence of superficial convexal SAH along bilateral posterior frontal lobes (arrows). (B) Conventional angiogram performed a day later shows multiple vessel narrowings (arrows) involving the branches of the posterior and anterior cerebral arteries. A repeat angiogram performed four weeks later showed restitution of normal arterial caliber (not shown). SAH: subarachnoid hemorrhage. From: Kumar S, Goddeau RP Jr, Selim MH, et al. Atraumatic convexal subarachnoid hemorrhage: Clinical presentation, imaging patterns, and etiologies. Neurology 2010; 74:893. Copyright 2010 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 101281 Version 5.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 32/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Resolution of vasoconstriction in a patient with reversible cerebral vasoconstriction syndrome

Postcarotid endarterectomy Posterior reversible encephalopathy syndrome (PRES) Neurosurgical manipulation of intracerebral arteries Spinal subdural hematoma Unruptured saccular cerebral aneurysm Adapted from: Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 3:91. Graphic 101277 Version 4.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 25/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 26/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 27/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Typical neuroimaging features of reversible cerebral vasoconstriction syndrome (A) Head CT angiogram: sagittal, maximum-intensity projection image showing the classic "sausage on a string" appearance of both anterior cerebral arteries. (B) Head CT: axial image showing subarachnoid hemorrhage overlying the right frontal lobe (arrow). (C) Brain MRI: axial FLAIR image in the same patient showing the right frontal subarachnoid hemorrhage (arrow) as well as multiple dot-shaped hyperintensities (arrowhead) within the sulci of both hemispheres, suggesting the presence of dilated cortical surface arteries. (D) Brain MRI: axial FLAIR image showing the posterior-predominant crescentic hyperintense signal in the cortical-subcortical regions (dashed arrow). Corresponding DWI and SWI (not shown) were normal. These findings suggest the presence of brain edema as described in the posterior reversible leukoencephalopathy syndrome. (E) Brain MRI: axial DWI showing ischemic lesions (short arrows) in the bilateral "watershed" regions of the middle and posterior cerebral arteries. (F) Head CT scan: axial image showing a left frontal parenchymal hemorrhage. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 28/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS: reversible cerebral vasoconstriction syndrome; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted image; SWI: susceptibility-weighted image. Reproduced with permission from: Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: Analysis of 139 cases. Arch Neurol 2011; 68:1005. Copyright 2011 American Medical Association. All rights reserved. Graphic 101799 Version 9.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 29/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Brain lesions in reversible cerebral vasoconstriction syndrome Representative brain images from patients with RCVS are shown to highlight different lesion patterns. The numbers in parenthesis show the percentages of the lesion patterns; totals exceed 100% due to lesion combinations. (A) No acute parenchymal lesion (24%). Normal axial DWI, GRE, and FLAIR images are shown. The hyperintense dot sign is present on FLAIR (far right, arrow). (B) Border zone/watershed infarcts (25%). On the far left, DWI shows typical symmetric, posterior infarcts that spare the cortical ribbon. In https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 30/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate the middle and on the far right, DWI shows widespread watershed infarcts. (C) Vasogenic edema (28%). Subcortical crescent-shaped T2- hyperintense lesions consistent with the posterior reversible encephalopathy syndrome are seen on FLAIR. (D) Hemorrhagic lesions (42%). The two images on the left (axial GRE) show simultaneous lobar and deep intraparenchymal hemorrhages. The two images on the right show convexal subarachnoid hemorrhages on CT and axial GRE. (E) Lesion combinations (28%). The two images on the left show bilateral watershed infarcts on DWI and the two images on the right show lobar as well as convexal subarachnoid hemorrhages on axial FLAIR and CT, all in the same patient. RCVS: reversible cerebral vasoconstriction syndrome; DWI: diffusion- weighted images; GRE: gradient-echo; FLAIR: fluid-attenuated inversion recovery; CT: computed tomography. From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109962 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 31/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Convexal subarachnoid hemorrhage in a patient with reversible cerebral vasoconstriction syndrome (A) CT scan of a 56-year-old man with severe headaches showing presence of superficial convexal SAH along bilateral posterior frontal lobes (arrows). (B) Conventional angiogram performed a day later shows multiple vessel narrowings (arrows) involving the branches of the posterior and anterior cerebral arteries. A repeat angiogram performed four weeks later showed restitution of normal arterial caliber (not shown). SAH: subarachnoid hemorrhage. From: Kumar S, Goddeau RP Jr, Selim MH, et al. Atraumatic convexal subarachnoid hemorrhage: Clinical presentation, imaging patterns, and etiologies. Neurology 2010; 74:893. Copyright 2010 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 101281 Version 5.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 32/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Resolution of vasoconstriction in a patient with reversible cerebral vasoconstriction syndrome MR angiogram shows multiple focal stenoses involving peripheral branches of both middle (arrows) and posterior (arrowheads) cerebral arteries (A). Repeat imaging six weeks later shows spontaneous resolution of several areas of stenosis (B). https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 33/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate MR: magnetic resonance. Courtesy of Glenn A Tung, MD, FACR. Graphic 135022 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 34/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome Note the multiple areas of stenosis (arrows) and dilatation in multiple vessels (arrowheads) of the M2 branch of the middle cerebral artery (A) and their resolution after one month (B). Reproduced with permission from: Hajj-Ali RA, Furlan A, Abou-Chebel A, Calabrese LH. Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup. Arthritis Rheum 2002; 47:662. Copyright 2002 John Wiley & Sons, Inc. Graphic 66139 Version 4.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 35/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Summary of critical elements for the diagnosis of reversible cerebral vasoconstriction syndromes (RCVS) 1. Single or (most often) recurrent thunderclap headaches. 2. Multifocal segmental cerebral artery vasoconstriction demonstrated on cerebral angiography (with CTA, MRA, or DSA) that usually develops within a week of symptom onset. 3. No evidence for aneurysmal SAH. 4. Brain imaging findings are often normal, or may show vasogenic edema (PRES) and/or FLAIR sulcal hyperintensities (dot sign). Infarcts, if present, are usually symmetric and distributed along border zones of arterial territories. Intraparenchymal hemorrhage and/or nonaneurysmal convexity SAH may be present in some cases of RCVS. RCVS: reversible cerebral vasoconstriction syndromes; CTA: computed tomography angiography; MRA: magnetic resonance angiography; DSA: digital subtraction angiography; FLAIR: fluid-attenuated inversion recovery; PRES: posterior reversible encephalopathy syndrome; SAH: subarachnoid hemorrhage. Modi ed from Annals of Internal Medicine, Calabrese LH, Dodick DW, Schwedt TJ, et al. Narrative review: Reversible cerebral vasoconstriction syndromes, Volume 146, Issue 1, Pages 34-44. Copyright 2007 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc. Graphic 101236 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 36/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS score 2 Criteria Value Recurrent or single TCH Present 5 Absent 0 Carotid artery (intracranial) narrowing Affected 2 Not affected 0 Vasoconstrictive trigger Present 3 Absent 0 Sex Female 1 Male 0 Subarachnoid hemorrhage Present 1 Absent 0 In a retrospective study of consecutive patients with RCVS (n = 30) or non-RCVS arteriopathy (n = 80), recurrent or single thunderclap headache, vasoconstrictive trigger, female sex, and convexity subarachnoid hemorrhage were predictors of RCVS; intracranial carotid artery involvement (ie, segmental narrowing) was a negative predictor. In the derivation cohort, RCVS scores 5 had a high specificity and sensitivity (99 and 90%, respectively) for diagnosing RCVS, while scores 2 had a high specificity and sensitivity (100 and 85%) for excluding RCVS; intermediate scores of 3 to 4 had a lower 2 specificity and sensitivity (86 and 10%) for diagnosing RCVS. Performance was similar in the validation cohort. RCVS: reversible cerebral vasoconstriction syndrome; TCH: thunderclap headache. From: Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. RCVS score and diagnostic approach for reversible cerebral 2 vasoconstriction syndrome. Neurology 2019; 92:e639. DOI: 10.1212/WNL.0000000000006917. Copyright 2019 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121439 Version 3.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 37/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate RCVS score performance 2 RCVS2 score Specificity Sensitivity PPV NPV Derivation cohort Score 5 or 99 (93, 100) 90 (73, 98) 96 (82, 100) 96 (90, 99) higher* Score 3 or 4* 86 (77, 93) 10 (2, 27) 21 (5, 51) 72 (62, 80) Score 2 or 100 (88, 100) 85 (75, 92) 100 (95, 100) 71 (55, 84) lower Validation cohort Score 5 or 94 (82, 99) 86 (80, 91) 98 (94, 100) 67 (54, 78) higher* Score 3 or 4* 83 (69, 92) 11 (6, 17) 68 (46, 85) 22 (16, 28) Score 2 or lower 96 (92, 99) 77 (62, 88) 86 (71, 95) 93 (88, 97) NPV: negative predictive value; PPV: positive predictive value; RCVS: reversible cerebral vasoconstriction syndrome. Values for a RCVS diagnosis. Values for a non-RCVS diagnosis. From: Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. RCVS score and diagnostic approach for reversible cerebral vasoconstriction syndrome. Neurology 2019; 92:e639. DOI: 10.1212/WNL.0000000000006917. Copyright 2019 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material 2 is prohibited. Graphic 121448 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 38/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Distinguishing reversible cerebral vasoconstriction syndrome (RCVS) from primary angiitis of the central nervous system (PACNS) Sensitivity Specificity PPV NPV Variable (95% CI) (95% CI) (95% CI) (95% CI) Recurrent TCH* 74 (67-81) 98 (89-100) 99 (95-100) 53 (43-64) Single TCH* 15 (10-22) 96 (85-99) 92 (75-99) 25 (19-32) Plus normal brain MRI 2 (0-5) 100 (92-100) 100 (30-100) 23 (18-30) Plus FLAIR dot sign 10 (6-16) 100 (92-100) 100 (79-100) 25 (19-32) Plus border zone-only 3 (1-6) 100 (92-100) 100 (40-100) 23 (18-30) infarcts Plus vasogenic edema (PRES) 4 (1-8) 100 (92-100) 100 (54-100) 24 (18-30) Plus ICH or cSAH 9 (5-15) 96 (85-99) 88 (64-98) 24 (18-31) No TCH; positive angiogram* 11 (6-17) 49 (34-64) 42 (23-58) 14 (9-20) Plus normal brain MRI 1 (0-3) 100 (92-100) 100 (17-100) 23 (17-29) Plus border zone-only infarcts 5 (2-9) 98 (89-100) 88 (47-98) 23 (18-30) Plus ICH or cSAH 3 (1-6) 98 (89-100) 80 (29-97) 23 (17-29) Plus vasogenic edema (PRES) 3 (1-7) 100 (92-100) 100 (48-100) 23 (18-30) Plus FLAIR dot sign 6 (3-11) 94 (83-99) 75 (43-94) 23 (18-30) No TCH; positive angiogram; for the diagnosis of PACNS: Plus deep/brainstem 38 (35-54) 100 (98-100) 100 (81-100) 85 (79-89) infarcts Plus CSF abnormal 28 (16-43) 99 (95-100) 87 (60-98) 82 (76-88) Plus both of the above 28 (16-43) 100 (98-100) 100 (75-100) 83 (77-87) CI: confidence intervals; PPV: positive predictive value; NPV: negative predictive value; TCH: thunderclap headache; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; ICH: intracerebral hemorrhage; cSAH: convexal subarachnoid hemorrhage; CSF: cerebrospinal fluid. Values shown are for the diagnosis of RCVS. Abnormal is >5 cells and >80 mg/dL. https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 39/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate From: Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016; 79:882. http://onlinelibrary.wiley.com/wol1/doi/10.1002/ana.24652/abstract. Copyright 2016 American Neurological Association. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 109960 Version 2.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 40/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Distinguishing reversible posterior leukoencephalopathy syndrome (RPLS) and reversible cerebral vasoconstriction syndrome (RCVS) Reversible posterior Reversible cerebral Feature leukoencephalopathy vasoconstriction syndrome syndrome Clinical Encephalopathy 50-80% 10-15% Seizures 60-75% 0-20% Status epilepticus 5-15% Rare Headache 50% 90-95% Visual deficits 33% 30-40% Focal neurologic deficit 10-15% 9-63% Imaging Vasogenic cerebral edema 100% 15-40% Ischemic stroke 15-30% 33% Lobar hemorrhage 10-25% 15% Sulcal subarachnoid blood 3-8% 40% Segmental vasoconstriction 30-70% 100% Coexisting vascular lesion (eg, dissection, aneurysm) Uncommon 20% Contrast enhancement 20% Uncommon From: Singal AB. Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome as syndromes of cerebrovascular dysregulation. Continuum 2021; 27:1301. DOI: 10.1212/CON.0000000000001037. Copyright 2021 American Academy of Neurology. Adapted with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 135024 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 41/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Diagnostic findings for the more common causes of thunderclap headache Clinical Lumbar Cause Brain CT Angiography Brain MRI features puncture Aneurysmal Altered Subarachnoid Elevated red Ruptured Subarachnoid subarachnoid hemorrhage consciousness, seizures, blood in basilar blood cells, xanthochromia aneurysm, vasospasm blood in basilar cisterns and meningismus cisterns and sylvian sylvian fissures fissures Reversible cerebral Recurrent thunderclap Normal, or subarachnoid Normal, mild white blood Multifocal multivessel Normal, or subarachnoid vasoconstriction headaches blood along cell elevation, vasoconstriction blood along syndrome cortical surface/sulci mild protein elevation cortical surface/sulci, ischemic stroke, cerebral edema, intracerebral hemorrhage Carotid and Neck pain, Normal, or Normal Dissected Normal, or vertebral artery dissection symptoms related to cerebral ischemia, Horner syndrome (carotid ischemic stroke artery, multifocal, segmental vasoconstriction if associated with reversible cerebral ischemic stroke dissection) vasoconstriction syndrome Cerebral venous sinus Focal neurologic Dense triangle sign Elevated opening Venous sinus thrombosis Normal, or venous thrombosis deficits, (clot inside pressure, high infarctions with altered mental status, visual the sinus), cord sign protein hemorrhage; MRI evidence of changes (thrombosed cortical or intraluminal thrombus on T1, deep vein), venous T2, and susceptibility- hemorrhages weighted imaging sequences Spontaneous Orthostatic Normal, or Low opening Normal Pachymeningeal intracranial headache, subdural pressure enhancement, https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 42/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate hypotension auditory collections sagging brain, muffling subdural collections CT: computed tomography; MRI: magnetic resonance imaging. From: Schwedt TJ. Thunderclap Headache. Continuum (Minneap Minn) 2015; 21:1058. DOI: 10.1212/CON.0000000000000201. Copyright 2015 American Academy of Neurology. Reproduced with permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited. Graphic 113418 Version 5.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 43/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Basilar artery vasoconstriction in RCVS DSA (left vertebral artery injection) shows well-opacified extradural left vertebral artery (arrows) and multiple of narrowing of the intracranial vertebral, basilar, and posterior cerebral arteries (arrowheads) (A). High-reso contrast-enhanced vessel wall MR image shows wall of the basilar artery uniformly thickened and without enhancement, consistent with vasoconstriction (B and inset). RCVS: reversible cerebral vasoconstriction syndrome; DSA: digital subtraction angiography; MR: magnetic resonance. Courtesy of Glenn A Tung, MD, FACR. Graphic 135025 Version 1.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 44/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 45/46 7/6/23, 12:35 PM Reversible cerebral vasoconstriction syndrome - UpToDate Contributor Disclosures Aneesh Singhal, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/reversible-cerebral-vasoconstriction-syndrome/print 46/46

7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Subclavian steal syndrome : John F Eidt, MD : Joseph L Mills, Sr, MD : Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 01, 2022. INTRODUCTION The term "subclavian steal" refers to a phenomenon of flow reversal in the vertebral artery ipsilateral to a hemodynamically significant stenosis or occlusion of the prevertebral subclavian artery [1-3]. In most cases, subclavian steal is asymptomatic (ie, subclavian steal phenomenon), does not warrant invasive evaluation or treatment, and represents an appropriate physiological response to proximal arterial disease. Subclavian steal syndrome implies the presence of significant symptoms due to arterial insufficiency in the brain (ie, vertebrobasilar insufficiency) or upper extremity, which is supplied by the subclavian artery ( figure 1). The physiology, diagnosis, and treatment of subclavian steal will be reviewed here. General considerations for patients with symptoms of vertebrobasilar ischemia are discussed in detail elsewhere. (See "Posterior circulation cerebrovascular syndromes".) The clinical presentations and diagnosis of upper extremity ischemia (eg, exertional pain, digital ischemia, gangrene) are reviewed in detail separately. (See "Overview of upper extremity ischemia", section on 'Clinical presentation'.) DEFINITION AND PHYSIOLOGY Classic subclavian steal Subclavian artery occlusion or a hemodynamically significant stenosis proximal to the origin of the vertebral artery results in lower pressure in the distal subclavian artery [4,5]. As a result, blood flows from the contralateral vertebral artery to the basilar artery and may flow in a retrograde direction down the ipsilateral vertebral artery, away https://www.uptodate.com/contents/subclavian-steal-syndrome/print 1/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate from the brainstem ( figure 2) [6,7]. Reversed vertebral artery flow, although it may have deleterious neurologic effects, serves as an important collateral artery for the arm in this setting. Coronary-subclavian steal A coronary-subclavian steal phenomenon has been described in patients who have undergone prior coronary artery bypass surgery (CABG) using the internal mammary artery (IMA) [8-10]. The prevalence of subclavian artery stenosis is 2.5 to 4.5 percent in patients referred for coronary artery bypass grafting [11]. In the presence of a hemodynamically significant subclavian artery stenosis proximal to the origin of the ipsilateral IMA, flow through the internal mammary artery may reverse and "steal" flow from the coronary circulation. This may be exacerbated during upper extremity exercise ( figure 3). Coronary and graft angiography may demonstrate retrograde flow in the involved IMA during selective catheterization of the grafted coronary artery [12]. Simultaneous coronary and cerebrovascular ischemia has also been reported [10,13]. Identification of a significant subclavian artery stenosis prior to CABG can prevent this important problem. Those patients with a high-grade subclavian artery stenosis should be treated (percutaneously or surgically) prior to CABG [14]. For patients with symptomatic subclavian lesions who require coronary artery bypass, no differences were seen for complications, mortality, or symptom recurrence, using a combined or staged approach to revascularization [15]. EPIDEMIOLOGY AND RISK FACTORS The incidence/prevalence of subclavian steal syndrome is not well defined. Among individuals with documented peripheral artery disease, the prevalence of upper extremity atherosclerotic disease is much lower compared with lower extremities. Approximately 30 percent of such patients have subclavian artery stenosis; however, only a minority develop symptoms, predominantly because of the extensive collateral network of vessels around the shoulder ( figure 4) [7]. (See "Overview of upper extremity peripheral artery disease".) In a large study of extracranial arterial disease, the incidence of subclavian/innominate stenosis/occlusion was 17 percent, but only 2.5 percent fulfilled the criteria for subclavian steal [16]. A later study identified subclavian stenosis/occlusion in 432 of 7881 patients presenting for ultrasound exam of the extracranial neck vessels; among these, 38 (8.8 percent) experienced symptoms [17]. Therefore, subclavian steal syndrome occurs in only a minority of patients with subclavian stenosis [18]. (See 'Duplex ultrasound' below.) Risk factors Atherosclerosis is the most common cause of subclavian artery stenosis. The risk factors associated with atherosclerosis are discussed elsewhere. (See "Overview of established https://www.uptodate.com/contents/subclavian-steal-syndrome/print 2/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate risk factors for cardiovascular disease".) Males are more commonly affected compared with females. Subclavian stenosis and therefore subclavian steal occurs more commonly on the left side (>75 percent), possibly due to a more acute origin of the left subclavian artery, resulting in accelerated atherosclerosis from increased turbulence [4,17,19-22]. Other conditions that increase the risk for subclavian stenosis that may lead to subclavian steal include: Takayasu arteritis [23]. These patients present at a younger age. (See "Clinical features and diagnosis of Takayasu arteritis".) Compression of the subclavian artery in the thoracic outlet ( figure 5). The site of arterial compression in thoracic outlet syndrome is most often distal to the origin of the vertebral artery. Therefore, the potential for symptomatic steal is low. However, these patients can have posterior circulation strokes due to retrograde propagation of thrombus. Athletes, such as baseball pitchers, cricket bowlers, and swimmers, are the most likely to be affected due to neurovascular compression as the subclavian artery crosses over the first rib. (See "Overview of thoracic outlet syndromes", section on 'Arterial TOS'.) Following surgical repair of coarctation of the aorta [24]. (See "Clinical manifestations and diagnosis of coarctation of the aorta".) Following surgical repair of tetralogy of Fallot with a Blalock-Taussig anastomosis [25]. (See "Management and outcome of tetralogy of Fallot".) Congenital abnormalities such as right aortic arch with isolation of the left subclavian artery and anomalies of the brachiocephalic arteries [26-29]. (See "Vascular rings and slings".) CLINICAL FEATURES The incidence of the subclavian/innominate stenosis and the subclavian steal phenomenon is much higher than that of the symptomatic clinical syndrome. (See 'Epidemiology and risk factors' above.) Clinical presentations Asymptomatic Most patients with subclavian artery stenosis are asymptomatic. In many patients, subclavian artery occlusive disease is found incidentally by noting a blood pressure https://www.uptodate.com/contents/subclavian-steal-syndrome/print 3/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate discrepancy between arm pressures or on ultrasound testing of patients with carotid or coronary artery disease. A careful history and physical examination may identify subtle findings. For the majority of patients, the finding of "angiographic steal" is clinically insignificant and is not associated with an increased risk of vertebrobasilar ischemia [17,30]. A steal phenomenon is apparent on duplex scanning in approximately 6 percent of patients with asymptomatic neck bruits, but in one series, none of the patients developed symptoms during a two-year follow-up period [31]. Even when reversed flow occurs in the vertebral artery, antegrade basilar arterial flow persists and may even be increased. In one prospective study, 500 patients with asymptomatic neck bruits were followed over a four- year period [31]. Of these patients, 9 percent had severe subclavian stenosis, and over one half of these patients (64 percent) had a steal phenomenon. None of the patients had symptoms as a result of arm exercise. Symptomatic When symptoms occur, they are most often due to arm ischemia, but this is uncommon as well. Symptoms of vertebrobasilar ischemia are also uncommon and tend to develop only when there are concurrent cerebrovascular lesions. Anomalies of the circle of Willis ( figure 1), the most important collateral route in the cerebrovascular circulation, occur with increased frequency in patients with symptomatic subclavian steal [32]. Upper extremity ischemia Symptoms, when they occur, are due mainly to ischemia of the ipsilateral upper extremity. Exercise-induced arm pain, fatigue, coolness, paresthesias, or numbness, occurs in approximately one third of patients, but chronic ischemic and trophic changes are rare. A large pressure difference (>40 mmHg) between the arms is more commonly associated with symptoms and the need for intervention [17].(See "Overview of upper extremity ischemia".) Ischemic symptoms may also result from embolism of atherosclerotic or thrombotic debris from the subclavian lesion. (See "Embolism to the upper extremities".) Neurologic symptoms Less often, neurologic symptoms can be caused by vertebrobasilar ischemia of the brainstem. However, whether the steal phenomenon is the principal cause of cerebral ischemic symptoms remains controversial. This is based upon a number of observations: Reestablishment of antegrade blood flow may not relieve symptoms. Exercise rarely provokes cerebral symptoms. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 4/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Occlusive arterial disease in the other extracranial arteries is often present and may be a confounding source of symptoms. Retrograde flow in the vertebral arteries is commonly identified with duplex ultrasound and is often not associated with neurologic symptoms [18]. Symptoms and signs of vertebrobasilar ischemia may include the following (see "Posterior circulation cerebrovascular syndromes"): Dizziness Vertigo Ataxia Dysequilibrium "Drop attacks" Diplopia Nystagmus Graying of vision Hemianopia Bilateral visual blurring Syncope Tinnitus Hearing loss Bilateral brachial diplegia Upper extremity exercise, which increases blood flow to the arm and decreases arterial resistance, can precipitate central nervous system symptoms. The presence of collateral blood supply and the capacity to increase collateral flow may be the principal determinants of which patients develop neurologic symptoms in this setting. Vertebral artery compression and neurologic symptoms can also occur with head movements, usually rotation of the face toward the opposite side [17]. This association can usually be detected by a careful history. Although patients with documented subclavian steal have a very low incidence of posterior circulation ischemic events, these patients are more likely to develop hemispheric ischemia due to concurrent progressive carotid disease [18]. Collateral pathways are usually compromised in symptomatic patients, placing them at increased risk, principally from carotid territory cerebrovascular events. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 5/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Bilateral vertebral flow reversal may be associated with an increased risk of nonlateralizing cerebral ischemia. In one study, brainstem dysfunction from upper extremity exercise was seen only in patients with bilateral reversed flow [33]. However, persistent retrograde flow in the basilar artery, with collateral blood supply from the internal carotid arteries, has been reported in a patient without any neurologic or upper extremity symptoms [34]. Physical examination On examination, there is usually a difference in brachial systolic blood pressure between the affected and normal arm of at least 15 mmHg. In addition, simultaneous palpation of both radial artery pulses will usually disclose a decrease in amplitude and delay in arrival on the affected side ( waveform 1). The carotid arteries should be carefully examined, using palpation and auscultation, for evidence of occlusive arterial disease. Auscultation over the suboccipital region for vertebral artery bruits should also be performed. It is important to examine the subclavian arteries in the supraclavicular fossa using palpation (pulse character and thrills) and auscultation for paraclavicular bruits. Other parts of the physical examination should include: Performance of thoracic outlet maneuvers to exclude other causes of a subclavian stenosis. (See "Brachial plexus syndromes", section on 'Thoracic outlet syndrome'.) All major pulses should be palpated. The presence of multiple pulse deficits (subclavian and carotid) raises the possibility of Takayasu's disease. (See "Clinical features and diagnosis of Takayasu arteritis".) The skin of the hands and nail beds of the affected extremity should be thoroughly examined. Atheroembolism from atherosclerotic lesions of the subclavian artery may result in blue fingers, livedo reticularis, digital ischemia, or ulceration or splinter hemorrhages under the nail beds. (See "Embolism to the upper extremities".) DIAGNOSIS A difference in upper extremity pressures in a patient with appropriate symptoms suggests subclavian steal syndrome; however, imaging confirmation is necessary to definitively establish the diagnosis. Noninvasive imaging of the cerebrovascular and upper extremity arterial circulation demonstrates the lesion and appropriate physiology. Duplex ultrasound is the first-line imaging modality for the detection of the subclavian stenosis causing subclavian steal phenomenon. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 6/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate However, due to inherent limitations, ultrasound cannot reliably evaluate the origin of the aortic branches. Consequently, arteriography, typically magnetic resonance (MR) or computed tomographic (CT) angiography, is needed to confirm and grade the subclavian artery stenosis. Catheter-based cerebral angiography ( image 1) is generally not needed to establish a diagnosis, but when performed prior to endovascular intervention, concurrent intracranial atherosclerotic disease and anomalies of the circle of Willis can also be identified. Duplex ultrasound Duplex ultrasound (combined two-dimensional ultrasound and pulsed- wave Doppler) can readily diagnose and semiquantify proximal subclavian artery stenoses and demonstrate reversal of flow, if present, in the ipsilateral vertebral artery ( image 2). A subclavian artery peak systolic velocity >240 cm/second is predictive of a significant (>70 percent) subclavian artery stenosis [35]. Duplex ultrasound is limited in the evaluation of the origin of the vertebral artery for evidence of occlusive disease due to its intrathoracic location, but is extremely accurate for the assessment and identification of significant extracranial carotid artery occlusive disease. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.) When severe stenosis (>80 percent narrowing) of the proximal subclavian artery is present, 65 percent of patients have permanent flow reversal in the ipsilateral vertebral artery, and 30 percent have intermittent flow reversal (ie, "to and fro" waveform pattern on duplex) [18,36]. In patients with moderate subclavian artery stenosis (approximately 50 percent narrowing), flow reversal in the vertebral artery is permanent in 56 percent and intermittent in 36 percent. While not commonly needed or performed on a routine basis, a reactive hyperemia type test can be performed to uncover occult or intermittent subclavian steal [37-39]. To do this, a blood pressure cuff is applied to the ipsilateral extremity and inflated at least 20 mmHg above systolic pressure for three to four minutes. This produces ischemia and compensatory vasodilation distal to the cuff. After deflation of the cuff, blood flow will increase in the upper extremity, and for patients with an otherwise asymptomatic subclavian stenosis, reversal of blood flow in the ipsilateral vertebral artery may provoke symptoms. During these maneuvers, retrograde flow can be observed with the concomitant use of ultrasound [40]. Magnetic resonance angiography MR angiography is an accurate and reliable imaging modality for patients with suspected subclavian steal syndrome [41]. Contrast-enhanced MR angiography combined with phase-contrast MR imaging enables visualization and characterization of the majority of supraaortic arteries, with excellent image quality and diagnostic values comparable to CT angiography or conventional catheter-based arteriography https://www.uptodate.com/contents/subclavian-steal-syndrome/print 7/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate for detection of arterial stenoses [42,43]. In addition to evaluation of the extracranial vessels, MR also provides detailed anatomic information of the intracranial cerebrovascular circulation. Flow reversal in the vertebral artery ipsilateral to a subclavian stenosis is inferred from presence of vertebral artery patency on three-dimensional contrast-enhanced MR but absence of flow on time-of-flight localizer images [44]. Pitfalls in using MR to evaluate the subclavian artery include the possibility of overestimating stenosis severity and the inability to discriminate between near-complete and complete arterial occlusion. CT angiography Multidetector CT angiography can confirm and grade subclavian artery stenosis, as well as reveal other pathology involving the subclavian artery. CT angiography is indicated in patients with subclavian steal syndrome who have abnormal or nondiagnostic findings on duplex ultrasound to identify and characterize the underlying pathology and any anatomic abnormalities [17,45]. CT angiography can detect arterial stenosis, thrombosis, occlusion, aneurysm formation, and vasculitis within the subclavian artery [46]. Transcranial Doppler When flow reversal of the vertebral artery is identified, some authors have suggested the use of transcranial Doppler (TCD) to evaluate the direction of flow in the basilar artery [39]. A finding of reversed flow at the level of the basilar artery is more predictive of symptoms than reversal of flow in the vertebral artery only. In one study of patients with flow reversal of the vertebral artery ipsilateral to a subclavian stenosis/occlusion, 76 percent had antegrade flow in the basilar artery [36]. Patients with antegrade flow in the basilar artery are not likely to have symptoms. DIFFERENTIAL DIAGNOSIS The diagnosis of subclavian steal includes vascular pathologies that may also cause occlusion of the proximal subclavian artery, which may or may not have symptoms of upper extremity ischemia, as well as other predominantly neurologic conditions that lead to symptoms associated with basilar insufficiency. (See "Overview of upper extremity ischemia" and "Overview of upper extremity peripheral artery disease" and "Posterior circulation cerebrovascular syndromes".) There is a subset of patients with primary proximal subclavian artery lesions who embolize through the ipsilateral vertebral artery, leading to symptoms of transient vertebrobasilar ischemia that is not due to the steal phenomenon. (See "Posterior circulation cerebrovascular syndromes".) https://www.uptodate.com/contents/subclavian-steal-syndrome/print 8/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate MANAGEMENT Risk modification Subclavian stenosis/occlusion is a marker for atherosclerotic disease (eg, carotid, coronary, lower extremity arteries) and future adverse cardiovascular events. Subclavian artery stenosis is associated with an increased risk of both overall mortality and mortality related to cardiovascular disease (CVD). In a study of 157 patients with subclavian artery stenosis (diagnosed as brachial systolic pressure difference 15 mmHg), the presence of subclavian stenosis was significantly associated with increased total mortality and CVD mortality (hazard ratios 1.40 and 1.57, respectively) after adjusting for other demographic and CVD disease risk factors [47]. Thus, the detection of subclavian stenosis identifies patients who may benefit from secondary prevention measures such as the following: Control of hypertension Treatment of dyslipidemia Glycemic control in diabetes Smoking cessation Antithrombotic therapy Lifestyle changes The importance of these risk reduction strategies for secondary prevention of CVD and stroke is discussed in detail separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of secondary prevention of ischemic stroke".) INTERVENTION The approach to therapy of subclavian steal associated with symptoms varies with the clinical setting. In many patients, symptoms improve over time without treatment. Interventional treatment is not usually warranted in patients with asymptomatic subclavian stenosis/occlusion. Patients with unacceptable surgical risk or anatomy unfavorable for intervention can be treated with antiplatelet therapy (and possibly oral anticoagulation), but no prospective trials have evaluated the effectiveness of this option. Open surgical bypass Symptomatic patients with an ulcerated lesion in the subclavian artery as a cause of distal embolization can be successfully treated by surgical exclusion of the lesion from the circulation, usually accomplished by arterial bypass or carotid transposition [48,49]. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 9/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate (See "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization", section on 'Open surgical repair'.) Extra-anatomic revascularization (eg, carotid-subclavian bypass, carotid transposition) is the most common form of surgical correction for symptomatic subclavian artery stenosis. Overall patency rates of 95 percent at one year, 86 percent at three years, and 73 percent at five years have been reported [33]. Procedures using the common carotid artery as the donor vessel generally have high patency rates at five years compared with those using the contralateral subclavian or axillary arteries (83 versus 46 percent) [33]. Axillo-axillary bypass is an alternative method of extra-anatomic revascularization that can be used in high-risk surgical patients [50]. Surgical treatment for patients with a subclavian steal and coexisting severe carotid stenosis is controversial. Because a significant percentage of patients with subclavian steal have concomitant severe extracranial atherosclerotic disease, carotid artery endarterectomy should generally be performed first, and, if the patient's symptoms improve, other treatment may not be necessary [51]. (See "Management of symptomatic carotid atherosclerotic disease" and "Carotid endarterectomy".) Endovascular intervention Endovascular intervention (with embolic protection) for embolism related to proximal subclavian artery is appropriate for patients with appropriate anatomy (short proximal stenosis or occlusion). If percutaneous treatment will jeopardize the integrity of the vertebral artery, we prefer surgical revascularization. (See "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization".) Although data are limited and no randomized trials are available, retrospective observational studies suggest that endovascular intervention is safe with low morbidity and mortality (3.6 percent combined stroke and death rate in one study [52]) [53]. Immediate technical success is achieved in greater than 93 percent of patients, with failures usually related to an inability to cross occlusive lesions [54-56]. Five-year primary patency rates are approximately 85 percent [55]. In a single-center retrospective review of 167 patients with left subclavian artery stents who were being evaluated for coronary artery bypass, stent patency rates were 75.2 percent at 10 years [57]. Freedom from reintervention for the target vessel and sustained resolution of ischemic symptoms is observed in most patients (>95 percent) [52,55,56,58-60]. Whether angioplasty alone has inferior outcomes compared with angioplasty and stenting depends on the nature of the lesion being treated [23,61]. This issue is discussed separately. (See "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization", section on 'Angioplasty/stenting'.) https://www.uptodate.com/contents/subclavian-steal-syndrome/print 10/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Symptoms due to significant (>70 percent) recurrent stenosis or obstruction occur in approximately 10 percent of patients and are typically treated with repeat angioplasty; however, surgery may be required in up to 5 percent of patients [52]. Patients with a continuous (compared with intermittent) subclavian and coronary artery steal may have a higher risk of subclavian artery restenosis following endovascular intervention [62]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS Subclavian steal Subclavian steal refers to a phenomenon of flow reversal in the vertebral artery ipsilateral to a hemodynamically significant stenosis or occlusion of the prevertebral subclavian artery. Subclavian steal represents an appropriate physiological compensation to proximal subclavian artery disease. Subclavian steal syndrome refers to the presence of significant symptoms due to arterial insufficiency. (See 'Introduction' above.) Pathophysiology A hemodynamically significant stenosis proximal to the origin of the vertebral artery results in lower pressure in the distal subclavian artery. As a result, blood flows from the contralateral vertebral artery to the basilar artery, and blood may flow in a retrograde direction down the ipsilateral vertebral artery, away from the brainstem ( figure 2). In patients with an internal mammary artery bypass graft to the heart, proximal ipsilateral stenosis relative to the graft may reverse and "steal" flow from the coronary circulation during upper extremity exercise (ie, coronary-subclavian steal syndrome) ( figure 3). (See 'Definition and physiology' above.) Symptoms Most patients with subclavian artery stenosis are asymptomatic. For many, subclavian artery occlusive disease is found incidentally. When symptoms occur, they are most commonly due to arm ischemia or symptoms of vertebrobasilar ischemia. (See 'Clinical features' above.) Physical examination Pulse examination and duplex ultrasound evaluation of the cerebrovascular and upper extremity arterial circulation establish the diagnosis in most patients. On examination, the patient often has a significant difference in brachial systolic https://www.uptodate.com/contents/subclavian-steal-syndrome/print 11/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate blood pressure (>15 mmHg differential) between the affected and normal arm. Duplex ultrasound can readily diagnose and semiquantify proximal subclavian artery stenoses and demonstrate reversal of flow in the ipsilateral vertebral artery, if present. If needed, arteriography that includes the aortic arch vessels and intracranial vessels can be accomplished with magnetic resonance angiography, CT angiography, or occasionally catheter-based arteriography. (See 'Diagnosis' above.) Risk modification Subclavian stenosis/occlusion is a marker for atherosclerotic disease (eg, carotid, coronary, lower extremity arteries) and is associated with an increased risk of morbidity and mortality related to cardiovascular disease. Patients with atherosclerosis benefit from secondary prevention measures (ie, treatment of modifiable cardiovascular risk factors). (See 'Risk modification' above.) Treatment We treat patients with subclavian steal syndrome. The choice of intervention (surgical, endovascular) depends upon the patient's specific anatomy, the presence of concomitant ipsilateral carotid disease, and the patient's overall medical status. Patients with subclavian steal syndrome who are not candidates for intervention are treated with antithrombotic therapy. For asymptomatic patients, the emphasis is on secondary prevention. (See 'Management' above and "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization".) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Peter C Spittell, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. CONTORNI L. 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Stenting for atherosclerotic occlusive https://www.uptodate.com/contents/subclavian-steal-syndrome/print 13/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate disease of the subclavian artery. Ann Vasc Surg 1999; 13:254. 22. Gutierrez GR, Mahrer P, Aharonian V, et al. Prevalence of subclavian artery stenosis in patients with peripheral vascular disease. Angiology 2001; 52:189. 23. Chatterjee S, Nerella N, Chakravarty S, Shani J. Angioplasty alone versus angioplasty and stenting for subclavian artery stenosis a systematic review and meta-analysis. Am J Ther 2013; 20:520. 24. Saalouke MG, Perry LW, Breckbill DL, et al. Cerebrovascular abnormalities in postoperative coarctation of aorta. Four cases demonstrating left subclavian steal on aortography. Am J Cardiol 1978; 42:97. 25. Kurlan R, Krall RL, Deweese JA. Vertebrobasilar ischemia after total repair of tetralogy of Fallot: significance of subclavian steal created by Blalock-Taussig anastomosis. Vertebrobasilar ischemia after correction of tetralogy of Fallot. Stroke 1984; 15:359. 26. MASSUMI RA. THE CONGENITAL VARIETY OF THE "SUBCLAVIAN STEAL" SYNDROME. Circulation 1963; 28:1149. 27. Luetmer PH, Miller GM. Right aortic arch with isolation of the left subclavian artery: case report and review of the literature. Mayo Clin Proc 1990; 65:407. 28. Kajinami K, Mori K, Masuda S, et al. Asymptomatic congenital subclavian steal in a young male patient with right aortic arch. Chest 1990; 97:481. 29. Savastano S, Feltrin GP, Chiesura-Corona M, Miotta D. Cerebral ischemia due to congenital malformations of brachiocephalic arteries case reports. Angiology 1992; 43:76. 30. Bornstein NM, Krajewski A, Norris JW. Basilar artery blood flow in subclavian steal. Can J Neurol Sci 1988; 15:417. 31. Bornstein NM, Norris JW. Subclavian steal: a harmless haemodynamic phenomenon? Lancet 1986; 2:303. 32. Lord RS, Adar R, Stein RL. Contribution of the circle of Willis to the subclavian steal syndrome. Circulation 1969; 40:871. 33. Salam TA, Lumsden AB, Smith RB 3rd. Subclavian artery revascularization: a decade of experience with extrathoracic bypass procedures. J Surg Res 1994; 56:387. 34. Klingelh fer J, Conrad B, Benecke R, Frank B. Transcranial Doppler ultrasonography of carotid-basilar collateral circulation in subclavian steal. Stroke 1988; 19:1036. 35. Mousa AY, Morkous R, Broce M, et al. Validation of subclavian duplex velocity criteria to grade severity of subclavian artery stenosis. J Vasc Surg 2017; 65:1779. 36. Harper C, Cardullo PA, Weyman AK, Patterson RB. Transcranial Doppler ultrasonography of the basilar artery in patients with retrograde vertebral artery flow. J Vasc Surg 2008; 48:859. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 14/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate 37. Sharma VK, Chuah B, Teoh HL, et al. Chronic brainstem ischemia in subclavian steal syndrome. J Clin Neurosci 2010; 17:1339. 38. Dieter RS. The Dieter test. Expert Rev Cardiovasc Ther 2009; 7:221. 39. Huang Y, Gao S, Wang B, Li S. The evaluation of intra- and extra-cranial circulation in subclavian steal syndrome. Chin Med J (Engl) 1997; 110:286. 40. Kliewer MA, Hertzberg BS, Kim DH, et al. Vertebral artery Doppler waveform changes indicating subclavian steal physiology. AJR Am J Roentgenol 2000; 174:815. 41. Van Grimberge F, Dymarkowski S, Budts W, Bogaert J. Role of magnetic resonance in the diagnosis of subclavian steal syndrome. J Magn Reson Imaging 2000; 12:339. 42. Nael K, Villablanca JP, Pope WB, et al. Supraaortic arteries: contrast-enhanced MR angiography at 3.0 T highly accelerated parallel acquisition for improved spatial resolution over an extended field of view. Radiology 2007; 242:600. 43. Tsao TF, Cheng KL, Shen CY, et al. Diagnostic Performance of Combined Contrast-Enhanced Magnetic Resonance Angiography and Phase-Contrast Magnetic Resonance Imaging in Suspected Subclavian Steal Syndrome. Can Assoc Radiol J 2016; 67:190. 44. Sheehy N, MacNally S, Smith CS, et al. Contrast-enhanced MR angiography of subclavian steal syndrome: value of the 2D time-of-flight "localizer" sign. AJR Am J Roentgenol 2005; 185:1069. 45. Park KH, Lee HY, Lim C, et al. Clinical impact of computerised tomographic angiography performed for preoperative evaluation before coronary artery bypass grafting. Eur J Cardiothorac Surg 2010; 37:1346. 46. Rafailidis V, Li X, Chryssogonidis I, et al. Multimodality Imaging and Endovascular Treatment Options of Subclavian Steal Syndrome. Can Assoc Radiol J 2018; 69:493. 47. Aboyans V, Criqui MH, McDermott MM, et al. The vital prognosis of subclavian stenosis. J Am Coll Cardiol 2007; 49:1540. 48. Vitti MJ, Thompson BW, Read RC, et al. Carotid-subclavian bypass: a twenty-two-year experience. J Vasc Surg 1994; 20:411. 49. Walker PM, Paley D, Harris KA, et al. What determines the symptoms associated with subclavian artery occlusive disease? J Vasc Surg 1985; 2:154. 50. Chang JB, Stein TA, Liu JP, Dunn ME. Long-term results with axillo-axillary bypass grafts for symptomatic subclavian artery insufficiency. J Vasc Surg 1997; 25:173. 51. Smith JM, Koury HI, Hafner CD, Welling RE. Subclavian steal syndrome. A review of 59 consecutive cases. J Cardiovasc Surg (Torino) 1994; 35:11. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 15/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate 52. De Vries JP, Jager LC, Van den Berg JC, et al. Durability of percutaneous transluminal angioplasty for obstructive lesions of proximal subclavian artery: long-term results. J Vasc Surg 2005; 41:19. 53. Iared W, Mour o JE, Puchnick A, et al. Angioplasty versus stenting for subclavian artery stenosis. Cochrane Database Syst Rev 2014; :CD008461. 54. Hadjipetrou P, Cox S, Piemonte T, Eisenhauer A. Percutaneous revascularization of atherosclerotic obstruction of aortic arch vessels. J Am Coll Cardiol 1999; 33:1238. 55. Wang KQ, Wang ZG, Yang BZ, et al. Long-term results of endovascular therapy for proximal subclavian arterial obstructive lesions. Chin Med J (Engl) 2010; 123:45. 56. Onishi H, Naganuma T, Hozawa K, et al. Periprocedural and Long-Term Outcomes of Stent Implantation for De Novo Subclavian Artery Disease. Vasc Endovascular Surg 2019; 53:284. 57. Che WQ, Dong H, Jiang XJ, et al. Stenting for left subclavian artery stenosis in patients scheduled for left internal mammary artery-coronary artery bypass grafting. Catheter Cardiovasc Interv 2016; 87 Suppl 1:579. 58. Patel SN, White CJ, Collins TJ, et al. Catheter-based treatment of the subclavian and innominate arteries. Catheter Cardiovasc Interv 2008; 71:963. 59. Sixt S, Rastan A, Schwarzw lder U, et al. Results after balloon angioplasty or stenting of atherosclerotic subclavian artery obstruction. Catheter Cardiovasc Interv 2009; 73:395. 60. Mahmud E, Cavendish JJ, Salami A. Current treatment of peripheral arterial disease: role of percutaneous interventional therapies. J Am Coll Cardiol 2007; 50:473. 61. Ahmed AT, Mohammed K, Chehab M, et al. Comparing Percutaneous Transluminal Angioplasty and Stent Placement for Treatment of Subclavian Arterial Occlusive Disease: A

152:131. 16. Fields WS, Lemak NA. Joint Study of extracranial arterial occlusion. VII. Subclavian steal a review of 168 cases. JAMA 1972; 222:1139. 17. Labropoulos N, Nandivada P, Bekelis K. Prevalence and impact of the subclavian steal syndrome. Ann Surg 2010; 252:166. 18. Nicholls SC, Koutlas TC, Strandness DE. Clinical significance of retrograde flow in the vertebral artery. Ann Vasc Surg 1991; 5:331. 19. Shadman R, Criqui MH, Bundens WP, et al. Subclavian artery stenosis: prevalence, risk factors, and association with cardiovascular diseases. J Am Coll Cardiol 2004; 44:618. 20. KESTELOOT H, VANHOUTE O. REVERSED CIRCULATION THROUGH THE VERTEBRAL ARTERY. Acta Cardiol 1963; 18:285. 21. Rodriguez-Lopez JA, Werner A, Martinez R, et al. Stenting for atherosclerotic occlusive https://www.uptodate.com/contents/subclavian-steal-syndrome/print 13/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate disease of the subclavian artery. Ann Vasc Surg 1999; 13:254. 22. Gutierrez GR, Mahrer P, Aharonian V, et al. Prevalence of subclavian artery stenosis in patients with peripheral vascular disease. Angiology 2001; 52:189. 23. Chatterjee S, Nerella N, Chakravarty S, Shani J. Angioplasty alone versus angioplasty and stenting for subclavian artery stenosis a systematic review and meta-analysis. Am J Ther 2013; 20:520. 24. Saalouke MG, Perry LW, Breckbill DL, et al. Cerebrovascular abnormalities in postoperative coarctation of aorta. Four cases demonstrating left subclavian steal on aortography. Am J Cardiol 1978; 42:97. 25. Kurlan R, Krall RL, Deweese JA. Vertebrobasilar ischemia after total repair of tetralogy of Fallot: significance of subclavian steal created by Blalock-Taussig anastomosis. Vertebrobasilar ischemia after correction of tetralogy of Fallot. Stroke 1984; 15:359. 26. MASSUMI RA. THE CONGENITAL VARIETY OF THE "SUBCLAVIAN STEAL" SYNDROME. Circulation 1963; 28:1149. 27. Luetmer PH, Miller GM. Right aortic arch with isolation of the left subclavian artery: case report and review of the literature. Mayo Clin Proc 1990; 65:407. 28. Kajinami K, Mori K, Masuda S, et al. Asymptomatic congenital subclavian steal in a young male patient with right aortic arch. Chest 1990; 97:481. 29. Savastano S, Feltrin GP, Chiesura-Corona M, Miotta D. Cerebral ischemia due to congenital malformations of brachiocephalic arteries case reports. Angiology 1992; 43:76. 30. Bornstein NM, Krajewski A, Norris JW. Basilar artery blood flow in subclavian steal. Can J Neurol Sci 1988; 15:417. 31. Bornstein NM, Norris JW. Subclavian steal: a harmless haemodynamic phenomenon? Lancet 1986; 2:303. 32. Lord RS, Adar R, Stein RL. Contribution of the circle of Willis to the subclavian steal syndrome. Circulation 1969; 40:871. 33. Salam TA, Lumsden AB, Smith RB 3rd. Subclavian artery revascularization: a decade of experience with extrathoracic bypass procedures. J Surg Res 1994; 56:387. 34. Klingelh fer J, Conrad B, Benecke R, Frank B. Transcranial Doppler ultrasonography of carotid-basilar collateral circulation in subclavian steal. Stroke 1988; 19:1036. 35. Mousa AY, Morkous R, Broce M, et al. Validation of subclavian duplex velocity criteria to grade severity of subclavian artery stenosis. J Vasc Surg 2017; 65:1779. 36. Harper C, Cardullo PA, Weyman AK, Patterson RB. Transcranial Doppler ultrasonography of the basilar artery in patients with retrograde vertebral artery flow. J Vasc Surg 2008; 48:859. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 14/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate 37. Sharma VK, Chuah B, Teoh HL, et al. Chronic brainstem ischemia in subclavian steal syndrome. J Clin Neurosci 2010; 17:1339. 38. Dieter RS. The Dieter test. Expert Rev Cardiovasc Ther 2009; 7:221. 39. Huang Y, Gao S, Wang B, Li S. The evaluation of intra- and extra-cranial circulation in subclavian steal syndrome. Chin Med J (Engl) 1997; 110:286. 40. Kliewer MA, Hertzberg BS, Kim DH, et al. Vertebral artery Doppler waveform changes indicating subclavian steal physiology. AJR Am J Roentgenol 2000; 174:815. 41. Van Grimberge F, Dymarkowski S, Budts W, Bogaert J. Role of magnetic resonance in the diagnosis of subclavian steal syndrome. J Magn Reson Imaging 2000; 12:339. 42. Nael K, Villablanca JP, Pope WB, et al. Supraaortic arteries: contrast-enhanced MR angiography at 3.0 T highly accelerated parallel acquisition for improved spatial resolution over an extended field of view. Radiology 2007; 242:600. 43. Tsao TF, Cheng KL, Shen CY, et al. Diagnostic Performance of Combined Contrast-Enhanced Magnetic Resonance Angiography and Phase-Contrast Magnetic Resonance Imaging in Suspected Subclavian Steal Syndrome. Can Assoc Radiol J 2016; 67:190. 44. Sheehy N, MacNally S, Smith CS, et al. Contrast-enhanced MR angiography of subclavian steal syndrome: value of the 2D time-of-flight "localizer" sign. AJR Am J Roentgenol 2005; 185:1069. 45. Park KH, Lee HY, Lim C, et al. Clinical impact of computerised tomographic angiography performed for preoperative evaluation before coronary artery bypass grafting. Eur J Cardiothorac Surg 2010; 37:1346. 46. Rafailidis V, Li X, Chryssogonidis I, et al. Multimodality Imaging and Endovascular Treatment Options of Subclavian Steal Syndrome. Can Assoc Radiol J 2018; 69:493. 47. Aboyans V, Criqui MH, McDermott MM, et al. The vital prognosis of subclavian stenosis. J Am Coll Cardiol 2007; 49:1540. 48. Vitti MJ, Thompson BW, Read RC, et al. Carotid-subclavian bypass: a twenty-two-year experience. J Vasc Surg 1994; 20:411. 49. Walker PM, Paley D, Harris KA, et al. What determines the symptoms associated with subclavian artery occlusive disease? J Vasc Surg 1985; 2:154. 50. Chang JB, Stein TA, Liu JP, Dunn ME. Long-term results with axillo-axillary bypass grafts for symptomatic subclavian artery insufficiency. J Vasc Surg 1997; 25:173. 51. Smith JM, Koury HI, Hafner CD, Welling RE. Subclavian steal syndrome. A review of 59 consecutive cases. J Cardiovasc Surg (Torino) 1994; 35:11. https://www.uptodate.com/contents/subclavian-steal-syndrome/print 15/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate 52. De Vries JP, Jager LC, Van den Berg JC, et al. Durability of percutaneous transluminal angioplasty for obstructive lesions of proximal subclavian artery: long-term results. J Vasc Surg 2005; 41:19. 53. Iared W, Mour o JE, Puchnick A, et al. Angioplasty versus stenting for subclavian artery stenosis. Cochrane Database Syst Rev 2014; :CD008461. 54. Hadjipetrou P, Cox S, Piemonte T, Eisenhauer A. Percutaneous revascularization of atherosclerotic obstruction of aortic arch vessels. J Am Coll Cardiol 1999; 33:1238. 55. Wang KQ, Wang ZG, Yang BZ, et al. Long-term results of endovascular therapy for proximal subclavian arterial obstructive lesions. Chin Med J (Engl) 2010; 123:45. 56. Onishi H, Naganuma T, Hozawa K, et al. Periprocedural and Long-Term Outcomes of Stent Implantation for De Novo Subclavian Artery Disease. Vasc Endovascular Surg 2019; 53:284. 57. Che WQ, Dong H, Jiang XJ, et al. Stenting for left subclavian artery stenosis in patients scheduled for left internal mammary artery-coronary artery bypass grafting. Catheter Cardiovasc Interv 2016; 87 Suppl 1:579. 58. Patel SN, White CJ, Collins TJ, et al. Catheter-based treatment of the subclavian and innominate arteries. Catheter Cardiovasc Interv 2008; 71:963. 59. Sixt S, Rastan A, Schwarzw lder U, et al. Results after balloon angioplasty or stenting of atherosclerotic subclavian artery obstruction. Catheter Cardiovasc Interv 2009; 73:395. 60. Mahmud E, Cavendish JJ, Salami A. Current treatment of peripheral arterial disease: role of percutaneous interventional therapies. J Am Coll Cardiol 2007; 50:473. 61. Ahmed AT, Mohammed K, Chehab M, et al. Comparing Percutaneous Transluminal Angioplasty and Stent Placement for Treatment of Subclavian Arterial Occlusive Disease: A Systematic Review and Meta-Analysis. Cardiovasc Intervent Radiol 2016; 39:652. 62. Filippo F, Francesco M, Francesco R, et al. Percutaneous angioplasty and stenting of left subclavian artery lesions for the treatment of patients with concomitant vertebral and coronary subclavian steal syndrome. Cardiovasc Intervent Radiol 2006; 29:348. Topic 8183 Version 19.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 16/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate GRAPHICS Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 17/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Subclavian steal Subclavian artery occlusion or a hemodynamically significant stenosis proximal to the origin of the vertebral artery results in lower pressure in the distal subclavian artery. As a result, blood is "stolen" from the cerebral circulation to perfuse the arm. Blood flows up the contralateral vertebral artery to the basilar artery, and retrograde down the ipsilateral vertebral artery away from the brainstem. Graphic 62622 Version 6.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 18/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Coronary steal physiology In coronary-subclavian steal, severe stenosis or occlusion of the left subclavian artery proximal to the origin of a left internal mammary-to- coronary artery bypass graft may cause "steal" from the coronary graft to maintain perfusion to the arm via the left subclavian artery during upper extremity exercise. Graphic 76733 Version 3.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 19/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Collateral circulation around the shoulder The thyrocervical trunk, dorsal scapular artery, and internal thoracic artery provide important collateral channels of blood flow to the ipsilateral brain and upper extremity when a significant stenosis or occlusion of the brachiocephalic or subclavian artery is present. Graphic 66933 Version 4.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 20/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Anatomy of the thoracic outlet The thoracic outlet refers to the confined space between the clavicle and first rib. Structures that pass through this region include the nerves of the brachial plexus, the subclavian artery, and the subclavian vein. Graphic 59433 Version 7.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 21/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Radial pulse delay in subclavian steal syndrome Simultaneous right and left radial pulse volumes in a patient with dizziness induced by left upper extremity exercise shows late arrival of the left subclavian artery pulsation, which can be appreciated by simultaneous palpation of the radial arteries. Note the delay in the left radial pulse at the brown bar. Courtesy of Peter Spittell, MD. Graphic 61635 Version 4.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 22/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Arteriogram of the aortic vessels in subclavian steal (A) Arteriography of the aortic arch vessels demonstrates a significant stenosis of the proximal innominate artery. (B) Reversal of flow in the right vertebral artery. Courtesy of Peter Spittell, MD. Graphic 63380 Version 7.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 23/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Vertebral artery flow in subclavian steal syndrome The pulse-waved Doppler spectral display shows retrograde flow in the left vertebral artery in a patient with a hemodynamically significant left subclavian artery stenosis. Courtesy of Peter Spittell, MD. Graphic 80201 Version 3.0 https://www.uptodate.com/contents/subclavian-steal-syndrome/print 24/25 7/6/23, 12:36 PM Subclavian steal syndrome - UpToDate Contributor Disclosures John F Eidt, MD Grant/Research/Clinical Trial Support: Syntactx [Clinical events, data/safety monitoring for medical device trials]. All of the relevant financial relationships listed have been mitigated. Joseph L Mills, Sr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kathryn A Collins, MD, PhD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/subclavian-steal-syndrome/print 25/25

7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antihypertensive therapy for secondary stroke prevention : Raymond R Townsend, MD, Natalia S Rost, MD, MPH, Adam de Havenon, MD, MS : George L Bakris, MD, Scott E Kasner, MD : John P Forman, MD, MSc, John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 03, 2022. INTRODUCTION Hypertension is a major risk factor for stroke and transient ischemic attack (TIA) [1]. The risk can be reduced by persistent correction of the hypertension [2]. (See "Overview of primary prevention of cardiovascular disease", section on 'Hypertension control'.) In addition, among patients who have had a stroke or TIA, antihypertensive therapy can reduce the rate of recurrence. (See 'Management after the acute phase of stroke' below.) This topic will review the management of blood pressure for prevention of a recurrent stroke, including the timing of initiation (or reinstatement) of antihypertensive therapy following stroke or TIA, the choice of antihypertensive drugs, and the management of nonhypertensive patients. Long-term goal blood pressure in patients who have cerebrovascular disease is presented elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.) The diagnosis of stroke subtypes and risk factor reduction for the secondary prevention of stroke other than blood pressure control are discussed separately: (See "Clinical diagnosis of stroke subtypes".) (See "Overview of secondary prevention of ischemic stroke".) https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 1/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate TREATMENT IN THE ACUTE PHASE OF STROKE Treatment of hypertension may be an immediate concern in patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. However, blood pressure management in the acute phase of stroke is different from chronic therapy. Acute blood pressure management is discussed in detail elsewhere for each of the major stroke types: (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) The following sections provide a brief overview of blood pressure management in the acute phase of stroke, which necessarily transitions to decisions about long-term antihypertensive management. Who should be treated with pharmacologic therapy? Similar to American Heart Association (AHA) and American Stroke Association (ASA) guidelines, we recommend resumption of antihypertensive therapy for previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events [3]. In addition, we recommend initiation of antihypertensive therapy for previously untreated, neurologically stable patients with any type of stroke or transient ischemic attack (TIA) who have an established blood pressure that is above goal ( table 1) [4]. When to initiate (or reinstate) antihypertensive therapy The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA can vary according to a number of factors, including stroke mechanism (eg, whether the stroke was ischemic or hemorrhagic), neurologic stability, and comorbid medical problems. Patients with transient ischemic attack In patients with a TIA, who by definition have recovered to their neurologic baseline and have no other evidence of infarction, we initiate (or reinstate) oral antihypertensive drug therapy without further delay. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Patients with ischemic stroke In patients with acute ischemic stroke, elevated blood pressures are typically tolerated (ie, "permissive hypertension") during the first 24 to 48 hours (the acute phase of an ischemic stroke) to theoretically augment cerebral blood flow https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 2/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate and reduce expansion of the ischemic infarct core. Exceptions that require treatment are patients with extreme hypertension (>220/120 mmHg), with other acute hypertension- related end-organ failure (eg, cardiac), patients with active ischemic coronary disease, patients with aortic dissection, patients with pre-eclampsia/eclampsia, and patients who are candidates for reperfusion therapy who have persistent blood pressure elevation greater than 185/110 mmHg. (See "Initial assessment and management of acute stroke", section on 'Blood pressure in acute ischemic stroke' and "Management of acute type B aortic dissection".) Beyond the acute period, we approach the time to start or resume antihypertensive medication as follows: For patients with hypertension who are neurologically improving or stable and able to safely swallow oral medications or receive them through a feeding tube, we initiate (or reinstate) antihypertensive drug therapy 24 to 48 hours after ischemic stroke onset and during hospitalization. For patients with hypertension who are neurologically unstable with fluctuating deficits or progressive deterioration, we delay starting or resuming antihypertensive drug therapy until the stroke-related deficits have stabilized or reached a nadir since blood pressure lowering may induce ischemic symptoms. This is discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Blood pressure in acute ischemic stroke'.) Patients with intracerebral hemorrhage In patients with spontaneous intracerebral hemorrhage (ICH), there is often a need for intravenous antihypertensive treatment during the acute phase (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'). Intravenous antihypertensive therapy is then transitioned to oral therapy, when appropriate. Patients with subarachnoid hemorrhage In patients with subarachnoid hemorrhage, who are typically managed initially in the intensive care unit, antihypertensive therapy for secondary prevention is started if cerebral perfusion pressure is judged to be adequate, either by direct measurement or by an assessment of the patient's cognitive status. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) MANAGEMENT AFTER THE ACUTE PHASE OF STROKE https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 3/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Selection of long-term antihypertensive medication In patients with a history of stroke or transient ischemic attack (TIA), antihypertensive therapy can prevent future strokes and cardiovascular death. The choice of drug is similar in patients who have had a previous stroke or TIA as in other hypertensive patients: Monotherapy is recommended when blood pressure is <20/10 mmHg above goal. Although the largest studies of secondary stroke prevention examined the effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics, there is no compelling evidence favoring one class of antihypertensive drugs over another as monotherapy for secondary prevention in such patients. ACE inhibitors, ARBs, calcium channel blockers, and diuretics are all reasonable options for initial antihypertensive monotherapy. (See "Choice of drug therapy in primary (essential) hypertension".) There is some evidence from clinical trials that beta blockers may not reduce stroke risk compared with angiotensin inhibitors (ACE inhibitor or ARB), calcium channel blockers, and, in some trials, placebo [5-7]. Thus, unless there is a compelling indication for their use, beta blockers should not be used as monotherapy for prevention of recurrent stroke. Combination therapy is recommended when blood pressure is 20/10 mmHg above goal. We use the combination of an angiotensin inhibitor plus a long-acting dihydropyridine calcium channel blocker among patients who should initiate therapy with two agents. This approach is consistent with our recommendations for other hypertensive patients who have not had a stroke or TIA. (See "Choice of drug therapy in primary (essential) hypertension".) In a meta-analysis of eight trials and more than 35,000 patients with a prior stroke or TIA, antihypertensive drug therapy reduced the rate of stroke (8.7 versus 10.1 percent) and cardiovascular death (4.0 versus 4.7 percent) [8]. There was also a nonsignificantly lower incidence of major adverse cardiovascular events (13.6 versus 15.1 percent). The largest studies included in this meta-analysis (the Perindopril Protection Against Recurrent Stroke Study [PROGRESS], Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS], and Post-stroke Antihypertensive Treatment Study [PATS] trials) examined ACE inhibitors, ARBs, and diuretics; therefore, many experts and the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend ACE inhibitors and diuretics for patients with prior stroke or TIA [4,9-11]. In several meta-analyses, however, the effects of calcium channel blockers were not statistically different from those of angiotensin inhibitors and diuretics [12-14]. In addition, among patients who require two antihypertensive https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 4/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate agents, a calcium channel blocker plus an ACE inhibitor (or ARB) is the ideal combination. (See "Choice of drug therapy in primary (essential) hypertension".) Goal blood pressure Patients with ischemic stroke or TIA and atherosclerotic disease The majority of patients who have had an ischemic stroke or transient ischemic attack (TIA) are at high risk for a future atherosclerotic cardiovascular event. Thus, in most such patients, we use a more intensive blood pressure goal, if tolerated ( table 1). Patients who become symptomatic with intensive blood pressure lowering may require a less intensive goal. Goal blood pressure in these higher-risk patients is discussed in detail elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.) Patients with ischemic stroke in the absence of atherosclerotic disease We do not consider a stroke or TIA that was caused by a cardioembolic phenomenon (eg, atrial fibrillation) or by a paradoxical embolus as evidence of atherosclerotic cardiovascular disease. Thus, in such patients who are not otherwise at high risk for a future atherosclerotic cardiovascular event, we use a less intensive goal blood pressure than we use for higher-risk patients ( table 1). Goal blood pressure in these lower-risk patients is discussed in detail elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Goal blood pressure in lower-risk patients'.) However, patients with cardioembolic stroke may have heart failure or other types of heart disease that would indicate lower blood pressure targets. Patients with intracerebral hemorrhage For prevention of recurrent intracerebral hemorrhage (ICH) in patients with spontaneous ICH, we suggest a more intensive blood pressure goal, similar to the goal in patients with ischemic stroke due to atherosclerotic disease ( table 1). In the PROGRESS trial, among the subgroup of 611 hypertensive patients with prior ICH, a modest reduction in blood pressure of 9/4 mmHg produced a 49 percent relative reduction in the risk for recurrent stroke (95% CI 18-68 percent) [15]. Post-hoc analyses found that the relationship of blood pressure lowering with reduced stroke risk was stronger for subjects with prior ICH than for those with prior ischemic stroke and that the lowest risk of recurrence was present in the patients with the lowest follow-up blood pressure levels [16]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Blood pressure management'.) https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 5/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Patients with subarachnoid hemorrhage Hypertension is a major risk factor for subarachnoid hemorrhage. However, the optimal goal blood pressure for prevention of recurrent subarachnoid hemorrhage is unknown; for patients who are not otherwise at high risk for atherosclerotic cardiovascular events, a less intensive blood pressure goal as defined in the table is reasonable ( table 1). Rapidity by which goal is attained Gradual blood pressure reduction (eg, approximately 10 percent per day, although there is no consensus on the definition of gradual lowering) is recommended in patients with known cerebrovascular disease or long-standing uncontrolled hypertension unless there is a hypertensive emergency. The normal response to an acute reduction in blood pressure is to maintain tissue perfusion by autoregulatory precapillary vasodilation. Since flow is equal to pressure divided by resistance, parallel reductions in both parameters allow flow to be maintained. This response may be impaired in patients with chronic hypertension, including those who have not had a stroke. Persistent hypertension leads to arteriolar thickening. In the cerebral and other circulations, this is in part an appropriate adaptation in that it prevents the increase in pressure from being transmitted to the capillary circulation [17]. However, arteriolar thickening can also limit the ability to maintain perfusion when the blood pressure is lowered with antihypertensive therapy since the vasodilator response is often impaired. As a result, the lower blood pressure limit at which cerebral perfusion is maintained is higher in hypertensive than in normotensive subjects ( figure 1) [18]. In general, ischemic symptoms are not likely to occur unless the blood pressure is acutely reduced by more than 25 percent below the baseline level; gradual blood pressure reduction of approximately 10 percent per day is generally well tolerated. Gradual blood pressure reduction can be aided by home blood pressure monitoring. (See "Evaluation and treatment of hypertensive emergencies in adults" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".) RECOMMENDATIONS OF OTHERS Guidelines for the prevention of recurrent stroke and transient ischemic attack (TIA) issued in 2021 by the American Stroke Association (ASA) and American Heart Association (AHA) recommend initiation of blood pressure therapy for previously untreated patients with ischemic stroke or TIA who, after the first few days (because blood pressure is typically elevated above baseline upon presentation), have an established blood pressure of 130 mmHg systolic or 80 https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 6/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate mmHg diastolic [19]. The guidelines also recommend resumption of blood pressure therapy for previously treated patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events in those who have had an ischemic stroke or TIA and are beyond the first three days after stroke onset. The suggested goal blood pressure of <130/<80 mmHg is reasonable for secondary stroke prevention in all patients. European, Canadian, and Asian secondary stroke prevention guidelines have similar blood pressure goals as the United States guidelines [20]. For patients with intracerebral hemorrhage (ICH), 2022 guidelines from the AHA/ASA suggest a goal blood pressure of <130 mmHg systolic and <80 mmHg diastolic [21]. We generally agree with these recommendations, although our approach to goal blood pressure is more nuanced. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)") https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 7/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Hypertension is a major risk factor for stroke and transient ischemic attack (TIA). The risk can be reduced by persistent correction of the hypertension. (See 'Introduction' above.) After the acute phase of stroke, antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events. In addition, antihypertensive therapy should be initiated in previously untreated, neurologically stable patients with any type of stroke or TIA who have an established blood pressure that is above goal ( table 1). (See 'Who should be treated with pharmacologic therapy?' above.) The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA varies (see 'When to initiate (or reinstate) antihypertensive therapy' above): In patients with a TIA, we initiate (or reinstate) oral antihypertensive drug therapy without further delay. For patients with acute ischemic stroke and hypertension who are neurologically improving or stable and able to safely swallow oral medications or receive them through a feeding tube, we initiate (or reinstate) antihypertensive drug therapy 24 to 48 hours after ischemic stroke onset and during hospitalization. For patients with hypertension who are neurologically unstable with fluctuating deficits or progressive deterioration, we delay starting or resuming antihypertensive drug therapy until the stroke-related deficits have stabilized or reached a nadir since blood pressure lowering may induce ischemic symptoms. In patients with spontaneous intracerebral hemorrhage (ICH), there is often a need for intravenous antihypertensive treatment during the acute phase. In patients with subarachnoid hemorrhage, antihypertensive therapy for secondary prevention is begun if cerebral perfusion pressure is judged to be adequate, either by direct measurement or by an assessment of the patient's cognitive status. The choice of drug is similar in patients who have had a previous stroke or TIA as in other hypertensive patients. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 8/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate receptor blockers (ARBs), calcium channel blockers, and diuretics are all reasonable options for initial antihypertensive monotherapy. (See 'Selection of long-term antihypertensive medication' above.) The majority of patients who have had an ischemic stroke or TIA are at high risk for a future atherosclerotic cardiovascular event. Thus, in most such patients, we use a more intensive blood pressure goal, if tolerated ( table 1). Patients who become symptomatic with intensive blood pressure lowering may require a less intensive goal. (See 'Patients with ischemic stroke or TIA and atherosclerotic disease' above.) We do not consider an ischemic stroke or TIA that was caused by a cardioembolic phenomenon (eg, atrial fibrillation) or by a paradoxical embolus as evidence of atherosclerotic cardiovascular disease. Thus, in such patients who are not otherwise at high risk for a future atherosclerotic cardiovascular event, we use a less intensive goal blood pressure than we use for higher-risk patients ( table 1). (See 'Patients with ischemic stroke in the absence of atherosclerotic disease' above.) For prevention of recurrent ICH in patients with spontaneous ICH, we suggest a more intensive blood pressure goal, similar to the goal in patients with ischemic stroke due to atherosclerotic disease ( table 1). (See 'Patients with intracerebral hemorrhage' above.) The optimal goal blood pressure for prevention of recurrent subarachnoid hemorrhage is unknown; for patients who are not otherwise at high risk for atherosclerotic cardiovascular events, a less intensive blood pressure goal as defined in the table is reasonable ( table 1). (See 'Patients with subarachnoid hemorrhage' above.) Gradual blood pressure reduction (eg, approximately 10 percent per day, although there is no consensus on the definition of gradual lowering) is recommended in patients with known cerebrovascular disease or long-standing uncontrolled hypertension unless there is a hypertensive emergency. (See 'Rapidity by which goal is attained' above.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Norman M Kaplan, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 9/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate 1. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. 2. Messerli FH, Bangalore S. Blood pressure and stroke: findings from recent trials. J Am Coll Cardiol 2011; 57:114. 3. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2160. 4. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71:e13. 5. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007; :CD002003. 6. Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol 2007; 100:1254. 7. Bangalore S, Wild D, Parkar S, et al. Beta-blockers for primary prevention of heart failure in patients with hypertension insights from a meta-analysis. J Am Coll Cardiol 2008; 52:1062. 8. Zonneveld TP, Richard E, Vergouwen MD, et al. Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. Cochrane Database Syst Rev 2018; 7:CD007858. 9. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033. 10. Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359:1225. 11. Liu L, Wang Z, Gong L, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res 2009; 32:1032. 12. Lee M, Saver JL, Hong KS, et al. Renin-Angiotensin system modulators modestly reduce vascular risk in persons with prior stroke. Stroke 2012; 43:113. https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 10/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate 13. Chen GJ, Yang MS. The effects of calcium channel blockers in the prevention of stroke in adults with hypertension: a meta-analysis of data from 273,543 participants in 31 randomized controlled trials. PLoS One 2013; 8:e57854. 14. Wang WT, You LK, Chiang CE, et al. Comparative Effectiveness of Blood Pressure-lowering Drugs in Patients who have Already Suffered From Stroke: Traditional and Bayesian Network Meta-analysis of Randomized Trials. Medicine (Baltimore) 2016; 95:e3302. 15. Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressure- lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 2004; 35:116. 16. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006; 24:1201. 17. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003; 34:2741. 18. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973; 1:507. 19. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 20. McGurgan IJ, Kelly PJ, Turan TN, Rothwell PM. Long-Term Secondary Prevention: Management of Blood Pressure After a Transient Ischemic Attack or Stroke. Stroke 2022; 53:1085. 21. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. Topic 3823 Version 40.0 https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 11/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate GRAPHICS Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or oscillometric device)* blood pressure Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 12/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 13/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Cerebral autoregulation in hypertension Schematic representation of autoregulation of cerebral blood flow in normotensive and hypertensive subjects. In both groups, initial increases or decreases in mean arterial pressure are associated with maintenance of cerebral blood flow due to appropriate changes in arteriolar resistance. More marked changes in pressure are eventually associated with loss of autoregulation, leading to a reduction (with hypotension) or an elevation (with marked hypertension) in cerebral blood flow. These changes occur at higher pressures in patients with hypertension, presumably due to arteriolar thickening. Thus, aggressive antihypertensive therapy will produce cerebral ischemia at a higher mean arterial pressure in patients with underlying hypertension. Redrawn from: Kaplan NM. Management of hypertensive emergencies. Lancet 1994; 344:1335. Based on data from: Strandgaard S, Paulson OB. Cerebral blood ow and its pathophysiology in hypertension. Am J Hypertens 1989; 2:486. Graphic 57676 Version 5.0 https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 14/15 7/6/23, 12:38 PM Antihypertensive therapy for secondary stroke prevention - UpToDate Contributor Disclosures Raymond R Townsend, MD Consultant/Advisory Boards: Backbeat [Hypertension]; BD [Hypertension]; Janssen [Hypertension]; Medtronic [Hypertension]. All of the relevant financial relationships listed have been mitigated. Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Adam de Havenon, MD, MS Equity Ownership/Stock Options: Certus Critical Care [Stroke treatment]; TitinKM [Shoulder rehabilitation]. Consultant/Advisory Boards: Integra [Intracranial ventricular drain]; NovoNordisk [Diabetes]. All of the relevant financial relationships listed have been mitigated. George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer [Diabetic nephropathy]; KBP Biosciences [Resistant hypertension]; Novo Nordisk [Diabetic kidney disease]. Consultant/Advisory Boards: Alnylam [Resistant hypertension]; AstraZeneca [Diabetic nephropathy]; Bayer [Nephropathy]; Ionis [Resistant hypertension]; KBP BioSciences [Resistant hypertension]; Vifor [Hyperkalemia]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John P Forman, MD, MSc No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antihypertensive-therapy-for-secondary-stroke-prevention/print 15/15

7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Selection of candidates for anticoagulation : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 23, 2022. INTRODUCTION Atrial fibrillation (AF) is a major cause of morbidity and mortality in adults. While ischemic stroke due to embolization of left atrial thrombi is the most frequent clinical manifestation of embolization, embolization to other locations in the systemic circulation (and in the pulmonary circulation from right atrial thrombi) also occurs, but is less commonly recognized. Stroke associated with AF tends to be more extensive/larger than stroke related to carotid artery disease. Chronic oral anticoagulation (OAC) is recommended to reduce the risk of thromboembolism for most patients with AF. However, such therapy is associated with an increased risk of bleeding, and recommendations for its use must take both benefit and risk into account through shared decision-making with the patient. (See "Stroke in patients with atrial fibrillation".) This topic will focus on identifying which patients with AF require long-term/chronic OAC with either vitamin K antagonist (VKA; eg, warfarin) or direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]). The discussion here excludes patients with 2 rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ), a bioprosthetic valve (surgical or bioprosthetic) within the first three to six months after implantation, or a mechanical heart valve. Management for patients with these valve conditions is briefly discussed in a section below that provides links to related topics. (See 'Patients with valvular heart disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 1/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Other potentially relevant topics to the reader include: Choice of OAC for AF (see "Atrial fibrillation in adults: Use of oral anticoagulants") (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO DECIDING WHETHER TO ANTICOAGULATE Decision-making based upon risk assessment A first step in deciding which patients with AF should receive long-term oral anticoagulation (OAC) is to assess the individual patient s risks of thromboembolism and bleeding along with patient preferences. Long-term anticoagulation lowers the risk of clinical embolization in patients with AF, but its use is associated with an increased risk of bleeding. The benefits and risks of OAC with respect to reduction in risk of stroke and increment in risk of bleeding must be carefully considered and discussed with each patient. The greater the estimated reduction in absolute stroke risk compared with the increase in absolute risk of life- threatening or severely debilitating bleeding (such as intracranial hemorrhage), the more likely a patient is to benefit from long-term OAC. The benefit generally outweighs the risk for all but those with the lowest risk of thromboembolism. In cases of more balanced stroke reduction and bleeding risks, OAC is less likely to provide a net benefit. Risk scores are commonly used to assess thromboembolic and bleeding risks, although these tools are subject to a number of limitations. (See 'CHA2DS2-VASc score' below and 'Bleeding risk' below.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Our approach to deciding whether to prescribe anticoagulant therapy for patients with AF (without severe or clinically significant rheumatic mitral stenosis [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) is as follows: For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC. For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1), the 2 2 specific nonsex risk factor present and the documented burden of AF influences decision making: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 2/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC. Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score point [1]. 2 2 For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. The frequency and duration of AF episodes vary widely over time and episodes are often asymptomatic. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1)( table 1), 2 2 we suggest against anticoagulant therapy. Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' below) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated, and to flag patients with high bleeding risk for early review and follow-up and to identify potential candidates for left atrial appendage occlusion [2-6]. (See 'Bleeding risk' below and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding'.) Effects of anticoagulation In identifying which patients with AF are likely to benefit from OAC, the relative risk reduction in thromboembolism with OAC identified in randomized trials (see 'General efficacy' below) is combined with estimates of baseline risk using the CHA DS - 2 2 VASc score to estimate the expected absolute risk reduction from OAC (see 'CHA2DS2-VASc score' below). The estimated absolute risk reduction for thromboembolic events is weighed against the estimated increase in absolute risk of intracranial hemorrhage (ICH) and other major bleeding complications. (See 'Bleeding risk' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 3/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate General efficacy For patients with AF, randomized trials have shown that therapeutic OAC (vitamin K antagonist [VKA] or DOAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo irrespective of baseline risk ( figure 1) [7-17]. A meta-analysis included six randomized trials comparing VKA (warfarin) with placebo or no treatment in a total of 2900 participants with AF (mean age at entry 69 years, 20 percent with prior stroke or transient ischemic attack) [14]. The overall rate of stroke was 2.2 percent/patient year in the warfarin group and 6.0 percent/patient year in the control group (relative risk reduction 0.64; 95% CI 0.49-0.74). The absolute risk reduction was 2.7 percent/year for primary prevention and 8.4 percent/year for secondary prevention. With warfarin therapy, all-cause mortality was reduced by 1.6 percent/year (relative risk reduction 0.26; 95% CI 0.03-0.43). While most of the evidence comparing OAC with placebo in patients involved treatment with VKA, a trial comparing edoxaban 15 mg daily with placebo in patients with AF 80 years old with low body weight found a similar relative reduction in risk of stroke or systemic embolism (2.3 versus 6.7 percent/year; hazard ratio 0.34, 95% CI 0.19-0.61) [18]. The possible implications of this study for edoxaban dose are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) CHA2DS2-VASc score Use We use the CHA DS -VASc score (calculator 1) to estimate thromboembolic risk in 2 2 patients with AF, while recognizing its limitations (see 'Potential alternatives' below and 'Limitations' below). This estimation of baseline thromboembolic risk is combined with the above information on relative risk reduction (see 'General efficacy' above) to estimate the expected absolute risk reduction. The annual risk of ischemic stroke in untreated patients is estimated to be 0.2, 0.6, and 2.2 percent for those with CHA DS -VASc scores of 0, 1, and 2 ( table 1) [19]. However, stroke 2 2 rates have varied substantially among studies, which may be due to differences in study populations and methodologies [2,20-24]. As an example, studies examining ischemic stroke rates in patients with a single risk factor have identified risks of <1 to 2.7 percent/year [25-27]. Among patients with AF, ischemic stroke is the dominant type of thromboembolic event. As an example, in a study including data on 39,973 participants in four randomized trials of anticoagulation, the incidence of nonstroke systemic embolic events (SEEs) was 0.23/100 person-years, and the incidence of cerebral embolism was 1.92/100 person-years [28]. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 4/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among those with SEEs, 58 percent occurred in the lower extremities, 31 percent in the visceral-mesenteric system, and 11 percent in the upper extremities. Among patients with AF treated with OAC, annual stroke risk is lowered by approximately two-thirds to <0.1, 0.2, and 0.6 percent, respectively. In addition to the lowering of stroke risk, there is evidence that warfarin, compared with no anticoagulant therapy, leads to less severe stroke episodes and lower 30-day stroke mortality [14,29]. The annual risk of intracranial bleeding with warfarin is 0.2, 0.3, and 0.5 percent, respectively. The risk of ICH with DOAC is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Among adults with AF, females have a modestly higher risk of thromboembolism than males, but female sex is associated with increased risk primarily in patients with at least two CHA DS - 2 2 VASc score non-sex risk score points [1,30]. Thus, we focus on non-sex risk factors when deciding whether OAC is indicated. For CHA DS -VASc score 2 in males or 3 in females (when the risk score points are 2 2 from two or more non-sex risk factors), the benefit from OAC generally exceeds the risks of severe bleeding [19,31-33]. For CHA DS -VASc score of 1 in males or 2 in females (one non-sex risk factor with a 2 2 value of 1), the risk of thromboembolism varies depending upon the non-sex risk factor [1]. Among the risk factors with a one-point value, age 65 to 74 years and the presence of heart failure have the greatest effect on thromboembolic risk [1], and OAC is recommended in patients with any of these risk factors. For CHA DS - VASc score of 0 in males or 1 in females (zero nonsex risk factors), the 2 2 thromboembolic risk is low [27], so no OAC is suggested. (See 'Approach to deciding whether to anticoagulate' above.) The warfarin versus placebo or aspirin trials were reported in the early 1990s, raising concerns that the findings may not be applicable to contemporary clinical practice [31,34,35]. Studies evaluating more contemporary data have found that the absolute risk of stroke in untreated patients has fallen from approximately 8 percent/year to 4 or 5 percent/year ( table 1), but the relative risk reduction attributable to anticoagulant therapy is in the same range as earlier studies [36,37]. A two-thirds risk reduction in thromboembolism using the more contemporary lower absolute risks is clinically important for patients with two or more nonsex risk factors and for selected patients with one nonsex risk factor. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 5/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Comparisons of the effects of VKA and DOAC are presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Potential alternatives A variety of risk scores, imaging methods, and biomarkers have been studied for their potential predictive value for thromboembolic risk in patients with AF [38]. The CHA DS -VASc score has been compared with potential alternatives including the CHADS 2 2 2 and ATRIA risk scores ( table 1 and table 5). The clinical utility of a risk score for individuals with AF hinges primarily on its accuracy in identifying those at lowest risk for thromboembolism, as anticoagulation is generally recommended for individuals with all but the lowest level of risk. Systematic reviews suggest that the CHA DS -VASc score generally performs better than the 2 2 CHADS and ATRIA scores in identifying low-risk patients, although there have been some 2 discrepant results for comparisons of CHA DS -VASc and ATRIA [38]. However, all these risk 2 2 scores are subject to the limitations discussed below. (See 'Limitations' below.) A potential alternative to the risk score approach is to calculate the risk for each patient based upon risk factors including age as a continuous variable using the Calculator of Absolute Stroke Risk (CARS) [1]. For patients with AF, there is no established role for routine cardiac imaging to assess thromboembolic risk. Transesophageal echocardiography (TEE) is used in patients with AF primarily to evaluate left and right atrial appendage anatomy/function to identify individuals who are free of atrial thrombi and are therefore candidates for early cardioversion (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation"). Thromboembolic risk is associated with cardiac imaging findings, including evidence of left atrial thrombus (generally assessed by TEE; less commonly assessed by cardiovascular magnetic resonance [CMR] or cardiac computed tomography [CCT]) and depressed left ventricular ejection fraction (which can be assessed by transthoracic echocardiography, TEE, CMR, CCT, or nuclear methods) [39]. However, imaging findings have not been shown to improve risk stratification in patients with AF [2]. Limitations Risk scores to estimate thromboembolic risk in patients with AF have limited predictive value when applied to individual patients. One limitation is that risk scores utilize point systems that do not reflect differences in risk among included risk factors. Risk factors assigned equal point values are associated with substantially different risks, as illustrated by the following examples for the CHA DS -VASc score 2 2 ( table 1) [1]: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 6/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Age 65 to 74 years is associated with substantially greater stroke risk than other risk factors assigned one point. A history of prior stroke, transient ischemic attack, or thromboembolic event is assigned two points, but the risk associated with this risk factor is more than five times the risk associated with risk factors assigned one point. The continuous risk of age is lumped into categories, so that ages 65 years and 74 years each confer one point, despite the much higher actual risk associated with the older age. Another limitation is that the event rates observed in populations used to generate risk score may differ from those occurring in different clinical settings (eg, community versus hospitalized) and patient populations with differing risk profiles. Also, some clinical features or conditions may impact the risk of thromboembolism but are not included in risk models; these include the duration or frequency of episodes of paroxysmal AF and the presence of conditions such as chronic kidney disease and elevated troponin level. Prediabetes has also been implicated as a possible risk factor for stroke in patients with AF [40]. The potential role of troponin measurement in the assessment of the risk of embolization in patients with AF is discussed separately. (See 'Chronic kidney disease' below and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Atrial fibrillation'.) Bleeding risk When OAC is considered, the major safety concern is the increased risk of bleeding, especially major bleeding, which includes events that require hospitalization, transfusion, or surgery, or that involve particularly sensitive anatomic locations. Thus, bleeding risk and related contraindications to OAC should be reviewed ( table 2). A systematic review comparing various bleeding risk scores in patients with AF found that the HAS-BLED risk score ( table 3) was the best predictor of bleeding risk [2], although all bleeding risk scores provide imprecise estimates for individual patients, do not provide estimates for specific types of major bleeds, and are based upon bleeding risk with warfarin. Two more recent studies confirmed the efficacy of the HAS-BLED score was comparable to or better than ORBIT score in patients treated with DOACs [41,42]. Among patients with AF, the three most important predictors of major bleeding (including ICH) are overanticoagulation with warfarin (defined as an international normalized ratio greater than 3.0), prior stroke, and older patient age [31,43-45]. (See "Risks and prevention of bleeding with oral anticoagulants".) The risk of bleeding was evaluated in a cohort of over 16,000 patients diagnosed with AF between 2005 and 2010 [37]. The incidence of major bleeding with current, recent, past, or no https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 7/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate VKA (warfarin) exposure was 3.8, 4.5, 2.7, and 2.9/100 patient-years, respectively. However, major bleeding includes ICH and extracranial bleeding, particularly gastrointestinal bleeding. ICH is the most serious bleeding complication, since the likelihood of mortality or subsequent major disability is substantially higher than with bleeding at other sites [46]. In this study and others, the annual risk of ICH in patients with AF who are not anticoagulated is estimated to be 0.2 percent/year; that risk approximately doubles with OAC with VKA [34,37]. Randomized trials have shown that the risk of ICH with DOAC (both direct thrombin and factor Xa inhibitors) is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Given differences in morbidity associated with different types of bleeding, we think most patients would weigh the reduction in risk of ischemic stroke primarily against the increase in risk of ICH, with less weight given to the risk of gastrointestinal bleed or other less serious bleeding. While the incremental absolute risk of ICH with VKA (approximately 0.2 percent/year) is not trivial, it is substantially less than the expected absolute reduction in risk of ischemic stroke from OAC for most patients with AF and two or more nonsex CHA DS -VASc risk factors. 2 2 One problem with the bleeding risk scores is that they were developed from studies that included bleeds of differing severity. While any bleed can lead to death or severe disability, most do not; the major exception is ICH. The morbidity associated with ICH is similar to that for ischemic stroke, while the morbidity associated with gastrointestinal bleeding is generally not as severe. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) For patients in the following clinical settings, the bleeding risk is significantly higher: Thrombocytopenia or known coagulation defect associated with bleeding Active bleeding or recent surgery with a concern for ongoing bleeding Prior severe bleeding (including ICH) while on an oral anticoagulant Aortic dissection Malignant hypertension Combined use of anticoagulant and antiplatelet (including regular use of nonsteroidal antiinflammatory) agents SPECIFIC PATIENT GROUPS Patients with valvular heart disease For patients with valvular heart disease (excluding those with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 8/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate implantation, or a mechanical heart valve), the above general approach to deciding on oral anticoagulation (OAC) applies, although the evidence in patients with severe native valve disease is more limited than for the general population of patients with AF [47]. (See 'Approach to deciding whether to anticoagulate' above.) Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with specific valve conditions are discussed separately: 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. (See "Antithrombotic therapy for mechanical heart valves".) Transcatheter bioprosthetic valve. (See "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach'.) AF type and management Paroxysmal AF Our approach to deciding whether to anticoagulate is generally similar for patients with paroxysmal AF (PAF; with or without symptoms) as for persistent, or permanent, AF, as described above (see 'Decision-making based upon risk assessment' above). However, the burden of AF (duration and frequency of episodes) is a factor for decision-making for selected patients in whom the balance of benefit versus risk of anticoagulation is uncertain, recognizing that it may not be possible to accurately estimate AF burden except in patients with cardiac implantable electronic devices that can measure AF burden. We consider the burden of AF in decision-making for patients aged <65 years and who have one nonsex CHA DS -VASc risk 2 2 factor. On the other hand, patients with AF with past history of embolic stroke are at high risk for a recurrent thromboembolic event, so the burden of AF would generally not impact the decision to anticoagulate. (See 'Decision-making based upon risk assessment' above.) As discussed separately, the risk of thromboembolism in patients with PAF appears to be lower than in patients with persistent AF, and thromboembolic risk is higher in those with greater AF burden (percentage of time in AF). (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) There are no definitive data to establish a threshold duration of AF episodes for the initiation of anticoagulant therapy. Some of our experts recommend a single threshold for duration of AF of https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 9/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 30 seconds, and others use a threshold as long as 24 hours [48]. Those experts who do not routinely anticoagulate patients with shorter-duration AF believe that the benefit is small and potentially outweighed by the bleeding risk. However, the AF burden is likely to vary over time, so a patient with 30 seconds of AF in one monitoring period may well have 30 hours of AF in the next monitoring period. While a large proportion of patients with short episodes of AF will go on to experience longer episodes, it is also true that the reverse occurs in a sizable percentage of patients experiencing long episodes of AF [49]. Also, the extent to which thromboembolic risk may continue during periods of sinus rhythm is uncertain. (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) Rhythm versus rate control For patients with AF, the process of deciding whether to anticoagulate is generally the same regardless of the choice between rhythm control or rate control strategies. As discussed separately, the risk of thromboembolism is not reduced by clinical maintenance of sinus rhythm. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Thromboembolic risk'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Older adults For older adults, we follow the general approach described above, including careful assessment the relative benefits and risks of OAC (see 'Decision-making based upon risk assessment' above). The approach to chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) In patients with documented frequent falls but without prior trauma (eg, fracture, subdural), we weight the risks and benefits of OAC versus left atrial appendage occlusion. In this clinical setting, we often recommend OAC and work to reduce the risk of falls. The risk of falls leading to subdural hematomas is increased in older adult patients taking oral anticoagulants independent of the agent chosen. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex' and "Atrial fibrillation: Left atrial appendage occlusion".) A Taiwanese database study compared 15,756 older ( 90 years of age) adults with AF (11,064 receiving no antithrombotic therapy, 4075 receiving antiplatelet therapy, and 617 on warfarin) with 14,658 older adult patients without AF and without antithrombotic therapy [50]: Patients with AF had a greater risk of ischemic stroke (5.75 versus 3.00 percent/year; hazard ratio [HR] 1.93, 95% CI 1.74-2.14) and a similar risk of intracranial hemorrhage (ICH; 0.97 versus 0.54 percent/year; HR 0.85, 95% CI 0.66-1.09) compared with those without AF. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 10/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among patients with AF, warfarin use was associated with a lower stroke risk (3.83 versus 5.75 percent/year; HR 0.69, 95% CI 0.49-0.96) compared with no antithrombotic therapy. There was a nominal but nonsignificant increase in risk of ICH (HR 1.26, 95% CI 0.70-2.25). In a second, later cohort of patients 90 years of age with AF, 768 patients treated with warfarin were compared with 978 patients treated with a direct oral anticoagulant (DOAC) [50]. DOACs were associated with a lower risk of ICH compared with warfarin (0.42 versus 1.63 percent/year; HR 0.32, 95% CI 0.10-0.97) and similar rate of ischemic stroke (4.07 versus 4.59 percent/year; HR 1.16; 95% CI 0.61 2.22). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Older adults'.) Potential use of reduced-dose DOAC (edoxaban) in selected older adults with AF with low body weight is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) Chronic kidney disease For most patients with AF and chronic kidney disease (CKD), we follow the general approach to selection of candidates for OAC described above (see 'Approach to deciding whether to anticoagulate' above). However, some of our authors consider anticoagulation for the very uncommon CKD patient with a CHA DS -VASc score of 0 in males or 2 2 1 in females. For patients with CKD and AF, the following is our approach for deciding whether to anticoagulate ( figure 2): Stages 2, 3, and 4 and 5 (not on dialysis) For patients with estimated glomerular 2 filtration rate (eGFR) of 15 to 89 mL/min/1.73 m , our approach is similar to the general approach described above (see 'Decision-making based upon risk assessment' above), although there are very limited data for patients with end-stage kidney disease. Individualized risk assessment is performed to carefully weigh the benefits and risks of anticoagulation, with special attention to the bleeding risk associated with CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Uremic bleeding'.) Stage 5 on dialysis Among patients with end-stage kidney disease on dialysis, we anticoagulate some higher-risk individuals (based on the CHA DS VASc score) after shared 2 2- decision-making and discussion of risks and benefits between the clinician and the patient. However, it is reasonable to not anticoagulate the following groups of individuals with AF and eGFR <30 mL/min (stages 4 and 5) given our uncertainty of the benefit-to-risk ratio for antithrombotic therapy in these patients: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 11/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to

11/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to OAC with a VKA (target INR 2.0 to 3.0) [79]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because VKA lowered the annual rate of the primary endpoint compared with combined antiplatelet therapy (3.9 versus 5.6 percent; relative risk [RR] 0.69, 95% CI 0.57-0.85). The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin OAC and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [80]. After a median follow- up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined endpoint (6.8 versus 7.8 percent; RR 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent; RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy resulted in a higher rate of major bleeding (2.0 versus 1.3 percent/year; RR 1.57, 95% CI 1.29-1.92). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 14/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Aspirin monotherapy Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. In patients with AF, some but not all meta-analyses of clinical trials comparing aspirin with placebo have found that aspirin reduced the risk of stroke and systemic embolism ( table 6) [14,38,81]. In contrast, clinical trials have demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin ( table 6) [9,14-17,82-84]. Aspirin plus low-dose warfarin In contrast to therapeutic adjusted-dose warfarin (target INR 2.0 to 3.0), low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [17,85,86]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of ischemic stroke and systemic embolism than therapeutic adjusted-dose warfarin ( figure 4A-B) [85]. Aspirin plus full-dose warfarin Limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF. In a post-hoc analysis of the SPORTIF trials in patients with AF, among patients taking aspirin plus warfarin (or aspirin plus the factor Xa inhibitor ximelagatran) experienced similar rates of stroke and systemic embolism as those taking warfarin alone (or ximelagatran alone) [87]. The risk of major bleeding was higher with aspirin plus warfarin compared with warfarin alone (3.9 versus 2.3 percent/year). The management of antithrombotic therapy for patients with AF treated with OAC who have a concurrent indication for antiplatelet therapy is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Concomitant antiplatelet therapy'.) RECOMMENDATIONS OF OTHERS Recommendations for choosing which patients with atrial fibrillation should be anticoagulated are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [38,88-90]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 15/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of oral anticoagulation (OAC) in atrial fibrillation (AF) In patients with AF, OAC reduces the risk of thromboembolism by approximately two-thirds across clinical risk factor profiles but also entails an increased risk of major bleeding. Deciding whether to anticoagulate For each patient, their estimated absolute risk reduction for thromboembolic events is weighed against their estimated increase in absolute risk of intracranial hemorrhage and other life-threatening or severely debilitating bleeding complications. (See 'Approach to deciding whether to anticoagulate' above.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 16/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate CHA DS -VASc risk score Our approach to deciding whether to prescribe anticoagulant 2 2 therapy for patients with AF (excluding those with rheumatic mitral stenosis that is severe 2 or clinically significant [mitral valve area 1.5 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after implantation, or a mechanical heart valve) is as follows (see 'Approach to deciding whether to anticoagulate' above): For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC (Grade 1A). For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1): 2 2 For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC (Grade 1A). Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score 2 2 point. For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1) ( table 1), 2 2 we suggest against OAC (Grade 2C). Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' above) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). Bleeding risk For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). (See 'Bleeding risk' above.) The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated to flag high-bleeding-risk patients for early https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 17/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate review and follow-up. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) Specific patient groups Our approach to OAC for patients with AF who are older, have chronic kidney disease, hyperthyroidism, and hypertrophic cardiomyopathy can sometimes differ for patients who are younger or do not have these conditions. (See 'Specific patient groups' above.) Contraindication to OAC For patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a surgical bioprosthetic valve within the first three to six months after implantation, or a mechanical valve) with an indication for OAC but who have a contraindication for long-term OAC, the primary alternative is left atrial appendage occlusion. For such patients, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic OAC. (See 'Alternatives to anticoagulation' above and "Atrial fibrillation: Left atrial appendage occlusion".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lee CJ, Toft-Petersen AP, Ozenne B, et al. Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach. Eur Heart J Cardiovasc Pharmacother 2021; 7:f3. 2. Borre ED, Goode A, Raitz G, et al. 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Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2

63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 26/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 27/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia (platelet count <50,000/microL) Absolute platelet count, platelet count trend, and platelet function (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or planned) Type of procedure and associated bleeding risk, interval between procedure and anticoagulation Previous intracranial hemorrhage Time interval since hemorrhage and underlying cause (eg, trauma or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled hypertension Absolute blood pressure and blood pressure trend This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 28/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 29/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 30/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Benefit of warfarin in chronic atrial fibrillation Efficacy of anticoagulation with warfarin to prevent ischemic stroke and other thromboemboli in 4 major studies. An intention to treat approach was used, and transient ischemic attack and hemorrhage were excluded. The numbers at the top represent the risk reduction with warfarin therapy, which ranged from 45 to 82%. SPAF: Stroke Prevention in Atrial Fibrillation; AFASAK: Copenhagen AFASAK Study; BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation Study. The data in the warfarin group in the SPAF assumes that half of the events were attributable to warfarin toxicity. Data from: Connolly SJ, Laupacis AN, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349. Graphic 79839 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 31/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 32/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 33/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 34/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ATRIA stroke risk model point scoring system Points without prior Risk factor Points with prior stroke stroke Age, y 85 6 9 75 to 84 5 7 65 to 74 3 7 <65 0 8 Female 1 1 Diabetes 1 1 CHF 1 1 Hypertension 1 1 Proteinuria 1 1 eGFR <45 or ESRD 1 1 Possible point scores range from 0 to 12 for those without a prior stroke and from 7 to 15 for those with a prior stroke. ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease. Reprinted with permission. J Am Heart Assoc 2013; 2:e000250. Copyright 2013 American Heart Association, Inc. Graphic 90032 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 35/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 36/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Prevalence of atrial fibrillation in chronic kidney disease patients The prevalence (percent) of atrial fibrillation in the general population and different cohorts of patients with CKD are shown: While patients with peritoneal dialysis appear to suffer less frequently from atrial fibrillation, in those on hemodialysis, the prevalence was observed to be 10- to 20-fold higher than in the general population. Age was in all groups a key factor. CKD: chronic kidney disease. Reproduced with permission from: Reinecke H, Brand E, Mesters R, et al. Dilemmas in the management of atrial brillation in chronic kidney disease. J Am Soc Nephrol 2009; 20:705. Copyright 2009 American Society of Nephrology. Graphic 55373 Version 6.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 37/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Meta-analysis of randomized controlled trials of warfarin and aspirin for primary prevention of stroke in atrial fibrillation Stroke Major bleeding Comparison Odds ratio, p Odds ratio, 95 p 95% CI value percent CI value Conventional dose warfarin versus placebo 0.31 (0.19 to 0.50) <0.001 1.88 (0.88 to 4.0) 0.10 Aspirin versus placebo 0.68 (0.46 to 0.06 0.82 (0.37 to 1.78) >0.2 1.02) Conventional dose warfarin versus aspirin 0.66 (0.45 to 0.04 1.61 (0.75 to 3.44) >0.2 0.99) Conventional dose warfarin versus low dose warfarin 0.52 (0.25 to 1.08) 0.08 2.21 (0.67 to 7.25) 0.19 Conventional dose warfarin versus low dose warfarin plus aspirin 0.44 (0.14 to 1.39) 0.16 1.14 (0.55 to 2.36) >0.2 Low dose warfarin versus aspirin 1.01 (0.49 to 2.06) >0.2 1.04 (0.43 to 2.48) >0.2 NOTE: The data in this table cannot be directly applied to clinical practice (an individual patient) since the decision to use warfarin or aspirin is importantly related to a patient's estimated risk of embolic events. Adapted from McNamara RL, Tamariz LJ, Segal JB, Bass EB. Ann Intern Med 2004; 139:1018. Graphic 66736 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 38/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Low-dose warfarin plus aspirin is not optimal in high-risk AF Cumulative event rate of patients with AF at high risk for thromboembolism in the SPAF III trial. High risk was defined as the presence of at least 1 of the following: previous thromboembolism, female older than 75 years of age, heart failure or severe left ventricular systolic dysfunction, and systolic pressure >160 mmHg. There was a much lower incidence of events with standard adjusted- dose warfarin therapy (INR 2 to 3) compared with treatment with aspirin and low-dose warfarin (INR 1.2 to 1.5; p<0.0001). AF: atrial fibrillation; INR: international normalized ratio. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 72790 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 39/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Increased stroke risk with low-dose warfarin plus aspirin in AF Results from the SPAF III trial of high-risk patients showing significantly higher event rates for intracranial hemorrhage and ischemic stroke in patients treated with fixed low-dose warfarin plus aspirin compared with standard adjusted-dose warfarin. The risk was greater in those with a previous thromboembolic event. AF: atrial fibrillation. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 62833 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 40/41 7/6/23, 12:39 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 41/41

7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Use of oral anticoagulants : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Most patients with atrial fibrillation (AF) should receive long-term oral anticoagulation to decrease the risk of ischemic stroke and other embolic events. For most patients, the benefit from anticoagulation outweighs the associated increase in the risk of bleeding. The use of anticoagulant therapy for patients with AF who are not pregnant (excluding those 2 with rheumatic mitral stenosis that is moderate or severe [mitral valve area 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve) will be reviewed here. Management for patients with valve disease is briefly discussed in a section below that provides links to related topics on these specific valve conditions. (See 'Patients with valvular heart disease' below.) Related topics include: (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation for atrial fibrillation during pregnancy. (See "Supraventricular arrhythmias during pregnancy", section on 'Atrial fibrillation and flutter' and "Use of anticoagulants during pregnancy and postpartum".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 1/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO ANTICOAGULATION Choice of anticoagulant For patients with AF, we suggest the following sequential steps (related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation): Determine if anticoagulation is indicated. The identification of patients who should receive long-term oral anticoagulation is discussed separately. Prior to initiation of anticoagulant therapy, possible contraindications should be weighed ( table 1). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Select an anticoagulant. The following discussion applies to patients who are not pregnant. Selection of anticoagulant for use during pregnancy is discussed separately. (See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation' and "Use of anticoagulants during pregnancy and postpartum".) For most patients with AF with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than vitamin K antagonist (VKA; eg, warfarin). For most patients with AF who have been treated with warfarin with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to a DOAC. However, it is reasonable to continue VKA in these patients for financial or other preferences. Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include: Clinical settings in which VKA (eg, warfarin; target international normalized ratio [INR] 2.0 to 3.0; TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' below): Patients with a mechanical heart valve of any type and location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 2/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) ( table 2A-C) [1]. (See 'Drug interactions' below and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose creatinine clearance (CrCl by Cockcroft-Gault equation) is less than 25 to 30 mL/min. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting, as described below. (See 'Chronic kidney disease' below.) Evidence supporting this approach comes from randomized trials in patients with nonvalvular AF in which DOAC use resulted in similar or lower rates of both ischemic stroke and major bleeding compared with treatment with adjusted-dose warfarin (INR of 2.0 to 3.0) ( table 3) [2-8]. Important additional advantages of the DOAC agents include a high relative but small absolute reduction in the risk of intracranial hemorrhage (ICH), convenience (no requirement for routine testing of the INR), lack of susceptibility to dietary interactions, and markedly reduced susceptibility to drug interactions [3-6]. Disadvantages of DOAC include lack of efficacy and safety data in patients with severe chronic kidney disease, lack of easily available monitoring of blood levels and compliance, and higher patient cost in some health care settings. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) A meta-analysis including the RE-LY (dabigatran) [3,9], ARISTOTLE (apixaban) [5], ROCKET AF (rivaroxaban) [4], and ENGAGE AF-TIMI 48 (edoxaban) [10] trials supports the broad conclusion that DOAC agents are preferable to adjusted-dose VKA for most patients [2]. Compared with VKA (warfarin), DOAC reduced rates of mortality, stroke or systemic embolic event, and hemorrhagic stroke ( table 3). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 3/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Regarding the relative efficacy and safety of the DOAC agents, no randomized controlled trials (RCTs) directly comparing the DOACs have been published. Published observational studies have many limitations and are no substitute for head to head RCTs [11-16]. Initiation DOAC For patients with AF starting DOAC, effective anticoagulation is achieved within a few hours. We do not use heparin to bridge patients starting DOAC. For patients prescribed one of the DOACs, we suggest that clinicians review dosing recommendations from regulatory agencies and available in drug information compendia such as Lexicomp. (See 'Dosing' below.) Vitamin K antagonist Protocols for initiating VKA (eg, warfarin) are discussed separately. All patients should have an INR measured before starting therapy. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and 'Dosing' below.) For patients with AF starting VKA (eg, warfarin): With no intracardiac thrombus or prior history of thromboembolism, the risk of a thromboembolic event during the several days typically required to achieve therapeutic anticoagulation with warfarin is generally very low. Thus, it is reasonable for outpatients to initiate warfarin without low molecular weight heparin bridging. (See "Warfarin and other VKAs: Dosing and adverse effects".) With high risk of thromboembolism (eg, prior cerebrovascular event/transient ischemic attack or current intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen may be reasonable in some clinical settings (eg, patient who is hospitalized for another condition such as heart failure and has no acute stroke) although there is no high quality evidence to support this approach. Management for patients with acute stroke is discussed below. (See 'Acute stroke' below.) Dosing DOACs Dosing recommendations for DOACs are largely derived from the doses tested in the randomized clinical trials ( table 3) [3-5,10,17,18]. Given differences in the characteristics and availability of DOACs, it is important for practitioners to develop familiarity with the clinical use of multiple DOAC agents. DOACs are generally administered at fixed doses without laboratory monitoring. Use in patients with chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 4/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Use of these agents including drug interactions ( table 2A-C) and dosing in patients with chronic renal insufficiency is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.): Apixaban The dose of apixaban is 5 mg twice daily (approximately 12 hours apart) unless the patient has two or more of the following: age 80 years, body weight 60 kg, or serum creatinine level 1.5 mg/dL [133 micromol/L]). Then the dose of apixaban is 2.5 mg twice daily. This dose adjustment is for moderate renal impairment. Data are lacking to inform use in patients with CrCL <15 mL/min or on dialysis. (See 'Chronic kidney disease' below.) Dabigatran For patients with CrCl >30 mL/min, the dose is 150 mg twice daily (approximately 12 hours apart). For most patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, based upon the results of the RE-LY trial. Where available, the 110 mg twice daily dose may be preferred in patients assessed to be at increased risk of bleeding or who are particularly concerned about the risk of bleeding. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For patients with CrCL 15 to 30 mL/min, the dose is 75 mg orally, twice daily. Concomitant use of a P-gp inhibitor or antiviral should be avoided. We generally avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) For patients with CrCl <15 mL/min or on dialysis, no dosing recommendations are available. We avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) Edoxaban dosing varies according to the estimated glomerular filtration rate: For patients with a Cockcroft-Gault equation CrCl >95 mL/min, edoxaban should not be used due to lesser efficacy compared with warfarin in preventing stroke in this group due to high renal clearance. For such patients, another DOAC is an alternative. For patients with a CrCl of >50 to 95 mL/min, an edoxaban dose of 60 mg once daily is used. For patients with a CrCl of 15 to 50 mL/min, the dose is 30 mg once daily. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 5/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For patients with a CrCl of <15 mL/min, there are limited data, so edoxaban is avoided in these patients. For patients 65 years of age and with at least one of the following characteristics, the dose is 30 mg once daily: weight 60 kg or concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine). For patients with advanced age ( 80 years) and low body weight (ie, 45 kg or 60 kg plus an additional risk factor), a lower dose of edoxaban (15 mg once daily) may be safe and effective. This approach is supported by the results of the ELDERCARE-AF trial in which 984 Japanese patients age 80 years or older were randomly assigned to receive edoxaban 15 mg or placebo daily [19]. The mean body weight of participants was low (50.6 11 kg). All patients were considered inappropriate candidates for standard oral anticoagulant regimens due to one or more of the following concerns: a low CrCL ( 15 and <30 mL/min), a history of bleeding, low body weight ( 45 kg), or use of a nonsteroidal antiinflammatory drug or an antiplatelet drug. The annualized rate of stroke or systemic embolism was 2.3 and 6.7 percent in the two groups, respectively (hazard ratio [HR] 0.34, 95% CI 0.19-0.61), and the rate of major bleeding was 3.3 and 1.8 percent, respectively (HR 1.87, 95% CI 0.90-3.89). ICH was rare in both groups (0.3 and 0.6 percent). In a prespecified subanalysis of this trial, findings were largely similar across different categories of renal dysfunction (ie, mild, moderate, and severe) [20]. (See 'Older adults' below.) Rivaroxaban If the CrCl is >50 mL/min, the rivaroxaban dose is 20 mg once daily with the largest meal of the day (>500 calories), usually the evening meal. If the CrCl is 15 to 50 mL/min, the rivaroxaban dose is 15 mg once daily with the largest meal of the day (>500 calories). If the CrCl <15 mL/min, avoid use of rivaroxaban. (See 'Chronic kidney disease' below.) Vitamin K antagonist For patients with AF treated with VKA (eg, warfarin), an INR between 2.0 and 3.0 is recommended with an average annual TTR >70 percent [21,22]. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1) [23-27]. Dosing of warfarin is discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 6/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation as well as a risk factor for stroke. However, we recommend an INR between 2.0 and 3.0 for these patients as well [27]. Temporary interruption of anticoagulation Temporary interruption of oral anticoagulation for reasons of bleeding or urgent/elective surgery/invasive procedure results in an increased risk of thromboembolism after the period of effective anticoagulation has ended [28]. The optimal approach to such patients is unclear and likely depends on issues such as baseline thromboembolic risk, duration of anticoagulant interruption, and bleeding risk. These issues are discussed in detail separately. (See "Perioperative management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Use of anticoagulants during pregnancy and postpartum" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'.) The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found separately [29,30]. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The reversal of the anticoagulant effect of warfarin and DOAC agents is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) Anticoagulant failure Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'): Transesophageal echocardiographic (TEE) evidence of dense spontaneous echo contrast and low left atrial appendage ejection velocity [31]. TEE evidence of complex aortic plaque [31]. TEE-detected thrombi can be related to clinical risk factors [32]. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.) Subtherapeutic INR on VKA [33] or noncompliance in patients taking DOAC agents. Elevated D-dimer levels. In a single-center, prospective, observational study of 269 patients, D-dimer levels were elevated (at least 0.5 mcg/mL) in 23 percent, and elevated levels were significantly associated with a higher rate of thromboembolism (HR 15.8, 95% CI 3.33-75.5) [34]. Similarly, in a study of 829 patients with AF, elevated von Willebrand factor levels were associated with risk of thrombotic events [35]. However, we do not recommend routine https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 7/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate testing of D-dimer or von Willebrand factor in patients with AF, as incorporating such testing in anticoagulation decision-making has not been shown to alter outcomes in this setting. There are no studies of the optimal anticoagulation strategy for those experiencing a thromboembolic event. For those patients with a subtherapeutic INR with warfarin at the time of the event, an attempt should be made to identify the cause (compliance, drug/food interaction) and to consider switching to a DOAC if the annual TTR has been less than 70 percent [36]. For those on a twice-a-day DOAC, consideration of a once-a-day DOAC should be made if noncompliance is an issue. For those on a once-a-day DOAC, a different once-daily agent may be considered (eg, another once-daily DOAC or possibly warfarin because the INR can be followed). Though reasonable, none of these approaches is of proven benefit. Ischemic strokes with nonembolic causes occur in patients with AF as in patients without AF. These are not the target of anticoagulants. Occurrence of such a stroke is not a "failure" of anticoagulation. Other reasons for switching agents Some patients with AF may need to be switched from DOAC agent to VKA, from VKA to DOAC, or between DOAC agents for reasons other than anticoagulant failure (which is discussed above). (See 'Anticoagulant failure' above.) Reasons for switching from VKA to DOAC: As discussed above, most patients with AF treated with VKA should be switched to DOAC. (See 'Choice of anticoagulant' above.) Need for repeated invasive procedures, annual TTR <70 percent, convenience. Possible reasons for switching from DOAC to VKA: Out-of-pocket cost Development of severe kidney disease (see 'Chronic kidney disease' below) Development of a contraindication to DOAC use, as discussed above (see 'Choice of anticoagulant' above) Information on switching oral agents is provided separately ( table 4). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.) Recommendations for transitioning between DOACs and parenteral anticoagulants, including unfractionated heparin and low molecular weight heparin, are available in the individual drug https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 8/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate monographs for each DOAC. Drug interactions The individual DOACs are in varying degrees eliminated by CYP3A4 metabolism or are substrates of P-glycoprotein (P-gp) efflux pump and subject to pharmacokinetic drug interactions, although fewer in number than warfarin interactions. Drugs that inhibit CYP3A4 metabolism or P-gp efflux can increase DOAC levels (ie, greater anticoagulant effect and bleeding), whereas drugs that are inducers can decrease DOAC effect, which can lead to therapeutic failure. A detailed review of the different drug interactions can be found in tables ( table 2A-C) and the Lexicomp drug interaction program within UpToDate. Additional related content is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) SPECIFIC PATIENT GROUPS Patients with valvular heart disease The above general considerations regarding choice of anticoagulant (DOAC versus VKA) apply to patients with valvular heart disease (excluding patients with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 2 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve in any location), although the evidence in patients with severe native valve disease is more limited than for the general population of AF patients [37]. (See 'Choice of anticoagulant' above.) Some patients with valvular lesions (without heart failure), such as mitral valve prolapse, nonrheumatic moderate or severe mitral regurgitation, mitral valve repair (except for the first three to six months postoperatively), or moderate or less aortic valvular conditions, have been enrolled in clinical trials of the DOACs. These trials also included a few patients (with or without heart failure) with severe native valvular conditions who were not scheduled to undergo valve replacement. As an example, in the ARISTOTLE trial, which compared apixaban with warfarin ( table 3), approximately 26 percent of the patients had a history of moderate or severe valvular heart disease or previous valve surgery (not including placement of a mechanical heart valve) [38]. While these patients had higher rates of stroke and systemic embolism than those without, the benefits of a lower rate of stroke/systemic embolism and major bleeding with apixaban (compared with warfarin) were similar to those without valvular heart disease. Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with the following specific valve conditions are discussed separately: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 9/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Antithrombotic therapy for mechanical heart valves" and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve in any location. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. The choice of anticoagulant after surgical valve procedures is discussed separately. (See "Antithrombotic therapy for mechanical heart valves" and 'Choice of anticoagulant' above.) Transcatheter bioprosthetic valve. The choice of anticoagulant after transcatheter valve procedures is discussed separately. (See 'Choice of anticoagulant' above and "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach' and "Transcatheter mitral valve repair", section on 'Antithrombotic therapy'.) Older adults For most older patients, including those over the age of 75 years, we prefer DOACs (also referred to as non-vitamin K oral anticoagulants [NOACs]) to warfarin because of the reduced risk of intracranial hemorrhage versus warfarin. Since there are no head to head randomized trials comparing DOACs in this patient group, we do not have a preference for a specific DOAC. Dose adjustment should be made if the patient meets relevant criteria such as renal function for the DOAC. The results of the ELDERCARE-AF trial are discussed separately. (See 'Dosing' above and 'Chronic kidney disease' below.) Chronic kidney disease Who to anticoagulate Our approach to deciding which AF patients with chronic kidney disease (CKD) to anticoagulate is presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) Choice of anticoagulant For patients with AF and CKD stage G2 or G3 ( figure 2) treated with oral anticoagulation, most of our contributors choose a DOAC rather than VKA. However, the evidence to support this choice in patients with CKD is limited [39-43]. One contributor prefers VKA in this setting given wider clinical experience. For patients with AF and severe kidney disease (stage G4 or G5; estimated glomerular filtration 2 rate <30 mL/min/1.73 m ), on dialysis, or with acute renal injury, DOAC is generally avoided and VKA is generally the preferred long-term anticoagulant. Patients with stage 4 and 5 CKD are at higher risk of having unpredictable sudden deterioration in renal function than patients with https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 10/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate normal renal function, and such deterioration could cause an abrupt reduction in clearance of a DOAC that depends on renal metabolism. In such a setting, use of an agent such as warfarin that allows for therapeutic drug monitoring may be preferred. An annual time in the therapeutic range of >70 percent is desirable. (See "Direct oral anticoagulants (DOACs) and parenteral direct- acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) If a DOAC is chosen for a patient with stage 4 or 5 CKD or on dialysis, our contributors prefer apixaban, in part because apixaban is less dependent on kidney function for clearance than other DOACs available in the US ( table 2A). The support for use of apixaban in these patients is largely based upon our clinical experience and observational studies [40,41]. In a subgroup analysis of the ARISTOTLE trial in patients with creatinine clearance (CrCl) 25 to 30 mL/min, the risk of major bleeding was significantly less with apixaban compared with warfarin (hazard ratio [HR] 0.34, 95% CI 0.14-0.80) [41]. We avoid dabigatran in patients with stage 4 or 5 CKD because a high percentage of the drug is renally cleared. These issues are discussed further separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Based upon pharmacokinetic modeling, the US Food and Drug Administration approved DOAC dosing for use in selected patients with CKD based upon Cockcroft-Gault CrCl as described above (see 'Dosing' above). Patients at risk for gastrointestinal bleeding Risk factors for gastrointestinal bleeding in patients on oral anticoagulants have been identified. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastrointestinal'.) Choosing apixaban or dabigatran over rivaroxaban or warfarin may be prudent to prevent major bleeding outcomes in AF patients at high risk of gastrointestinal bleeding. In a subgroup analysis of the ARISTOPHANES observational study, 381,054 individuals anticoagulated for nonvalvular AF and who were at high risk of gastrointestinal bleeding were followed for major bleeding outcomes [44]. Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major bleeding (apixaban: HR 0.59, 95% CI 0.56-0.63; dabigatran: HR 0.78, 95% CI 0.70-0.86), whereas rivaroxaban was associated with a higher gastrointestinal bleeding risk (HR 1.11, 95% CI 1.05-1.16). Acute stroke Recommendations for the management (including the role of antithrombotic therapy) of patients with AF with an acute stroke are presented separately. Patients with AF for whom anticoagulant therapy is being considered and who have had an ischemic stroke within 30 days should be referred to a neurologist or other clinician who is experienced in managing https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 11/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate antithrombotic care in such patients. Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke is generally avoided as studies have shown that such treatment causes more harm than good (See "Stroke in patients with atrial fibrillation" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Concomitant antiplatelet therapy For patients with indications for both anticoagulant for AF and for antiplatelet therapy (for a concurrent condition), any potential benefit must take into account an increased risk of bleeding with concomitant antiplatelet and anticoagulant therapy. The combination of antiplatelet and anticoagulant increases the risk of bleeding compared with either alone [45]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) The potential use of both anticoagulant and antiplatelet therapies in patients with AF is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients" and "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The issue of whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF is discussed in detail separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The impact of antiplatelet therapy on bleeding (and efficacy) outcomes in patients taking either warfarin or dabigatran was evaluated in a post-hoc subgroup analysis of the RE-LY trial (see 'Choice of anticoagulant' above) in which approximately 40 percent of patients were taking concomitant aspirin or clopidogrel at some point during the study [46]. Very few patients were taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct

taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct factor Xa inhibitors (eg, apixaban, edoxaban, and rivaroxaban). DOACs are generally https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 15/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate administered at fixed doses without laboratory monitoring. Given differences in the characteristics and availability of DOACs, it is important for clinicians to be familiar with the clinical use of multiple DOAC agents ( table 2A and table 3). (See 'DOACs' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.) Target INR For patients with AF treated with VKA (eg, warfarin), the target INR is between 2.0 and 3.0 with an average annual TTR 70 percent. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1). (See 'Vitamin K antagonist' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bellesini M, Bianchin M, Corradi C, et al. Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review. Clin Drug Investig 2020; 40:1001. 2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. 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J Am Coll Cardiol 2010; 55:2225. 35. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 36. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 37. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 38. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015; 132:624. 39. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. 40. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation 2018; 138:1519. 41. Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020; 141:1384. 42. Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020; 223:3. 43. Su X, Yan B, Wang L, et al. Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis. Am J Kidney Dis 2021; 78:678. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 19/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 44. Lip GYH, Keshishian AV, Zhang Y, et al. Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 2021; 4:e2120064. 45. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185. 46. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. 49. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 50. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1031 Version 139.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 20/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate GRAPHICS Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (platelet count <50,000/microL) (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or Type of procedure and associated bleeding risk, interval between procedure and anticoagulation planned) Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma hemorrhage or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled Absolute blood pressure and blood pressure trend hypertension This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 21/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic Anticoagulant Bioavailability and Half-life drug clearance* interactions* Dabigatran 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase (Pradaxa) kidney dabigatran effect Unaffected by Prolonged food P-gp with kidney P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact and requires adults effect gastric acidity for absorption Avoidance of some combinations or dose adjustment may be needed Apixaban (Eliquis) 50% bioavailable 27% cleared by the kidney 12 hours Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect Prolonged in older adults Unaffected by food Metabolized, primarily by CYP3A4 Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase (Savaysa, Lixiana) edoxaban effect Unaffected by Reduced Prolonged in food efficacy in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 22/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate and CrCl >95 dose adjustment mL/minute may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% bioavailable Prolonged to 11 to 13 inhibitors can increase Metabolized, primarily by CYP3A4 hours in older adults Unaffected rivaroxaban effect by food P-gp substrate* 20 mg dose: Strong CYP3A4 66% inducers and/or P-gp inducers can decrease rivaroxaban bioavailable if taken when fasting; increased if taken with food effect Avoidance of some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 23/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown. [1] Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 24/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate Strong inducers Moderate inducers inhibitors Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone therapy pack Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- Netupitant Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 25/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]).

Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 30/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 31/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 32/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 33/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Switching between oral anticoagulants Switching from a DOAC to warfarin Dabigatran Overlap warfarin with dabigatran for 3 days (normal renal function); 2 days (CrCl 30 to 50 mL/min); or 1 day (CrCl 15 to 30 mL/min); note that dabigatran can contribute to INR elevation. or- Overlap warfarin with dabigatran until the INR is therapeutic on warfarin (ASH).* Apixaban If continuous anticoagulation is needed, discontinue apixaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that apixaban can contribute to INR elevation. or- Overlap warfarin with apixaban until the INR is therapeutic on warfarin, testing right before the next apixaban dose to minimize the effect of apixaban on INR elevation (ASH).* Edoxaban Reduce dose by half (eg, from 60 to 30 mg daily or from 30 to 15 mg daily) and begin warfarin concurrently (PI). Discontinue edoxaban when the INR is 2; note that edoxaban can contribute to INR elevation. or- Discontinue edoxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). or- Overlap warfarin with edoxaban until the INR is therapeutic on warfarin, testing right before the next edoxaban dose to minimize the effect of edoxaban on INR elevation (ASH).* Rivaroxaban Discontinue rivaroxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that rivaroxaban can contribute to INR elevation. or- Overlap warfarin with rivaroxaban until the INR is therapeutic on warfarin, testing right before the next rivaroxaban dose to minimize the effect of rivaroxaban on INR elevation (ASH).* Switching from warfarin to a DOAC Dabigatran Stop warfarin, monitor the PT/INR, and start dabigatran when the INR https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 34/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate is <2 (PI). Apixaban Stop warfarin, monitor the PT/INR, and start apixaban when the INR is <2 (PI). Edoxaban Stop warfarin, monitor the PT/INR, and start edoxaban when the INR is 2.5 (PI). Rivaroxaban Stop warfarin, monitor the PT/INR, and start rivaroxaban when the INR is <3 (PI). Switching from one DOAC to a different DOAC Any DOAC Start the second DOAC when the next dose of the first DOAC would have been due; do not overlap. This table presents a reasonable approach to switching between oral anticoagulants. It does not substitute for clinical judgment regarding individual patient risks of thrombosis and bleeding. Individuals switching from a DOAC to warfarin are more likely to require continuous anticoagulation if they have had a recent thromboembolic event or if they are at especially high risk of thromboembolism. Refer to UpToDate topics on specific indications, perioperative management, and the use of DOACs and warfarin for further details. DOAC: direct oral anticoagulant; CrCl: creatinine clearance; INR: international normalized ratio; ASH: American Society of Hematology clinical practice guideline; PI: package insert; PT: prothrombin time. Two to three days of overlap after the INR becomes therapeutic may be needed in individuals with higher thrombosis risk, because the PT/INR will enter the therapeutic range before full anticoagulation occurs. In individuals overlapping warfarin and a DOAC, the DOAC may contribute to INR elevation. Prepared with information from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. PRADAXA (dabigatran etexilate mesylate) capsules. US FDA approval 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf (Accessed on April 25, 2019). 3. ELIQUIS (apixaban) tablets. US FDA approval 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s020lbl.pdf (Accessed on April 25, 2019). 4. SAVAYSA (edoxaban) tablets. US FDA approval 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206316s012lbl.pdf (Accessed on April 25, 2019). 5. XARELTO (rivaroxaban) tablets. US FDA approval 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022406s030s032lbledt.pdf (Accessed on April 25, 2019). Graphic 120639 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 35/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 36/37 7/6/23, 12:46 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 37/37

7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Long-term antithrombotic therapy for the secondary prevention of ischemic stroke : Brett L Cucchiara, MD, Steven R Mess , MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 08, 2023. INTRODUCTION Antiplatelet therapy is used for both the management of acute ischemic stroke and for the prevention of stroke. Antiplatelet therapy reduces the incidence of stroke in patients at high risk for atherosclerosis and in those with known symptomatic cerebrovascular disease. Antiplatelet therapy for secondary stroke prevention will be reviewed here. Antiplatelet therapy for acute ischemic stroke and for primary stroke prevention is discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Overview of primary prevention of cardiovascular disease".) Prevention of recurrent stroke with antithrombotic therapy in patients with atrial fibrillation is reviewed elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) IMMEDIATE TREATMENT Short-term antithrombotic therapy after acute ischemic stroke or transient ischemic attack (TIA) may differ from long-term therapy. Antithrombotic treatment for patients in the first days to weeks after the onset of acute ischemic stroke or TIA, including the short-term use of dual antiplatelet therapy, is summarized in the algorithms ( algorithm 1 and algorithm 2) and discussed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 1/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Importantly, despite evidence of benefit with short-term use in acute ischemic stroke, aspirin and clopidogrel should not be used in combination for long-term stroke prevention, given the lack of greater efficacy compared with either agent alone, and given the substantially increased risk of bleeding complications. (See 'Aspirin plus clopidogrel' below.) LONG-TERM TREATMENT Choosing therapy For the long-term secondary prevention of stroke in patients with a history of noncardioembolic ischemic stroke or transient ischemic attack (TIA) of atherothrombotic, lacunar (small vessel occlusive type), or cryptogenic type, we recommend treatment with an antiplatelet agent using either aspirin, clopidogrel, or aspirin-extended-release dipyridamole. (See 'Aspirin' below and 'Clopidogrel' below and 'Aspirin plus dipyridamole' below.) The choice between aspirin, clopidogrel, and aspirin-extended-release dipyridamole is dependent mainly on patient tolerance, contraindications, availability, and cost. All three are acceptable options for preventing recurrent noncardioembolic ischemic stroke [1,2]. We suggest antiplatelet therapy using either clopidogrel (75 mg daily) as monotherapy or the combination of aspirin-extended-release dipyridamole (25 mg/200 mg twice a day), rather than aspirin alone [1]. Compared with aspirin for the long-term secondary prevention of serious vascular events (ie, nonfatal stroke, nonfatal myocardial infarction, or vascular death), the benefit appears to be modestly greater with clopidogrel alone and with aspirin-extended-release dipyridamole [3]. (See 'Clopidogrel' below and 'Aspirin plus dipyridamole' below.) Nevertheless, aspirin is often used as the first-line agent [4], given that the apparent modest advantage in benefit of alternative antiplatelet regimens (clopidogrel or aspirin-extended- release dipyridamole) is potentially offset by a disadvantage in cost and access, since aspirin is available without a prescription. In addition, headache and gastrointestinal symptoms have limited the use of aspirin-extended-release dipyridamole [4]. Aspirin use is also associated with a decreased risk of colorectal cancer. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer" and "Aspirin in the primary prevention of cardiovascular disease and cancer".) Other antiplatelet agents have a more limited role. Cilostazol is a reasonable option for patients of East Asian ethnicity or for patients with allergies that preclude use of the other recommended antiplatelet medications, but there are no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-East Asian ethnic groups. Also, the twice daily dosing, lower tolerability, and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention. (See 'Cilostazol' below.) https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 2/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is another reasonable treatment option for some patients with non-lacunar, non-cardioembolic ischemic stroke and evidence of systemic atherosclerosis. (See 'Combination antiplatelet and anticoagulant therapy' below.) Specific clinical situations Antiplatelet intolerance or allergy Clopidogrel is an appropriate option for patients unable to tolerate aspirin (including the combination drug aspirin-extended-release dipyridamole) due to allergy or gastrointestinal upset. Cilostazol is a reasonable option if the other agents are not available or tolerated. Ticagrelor is another option for the small subset of patients who cannot take another first-line agent; examples include a patient allergic to aspirin who is also intolerant of clopidogrel or has a clopidogrel CYP2C19 poor metabolizer genotype. (See 'Clopidogrel resistance' below.) Patients having carotid revascularization Most patients having carotid endarterectomy are treated with aspirin (81 to 325 mg daily) monotherapy started before surgery and continued indefinitely, barring a long-term indication for anticoagulation such as concomitant atrial fibrillation, while most patients having carotid stenting are treated with aspirin plus clopidogrel for 30 days, followed by long-term single-agent antiplatelet therapy ( algorithm 1 and algorithm 2). The use of antiplatelet therapy for patients undergoing carotid endarterectomy or carotid stenting is discussed in greater detail separately. (See "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Patients of East Asian ethnicity Randomized controlled trial data support the safety and efficacy of cilostazol for secondary stroke prevention in East Asian populations. Therefore, cilostazol is a reasonable antiplatelet treatment option for patients of East Asian ethnicity. Efficacy may be similar in non-East Asian populations, but data are extremely limited. (See 'Cilostazol' below.) Patients with an indication for anticoagulation In general, patients with a history of ischemic stroke or TIA due to atrial fibrillation or another condition that requires anticoagulation are not treated with antiplatelet therapy due to the increased risk of bleeding. Note that a history of cryptogenic stroke, including embolic stroke of undetermined source (ESUS), is generally not an indication for anticoagulation, and antiplatelet therapy is preferred in most such cases. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Lack of benefit with anticoagulation'.) https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 3/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Patients with coronary artery disease Some patients with coronary artery disease have indications for up to 12 months of dual antiplatelet therapy (eg, recent coronary artery stent placement, acute coronary syndrome) or combined antiplatelet and anticoagulant therapy, as reviewed elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".) Decisions regarding antithrombotic therapy for these patients should be individualized in consultation with neurology and cardiology, while accounting for patient preferences. Limited role of long-term dual antiplatelet therapy for stroke prevention For the vast majority of patients with a noncardioembolic stroke or TIA, we recommend not using aspirin and clopidogrel in combination for long-term stroke prevention, given the lack of greater efficacy for dual therapy compared with either medicine alone and the substantially increased risk of bleeding complications. (See 'Dual antiplatelet therapy' below.) Treatment with combination antiplatelet therapy has a limited role in other settings. As examples, selected patients with a recent acute myocardial infarction, other acute coronary syndrome, or arterial stent placement, including carotid stenting, are treated with aspirin plus an oral platelet P2Y receptor blocker (ie, clopidogrel, ticagrelor, or prasugrel). In these settings, 12 most patients are not treated with dual therapy indefinitely; the exact duration is influenced by the assessment of bleeding and ischemic risks. Importantly, prasugrel is generally avoided due to an increased risk of bleeding in patients with a history of TIA or stroke, and there are essentially no long-term data for the use of ticagrelor in patients with a history of TIA or stroke. Recommendations for combination antiplatelet therapy in these settings are discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non- ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Prevention of gastroduodenal toxicity For patients at increased risk of gastroduodenal toxicity from antiplatelet agents, particularly those 75 years of age or older, it is reasonable to coadminister a proton pump inhibitor [5]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".) Risk of stopping antiplatelet treatment Stopping antiplatelet therapy in high-risk patients may itself increase the risk of stroke. One study found that 13 of 289 patients hospitalized with https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 4/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate cerebral infarction had recently stopped antiplatelet therapy; most had been taking aspirin [6]. In all 13, the antiplatelet agent had been discontinued within 6 to 10 days of stroke onset, a time course consistent with the known lifespan (approximately 10 days) of inhibited platelets. Additionally, a case-control study comparing 309 patients with stroke to 309 matched controls found that discontinuation of aspirin was associated with a significantly increased risk of TIA or ischemic stroke (odds ratio 3.4, 95% CI 1.08-10.63) [7]. Antiplatelet treatment failure Treatment failure is defined by the occurrence of a thrombotic or ischemic event (eg, stroke, TIA, or other cardiovascular occlusive event) despite adherence to antiplatelet therapy at recommended doses. Some experts prefer the term "breakthrough stroke" for a stroke that occurs despite antiplatelet therapy [8]. Explanations Possible explanations for antiplatelet treatment failure include antiplatelet nonresponsiveness or resistance, alternative mechanisms of stroke, poor control of modifiable comorbid stroke risk factors (eg, hypertension, diabetes mellitus, dyslipidemia, smoking, inadequate exercise), and presence of nonmodifiable risk factors (eg, increased age). Nonadherence to antiplatelet treatment is believed to be the most frequent cause of apparent antiplatelet resistance [9]. The issues of nonresponse and resistance to aspirin, and the effect of enteric coating on antiplatelet activity, are reviewed in detail elsewhere. (See "Nonresponse and resistance to aspirin" and "Clopidogrel resistance and clopidogrel treatment failure".) Re-evaluation In cases of antiplatelet treatment failure, it is important to determine the correct mechanism of stroke, including a thorough evaluation for mechanisms that are unlikely to be optimally treated with antiplatelet therapy. These include atrial fibrillation, paradoxical embolism, hemodynamic insufficiency, inflammatory or infectious vasculopathies, hypercoagulable states (eg, due to cancer), and certain genetic disorders [8]. Role of laboratory testing There is no proven role for routinely evaluating patients with antiplatelet treatment failure for aspirin or clopidogrel resistance, whether by laboratory assessment or by genetic testing. (See "Nonresponse and resistance to aspirin", section on 'Laboratory testing' and "Clopidogrel resistance and clopidogrel treatment failure", section on 'Screening'.) Treatment considerations The optimal antiplatelet strategy for breakthrough ischemic stroke is unknown [8]. Options include modifying the antiplatelet regimen by switching to another antiplatelet agent or continuing the existing regimen. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 5/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate When the most likely mechanism is noncardioembolic ischemic stroke, short-term dual antiplatelet therapy with aspirin plus clopidogrel may be indicated in the acute phase, as illustrated by the algorithm ( algorithm 2 and algorithm 1), followed by long-term single agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyridamole. In general, we suggest switching to a different antiplatelet agent from the one that the patient was taking when the most recent stroke occurred. It is also important to optimize the treatment of other major cardiovascular risk factors (eg, hypertension, dyslipidemia, diabetes). These issues are discussed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment by ischemic mechanism' and "Overview of secondary prevention of ischemic stroke".) ANTIPLATELET AGENTS Aspirin Aspirin, the most commonly used antiplatelet agent, inhibits the enzyme cyclooxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation. This interferes with the formation of thrombi, thereby reducing the risk of stroke. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) Aspirin is a first-line antiplatelet agent for the secondary prevention of ischemic stroke. (See 'Long-term treatment' above.) Efficacy The effectiveness of aspirin for preventing ischemic stroke and cardiovascular events is supported by high-quality data. A 2002 meta-analysis from the Antithrombotic Trialists Collaboration (ATC) included 195 randomized controlled trials of high-risk patients found that antiplatelet treatment led to a 25 percent relative risk reduction in nonfatal stroke compared with placebo [10]. Among the subset of patients with prior cerebrovascular disease (transient ischemic attack [TIA] or stroke), antiplatelet therapy reduced the risk of recurrent stroke, myocardial infarction (MI), or vascular death by 22 percent; the absolute benefit was 36 events prevented per 1000 patients treated for 29 months. The benefit of antiplatelet therapy was independent of sex, age (greater or less than 65), diabetes, and hypertension. Similarly, a 2009 ATC meta-analysis of 16 placebo-controlled secondary prevention trials showed that aspirin reduced the risk of any serious vascular event by 19 percent and reduced the risk of ischemic stroke by 22 percent [11]. In addition to its benefit for secondary stroke prevention, treatment with aspirin decreases the risk of other cardiovascular events in a wide range of patients with established disease. Furthermore, there is considerable evidence that long-term aspirin use reduces the risk of death https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 6/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate from certain cancers. (See "Overview of cancer prevention", section on 'Aspirin and other antiinflammatory drugs' and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) Early benefit In a 2016 pooled analysis of data from over 15,000 subjects in 12 trials evaluating aspirin for secondary prevention, the benefit of aspirin was strongest in the early weeks after TIA or ischemic stroke [12]. Aspirin reduced the relative risk of recurrent ischemic stroke within the first six weeks by 58 percent (1 versus 2.4 percent, absolute risk reduction 1.4 percent, hazard ratio [HR] 0.42, 95% CI 0.32-0.55). The benefit of aspirin in this time frame was greatest for the subgroup of patients with TIA or minor stroke (relative risk reduction of 80 percent, absolute risk reduction 0.7 percent, HR 0.19, 95% CI 0.11-0.34). Although the included secondary prevention trials treated few patients in the first days after the index stroke or TIA, similar risk reductions with aspirin were found in trials of aspirin for acute stroke and TIA, as reviewed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of aspirin'.) Dose of aspirin Given the apparent equivalent benefit of different doses of aspirin for ischemic stroke prevention, and the increased risk of bleeding complications with higher dose aspirin discussed below, we suggest a dose of 50 to 100 mg/day when using aspirin for the secondary prevention of noncardioembolic ischemic stroke. This recommendation is similar to the dose of 75 to 100 mg/day recommended by 2012 guidelines from the American College of Chest Physicians [1]. The 2021 American Heart Association/American Stroke Association guidelines recommend a dose of 50 to 325 mg daily [2]. Dose and efficacy The dose of aspirin in secondary stroke prevention studies ranged between 20 to 1300 mg. Most studies have found that 50 to 325 mg/day of aspirin is as effective as higher doses [10,13-18]. Furthermore, lower doses within this range appear to provide the same benefit as higher doses [10,14,18,19]. As an example, a review of 195 trials of secondary prevention by the ATC showed that doses of 75 to 150 mg/day produced the same risk reduction, compared with placebo, as doses of 150 to 325 mg/day [10]. In the ATC analysis of trials directly comparing aspirin <75 mg/day with aspirin 75 mg/day, there was no significant difference in effectiveness between the two regimens. Even lower doses may be effective, as demonstrated in the Dutch TIA Trial [20]. This study found similar efficacy for stroke prevention with 30 mg compared with 283 mg of aspirin per day in patients who had had a TIA or minor ischemic stroke. In the European Stroke Prevention Study-2 (ESPS-2), 50 mg of aspirin daily reduced stroke risk by 18 percent compared with placebo (29 strokes prevented per 1000 treated), an effect of comparable magnitude to the other trials cited above [14]. This benefit seen with very low-dose aspirin https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 7/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate is consistent with laboratory observations that 30 mg of aspirin per day results in complete suppression of thromboxane A2 production [21]. Dose and risk of bleeding Lower doses of aspirin appear to be associated with less gastrointestinal toxicity [13,20,22]. In the United Kingdom TIA trial, for example, gastrointestinal hemorrhage occurred in 1.6 percent of patients on placebo, 2.6 percent on 300 mg aspirin, and 4.7 percent on 1200 mg aspirin [13]. A similar dose relationship was seen for milder gastrointestinal symptoms. In an analysis of data from 31 randomized, controlled trials, aspirin doses 200 mg/day were associated with a significantly lower rate of major bleeding events compared with higher doses [23]. However, there was no difference in major bleeding when aspirin <100 mg/day was compared with 100 to 200 mg/day. When the overall rate of bleeding complications (including major, minor, and insignificant events) was considered, aspirin <100 mg/day was associated with a lower risk compared with the 100 to 200 mg/day and >200 mg/day groups. A later meta-analysis of 22 randomized trials of low-dose aspirin (75 to 325 mg/day) versus placebo for cardiovascular prophylaxis reached similar conclusions within the low-dose range [24]. Compared with placebo, aspirin increased the relative risk of any major bleeding, major gastrointestinal bleeding, and intracranial bleeding by 1.7- to 2.1-fold. However, the absolute annual increase in risk for any major bleeding episode (mostly gastrointestinal) and for intracranial bleeding was 0.13 and 0.03 percent, respectively. Furthermore, there was no evidence of an increased risk of bleeding with "high" low-dose aspirin (>162 to 325 mg/day) compared with "low" low-dose aspirin (75 to 162 mg/day). Aspirin resistance Proposed mechanisms of aspirin resistance include reduced bioavailability (eg, poor compliance with therapy, reduced absorption, use of enteric-coated aspirin, inadequate dosing, drug interactions), genetic variability (eg, polymorphisms affecting cyclooxygenase-1 [COX-1], cyclooxygenase-2 [COX-2], thromboxane A2 synthase), and other factors (eg, increased isoprostane activity, accelerated platelet turnover from inflammation, infection, surgery, or stress) [8]. There is no established role for routine testing of patients for aspirin resistance/nonresponsiveness. Aspirin nonresponsiveness is rare in compliant patients and is not strongly associated with clinical outcomes in published studies. (See "Nonresponse and resistance to aspirin".) Adverse effects The main adverse effects of aspirin involve gastrointestinal toxicity (eg, ulceration, erosion) and an increased risk of gastrointestinal, intracranial, and systemic bleeding. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 8/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Other adverse effects include renal complications (eg, renal insufficiency and renal failure), angioedema, bronchospasm, rash, hearing loss, tinnitus, hepatoxicity, and both allergic and pseudoallergic reactions. Salicylate toxicity may occur when higher salicylate levels are achieved. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".) The potential use of aspirin desensitization to allow for the chronic use of aspirin in individuals who are known to be sensitive or "allergic" is discussed separately. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".) Clopidogrel Clopidogrel is a thienopyridine that inhibits adenosine diphosphate (ADP)- dependent platelet aggregation. Clopidogrel is a first-line antiplatelet agent for the secondary prevention of ischemic stroke. (See 'Long-term treatment' above.) Efficacy The CAPRIE trial randomly assigned 19,185 patients with recent stroke, MI, or symptomatic peripheral artery disease (divided roughly equally between these three enrolling diseases) to treatment with aspirin (325 mg) or clopidogrel (75 mg) [25]. The primary end point, a composite outcome of stroke, MI, or vascular death, was significantly reduced with clopidogrel treatment compared with aspirin treatment (5.3 versus 5.8 percent annually, relative risk reduction 8.7 percent, 95% CI 0.3-16.5 percent, absolute risk reduction 0.5 percent). The benefit of clopidogrel over aspirin in the CAPRIE trial varied based on enrolling disease [25]. Most of the benefit was observed in patients with peripheral artery disease, and the difference in composite outcome between clopidogrel and aspirin treatment in patients with recent stroke and MI was not significant. However, the strength of these observations is limited since they are based on subgroup analyses. Dose The usual dose of clopidogrel monotherapy for secondary stroke prevention is 75 mg daily. Clopidogrel resistance Polymorphisms in the hepatic enzymes involved in the metabolism of clopidogrel (eg, CYP2C19, CYP1A2, CYP3A4) or within the platelet P2Y receptor may affect 12 the ability of clopidogrel to inhibit platelet aggregation. However, there are no convincing prospective data to support routine testing for clopidogrel resistance with in vitro tests of platelet function or genotyping in patients with cardiovascular disease, particularly for those with a history of stroke or TIA, and the role of platelet function testing remains unclear [2]. The issue of resistance/nonresponse to clopidogrel in cardiovascular disease is discussed in greater detail separately. (See "Clopidogrel resistance and clopidogrel treatment failure".) Adverse effects The side effect profile of clopidogrel is favorable compared with aspirin, with a slightly higher frequency of rash and diarrhea, but a slightly lower frequency of gastric https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 9/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate upset or gastrointestinal bleeding [24]. Unlike its close relative ticlopidine (see 'Ticlopidine' below), severe neutropenia is not seen more frequently with clopidogrel than with aspirin [25]. Aspirin plus dipyridamole Dipyridamole impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides, and cyclic adenosine monophosphate (AMP). Dipyridamole may also cause vasodilation. The discussion below is focused on the role of the combination drug aspirin-extended-release dipyridamole, which is a first-line agent for the secondary prevention of ischemic stroke (see 'Long-term treatment' above). Immediate-release dipyridamole is not routinely recommended for secondary prevention of ischemic stroke, given the limited evidence supporting its effectiveness and the significant pharmacokinetic differences between it and extended-release dipyridamole. Efficacy The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive such that the combination of aspirin-extended-release dipyridamole is more effective than aspirin alone [14,26,27] and similar in effectiveness to clopidogrel [28]. More effective than aspirin In a meta-analysis of six randomized trials with 7648 patients, stroke risk was significantly reduced with aspirin plus dipyridamole (including immediate- and extended-release formulations of dipyridamole) compared with aspirin alone (relative risk 0.77, 95% CI 0.67-0.89) [26]. Nearly 80 percent of the patients in this meta-analysis came from just two trials, ESPS-2 and ESPRIT. The ESPS-2 trial randomly assigned 6602 patients with a recent TIA or ischemic stroke to one of four groups: 200 mg extended-release dipyridamole alone given twice daily; 25 mg aspirin alone given twice daily; a combination of 25 mg aspirin plus 200 mg extended- release dipyridamole given twice daily; or placebo [14]. At 24 months of follow-up, the risk of stroke compared with placebo was reduced for both extended-release dipyridamole monotherapy (odds ratio [OR] 0.81, 95% CI 0.76-0.99) and aspirin monotherapy (OR 0.79, 95% CI 0.65-0.97). The benefit of combination aspirin-extended-release dipyridamole was greater still than the two components alone and greater than placebo (OR 0.59, 95% CI 0.48-0.73). The stroke rate was lower in the aspirin-extended-release dipyridamole group compared with the aspirin alone group (9.9 versus 12.9 percent, absolute risk reduction 3 percent) [14]. There was no difference in the risk of death or bleeding complications between the two groups, whereas both groups experienced a greater frequency of bleeding complications than the placebo group. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 10/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate In the later ESPRIT trial, 2739 patients within six months of a TIA or minor stroke of presumed arterial origin were randomly assigned to open-label treatment with aspirin (30 to 325 mg/day) alone or aspirin plus dipyridamole (200 mg twice daily). The median aspirin dose was 75 mg/day in both treatment groups, and the dipyridamole formulation used by most patients (83 percent) was extended release rather than immediate release [27]. Over a mean follow-up of 3.5 years, the composite primary outcome (death from all vascular causes, nonfatal stroke, nonfatal MI, or major bleeding complication) was less frequent in the aspirin plus dipyridamole group than the aspirin alone group (13 versus 16 percent, HR 0.80, 95% CI 0.66-0.98, absolute risk reduction 1.0 percent per year). Efficacy similar to clopidogrel The PRoFESS trial showed that clopidogrel monotherapy and aspirin-extended-release dipyridamole have similar risks and benefits for secondary stroke prevention [28]. The trial enrolled 20,332 patients with noncardioembolic ischemic stroke and randomly assigned them to treatment with either aspirin-extended-release dipyridamole (25/200 mg twice daily) or clopidogrel (75 mg once daily). At an average follow-up of 2.5 years, there was no difference between treatment with aspirin-extended- release dipyridamole or clopidogrel for the outcome of recurrent stroke (9.0 versus 8.8 percent, HR 1.01, 95% CI 0.92-1.11) or the composite outcome of stroke, MI, or vascular death (13.1 versus 13.1 percent, HR 0.99, 95% CI 0.92-1.07). Despite the nearly identical event rates for these outcomes, the trial failed to meet the prespecified noninferiority criteria for treatment with aspirin-extended-release dipyridamole. Among patients who had recurrent strokes, the rate of recurrent ischemic stroke was slightly lower in those assigned to aspirin-extended-release dipyridamole compared with clopidogrel (7.7 versus 7.9 percent), but hemorrhagic strokes were slightly increased (0.9 versus 0.5 percent). Thus, the net risk (ie, the combination of recurrent stroke plus major hemorrhage) was similar between aspirin-extended-release dipyridamole and clopidogrel (11.7 versus 11.4 percent; HR 1.03, 95% CI 0.95-1.11). New or worsening heart failure was slightly less frequent in patients assigned to aspirin- extended-release dipyridamole compared with those assigned to clopidogrel; the difference was significant (1.4 versus 1.8 percent, 95% CI 0.62-0.96). PRoFESS had a 2x2 factorial design in which the patients were also randomly assigned to telmisartan or placebo, the results of which are discussed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".) Dose Aspirin-extended-release dipyridamole, containing aspirin (25 mg) plus extended- release dipyridamole (200 mg), is given two times per day. Dipyridamole is also available as an https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 11/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate immediate-release form, usually given as 50 to 100 mg three times per day, but this is seldom used alone for secondary stroke prevention. The specific dipyridamole preparation may be important. In a meta-analysis cited above, the combination of aspirin and immediate-release dipyridamole was nonsignificantly better than aspirin alone for secondary prevention of stroke (relative risk 0.83, 95% CI 0.59-1.15) [26]. By contrast, extended release dipyridamole was used in all or the vast majority of patients in the much larger ESPS-2 and ESPRIT trials [14,27], and aspirin-extended-release dipyridamole led to a greater reduction in stroke risk compared with aspirin alone [26]. Adverse effects Headache is the most common adverse effect of aspirin-extended-release dipyridamole, and one that most often leads to discontinuation of treatment. Other adverse reactions include abdominal pain, nausea, diarrhea, and vomiting. Headache was the most frequent adverse event associated with aspirin-extended-release dipyridamole in two large clinical trials, ESPS-2 and ESPRIT [14,27]. In the PRoFESS trial, discontinuation due to headache was more frequent with aspirin-extended-release dipyridamole compared with clopidogrel (5.9 versus 0.9 percent) [28]. In a study of subjects aged 55 or older treated with the combination of aspirin-extended-release dipyridamole, headache developed in 39.7 percent after a single dose, and women were significantly more likely to develop headache than men (49.6 and 28.6 percent, respectively) [29]. The headaches associated with aspirin- extended-release dipyridamole treatment were mostly self-limited, and treatment of headache with acetaminophen was not significantly better than with placebo, as measured by response at two hours (75.5 and 69.4 percent). The overall incidence of headache declined markedly over seven days to less than 20 percent. Gastric upset and/or diarrhea requiring drug cessation was also more common with dipyridamole compared with aspirin or placebo in ESPS-2. Notably, aspirin use was associated with significantly greater overall bleeding and gastrointestinal bleeding compared with dipyridamole or placebo in ESPS-2 and a subsequent meta-analysis [14,30]. In fact, in ESPS-2, the frequency of bleeding complications with dipyridamole was comparable to placebo. Concern that dipyridamole use might lead to increased rates of myocardial ischemia has been largely laid to rest by data from two large clinical trials (ESPS-2 and ESPRIT) and a meta-analysis [14,27,30,31]. This concern was related to the potential for dipyridamole to cause vasodilation of coronary vessels [32], and it first arose with the use of intravenous dipyridamole in cardiac stress testing [33]. However, accumulating data suggest that extended-release dipyridamole use for stroke prevention is not associated with an increased risk of myocardial ischemia or infarction. An analysis of data from ESPS-2 found that use of extended-release dipyridamole was not https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 12/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate associated with increased cardiac ischemia or mortality in patients with a history of coronary artery disease [31], and a meta-analysis found that oral dipyridamole did not alter the rate of MI in patients with previous stroke or TIA, either when compared with control, or when administered in combination with aspirin and compared with aspirin alone [30]. In ESPRIT, the use of combination therapy with aspirin and dipyridamole, mainly extended-release dipyridamole, was associated with a nonsignificant decrease in the outcome of first cardiac event, and a significant decrease in the primary composite outcome that included death from all vascular causes and nonfatal MI [27]. Cilostazol The antiplatelet agent cilostazol is a phosphodiesterase 3 inhibitor that increases cyclic AMP and leads to reversible inhibition of platelet aggregation and arterial vasodilation. Efficacy Several randomized controlled trials and meta-analyses have found that cilostazol is effective for preventing cerebral infarction [34-36]. In the CSPS trial of over 1000 patients from Japan, cilostazol (100 mg twice daily) compared with placebo reduced the risk of stroke (relative risk reduction [RRR] 42 percent, 95% CI 9.2-62.5 percent) [34]. The CSPS II trial randomly assigned 2757 patients in Japan with a recent noncardioembolic cerebral infarction to cilostazol (100 mg twice daily) or aspirin (81 mg daily) [35]. At a mean follow-up of 29 months, the yearly rates of recurrent stroke (infarction or hemorrhage) for cilostazol and aspirin were 2.7 and 3.7 percent (HR 0.74, 95% CI 0.56-0.98), confirming that cilostazol is noninferior to aspirin for stroke prevention. Annual rates of intracranial hemorrhage or other hemorrhage requiring hospitalization were lower with cilostazol than with aspirin (0.8 versus 1.8 percent, HR 0.46, 95% CI 0.30-0.71). In the CASISP trial from China of 720 patients with recent ischemic stroke, the composite endpoint (any stroke, ischemic or hemorrhagic) at 12 to 18 months of follow-up was lower in the cilostazol group compared with the aspirin group (3.3 versus 5.6 percent), but this result was not statistically significant (HR 0.62, 95% CI 0.30-1.26) [37]. These data support the safety and efficacy of cilostazol for secondary stroke prevention in East Asian populations. However, there are as yet no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-East Asian ethnic groups. Also, the twice daily dosing, lower tolerability, and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention. Dosing The dose of cilostazol is 100 mg twice daily. Adverse effects In the CSPS II trial of cilostazol versus aspirin, headache, diarrhea, palpitation, dizziness, and tachycardia were more frequent with cilostazol, and more patients https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 13/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate discontinued cilostazol than aspirin (20 versus 12 percent) [35]. Other potential adverse reactions include diarrhea, infection, and rhinitis. Others Ticlopidine Ticlopidine is a thienopyridine with a chemical structure and mechanism of

assigned to aspirin-extended-release dipyridamole compared with clopidogrel (7.7 versus 7.9 percent), but hemorrhagic strokes were slightly increased (0.9 versus 0.5 percent). Thus, the net risk (ie, the combination of recurrent stroke plus major hemorrhage) was similar between aspirin-extended-release dipyridamole and clopidogrel (11.7 versus 11.4 percent; HR 1.03, 95% CI 0.95-1.11). New or worsening heart failure was slightly less frequent in patients assigned to aspirin- extended-release dipyridamole compared with those assigned to clopidogrel; the difference was significant (1.4 versus 1.8 percent, 95% CI 0.62-0.96). PRoFESS had a 2x2 factorial design in which the patients were also randomly assigned to telmisartan or placebo, the results of which are discussed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".) Dose Aspirin-extended-release dipyridamole, containing aspirin (25 mg) plus extended- release dipyridamole (200 mg), is given two times per day. Dipyridamole is also available as an https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 11/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate immediate-release form, usually given as 50 to 100 mg three times per day, but this is seldom used alone for secondary stroke prevention. The specific dipyridamole preparation may be important. In a meta-analysis cited above, the combination of aspirin and immediate-release dipyridamole was nonsignificantly better than aspirin alone for secondary prevention of stroke (relative risk 0.83, 95% CI 0.59-1.15) [26]. By contrast, extended release dipyridamole was used in all or the vast majority of patients in the much larger ESPS-2 and ESPRIT trials [14,27], and aspirin-extended-release dipyridamole led to a greater reduction in stroke risk compared with aspirin alone [26]. Adverse effects Headache is the most common adverse effect of aspirin-extended-release dipyridamole, and one that most often leads to discontinuation of treatment. Other adverse reactions include abdominal pain, nausea, diarrhea, and vomiting. Headache was the most frequent adverse event associated with aspirin-extended-release dipyridamole in two large clinical trials, ESPS-2 and ESPRIT [14,27]. In the PRoFESS trial, discontinuation due to headache was more frequent with aspirin-extended-release dipyridamole compared with clopidogrel (5.9 versus 0.9 percent) [28]. In a study of subjects aged 55 or older treated with the combination of aspirin-extended-release dipyridamole, headache developed in 39.7 percent after a single dose, and women were significantly more likely to develop headache than men (49.6 and 28.6 percent, respectively) [29]. The headaches associated with aspirin- extended-release dipyridamole treatment were mostly self-limited, and treatment of headache with acetaminophen was not significantly better than with placebo, as measured by response at two hours (75.5 and 69.4 percent). The overall incidence of headache declined markedly over seven days to less than 20 percent. Gastric upset and/or diarrhea requiring drug cessation was also more common with dipyridamole compared with aspirin or placebo in ESPS-2. Notably, aspirin use was associated with significantly greater overall bleeding and gastrointestinal bleeding compared with dipyridamole or placebo in ESPS-2 and a subsequent meta-analysis [14,30]. In fact, in ESPS-2, the frequency of bleeding complications with dipyridamole was comparable to placebo. Concern that dipyridamole use might lead to increased rates of myocardial ischemia has been largely laid to rest by data from two large clinical trials (ESPS-2 and ESPRIT) and a meta-analysis [14,27,30,31]. This concern was related to the potential for dipyridamole to cause vasodilation of coronary vessels [32], and it first arose with the use of intravenous dipyridamole in cardiac stress testing [33]. However, accumulating data suggest that extended-release dipyridamole use for stroke prevention is not associated with an increased risk of myocardial ischemia or infarction. An analysis of data from ESPS-2 found that use of extended-release dipyridamole was not https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 12/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate associated with increased cardiac ischemia or mortality in patients with a history of coronary artery disease [31], and a meta-analysis found that oral dipyridamole did not alter the rate of MI in patients with previous stroke or TIA, either when compared with control, or when administered in combination with aspirin and compared with aspirin alone [30]. In ESPRIT, the use of combination therapy with aspirin and dipyridamole, mainly extended-release dipyridamole, was associated with a nonsignificant decrease in the outcome of first cardiac event, and a significant decrease in the primary composite outcome that included death from all vascular causes and nonfatal MI [27]. Cilostazol The antiplatelet agent cilostazol is a phosphodiesterase 3 inhibitor that increases cyclic AMP and leads to reversible inhibition of platelet aggregation and arterial vasodilation. Efficacy Several randomized controlled trials and meta-analyses have found that cilostazol is effective for preventing cerebral infarction [34-36]. In the CSPS trial of over 1000 patients from Japan, cilostazol (100 mg twice daily) compared with placebo reduced the risk of stroke (relative risk reduction [RRR] 42 percent, 95% CI 9.2-62.5 percent) [34]. The CSPS II trial randomly assigned 2757 patients in Japan with a recent noncardioembolic cerebral infarction to cilostazol (100 mg twice daily) or aspirin (81 mg daily) [35]. At a mean follow-up of 29 months, the yearly rates of recurrent stroke (infarction or hemorrhage) for cilostazol and aspirin were 2.7 and 3.7 percent (HR 0.74, 95% CI 0.56-0.98), confirming that cilostazol is noninferior to aspirin for stroke prevention. Annual rates of intracranial hemorrhage or other hemorrhage requiring hospitalization were lower with cilostazol than with aspirin (0.8 versus 1.8 percent, HR 0.46, 95% CI 0.30-0.71). In the CASISP trial from China of 720 patients with recent ischemic stroke, the composite endpoint (any stroke, ischemic or hemorrhagic) at 12 to 18 months of follow-up was lower in the cilostazol group compared with the aspirin group (3.3 versus 5.6 percent), but this result was not statistically significant (HR 0.62, 95% CI 0.30-1.26) [37]. These data support the safety and efficacy of cilostazol for secondary stroke prevention in East Asian populations. However, there are as yet no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-East Asian ethnic groups. Also, the twice daily dosing, lower tolerability, and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention. Dosing The dose of cilostazol is 100 mg twice daily. Adverse effects In the CSPS II trial of cilostazol versus aspirin, headache, diarrhea, palpitation, dizziness, and tachycardia were more frequent with cilostazol, and more patients https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 13/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate discontinued cilostazol than aspirin (20 versus 12 percent) [35]. Other potential adverse reactions include diarrhea, infection, and rhinitis. Others Ticlopidine Ticlopidine is a thienopyridine with a chemical structure and mechanism of action similar to clopidogrel. Despite the evidence of benefit in randomized trials, ticlopidine is not considered a first-line antiplatelet agent for stroke prevention because of the risk of severe neutropenia and relatively high cost. Efficacy The CATS trial enrolled over 1000 patients between one week and four months after ischemic stroke [38]. At a mean of 24 months, the primary composite end point of stroke, MI, and vascular death was lower with ticlopidine compared with placebo (10.8 versus 15.3 percent, RRR 30 percent). The benefit was smaller by intention-to-treat analysis (RRR 23 percent). The TASS trial compared ticlopidine (500 mg/d) with aspirin (1300 mg/d) in 3069 patients with a recent TIA or mild stroke [39]. At three-year follow-up, ticlopidine reduced the primary end point (nonfatal stroke or death) compared with aspirin (17 versus 19 percent). Ticlopidine also reduced the rate of fatal and nonfatal stroke compared with aspirin (10 versus 13 percent, respectively, RRR 21 percent, 95% CI 4-38). The AAASPS trial compared ticlopidine (500 mg/day) with aspirin (650 mg/day) in 1809 Black patients with noncardioembolic ischemic stroke [40]. At two-year follow-up, there was no significant difference in the primary end point (stroke, MI, vascular death) between ticlopidine and aspirin. Dose The dose of ticlopidine is 250 mg twice daily. The drug is no longer available in the United States. Adverse effects The most serious complication of ticlopidine therapy is severe neutropenia, which occurs in approximately 1 percent of patients. Thus, patients must have a complete blood count with differential prior to treatment initiation and then weekly for the first three months of therapy; more frequent monitoring is recommended for patients whose absolute neutrophil counts are consistently declining or are 30 percent less than baseline. Other common side effects, which occur more frequently with ticlopidine than aspirin, are rash and diarrhea. Triflusal Triflusal is an antiplatelet agent that is structurally related to aspirin. It is available as a licensed pharmaceutical in some European and Latin American countries but is considered investigational in the United States. In a randomized trial with 2113 patients, the effectiveness of triflusal (600 mg/day) was similar to aspirin (325 mg/day) at preventing vascular events after https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 14/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate stroke, but it did have a lower rate of hemorrhagic complications [41]. Similar findings were noted in a smaller randomized trial and a meta-analysis of four trials [42,43]. It is not clear whether triflusal would have had a lower rate of hemorrhagic complications than lower-dose aspirin [44]. Dual antiplatelet therapy The short-term use of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is beneficial compared with aspirin alone in some patients with acute ischemic stroke syndromes ( algorithm 1 and algorithm 2), as reviewed elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) However, evidence from randomized trials suggests that long-term DAPT has no such benefit for stroke risk reduction, but rather appears to be harmful due to an increased risk of bleeding. Aspirin plus clopidogrel For the vast majority of patients with ischemic stroke, the long- term use of DAPT with aspirin and clopidogrel does not offer greater benefit for stroke prevention than either agent alone but does substantially increase the risk of bleeding complications [45-49]. The MATCH trial enrolled 7599 patients with stroke or TIA who also had some additional "high-risk" feature, defined as prior MI, prior stroke (in addition to the index event), diabetes, angina, or symptomatic peripheral artery disease [45]. Patients were randomly assigned to the combination of clopidogrel (75 mg daily) plus aspirin (75 mg daily) or clopidogrel (75 mg daily) alone. Follow-up was 18 months. Compared with clopidogrel alone, aspirin plus clopidogrel treatment did not reduce the risk of major vascular events (relative risk reduction 6.4 percent, 95% CI -4.6 to 16.3 percent) but did result in more life- threatening bleeding complications, mainly intracranial and gastrointestinal. Over the 18- month trial period, there was an absolute excess of 1.3 percent for life-threatening hemorrhage (95% CI 0.6-1.9) and an additional 1.3 percent for major hemorrhage in patients assigned combination therapy. Overall, treatment with aspirin and clopidogrel compared with clopidogrel alone might prevent 10 ischemic events per 1000 at the cost of 13 life-threatening hemorrhages per 1000 treated. There are several limitations of MATCH. For instance, 54 percent of MATCH subjects qualified for trial entry because of a lacunar stroke, a stroke subtype that has the lowest recurrence risk [50]. Furthermore, data regarding interaction between treatment and stroke mechanism were not reported, raising the question of whether combination therapy might still play a role in particular stroke subtypes. The CHARISMA trial evaluated aspirin plus clopidogrel versus aspirin alone in 15,603 patients with either documented cardiovascular disease (coronary, ischemic https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 15/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate cerebrovascular, or peripheral arterial) or, in 21 percent of patients, multiple atherothrombotic risk factors (eg, diabetes, hypertension, primary hypercholesterolemia, current smoking, asymptomatic carotid stenosis 70 percent) [46]. Patients were randomly assigned to low-dose aspirin (75 to 162 mg/day) plus either clopidogrel (75 mg/day) or placebo. At a median follow-up of 28 months, combined aspirin plus clopidogrel treatment did not reduce the risk of the composite end point (MI, stroke of any cause, or death from cardiovascular causes) compared with aspirin alone (6.8 versus 7.3 percent, relative risk 0.93, 95% CI 0.83-1.05), but did increase in moderate bleeding (2.1 versus 1.3 percent) and severe bleeding (1.7 versus 1.3 percent), although the latter did not reach statistical significance. The SPS3 trial evaluated over 3000 patients with subcortical (ie, lacunar) stroke confirmed by magnetic resonance imaging (MRI) [51]. The arm testing the combination of aspirin plus clopidogrel versus aspirin alone was terminated before completion because of a higher frequency of bleeding events (mostly systemic) and a higher mortality rate in patients assigned to DAPT compared with those assigned to aspirin only. In the final analysis, subjects treated with aspirin plus clopidogrel compared with aspirin alone had a significantly increased annual rate of both major hemorrhage (2.1 versus 1.1 percent, HR 1.97, 95% CI 1.41-2.71) and all-cause mortality (2.1 versus 1.4 percent, HR 1.52, 95% CI 1.14- 2.04) [49]. Furthermore, treatment with aspirin and clopidogrel compared with aspirin alone in did not reduce the risk of recurrent stroke [49]. Cilostazol plus aspirin or clopidogrel The potential utility of DAPT using cilostazol was explored in the open-label CSPS.com trial in Japan, which enrolled 1884 adult patients with noncardioembolic ischemic stroke who had 50 percent stenosis of a major intracranial or extracranial artery, or two or more vascular risk factors [52]. The patients were assigned in a 1:1 ratio to antiplatelet monotherapy using either aspirin or clopidogrel, or to DAPT using cilostazol combined with either aspirin or clopidogrel [52]. During a median follow-up of 1.4 years, the rate of recurrent ischemic stroke was lower for the DAPT group compared with the monotherapy group (3 versus 7 percent, HR 0.49, 95% CI 0.31-0.76). The rates of serious adverse events and bleeding events were similar between the groups. Limitations to this trial include early stopping before reaching the planned 4000 enrollment due to slow recruitment, resulting in a lower number of event rates, the varying combinations of antiplatelet medications and dosages of aspirin, and the unblinded treatment. Combination antiplatelet and anticoagulant therapy Aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is another reasonable treatment option for some patients with non-lacunar, non-cardioembolic ischemic stroke and evidence of systemic atherosclerosis. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 16/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate This approach is based primarily on the results of the COMPASS trial, which randomly assigned over 27,000 patients with stable coronary artery disease or peripheral arterial disease to one of three treatment arms: one, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily; two, rivaroxaban 5 mg twice daily; or three, aspirin 100 mg daily [53]. Patients with a history of lacunar stroke or with cardioembolic stroke requiring anticoagulation were excluded from enrollment. The mean follow-up was 23 months. Compared with those assigned to aspirin alone, patients assigned to rivaroxaban plus aspirin had a decrease in the annualized composite outcome of cardiovascular mortality, stroke, or myocardial infarction (4.1 versus 5.4 percent, absolute risk reduction [ARR] 1.3 percent, HR 0.76, 95% CI 0.66 to 0.86) and a decrease in ischemic stroke (0.7 versus 1.4 percent, ARR 0.7 percent, HR 0.51, 95% CI 0.38-0.68). Similarly, in the subgroup of 1032 patients with prior stroke, aspirin and rivaroxaban decreased the composite rate of cardiovascular death, stroke, or myocardial infarction (3.7 percent, versus 6.5 percent with aspirin alone, ARR 2.8 percent, HR 0.57, 95% CI 0.34-0.96) [54]; thus, the ARR for patients with prior stroke was more than double that observed for the overall trial cohort. As expected, those assigned to combination therapy in COMPASS had an increase in major bleeding events (3.1 versus 1.9 percent, absolute risk increase 1.2 percent, HR 1.70, 95% CI 1.40- 2.05), with the gastrointestinal tract being the most common site of major bleeding [53]. However, there was no difference between the two groups in fatal bleeding (0.2 versus 0.1 percent) or intracranial bleeding (0.2 percent in both arms). Similar findings for risk reduction of ischemic stroke were reported in the COMMANDER-HF trial, which randomly assigned over 5000 patients with chronic heart failure, left ventricular ejection fraction 40 percent, coronary artery disease, elevated plasma natriuretic peptide level, and no atrial fibrillation to receive rivaroxaban 2.5 mg twice daily or placebo [55]. At baseline, approximately 93 percent of the patients were on aspirin (alone or in combination with a thienopyridine), and approximately 35 percent were taking DAPT. During a median follow-up of 21 months, there was no significant difference in all-cause mortality between the rivaroxaban and placebo groups, but the risk of stroke was reduced in the group assigned to rivaroxaban (2 versus 3 percent, ARR 1 percent, HR 0.66, 95% CI 0.47-0.95). The risk of major bleeding was higher in the rivaroxaban group (3.3 versus 2.0 percent), but there was no significant difference between groups for fatal bleeding (0.4 percent in both groups) or for bleeding into a critical space (0.5 versus 0.8 percent). SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 17/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Transient ischemic attack (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Acute antiplatelet therapy The use of antiplatelet therapy in the acute period of ischemic stroke and transient ischemic attack (TIA), including the short-term use of dual antiplatelet therapy (DAPT), is discussed in detail elsewhere ( algorithm 1 and algorithm 2). (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Options for long-term antiplatelet therapy Aspirin, clopidogrel, and the combination of aspirin-extended-release dipyridamole are all acceptable options for preventing recurrent noncardioembolic ischemic stroke. Cilostazol is a reasonable option for patients of East Asian ethnicity, and for all patients if the other agents are not available or tolerated. (See 'Aspirin' above and 'Clopidogrel' above and 'Aspirin plus dipyridamole' above.) Our recommendations For secondary prevention of stroke in patients with a history of noncardioembolic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive type), or cryptogenic type, we recommend treatment with an antiplatelet agent using either https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 18/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate aspirin, clopidogrel, or aspirin-extended-release dipyridamole (Grade 1A). We suggest antiplatelet therapy using either clopidogrel (75 mg daily) as monotherapy or the combination of aspirin-extended-release dipyridamole (25 mg/200 mg twice a day), rather than aspirin alone (Grade 2B). The choice between clopidogrel and aspirin-extended- release dipyridamole is dependent mainly on patient tolerance and contraindications. Aspirin is appropriate for patients who cannot afford or tolerate clopidogrel or aspirin- extended-release dipyridamole. (See 'Aspirin' above and 'Clopidogrel' above and 'Aspirin plus dipyridamole' above.) Aspirin dose Although the optimal dose of aspirin is uncertain, there is no compelling evidence that any specific dose is more effective than another, and fewer gastrointestinal side effects and bleeding occur with lower doses ( 325 mg a day). We recommend a dose of 50 to 100 mg daily when using aspirin for the secondary prevention of ischemic stroke (Grade 1B). (See 'Dose of aspirin' above.) Limited role for long-term dual antiplatelet therapy For most patients with a noncardioembolic stroke or TIA, we recommend not using aspirin and clopidogrel in combination for long-term stroke prevention, given the lack of greater efficacy compared with clopidogrel alone and the substantially increased risk of bleeding complications (Grade 1A). (See 'Aspirin plus clopidogrel' above.) Possible exceptions include patients with concurrent indications for dual antiplatelet therapy (eg, selected patients with a recent acute myocardial infarction, other acute coronary syndrome, or arterial stent placement including carotid stenting); these are discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting".) Role of combined antiplatelet and anticoagulant therapy For high-risk patients with noncardioembolic, nonlacunar stroke and evidence of peripheral, coronary, or cerebrovascular atherosclerosis, aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is a reasonable treatment option. (See 'Combination antiplatelet and anticoagulant therapy' above.) Atrial fibrillation Prevention of recurrent cardioembolic stroke in patients with atrial fibrillation is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 19/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 2. 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The ESPS Group. Lancet 1987; 2:1351. 18. Johnson ES, Lanes SF, Wentworth CE 3rd, et al. A metaregression analysis of the dose- response effect of aspirin on stroke. Arch Intern Med 1999; 159:1248. 19. Jones WS, Mulder H, Wruck LM, et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med 2021; 384:1981. 20. Dutch TIA Trial Study Group, van Gijn J, Algra A, et al. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991; 325:1261. 21. Patrono C, Garc a Rodr guez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373. 22. Hirsh J, Dalen JE, Fuster V, et al. Aspirin and other platelet-active drugs. The relationship among dose, effectiveness, and side effects. Chest 1995; 108:247S. 23. Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol 2005; 95:1218. 24. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006; 119:624. 25. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329. 26. Verro P, Gorelick PB, Nguyen D. Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke 2008; 39:1358. 27. ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 21/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate 28. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008; 359:1238. 29. Lipton RB, Bigal ME, Kolodner KB, et al. Acetaminophen in the treatment of headaches associated with dipyridamole-aspirin combination. Neurology 2004; 63:1099. 30. Leonardi-Bee J, Bath PM, Bousser MG, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke 2005; 36:162. 31. Diener HC, Darius H, Bertrand-Hardy JM, et al. Cardiac safety in the European Stroke Prevention Study 2 (ESPS2). Int J Clin Pract 2001; 55:162. 32. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004; 292:1867. 33. Pfisterer M. Intravenous dipyridamole for stress thallium-201 perfusion scintigraphy. Cardiovasc Imag 1992; 4:31. 34. Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. Atheroscler Suppl 2005; 6:33. 35. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9:959. 36. Kim SM, Jung JM, Kim BJ, et al. Cilostazol Mono and Combination Treatments in Ischemic Stroke: An Updated Systematic Review and Meta-Analysis. Stroke 2019; 50:3503. 37. Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008; 7:494. 38. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215. 39. Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321:501. 40. Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289:2947. 41. Mat as-Guiu J, Ferro JM, Alvarez-Sab n J, et al. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke 2003; 34:840. 42. Culebras A, Rotta-Escalante R, Vila J, et al. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 2004; 62:1073. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 22/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate 43. Costa J, Ferro JM, Matias-Guiu J, et al. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005; :CD004296. 44. Anderson DC, Goldstein LB. Aspirin: it's hard to beat. Neurology 2004; 62:1036. 45. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331. 46. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706. 47. Usman MH, Notaro LA, Nagarakanti R, et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009; 103:1107. 48. Lee M, Saver JL, Hong KS, et al. Risk-benefit profile of long-term dual- versus single- antiplatelet therapy among patients with ischemic stroke: a systematic review and meta- analysis. Ann Intern Med 2013; 159:463. 49. SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367:817. 50. Amarenco P, Donnan GA. Should the MATCH results be extrapolated to all stroke patients and affect ongoing trials evaluating clopidogrel plus aspirin? Stroke 2004; 35:2606. 51. Clinical advisory: Secondary Prevention of Small Subcortical Strokes trial: NINDS stops treat ment with combination antiplatelet therapy (clopidogrel plus aspirin) due to higher risk of major hemorrhage and death. www.nlm.nih.gov/databases/alerts/2011_ninds_stroke.html (Accessed on November 28, 2011). 52. Toyoda K, Uchiyama S, Yamaguchi T, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol 2019; 18:539. 53. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017; 377:1319. 54. Sharma M, Hart RG, Connolly SJ, et al. Stroke Outcomes in the COMPASS Trial. Circulation 2019; 139:1134. 55. Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease. N Engl J Med 2018; 379:1332. Topic 1086 Version 56.0 https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 23/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate GRAPHICS Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 24/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Graphic 131695 Version 3.0 https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 25/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 26/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused.

32. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004; 292:1867. 33. Pfisterer M. Intravenous dipyridamole for stress thallium-201 perfusion scintigraphy. Cardiovasc Imag 1992; 4:31. 34. Matsumoto M. Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study. Atheroscler Suppl 2005; 6:33. 35. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010; 9:959. 36. Kim SM, Jung JM, Kim BJ, et al. Cilostazol Mono and Combination Treatments in Ischemic Stroke: An Updated Systematic Review and Meta-Analysis. Stroke 2019; 50:3503. 37. Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008; 7:494. 38. Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1:1215. 39. Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989; 321:501. 40. Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289:2947. 41. Mat as-Guiu J, Ferro JM, Alvarez-Sab n J, et al. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke 2003; 34:840. 42. Culebras A, Rotta-Escalante R, Vila J, et al. Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 2004; 62:1073. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 22/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate 43. Costa J, Ferro JM, Matias-Guiu J, et al. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005; :CD004296. 44. Anderson DC, Goldstein LB. Aspirin: it's hard to beat. Neurology 2004; 62:1036. 45. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331. 46. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706. 47. Usman MH, Notaro LA, Nagarakanti R, et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009; 103:1107. 48. Lee M, Saver JL, Hong KS, et al. Risk-benefit profile of long-term dual- versus single- antiplatelet therapy among patients with ischemic stroke: a systematic review and meta- analysis. Ann Intern Med 2013; 159:463. 49. SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367:817. 50. Amarenco P, Donnan GA. Should the MATCH results be extrapolated to all stroke patients and affect ongoing trials evaluating clopidogrel plus aspirin? Stroke 2004; 35:2606. 51. Clinical advisory: Secondary Prevention of Small Subcortical Strokes trial: NINDS stops treat ment with combination antiplatelet therapy (clopidogrel plus aspirin) due to higher risk of major hemorrhage and death. www.nlm.nih.gov/databases/alerts/2011_ninds_stroke.html (Accessed on November 28, 2011). 52. Toyoda K, Uchiyama S, Yamaguchi T, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol 2019; 18:539. 53. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017; 377:1319. 54. Sharma M, Hart RG, Connolly SJ, et al. Stroke Outcomes in the COMPASS Trial. Circulation 2019; 139:1134. 55. Zannad F, Anker SD, Byra WM, et al. Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease. N Engl J Med 2018; 379:1332. Topic 1086 Version 56.0 https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 23/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate GRAPHICS Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 24/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Graphic 131695 Version 3.0 https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 25/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 26/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 27/28 7/6/23, 12:47 PM Long-term antithrombotic therapy for the secondary prevention of ischemic stroke - UpToDate Contributor Disclosures Brett L Cucchiara, MD No relevant financial relationship(s) with ineligible companies to disclose. Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/long-term-antithrombotic-therapy-for-the-secondary-prevention-of-ischemic-stroke/print 28/28

7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of hypertension in adults : Jan Basile, MD, Michael J Bloch, MD, FACP, FASH, FSVM, FNLA : George L Bakris, MD, William B White, MD : John P Forman, MD, MSc, Karen Law, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 05, 2023. INTRODUCTION The global prevalence of hypertension is high, and among nonpregnant adults in the United States, treatment of hypertension is the most common reason for office visits and for the use of chronic prescription medications [1-3]. In addition, roughly one-half of hypertensive individuals do not have adequate blood pressure control. The prevalence and control of hypertension are discussed in other topics. (See "The prevalence and control of hypertension in adults" and "Patient adherence and the treatment of hypertension".) This topic provides a broad overview of the definitions, pathogenesis, complications, diagnosis, evaluation, and management of hypertension. Detailed discussions of all these issues are found separately. The reader is directed, when necessary, to more detailed discussions of these issues in other topics. DEFINITIONS Hypertension The following definitions and staging system, which are based upon appropriately measured blood pressure ( table 1), were suggested in 2017 by the American College of Cardiology/American Heart Association (ACC/AHA) [4]; proper measurement technique, which is detailed below, is of paramount importance when identifying patients as having hypertension (see 'Blood pressure measurement' below): Normal blood pressure Systolic <120 mmHg and diastolic <80 mmHg https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 1/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Elevated blood pressure Systolic 120 to 129 mmHg and diastolic <80 mmHg Hypertension: Stage 1 Systolic 130 to 139 mmHg or diastolic 80 to 89 mmHg Stage 2 Systolic at least 140 mmHg or diastolic at least 90 mmHg If there is a disparity in category between the systolic and diastolic pressures, the higher value determines the stage. Isolated systolic hypertension is defined as a blood pressure 130 mmHg systolic and <80 mmHg diastolic, and isolated diastolic hypertension is defined as a blood pressure <130 mmHg systolic and 80 mmHg diastolic. Patients with a blood pressure 130 mmHg systolic and 80 mmHg diastolic are considered to have mixed systolic/diastolic hypertension. In clinical practice, patients who are taking medications for hypertension are usually defined as having hypertension, specifically treated hypertension, regardless of their observed blood pressure. European guidance on the definition of hypertension contrasts with that of the ACC/AHA. The European Society of Cardiology and European Society of Hypertension (ESC/ESH), the International Society of Hypertension (ISH), as well as the National Institute for Health and Care Excellence (NICE) guidelines, define hypertension, using office-based blood pressure, as a systolic pressure 140 mmHg or diastolic pressure 90 mmHg ( table 2) [5-7]. In general, definitions for hypertension are based upon the relationship between blood pressure and the incidence of cardiovascular events in large populations, derived from numerous observational studies and randomized trials, in which blood pressure was measured in various types of office settings with variable equipment and technique [8]. (See 'Complications of hypertension' below.) When evaluating an individual patient, making the diagnosis of hypertension is complex and requires integration of repeated blood pressure measurements, using appropriate technique, both in and out of the office. The schema for establishing the diagnosis of hypertension is presented below ( algorithm 1 and table 3). (See 'Making the diagnosis of hypertension' below.) Definitions based upon ambulatory and home readings The diagnosis of hypertension requires integration of home or ambulatory blood pressure monitoring (ABPM), whereas routine measurements made in the clinical setting should be used primarily for detection purposes. (See 'Making the diagnosis of hypertension' below.) https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 2/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate The use of ABPM and home blood pressure monitoring in adults is discussed in detail elsewhere. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring" and "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Ambulatory blood pressure monitoring'.) The following diagnostic criteria were suggested by the 2017 ACC/AHA guidelines; meeting one or more of these criteria using ABPM qualifies as confirmation of hypertension ( table 3) [4]. A 24-hour mean of 125 mmHg systolic or 75 mmHg diastolic Daytime (awake) mean of 130 mmHg systolic or 80 mmHg diastolic Nighttime (asleep) mean of 110 mmHg systolic or 65 mmHg diastolic We find the daytime (awake) average of 130 mmHg systolic or 80 mmHg diastolic to be the most useful of these definitions. Home readings correlate more closely with the results of daytime ambulatory measurements than with blood pressures that are typically obtained in the clinician's office (ie, using a manual cuff and stethoscope or using an oscillometric device with the care provider present in the room). We believe that hypertension can be confirmed by repeated home blood pressure readings that average 130/ 80 mmHg. Guidelines from the ESC/ESH, ISH, and NICE differ somewhat from the ACC/AHA guidelines; using ambulatory or home blood pressures, the ESC/ESH, ISH, and NICE define hypertension as a 24-hour mean of 130 mmHg systolic or 80 mmHg diastolic or a daytime mean (or an average of home readings) that is 135 mmHg systolic or 85 mmHg diastolic ( table 2) [5-7]. Both white coat hypertension and masked hypertension are conditions that can only be defined based upon the comparison of out-of-office blood pressure measurements (ABPM and home) with office-based blood pressure measurements. White coat hypertension White coat hypertension is defined as blood pressure that is consistently elevated by office readings but does not meet diagnostic criteria for hypertension based upon out-of-office readings. Identifying patients who should be evaluated for white coat hypertension, and the diagnosis of white coat hypertension, is presented elsewhere ( table 4). (See "White coat and masked hypertension" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".) Masked hypertension Masked hypertension is defined as blood pressure that is consistently elevated by out-of-office measurements but does not meet the criteria for https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 3/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate hypertension based upon office readings. Identifying patients who should be evaluated for masked hypertension, and the diagnosis of masked hypertension, is discussed separately ( table 4). (See "White coat and masked hypertension" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".) BLOOD PRESSURE MEASUREMENT Appropriate, standardized technique for blood pressure measurement, as described below, is critically important both in the office and at home [9,10]. Detailed discussions on ambulatory blood pressure monitoring (ABPM), home blood pressure monitoring, and office-based blood pressure measurement can be found in other topics. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring" and "Blood pressure measurement in the diagnosis and management of hypertension in adults".) Office-based blood pressure measurement Proper technique and interpretation of the blood pressure is essential in the diagnosis and management of hypertension. A number of steps should ideally be followed to achieve maximum accuracy ( table 1) [5,9-11]. An appropriately sized cuff must be used ( table 5). (See "Blood pressure measurement in the diagnosis and management of hypertension in adults".) Rather than an auscultatory device (one that requires a stethoscope), we recommend using an oscillometric blood pressure device designed specifically for the office setting. Automated devices can take multiple consecutive readings in the office with the patient sitting and resting alone (ie, unattended measurement) or with an observer present. Either unattended or attended automated office blood pressure (AOBP) measurement predict the results of awake ABPM better than traditional office blood pressure measurement and may reduce the white coat effect [12]. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Automated office blood pressure measurement'.) Given the importance of obtaining accurate and reproducible blood pressure readings, we suggest that all providers work towards having access to ABPM, automated office blood pressure monitoring (AOBPM), or both. However, if AOBP measurement is not available, office measurements should be performed with the patient positioned properly and allowed to rest comfortably for at least five minutes, and measurements should be repeated at least twice ( table 1). The average of these readings should also be provided to the patient. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 4/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate In addition to obtaining multiple blood pressure measurements, blood pressure should be measured in both arms, at least at the initial visit. In older individuals or those with potential orthostatic symptoms, postural measurements should also be taken: Systolic blood pressure readings in the left and right arms should be roughly equivalent. A discrepancy of more than 15 mmHg may indicate subclavian stenosis and, hence, peripheral arterial disease. If there is a significant difference in blood pressure between the two arms, the higher of the two should be used for measurement at subsequent visits. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults".) Postural hypotension, defined as a 20 mmHg or greater fall in systolic pressure upon rising from supine to an unassisted upright position, should be pursued in patients over age 65 years, those experiencing dizziness or weakness upon standing, or those with diabetes or Parkinson disease. (See "Mechanisms, causes, and evaluation of orthostatic hypotension".) Ambulatory blood pressure monitoring Twenty-four-hour ABPM is the preferred method for confirming the diagnosis of hypertension and white coat hypertension but has limited availability in routine clinical practice. High-quality data suggest that ABPM predicts target-organ damage and cardiovascular events better than office blood pressure readings. ABPM records the blood pressure at preset intervals (usually every 15 to 20 minutes during the day and every 30 to 60 minutes during sleep). ABPM can identify or confirm white coat and masked hypertension and can also be used to confirm normal blood pressure readings obtained by self-monitoring at home ( table 3) [13]. It is also the only method of blood pressure measurement that can reliably obtain nocturnal readings. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".) In addition to patients with suspected white coat hypertension, ABPM should be considered in the following circumstances: Suspected episodic hypertension (eg, pheochromocytoma) Determining therapeutic response (ie, blood pressure control) in patients who are known to have a substantial white coat effect) Hypotensive symptoms while taking antihypertensive medications Resistant hypertension Autonomic dysfunction Suspected masked hypertension Home blood pressure monitoring Appropriate training and equipment are paramount to obtaining accurate home blood pressure readings. Patients should be instructed to use a https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 5/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate validated, automated oscillometric device that measures blood pressure in the brachial artery (upper arm) and to perform measurements in a quiet room after five minutes of rest in the seated position with the back and arm supported and legs uncrossed. At least 12 to 14 measurements should be obtained, with both morning and evening measurements taken, over a period of one week every month ( table 6). Many patients require the use of a large cuff, usually sold separately. The mean of all available readings should be used for clinical decision- making. Moderate-quality data suggest that blood pressure taken at home or work by the patient correlates more closely with the results of 24-hour or daytime ambulatory monitoring, with AOBPM, and with target-organ damage than usual blood pressure taken in the office [14,15]. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Home blood pressure monitoring' and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".) Home readings should be used to complement office readings to determine whether a patient's blood pressure is under control. If there is a discrepancy between office and home blood pressures (ie, white coat or masked hypertension), ABPM should be obtained, if possible, to confirm the accuracy of home blood pressure measurements. If ABPM is not available, AOBPM can be used. (See 'Making the diagnosis of hypertension' below.) PRIMARY HYPERTENSION Pathogenesis Maintenance of arterial blood pressure is necessary for organ perfusion. In general, the arterial blood pressure is determined by the following equation: Blood pressure (BP) = Cardiac output (CO) x Systemic vascular resistance (SVR) Blood pressure reacts to changes in the environment to maintain organ perfusion over a wide variety of conditions. The primary factors determining the blood pressure are the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the plasma volume (largely mediated by the kidneys). The pathogenesis of primary hypertension (formerly called "essential" hypertension) is poorly understood but is most likely the result of numerous genetic and environmental factors that have multiple compounding effects on cardiovascular and kidney structure and function. Some of these factors are discussed in the ensuing section. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 6/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Risk factors for primary (essential) hypertension Although the exact etiology of primary hypertension remains unclear, a number of risk factors are strongly and independently associated with its development, including: Age Advancing age is associated with increased blood pressure, particularly systolic blood pressure, and an increased incidence of hypertension. Obesity Obesity and weight gain are major risk factors for hypertension and are also determinants of the rise in blood pressure that is commonly observed with aging [16,17]. (See "Overweight, obesity, and weight reduction in hypertension".) Family history Hypertension is approximately twice as common in subjects who have one or two hypertensive parents, and multiple epidemiologic studies suggest that genetic factors account for approximately 30 percent of the variation in blood pressure in various populations [18,19]. (See "Genetic factors in the pathogenesis of hypertension".) Race Hypertension tends to be more common, be more severe, occur earlier in life, and be associated with greater target-organ damage in Black patients. (See "Burden of hypertension in Black individuals".) Reduced nephron number Reduced adult nephron mass may predispose to hypertension, which may be related to genetic factors, intrauterine developmental disturbance (eg, hypoxia, drugs, nutritional deficiency), premature birth, and postnatal environment (eg, malnutrition, infections). (See "Possible role of low birth weight in the pathogenesis of primary (essential) hypertension".) High-sodium diet Excess sodium intake (eg, >3 g/day [sodium chloride]) increases the risk for hypertension, and sodium restriction lowers blood pressure in those with a high sodium intake. (See "Salt intake, salt restriction, and primary (essential) hypertension".) Excessive alcohol consumption Excess alcohol intake is associated with the development of hypertension, and alcohol restriction lowers blood pressure in those with increased intake. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Hypertension'.) Physical inactivity Physical inactivity increases the risk for hypertension, and exercise (aerobic, dynamic resistance, and isometric resistance) is an effective means of lowering blood pressure [16,20]. (See "Exercise in the treatment and prevention of hypertension".) Insufficient sleep Short sleep duration (eg, <7 hours per night) is associated with a higher risk of hypertension [21-23], and increasing the duration of sleep may lower blood pressure https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 7/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate [24,25]. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes".) Social determinants Social determinants of health, such as low socioeconomic status, lack of health insurance, food and housing insecurity, and lack of access to safe spaces for exercise may underlie several of the above risk factors for hypertension (obesity, poor diet, physical inactivity, etc) [26,27]. These social factors likely account in large part for racial disparities in hypertension. (See "Burden of hypertension in Black individuals".) SECONDARY OR CONTRIBUTING CAUSES OF HYPERTENSION A number of common and uncommon medical conditions may increase blood pressure and lead to secondary hypertension. In many cases, these causes may coexist with risk factors for primary hypertension and are significant barriers to achieving adequate blood pressure control. (See "Evaluation of secondary hypertension" and "Definition, risk factors, and evaluation of resistant hypertension", section on 'Secondary causes of hypertension'.) Major causes of secondary hypertension include: Prescription or over-the-counter medications [4,5]: Oral contraceptives, particularly those containing higher doses of estrogen (see "Contraception: Hormonal contraception and blood pressure") Nonsteroidal antiinflammatory agents (NSAIDs), particularly chronic use (see "NSAIDs and acetaminophen: Effects on blood pressure and hypertension") Antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors Corticosteroids, including both glucocorticoids and mineralocorticoids Decongestants, such as phenylephrine and pseudoephedrine Some weight-loss medications Sodium-containing antacids Erythropoietin Cyclosporine or tacrolimus Stimulants, including methylphenidate and amphetamines https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 8/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Atypical antipsychotics, including clozapine and olanzapine Angiogenesis inhibitors, such as bevacizumab Tyrosine kinase inhibitors, such as sunitinib and sorafenib Illicit drug use Drugs such as methamphetamines and cocaine can raise blood pressure. Primary kidney disease Both acute and chronic kidney disease can lead to hypertension. (See "Overview of hypertension in acute and chronic kidney disease".) Primary aldosteronism The presence of primary mineralocorticoid excess, primarily aldosterone, should be suspected in any patient with the triad of hypertension, unexplained hypokalemia, and metabolic alkalosis. However, up to 50 to 70 percent of patients will have a normal plasma potassium concentration. Other disorders or ingestions can mimic primary aldosteronism (apparent mineralocorticoid excess syndromes), including chronic licorice intake. (See "Pathophysiology and clinical features of primary aldosteronism" and "Diagnosis of primary aldosteronism" and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".) Renovascular hypertension Renovascular hypertension is often due to fibromuscular dysplasia in younger patients and to atherosclerosis in older patients. (See "Establishing the diagnosis of renovascular hypertension".) Obstructive sleep apnea Disordered breathing during sleep appears to be an independent risk factor for systemic hypertension. (See "Obstructive sleep apnea and cardiovascular disease in adults".) Pheochromocytoma Pheochromocytoma is a rare cause of secondary hypertension. Approximately one-half of patients with pheochromocytoma have paroxysmal hypertension; most of the rest have what appears to be primary hypertension. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Treatment of pheochromocytoma in adults".) Cushing's syndrome Cushing's syndrome is a rare cause of secondary hypertension, but hypertension is a major cause of morbidity and death in patients with Cushing's syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome".) Other endocrine disorders Hypothyroidism, hyperthyroidism, and hyperparathyroidism may also induce hypertension. (See "Cardiovascular effects of hypothyroidism" and https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 9/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate "Cardiovascular effects of hyperthyroidism" and "Primary hyperparathyroidism: Clinical manifestations", section on 'Cardiovascular'.) Coarctation of the aorta Coarctation of the aorta is one of the major causes of secondary hypertension in young children, but it may also be diagnosed in adulthood [28]. (See "Clinical manifestations and diagnosis of coarctation of the aorta".) COMPLICATIONS OF HYPERTENSION Hypertension is associated with a significant increase in risk of adverse cardiovascular and kidney outcomes. Each of the following complications is closely associated with the presence of hypertension (see "Cardiovascular risks of hypertension"): Left ventricular hypertrophy (LVH) ( figure 1) [29,30] Heart failure, both reduced ejection fraction (systolic) and preserved ejection fraction (diastolic) [31] (see "Epidemiology of heart failure") Ischemic stroke [32,33] (see "Clinical diagnosis of stroke subtypes", section on 'Ecology and risk factors') Intracerebral hemorrhage [32,34] (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis") Ischemic heart disease, including myocardial infarction and coronary interventions [32,35] (see "Overview of established risk factors for cardiovascular disease") Chronic kidney disease and end-stage kidney disease [36,37] (see "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults") Quantitatively, hypertension is the most prevalent modifiable risk factor for premature cardiovascular disease, being more common than cigarette smoking, dyslipidemia, or diabetes, which are the other major risk factors [35]. Hypertension often coexists with these other risk factors as well as with overweight/obesity, an unhealthy diet, and physical inactivity. The presence of more than one risk factor increases the risk of adverse cardiovascular events [4]. The likelihood of having a cardiovascular event increases as blood pressure increases. In a meta- analysis of over one million adults, risk began to rise in all age groups with blood pressures >115 mmHg systolic or >75 mmHg diastolic ( figure 2A-B) [8]. For every 20 mmHg higher systolic https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 10/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate and 10 mmHg higher diastolic blood pressure, the risk of death from heart disease or strokes doubles. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of hypertension summarized the available meta-analyses of observational data by comparing the cardiovascular risk of different blood pressure strata with a reference group that had a blood pressure <120 mmHg systolic and <80 mmHg diastolic [4]. A blood pressure of 120 to 129 mmHg systolic and 80 to 84 mmHg diastolic was associated with a hazard ratio of 1.1 to 1.5 for cardiovascular events, and blood pressure of 130 to 139 mmHg systolic and 85 to 89 mmHg diastolic was associated with a hazard ratio of 1.5 to 2.0. This relationship was consistent across sex and race/ethnic subgroups but was somewhat attenuated among older adults. The prognostic significance of systolic and diastolic blood pressure as a cardiovascular risk factor appears to be age dependent. The systolic pressure and the pulse pressure are greater predictors of risk in patients over the age of 50 to 60 years [38]. Under age 50 years, diastolic blood pressure is a better predictor of mortality than systolic readings [39]. When the systolic blood pressure is <130 mmHg, isolated diastolic hypertension does not predict an increased cardiovascular risk, regardless of age [40]. Systolic hypertension and pulse pressure in older individuals are discussed in detail separately. (See "Treatment of hypertension in older adults, particularly isolated systolic hypertension" and "Increased pulse pressure".) While hypertension is associated with a relative increase in cardiovascular risk regardless of other cardiovascular risk factors, importantly, the absolute risk of cardiovascular risk is dependent on age and other cardiovascular risk factors in addition to the level of blood pressure ( figure 3) [41]. (See "Cardiovascular risks of hypertension".) MAKING THE DIAGNOSIS OF HYPERTENSION Different clinical trials have used different definitions of hypertension and different methodology for measuring blood pressure. In addition, the relationship between blood pressure and cardiovascular risk is graded and continuous, without an obvious inflection point. Thus, we believe that the data supporting any particular threshold for the definition of hypertension is relatively weak. In an individual patient, we feel that making the diagnosis of hypertension requires the integration of multiple blood pressure readings, the use of appropriate technique, and also the use of measurements made outside of the usual office setting. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 11/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Detection For patients without a previous history of hypertension, we agree with the 2021 US Preventive Services Task Force (USPSTF) guidelines, the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, and the 2018 European Society of Cardiology and European Society of Hypertension (ESC/ESH) guidelines that all individuals 18 years or older should be properly evaluated, with appropriate technique, for elevated blood pressure in the office or other clinical setting [4,5,42]. In practice, blood pressure measurement is simple and quick and should be performed at every clinical encounter. At a minimum, the frequency of evaluation should be as follows: Adults with normal blood pressure should have reassessment of their blood pressure every year. Adults should be evaluated at least semiannually if they have risk factors for hypertension (eg, obesity) or if their previously measured systolic blood pressure was 120 to 129. Diagnosis Our approach is consistent with but not identical to recommendations from the USPSTF, the 2017 ACC/AHA guidelines, the 2018 ESC/ESH guidelines, the 2020 ISH guidelines, and the Canadian Hypertension Education Program (CHEP) ( algorithm 1) [4-6,43,44]: A diagnosis can be made, without further confirmatory readings, in the following uncommon scenarios: A patient who presents with hypertensive urgency or emergency (ie, patients with blood pressure 180 mmHg systolic or 120 mmHg diastolic) (see "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults" and "Evaluation and treatment of hypertensive emergencies in adults") A patient who presents with an initial blood pressure 160 mmHg systolic or 100 mmHg diastolic and who also has known target end-organ damage (eg, left ventricular hypertrophy [LVH], hypertensive retinopathy, ischemic cardiovascular disease) In all other patients who have an elevated office blood pressure, the diagnosis of hypertension should be confirmed using out-of-office blood pressure measurement whenever possible. Ambulatory blood pressure monitoring (ABPM) is considered the gold standard in determining out-of-office blood pressure. However, many payers require evidence of normal out-of-office readings (suspected white coat hypertension) for reimbursement of ABPM. As such, we suggest home blood pressure measurement as the initial strategy to confirm the diagnosis of hypertension in most patients [14,15,45]: https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 12/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Hypertension is diagnosed if the mean home blood pressure, when measured with appropriate technique and with a device that has been validated in the office, is 130 mmHg systolic or 80 mmHg diastolic. ABPM is an alternative to home blood pressure monitoring in settings where ABPM is readily available, particularly if adequate home blood pressures cannot be obtained, if there is doubt about the validity of home readings or if there is a large discrepancy between office and home readings. When using ABPM, hypertension is diagnosed if the mean daytime blood pressure is 130 mmHg systolic or 80 mmHg diastolic. Occasionally, out-of-office confirmation of hypertension is not possible because of issues with availability of equipment, insurance, and cost. In these situations, a diagnosis of hypertension can be confirmed by serial (at least three) office-based blood pressure measurements spaced over a period of weeks to months with a mean of 130 mmHg systolic or 80 mmHg diastolic. While use of appropriate technique is important in all patients, it is particularly essential in those in whom the diagnosis of hypertension is based solely upon office readings ( table 1). In settings where out-of-office blood pressure measurement is not readily available, we suggest using automated office blood pressure monitoring (AOBPM). Patients found to have an office blood pressure of 130 mmHg systolic or 80 mmHg diastolic but an out-of-office blood pressure (either mean daytime or mean home) of <130 mmHg systolic and <80 mmHg diastolic have white coat hypertension rather than true hypertension [4]. In patients with home readings suggestive of white coat hypertension, we recommend confirmation with ABPM ( algorithm 1). Patients with white coat hypertension should undergo reevaluation with out-of-office blood pressure monitoring at least yearly since these patients can develop hypertension over time. Patients who have office readings of 120 to 129 mmHg systolic or 75 to 79 mmHg diastolic and established cardiovascular disease, known kidney disease, or elevated cardiovascular risk should also undergo out-of-office blood pressure measurement [4]. Patients with office blood pressure <130 mmHg systolic and <80 mmHg diastolic but an out-of-office blood pressure (either mean daytime or mean home) 130 mmHg systolic or 80 mmHg diastolic have masked hypertension. Although there are no randomized clinical trials, based upon risk, we believe that patients with masked hypertension should be treated the same as other patients with the diagnosis of hypertension. EVALUATION https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 13/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate When hypertension is suspected based upon office readings or confirmed based upon out-of- office blood pressure readings, an evaluation should be performed to determine the following (see "Initial evaluation of adults with hypertension"): The extent of target-organ damage, if any The presence of established cardiovascular or kidney disease The presence or absence of other cardiovascular risk factors (see "Overview of established risk factors for cardiovascular disease") Lifestyle factors that could potentially contribute to hypertension (see 'Risk factors for primary (essential) hypertension' above) Potential interfering substances (eg, chronic use of nonsteroidal antiinflammatory drugs [NSAIDs], estrogen-containing oral contraceptives) (see 'Secondary or contributing causes of hypertension' above) History The history should search for those facts that help to determine the presence of precipitating or aggravating factors (including prescription medications, nonprescription NSAIDs, and alcohol consumption), the duration of hypertension, previous attempts at treatment, the extent of target-organ damage, and the presence of other known risk factors for cardiovascular disease ( table 7). Physical examination The main goals of the physical examination are to evaluate for signs of end-organ damage, for established cardiovascular disease, and for evidence of potential causes of secondary hypertension. The physical examination should include the underutilized but important funduscopic examination to evaluate for hypertensive retinopathy ( table 8). Laboratory testing The following tests should be performed in all patients with newly diagnosed hypertension [4,46,47] (see "Initial evaluation of adults with hypertension", section on 'Laboratory testing'): Electrolytes (including calcium) and serum creatinine (to calculate the estimated glomerular filtration rate) Fasting glucose Urinalysis Complete blood count Thyroid-stimulating hormone Lipid profile Electrocardiogram https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 14/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Calculate 10-year atherosclerotic cardiovascular disease risk (calculator 1) Additional tests Additional tests may be indicated in certain settings: Urinary albumin to creatinine ratio. Increased albuminuria is recognized as an independent risk factor for cardiovascular disease; it should be performed in all patients with diabetes or chronic kidney disease [48]. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease" and "Epidemiology of chronic kidney disease".) Echocardiography is a more sensitive means of identifying the presence of left ventricular hypertrophy (LVH) than an electrocardiogram, but its use is limited by expense and the lack of clinical trials that define outcome-based treatment differences when LVH is diagnosed [49]. Testing for secondary hypertension Secondary causes of hypertension are relatively uncommon, and testing for secondary hypertension may produce false-positive results. Thus, evaluation for secondary causes is not recommended for all patients with primary hypertension. Instead, a targeted approach is indicated whereby evaluation for secondary causes should be performed only in patients with one or more of the following features (see "Evaluation of secondary hypertension"): An unusual presentation of hypertension (eg, new onset at an especially young or especially old age, presentation with stage 2 hypertension, abrupt onset of hypertension in a patient with previously normal blood pressure, or significant recent elevation in blood pressure in a patient with previously well-controlled hypertension despite adherence to their antihypertensive regimen) Drug-resistant hypertension The presence of a clinical clue for a specific cause of hypertension, such as an abdominal bruit (suggestive of renovascular hypertension) or low serum potassium (suggestive of primary aldosteronism) TREATMENT Lifestyle modification should be prescribed to all patients with elevated blood pressure or hypertension; however, not all patients diagnosed with hypertension require pharmacologic therapy. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 15/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate There are strong data supporting treatment decisions in some patient populations, such as those with severely elevated blood pressure, those at high cardiovascular risk, and older adults. However, data are weak and largely indirect for many other patient populations. As such, good clinical judgment and shared decision-making between patient and provider are paramount. Nonpharmacologic therapy Treatment of hypertension should involve nonpharmacologic therapy (also called lifestyle modification) alone or in concert with antihypertensive drug therapy ( table 9) [4,5,50]. We suggest that at least one aspect of nonpharmacologic therapy should be addressed at every office visit. Dietary salt restriction In well-controlled randomized trials, the overall impact of moderate sodium reduction is a fall in blood pressure in hypertensive and normotensive individuals of 4.8/2.5 and 1.9/1.1 mmHg, respectively ( figure 4) [51,52]. The effects of sodium restriction on blood pressure, cardiovascular disease, and mortality as well as specific recommendations for sodium intake, are discussed in detail elsewhere. (See "Salt intake, salt restriction, and primary (essential) hypertension".) Potassium supplementation, preferably by dietary modification, unless contraindicated by the presence of chronic kidney disease or use of drugs that reduce potassium excretion [4]. (See "Potassium and hypertension".) Weight loss Weight loss in overweight or obese individuals can lead to a significant fall in blood pressure independent of exercise. The decline in blood pressure induced by weight loss can also occur in the absence of dietary sodium restriction [53], but even modest sodium restriction may produce an additive antihypertensive effect [54]. The weight loss- induced decline in blood pressure generally ranges from 0.5 to 2 mmHg for every 1 kg of weight lost ( figure 5) [55]. (See "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension".) DASH diet The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is high in vegetables, fruits, low-fat dairy products, whole grains, poultry, fish, and nuts and low in sweets, sugar-sweetened beverages, and red meats. The DASH dietary pattern is consequently rich in potassium, magnesium, calcium, protein, and fiber but low in

patients with home readings suggestive of white coat hypertension, we recommend confirmation with ABPM ( algorithm 1). Patients with white coat hypertension should undergo reevaluation with out-of-office blood pressure monitoring at least yearly since these patients can develop hypertension over time. Patients who have office readings of 120 to 129 mmHg systolic or 75 to 79 mmHg diastolic and established cardiovascular disease, known kidney disease, or elevated cardiovascular risk should also undergo out-of-office blood pressure measurement [4]. Patients with office blood pressure <130 mmHg systolic and <80 mmHg diastolic but an out-of-office blood pressure (either mean daytime or mean home) 130 mmHg systolic or 80 mmHg diastolic have masked hypertension. Although there are no randomized clinical trials, based upon risk, we believe that patients with masked hypertension should be treated the same as other patients with the diagnosis of hypertension. EVALUATION https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 13/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate When hypertension is suspected based upon office readings or confirmed based upon out-of- office blood pressure readings, an evaluation should be performed to determine the following (see "Initial evaluation of adults with hypertension"): The extent of target-organ damage, if any The presence of established cardiovascular or kidney disease The presence or absence of other cardiovascular risk factors (see "Overview of established risk factors for cardiovascular disease") Lifestyle factors that could potentially contribute to hypertension (see 'Risk factors for primary (essential) hypertension' above) Potential interfering substances (eg, chronic use of nonsteroidal antiinflammatory drugs [NSAIDs], estrogen-containing oral contraceptives) (see 'Secondary or contributing causes of hypertension' above) History The history should search for those facts that help to determine the presence of precipitating or aggravating factors (including prescription medications, nonprescription NSAIDs, and alcohol consumption), the duration of hypertension, previous attempts at treatment, the extent of target-organ damage, and the presence of other known risk factors for cardiovascular disease ( table 7). Physical examination The main goals of the physical examination are to evaluate for signs of end-organ damage, for established cardiovascular disease, and for evidence of potential causes of secondary hypertension. The physical examination should include the underutilized but important funduscopic examination to evaluate for hypertensive retinopathy ( table 8). Laboratory testing The following tests should be performed in all patients with newly diagnosed hypertension [4,46,47] (see "Initial evaluation of adults with hypertension", section on 'Laboratory testing'): Electrolytes (including calcium) and serum creatinine (to calculate the estimated glomerular filtration rate) Fasting glucose Urinalysis Complete blood count Thyroid-stimulating hormone Lipid profile Electrocardiogram https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 14/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Calculate 10-year atherosclerotic cardiovascular disease risk (calculator 1) Additional tests Additional tests may be indicated in certain settings: Urinary albumin to creatinine ratio. Increased albuminuria is recognized as an independent risk factor for cardiovascular disease; it should be performed in all patients with diabetes or chronic kidney disease [48]. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease" and "Epidemiology of chronic kidney disease".) Echocardiography is a more sensitive means of identifying the presence of left ventricular hypertrophy (LVH) than an electrocardiogram, but its use is limited by expense and the lack of clinical trials that define outcome-based treatment differences when LVH is diagnosed [49]. Testing for secondary hypertension Secondary causes of hypertension are relatively uncommon, and testing for secondary hypertension may produce false-positive results. Thus, evaluation for secondary causes is not recommended for all patients with primary hypertension. Instead, a targeted approach is indicated whereby evaluation for secondary causes should be performed only in patients with one or more of the following features (see "Evaluation of secondary hypertension"): An unusual presentation of hypertension (eg, new onset at an especially young or especially old age, presentation with stage 2 hypertension, abrupt onset of hypertension in a patient with previously normal blood pressure, or significant recent elevation in blood pressure in a patient with previously well-controlled hypertension despite adherence to their antihypertensive regimen) Drug-resistant hypertension The presence of a clinical clue for a specific cause of hypertension, such as an abdominal bruit (suggestive of renovascular hypertension) or low serum potassium (suggestive of primary aldosteronism) TREATMENT Lifestyle modification should be prescribed to all patients with elevated blood pressure or hypertension; however, not all patients diagnosed with hypertension require pharmacologic therapy. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 15/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate There are strong data supporting treatment decisions in some patient populations, such as those with severely elevated blood pressure, those at high cardiovascular risk, and older adults. However, data are weak and largely indirect for many other patient populations. As such, good clinical judgment and shared decision-making between patient and provider are paramount. Nonpharmacologic therapy Treatment of hypertension should involve nonpharmacologic therapy (also called lifestyle modification) alone or in concert with antihypertensive drug therapy ( table 9) [4,5,50]. We suggest that at least one aspect of nonpharmacologic therapy should be addressed at every office visit. Dietary salt restriction In well-controlled randomized trials, the overall impact of moderate sodium reduction is a fall in blood pressure in hypertensive and normotensive individuals of 4.8/2.5 and 1.9/1.1 mmHg, respectively ( figure 4) [51,52]. The effects of sodium restriction on blood pressure, cardiovascular disease, and mortality as well as specific recommendations for sodium intake, are discussed in detail elsewhere. (See "Salt intake, salt restriction, and primary (essential) hypertension".) Potassium supplementation, preferably by dietary modification, unless contraindicated by the presence of chronic kidney disease or use of drugs that reduce potassium excretion [4]. (See "Potassium and hypertension".) Weight loss Weight loss in overweight or obese individuals can lead to a significant fall in blood pressure independent of exercise. The decline in blood pressure induced by weight loss can also occur in the absence of dietary sodium restriction [53], but even modest sodium restriction may produce an additive antihypertensive effect [54]. The weight loss- induced decline in blood pressure generally ranges from 0.5 to 2 mmHg for every 1 kg of weight lost ( figure 5) [55]. (See "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension".) DASH diet The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is high in vegetables, fruits, low-fat dairy products, whole grains, poultry, fish, and nuts and low in sweets, sugar-sweetened beverages, and red meats. The DASH dietary pattern is consequently rich in potassium, magnesium, calcium, protein, and fiber but low in saturated fat, total fat, and cholesterol. A trial in which all food was supplied to normotensive or mildly hypertensive adults found that the DASH dietary pattern reduced blood pressure by 6/4 mmHg compared with a typical American-style diet that contained the same amount of sodium and the same number of calories. Combining the DASH dietary pattern with modest sodium restriction produced an additive antihypertensive https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 16/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate effect. These trials and a review of diet in the treatment of hypertension are discussed in detail elsewhere. (See "Diet in the treatment and prevention of hypertension".) Exercise Aerobic, dynamic resistance and isometric resistance exercise can decrease systolic and diastolic pressure by, on average, 4 to 6 mmHg and 3 mmHg, respectively, independent of weight loss. Most studies demonstrating a reduction in blood pressure have employed at least three to four sessions per week of moderate-intensity aerobic exercise lasting approximately 40 minutes for a period of 12 weeks. (See "Exercise in the treatment and prevention of hypertension".) Limited alcohol intake Women who consume two or more alcoholic beverages per day and men who have three or more drinks per day have a significantly increased incidence of hypertension compared with nondrinkers [16,56]. Adult men and women with hypertension should consume, respectively, no more than two and one alcoholic drinks daily [4]. (See "Cardiovascular benefits and risks of moderate alcohol consumption".) The benefits of comprehensive lifestyle modification, including the DASH diet and increased exercise, were tested in the PREMIER trial [57]. At 18 months, there was a lower prevalence of hypertension (22 versus 32 percent) and less use of antihypertensive medications (10 to 14 versus 19 percent), although the difference was not statistically significant. (See "Diet in the treatment and prevention of hypertension", section on 'Dietary Approaches to Stop Hypertension (DASH) diet'.) Pharmacologic therapy In large-scale randomized trials, pharmacologic antihypertensive therapy, as compared with placebo, produces a nearly 50 percent relative risk reduction in the incidence of heart failure, a 30 to 40 percent relative risk reduction in stroke, and a 20 to 25 percent relative risk reduction in myocardial infarction [58]. These relative risk reductions correspond to the following absolute benefits: antihypertensive therapy for four to five years in patients whose blood pressure is 140 to 159 mmHg systolic or 90 to 99 mmHg diastolic prevents a coronary event in 0.7 percent of patients and a cerebrovascular event in 1.3 percent of patients for a total absolute benefit of approximately 2 percent ( figure 6) [59]. Thus, 100 patients must be treated for four to five years to prevent an adverse cardiovascular event in two patients. It is presumed that these statistics underestimate the true benefit of treating hypertension since these data were derived from trials of relatively short duration (five to seven years); this may be insufficient to determine the efficacy of antihypertensive therapy on longer-term diseases such as atherosclerosis and heart failure. (See "Goal blood pressure in adults with hypertension".) Equal if not greater relative risk reductions have been demonstrated with antihypertensive treatment of older hypertensive patients (over age 65 years), most of whom have isolated https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 17/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate systolic hypertension. Because advanced age is associated with higher overall cardiovascular risk, even modest and relatively short-term reductions in blood pressure may provide absolute benefits that are greater than that observed in younger patients [60]. (See "Treatment of hypertension in older adults, particularly isolated systolic hypertension".) The benefits of antihypertensive therapy are less clear and more controversial in patients who have stage 1 hypertension and no preexisting cardiovascular disease, in those with an estimated 10-year cardiovascular risk <10%, and in those >75 years of age who are nonambulatory or living in nursing homes. (See "Goal blood pressure in adults with hypertension" and "Treatment of hypertension in older adults, particularly isolated systolic hypertension", section on 'Problem of frailty'.) Who should be treated with pharmacologic therapy? Randomized trials that demonstrated benefit from treating hypertension with antihypertensive drug therapy used a wide variety of inclusion criteria and variable techniques for measuring blood pressure. As a result, the decision to initiate antihypertensive therapy in individual patients, particularly those not well-represented in clinical trials, is sometimes uncertain. The decision to initiate drug therapy should be individualized and involve shared decision- making between patient and provider. In general, we suggest that antihypertensive drug therapy be initiated in the following hypertensive patients (our suggestions broadly agree with those recommendations made by the 2017 American College of Cardiology/American Heart Association [ACC/AHA] guidelines) [4]: Patients with out-of-office daytime blood pressure 135 mmHg systolic or 85 mmHg diastolic (or an average office blood pressure 140 mmHg systolic or 90 mmHg diastolic if out-of-office readings are not available) Patients with an out-of-office blood pressure (mean home or daytime ambulatory) 130 mmHg systolic or 80 mmHg diastolic (or, if out-of-office readings are unavailable, the average of appropriately measured office readings 130 mmHg systolic or 80 mmHg diastolic) who have one or more of the following features: Established clinical cardiovascular disease (eg, chronic coronary syndrome [stable ischemic heart disease], heart failure, carotid disease, previous stroke, or peripheral arterial disease) Type 2 diabetes mellitus Chronic kidney disease https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 18/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Age 65 years or older An estimated 10-year risk of atherosclerotic cardiovascular disease of at least 10 percent (calculator 1) However, data are limited on the risks and benefits of initiating antihypertensive therapy in patients who have stage 1 hypertension (130 to 139 mmHg systolic and 80 to 89 mmHg diastolic) and who are either over the age of 75 or who have an estimated 10-year risk of atherosclerotic cardiovascular disease of at least 10 percent (but no clinical cardiovascular disease, diabetes, or chronic kidney disease). For these specific patient populations, we suggest an individualized approach with shared decision-making and would consider withholding antihypertensive therapy among those with recurrent falls, dementia, multiple comorbidities, orthostatic hypotension, residence in a nursing home, or limited life expectancy. Choice of initial antihypertensive agents Multiple guidelines and meta-analyses conclude that the degree of blood pressure reduction, not the choice of antihypertensive medication, is the major determinant of reduction in cardiovascular risk in patients with hypertension [58,61- 63]. Recommendations for the use of specific classes of antihypertensive medications are based upon clinical trial evidence of decreased cardiovascular risk, blood pressure-lowering efficacy, safety, and tolerability. Most patients with hypertension will require more than one blood pressure medication to reach goal blood pressure. Having multiple available classes of blood pressure medication permits clinicians to individualize therapy based upon individual patient characteristics and preferences. Some patients have a "compelling" indication for a specific drug or drugs that is unrelated to primary hypertension ( table 10). If there are no specific indications for a particular medication based upon comorbidities, most guidelines and recommendations, including the 2017 ACC/AHA guidelines, recommend that initial therapy be chosen from among the following four classes of medications [4]. (See "Choice of drug therapy in primary (essential) hypertension".) Thiazide-like or thiazide-type diuretics Long-acting calcium channel blockers (most often a dihydropyridine such as amlodipine) Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) A systematic review of the available data published in conjunction with the 2017 ACC/AHA guidelines demonstrated no significant difference in cardiovascular mortality between patients treated with these four drug classes [64]. Additional considerations in choice of initial therapy: https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 19/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate An ACE inhibitor or an ARB should be used for initial monotherapy in patients who have diabetic nephropathy or nondiabetic chronic kidney disease, especially when complicated by proteinuria. (See "Treatment of hypertension in patients with diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".) Beta blockers are no longer recommended as initial monotherapy in the absence of a specific (compelling) indication for their use, such as ischemic heart disease or heart failure with decreased ejection fraction [65,66]. (See "Choice of drug therapy in primary (essential) hypertension".) When choosing among the main classes of drugs that are appropriate for initial monotherapy, many experts consider the patient's race in the decision. This issue is controversial and is discussed separately. (See "Choice of drug therapy in primary (essential) hypertension".) Combination therapy Single-agent therapy will not adequately control blood pressure in most patients whose baseline systolic blood pressure is 15 mmHg or more above their goal. Combination therapy with drugs from different classes has a substantially greater blood pressure-lowering effect than doubling the dose of a single agent, often with a reduction in side effects seen with a higher dose of monotherapy [67]. When more than one agent is needed to control the blood pressure, we recommend therapy with a long-acting ACE inhibitor or ARB in concert with a long-acting dihydropyridine calcium channel blocker. Combination of an ACE inhibitor or ARB with a thiazide diuretic can also be used but may be less beneficial when hydrochlorothiazide is used. ACE inhibitors and ARBs should not be used together. The supportive data for these recommendations are presented elsewhere. (See "Choice of drug therapy in primary (essential) hypertension".) Initial combination antihypertensive therapy with two first-line agents of different classes is suggested in any patient whose blood pressure is more than 20 mmHg systolic or 10 mmHg diastolic above their goal blood pressure [4,5]. (See 'Blood pressure goals (targets)' below.) If blood pressure remains uncontrolled (see 'Blood pressure goals (targets)' below) despite use of two antihypertensive medications, we recommend therapy with ACE inhibitor or ARB in conjunction with both a long-acting dihydropyridine calcium channel blocker and a thiazide-like diuretic (chlorthalidone preferred). If a long-acting dihydropyridine calcium channel blocker is not tolerated due to leg swelling, a non-dihydropyridine calcium channel blocker (ie, verapamil or diltiazem) may be used instead. If a thiazide-like diuretic is not tolerated or is contraindicated, a mineralocorticoid receptor antagonist (ie, spironolactone or eplerenone) may be used. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 20/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate If the above drug classes cannot be used due to intolerance or contraindication, a beta blocker, alpha blocker, or direct arterial vasodilators present other options. Generally, concomitant use of beta blockers and non-dihydropyridine calcium channel blockers should be avoided. Patients not controlled on a combination of three antihypertensive medications that are taken at reasonable doses and that include a diuretic are considered to have drug-resistant hypertension (once nonadherence and white coat effect have been eliminated as possibilities). Diagnosis and management of drug-resistant hypertension is discussed in detail elsewhere. (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".) Fixed-dose, single-pill combination medications should be used whenever feasible to reduce the pill burden on patients and improve medication adherence. (See "The prevalence and control of hypertension in adults", section on 'Methods to improve control rates'.) Blood pressure goals (targets) The ultimate goal of antihypertensive therapy is a reduction in cardiovascular events. The higher the absolute cardiovascular risk, the more likely it is that a patient will benefit from a more aggressive blood pressure goal. However, although cardiovascular events generally decrease with more intensive lowering of blood pressure, the risk of adverse effects, cost, and patient inconvenience increase as more medication is added. (See "Goal blood pressure in adults with hypertension" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus" and "Antihypertensive therapy for secondary stroke prevention" and "Treatment of hypertension in older adults, particularly isolated systolic hypertension" and "Overview of secondary prevention of ischemic stroke".) The authors suggestions for goal blood pressure are as follows, and depend upon the patient s baseline risk of having a cardiovascular event; these suggestions broadly agree with those recommendations made by the 2017 ACC/AHA guidelines but contrast with other guidelines (see "Goal blood pressure in adults with hypertension", section on 'Recommendations of others') [4]: The authors suggest a goal blood pressure of <130 mmHg systolic and <80 mmHg diastolic using out-of-office measurements (or, if out-of-office blood pressure is not available, then an average of appropriately measured office readings) in most patients who qualify for antihypertensive pharmacologic therapy. Identifying patients for initiation of antihypertensive drug therapy is presented above. (See 'Who should be treated with pharmacologic therapy?' above.) However, there is some disagreement among UpToDate authors and editors. Some believe that, among selected hypertensive patients who qualify for antihypertensive therapy but https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 21/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate who are at low absolute cardiovascular risk, a less aggressive goal blood pressure of <135 mmHg systolic and <85 mmHg diastolic (using out-of-office measurement) or <140 mmHg systolic and <90 mmHg diastolic (using an average of appropriately measured office readings) is appropriate. We suggest a less aggressive goal blood pressure of <135 mmHg systolic and <85 mmHg diastolic (using out-of-office measurement) or <140 mmHg systolic and <90 mmHg diastolic (using an average of appropriately measured office readings) in the following groups of hypertensive patients: Patients with labile blood pressure or postural hypotension Patients with side effects to multiple antihypertensive medications Patients 75 years or older with a high burden of comorbidity or a diastolic blood pressure <55 mmHg In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals mentioned above. Once the blood pressure goal is determined in an individual patient, it should be recorded in the patient s medical record, explicitly explained to the patient, and communicated to other members of the health care team. At every visit, a determination should be made as to whether or not blood pressure is at goal. After antihypertensive therapy is initiated, patients should be re-evaluated and therapy should be increased monthly until adequate blood pressure control is achieved [4]. Once blood pressure control is achieved, patients should be reevaluated every three to six months to ensure maintenance of control [4]. Resistant hypertension Resistant hypertension is defined as blood pressure that is not controlled to goal despite adherence to an appropriate regimen of three antihypertensive drugs of different classes (including a diuretic) in which all drugs are prescribed at suitable antihypertensive doses and after white coat effect has been excluded. Blood pressure that requires at least four medications to achieve control is considered controlled resistant hypertension [68]. The definition, evaluation, and treatment of resistant hypertension are discussed in detail elsewhere. (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".) https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 22/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Many patients who appear to have resistant hypertension actually have pseudoresistance rather than true resistance. Pseudoresistance results from some or all of the following problems (see "Definition, risk factors, and evaluation of resistant hypertension", section on 'Apparent, true, and pseudoresistant hypertension'): Inaccurate blood pressure measurement (eg, use of an inappropriately small blood pressure cuff, not allowing a patient to rest quietly before taking readings) Poor adherence to blood pressure medications Poor adherence to lifestyle and dietary approaches to lower blood pressure Suboptimal antihypertensive therapy, due either to inadequate doses, an inappropriate drug combination, or exclusion of a diuretic from the antihypertensive regimen White coat hypertension One or more of the following issues may contribute to true resistant hypertension (see "Definition, risk factors, and evaluation of resistant hypertension", section on 'Risk factors'): Extracellular volume expansion Increased sympathetic activation Ingestion of substances that can elevate the blood pressure, such as nonsteroidal antiinflammatory drugs (NSAIDs) or stimulants Secondary or contributing causes of hypertension The evaluation and management of resistant hypertension is discussed in detail elsewhere. (See "Treatment of resistant hypertension".) Hypertensive urgency and emergency Severe hypertension (usually a diastolic blood pressure above 120 mmHg) with evidence of acute end-organ damage is defined as a hypertensive emergency [4]. Hypertensive emergencies can be life-threatening and require immediate treatment, usually with parenteral medications in a monitored setting ( table 11). The causes and treatment of hypertensive emergency are presented elsewhere. (See "Evaluation and treatment of hypertensive emergencies in adults".) Severe hypertension (usually a diastolic blood pressure above 120 mmHg) in asymptomatic patients who are not experiencing acute end-organ damage is referred to as hypertensive urgency [4]. There is no proven benefit from rapid reduction in blood pressure in such patients [4,69-71]. Hypertensive urgency is common in clinical practice, especially among patients with known hypertension who are not fully adherent to their medications. Most cases of https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 23/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate asymptomatic blood pressure elevations can be addressed in the office setting without referral to a higher level of care. Management of severe asymptomatic hypertension is discussed separately. (See "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults".) Discontinuing therapy Some patients with stage 1 hypertension are well controlled, often on a single medication. After a period of years, the question arises as to whether antihypertensive therapy can be gradually diminished or even discontinued. After discontinuation of treatment, a substantial proportion of patients remain normotensive for at least one to two years [72]; a larger fraction of patients do well with a decrease in the number and/or dose of medications taken [73,74]. More gradual tapering of drug dose is indicated in well-controlled patients taking multiple drugs [75]. (See "Can drug therapy be discontinued in well-controlled hypertension?".) Abrupt cessation of some antihypertensive drugs, especially higher doses of short-acting beta blockers (such as propranolol) or the short-acting alpha-2 agonist (clonidine) can lead to a potentially fatal withdrawal syndrome. Gradual discontinuation of these agents over a period of weeks should prevent this problem. (See "Withdrawal syndromes with antihypertensive drug therapy".) Systems approach to blood pressure management Multiple clinical trials have demonstrated that enhancements to usual care can improve blood pressure control. Many of these enhancements involve changes in the overall approach to the management of hypertension. To improve blood pressure control rates, we recommend adoption of one or more of the following team-based strategies [4]: Electronic or telephonic transfer of home blood pressure readings using validated devices Increased availability of ambulatory blood pressure monitoring (ABPM) and/or clinic automated office blood pressure monitoring (AOBPM) Increased communication (in person, by phone, or electronically) with medical assistants and/or nurses who can assess blood pressure control and work with providers to adjust medications if not controlled Integration of clinical pharmacists into the treatment team Use of fixed stepped care algorithms for titration of medications https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 24/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Increased availability of clinical hypertension specialists to evaluate patients with difficult- to-control blood pressure Increasingly, incomplete adherence is being identified as a primary contributor to poorly controlled and resistant hypertension. (See "Patient adherence and the treatment of hypertension".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: High blood pressure in adults (The Basics)" and "Patient education: Controlling your blood pressure through lifestyle (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Medicines for high blood pressure (The Basics)" and "Patient education: High blood pressure emergencies (The Basics)") Beyond the Basics topics (see "Patient education: High blood pressure in adults (Beyond the Basics)" and "Patient education: High blood pressure treatment in adults (Beyond the Basics)" and "Patient education: High blood pressure, diet, and weight (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 25/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate SUMMARY AND RECOMMENDATIONS Definition of hypertension The following definitions and staging system, which are based upon appropriately measured blood pressure ( table 1), were suggested in 2017 by the American College of Cardiology/American Heart Association (ACC/AHA) (see 'Definitions' above): Normal blood pressure Systolic <120 mmHg and diastolic <80 mmHg Elevated blood pressure Systolic 120 to 129 mmHg and diastolic <80 mmHg Hypertension: - Stage 1 Systolic 130 to 139 mmHg or diastolic 80 to 89 mmHg Stage 2 Systolic at least 140 mmHg or diastolic at least 90 mmHg If there is a disparity in category between the systolic and diastolic pressures, the higher value determines the stage. The diagnosis of hypertension requires integration of home or ambulatory blood pressure monitoring (ABPM) in addition to measurements made in the clinical setting ( table 3). Meeting one or more of these criteria using ABPM qualifies as hypertension (see 'Definitions based upon ambulatory and home readings' above): A 24-hour mean of 125 mmHg systolic or 75 mmHg diastolic Daytime (awake) mean of 130 mmHg systolic or 80 mmHg diastolic Nighttime (asleep) mean of 110 mmHg systolic or 65 mmHg diastolic We find the daytime (awake) average of 130 mmHg systolic or 80 mmHg diastolic to be the most useful of these definitions. Measurement of blood pressure Proper technique and interpretation of the blood pressure is essential in the diagnosis and management of hypertension (see 'Blood pressure measurement' above): A number of steps should ideally be followed to achieve maximum accuracy of office measurement ( table 1). Rather than an auscultatory device (one that requires a stethoscope), we recommend using an oscillometric blood pressure device designed https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 26/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate specifically for the office setting. Automated office blood pressure (AOBP) devices can take multiple consecutive readings in the office with the patient sitting and resting alone (ie, unattended measurement) or with an attendant present. Either unattended or attended AOBP better predicts the results of awake (daytime) ABPM than traditional office blood pressure measurement and may reduce the white coat effect. (See 'Office- based blood pressure measurement' above.) ABPM is the preferred method for confirming the diagnosis of hypertension. High- quality data suggest that ABPM predicts target organ damage and cardiovascular events better than office blood pressure readings. (See 'Ambulatory blood pressure monitoring' above.) To measure blood pressure at home, patients should be instructed to use a validated, automated oscillometric device that measures blood pressure in the brachial artery (upper arm) and to perform measurements in a quiet room after five minutes of rest in the seated position with the back and arm supported and legs uncrossed. At least 12 to 14 measurements should be obtained, with both morning and evening measurements taken, over a period of one week each month. (See 'Home blood pressure monitoring' above.) Diagnosis of hypertension In an individual patient, we feel that making the diagnosis of hypertension requires the integration of multiple blood pressure readings, the use of appropriate technique, and also the use of measurements made outside of the usual office setting ( algorithm 1). (See 'Making the diagnosis of hypertension' above.) A diagnosis can be made, without further confirmatory readings, in the following uncommon scenarios: A patient who presents with hypertensive urgency or emergency (ie, patients with blood pressure 180 mmHg systolic or 120 mmHg diastolic). A patient who presents with an initial blood pressure 160 mmHg systolic or 100 mmHg diastolic and who also has known target end-organ damage (eg, left ventricular hypertension [LVH], hypertensive retinopathy, ischemic cardiovascular disease). In all other patients who have an elevated office blood pressure, the diagnosis of hypertension should be confirmed using out-of-office blood pressure measurement whenever possible. ABPM is considered the gold standard in determining out-of-office blood pressure. However, many payers require evidence of normal out-of-office readings https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 27/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate (suspected white coat hypertension) for reimbursement of ABPM. As such, we suggest home blood pressure measurement as the initial strategy to confirm the diagnosis of hypertension in most patients: Hypertension is diagnosed if the mean home blood pressure, when measured with appropriate technique and with a device that has been validated in the office, is 130 mmHg systolic or 80 mmHg diastolic. ABPM is an alternative to home blood pressure monitoring in settings where ABPM is readily available, particularly if adequate home blood pressures cannot be obtained, if there is doubt about the validity of home readings, or if there is a large discrepancy between office and home readings. When using ABPM, hypertension is diagnosed if the mean daytime blood pressure is 130 mmHg systolic or 80 mmHg diastolic. Occasionally, out-of-office confirmation of hypertension is not possible because of issues with availability of equipment, insurance, and cost. In these situations, a diagnosis of hypertension can be confirmed by serial (at least three) office-based blood pressure measurements spaced over a period of weeks to months with a mean of 130 mmHg systolic 80 mmHg diastolic. While use of appropriate technique is important in all patients, it is particularly essential in those in whom the diagnosis of hypertension is based solely upon office readings ( table 1). In settings where out-of-office blood pressure measurement is not readily available, we suggest using AOBPM. Evaluation of hypertension When hypertension is suspected based upon office readings or confirmed based upon out- of-office blood pressure readings, an evaluation should be performed to determine the following (see 'Evaluation' above): The extent of target-organ damage, if any The presence of established cardiovascular or kidney disease The presence or absence of other cardiovascular risk factors Lifestyle factors that could potentially contribute to hypertension Potential interfering substances (eg, chronic use of nonsteroidal antiinflammatory drugs [NSAIDs], oral contraceptives) Treatment of hypertension Lifestyle modification should be prescribed to all patients with elevated blood pressure or hypertension (

medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: High blood pressure in adults (The Basics)" and "Patient education: Controlling your blood pressure through lifestyle (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Medicines for high blood pressure (The Basics)" and "Patient education: High blood pressure emergencies (The Basics)") Beyond the Basics topics (see "Patient education: High blood pressure in adults (Beyond the Basics)" and "Patient education: High blood pressure treatment in adults (Beyond the Basics)" and "Patient education: High blood pressure, diet, and weight (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 25/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate SUMMARY AND RECOMMENDATIONS Definition of hypertension The following definitions and staging system, which are based upon appropriately measured blood pressure ( table 1), were suggested in 2017 by the American College of Cardiology/American Heart Association (ACC/AHA) (see 'Definitions' above): Normal blood pressure Systolic <120 mmHg and diastolic <80 mmHg Elevated blood pressure Systolic 120 to 129 mmHg and diastolic <80 mmHg Hypertension: - Stage 1 Systolic 130 to 139 mmHg or diastolic 80 to 89 mmHg Stage 2 Systolic at least 140 mmHg or diastolic at least 90 mmHg If there is a disparity in category between the systolic and diastolic pressures, the higher value determines the stage. The diagnosis of hypertension requires integration of home or ambulatory blood pressure monitoring (ABPM) in addition to measurements made in the clinical setting ( table 3). Meeting one or more of these criteria using ABPM qualifies as hypertension (see 'Definitions based upon ambulatory and home readings' above): A 24-hour mean of 125 mmHg systolic or 75 mmHg diastolic Daytime (awake) mean of 130 mmHg systolic or 80 mmHg diastolic Nighttime (asleep) mean of 110 mmHg systolic or 65 mmHg diastolic We find the daytime (awake) average of 130 mmHg systolic or 80 mmHg diastolic to be the most useful of these definitions. Measurement of blood pressure Proper technique and interpretation of the blood pressure is essential in the diagnosis and management of hypertension (see 'Blood pressure measurement' above): A number of steps should ideally be followed to achieve maximum accuracy of office measurement ( table 1). Rather than an auscultatory device (one that requires a stethoscope), we recommend using an oscillometric blood pressure device designed https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 26/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate specifically for the office setting. Automated office blood pressure (AOBP) devices can take multiple consecutive readings in the office with the patient sitting and resting alone (ie, unattended measurement) or with an attendant present. Either unattended or attended AOBP better predicts the results of awake (daytime) ABPM than traditional office blood pressure measurement and may reduce the white coat effect. (See 'Office- based blood pressure measurement' above.) ABPM is the preferred method for confirming the diagnosis of hypertension. High- quality data suggest that ABPM predicts target organ damage and cardiovascular events better than office blood pressure readings. (See 'Ambulatory blood pressure monitoring' above.) To measure blood pressure at home, patients should be instructed to use a validated, automated oscillometric device that measures blood pressure in the brachial artery (upper arm) and to perform measurements in a quiet room after five minutes of rest in the seated position with the back and arm supported and legs uncrossed. At least 12 to 14 measurements should be obtained, with both morning and evening measurements taken, over a period of one week each month. (See 'Home blood pressure monitoring' above.) Diagnosis of hypertension In an individual patient, we feel that making the diagnosis of hypertension requires the integration of multiple blood pressure readings, the use of appropriate technique, and also the use of measurements made outside of the usual office setting ( algorithm 1). (See 'Making the diagnosis of hypertension' above.) A diagnosis can be made, without further confirmatory readings, in the following uncommon scenarios: A patient who presents with hypertensive urgency or emergency (ie, patients with blood pressure 180 mmHg systolic or 120 mmHg diastolic). A patient who presents with an initial blood pressure 160 mmHg systolic or 100 mmHg diastolic and who also has known target end-organ damage (eg, left ventricular hypertension [LVH], hypertensive retinopathy, ischemic cardiovascular disease). In all other patients who have an elevated office blood pressure, the diagnosis of hypertension should be confirmed using out-of-office blood pressure measurement whenever possible. ABPM is considered the gold standard in determining out-of-office blood pressure. However, many payers require evidence of normal out-of-office readings https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 27/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate (suspected white coat hypertension) for reimbursement of ABPM. As such, we suggest home blood pressure measurement as the initial strategy to confirm the diagnosis of hypertension in most patients: Hypertension is diagnosed if the mean home blood pressure, when measured with appropriate technique and with a device that has been validated in the office, is 130 mmHg systolic or 80 mmHg diastolic. ABPM is an alternative to home blood pressure monitoring in settings where ABPM is readily available, particularly if adequate home blood pressures cannot be obtained, if there is doubt about the validity of home readings, or if there is a large discrepancy between office and home readings. When using ABPM, hypertension is diagnosed if the mean daytime blood pressure is 130 mmHg systolic or 80 mmHg diastolic. Occasionally, out-of-office confirmation of hypertension is not possible because of issues with availability of equipment, insurance, and cost. In these situations, a diagnosis of hypertension can be confirmed by serial (at least three) office-based blood pressure measurements spaced over a period of weeks to months with a mean of 130 mmHg systolic 80 mmHg diastolic. While use of appropriate technique is important in all patients, it is particularly essential in those in whom the diagnosis of hypertension is based solely upon office readings ( table 1). In settings where out-of-office blood pressure measurement is not readily available, we suggest using AOBPM. Evaluation of hypertension When hypertension is suspected based upon office readings or confirmed based upon out- of-office blood pressure readings, an evaluation should be performed to determine the following (see 'Evaluation' above): The extent of target-organ damage, if any The presence of established cardiovascular or kidney disease The presence or absence of other cardiovascular risk factors Lifestyle factors that could potentially contribute to hypertension Potential interfering substances (eg, chronic use of nonsteroidal antiinflammatory drugs [NSAIDs], oral contraceptives) Treatment of hypertension Lifestyle modification should be prescribed to all patients with elevated blood pressure or hypertension ( table 9); however, not all patients diagnosed with hypertension require pharmacologic therapy. (See 'Nonpharmacologic therapy' above.) https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 28/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate The decision to initiate drug therapy should be individualized and involve shared decision- making between patient and provider. In general, we suggest that antihypertensive drug therapy be initiated in the following hypertensive patients (see 'Who should be treated with pharmacologic therapy?' above): Patients with out-of-office daytime blood pressure 135 mmHg systolic or 85 mmHg diastolic (or an average office blood pressure 140 mmHg systolic or 90 mmHg diastolic if out-of-office readings not available) Patients with an out-of-office blood pressure (mean home or daytime ambulatory) 130 mmHg systolic or 80 mmHg diastolic (or, if out-of-office readings are unavailable, the average of appropriately measured office readings 130 mmHg systolic or 80 mmHg diastolic) who have one or more of the following features: Established clinical cardiovascular disease (eg, chronic coronary syndrome [stable ischemic heart disease], heart failure, carotid disease, previous stroke, or peripheral arterial disease) - - - Type 2 diabetes mellitus Chronic kidney disease Age 65 years or older An estimated 10-year risk of atherosclerotic cardiovascular disease of at least 10 percent (calculator 1) However, in patients who have stage 1 hypertension (130 to 139 mmHg systolic or 80 to 89 mmHg diastolic), we would consider withholding antihypertensive therapy among those 75 years or older or those who do not have established cardiovascular disease, diabetes, or chronic kidney disease if, in addition, they have recurrent falls, dementia, multiple comorbidities, orthostatic hypotension, residence in a nursing home, or limited life expectancy. (See 'Who should be treated with pharmacologic therapy?' above.) Some patients have a compelling indication for a specific drug or drugs that are unrelated to primary hypertension ( table 10). If there are no specific indications for a particular medication based upon comorbidities, we recommend that initial therapy be chosen from among the following four classes of medications (see 'Choice of initial antihypertensive agents' above): Thiazide-like or thiazide-type diuretics Long-acting calcium channel blockers (most often a dihydropyridine such as amlodipine) Angiotensin-converting enzyme (ACE) inhibitors https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 29/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Angiotensin II receptor blockers (ARBs) Our suggestions for goal blood pressure are as follows and depend upon the patient s baseline risk of having a cardiovascular event (see 'Blood pressure goals (targets)' above): We suggest a goal blood pressure of <130 mmHg systolic and <80 mmHg diastolic using out-of-office measurements (or, if out-of-office blood pressure is not available, then an average of appropriately measured office readings) in most patients who qualify for antihypertensive pharmacologic therapy. However, there is some disagreement among UpToDate authors and editors. Some believe that, among selected hypertensive patients who qualify for antihypertensive therapy but who are at low absolute cardiovascular risk, a less aggressive goal blood pressure of <135 mmHg systolic and <85 mmHg diastolic (using out-of-office measurement) or <140 mmHg systolic and <90 mmHg diastolic (using an average of appropriately measured office readings) is appropriate. We suggest a less aggressive goal blood pressure of <135 mmHg systolic and <85 mmHg diastolic (using out-of-office measurement) or <140 mmHg systolic and <90 mmHg diastolic (using an average of appropriately measured office readings) in the following groups of hypertensive patients: - - Patients with highly variable (labile) blood pressure or postural hypotension Patients with side effects to multiple antihypertensive medications Patients 75 years or older with a high burden of comorbidity or a diastolic blood pressure <55 mmHg In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals mentioned above. ACKNOWLEDGMENT The authors and UpToDate thank Dr. Frank Domino and Dr. Norman Kaplan for authoring and contributing to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 30/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate REFERENCES 1. Muntner P, Carey RM, Gidding S, et al. Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation 2018; 137:109. 2. Yoon SS, Gu Q, Nwankwo T, et al. Trends in blood pressure among adults with hypertension: United States, 2003 to 2012. Hypertension 2015; 65:54. 3. https://www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf. 4. 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Correlation between sleep duration and hypertension: a dose- response meta-analysis. J Hum Hypertens 2019; 33:218. 24. Hartescu I, Stensel DJ, Thackray AE, et al. Sleep extension and metabolic health in male overweight/obese short sleepers: A randomised controlled trial. J Sleep Res 2022; 31:e13469. 25. Stock AA, Lee S, Nahmod NG, Chang AM. Effects of sleep extension on sleep duration, sleepiness, and blood pressure in college students. Sleep Health 2020; 6:32. 26. Carey RM, Moran AE, Whelton PK. Treatment of Hypertension: A Review. JAMA 2022; 328:1849. 27. Nakagomi A, Yasufuku Y, Ueno T, Kondo K. Social determinants of hypertension in high- income countries: A narrative literature review and future directions. Hypertens Res 2022; https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 32/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate 45:1575. 28. 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Impact of diastolic and systolic blood pressure on mortality: implications for the definition of "normal". J Gen Intern Med 2011; 26:685. 40. McGrath BP, Kundu P, Daya N, et al. Isolated Diastolic Hypertension in the UK Biobank: Comparison of ACC/AHA and ESC/NICE Guideline Definitions. Hypertension 2020; 76:699. 41. Jackson R, Lawes CM, Bennett DA, et al. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk. Lancet 2005; 365:434. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 33/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate 42. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for Hypertension in Adults: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2021; 325:1650. 43. Siu AL, U.S. Preventive Services Task Force. Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2015; 163:778. 44. Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada's 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children. Can J Cardiol 2018; 34:506. 45. Bloch MJ, Basile JN. Ambulatory blood pressure monitoring to diagnose hypertension an idea whose time has come. J Am Soc Hypertens 2016; 10:89. 46. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560. 47. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105. 48. Forman JP, Brenner BM. 'Hypertension' and 'microalbuminuria': the bell tolls for thee. Kidney Int 2006; 69:22. 49. Cuspidi C, Lonati L, Macca G, et al. Cardiovascular risk stratification in hypertensive patients: impact of echocardiography and carotid ultrasonography. J Hypertens 2001; 19:375. 50. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:2960. 51. He FJ, Li J, Macgregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013; 346:f1325. 52. Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension 2006; 47:296. 53. Tuck ML, Sowers J, Dornfeld L, et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304:930. 54. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 34/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA 1998; 279:839. 55. Stevens VJ, Corrigan SA, Obarzanek E, et al. Weight loss intervention in phase 1 of the Trials of Hypertension Prevention. The TOHP Collaborative Research Group. Arch Intern Med 1993; 153:849. 56. Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study of nutritional factors and hypertension among US men. Circulation 1992; 86:1475. 57. Elmer PJ, Obarzanek E, Vollmer WM, et al. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial. Ann Intern Med 2006; 144:485. 58. Blood Pressure Lowering Treatment Trialists' Collaboration, Turnbull F, Neal B, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ 2008; 336:1121. 59. Hebert PR, Moser M, Mayer J, et al. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med 1993; 153:578. 60. Blood Pressure Lowering Treatment Trialists' Collaboration. Age-stratified and blood- pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis. Lancet 2021; 398:1053. 61. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31:1281. 62. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007; 115:2761. 63. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338:b1665. 64. Reboussin DM, Allen NB, Griswold ME, et al. Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71:e116. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 35/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate 65. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507. 66. Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta- analysis. Lancet 2010; 375:906. 67. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009; 122:290. 68. Carey RM, Calhoun DA, Bakris GL, et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension 2018; 72:e53. 69. Severe symptomless hypertension. Lancet 1989; 2:1369. 70. O'Mailia JJ, Sander GE, Giles TD. Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987; 107:185. 71. Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996; 276:1328. 72. Schmieder RE, Rockstroh JK, Messerli FH. Antihypertensive therapy. To stop or not to stop? JAMA 1991; 265:1566. 73. Nelson MR, Reid CM, Krum H, et al. Short-term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in the second Australian National Blood Pressure Study (ANBP2). Am J Hypertens 2003; 16:39. 74. Freis ED, Thomas JR, Fisher SG, et al. Effects of reduction in drugs or dosage after long-term control of systemic hypertension. Am J Cardiol 1989; 63:702. 75. Finnerty FA Jr. Stepped-down therapy versus intermittent therapy in systemic hypertension. Am J Cardiol 1990; 66:1373. Topic 3852 Version 78.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 36/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate GRAPHICS Checklist for accurate measurement of blood pressure Key steps for proper BP Specific instructions measurements Step 1: Properly prepare the 1. Have the patient relax, sitting in a chair (feet on floor, back patient supported) for >5 minutes. 2. The patient should avoid caffeine, exercise, and smoking for at least 30 minutes before measurement. 3. Ensure patient has emptied their bladder. 4. Neither the patient nor the observer should talk during the rest period or during the measurement. 5. Remove all clothing covering the location of cuff placement. 6. Measurements made while the patient is sitting or lying on an examining table do not fulfill these criteria. Step 2: Use proper technique for BP measurements 1. Use a BP measurement device that has been validated, and ensure that the device is calibrated periodically.* 2. Support the patient's arm (eg, resting on a desk). 3. Position the middle of the cuff on the patient's upper arm at the level of the right atrium (the midpoint of the sternum). 4. Use the correct cuff size, such that the bladder encircles 80% of the arm, and note if a larger- or smaller-than-normal cuff size is used. 5. Either the stethoscope diaphragm or bell may be used for auscultatory readings. Step 3: Take the proper measurements needed for diagnosis and treatment of elevated BP/hypertension 1. At the first visit, record BP in both arms. Use the arm that gives the higher reading for subsequent readings. 2. Separate repeated measurements by 1 to 2 minutes. 3. For auscultatory determinations, use a palpated estimate of radial pulse obliteration pressure to estimate SBP. Inflate the cuff 20 to 30 mmHg above this level for an auscultatory determination of the BP level. 4. For auscultatory readings, deflate the cuff pressure 2 mmHg per second, and listen for Korotkoff sounds. Step 4: Properly document accurate BP readings 1. Record SBP and DBP. If using the auscultatory technique, record SBP and DBP as onset of the first Korotkoff sound and disappearance of all Korotkoff sounds, respectively, using the nearest even number. 2. Note the time of most recent BP medication taken before measurements. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 37/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Step 5: Average the readings 1. Use an average of 2 readings obtained on 2 occasions to estimate the individual's level of BP. Step 6: Provide BP readings 1. Provide patients the SBP/DBP readings both verbally and in to patient writing. BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Reproduced from: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 115862 Version 3.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 38/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Definition of hypertension according to office, ambulatory, and home BP levels per guideline statements Daytime Nighttime 24-hour SBP/DBP Clinic HBPM ABPM ABPM ABPM 130/80 130/80 130/80 110/65 125/75 ACC/AHA Guidelines [1] 2017 140/90 135/85 135/85 120/70 130/80 ESC/ESH Guidelines [2] 2018 BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; HBPM: home blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ACC/AHA: American College of Cardiology/American Heart Association; ESC/ESH: European Society of Cardiology/European Society of Hypertension. Data from: 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71:e127. 2. Williams B, Giuseppe M, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39:3021. Graphic 119219 Version 1.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 39/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Diagnosis of hypertension in adults https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 40/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 41/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate ABPM: ambulatory blood pressure monitoring; AOBPM: automated office blood pressure monitoring. Home blood pressure must be performed adequately in order for the measurements to be used for diagnosis and management. To be adequate: The accuracy of the home device should be verified in the clinician's office; the patient should measure their blood pressure while seated (with feet flat on the floor), with arm supported (such as on a table), and after several minutes of rest; the blood pressure should be measured at different times per day and over a series of multiple days. A common strategy is to have the patient measure their blood pressure twice daily (once in the morning and once in the evening) for 7 days. Readings from the first day are discarded, and the remaining 12 measurements are averaged. Home blood pressure should not be used for diagnosis and management if it cannot be performed adequately. Adequate home blood pressure should be possible in most cases. Inexpensive devices to measure blood pressure at home are available over the counter. Alternatively, such devices can be borrowed (eg, provided by the clinic). Only rarely are such devices unavailable or unaffordable. ABPM is performed by having the patient wear, typically for 24 hours, an electronic blood pressure device that automatically measures the blood pressure, usually every half-hour during the day and hourly at night. We use the mean daytime value to determine the presence of hypertension. ABPM is possible if it is available in the clinic or via an external vendor and if it can be paid for by the patient's insurance or by the patient. Blood pressure measured in the office may vary according to the manner in which it is obtained. If blood pressure in the office is to be used for the diagnosis of hypertension (rather than using out-of- office blood pressures), we suggest performing unattended AOBPM (using a device that can average multiple readings while the patient sits alone in a room). Unattended AOBPM may provide a measurement that is 5 to 10 mmHg less than a manual measurement (ie, with a stethoscope). Office blood pressure must be performed with proper technique (eg, patient given time to rest, seated with feet flat on the floor, use of multiple measurements, appropriate-sized cuff placed on bare arm, etc). Office blood pressure measured with improper technique should not be used for diagnosis and management of hypertension. Refer to UpToDate topics on measurement of blood pressure for details of proper technique. Graphic 105050 Version 7.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 42/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Corresponding values of SBP/DBP for clinic, HBPM, daytime, nighttime, and 24-hour ABPM measurements Daytime Nighttime Clinic HBPM 24-hour ABPM ABPM ABPM 120/80 120/80 120/80 100/65 115/75 130/80 130/80 130/80 110/65 125/75 140/90 135/85 135/85 120/70 130/80 160/100 145/90 145/90 140/85 145/90 SBP: systolic blood pressure; DBP: diastolic blood pressure; HBPM: home blood pressure monitoring; ABPM: ambulatory blood pressure monitoring. References: 1. Uhlig K, Balk EM, Patel K, et al. Self-Measured Blood Pressure Monitoring: Comparative E ectiveness. Agency for Healthcare Research and Quality, Rockville, MD 2012. 2. Margolis KL, Asche SE, Bergdall AR, et al. E ect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA 2013; 310:46. 3. McManus RJ, Mant J, Haque MS, et al. E ect of self-monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular disease: the TASMIN-SR randomized clinical trial. JAMA 2014; 312:799. 4. Siu AL. Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2015; 163:778. 5. Yi SS, Tabaei BP, Angell SY, et al. Self-blood pressure monitoring in an urban, ethnically diverse population: a randomized clinical trial utilizing the electronic health record. Circ Cardiovasc Qual Outcomes 2015; 8:138. 6. Agarwal R, Bills JE, Hecht TJW, et al. Role of home blood pressure monitoring in overcoming therapeutic inertia and improving hypertension control: a systematic review and meta-analysis. Hypertension 2011; 57:29. 7. O'Brien E, Stergiou GS. The pursuit of accurate blood pressure measurement: a 35-year travail. J Clin Hypertens (Greenwich) 2017; 19:746. 8. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159. 9. Pickering TG, Miller NH, Ogedegbe G, et al. Call to action on use and reimbursement for home blood pressure monitoring: a joint scienti c statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association. Hypertension 2008; 52:10. 10. National Clinical Guideline Centre. Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34. Roayl College of Physicians, London 2011. Reproduced from: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 116037 Version 1.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 43/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Reasons to evaluate a patient for masked or white coat hypertension Antihypertensive Suspected Reason treatment status classification Not on treatment Masked hypertension Office-based blood pressures 10 mmHg or less below the patient's goal (eg, systolic pressure 120 to 129 mmHg) On treatment Masked uncontrolled Office-based blood pressures below the patient's goal plus any of the following: hypertension Elevated atherosclerotic cardiovascular disease risk (eg, 10-year atherosclerotic cardiovascular disease risk >10%) Chronic kidney disease Diabetes mellitus Evidence of new or worsening end-organ

2017 140/90 135/85 135/85 120/70 130/80 ESC/ESH Guidelines [2] 2018 BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure; HBPM: home blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ACC/AHA: American College of Cardiology/American Heart Association; ESC/ESH: European Society of Cardiology/European Society of Hypertension. Data from: 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71:e127. 2. Williams B, Giuseppe M, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39:3021. Graphic 119219 Version 1.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 39/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Diagnosis of hypertension in adults https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 40/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 41/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate ABPM: ambulatory blood pressure monitoring; AOBPM: automated office blood pressure monitoring. Home blood pressure must be performed adequately in order for the measurements to be used for diagnosis and management. To be adequate: The accuracy of the home device should be verified in the clinician's office; the patient should measure their blood pressure while seated (with feet flat on the floor), with arm supported (such as on a table), and after several minutes of rest; the blood pressure should be measured at different times per day and over a series of multiple days. A common strategy is to have the patient measure their blood pressure twice daily (once in the morning and once in the evening) for 7 days. Readings from the first day are discarded, and the remaining 12 measurements are averaged. Home blood pressure should not be used for diagnosis and management if it cannot be performed adequately. Adequate home blood pressure should be possible in most cases. Inexpensive devices to measure blood pressure at home are available over the counter. Alternatively, such devices can be borrowed (eg, provided by the clinic). Only rarely are such devices unavailable or unaffordable. ABPM is performed by having the patient wear, typically for 24 hours, an electronic blood pressure device that automatically measures the blood pressure, usually every half-hour during the day and hourly at night. We use the mean daytime value to determine the presence of hypertension. ABPM is possible if it is available in the clinic or via an external vendor and if it can be paid for by the patient's insurance or by the patient. Blood pressure measured in the office may vary according to the manner in which it is obtained. If blood pressure in the office is to be used for the diagnosis of hypertension (rather than using out-of- office blood pressures), we suggest performing unattended AOBPM (using a device that can average multiple readings while the patient sits alone in a room). Unattended AOBPM may provide a measurement that is 5 to 10 mmHg less than a manual measurement (ie, with a stethoscope). Office blood pressure must be performed with proper technique (eg, patient given time to rest, seated with feet flat on the floor, use of multiple measurements, appropriate-sized cuff placed on bare arm, etc). Office blood pressure measured with improper technique should not be used for diagnosis and management of hypertension. Refer to UpToDate topics on measurement of blood pressure for details of proper technique. Graphic 105050 Version 7.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 42/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Corresponding values of SBP/DBP for clinic, HBPM, daytime, nighttime, and 24-hour ABPM measurements Daytime Nighttime Clinic HBPM 24-hour ABPM ABPM ABPM 120/80 120/80 120/80 100/65 115/75 130/80 130/80 130/80 110/65 125/75 140/90 135/85 135/85 120/70 130/80 160/100 145/90 145/90 140/85 145/90 SBP: systolic blood pressure; DBP: diastolic blood pressure; HBPM: home blood pressure monitoring; ABPM: ambulatory blood pressure monitoring. References: 1. Uhlig K, Balk EM, Patel K, et al. Self-Measured Blood Pressure Monitoring: Comparative E ectiveness. Agency for Healthcare Research and Quality, Rockville, MD 2012. 2. Margolis KL, Asche SE, Bergdall AR, et al. E ect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA 2013; 310:46. 3. McManus RJ, Mant J, Haque MS, et al. E ect of self-monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular disease: the TASMIN-SR randomized clinical trial. JAMA 2014; 312:799. 4. Siu AL. Screening for high blood pressure in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2015; 163:778. 5. Yi SS, Tabaei BP, Angell SY, et al. Self-blood pressure monitoring in an urban, ethnically diverse population: a randomized clinical trial utilizing the electronic health record. Circ Cardiovasc Qual Outcomes 2015; 8:138. 6. Agarwal R, Bills JE, Hecht TJW, et al. Role of home blood pressure monitoring in overcoming therapeutic inertia and improving hypertension control: a systematic review and meta-analysis. Hypertension 2011; 57:29. 7. O'Brien E, Stergiou GS. The pursuit of accurate blood pressure measurement: a 35-year travail. J Clin Hypertens (Greenwich) 2017; 19:746. 8. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159. 9. Pickering TG, Miller NH, Ogedegbe G, et al. Call to action on use and reimbursement for home blood pressure monitoring: a joint scienti c statement from the American Heart Association, American Society of Hypertension, and Preventive Cardiovascular Nurses Association. Hypertension 2008; 52:10. 10. National Clinical Guideline Centre. Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34. Roayl College of Physicians, London 2011. Reproduced from: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 116037 Version 1.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 43/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Reasons to evaluate a patient for masked or white coat hypertension Antihypertensive Suspected Reason treatment status classification Not on treatment Masked hypertension Office-based blood pressures 10 mmHg or less below the patient's goal (eg, systolic pressure 120 to 129 mmHg) On treatment Masked uncontrolled Office-based blood pressures below the patient's goal plus any of the following: hypertension Elevated atherosclerotic cardiovascular disease risk (eg, 10-year atherosclerotic cardiovascular disease risk >10%) Chronic kidney disease Diabetes mellitus Evidence of new or worsening end-organ damage (eg, prior atherosclerotic cardiovascular event, heart failure, left ventricular hypertrophy, hypertensive retinopathy) Not on treatment White coat hypertension Office-based blood pressures above the patient's goal (but <180/120 mmHg) despite a 3-month trial of lifestyle modifications, and no evidence of hypertensive end-organ damage On a minimum of 3 medications White coat effect Office-based blood pressures above the patient's goal On treatment White coat effect Office-based blood pressures at or above the patient's goal with symptoms of hypotension (eg, lightheadedness, falls) at home or work Not on treatment or on All of the above Labile office-based blood pressures treatment Adapted from: 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension 2018; 71:e13. 2. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39:3021. 3. Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada's 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 2018; 34:506. Graphic 126949 Version 1.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 44/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Selection criteria for blood pressure cuff size for measurement of blood pressure in adults [1,2] Arm circumference Usual cuff size 22 to 26 cm Small adult 27 to 34 cm Adult 35 to 44 cm Large adult 45 to 52 cm Adult thigh References: 1. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 2005; 111:697. 2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension 2018; 71:e13. Graphic 115863 Version 2.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 45/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Procedures for use of home blood pressure monitoring Patient training should occur under medical supervision, including: Information about hypertension. Selection of equipment. Acknowledgment that individual BP readings may vary substantially. Interpretation of results. Devices: Verify use of automated validated devices. Use of auscultatory devices (mercury, aneroid, or other) is not generally useful for HBPM because patients rarely master the technique required for measurement of BP with auscultatory devices. Monitors with provision for storage of readings in memory are preferred. Verify use of appropriate cuff size to fit the arm. Verify that left/right inter-arm differences are insignificant. If differences are significant, instruct patient to measure BPs in the arm with higher readings. Instructions on HBPM procedures: Remain still: Avoid smoking, caffeinated beverages, or exercise within 30 minutes before BP measurements. Ensure 5 minutes of quiet rest before BP measurements. Sit correctly: Sit with back straight and supported (on a straight-backed dining chair, for example, rather than a sofa). Sit with feet flat on the floor and legs uncrossed. Keep arm supported on a flat surface (such as a table), with the upper arm at heart level. Bottom of the cuff should be placed directly above the antecubital fossa (bend of the elbow). Take multiple readings: Take at least 2 readings 1 minute apart in morning before taking medications and in evening before supper. Optimally, measure and record BP daily. Ideally, obtain weekly BP readings https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 46/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate beginning 2 weeks after a change in the treatment regimen and during the week before a clinic visit. Record all readings accurately: Monitors with built-in memory should be brought to all clinic appointments. BP should be based on an average of readings on 2 occasions for clinical decision making. The information above may be reinforced with videos available online: https://www.heart.org/en/health-topics/high-blood-pressure/understanding-blood-pressure- readings/monitoring-your-blood-pressure-at-home https://targetbp.org/tools_downloads/self-measured-blood-pressure-video/ BP: blood pressure; HBPM: home blood pressure monitoring. Reproduced from: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 115864 Version 5.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 47/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Cardiovascular risk with LVH by echocardiography Four-year, age-adjusted incidence of cardiovascular events in men and women in the Framingham Study according to left ventricular mass determined by echocardiography. Subjects with increased left ventricular mass (far right panel) had a marked increase in cardiovascular risk. LVH: left ventricular hypertrophy; CV: cardiovascular. Adapted from: Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322:1561. Graphic 52329 Version 4.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 48/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Coronary heart disease mortality related to blood pressure and age Coronary heart disease (CHD) mortality rate, pictured on a log scale with 95% confidence intervals (CI), in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. CHD mortality increases with both higher pressures and older ages. For diastolic pressure, each age- specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). IHD: ischemic heart disease. Reproduced from: Lewington S, Clarke R, Qizilbash N, et al. Age-speci c relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. Illustration used with the permission of Elsevier. All rights reserved. Graphic 75106 Version 9.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 49/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Stroke mortality related to blood pressure and age Stroke mortality rate, pictured on a log scale with 95% CI, in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. Stroke mortality increases with both higher pressures and older ages. For diastolic pressure, each age-specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). CI: confidence interval. Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. Graphic 66793 Version 5.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 50/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Additive effects of risk factors on cardiovascular disease at 5 years Cumulative absolute risk of CVD at 5 years according to systolic blood pressure and specified levels of other risk factors. The reference category is a non-diabetic, non-smoking 50-year-old woman with a serum TC of 154 mg/dL (4.0 mmol/L) and HDL cholesterol of 62 mg/dL (1.6 mmol/L). The CVD risks are given for systolic blood pressure levels of 110, 130, 150, and 170 mmHg. In the other categories, the additional risk factors are added consecutively. As an example, the diabetes category is a 50-year-old diabetic man who is a smoker and has a TC of 270 mg/dL (7 mmol/L) and HDL cholesterol of 39 mg/dL (1 mmol/L). BP: blood pressure; CVD: cardiovascular disease; HDL: high-density lipoprotein; TC: total cholesterol. Adapted from: Jackson R, Lawes CM, Bennett DA, et al. Lancet 2005; 365:434. Graphic 55353 Version 12.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 51/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Important aspects of the history in the patient with hypertension Duration of hypertension Presence of other risk factors Last known normal blood pressure Smoking Course of the blood pressure Diabetes Dyslipidemia Prior treatment of hypertension Physical inactivity Drugs: types, doses, side effects Dietary history Intake of agents that may cause hypertension Sodium Nonsteroidal antiinflammatory drugs Processed foods Estrogens Alcohol Adrenal steroids Saturated fats Cocaine Psychosocial factors Sympathomimetics Family structure Excessive sodium Work status Family history Educational level Hypertension Sexual function Premature cardiovascular disease or death Features of sleep apnea Familial diseases: pheochromocytoma, renal disease, diabetes, gout Early morning headaches Daytime somnolence Symptoms of secondary causes Loud snoring Muscle weakness Erratic sleep Spells of tachycardia, sweating, tremor Thinning of the skin Flank pain Symptoms of target-organ damage Headaches Transient weakness or blindness Loss of visual acuity Chest pain Dyspnea Claudication https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 52/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Graphic 77599 Version 6.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 53/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Important aspects of the physical examination in the hypertensive patient Accurate measurement of blood pressure General appearance Distribution of body fat Skin lesions Muscle strength Alertness Fundoscopy Hemorrhage Papilledema Cotton wool spots Arteriolar narrowing and arteriovenous nicking Neck Palpation and auscultation of carotids Thyroid Heart Size Rhythm Sounds Lungs Rhonchi Rales Abdomen Renal masses Bruits over aorta or renal arteries Femoral pulses Extremities Peripheral pulses Edema Neurologic assessment https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 54/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Visual disturbance Focal weakness Confusion Graphic 69470 Version 4.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 55/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Best proven nonpharmacologic interventions for prevention and treatment of hypertension* Approximate impact on SBP Nonpharmacologic Dose intervention Hypertension Normotension Refere Weight loss Weight/body fat 5 mmHg 3 mmHg [1] Best goal is ideal body weight, but aim for at least a 1 kg reduction in body weight for most adults who are overweight. Expect about 1 mmHg for every 1 kg reduction in body weight. Healthy diet DASH dietary pattern 11 mmHg 3 mmHg [2,3] Consume a diet rich in fruits, vegetables, whole grains, and low-fat dairy products, with reduced content of saturated and total fat. Reduced intake of Dietary sodium 5 to -6 mmHg 2 to -3 mmHg [4,5] Optimal goal is <1500 mg/day, but aim for at dietary sodium least a 1000 mg/day reduction in most adults. Enhanced Dietary potassium 4 mmHg 2 mmHg [6] Aim for 3500 to 5000 intake of dietary mg/day, preferably by potassium https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 56/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate consumption of a diet rich in potassium. Physical activity Aerobic 5 to -8 mmHg 2 to -4 mmHg [7,8] 90 to 150 minutes/week. 65 to 75% heart rate reserve. Dynamic resistance 4 mmHg 2 mmHg [7] 90 to 150 minutes/week. 50 to 80% of maximum 1 repetition weight. 6 exercises, 3 sets/exercise, 10 repetitions/set. Isometric resistance 5 mmHg 4 mmHg [9,10] 4 2 minutes (hand grip), 1 minute rest between exercises, 30 to 40% maximum voluntary contraction, 3 sessions/week. 8 to 10 weeks. Moderation Alcohol consumption 4 mmHg 3 mmHg [11-13] In individuals in alcohol who drink alcohol, intake reduce alcohol to: Men: 2 drinks daily. Women: 1 drink daily. SBP: systolic blood pressure; DASH: Dietary Approaches to Stop Hypertension. https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 57/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Type, dose, and expected impact on BP in adults with a normal BP and with hypertension. In the United States, one "standard" drink contains roughly 14 g of pure alcohol, which is typically found in 12 oz of regular beer (usually about 5% alcohol), 5 oz of wine (usually about 12% alcohol), [14] and 1.5 oz of distilled spirits (usually about 40% alcohol). Resources: National Heart, Lung, and Blood Institute. Your Guide to Lowering Your Blood Pressure With DASH. Available at: https://www.nhlbi.nih.gov/ les/docs/public/heart/new_dash.pdf (Accessed on August 16, 2019). Top 10 DASH Diet Tips. Available at: http://dashdiet.org/dash_diet_tips.asp (Accessed on September 18, 2017). References: 1. Neter JE, Stam BE, Kok FJ, et al. In uence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2003; 42:878. 2. Appel LJ, Champagne CM, Harsha DW, et al. E ects of comprehensive lifestyle modi cation on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003; 289:2083. 3. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the e ects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336:1117. 4. Aburto NJ, Ziolkovska A, Hooper L, et al. E ect of lower sodium intake on health: systematic review and metaanalyses. BMJ 2013; 346:f1326. 5. He FJ, Li J, MacGregor GA. E ect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013; 346:f1325. 6. Whelton PK, He J, Cutler JA, et al. E ects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. JAMA 1997; 277:1624. 7. Cornelissen VA, Smart NA. Exercise training for blood pressure: a systematic review and meta-analysis. J Am Heart Assoc 2013; 2:e004473. 8. Whelton SP, Chin A, Xin X, et al. E ect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med 2002; 136:493. 9. Carlson DJ, Dieberg G, Hess NC, et al. Isometric exercise training for blood pressure management: a systematic review and meta-analysis. Mayo Clin Proc 2014; 89:327. 10. Inder JD, Carlson DJ, Dieberg G, et al. Isometric exercise training for blood pressure management: a systematic review and meta-analysis to optimize bene t. Hypertens Res 2016; 39:88. 11. Whelton SP, Chin A, Xin X, et al. E ect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med 2002; 136:493. 12. Xin X, He J, Frontini MG, et al. E ects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2001; 38:1112. 13. Roerecke M, Kaczorowski J, Tobe SW, et al. The e ect of a reduction in alcohol consumption on blood pressure: a systematic review and meta-analysis. Lancet Public Health 2017; 2:e108. 14. National Institute on Alcohol Abuse and Alcoholism (NIAAA). What Is A Standard Drink? Available at: https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/what-standard-drink (Accessed on August 16, 2017). Reproduced from: Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol 2017. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 116041 Version 3.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 58/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Blood pressure change and sodium reduction Pooled results from all sodium-reduction trials concerning the mean net change in blood pressure due to restrictions in sodium intake among various subsets of patients. SBP: systolic blood pressure; DBP: diastolic blood pressure. The mean change is compared with control values. Data from: Cutler JA, Follmann D, Allender PS. Am J Clin Nutr 1997; 65:643S. Graphic 81634 Version 4.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 59/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Weight loss-induced reduction in diastolic blood pressure Relationship between the quantity of weight lost and the fall in diastolic blood pressure in 308 moderately obese patients given a weight reduction regimen for 18 months. The patients began with a diastolic pressure between 80 and 89 mmHg; those who lost the most weight had the largest reduction in diastolic pressure. The decreases in the systolic pressure were similar. BP: blood pressure. Data from: Stevens VJ, Corrigan SA, Obarzanek E, et al. Weight loss intervention in phase 1 of the Trials of Hypertension Prevention. The TOHP Collaborative Research Group. Arch Intern Med 1993; 153:849. Graphic 60178 Version 6.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 60/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Cardiovascular benefit of treating mild hypertension Reduced incidence of fatal and total coronary heart disease (CHD) events and strokes following antihypertensive therapy in 17 controlled studies involving almost 48,000 patients with mild to moderate hypertension. The number of patients having each of these events is depicted, with active treatment lowering the incidence of coronary events by 16 percent and stroke by 40 percent. However, the absolute benefit (as shown, in percent, by the numbers at the top of the graph) was much less. Treatment for approximately four to five years prevented a coronary event or a stroke in 2 percent of patients (0.7 + 1.3), including prevention of death in 0.8 percent. CVA: cerebrovascular accident (stroke). Data from: Hebert PR, Moser M, Mayer J, et al. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med 1993; 153:578. Graphic 52231 Version 8.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 61/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 62/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 63/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Hypertensive emergencies Grades III to IV hypertensive retinopathy with severely elevated blood pressures Cerebrovascular Hypertensive encephalopathy Atherothrombotic brain infarction with severe hypertension Intracerebral hemorrhage Subarachnoid hemorrhage Cardiac Acute aortic dissection Acute left ventricular failure Acute or impending myocardial infarction After coronary bypass surgery Renal Acute glomerulonephritis Renal crises from collagen vascular diseases Severe hypertension after kidney transplantation Microangiopathic hemolytic anemia Excessive circulating catecholamines Pheochromocytoma crisis Food or drug interactions with monoamine-oxidase inhibitors Sympathomimetic drug use (cocaine) Rebound hypertension after sudden cessation of antihypertensive drugs Eclampsia Surgical Severe hypertension in patients requiring immediate surgery Postoperative hypertension Postoperative bleeding from vascular suture lines Severe body burns Severe epistaxis Graphic 54145 Version 5.0 https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 64/65 7/6/23, 12:49 PM Overview of hypertension in adults - UpToDate Contributor Disclosures Jan Basile, MD Grant/Research/Clinical Trial Support: Ablative Solutions [Hypertension]; Recor Pharma [Hypertension]. Consultant/Advisory Boards: Eli Lilly [SURPASS Diabetes Trial]. All of the relevant financial relationships listed have been mitigated. Michael J Bloch, MD, FACP, FASH, FSVM, FNLA Grant/Research/Clinical Trial Support: Amgen [Lipids]; Recor [Hypertension]. Consultant/Advisory Boards: Amgen [Lipids]; Esperion [Lipids]; Janssen [Hypertension]; Medtronic [Hypertension]; Novartis [Lipids]; Recor [Hypertension]. Speaker's Bureau: Esperion [Lipids]; Janssen [Anticoagulation]. All of the relevant financial relationships listed have been mitigated. George L Bakris, MD Grant/Research/Clinical Trial Support: Bayer [Diabetic nephropathy]; KBP Biosciences [Resistant hypertension]; Novo Nordisk [Diabetic kidney disease]. Consultant/Advisory Boards: Alnylam [Resistant hypertension]; AstraZeneca [Diabetic nephropathy]; Bayer [Nephropathy]; Ionis [Resistant hypertension]; KBP BioSciences [Resistant hypertension]; Vifor [Hyperkalemia]. All of the relevant financial relationships listed have been mitigated. William B White, MD Consultant/Advisory Boards: AB Science [Alzheimer's disease, mastocytosis]; Alynam [Heart failure]; AstraZeneca [Lupus, lung disease]; Bristol-Myers Squibb [Psoriasis]; Cadence [Oral contraception]; Cerevel Therapeutics [Cancer, schizophrenia]; Chinook [IgA nephropathy]; JAZZ [Narcolepsy]; Marius [Hypogonadism]; Medtronics [Renal denervation]; Takeda [Gout, narcolepsy, cancer]; Travere [IgA nephropathy]; UCB [Psoriasis, arthritis]. All of the relevant financial relationships listed have been mitigated. John P Forman, MD, MSc No relevant financial relationship(s) with ineligible companies to disclose. Karen Law, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-hypertension-in-adults/print 65/65

7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of primary prevention of cardiovascular disease : Charles H Hennekens, MD, DrPH : David Seres, MD, Freek Verheugt, MD, FACC, FESC : Sara Swenson, MD, Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 25, 2022. INTRODUCTION In the United States and most resource-abundant countries, cardiovascular disease (CVD), which includes coronary heart disease (CHD), stroke, heart failure and peripheral artery disease, are leading causes of morbidity and mortality in adults [1,2]. Further, CVD is becoming the leading cause of death worldwide. An overview of the primary prevention of CVD is presented here, including a discussion of the additive benefits of risk factor reductions through therapeutic lifestyle changes (TLCs) and adjunctive drug therapies of proven benefit. Secondary prevention of CVD, emerging risk factors, and determining individual risk of a patient without known CVD are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of established risk factors for cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".) RATIONALE The following have been identified as major risk factors for cardiovascular disease (CVD). These factors can be modified with therapeutic lifestyle changes (TLCs) or treatment [3]: Smoking Overweight and obesity Unhealthy diet https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 1/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Physical inactivity Dyslipidemia Hypertension Diabetes mellitus (considered in some guidelines as a coronary heart disease [CHD] risk equivalent) Globally, up to 90 percent of the stroke burden may be attributable to modifiable risk factors, which can be substantially reduced by effective implementation of TLCs and adjunctive drug therapies of proven benefit. Additionally, in the descriptive INTERHEART study of patients from 52 countries, nine potentially modifiable factors accounted for over 90 percent of the population-attributable risk of a first myocardial infarction (MI) [4,5]. These included cigarette smoking, dyslipidemia, hypertension, diabetes, abdominal obesity, and psychosocial factors. Additional factors associated with lowered risks included regular physical activity, daily consumption of fruits and vegetables, and daily consumption of small amounts of alcohol. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Patients without known CVD'.) In descriptive data from a nationally representative survey, five modifiable risk factors for CVD (elevated cholesterol, diabetes, hypertension, obesity, and smoking) accounted for one-half of CVD deaths in United States adults aged 45 to 79 from 2009 to 2010 [6]. The preventable fraction of CVD mortality based on these risk factors was 54 percent for men and 50 percent for women. The deleterious consequences of multiple risk factors are, at least, additive. In the Framingham Heart Study of over 5000 adults, those with five risk factors had a 10-year risk of a first CHD event of 25 to 30 percent, which is comparable to the absolute risk of a recurrent event for many patients who have survived a prior MI or occlusive stroke ( figure 1) [7]. The majority of risk factors for a first CVD and stroke are modifiable by TLCs and adjunctive drug therapies of proven benefit [8]. In the United States, CVD mortality has been declining over the past several decades; however, due in part to increasing overweight and obesity as well as decreasing regular physical activity, the rates of decline have slowed since 2011 and are no longer evident [9]. It had been estimated that nearly half of the recent decline was due to earlier diagnosis and more aggressive treatment of modifiable risk factors, especially of lipids and blood pressure with adjunctive drug therapies, including statins, aspirin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and beta adrenergic blockers [10]. The remaining half of the decline in CVD mortality is attributable to primary prevention, in particular TLCs. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 2/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate The benefits of maintaining a healthy lifestyle in the primary prevention of CVD were apparent in observational data from the Nurses Health Study, a large, prospective cohort of over 121,701 female nurses in the United States followed for over 20 years. Women who maintained a desirable body weight, ate a healthy diet, exercised regularly, and did not smoke cigarettes experienced an 84 percent reduction in risk of clinical CVD events [11]. Further, in the Women's Health Study of 39,872 female health professionals in the United States, those practicing healthy lifestyle behaviors had a 55 percent lower risk of subsequent stroke [12]. MAJOR COMPONENTS Healthy diet Individuals who self-select for a healthy diet have significantly lower risks of cardiovascular disease (CVD), including both coronary heart disease (CHD) and stroke. Components of a healthy diet include intakes of: Fruits and vegetables Fiber, including cereals Foods with a low glycemic index and low glycemic load Monounsaturated fat rather than trans fatty acids or saturated fats Omega-3 fatty acids (from fish or plant sources) (see 'Omega-3 fatty acids' below and "Dietary fat", section on 'Polyunsaturated fatty acids' and "Healthy diet in adults", section on 'Protein-rich foods') Observational studies have consistently shown that individuals consuming diets high in vegetables and fruits, such as the Mediterranean diet, have a reduced risk of CVD [13]. Individuals who consume more vegetables and fruits also tend to eat less meat and saturated fat. It is plausible, but unproven, that the apparent benefit may be due to specific compounds in vegetables and fruits, but the results of large-scale randomized trials have not generally supported this possibility. (See "Healthy diet in adults", section on 'Mediterranean diet'.) A healthy diet and increased physical activity are therapeutic lifestyle changes (TLCs) to reduce risks of CVD that are supported by a large totality of evidence. Nonetheless, the United States may lead the world in overweight and obesity [14], and only 21 percent reach the daily minimum requirement for physical activity [15-17]. The US Preventive Services Task Force (USPSTF) recommends that adults with CVD risk factors receive behavioral counseling interventions to promote a healthy diet and increased physical activity [18]. CVD risk factors are defined as hypertension or elevated blood pressure, dyslipidemia, mixed or multiple risk factors, especially those with metabolic syndrome or an estimated 10-year CVD risk of 7.5 percent or greater. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 3/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Antioxidants as a component of a healthy diet show beneficial effects in basic research and observational studies, but randomized trials to detect the most plausible small to moderate benefits have generally shown no net benefit. Thus, the totality of evidence on supplements does not support their routine use for CVD prevention [19]. (See "Vitamin intake and disease prevention", section on 'Antioxidants'.) The role of folic acid supplementation in patients at risk for CVD is discussed separately. (See "Vitamin intake and disease prevention", section on 'Cardiovascular disease'.) Smoking avoidance and cessation Cigarette smoking remains both the leading avoidable cause of premature death worldwide as well as a major avoidable cause of morbidity. The totality of evidence indicates that the amount of cigarettes currently smoked increases morbidity and mortality from CVD, and benefits of cessation begin to appear after only a few months and reach that of the nonsmoker in several years, even among older adults [20]. Thus, for CVD, it is never too late to quit, whereas for cancer it is never too early. The risks of cancer are chiefly related to duration, and even 10 years after quitting the cancer risks remain about midway between those of the continuing and nonsmoker (See "Overview of smoking cessation management in adults" and "Cardiovascular risk of smoking and benefits of smoking cessation" and "Secondhand smoke exposure: Effects in adults".) All smokers should be counseled on a regular basis to quit. A number of approaches, including behavioral therapy, nicotine replacement therapy, varenicline, and other pharmacologic therapies, are available [21]. (See "Overview of smoking cessation management in adults".) Hypertension control Hypertension is a well-established risk factor for CVD, including morbidity and mortality from stroke, coronary heart disease (CHD), heart failure, and sudden death. (See "Cardiovascular risks of hypertension".) Definition Hypertension is defined in the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines as a systolic pressure 130 mmHg or a diastolic pressure 80 mmHg [22]. Goal blood pressure Goal blood pressure may depend in part upon comorbidities (eg, diabetes, chronic kidney disease) and estimated cardiovascular risk; these issues are presented separately. (See "Goal blood pressure in adults with hypertension".) Nonpharmacologic measures All patients with or without hypertension or elevated blood pressure should adhere to a healthy diet and increased physical activity. In addition, those with hypertension or elevated blood pressure should pay particular attention to nonpharmacologic TLCs which include weight reduction, salt restriction, and avoidance of https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 4/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate excess alcohol intake. (See "Overview of hypertension in adults", section on 'Nonpharmacologic therapy'.) Pharmacologic therapy Antihypertensive drugs are necessary for patients with persistent hypertension despite TLCs. Most patients will require multiple antihypertensive drug therapies to achieve their blood pressure goal. The choice of a specific agent for hypertension is presented separately. (See "Choice of drug therapy in primary (essential) hypertension".) Dyslipidemia Several large-scale randomized trials and their meta-analyses of statins in high-, moderate-, and low-risk primary prevention subjects without clinical evidence of CHD have demonstrated clinical benefits on CVD, including myocardial infarction (MI), stroke, and CVD death as well as total mortality [23]. Deciding who should be screened for dyslipidemia may vary based on different guidelines. This issue is discussed in detail separately. In contrast to blood pressure reduction where multiple therapies are commonly needed, statin therapy may be sufficient for the vast majority of patients requiring lipid modification. (See "Screening for lipid disorders in adults".) All primary prevention subjects, especially those with dyslipidemia, should be counseled to achieve and maintain a desirable body weight, engage in regular physical activity, and eat a healthy diet. Deciding when statin treatment should be initiated and the choice of adjunctive pharmacologic therapy of lipid disorders in primary prevention of CVD are discussed in detail separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".) Physical activity Numerous observational studies have consistently shown that individuals who self-select for increased physical activity have lower morbidity and mortality from CHD ( figure 2). Regular physical activity is recommended in the early school years and throughout life. Common recommendations include moderate-intensity exercise for 150 minutes a week, vigorous- intensity exercise for 75 minutes a week, or an equivalent combination of these activities. Adults with limited exercise capacity due to comorbidities should stay as physically active as their condition allows [15,16]. Even modest amounts of regular physical activity, such as brisk walking for 20 minutes daily, are associated with significant benefits on risk of CHD [17]. Nonetheless, perhaps less than 20 percent of United States adults achieve this level of daily activity [15,16]. Although beneficial for all Americans, the USPSTF recommends that adults with CVD risk factors receive behavioral counseling interventions to promote a healthy diet and physical activity [18]. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 5/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate (See 'Healthy diet' above.) The role of increased physical activity for primary prevention is discussed in detail separately. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".) Weight loss In the United States and worldwide, overweight and obesity are important modifiable causes of premature deaths [14]. Overweight and obesity increase risk for several major risk factors for CVD, including hypertension, dyslipidemia, and insulin resistance, while weight loss has been shown to improve these parameters [24-26]. Data from large prospective cohort studies have consistently shown that individuals with higher body weights have a linear increase in morbidity and mortality from CHD, after appropriate adjustment for smoking and other confounders. (See "Overweight and obesity in adults: Health consequences".) In addition, in data from a random sample of the United States population from the National Center for Health Statistics, over 40 percent of adults aged 40 and over have metabolic syndrome, which is defined by the presence of three or more of the following: abdominal obesity, hypertriglycerides 150 mg/dL, high-density lipoprotein (HDL) <40 mg/dL in men or <50 mg/dL in women, systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg, fasting glucose 100 mg/dL. These individuals have a 10-year risk of a first CHD event of 16 to 18 percent, which is as high as many individuals who have already had an MI or stroke [27]. Such high-risk primary prevention subjects should be considered for pharmacologic or perhaps even surgical therapeutic options [28]. Selection of treatment for overweight subjects is based upon an initial risk assessment. All should be evaluated for their willingness and ability to adopt TLCs as well as other interventions of proven benefit. All individuals who are willing, ready, and able to lose weight should receive information about behavior modification, diet, and increased physical activity. (See "Obesity in adults: Prevalence, screening, and evaluation" and "Obesity in adults: Overview of management", section on 'Morbidity' and "Obesity in adults: Overview of management", section on 'Mortality'.) Management of type 2 diabetes The prevalence of type 2 diabetes has increased to epidemic proportions, largely due to the increase in overweight status and obesity. Mortality from diabetes results mainly from macrovascular complications of CHD, stroke, and peripheral artery disease. In addition, there are several major microvascular complications, especially retinopathy, nephropathy, and neuropathy. To reduce macrovascular complications, multifactorial interventions are crucial, especially weight reduction, increased physical activity, and control of blood pressure, lipids, and glucose https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 6/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate [29]. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "Treatment of hypertension in patients with diabetes mellitus".) For microvascular complications, tight glycemic control reduces microvascular complications in both type 1 and type 2 diabetes mellitus. Tight glycemic control may also reduce risks of macrovascular complications in patients with type 1 and type 2 diabetes mellitus [30-32]. The target A1C levels in patients with diabetes should be tailored to the individual by weighing the benefits on morbidity and mortality against the risk of hypoglycemia. Details of glycemic control in patients with diabetes are discussed separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus".) Aspirin Any decision to recommend aspirin should be based upon an individual clinical judgment that includes an assessment of the magnitude of both the absolute CVD risk reduction and the absolute increase in major bleeding. Thus, prescription of aspirin should be based on consideration of benefits and risk, not age [33]. Aspirin use for primary prevention of CVD is discussed in more detail separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Possible benefits'.) Omega-3 fatty acids Omega-3 fatty acids significantly reduce triglycerides in a dose- dependent manner [34], but their independent benefits on clinical CVD are less clear, especially in those already treated with evidence-based doses of statins [35]. The role of this treatment in secondary prevention patients with hypertriglyceridemia is discussed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.) For patients without hypertriglyceridemia, the role of this treatment is uncertain, and practice varies. In a randomized trial in primary prevention of 25,871 adults without known cardiovascular disease (VITAL), after a median of 5.3 years, low-dose n-3 polyunsaturated fatty acid (PUFA; 1 g/day) did not reduce the primary endpoint of major cardiovascular events, which included both heart disease and stroke (hazard ratio [HR] 0.92, 95% CI 0.80-1.06) [36]. Among secondary outcomes, there was a reduction in total MI (HR 0.72, 95% CI 0.59-0.90), percutaneous intervention (HR 0.78, 95% CI 0.63-0.95), total CHD (HR 0.83, 95% CI 0.71-0.97), and death from MI (HR 0.50, 95% CI 0.26-0.97). Benefits and risks of small amounts of daily alcohol In numerous case-control and prospective cohort studies, individuals who consume small amounts of alcohol have lower risks of morbidity and mortality from CHD than nondrinkers. The benefit seems related to the small amount of alcohol consumed rather than the type of alcoholic beverage. In some, but not the majority of analytic studies, individuals who consume red wine tend to have lower risks than https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 7/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate those who consume other types of alcohol. This inconsistent finding may be due to other components in red wine or confounding by social class. A meta-analysis of nearly 600,000 individuals in 83 prospective studies who consumed alcohol found the lowest risk of all-cause mortality occurred at those whose alcohol intake was about 100 g/week (approximately six drinks/week) [37]. In this analysis, individuals self selection for the consumption of small amounts of daily alcohol intake had a decreased risk of mortality from MI but not from other causes. Thus, any benefit of daily alcohol intake for coronary artery disease must be weighed against the risks, which include hypertension, cerebral hemorrhage, and breast cancer. In addition, there have been significant increases in the United States in mortality from alcoholic cirrhosis [38]. The differences between consuming small and larger amounts of daily alcohol will mean the difference between avoidance and causation of premature death [3]. (See "Overview of the risks and benefits of alcohol consumption" and "Cardiovascular benefits and risks of moderate alcohol consumption".) ADDITIVE BENEFITS OF MULTIPLE RISK FACTOR REDUCTIONS Lifestyle changes In primary prevention, modification of multiple major risk factors will produce reductions in risk of coronary heart disease (CHD) and stroke that are at least additive [39]. A European prospective cohort study of 2339 individuals, including 1507 men and 832 women aged 70 to 90 without cardiovascular disease (CVD) or cancer at baseline, assessed whether self- selection for a Mediterranean diet, being physically active, having small to moderate alcohol intake daily, and/or not smoking reduced all-cause and cause-specific mortality [40]. After a mean follow-up of 10 years, compared with those who adopted zero or one lifestyle change, those who self-selected for all four therapeutic lifestyle changes (TLCs) had a 67 percent lower risk of CVD mortality and a 65 percent lower risk of total deaths. A prospective cohort study of over 20,000 Swedish men aged 45 to 79 without cancer, CVD, or CVD risk factors assessed whether individuals who self-selected for all of the five low-risk factors (healthy diet, moderate alcohol consumption, not smoking, being physically active, and having no abdominal adiposity) had lower risks of myocardial infarction (MI) [41]. During the 11-year follow-up, these men who practiced a healthy lifestyle had an 86 percent lower risk for MI (95% CI 0.04-0.43). Similar results for primary prevention of stroke derived from the analyses of combined data from two large prospective cohorts, the Health Professionals Follow-up Study (43,685 men) and https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 8/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Nurses' Health Study (71,243 women), in which a low-risk lifestyle was defined as not smoking, 2 body mass index (BMI) <25 kg/m , 30 minutes/day of moderate activity, modest alcohol consumption, and scoring in the top 40 percent on a healthy diet score [42]. Compared with participants having none, adults with all five low-risk factors had significantly lower risks of stroke (relative risks 0.31 in men and 0.21 in women). Polypills Polypills to reduce CVD contain various combinations of medications such as statins, antihypertensive medications, and aspirin [43]. From a population health standpoint, a polypill strategy is attractive because it seeks to minimize nonadherence, as it provides the major CV drug classes in one pill. Another potential advantage is decreased costs [44]. As such, they may be useful as a population-based strategy in resource-limited settings. The authors of TIPS-3 estimate that widespread use of the polypill may avert >3 to 5 million CVD events globally [45]. Potential disadvantages include increased adverse effects, individual patient variability concerning the optimal combination of medications, and difficulty in titration with fixed dosing. In addition, while many polypill formulations include aspirin, the role of aspirin in primary prevention is controversial. Finally, it may not be usable if a patient has an allergy to any of the drugs in the combination pill. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Possible benefits'.) Polypills are not available commercially in the United States or Europe. A 2017 systematic review of 13 randomized trials concluded that the effects of polypills on mortality or CVD events were inconclusive. However, most of the included trials evaluated changes in risk factors rather than CVD events [46]. In some but not all individual randomized trials, polypills increased adherence and decreased blood pressure and cholesterol but increased adverse events [45,47-51]. A 2021 individual-level meta-analysis examined three large RCTs of 18 162 individuals evaluating the effect of fixed dose polypills comprised of two antihypertensives and a low dose statin (with or without aspirin) on primary CVD prevention. [52] During a median follow-up of 5 years, the primary CVD outcome (a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularization) occurred in 3 percent of individuals given the polypill compared with 4.9 percent in the control group (hazard ratio [HR] 0.62, 95% CI 0.53 0.73). GI side effects were more common in those taking the additional aspirin, although other bleeding was neither common nor significantly different in those treated with aspirin versus not. The use of polypills has been proposed as a strategy to decrease CVD in underserved communities. In an open-label trial among 303 low-income adults in Alabama without CVD, 96 percent of whom were Black individuals, those randomized to receive a polypill containing https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 9/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate atorvastatin (10 mg), amlodipine (2.5 mg), losartan (25 mg), and hydrochlorothiazide (12.5 mg) had a greater decrease in mean blood pressure (9 versus 2 mmHg, -7 mmHg difference, 95% CI 12 to -2), and LDL cholesterol levels (15 versus 4 mg/dL, -11 mg/dL difference, 95% CI -18 to -5) at one year compared with those in the usual care group [50]. Adherence at one year was 86 percent. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Assessment of cardiovascular risk" and "Society guideline links: Primary prevention of cardiovascular disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Atherosclerosis (The Basics)") Beyond the Basics topics (see "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: Diet and health (Beyond the Basics)" and "Patient education: Quitting smoking (Beyond the Basics)" and "Patient education: Losing weight (Beyond the Basics)" and "Patient education: Aspirin in the primary prevention of cardiovascular disease and cancer (Beyond the Basics)" and "Patient education: High blood pressure in adults (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 10/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate SUMMARY AND RECOMMENDATIONS Major risk factors The following major risk factors for cardiovascular disease (CVD) are modifiable and should be considered in all adults: poor diet, smoking, hypertension, dyslipidemia, physical inactivity, overweight and obesity, and diabetes mellitus. (See "Healthy diet in adults" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Obesity in adults: Overview of management" and "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Overview of smoking cessation management in adults".) Multiple risk factor reduction Reductions of multiple risk factors, through therapeutic lifestyle changes (TLCs) and adjunctive drug therapies of proven benefit, are likely to have at least additive benefits in the primary prevention of CVD. (See 'Additive benefits of multiple risk factor reductions' above.) Role of aspirin The decision to recommend aspirin should be based upon an individual clinical judgment that includes an assessment of the magnitude of both the absolute CVD risk reduction and the absolute increase in major bleeding, not just age. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367:1747. 2. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021; 143:e254. 3. Caldwell M, Martinez L, Foster JG, et al. Prospects for the Primary Prevention of Myocardial Infarction and Stroke. J Cardiovasc Pharmacol Ther 2019; 24:207. 4. Feigin VL, Krishnamurthi RV, Parmar P, et al. 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Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388:2532. 24. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129:S102. 25. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393. 26. Douketis JD, Macie C, Thabane L, Williamson DF. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond) 2005; 29:1153. 27. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis 2017; 14:E24. 28. Sherling DH, Perumareddi P, Hennekens CH. Metabolic Syndrome. J Cardiovasc Pharmacol Ther 2017; 22:365. 29. Hennekens CH, Pfeffer MA, Newcomer JW, et al. Treatment of diabetes mellitus: the urgent need for multifactorial interventions. Am J Manag Care 2014; 20:357. 30. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643. 31. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 13/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 32. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129. 33. Kim K, Hennekens CH, Martinez L, et al. Primary care providers should prescribe aspirin to prevent cardiovascular disease based on benefit-risk ratio, not age. Fam Med Community Health 2021; 9. 34. Skulas-Ray AC, Kris-Etherton PM, Harris WS, et al. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr 2011; 93:243. 35. Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol 2018; 3:225. 36. Manson JE, Cook NR, Lee IM, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med 2019; 380:23. 37. Wood AM, Kaptoge S, Butterworth AS, et al. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. Lancet 2018; 391:1513. 38. Termeie O, Fiedler L, Martinez L, et al. Alarming Trends: Mortality from Alcoholic Cirrhosis in the United States. Am J Med 2022; 135:1263. 39. Leening MJ, Berry JD, Allen NB. Lifetime Perspectives on Primary Prevention of Atherosclerotic Cardiovascular Disease. JAMA 2016; 315:1449. 40. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 2004; 292:1433. 41. Akesson A, Larsson SC, Discacciati A, Wolk A. Low-risk diet and lifestyle habits in the primary prevention of myocardial infarction in men: a population-based prospective cohort study. J Am Coll Cardiol 2014; 64:1299. 42. Chiuve SE, Rexrode KM, Spiegelman D, et al. Primary prevention of stroke by healthy lifestyle. Circulation 2008; 118:947. 43. Castellano JM, Sanz G, Fernandez Ortiz A, et al. A polypill strategy to improve global secondary cardiovascular prevention: from concept to reality. 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Castellano JM, Sanz G, Pe alvo JL, et al. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol 2014; 64:2071. 49. Indian Polycap Study (TIPS), Yusuf S, Pais P, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009; 373:1341. 50. Mu oz D, Uzoije P, Reynolds C, et al. Polypill for Cardiovascular Disease Prevention in an Underserved Population. N Engl J Med 2019; 381:1114.

2000; 102:1511. 11. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med 2000; 343:16. 12. Kurth T, Moore SC, Gaziano JM, et al. Healthy lifestyle and the risk of stroke in women. Arch Intern Med 2006; 166:1403. 13. Sotos-Prieto M, Bhupathiraju SN, Mattei J, et al. Changes in Diet Quality Scores and Risk of Cardiovascular Disease Among US Men and Women. Circulation 2015; 132:2212. 14. Hennekens CH, Andreotti F. Leading avoidable cause of premature deaths worldwide: case for obesity. Am J Med 2013; 126:97. 15. Lewis SF, Hennekens CH. Regular Physical Activity: A 'Magic Bullet' for the Pandemics of Obesity and Cardiovascular Disease. Cardiology 2016; 134:360. 16. Lewis SF, Hennekens CH. Regular Physical Activity: Forgotten Benefits. Am J Med 2016; 129:137. 17. Manson JE, Hu FB, Rich-Edwards JW, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 1999; 341:650. 18. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Behavioral Counseling Interventions to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults With Cardiovascular Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA 2020; 324:2069. 19. Hollar D, Hennekens CH. Randomized trials fail to fulfill promises of observational epidemiol ogy. In: Antioxidants and Cardiovascular Disease, Tardiff JC, Bourassa MG (Eds), Springer, 20 https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 12/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 05. p.305. 20. LaCroix AZ, Lang J, Scherr P, et al. Smoking and mortality among older men and women in three communities. N Engl J Med 1991; 324:1619. 21. Gaballa D, Drowos J, Hennekens CH. Smoking Cessation: The Urgent Need for Increased Utilization of Varenicline. Am J Med 2017; 130:389. 22. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71:e13. 23. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388:2532. 24. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014; 129:S102. 25. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393. 26. Douketis JD, Macie C, Thabane L, Williamson DF. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond) 2005; 29:1153. 27. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis 2017; 14:E24. 28. Sherling DH, Perumareddi P, Hennekens CH. Metabolic Syndrome. J Cardiovasc Pharmacol Ther 2017; 22:365. 29. Hennekens CH, Pfeffer MA, Newcomer JW, et al. Treatment of diabetes mellitus: the urgent need for multifactorial interventions. Am J Manag Care 2014; 20:357. 30. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643. 31. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 13/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 32. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129. 33. Kim K, Hennekens CH, Martinez L, et al. Primary care providers should prescribe aspirin to prevent cardiovascular disease based on benefit-risk ratio, not age. Fam Med Community Health 2021; 9. 34. Skulas-Ray AC, Kris-Etherton PM, Harris WS, et al. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr 2011; 93:243. 35. Aung T, Halsey J, Kromhout D, et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol 2018; 3:225. 36. Manson JE, Cook NR, Lee IM, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med 2019; 380:23. 37. Wood AM, Kaptoge S, Butterworth AS, et al. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. Lancet 2018; 391:1513. 38. Termeie O, Fiedler L, Martinez L, et al. Alarming Trends: Mortality from Alcoholic Cirrhosis in the United States. Am J Med 2022; 135:1263. 39. Leening MJ, Berry JD, Allen NB. Lifetime Perspectives on Primary Prevention of Atherosclerotic Cardiovascular Disease. JAMA 2016; 315:1449. 40. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 2004; 292:1433. 41. Akesson A, Larsson SC, Discacciati A, Wolk A. Low-risk diet and lifestyle habits in the primary prevention of myocardial infarction in men: a population-based prospective cohort study. J Am Coll Cardiol 2014; 64:1299. 42. Chiuve SE, Rexrode KM, Spiegelman D, et al. Primary prevention of stroke by healthy lifestyle. Circulation 2008; 118:947. 43. Castellano JM, Sanz G, Fernandez Ortiz A, et al. A polypill strategy to improve global secondary cardiovascular prevention: from concept to reality. J Am Coll Cardiol 2014; 64:613. 44. Lonn E, Bosch J, Teo KK, et al. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation 2010; 122:2078. 45. Yusuf S, Joseph P, Dans A, et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. N Engl J Med 2021; 384:216. https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 14/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate 46. Bahiru E, de Cates AN, Farr MR, et al. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases. Cochrane Database Syst Rev 2017; 3:CD009868. 47. Selak V, Elley CR, Bullen C, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ 2014; 348:g3318. 48. Castellano JM, Sanz G, Pe alvo JL, et al. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol 2014; 64:2071. 49. Indian Polycap Study (TIPS), Yusuf S, Pais P, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009; 373:1341. 50. Mu oz D, Uzoije P, Reynolds C, et al. Polypill for Cardiovascular Disease Prevention in an Underserved Population. N Engl J Med 2019; 381:1114. 51. Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster- randomised trial. Lancet 2019; 394:672. 52. Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. Lancet 2021; 398:1133. Topic 7573 Version 75.0 https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 15/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate GRAPHICS Additive effects of risk factors on cardiovascular disease at 5 years Cumulative absolute risk of CVD at 5 years according to systolic blood pressure and specified levels of other risk factors. The reference category is a non-diabetic, non-smoking 50-year-old woman with a serum TC of 154 mg/dL (4.0 mmol/L) and HDL cholesterol of 62 mg/dL (1.6 mmol/L). The CVD risks are given for systolic blood pressure levels of 110, 130, 150, and 170 mmHg. In the other categories, the additional risk factors are added consecutively. As an example, the diabetes category is a 50-year-old diabetic man who is a smoker and has a TC of 270 mg/dL (7 mmol/L) and HDL cholesterol of 39 mg/dL (1 mmol/L). BP: blood pressure; CVD: cardiovascular disease; HDL: high-density lipoprotein; TC: total cholesterol. Adapted from: Jackson R, Lawes CM, Bennett DA, et al. Lancet 2005; 365:434. Graphic 55353 Version 12.0 https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 16/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Beneficial effects of any physical activity on coronary heart disease Coronary events are less frequent among those who exercise. In a study of 5159 men, aged 40 to 49 years, followed for an average of almost 19 years, the age-adjusted coronary heart disease event rate per 1000 person-years is lower in those who perform any physical activity compared with inactive subjects. Data from: Wannamethee SG, Shaper AG, Alberti KG. Arch Intern Med 2000; 160:2108. Graphic 81608 Version 4.0 https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 17/18 7/6/23, 12:50 PM Overview of primary prevention of cardiovascular disease - UpToDate Contributor Disclosures Charles H Hennekens, MD, DrPH Patent Holder: Brigham and Women's Hospital [Co-inventor on patents concerning inflammatory markers and cardiovascular disease, C-reactive protein]. Consultant/Advisory Boards: Amgen [Migraine, cardiovascular disease]; UCB [Osteoporosis]. All of the relevant financial relationships listed have been mitigated. David Seres, MD Equity Ownership/Stock Options: Medaware Systems [Biomedical informatics]. Consultant/Advisory Boards: Community Surgical Supply [Home nutrition support]. All of the relevant financial relationships listed have been mitigated. Freek Verheugt, MD, FACC, FESC Consultant/Advisory Boards: AstraZeneca [Thrombosis]; Bayer [Thrombosis]; BMS/Pfizer [Thrombosis]; Boehringer-Ingelheim [Thrombosis]; Boston Scientific [Thrombosis]; Daiichi-Sankyo [Thrombosis]; JenaValve [Thrombosis]. All of the relevant financial relationships listed have been mitigated. Sara Swenson, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-primary-prevention-of-cardiovascular-disease/print 18/18

7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of secondary prevention of ischemic stroke : Natalia S Rost, MD, MPH, Alexis Simpkins, MD, PhD, MSCR, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 27, 2023. INTRODUCTION The management of treatable risk factors and common mechanisms of brain ischemia is important for reducing the risk of ischemic stroke. This topic will review the risk factors for stroke, with a focus on secondary prevention in patients who have a history of transient ischemic attack or ischemic stroke, or who have an elevated risk of ischemic stroke due to the presence of coronary heart disease or diabetes. Risk factors for hemorrhagic stroke are reviewed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors' and "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Risk factors'.) The role of primary prevention for cardiovascular disease, including stroke, is discussed separately. (See "Overview of primary prevention of cardiovascular disease".) MAJOR RISK FACTORS Control of atherosclerotic risk factors is important for the primary and secondary prevention of stroke. Control of risk factors also reduces the risk of coronary events, a common comorbidity in patients with cerebrovascular disease. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 1/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate Modifiable risk factors The major modifiable risk factors for stroke are the following [1- 4]: Hypertension (see 'Hypertension' below) Dyslipidemia (see 'Dyslipidemia' below) Diabetes mellitus (see 'Diabetes mellitus' below) Smoking (see 'Smoking cessation' below) Physical inactivity (see 'Physical activity and exercise' below) Unmodifiable risk factors Important but unmodifiable risk factors for stroke include the following [3,5-8]: Older age, particularly age >80 years [3] Race and ethnicity, with risk higher for Black than for White patients [8] Sex, with risk higher at most ages for men compared with women, except for ages 35 to 44 years and >85 years, where women have a similar or higher risk than men [9,10] Family history and genetic disorders, with a higher risk for monozygotic twins and those with genetic disorders (see "Pathophysiology of ischemic stroke", section on 'Monogenic disorders') such as sickle cell disease or cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy [5-7] Stroke risk assessment The risk of stroke is particularly increased in patients with two or more risk factors, as suggested by calculators for female (calculator 1) and male (calculator 2) patients, derived from the Framingham Study [11]. These risk factor assessment tools incorporate atrial fibrillation, a common cause of ischemic stroke, and the presence of coronary heart disease and other types of cardiovascular disease ( table 1), which are markers of increased risk for subsequent cardiovascular and cerebrovascular events. When all of these risk factors and stroke mechanisms are considered together, they account for 60 to 80 percent of the population-attributable risk of ischemic stroke [2]. Treatment Most patients with an ischemic stroke or transient ischemic attack should be treated with all available risk reduction strategies, including blood pressure reduction, low- density lipoprotein cholesterol lowering therapy, antithrombotic therapy, and lifestyle modification [12]; select patients with symptomatic carotid disease may benefit from revascularization. By some estimates, treatment of all major stroke risk factors, compared with no treatment, would reduce the risk of recurrent stroke by 80 percent [13]. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 2/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate Guidelines from the American Heart Association and American Stroke Association advocate a multidisciplinary, team-based approach to effectively manage these risk factors, with treatment tailored to the individual patient [12]. To promote health equity and reduce healthcare disparities, the approach should evaluate and address social determinants of health, including literacy level, language proficiency, medication affordability, food insecurity, housing needs, and transportation obstacles. ANTITHROMBOTIC THERAPY Antithrombotic therapy with antiplatelet or anticoagulant agents is an important part of secondary stroke prevention for patients with ischemic stroke or transient ischemic attack (TIA) ( algorithm 1) [12]. Noncardioembolic ischemic stroke or TIA Antiplatelet agents are effective for the prevention of recurrent ischemic stroke in patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Aspirin (50 to 100 mg daily), clopidogrel (75 mg daily), and the combination of aspirin- extended-release dipyridamole (25 mg/200 mg twice a day) are all acceptable long-term options for preventing recurrent noncardioembolic ischemic stroke. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Role of DAPT Early, short-term dual antiplatelet therapy (DAPT), typically with aspirin plus clopidogrel, is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis, as outlined in the algorithms ( algorithm 2 and algorithm 3). (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Dissection For patients with ischemic neurologic symptoms caused by cervical artery dissection, antithrombotic therapy is indicated, but the choice between antiplatelet and anticoagulant therapy remains somewhat controversial. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Choosing between antiplatelet and anticoagulation therapy'.) Cardiogenic embolism Long-term anticoagulation with warfarin or a direct oral anticoagulant (dabigatran, apixaban, rivaroxaban, or edoxaban) is recommended as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. While the use of anticoagulant therapy is also associated with an increased risk of major bleeding, the benefit outweighs the risk in most patients. These https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 3/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate issues are discussed elsewhere. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) In addition to atrial fibrillation, other potential cardiac sources of embolism for which anticoagulation therapy may be indicated for select patients include the following (see "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism'): Mechanical heart valves and a subpopulation of high-risk patients with bioprosthetic valves (see "Antithrombotic therapy for mechanical heart valves") Left ventricular thrombus (see "Antithrombotic therapy in patients with heart failure", section on 'Left ventricular thrombus' and "Left ventricular thrombus after acute myocardial infarction", section on 'Prevention of embolic events') Dilated cardiomyopathy (see "Antithrombotic therapy in patients with heart failure") Rheumatic valve disease (see "Management and prevention of rheumatic heart disease", section on 'Management of carditis in acute rheumatic fever') Recent myocardial infarction in high-risk patients (see "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Management of anticoagulation" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients") HYPERTENSION Hypertension and stroke risk Hypertension, which promotes the formation of atherosclerotic lesions, is the single most important treatable risk factor for stroke [4]. Epidemiologic studies of treated and untreated patients reveal that there is a gradually increasing incidence of cardiovascular mortality as the blood pressure rises above 110/75 mmHg ( figure 1A-B) [14,15]. Hypertension is associated with an increased likelihood of subclinical or silent stroke, which in turn has been linked with an elevated risk of vascular dementia and recurrent stroke [16-18]. In addition to hypertension defined by systolic and diastolic blood pressure, stroke risk may be associated with other blood pressure variables including mean blood pressure, pulse pressure, blood pressure variability, blood pressure instability, and nocturnal nondipping [19,20]. However, these observations alone do not prove a causal relationship, since increasing blood pressure could be a marker for other risk factors such as increasing body weight, dyslipidemia, https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 4/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate glucose intolerance, and the metabolic syndrome. The best evidence supporting a causal role of increasing blood pressure in cardiovascular complications comes from studies that show outcome reduction in the risk of recurrent stroke with antihypertensive therapy. This evidence is reviewed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".) Antihypertensive therapy Treatment of hypertension is important for both prevention of recurrent stroke and prevention of other vascular events. We recommend antihypertensive therapy for patients with any type of ischemic stroke or transient ischemic attack (TIA) who have an established blood pressure that is above goal, as outlined in the table ( table 2) for higher- risk populations, which includes all patients with ischemic stroke or TIA. Similarly, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend an office measurement blood pressure goal of <130/80 mmHg for most patients to reduce the risk of recurrent stroke and vascular events [12]. Lifestyle modifications that have been associated with blood pressure reductions should be included as part of the antihypertensive regimen [12]. Important modifications include weight loss; salt restriction; a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption. (See 'Lifestyle modification' below.) The role of antihypertensive therapy in secondary stroke prevention is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention".) The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA can vary according to several factors, including stroke mechanism (eg, whether the stroke was ischemic or hemorrhagic), neurologic stability, and comorbid medical problems. This issue is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention", section on 'When to initiate (or reinstate) antihypertensive therapy'.) In patients with acute ischemic stroke (ie, the first hours and days after onset), it is important not to lower the blood pressure too quickly. The management of blood pressure in the setting of acute stroke is reviewed elsewhere. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) DYSLIPIDEMIA Lipids and stroke risk Hyperlipidemia is a major risk factor for atherosclerotic cardiovascular disease (see "Overview of established risk factors for cardiovascular disease"). However, the relationship between the serum cholesterol concentration and stroke incidence appears to be https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 5/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate more complex, in that cholesterol is an established risk factor for atherosclerosis, but the degree of risk varies for stroke subtypes [21]. Studies that have examined ischemic and hemorrhagic stroke types have generally found a weak but positive association of elevated cholesterol with ischemic stroke, particularly for large artery atherosclerotic and lacunar stroke subtypes, and an inverse association of cholesterol levels with hemorrhagic stroke [22]. Most [23-26] but not all [27,28] large observational studies have found that elevated cholesterol and low-density lipoprotein levels are associated with an increased risk of ischemic stroke [21]. The strong association between cholesterol and carotid atherosclerosis also supports the role of cholesterol in the pathogenesis of large artery ischemic stroke [29]. The relationship of cholesterol levels and statin therapy with intracerebral hemorrhage is discussed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors'.) LDL-C lowering therapy Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce the risk of major adverse cardiovascular events. Among these three, statins are the best studied and have proven efficacy for reducing the risk of recurrent ischemic stroke. The available evidence suggests that lipid lowering by other means (eg, fibrates, bile acid sequestrants, niacin, diet) has no significant impact on the secondary prevention of stroke or prevention of other cardiovascular events. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Lipid management with diet or dietary supplements" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Therefore, it seems plausible that the protective effects of statins are not mediated by cholesterol lowering alone [30], but by pleiotropic (eg, anti-atherothrombotic, anti-inflammatory) properties [31,32]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".) Even patients with "average" serum cholesterol concentrations appear to benefit from statin therapy in terms of stroke reduction. This was demonstrated in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [33], in which the mean baseline low- density lipoprotein cholesterol (LDL-C) level was 133 mg/dL (3.4 mmol/L), and in the Heart Protection Study trial [34], in which the mean baseline LDL-C level was 131 mg/dL (3.4 mmol/L). Approach to LDL-C lowering https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 6/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate High-risk patients For high-risk patients (eg, those with atherosclerotic cardiovascular disease, including with transient ischemic attack [TIA] or ischemic stroke) who are able to tolerate statins, we begin LDL-C lowering with high-intensity statin therapy, independent of the baseline LDL-C, to reduce the risk of stroke and cardiovascular events [12,35]. We generally treat with atorvastatin 80 mg/day, since this was the agent and dose used in the SPARCL trial that showed a benefit for secondary ischemic stroke prevention. (See "Statins: Actions, side effects, and administration".) While the entirety of the evidence does not clearly identify a threshold below which further LDL-C lowering leads to little benefit, we believe that efforts to lower the LDL-C to <70 mg/dL (1.8 mmol/L) should be made in most patients with cardiovascular disease. A similar approach is recommended for patients with other types of cardiovascular disease at high risk for a recurrent or initial cardiovascular event ( table 1). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Statin intolerance For patients who are intolerant of high-intensity statin therapy, the maximally tolerated dose of a statin can be used; alternatives are moderate-intensity statin therapy (eg, atorvastatin 10 to 20 mg daily, rosuvastatin 5 to 10 mg daily, simvastatin 20 to 40 mg daily, pravastatin 40 to 80 mg daily, lovastatin 40 mg daily, or fluvastatin 40 mg daily in two divided doses) or low-intensity statin therapy (eg, pravastatin 10 to 20 mg daily or lovastatin 20 mg daily). For patients whose LDL-C level remains 70 mg/dL ( 1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a PCSK9 inhibitor is reasonable [35]. For patients who are unable to tolerate any statin regimen, we treat with ezetimibe and consider adding a PCSK9 inhibitor if LDL-C remains 70 mg/dL ( 1.8 mmol/L) [35]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".) Monitoring Fasting lipid levels should be measured 4 to 12 weeks after starting LDL-C lowering therapy and then every 3 to 12 months thereafter. Benefit of LDL-C lowering Data from randomized controlled trials has established that LDL-C lowering, primarily with statins, reduces the risk of major cardiovascular events, including both initial and recurrent stroke, regardless of age, gender, or pretreatment blood lipid concentration. A systematic review of the literature up to July 2017 identified nine randomized controlled trials assessing statins in over 10,000 patients with ischemic https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 7/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate stroke or TIA [36]. A network meta-analysis of these data showed that the risk of ischemic stroke was reduced with statin treatment versus no statin (7.6 versus 9.3 percent, OR 0.81, 95% CI 0.70-0.93; absolute risk reduction [ARR] 1.6 percent, 95% CI 0.6-2.6), as was the risk of cardiovascular events (22.8 versus 28 percent, OR 0.75, 95% CI 0.69-0.83; ARR 5.4 percent, 95% CI 3.6-6.8). The greatest benefit was observed with high-dose statin treatment (eg, atorvastatin 80 mg daily or simvastatin 40 mg daily). The 2006 SPARCL trial was the first to show that statin treatment decreased the risk of recurrent ischemic stroke among patients with a history of stroke or TIA [33]. The trial enrolled 4731 ambulatory patients with no known coronary heart disease (CHD) who had a stroke or TIA within one to six months; patients were randomly assigned to treatment with either atorvastatin 80 mg/day or placebo. Patients were required to have a baseline LDL-C of 100 to 190 mg/dL (2.6 to 4.9 mmol/L). The mean baseline LDL-C level was 133 mg/dL (3.4 mmol/L). Patients with hemorrhagic stroke were included if they were deemed to be at risk for ischemic stroke or CHD. Patients were excluded if they had atrial fibrillation, other cardiac sources of embolism, or subarachnoid hemorrhage. At a median follow-up of 4.9 years, atorvastatin led to a mean reduction in LDL-C of 56 mg/dL (1.4 mmol/L) and reduced fatal or nonfatal stroke (11.2 versus 13.1 percent, adjusted hazard ratio [HR] 0.84, 95% CI 0.71-0.99, ARR at five years 2.2 percent, 95% CI 0.2- 4.2 percent) [33]. Atorvastatin also led to a reduction in all coronary events (5.2 versus 8.6 percent, HR 0.58, 95% CI 0.46-0.73) and all cardiovascular events (22.4 versus 29 percent, HR 0.74, 95% CI 0.66-0.83). There was no difference between the atorvastatin and placebo groups in overall mortality. The lower the LDL-C, the greater the benefit In the Treat Stroke to Target (TST) trial, patients with a recent ischemic stroke or TIA were randomly assigned to a lower target LDL-C level of <70 mg/dL (1.8 mmol/L) or to a higher target LDL-C level of 90 to 110 mg/dL (2.3 to 2.8 mmol/L) [37]. The mean LDL-C level at baseline was 135 mg/dL (3.5 mmol/L). The LDL-C level was lowered by adjustment of the statin dose in most cases, with addition of ezetimibe in approximately 34 percent of patients in the lower-target group. The trial was stopped early due to lack of funding, with data for 2860 patients who were followed for a median 3.5 years. The mean achieved LDL-C level in the lower-target group was 65 mg/dL (1.7 mmol/L) and in the higher-target group was 96 mg/dL (2.5 mmol/L). The composite primary end point of major cardiovascular events (ie, ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or cardiovascular death) was reduced in the lower-target LDL-C group compared with the higher-target group (8.5 versus 10.9 percent, adjusted HR 0.78, 95% CI 0.61-0.98, ARR 2.4 percent). https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 8/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate A 2022 meta-analysis identified 11 randomized trials (including the TST trial) that enrolled over 20,000 patients with stroke and compared more intensive versus less intensive LDL-C lowering statin-based therapies [38]. More intensive LDL-C lowering led to a reduced risk of recurrent stroke compared with less intensive LDL-C lowering (8.1 versus 9.3 percent; RR 0.88, 95% CI 0.80-0.96; number needed to treat, 90) and to a lower risk of major cardiovascular events (13.9 versus 16.7 percent; RR 0.83, 95% CI 0.78-0.89). The benefit of LDL-C lowering was similar among different LDL-C lowering strategies (statins versus no statins, more statins or ezetimibe versus less statins or ezetimibe, and PCSK9 inhibitors plus statins versus placebo plus statins). The benefit of more intensive LDL-C lowering may apply only to patients with atherosclerosis In the 2022 meta-analysis, more intensive LDL-C versus less intensive LDL-C-lowering led to a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR 0.79, 95% CI 0.69-0.91) but not in trials with most patients not having evidence of atherosclerosis (RR 0.95, 95% CI 0.85-1.07) [38]. LDL-C lowering and hemorrhagic stroke The 2022 meta-analysis found that more intensive versus less intensive LDL-C lowering led to a small increased risk of hemorrhagic stroke when patients with all types of stroke at entry were included (1.3 versus 0.9 percent; RR 1.46, 95% CI 1.11-1.91; number needed to harm 242) [38]. However, sensitivity tests restricting analysis to only patients with ischemic stroke as an entry event found that more intensive versus less intensive LDL-C lowering led to a nonsignificant increased risk of hemorrhagic stroke while maintaining a significant reduction in the risk of recurrent ischemic stroke. The relationship between statin therapy and hemorrhagic stroke is reviewed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors' and "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of statins'.) Lipoprotein(a) Lipoprotein(a), also referred to as Lp(a), is a modest independent risk factor for atherosclerotic cardiovascular disease and cerebrovascular events. Note that LDL-C measurements include the cholesterol component of Lp(a). In an occasional patient, a substantial fraction of LDL-C may be carried in Lp(a) particles rather than in normal LDL. In these cases, treatment with a statin may lead to a lesser reduction in LDL-C than expected, as statins do not effectively reduce Lp(a) levels. However, there is only limited evidence that Lp(a) lowering reduces atherosclerotic cardiovascular disease risk, as discussed separately. (See "Lipoprotein(a)".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 9/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate Hypertriglyceridemia Some [39-41], but not all [27,42,43] observational studies suggested that hypertriglyceridemia is a risk factor for ischemic stroke. Management involves lifestyle modification (eg, weight loss, smoking cessation, aerobic exercise, healthy diet, limited alcohol consumption), treatment of hypertension, glycemic control for patients with diabetes, and LDL-C lowering therapy (most LDL-C lowering medications also reduce triglyceride levels). (See "Hypertriglyceridemia in adults: Management", section on 'General measures'.) For patients with high atherosclerotic cardiovascular disease risk (including those with atherosclerotic ischemic stroke or TIA) whose triglyceride levels remain >150 mg/dL after lifestyle interventions and optimal LDL-C lowering therapy, it is reasonable to treat with high- dose marine omega-3 fatty acid using icosapent ethyl, 2 g twice daily. This in general agreement with the AHA/ASA guideline recommendation for the treatment of hypertriglyceridemia [12]. The evidence regarding the efficacy and safety of omega-3 fatty acid therapy for cardiovascular outcomes is reviewed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acid effects'.) DIABETES MELLITUS Diabetes and stroke risk Patients with diabetes mellitus have approximately twice the risk of ischemic stroke compared with those without diabetes [44-48]. In addition, the risk of stroke associated with diabetes is higher in women than in men [48]. Dyslipidemia, endothelial dysfunction, and platelet and coagulation abnormalities are among the risk factors that may promote the development of carotid atherosclerosis in diabetics. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".) However, there is no proven benefit of intensive glucose-lowering therapy for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes [12]. Impaired glucose tolerance may be a risk factor for ischemic stroke in patients with a history of transient ischemic attack (TIA) or minor ischemic stroke [49]. It may also be a risk factor for carotid atherosclerosis, as illustrated by studies in nondiabetics showing that elevated serum hemoglobin A1C is associated with an increased risk of carotid plaque development [50,51]. Glycemic control For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of 7 percent [12]. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 10/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate This recommendation is based on evidence that tight glucose control reduces microvascular complications. The available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy for macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. Nevertheless, for patients with ischemic stroke or TIA, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend screening for diabetes mellitus using A1C [12]. These issues are discussed in detail elsewhere: (See "Glycemic control and vascular complications in type 1 diabetes mellitus".) (See "Glycemic control and vascular complications in type 2 diabetes mellitus".) (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".) Metabolic syndrome The metabolic syndrome, defined as the presence of three or more components that include high fasting glucose, hypertension, low serum high-density lipoprotein, elevated serum triglycerides, and abdominal obesity, is considered a prediabetic condition linked to increased risk of cardiovascular disease. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".) However, it is unclear if the metabolic syndrome is an independent risk factor for ischemic stroke beyond the sum of its individual components, and the available evidence is inconsistent. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'A critical look at the metabolic syndrome'.) Furthermore, the utility of the metabolic syndrome to predict stroke risk does not appear to improve upon more conventional assessments such as the Framingham Risk Score [52]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".) Although the metabolic syndrome is not clearly established as an independent stroke risk factor, it is important to treat the underlying causes such as obesity and physical inactivity. Management should include counseling for lifestyle modification (diet, exercise, and weight loss) and appropriate treatment for individual components of the metabolic syndrome, particularly hypertension and dyslipidemia, which are also stroke risk factors. (See 'Hypertension' above and 'Dyslipidemia' above and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Therapy'.) Treatment of insulin resistance Pioglitazone treatment appears to reduce the risk of recurrent stroke and myocardial infarction in nondiabetic patients who have insulin resistance, though this benefit is partially offset by an increased risk of adverse effects such as bone https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 11/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate fracture. These points are illustrated by the findings of the multicenter Insulin Resistance Intervention After Stroke (IRIS) trial, which randomly assigned over 3800 subjects with recent ischemic stroke or TIA and insulin resistance to treatment with pioglitazone (target dose 45 mg daily) or placebo [53]. The trial defined insulin resistance as a value of >3 on the homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated as the level of fasting glucose (measured in mmol/L) times the level of fasting insulin (measured in microU/mL) divided by 22.5. Patients with diabetes, heart failure, or active liver disease were excluded. After 4.8 years, the composite outcome of stroke or myocardial infarction in IRIS was significantly reduced in the pioglitazone group compared with the placebo group (9 versus 11.8 percent, hazard ratio [HR] 0.76, 95% CI 0.62-0.93); the absolute risk reduction with pioglitazone for the composite outcome was 2.8 percent [53]. Several adverse effects were significantly more common with pioglitazone compared with placebo, including bone fracture requiring surgery or hospitalization (5.1 versus 3.2 percent), edema (36 versus 25 percent), and weight gain exceeding 4.5 kg (52 versus 34 percent). There was no difference between groups in the incidence of heart failure (the pioglitazone dose was adjusted for symptoms such as new or worsening edema, shortness of breath, or excessive weight gain during the trial). However, there is good evidence from other studies that thiazolidinediones increase the risk of heart failure. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Fluid retention/heart failure'.) Based upon the results of the IRIS trial [53], the number needed to treat (NNT) with pioglitazone to prevent one patient from developing stroke or myocardial infarction is 36, while the number needed to harm (NNH) to cause one patient to develop bone fracture requiring hospitalization is 53. Given the benefit of pioglitazone in this setting, it is an option for carefully selected nondiabetic patients with insulin resistance who are willing to accept the risk of adverse events such as bone fracture and heart failure. Since there is no validated test for measuring insulin resistance in clinical practice, clinicians should emulate the IRIS methodology as closely as possible by calculating the HOMA-IR index using laboratories that adapt the IRIS trial assays for plasma insulin level. LIFESTYLE MODIFICATION A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [12,54]. These include smoking cessation, regular aerobic physical activity, salt restriction, a Mediterranean diet, limited alcohol consumption, and https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 12/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate weight control. Our recommendations are in general agreement with the national guidelines [12]. Smoking cessation All patients who are recent or current tobacco smokers should be counseled routinely to quit smoking. (See "Overview of smoking cessation management in adults".) Cigarette smoking is associated with an increased risk for all stroke subtypes and has a strong, dose-response relationship for both ischemic stroke and subarachnoid hemorrhage [55-61]. In the Nurses' Health Study, smokers had a relative risk of stroke of 2.58 compared with never smokers [56]. Evaluation of former smokers found that the excess risk disappeared within two to four years after the cessation of smoking. In the Framingham Heart Study, the odds ratio for moderate carotid stenosis was 1.08 for each five pack-years of smoking [58]. Among 10,938 normotensive subjects in a prospective Swedish cohort study, approximately 39 percent of strokes were attributable to smoking [59]. There are no randomized controlled trials of smoking cessation compared with no intervention for stroke prevention. However, observational studies have shown that the elevated risk of stroke due to smoking declines after quitting and is eliminated by five years later [56,60,62]. Therefore, American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend smoking cessation for patients with stroke or transient ischemic attack (TIA) who smoke tobacco, counseling with or without pharmacologic therapy to assist in quitting, and avoidance of environmental tobacco smoke [12]. (See "Overview of smoking cessation management in adults".) Physical activity and exercise Patients with ischemic stroke or TIA who are capable of regular exercise should engage in moderate-intensity physical exercise performed for a minimum of 10 minutes four times a week or vigorous-intensity exercise performed for a minimum of 20 minutes twice a week. Moderate-intensity exercise is defined as activity sufficient to break a sweat or noticeably raise the heart rate (eg, walking briskly, using an exercise bicycle) [12]. (See "The benefits and risks of aerobic exercise", section on 'Benefits of exercise'.) Increasing evidence suggests that low physical activity and prolonged sitting increases the risk of cardiovascular disease, including stroke [4,63,64]. Additional support that physical inactivity is a risk factor for stroke comes from studies showing the benefit of increased physical activity and exercise for reducing the risk of cardiovascular events [65]. Diet Emerging evidence suggests that dietary interventions, and in particular a Mediterranean diet (see "Healthy diet in adults", section on 'Mediterranean diet'), improves https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 13/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate outcomes in patients with established cardiovascular disease [66]. Until further studies evaluate the magnitude of benefit of a Mediterranean diet, it is reasonable to advise all patients to adhere to its components. For patients with a history of stroke or TIA, we encourage patients to follow a Mediterranean-type diet that emphasizes the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. It limits the intake of sweets, sugar-sweetened beverages, and red meats. Calories from saturated fat should be limited to 5 to 6 percent and calories from trans-fat should be reduced. For patients who would benefit from blood pressure lowering, a reduction in sodium intake of at least 1 g/day (or daily sodium intake of <2.5 g per day) is also suggested. (See "Salt intake, salt restriction, and primary (essential) hypertension".) These recommendations are consistent with the 2021 AHA/ASA guideline for stroke prevention in patients with stroke or TIA [12] and the 2013 AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce cardiovascular risk [67]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) Supplementation with beta-carotene, vitamin E, and vitamin C, either alone or in combination with each other or other antioxidant vitamins does not appear to be effective in the primary or secondary prevention of cardiovascular disease. The data supporting these conclusions are reviewed elsewhere. Alcohol and substance use All patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their alcohol consumption because of the increased risk of stroke and high morbidity associated with alcoholism, despite the lack of clear evidence from clinical trials that reduction of alcohol intake decreases the risk of recurrent stroke [12]. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk' and "Screening for unhealthy use of alcohol and other drugs in primary care" and "Approach to treating alcohol use disorder" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial treatment".) Alcohol affects the risk of stroke in different directions depending upon level of consumption, type of stroke, and possibly ethnicity. Light drinking (one to two drinks per day) is associated with a reduced risk of ischemic stroke, while heavy drinking is associated with an increased risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 14/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate The risk of stroke is increased with infective endocarditis related to intravenous drug use, and with the use of certain stimulants (eg, cocaine, amphetamine and its derivatives) [68,69]. The

hospitalization (5.1 versus 3.2 percent), edema (36 versus 25 percent), and weight gain exceeding 4.5 kg (52 versus 34 percent). There was no difference between groups in the incidence of heart failure (the pioglitazone dose was adjusted for symptoms such as new or worsening edema, shortness of breath, or excessive weight gain during the trial). However, there is good evidence from other studies that thiazolidinediones increase the risk of heart failure. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Fluid retention/heart failure'.) Based upon the results of the IRIS trial [53], the number needed to treat (NNT) with pioglitazone to prevent one patient from developing stroke or myocardial infarction is 36, while the number needed to harm (NNH) to cause one patient to develop bone fracture requiring hospitalization is 53. Given the benefit of pioglitazone in this setting, it is an option for carefully selected nondiabetic patients with insulin resistance who are willing to accept the risk of adverse events such as bone fracture and heart failure. Since there is no validated test for measuring insulin resistance in clinical practice, clinicians should emulate the IRIS methodology as closely as possible by calculating the HOMA-IR index using laboratories that adapt the IRIS trial assays for plasma insulin level. LIFESTYLE MODIFICATION A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [12,54]. These include smoking cessation, regular aerobic physical activity, salt restriction, a Mediterranean diet, limited alcohol consumption, and https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 12/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate weight control. Our recommendations are in general agreement with the national guidelines [12]. Smoking cessation All patients who are recent or current tobacco smokers should be counseled routinely to quit smoking. (See "Overview of smoking cessation management in adults".) Cigarette smoking is associated with an increased risk for all stroke subtypes and has a strong, dose-response relationship for both ischemic stroke and subarachnoid hemorrhage [55-61]. In the Nurses' Health Study, smokers had a relative risk of stroke of 2.58 compared with never smokers [56]. Evaluation of former smokers found that the excess risk disappeared within two to four years after the cessation of smoking. In the Framingham Heart Study, the odds ratio for moderate carotid stenosis was 1.08 for each five pack-years of smoking [58]. Among 10,938 normotensive subjects in a prospective Swedish cohort study, approximately 39 percent of strokes were attributable to smoking [59]. There are no randomized controlled trials of smoking cessation compared with no intervention for stroke prevention. However, observational studies have shown that the elevated risk of stroke due to smoking declines after quitting and is eliminated by five years later [56,60,62]. Therefore, American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend smoking cessation for patients with stroke or transient ischemic attack (TIA) who smoke tobacco, counseling with or without pharmacologic therapy to assist in quitting, and avoidance of environmental tobacco smoke [12]. (See "Overview of smoking cessation management in adults".) Physical activity and exercise Patients with ischemic stroke or TIA who are capable of regular exercise should engage in moderate-intensity physical exercise performed for a minimum of 10 minutes four times a week or vigorous-intensity exercise performed for a minimum of 20 minutes twice a week. Moderate-intensity exercise is defined as activity sufficient to break a sweat or noticeably raise the heart rate (eg, walking briskly, using an exercise bicycle) [12]. (See "The benefits and risks of aerobic exercise", section on 'Benefits of exercise'.) Increasing evidence suggests that low physical activity and prolonged sitting increases the risk of cardiovascular disease, including stroke [4,63,64]. Additional support that physical inactivity is a risk factor for stroke comes from studies showing the benefit of increased physical activity and exercise for reducing the risk of cardiovascular events [65]. Diet Emerging evidence suggests that dietary interventions, and in particular a Mediterranean diet (see "Healthy diet in adults", section on 'Mediterranean diet'), improves https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 13/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate outcomes in patients with established cardiovascular disease [66]. Until further studies evaluate the magnitude of benefit of a Mediterranean diet, it is reasonable to advise all patients to adhere to its components. For patients with a history of stroke or TIA, we encourage patients to follow a Mediterranean-type diet that emphasizes the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. It limits the intake of sweets, sugar-sweetened beverages, and red meats. Calories from saturated fat should be limited to 5 to 6 percent and calories from trans-fat should be reduced. For patients who would benefit from blood pressure lowering, a reduction in sodium intake of at least 1 g/day (or daily sodium intake of <2.5 g per day) is also suggested. (See "Salt intake, salt restriction, and primary (essential) hypertension".) These recommendations are consistent with the 2021 AHA/ASA guideline for stroke prevention in patients with stroke or TIA [12] and the 2013 AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce cardiovascular risk [67]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) Supplementation with beta-carotene, vitamin E, and vitamin C, either alone or in combination with each other or other antioxidant vitamins does not appear to be effective in the primary or secondary prevention of cardiovascular disease. The data supporting these conclusions are reviewed elsewhere. Alcohol and substance use All patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their alcohol consumption because of the increased risk of stroke and high morbidity associated with alcoholism, despite the lack of clear evidence from clinical trials that reduction of alcohol intake decreases the risk of recurrent stroke [12]. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk' and "Screening for unhealthy use of alcohol and other drugs in primary care" and "Approach to treating alcohol use disorder" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial treatment".) Alcohol affects the risk of stroke in different directions depending upon level of consumption, type of stroke, and possibly ethnicity. Light drinking (one to two drinks per day) is associated with a reduced risk of ischemic stroke, while heavy drinking is associated with an increased risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 14/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate The risk of stroke is increased with infective endocarditis related to intravenous drug use, and with the use of certain stimulants (eg, cocaine, amphetamine and its derivatives) [68,69]. The AHA/ASA guideline recommends counseling patients about these risks and offering services to manage substance use disorders [12]. (See "Clinical assessment of substance use disorders".) Obesity and weight reduction Obesity is associated with an increased risk of cardiovascular disease, including ischemic stroke [12,70]. As with glycemic control, the available data do not show that weight reduction reduces the risk of recurrent stroke [12]. However, weight reduction for obese patients is potentially beneficial for improved control of other important parameters, including blood pressure, blood glucose, and serum lipid levels. Thus, the AHA/ASA guidelines for stroke prevention recommend screening all patients with stroke or TIA for obesity with measurement of body mass index, and recommend weight loss for patients who are overweight or obese [12]. Patients identified as candidates for weight loss should receive multidisciplinary team management and appropriate interventions, beginning with a combination of diet, exercise, and intensive behavioral intervention. These issues are reviewed in detail separately. (See "Obesity in adults: Overview of management".) OTHER RISK FACTORS In addition to the traditional stroke risk factors, myriad other risk factors and pathologic mechanisms are associated with ischemic stroke [71]. Sleep-related breathing disorders Patients with obstructive sleep apnea appear to be at increased risk for stroke. It is unknown whether patients with central sleep apnea syndrome, including Cheyne-Stokes breathing, also have an increased risk. (See "Sleep-related breathing disorders and stroke", section on 'Sleep apnea as a risk factor for stroke'.) Limited data suggest that the presence of sleep-related breathing disorders following a stroke may be a marker of a poorer long-term outcome. (See "Sleep-related breathing disorders and stroke", section on 'Complications'.) Clinically significant sleep apnea is highly prevalent in patients with acute stroke. Clinical features that have been associated with an increased risk for sleep-disordered breathing in patients with stroke include obesity, systolic hypertension, nocturnal oxygen desaturations, and increased stroke severity. The diagnosis of a sleep-related breathing disorder in patients with stroke requires a high index of suspicion and formal sleep testing, since clinical features and questionnaires lack high predictive value in patients with stroke. (See "Sleep-related breathing disorders and stroke", section on 'Diagnosis'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 15/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate Positive airway pressure therapy and behavioral modifications are the mainstays of treatment for patients diagnosed with sleep-related breathing disorders. These issues are reviewed elsewhere. (See "Sleep-related breathing disorders and stroke", section on 'Management'.) Hypercoagulability The approach to secondary stroke prevention for hypercoagulable states, including antiphospholipid syndrome, inherited thrombophilias, and cancer-related hypercoagulability, is reviewed separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Hypercoagulable states'.) Hyperhomocysteinemia Increased serum homocysteine concentrations are associated with an increased risk of coronary and cerebrovascular disease, as discussed separately (see "Overview of homocysteine"). Elevated homocysteine appears to be associated with an increased risk of the large artery subtype of ischemic stroke, and possibly to the small artery subtype; it does not appear to be associated with cardioembolic or other stroke subtypes [72,73]. However, there is evidence from several clinical trials that treatment with homocysteine-reducing vitamins is not beneficial for secondary prevention of cardiovascular disease or stroke [12]. Thus, we do not routinely screen patients with ischemic stroke or transient ischemic attack for homocysteine levels or vitamin levels associated with homocysteine metabolism. Head and neck radiotherapy Head and neck radiotherapy for cancer treatment may lead to a delayed vasculopathy of large and small vessels mediated by endothelial damage, fibrosis, and accelerated atherosclerosis [74-76]. Radiotherapy-related occlusive disease is often diffuse and occurs in uncommon locations, in contrast to the typical focal lesions that develop at vessel bifurcations from atherosclerosis in the absence of radiation. Depending on the site and dose of radiation, the involved vessels may include the extracranial carotid and vertebral arteries and the intracranial circle of Willis vessels [74,77]. This process may lead to symptomatic carotid disease, moyamoya syndrome, and ischemic stroke. (See "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery injury' and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Associated conditions'.) While data are limited, secondary prevention of stroke attributed to radiation-induced stenosis typically involves maximal medical therapy including an antiplatelet agent; revascularization with stenting may be appropriate for select patients with extracranial carotid involvement, whereas intracranial stenting is used as a last resort for intracranial large artery involvement, similar to patients with atherosclerotic intracranial large artery disease. Management should be multidisciplinary and tailored to the patient's anatomy and comorbidities. (See "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 16/36 7/6/23, 12:50 PM Overview of secondary prevention of ischemic stroke - UpToDate TREATMENT BY STROKE MECHANISM Several important mechanisms of ischemic stroke are amenable to effective secondary prevention, including anticoagulation for atrial fibrillation, revascularization for internal carotid artery stenosis, and device closure for patent foramen ovale with paradoxical embolism. An overview of the treatment for specific causes of ischemic stroke and transient ischemic attack, including large and small artery disease, cardiogenic embolism, aortic atherosclerosis, and blood disorders, is presented separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Lowering the risk of having a stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 17/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate SUMMARY AND RECOMMENDATIONS Major risk factors The major treatable stroke risk factors are hypertension, dyslipidemia, diabetes, smoking, and physical inactivity. Most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies, ideally by a multidisciplinary team, including antithrombotic therapy, blood pressure reduction, low-density lipoprotein (LDL)-lowering therapy, and lifestyle modification. (See 'Major risk factors' above.) Antithrombotic therapy Nearly all patients with TIA or ischemic stroke of atherosclerotic origin should be treated with an antiplatelet agent ( algorithm 2 and algorithm 3 and algorithm 1). Early short-term dual antiplatelet therapy (DAPT) is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis. The combination of aspirin- extended-release dipyridamole, clopidogrel alone, or aspirin alone are all acceptable options for long-term therapy. Long-term oral anticoagulation should be used as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. (See 'Antithrombotic therapy' above.) Antihypertensive therapy After the acute phase of stroke, antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events. In addition, antihypertensive therapy should be initiated in previously untreated, neurologically stable patients with stroke or TIA who have an established blood pressure that is above the goal blood pressure indicated in the table ( table 2) for higher-risk populations, which includes all patients with ischemic stroke or TIA. (See 'Hypertension' above and "Antihypertensive therapy for secondary stroke prevention".) LDL-C lowering therapy Detailed low-density lipoprotein cholesterol (LDL-C) lowering recommendations are provided separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) High-intensity statin therapy For patients with atherosclerotic cardiovascular disease, including TIA or ischemic stroke, we treat with high-intensity statin therapy (eg, atorvastatin 80 mg/day), independent of the baseline LDL-C, to lower the LDL-C to <70 mg/dL (1.8 mmol/L) in order to reduce the risk of stroke and cardiovascular events. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 18/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Intolerance of high-intensity statin therapy For patients who are intolerant of high- intensity statin therapy, the maximally tolerated dose of a statin therapy can be used. LDL-C above goal despite statin therapy For patients whose LDL-C level remains 70 mg/dL ( 1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is reasonable. Patients unable to tolerate statin therapy For patients who are unable to tolerate any statin regimen, we treat with ezetimibe; we consider adding a PCSK9 inhibitor if LDL-C remains 70 mg/dL ( 1.8 mmol/L). Glycemic control For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of 7 percent. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. (See 'Glycemic control' above.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease (see 'Lifestyle modification' above): Smoking cessation for tobacco smokers (see 'Smoking cessation' above) Eliminating or reducing alcohol consumption for heavy drinkers (see 'Alcohol and substance use' above) Regular exercise for patients who are capable of physical activity (see 'Physical activity and exercise' above) Healthy diet and salt restriction (see 'Diet' above) Weight reduction for obese patients (see 'Obesity and weight reduction' above) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Harmsen P, Lappas G, Rosengren A, Wilhelmsen L. Long-term risk factors for stroke: twenty- eight years of follow-up of 7457 middle-aged men in G teborg, Sweden. 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Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 13. Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke 2007; 38:1881. 14. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. 15. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1 25 million people. Lancet 2014; 383:1899. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 20/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 16. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007; 6:611. 17. Prabhakaran S, Wright CB, Yoshita M, et al. Prevalence and determinants of subclinical brain infarction: the Northern Manhattan Study. Neurology 2008; 70:425. 18. Das RR, Seshadri S, Beiser AS, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke 2008; 39:2929. 19. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375:895. 20. Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010; 375:938. 21. Yaghi S, Elkind MS. Lipids and Cerebrovascular Disease: Research and Practice. Stroke 2015; 46:3322. 22. Tirschwell DL, Smith NL, Heckbert SR, et al. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology 2004; 63:1868. 23. Lepp l JM, Virtamo J, Fogelholm R, et al. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999; 30:2535. 24. Zhang X, Patel A, Horibe H, et al. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol 2003; 32:563. 25. Kurth T, Everett BM, Buring JE, et al. Lipid levels and the risk of ischemic stroke in women. Neurology 2007; 68:556. 26. Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality in the Women's Pooling Project. Stroke 2002; 33:1863. 27. Shahar E, Chambless LE, Rosamond WD, et al. Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2003; 34:623. 28. Bots ML, Elwood PC, Nikitin Y, et al. Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health 2002; 56 Suppl 1:i19. 29. Amarenco P. Lipid lowering and recurrent stroke: another stroke paradox? Eur Heart J 2005; 26:1818. 30. Donnan GA, Davis SM. Stroke and cholesterol: weakness of risk versus strength of therapy. Stroke 2004; 35:1526. 31. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017; 120:229. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 21/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 32. Biasucci LM, Biasillo G, Stefanelli A. Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance. Clin Chem Lab Med 2010; 48:1685. 33. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549. 34. Collins R, Armitage J, Parish S, et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363:757. 35. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019; 73:e285. 36. Tramacere I, Boncoraglio GB, Banzi R, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med 2019; 17:67. 37. Amarenco P, Kim JS, Labreuche J, et al. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med 2020; 382:9. 38. Lee M, Cheng CY, Wu YL, et al. Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention: A Meta-analysis of Randomized Clinical Trials. JAMA Neurol 2022; 79:349. 39. Lindenstr m E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ 1994; 309:11. 40. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008; 300:2142. 41. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298:309. 42. H heim LL, Holme I, Hjermann I, Leren P. Risk factors of stroke incidence and mortality. A 12-year follow-up of the Oslo Study. Stroke 1993; 24:1484. 43. Bowman TS, Sesso HD, Ma J, et al. Cholesterol and the risk of ischemic stroke. Stroke 2003; 34:2930. 44. Arvanitakis Z, Schneider JA, Wilson RS, et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006; 67:1960. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 22/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 45. Janghorbani M, Hu FB, Willett WC, et al. Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses' Health Study. Diabetes Care 2007; 30:1730. 46. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375:2215. 47. Luitse MJ, Biessels GJ, Rutten GE, Kappelle LJ. Diabetes, hyperglycaemia, and acute ischaemic stroke. Lancet Neurol 2012; 11:261. 48. Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014; 383:1973. 49. Vermeer SE, Sandee W, Algra A, et al. Impaired glucose tolerance increases stroke risk in nondiabetic patients with transient ischemic attack or minor ischemic stroke. Stroke 2006; 37:1413. 50. Vitelli LL, Shahar E, Heiss G, et al. Glycosylated hemoglobin level and carotid intimal-medial thickening in nondiabetic individuals. The Atherosclerosis Risk in Communities Study. Diabetes Care 1997; 20:1454. 51. J rgensen L, Jenssen T, Joakimsen O, et al. Glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the Troms study. Circulation 2004; 110:466. 52. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005; 165:2644. 53. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016; 374:1321. 54. Zhang Y, Tuomilehto J, Jousilahti P, et al. Lifestyle factors on the risks of ischemic and hemorrhagic stroke. Arch Intern Med 2011; 171:1811. 55. Ockene IS, Miller NH. Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association. American Heart Association Task Force on Risk Reduction. Circulation 1997; 96:3243. 56. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 57. Kurth T, Kase CS, Berger K, et al. Smoking and risk of hemorrhagic stroke in women. Stroke 2003; 34:2792. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 23/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate 58. Wilson PW, Hoeg JM, D'Agostino RB, et al. Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med 1997; 337:516. 59. Li C, Engstr m G, Hedblad B, et al. Risk factors for stroke in subjects with normal blood pressure: a prospective cohort study. Stroke 2005; 36:234. 60. Wolf PA, D'Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259:1025. 61. Peters SA, Huxley RR, Woodward M. Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes. Stroke 2013; 44:2821. 62. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155. 63. Chomistek AK, Manson JE, Stefanick ML, et al. Relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the Women's Health Initiative. J Am Coll Cardiol 2013; 61:2346. 64. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1996; 143:860. 65. Billinger SA, Arena R, Bernhardt J, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2532. 66. English C, MacDonald-Wicks L, Patterson A, et al. The role of diet in secondary stroke prevention. Lancet Neurol 2021; 20:150. 67. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S76. 68. Indave BI, Sordo L, Bravo MJ, et al. Risk of stroke in prescription and other amphetamine- type stimulants use: A systematic review. Drug Alcohol Rev 2018; 37:56. 69. Sordo L, Indave BI, Barrio G, et al. Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 2014; 142:1. 70. Guo Y, Yue XJ, Li HH, et al. Overweight and Obesity in Young Adulthood and the Risk of Stroke: a Meta-analysis. J Stroke Cerebrovasc Dis 2016; 25:2995. 71. Bang OY, Ovbiagele B, Kim JS. Nontraditional Risk Factors for Ischemic Stroke: An Update. Stroke 2015; 46:3571. 72. Eikelboom JW, Hankey GJ, Anand SS, et al. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 24/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate ischemic stroke. Stroke 2000; 31:1069. 73. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109:2766. 74. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report. Neurology 2009; 73:1906. 75. Lam WW, Leung SF, So NM, et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer 2001; 92:2357. 76. Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42:2410. 77. Kasner SE. Treatment of "other" causes of stroke. In: Stroke: Pathophsyiology, Diagnosis, an d Management, 4th ed, Mohr JP, Choi DW, Grotta JC, et al (Eds), Churchill Livingstone, Philad elphia 2004. p.1059. Topic 1120 Version 65.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 25/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate GRAPHICS Known cardiovascular disease and similar risk Patients with the following are at high risk for a second (or first) cardiovascular disease event: Coronary heart disease Myocardial infarction Angina Coronary revascularization Cerebrovascular disease Stroke Transient ischemic attack Peripheral arterial disease Multiple risk factors that confer a 10-year risk of CVD >20% 2 Chronic kidney disease with estimated GFR <45 mL/min per 1.73 m * CVD: cardiovascular disease; GFR: glomerular filtration rate. Statin doses may require adjustment in patients with chronic kidney disease. Graphic 91576 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 26/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 27/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 28/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 29/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews.

pressure: a prospective cohort study. Stroke 2005; 36:234. 60. Wolf PA, D'Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259:1025. 61. Peters SA, Huxley RR, Woodward M. Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes. Stroke 2013; 44:2821. 62. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155. 63. Chomistek AK, Manson JE, Stefanick ML, et al. Relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the Women's Health Initiative. J Am Coll Cardiol 2013; 61:2346. 64. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1996; 143:860. 65. Billinger SA, Arena R, Bernhardt J, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2532. 66. English C, MacDonald-Wicks L, Patterson A, et al. The role of diet in secondary stroke prevention. Lancet Neurol 2021; 20:150. 67. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S76. 68. Indave BI, Sordo L, Bravo MJ, et al. Risk of stroke in prescription and other amphetamine- type stimulants use: A systematic review. Drug Alcohol Rev 2018; 37:56. 69. Sordo L, Indave BI, Barrio G, et al. Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 2014; 142:1. 70. Guo Y, Yue XJ, Li HH, et al. Overweight and Obesity in Young Adulthood and the Risk of Stroke: a Meta-analysis. J Stroke Cerebrovasc Dis 2016; 25:2995. 71. Bang OY, Ovbiagele B, Kim JS. Nontraditional Risk Factors for Ischemic Stroke: An Update. Stroke 2015; 46:3571. 72. Eikelboom JW, Hankey GJ, Anand SS, et al. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 24/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate ischemic stroke. Stroke 2000; 31:1069. 73. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109:2766. 74. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report. Neurology 2009; 73:1906. 75. Lam WW, Leung SF, So NM, et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer 2001; 92:2357. 76. Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42:2410. 77. Kasner SE. Treatment of "other" causes of stroke. In: Stroke: Pathophsyiology, Diagnosis, an d Management, 4th ed, Mohr JP, Choi DW, Grotta JC, et al (Eds), Churchill Livingstone, Philad elphia 2004. p.1059. Topic 1120 Version 65.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 25/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate GRAPHICS Known cardiovascular disease and similar risk Patients with the following are at high risk for a second (or first) cardiovascular disease event: Coronary heart disease Myocardial infarction Angina Coronary revascularization Cerebrovascular disease Stroke Transient ischemic attack Peripheral arterial disease Multiple risk factors that confer a 10-year risk of CVD >20% 2 Chronic kidney disease with estimated GFR <45 mL/min per 1.73 m * CVD: cardiovascular disease; GFR: glomerular filtration rate. Statin doses may require adjustment in patients with chronic kidney disease. Graphic 91576 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 26/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 27/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 28/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 29/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews. OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor). Refer to text and associated algorithm for details. Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 30/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable. Graphic 131697 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 31/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Stroke mortality related to blood pressure and age Stroke mortality rate, pictured on a log scale with 95% CI, in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. Stroke mortality increases with both higher pressures and older ages. For diastolic pressure, each age-specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). CI: confidence interval. Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. Graphic 66793 Version 5.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 32/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Coronary heart disease mortality related to blood pressure and age Coronary heart disease (CHD) mortality rate, pictured on a log scale with 95% confidence intervals (CI), in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. CHD mortality increases with both higher pressures and older ages. For diastolic pressure, each age- specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). IHD: ischemic heart disease. Reproduced from: Lewington S, Clarke R, Qizilbash N, et al. Age-speci c relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. Illustration used with the permission of Elsevier. All rights reserved. Graphic 75106 Version 9.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 33/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device)* Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 34/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 35/36 7/6/23, 12:51 PM Overview of secondary prevention of ischemic stroke - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Alexis Simpkins, MD, PhD, MSCR, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 36/36

7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk : Charles H Hennekens, MD, DrPH, Jose Lopez-Sendon, MD, PhD : Joann G Elmore, MD, MPH, Christopher P Cannon, MD, Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA : Sara Swenson, MD, Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 25, 2022. INTRODUCTION Patients with established cardiovascular disease (CVD) have a high risk of subsequent CVD events, including myocardial infarction (MI), stroke, and death. Many individuals without established CVD are also at very high risk, such as those with metabolic syndrome, multiple risk factors, diabetes, or chronic kidney disease. For all these high-risk patients, therapeutic lifestyle changes, which include increased physical activity, dietary modification/weight loss, and smoking cessation are of proven benefit and improve outcomes beginning within a matter of weeks. In addition, adjunctive drug therapies of proven benefit include statins and aspirin, whose benefits are at least additive. This topic is a broad overview of our approach to the prevention of CVD events in those with established CVD or at very high risk. Our approach in those without CVD is presented separately. (See "Overview of primary prevention of cardiovascular disease".) For the purpose of this topic, we are addressing the broad group of patients who have signs or symptoms of established CVD such as angina, transient ischemic attack, or claudication or those who have had a discrete adverse CVD event such as MI or stroke. In addition, this topic is meant to include recommendations for those at high risk but without overt CVD. High risk is defined directly below. (See 'Identifying patients at high risk' below.) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 1/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD IDENTIFYING PATIENTS AT HIGH RISK Among patients without established disease, very high-risk individuals are defined in most guidelines as those whose 10-year risk is >20 percent, and high-risk individuals are defined as those whose 10-year risk is >7.5 to 20 percent according to cardiovascular disease (CVD) risk factor tables or scores [1-3] (see "Cardiovascular disease risk assessment for primary prevention: Risk calculators"). These higher-risk subjects are likely to include most patients with diabetes or 2 chronic kidney disease with estimated glomerular filtration rate <60 mL/min/1.73 m , as well as many with metabolic syndrome (the constellation of overweight and obesity, dyslipidemia, hypertension, and insulin resistance), a precursor of diabetes. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Epidemiology and risk factors' and "Chronic kidney disease and coronary heart disease", section on 'Chronic kidney disease as an independent risk factor for CHD' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Reducing the risk of macrovascular disease'.) In addition, some guidelines define individuals to be at high risk if an imaging study documents atherosclerosis in the arterial circulation. Older adults Age is a major risk factor for all clinical manifestations of CVD. As the relative benefits of both therapeutic lifestyle changes and adjunctive drug therapies appear to be similar across all ages up to about 85 years, the absolute benefits are larger in older adults. We offer preventive strategies to older adults with the caveat that randomized trials have enrolled and followed patients into their 80s, but there are far more patients in middle than older ages. In addition, for many older adults, maintaining a high quality of life may be more important than quantity of life. These issues need to be considered by the health care provider and each of their older adult patients. Since older adults tend to be on many drug therapies, clinicians should be aware of the greater potential for drug-drug interactions, especially in those with high-risk comorbidities such as chronic kidney disease. DYSLIPIDEMIA We treat all patients with atherosclerotic cardiovascular disease (CVD), as well as individuals with a 10-year risk >20 percent, with evidence-based doses of a high-intensity statin regardless of the https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 2/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD baseline low-density lipoprotein (LDL) cholesterol. For patients with a 10-year risk between 7.5 and 20 percent, we treat with a moderate-intensity statin. In trials among patients with familial hypercholesterolemia, treated with either 80 mg atorvastatin or 40 mg of rosuvastatin and needing further lipid modification, PCSK9 inhibitors have demonstrated CVD benefits over three years [4]. PCSK9 inhibitor use is discussed in detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Our approach'.) HYPERTENSION Our recommendations for the establishment of goal blood pressure and the use of drug therapies are discussed separately. (See "Goal blood pressure in adults with hypertension" and "Choice of drug therapy in primary (essential) hypertension".) We recommend lifestyle changes for all apparently healthy individuals. In addition, this recommendation should be especially emphasized to patients with blood pressures of 120/80 mmHg or greater [5-7]. Therapeutic lifestyle changes of proven benefit include weight loss, increased physical activity, dietary sodium restriction, and reduction or avoidance of alcohol. Institution of these therapeutic lifestyle changes pose little or no risks, and all are likely to beneficial for all patients regardless of blood pressure. (See "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension" and 'Lifestyle modifications' below.) DIABETES MELLITUS The benefits of glycemic control on microvascular as well as macrovascular disease in patients with type 1 and type 2 diabetes are discussed in detail elsewhere. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Macrovascular disease' and "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Glycemic control for acute myocardial infarction in patients with and without diabetes mellitus".) LIFESTYLE MODIFICATIONS Lifestyle modifications such as smoking cessation, increase in physical activity, and improvement in diet have important beneficial effects on CVD morbidity and mortality that begin relatively shortly after their institution [8,9]. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 3/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Diet In observational studies, individuals who self-select for healthy diets experience significantly lower CVD event rates. Dietary interventions, in particular a Mediterranean diet, improve outcomes in patients with established CVD [10]. (See "Healthy diet in adults".) We agree with the following dietary recommendations of the 2019 American College of Cardiology/American Heart Association (ACC/AHA) guideline on primary prevention of CVD [11]: We encourage adherence to diets that emphasize high intakes of vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish. Diets should minimize the intake of trans fats, red meat and processed red meats, refined carbohydrates, and sweetened beverages. (See 'Dyslipidemia' above.) The European Society of Cardiology (ESC) guidelines on CVD prevention (both primary and secondary) make a recommendation for a Mediterranean or similar diet to reduce CVD risk [12]. Further, they suggest replacing saturated with unsaturated fats, reducing salt intake, choosing a plant-based food pattern high in fiber, and eating fish, preferably fatty, at least once a week. (See "Healthy diet in adults", section on 'Mediterranean diet' and "Overview of primary prevention of cardiovascular disease", section on 'Healthy diet'.) For patients with known CVD or those at high risk who consume fish or are willing to do so, we recommend that they consume at least one to two servings per week of oily fish, which is consistent with the AHA recommendations [13]. Consumption of fish as part of a healthy diet is discussed in detail elsewhere. (See "Healthy diet in adults", section on 'Protein-rich foods'.) Weight reduction In large-scale prospective studies [14], individuals who are overweight or obese have increased risks for CVD across a large range of levels. In the United States as well as other resource-rich countries, overweight and obesity may be overtaking smoking as the leading avoidable cause of premature death [15]. Weight reduction is difficult to achieve and maintain; among the 90 percent of subjects who are successful initially, about 90 percent of those eventually regain the lost weight. However, a clear benefit of weight reduction on cardiovascular outcomes has not been clearly demonstrated. (See "Overweight and obesity in adults: Health consequences" and "Obesity: Association with cardiovascular disease".) Overweight and obesity also are major contributors to metabolic syndrome a constellation of hypertension, dyslipidemia, and insulin resistance leading to diabetes. In the United States, metabolic syndrome, which confers high risk of a first CVD event, occurs in about 40 percent of individuals over age 40. In addition, overweight and obesity in the absence of metabolic syndrome also confer significantly increased risks of CVD [16-21]. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 4/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD All patients with CVD should have a measurement of waist circumference and a calculation of body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Weight reduction is optimally achieved with multiple strategies, including diet, increased physical activity, and possible pharmacologic therapy. (See "Obesity in adults: Overview of management".) The 2018 US Preventive Services Task Force (USPSTF) recommendation statement on weight loss to prevent obesity-related morbidity and mortality in adults recommends that clinicians offer or refer adults with a BMI of 30 or higher to intensive, multicomponent behavioral interventions [22]. Physical activity Regular physical activity has numerous cardiovascular benefits, including weight loss, improvements in lipid profile, and reductions in blood pressure, as well as prevention and management of type 2 diabetes. All these beneficial effects lead to improvements in CVD morbidity and mortality. This is discussed in detail elsewhere. (See "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease".) Prior to initiation of an activity program, most high-risk patients should undergo risk assessment with a physical activity history and/or an exercise test [23]. (See 'Cardiac rehabilitation programs' below.) We agree that the following recommendation for physical activity made in the 2019 ACC/AHA guideline on primary prevention of CVD is applicable to secondary prevention: Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity [11]. Smoking cessation Smoking cessation produces statistically significant and clinically important benefits on CVD, beginning within a matter of months and reaching the nonsmoker in three to five years. These benefits have been shown in secondary and primary prevention. (See "Cardiovascular risk of smoking and benefits of smoking cessation".) In a meta-analysis of observational studies, among 12,603 smokers who had a prior myocardial infarction (MI), coronary artery bypass graft surgery, angioplasty, or known coronary heart disease (CHD) [24], the relative risk (RR) of mortality for quitters compared with those who continued to smoke was 0.64 (95% CI 0.58-0.71). In a cohort study of 2619 patients who survived to hospital discharge after a first MI [25], among those who quit smoking (patients who quit and restarted were considered active smokers), the RR for recurrent events progressively and significantly decreased with longer https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 5/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD duration of cessation (RR 1.62 at 0 to <6 months, 1.60 from 6 to <18 months, 1.48 for 18 to <36 months, and 1.02 for 36 months). The various major effective modalities to attain and sustain smoking cessation are discussed separately. (See "Overview of smoking cessation management in adults".) Passive smoking has been clearly linked with a higher risk of CVD [26]. Banning smoking in public places quickly reduced the incidence of acute MI in many observational studies [27]. Alcohol Moderate alcohol consumption is associated with a reduced risk of CHD; however, binge drinking increases the risk for CHD [28-32]. The effect of alcohol consumption on CVD is discussed in greater detail elsewhere. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Effect of alcohol on cardiovascular risk'.) Cardiac rehabilitation programs We recommend referral to a comprehensive, outpatient cardiovascular rehabilitation program for all eligible patients with a recent acute coronary syndrome (ACS) or revascularization procedure [23]. Other patients, such as those with these diagnoses in the past year, those with chronic angina, or those with peripheral artery disease, may be candidates for referral. These programs are usually designed to provide the patient with assistance in lifestyle modification. (See "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart disease", section on 'Comprehensive risk factor intervention'.) Text messaging Not all patients are able to attend a cardiac rehabilitation program, and many programs limit the number of sessions. Another way to deliver assistance to patients in the adoption of a healthy lifestyle may be for the patient to receive mobile phone text messages periodically. The TEXT ME study randomly assigned 710 patients with CHD to a text message- based prevention program that delivered semi-personalized text messages four times per week with advice, motivation, and information to improve diet, increase physical activity, and encourage smoking cessation (if applicable) [33]. At six months, the intervention group had statistically significant improvements in LDL cholesterol (79 versus 84 mg/dL), systolic blood pressure (128.2 versus 135.8 mmHg, BMI 29.0 versus 30.3), physical activity (936 versus 642.7 metabolic equivalent minutes/week), and percent of patients who smoked (26.0 versus 42.9). ADJUNCTIVE THERAPIES All patients with established cardiovascular disease (CVD) and many other high-risk patients should receive aspirin and statin therapy. Other medications that may be of benefit in some patients include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone blockers, platelet P2Y receptor blockers, colchicine, and 12 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 6/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD oral anticoagulants. Administration of influenza vaccine also appears to be beneficial in patients with CVD. Antiplatelet therapy For patients with established CVD, we recommend long-term aspirin therapy. Long-term antiplatelet therapy with aspirin reduces the risk of subsequent myocardial infarction (MI), stroke, and cardiovascular death among patients with a wide range of manifestations of occlusive CVD. In patients who are unable to take aspirin and in those with a history of gastrointestinal bleeding, clopidogrel is a reasonable alternative. For patients who have undergone percutaneous coronary intervention (PCI) with stenting or those who have had an acute coronary syndrome (ACS), a P2Y receptor blocker is added to 12 aspirin for some period of time. The role of antiplatelet therapy in patients with CVD is discussed in numerous other topics: In atherosclerotic CVD (see "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease") In patients who have undergone coronary artery stent placement (see "Long-term antiplatelet therapy after coronary artery stenting in stable patients") In the first year following ACS (see "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy") In patients who have had a stroke (see "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke") The use of dual antiplatelet therapy has been evaluated in populations other than those with ACS or those who have had PCI. In the THEMIS trial, 19,220 patients with chronic coronary syndrome and type 2 diabetes mellitus were randomly assigned to ticagrelor 60 mg or placebo twice per day. All patients received low-dose aspirin once per day. Patients assigned at random to ticagrelor and aspirin had a 10 percent lower risk of ischemic CVD events (cardiovascular death, MI, or stroke) at 40 months when compared with aspirin alone (7.7 versus 8.5 percent; hazard ratio [HR] 0.90, 95% CI 0.81-0.99) but a highly significant and clinically important large increases of major bleeding (2.2 versus 1.0 percent; HR 2.32, 95% CI 1.82-2.94) and intracranial hemorrhage (0.7 versus 0.5 percent; HR 1.71, 95% CI 1.18-2.48) [34]. Based on these data, the US Food and Drug Administration (FDA) approved dual antiplatelet therapy for this population with or without diabetes. As is the case for all such patients, the health care provider must weigh the benefits on occlusion against the risks on bleeding for each of their individual patients. In a prespecified subgroup analysis of THEMIS (THEMIS-PCI) in the 11,154 patients with PCI, patients assigned to ticagrelor and aspirin had a 15 percent significant decreased incidence of https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 7/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD ischemic CVD events compared with those assigned to aspirin and placebo (7.3 versus 8.6 percent; HR 0.85, 95% CI 0.74-0.97). In this subgroup, those assigned to ticagrelor and aspirin also had an over 80 percent significantly increased risks of major bleeding (2.0 versus 1.1 percent) [35]. Intracranial hemorrhage occurred in 0.6 percent of both groups. In the subgroup of patients with chronic coronary syndrome and type 2 diabetes mellitus with no history of PCI, there was no apparent benefit. This subgroup analysis contributes to the formulation of the hypothesis that patients with stable coronary artery disease (CAD) and diabetes at very high ischemic risk and low bleeding risk may have a net benefit with long-term dual antiplatelet therapy with aspirin and ticagrelor. Health care providers may wish to consider these possibilities in discussions with their patients [36,37]. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".) The role of aspirin in patients without established CVD but at high risk is discussed separately. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'All- cause mortality'.) Anticoagulant therapy For most patients with stable CAD on antiplatelet therapy, rivaroxaban 2.5 mg orally twice per day and aspirin may be considered for some stable atherosclerotic CVD patients at high risk of cardiovascular events and low risk for bleeding, based on the COMPASS trial, which is presented below. Such patients include those with peripheral artery disease or a history of ischemic stroke, multivessel CAD, incomplete coronary revascularization, diabetes, patients with a body weight >60 kg (132 pounds), prior coronary artery bypass surgery, chronic kidney disease, or multiple prior ischemic events. We do not recommend substituting or adding full-dose oral anticoagulant therapy to aspirin therapy in an attempt to lower the risk of subsequent CVD events. The use of aspirin plus anticoagulant therapy in patients with a specific indication for anticoagulant, such as atrial fibrillation or venous thromboembolic disease, is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach' and "Atrial fibrillation in adults: Use of oral anticoagulants".) In stable patients, rivaroxaban, an oral direct Xa inhibitor, has been tested in secondary CVD prevention using a very low-dose regimen added to aspirin therapy. In the COMPASS trial, 27,395 patients with stable CAD or peripheral arterial disease were randomly assigned to rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone with a mean follow-up of 23 months [38]. The dose of rivaroxaban in the combination arm was 2.5 mg orally twice per day; in the rivaroxaban-only arm, the dose was 5 mg orally twice per day. Compared https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 8/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD with those assigned at random aspirin alone, patients assigned to rivaroxaban plus aspirin had a 22 percent significant decreases in cardiovascular mortality (1.7 versus 2.2 percent; HR 0.78, 95% CI 0.64-0.96) and 49 percent decrease in ischemic stroke (0.7 versus 1.4 percent; HR 0.51, 95% CI 0.38-0.68). There was also a possible but nonsignificant 14 percent reduction in MI (1.9 versus 2.2 percent; HR 0.86; 95% CI 0.70-1.05). As expected, those assigned to combination therapy had a 70 percent significant increase in major bleeding events (3.1 versus 1.9 percent; HR 1.70, 95% CI 1.40-2.05), with the gastrointestinal tract being the most common site of major bleeding. The risk of intracranial hemorrhage was comparable between the two groups. Mortality and cardiovascular outcomes were similar in the rivaroxaban-alone and aspirin-alone groups, but there were significantly more major bleeding events in those assigned to rivaroxaban and aspirin. Health care providers should be aware of the balance between prevention of thrombosis and causing serious bleeding. The optimal antithrombotic strategy in patients with other reasons for anticoagulation, such as atrial fibrillation, is discussed elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'After 12 months'.) The role of anticoagulant therapy in secondary prevention in patients with an ACS is discussed elsewhere. (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients".) Statins and other lipid-lowering agents The role of statin therapy in patients at high cardiovascular risk is discussed above. (See 'Dyslipidemia' above.) Beta blockers In patients with recent acute MI or in those with heart failure (HF) due to systolic dysfunction, oral beta blockers may be a part of their treatment regimen. The evidence supporting these recommendations is presented elsewhere. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In patients with chronic coronary syndrome and angina, beta blockers reduce the severity and frequency of anginal attacks. With the exception of patients with HF, the evidence is limited about whether beta blockers lower the risk of death in patients with chronic coronary syndrome when combined with contemporary secondary prevention strategies. Some of our contributors continue beta blockers indefinitely in patients with chronic coronary syndrome, while others stop them if they are not needed for control of symptomatic ischemia. (See "Beta blockers in the management of chronic coronary syndrome", section on 'Efficacy of beta blockers in stable angina' and "Beta blockers in the management of chronic coronary syndrome", section on 'Survival'.) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very- 9/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD ACE inhibitors or ARBs Many patients with established CVD will benefit from ACE inhibitor or ARB therapy. The most common indications are attainment of goal blood pressure, the treatment of acute MI, or the presence of HF, left ventricular ejection fraction below 40 percent, diabetes, or proteinuric kidney disease. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".) Other high-risk individuals include those with diabetes or chronic kidney disease. In these high- risk patients, ACE inhibitors and ARBs have been hypothesized to have cardioprotective effects independent of blood pressure lowering, but the available evidence suggests that the attained blood pressure is of primary importance. ACE inhibitors or ARBs may also be a first-line drug of choice to control blood pressure in diabetic and metabolic syndrome patients with or without prior MI. (See "Renin-angiotensin system inhibition in the treatment of hypertension", section on 'Specific indications for use'.) Polypill Polypills combine fixed doses of medications such as aspirin, ace-inhibitor and statin into one pill and have been proposed as a method to increase medication adherence. Their use in primary prevention of CVD is discussed elsewhere. (See "Overview of primary prevention of cardiovascular disease", section on 'Polypills'.) In the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial of nearly 2500 patients from 7 European countries with recent myocardial infarction (MI), treatment with a polypill containing aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg) was shown to lower risk of major adverse cardiovascular events compared with usual care [39]. Eligible patients were either older than 75 or at least 65 years of age with at least one additional risk factor [diabetes mellitus, mild or moderate kidney disease, previous myocardial infarction (defined as infarction occurring before the index event), previous coronary revascularization]. The mean age of participants was 76 years and 70 percent were male. Time from MI to randomization was a median of 8 days (interquartile range 3 to 37). After 36 months of follow-up, the following outcomes were observed: Those assigned to the polypill events had lower rates of cardiovascular events (cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization): 9.5 versus 12.7 percent; hazard ratio [HR] 0.76, 95% CI 0.60-0.96) compared with the usual care group. There were no differences in blood pressure and LDL cholesterol levels during follow-up between the two treatment groups. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 10/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Medication adherence as reported by the patients was higher in the polypill versus usual- care group. Adverse event rates were similar between treatment groups. The lack of difference in follow-up blood pressure or LDL cholesterol suggest that the ramipril and statin components of the polypill may have had pleiotropic effects, beyond the lowering of these risk factors, that resulted in lower rates of secondary CVD [40]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".) Mineralocorticoid receptor antagonist The use of a mineralocorticoid receptor antagonist (eg. spironolactone or epleronone) is recommended for certain patients with heart failure and reduced ejection fraction. This is described in detail elsewhere (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.) Colchicine For patients with chronic CAD who have been provided with recommendations for therapeutic lifestyle changes and prescribed appropriate preventive medications (which may include statins and aspirin), we suggest treatment with colchicine 0.5 (or 0.6) mg per day. In randomized trials in the secondary prevention of CAD, patients assigned to colchicine had improved outcomes. (See "Overview of established risk factors for cardiovascular disease", section on 'Inflammation'.) The most common side effects (diarrhea, nausea, vomiting, and abdominal pain) are usually mild. Transient, and usually painless, elevations of creatinine kinase have also been reported; this may be related to other drugs such as statins or other lipid-lowering drugs [41]. The dosage of colchicine may need to be reduced in patients taking P-glycoprotein (P-gp) inhibitors or strong CYP3A4 inhibitors, including certain beta blockers, calcium channel blockers, or amiodarone. Colchicine is contraindicated in patients with renal or hepatic impairment. Colchicine reduced risks of CAD in the LoDoCo2 trial. This trial randomly assigned 5522 patients, 85 percent men, with chronic CAD to 0.5 mg of colchicine once per day or placebo [42]. After two and half years, those assigned to colchicine had a decreased risk of the primary composite endpoint (HR 0.69, 95% CI 0.57-0.83), with reductions in MI (3.0 versus 4.2 percent; HR 0.70, 95% CI 0.53-0.93) and ischemia-driven coronary artery revascularization (4.9 versus 6.4 percent; HR 0.75, 95% CI 0.60-0.94). The incidence of death from non-cardiovascular causes appeared higher in the colchicine group; however, this finding did not achieve statistical significance (0.7 versus 0.5 percent; HR 1.51, 95% CI 0.99-2.31). All-cause mortality was similar in both groups (RR 1.08, 95% CI 0.71-1.62). Colchicine produced no significant adverse effects except for a somewhat higher rate of myalgia (21.2 versus 18.5 percent). In post hoc subgroup analyses, benefits were https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 11/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD similar among those with and without a history of prior ACS or timing of reported ACS [43]. A subsequent meta-analysis had similar findings to those of LoDoCo2 [44]. Prior studies have evaluated the use of colchicine in patients following ACS with similar results [45,46]. These are discussed in detail separately. (See "Overview of the nonacute management of ST-elevation myocardial infarction".) Sodium-glucose co-transporter 2 inhibitors Certain sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular outcomes in patients with heart failure with reduced ejection fraction (with or without diabetes mellitus) and in patients with type 2 diabetes mellitus and existing CVD. This is discussed in detail elsewhere. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.) Marine omega-3 fatty acids Many patients with established CVD or at high risk of CVD have hypertriglyceridemia. The role of marine omega-3 fatty acid therapy in patients with hypertriglyceridemia is discussed separately. (See "Hypertriglyceridemia in adults: Management" and "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.) We do not routinely recommend marine omega-3 fatty acids in individuals with CAD without hypertriglyceridemia. For such patients, there is less evidence supporting their use. The OMEMI trial randomly assigned 1027 patients aged 70 to 82 years with a recent (within two to eight weeks) MI to treatment with 1.8 g marine n-3 polyunsaturated fatty acid or corn oil [47]. Among enrolled patients, the mean triglyceride level was 111 mg/dL, that is, most did not have hypertriglyceridemia (defined as a triglyceride level 150 mg/dL). The rate of the primary composite endpoint (nonfatal MI, unscheduled revascularization, stroke, all-cause death, or heart failure hospitalization) after two years was similar in both treatment groups (21.4 versus 20.0 percent; HR 1.08, 95% CI 0.82-1.42). The small sample size may have limited the ability to detect statistically significant differences in outcomes. COVID-19 and influenza vaccination As with adults in the general population, we recommend annual influenza vaccine for patients with CVD [23]. (See "Seasonal influenza vaccination in adults".) We also encourage all patients with CVD to receive vaccination against COVID-19, due to increased risk of severity of COVID-19 infection ( table 1). (See "COVID-19: Myocardial infarction and other coronary artery disease issues" and "COVID-19: Vaccines".) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 12/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Individuals with established CVD and high-risk primary prevention subjects have increased risks for complications of influenza infection. In a cross-sectional study of 80,000 adults hospitalized with influenza (of whom 20 percent had chronic CVD, 20 percent chronic kidney disease, and 15 percent diabetes), 11.7 percent had an acute cardiovascular event during hospitalization, most commonly acute HF or acute ischemic heart disease [48]. Influenza vaccines may reduce mortality and CVD outcomes in these patients [49-53]. In a 2013 meta-analysis of trials conducted among persons with CVD or at high risk, those receiving an influenza vaccine had fewer cardiovascular events than those in the control group [54]. A randomized clinical trial of 2571 participants at 30 centers across eight countries found that primary outcomes (all-cause death, MI, and stent thrombosis) were less frequent in participants assigned influenza vaccine versus those assigned placebo (5.3 versus 7.2 percent) [55]. Therapies with uncertain or no benefit The following therapies have not been shown to improve outcomes in patients with CVD: Antioxidant vitamins Antioxidant vitamins, which are nonprescription and sold over the counter, have promising basic research and supportive observational data, but the randomized evidence has not demonstrated clinical benefits on CVD in secondary or primary prevention. The hypothesis that vitamin E, beta-carotene, and/or vitamin C decrease the risks of CVD has been tested in several large-scale randomized trials in secondary and primary prevention. The results have not supported either the potential beneficial mechanisms suggested from basic research or possible benefits hypothesized from observational studies [56-59]. (See "Vitamin intake and disease prevention".) Homocysteine and folic acid Although in observational studies, subjects with elevated levels of homocysteine have an increased risk of CHD, and given the fact that vitamin supplementation with folic acid lowers homocysteine levels, data from multiple randomized trials designed to test the hypothesis show no significant benefits of folic acid supplementation on the risks of CVD. Postmenopausal hormone therapy The relationship between postmenopausal hormone therapy and cardiovascular risk is discussed separately. (See "Menopausal hormone therapy and cardiovascular risk".) Chelation The totality of evidence does not support a recommendation for chelation therapy in patients with CAD. There is only one randomized trial of this issue, the TACT trial. TACT assigned 1708 patients with prior MI at random to 40 infusions of a chelation solution or placebo over one to two years [60]. The primary composite endpoint (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred less https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 13/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD frequently in the chelation group (26 versus 30 percent; HR 0.82, 95% CI 0.69-0.99) during a median follow-up of 4.6 years. This observed possible benefit needs to be interpreted in the context of the potential for unmasking and the use of multiple interim analyses, as well as the high rate of dropouts [61]. Further randomized evidence is necessary in order to make any evidence-based recommendations. Nonetheless, the 2014 American College of

Colchicine reduced risks of CAD in the LoDoCo2 trial. This trial randomly assigned 5522 patients, 85 percent men, with chronic CAD to 0.5 mg of colchicine once per day or placebo [42]. After two and half years, those assigned to colchicine had a decreased risk of the primary composite endpoint (HR 0.69, 95% CI 0.57-0.83), with reductions in MI (3.0 versus 4.2 percent; HR 0.70, 95% CI 0.53-0.93) and ischemia-driven coronary artery revascularization (4.9 versus 6.4 percent; HR 0.75, 95% CI 0.60-0.94). The incidence of death from non-cardiovascular causes appeared higher in the colchicine group; however, this finding did not achieve statistical significance (0.7 versus 0.5 percent; HR 1.51, 95% CI 0.99-2.31). All-cause mortality was similar in both groups (RR 1.08, 95% CI 0.71-1.62). Colchicine produced no significant adverse effects except for a somewhat higher rate of myalgia (21.2 versus 18.5 percent). In post hoc subgroup analyses, benefits were https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 11/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD similar among those with and without a history of prior ACS or timing of reported ACS [43]. A subsequent meta-analysis had similar findings to those of LoDoCo2 [44]. Prior studies have evaluated the use of colchicine in patients following ACS with similar results [45,46]. These are discussed in detail separately. (See "Overview of the nonacute management of ST-elevation myocardial infarction".) Sodium-glucose co-transporter 2 inhibitors Certain sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular outcomes in patients with heart failure with reduced ejection fraction (with or without diabetes mellitus) and in patients with type 2 diabetes mellitus and existing CVD. This is discussed in detail elsewhere. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.) Marine omega-3 fatty acids Many patients with established CVD or at high risk of CVD have hypertriglyceridemia. The role of marine omega-3 fatty acid therapy in patients with hypertriglyceridemia is discussed separately. (See "Hypertriglyceridemia in adults: Management" and "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.) We do not routinely recommend marine omega-3 fatty acids in individuals with CAD without hypertriglyceridemia. For such patients, there is less evidence supporting their use. The OMEMI trial randomly assigned 1027 patients aged 70 to 82 years with a recent (within two to eight weeks) MI to treatment with 1.8 g marine n-3 polyunsaturated fatty acid or corn oil [47]. Among enrolled patients, the mean triglyceride level was 111 mg/dL, that is, most did not have hypertriglyceridemia (defined as a triglyceride level 150 mg/dL). The rate of the primary composite endpoint (nonfatal MI, unscheduled revascularization, stroke, all-cause death, or heart failure hospitalization) after two years was similar in both treatment groups (21.4 versus 20.0 percent; HR 1.08, 95% CI 0.82-1.42). The small sample size may have limited the ability to detect statistically significant differences in outcomes. COVID-19 and influenza vaccination As with adults in the general population, we recommend annual influenza vaccine for patients with CVD [23]. (See "Seasonal influenza vaccination in adults".) We also encourage all patients with CVD to receive vaccination against COVID-19, due to increased risk of severity of COVID-19 infection ( table 1). (See "COVID-19: Myocardial infarction and other coronary artery disease issues" and "COVID-19: Vaccines".) https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 12/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Individuals with established CVD and high-risk primary prevention subjects have increased risks for complications of influenza infection. In a cross-sectional study of 80,000 adults hospitalized with influenza (of whom 20 percent had chronic CVD, 20 percent chronic kidney disease, and 15 percent diabetes), 11.7 percent had an acute cardiovascular event during hospitalization, most commonly acute HF or acute ischemic heart disease [48]. Influenza vaccines may reduce mortality and CVD outcomes in these patients [49-53]. In a 2013 meta-analysis of trials conducted among persons with CVD or at high risk, those receiving an influenza vaccine had fewer cardiovascular events than those in the control group [54]. A randomized clinical trial of 2571 participants at 30 centers across eight countries found that primary outcomes (all-cause death, MI, and stent thrombosis) were less frequent in participants assigned influenza vaccine versus those assigned placebo (5.3 versus 7.2 percent) [55]. Therapies with uncertain or no benefit The following therapies have not been shown to improve outcomes in patients with CVD: Antioxidant vitamins Antioxidant vitamins, which are nonprescription and sold over the counter, have promising basic research and supportive observational data, but the randomized evidence has not demonstrated clinical benefits on CVD in secondary or primary prevention. The hypothesis that vitamin E, beta-carotene, and/or vitamin C decrease the risks of CVD has been tested in several large-scale randomized trials in secondary and primary prevention. The results have not supported either the potential beneficial mechanisms suggested from basic research or possible benefits hypothesized from observational studies [56-59]. (See "Vitamin intake and disease prevention".) Homocysteine and folic acid Although in observational studies, subjects with elevated levels of homocysteine have an increased risk of CHD, and given the fact that vitamin supplementation with folic acid lowers homocysteine levels, data from multiple randomized trials designed to test the hypothesis show no significant benefits of folic acid supplementation on the risks of CVD. Postmenopausal hormone therapy The relationship between postmenopausal hormone therapy and cardiovascular risk is discussed separately. (See "Menopausal hormone therapy and cardiovascular risk".) Chelation The totality of evidence does not support a recommendation for chelation therapy in patients with CAD. There is only one randomized trial of this issue, the TACT trial. TACT assigned 1708 patients with prior MI at random to 40 infusions of a chelation solution or placebo over one to two years [60]. The primary composite endpoint (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred less https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 13/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD frequently in the chelation group (26 versus 30 percent; HR 0.82, 95% CI 0.69-0.99) during a median follow-up of 4.6 years. This observed possible benefit needs to be interpreted in the context of the potential for unmasking and the use of multiple interim analyses, as well as the high rate of dropouts [61]. Further randomized evidence is necessary in order to make any evidence-based recommendations. Nonetheless, the 2014 American College of Cardiology/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons focused update of prior guidelines for the diagnosis and management of patients with chronic coronary syndrome states that chelation therapy may be considered for reducing cardiovascular events [62]. Cholesteryl-ester transfer protein inhibitors Inhibition of the cholesteryl-ester transfer protein (CETP) leads to large increases in high-density lipoprotein (HDL) and modest reductions in low-density lipoprotein (LDL). Of four large trials, three were terminated early, two for lack of benefit and one due to clear evidence of harm [63]. In the fourth trial, the addition of the CETP inhibitor anacetrapib to intensive statin treatment in patients with atherosclerotic vascular disease resulted in a modest but significantly lower incidence of major coronary events than the addition of placebo during four years of treatment. One intriguing subgroup finding in the trial of dalcetrapib suggested there may be ADCY9 genotype-dependent effects of this CETP inhibitor on biomarkers as well as clinical cardiovascular outcomes. These observations, at least in part, formed the basis for the ongoing dal-GenE randomized trial [64]. The REVEAL trial compared anacetrapib with placebo in 30,449 patients with chronic atherosclerotic disease. After 4.1 years, anacetrapib-treated patients presented a lower incidence of the primary outcomes (major coronary event, a composite of coronary death, MI, or coronary revascularization) [10.8 versus 11.8 percent]). This benefit was considered statistically significant but not enough to continue research and development of the product [63]. Methotrexate Methotrexate has been postulated to lower the risk of CVD by reducing inflammation. However, in the Cardiovascular Inflammation Reduction Trial (CIRT) of 4786 patients with known MI or multivessel CAD who also had diabetes mellitus or metabolic syndrome, rates of the combined CVD outcome (nonfatal MI, nonfatal stroke, or cardiovascular death) were similar between the low-dose methotrexate (15 to 20 mg weekly) and placebo groups [65]. Allopurinol Among patients with gout, observational studies suggest that urate-lowering therapy with allopurinol is associated with lower CVD and mortality [66,67]. However, a https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 14/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD larger trial of allopurinol in patients with ischemic heart disease and no history of gout did not show that it was efficacious in reducing rates of cardiovascular disease [68]. In the ALL- HEART open-label multicenter trial in the United Kingdom, 5937 participants aged 60 years were randomly assigned to receive allopurinol or usual care and followed for the composite outcome of MI, stroke, or cardiovascular death. After an average of 5 years, those assigned to allopurinol and those assigned to usual care had similar rates of the composite endpoint (11 versus 11.3 percent; HR 1.04, 95% CI 0.89-1.21). These results do not support the hypothesis that allopurinol be given to individuals with ischemic heart disease for secondary CVD prevention. Revascularization The role of revascularization in patients with established CVD is discussed elsewhere. (See "Chronic coronary syndrome: Indications for revascularization", section on 'Indications'.) PATIENT EDUCATION Patient education regarding his or her risk factors and their management is central to secondary prevention. Patients with chronic coronary syndrome, also referred to as stable ischemic heart disease, should have an individualized education plan to optimize care and promote wellness that includes education on medication adherence; an explanation of medication management and cardiovascular risk reduction strategies in a manner that respects the patient s level of understanding; a comprehensive review of all therapeutic options; a description of appropriate levels of exercise; introduction to self-monitoring skills; and information on how to recognize worsening cardiovascular symptoms and take appropriate action. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 15/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Medicines after a heart attack (The Basics)") Beyond the Basics topics (see "Patient education: Quitting smoking (Beyond the Basics)" and "Patient education: Exercise (Beyond the Basics)" and "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: Aspirin in the primary prevention of cardiovascular disease and cancer (Beyond the Basics)" and "Patient education: High blood pressure treatment in adults (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Risks and benefits of alcohol (Beyond the Basics)" and "Patient education: Diet and health (Beyond the Basics)" and "Patient education: Losing weight (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Identifying patients at high risk Patients with established coronary heart disease (CHD) have higher risks of subsequent cardiovascular events, including myocardial infarction (MI), stroke, and death from cardiovascular disease (CVD). (See 'Identifying patients at high risk' above.) Lifestyle modifications Therapeutic lifestyle changes of proven benefit include avoidance or cessation of smoking, increasing levels of daily physical activity, and healthy diet. Modifications of multiple major risk factors may produce additive benefits. (See 'Lifestyle modifications' above.) Pharmacologic treatment Statins We treat all patients with atherosclerotic CVD, as well as individuals with a 10- year risk >20 percent, with evidence-based doses of a high-intensity statin regardless of the baseline LDL cholesterol. Specific recommendations are provided separately. (See https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 16/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Aspirin Patients with established atherosclerotic CVD are treated with long-term aspirin therapy. Specific recommendations are provided separately. (see "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease") Colchicine For patients with chronic coronary disease who are receiving other secondary preventive drug therapies, we suggest adding colchicine 0.5 (or 0.6) mg per day (Grade 2B). (See 'Colchicine' above.) Anticoagulant therapy for some patients For most patients with stable coronary artery disease (CAD) on antiplatelet therapy, we do not substitute or add a full-dose oral anticoagulant therapy to aspirin. For some stable atherosclerotic CVD patients who are at high risk of cardiovascular events and at low risk for bleeding, a regimen of rivaroxaban 2.5 mg orally twice per day and aspirin may be considered. (See 'Anticoagulant therapy' above.) Other potential treatments Other medications that may be of benefit in some patients include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or aldosterone blockers. (See 'Adjunctive therapies' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J 2021; 42:2439. 2. 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Effect of Lifestyle-Focused Text Messaging on Risk Factor Modification in Patients With Coronary Heart Disease: A Randomized Clinical Trial. JAMA 2015; 314:1255. 34. Steg PG, Bhatt DL, Simon T, et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med 2019; 381:1309. 35. Bhatt DL, Steg PG, Mehta SR, et al. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet 2019; 394:1169. 36. Hennekens CH, Demets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009; 302:2361. 37. Hennekens CH, DeMets D. Statistical association and causation: contributions of different types of evidence. JAMA 2011; 305:1134. 38. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. 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N Engl J Med 2019; 381:2497. https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 20/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD 46. Tong DC, Quinn S, Nasis A, et al. Colchicine in Patients With Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial. Circulation 2020; 142:1890. 47. Kalstad AA, Myhre PL, Laake K, et al. Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial. Circulation 2021; 143:528. 48. Chow EJ, Rolfes MA, O'Halloran A, et al. Acute Cardiovascular Events Associated With Influenza in Hospitalized Adults : A Cross-sectional Study. Ann Intern Med 2020; 173:605. 49. Gurfinkel EP, Leon de la Fuente R, Mendiz O, Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J 2004; 25:25. 50. Phrommintikul A, Kuanprasert S, Wongcharoen W, et al. Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome. Eur Heart J 2011; 32:1730. 51. Nguyen JL, Yang W, Ito K, et al. Seasonal Influenza Infections and Cardiovascular Disease Mortality. JAMA Cardiol 2016; 1:274. 52. Clar C, Oseni Z, Flowers N, et al. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev 2015; :CD005050. 53. Wu HH, Chang YY, Kuo SC, Chen YT. Influenza vaccination and secondary prevention of cardiovascular disease among Taiwanese elders-A propensity score-matched follow-up study. PLoS One 2019; 14:e0219172. 54. Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA 2013; 310:1711. 55. Fr bert O, G tberg M, Erlinge D, et al. Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Circulation 2021; 144:1476. 56. Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Dagenais G, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000; 342:154. 57. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999; 354:447. 58. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:23. 59. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 21/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD the Women's Antioxidant Cardiovascular Study. Arch Intern Med 2007; 167:1610. 60. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 2013; 309:1241. 61. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA 2013; 309:1293. 62. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014; 64:1929. 63. HPS3/TIMI55 REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med 2017; 377:1217. 64. Tardif JC, Dub MP, Pfeffer MA, et al. Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib. Am Heart J 2020; 222:157. 65. Ridker PM, Everett BM, Pradhan A, et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med 2019; 380:752. 66. Weisman A, Tomlinson GA, Lipscombe LL, et al. Association between allopurinol and cardiovascular outcomes and all-cause mortality in diabetes: A retrospective, population- based cohort study. Diabetes Obes Metab 2019; 21:1322. 67. Lai SW, Lin CL, Liao KF. Case-control study examining the association between allopurinol use and ischemic cerebrovascular disease. J Investig Med 2019; 67:48. 68. Mackenzie IS, Hawkey CJ, Ford I, et al. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. Lancet 2022; 400:1195. Topic 1505 Version 93.0 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 22/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD GRAPHICS [1-3] Comorbidities the CDC classifies as risk factors for severe COVID-19* Established, probable, and possible risk factors (comorbidities that have been associated with severe COVID-19 in at least 1 meta-analysis or systematic review, in observational studies, or in case series): Age 65 years Asthma Cancer Cerebrovascular disease Children with certain underlying conditions Chronic kidney disease Chronic lung disease (interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, COPD) Chronic liver disease (cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis) Cystic fibrosis Diabetes mellitus, type 1 and type 2 Disabilities (eg, ADHD, cerebral palsy, congenital malformations, limitations with self-care or activities of daily living, intellectual and developmental disabilities, learning disabilities, spinal cord injuries) Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies) HIV Mental health disorders (mood disorders including depression, schizophrenia spectrum disorders) Neurologic conditions (dementia) 2 2 th Obesity (BMI 30 kg/m ) and overweight (BMI 25 to 29 kg/m ), or 95 percentile in children Physical inactivity Pregnancy or recent pregnancy Primary immunodeficiencies Smoking (current and former) Sickle cell disease or thalassemia Solid organ or blood stem cell transplantation Substance use disorders Tuberculosis Use of corticosteroids or other immunosuppressive medications Possible risk factors but evidence is mixed (comorbidities have been associated with severe COVID-19 in at least 1 meta-analysis or systematic review, but other studies had reached different conclusions): Alpha 1 antitrypsin deficiency Bronchopulmonary dysplasia Hepatitis B https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 23/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Hepatitis C Hypertension CDC: Centers for Disease Control and Prevention; COVID-19: coronavirus disease 2019; COPD: chronic obstructive pulmonary disease; ADHD: attention deficit hyperactivity disorder; HIV: human immunodeficiency virus; BMI: body mass index. Listed comorbidities are associated with severe COVID-19 in all adults independent of age. People of color are also at increased risk of severe disease and death, often at a younger age, due to systemic health and social inequities. Risk of severe disease also rises steadily with age, with more than 93% of deaths occurring among adults 50 years and 74% of deaths occurring in adults 65 years. Underlying medical conditions are also associated with severe illness in children, but evidence implicating specific conditions is limited. Children with the following conditions might be at increased risk for severe illness: medical complexity; genetic, neurologic, or metabolic conditions; congenital heart disease; obesity; diabetes; asthma or other chronic lung disease; sickle cell disease; immunosuppression. References: 1. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk for severe COVID- 19: Information for healthcare providers. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical- care/underlyingconditions.html (Accessed on March 1, 2022). 2. Centers for Disease Control and Prevention. Science brief: Evidence used to update the list of underlying medical conditions that increase a person's risk of severe illness from COVID-19. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlying-evidence-table.html (Accessed on March 1, 2022). 3. Centers for Disease Control and Prevention. Risk for COVID-19 infection, hospitalization, and death by age group. Available at: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by- age.html (Accessed on June 16, 2022). Graphic 127477 Version 15.0 https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 24/25 7/6/23, 12:52 PM Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk - UpToD Contributor Disclosures Charles H Hennekens, MD, DrPH Patent Holder: Brigham and Women's Hospital [Co-inventor on patents concerning inflammatory markers and cardiovascular disease, C-reactive protein]. Consultant/Advisory Boards: Amgen [Migraine, cardiovascular disease]; UCB [Osteoporosis]. All of the relevant financial relationships listed have been mitigated. Jose Lopez-Sendon, MD, PhD Grant/Research/Clinical Trial Support: Amgen [Hyperlipemia]; Anthos [Atrial fibrillation]; AstraZeneca [Acute coronary syndrome]; Bayer [Heart failure]; Boehringer Ingleheim [Diabetes, heart failure]; Lilly Daichi-Sankio [Acute coronary syndrome]; Merck [Heart failure]; Pfizer [Atrial fibrillation and heart failure]; Sanofi [Diabetes]. Consultant/Advisory Boards: Menarini [Chronic angina]. All of the relevant financial relationships listed have been mitigated. Joann G Elmore, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Christopher P Cannon, MD Grant/Research/Clinical Trial Support: Amgen [Lipids, heart failure]; Applied Therapeutics [DM]; Ascendia [ACS]; Better therapeutics [Diabetes]; Biogen [Alzheimers]; Boehringer-Ingelheim [AF, DM, HF, CKD]; Daiichi Sankyo [AF]; Merck [Lipids, DM]; Novo Nordisk [DM]; Pfizer [DM, lipids]; Rhoshan [ACS]. Consultant/Advisory Boards: Aegerion/Amryt [Lipids]; Alnylam [Lipids]; Amarin [Lipids]; Amgen [Lipids]; BI [AF, DM]; Bristol-Myers Squibb [AF, ACS]; Eli Lilly [DM, ACS]; Janssen [AF, DM, ACS/CAD]; Lexicon [DM, CKD, HF]; Merck [Lipids, DM]; Pfizer [AF, DM, lipids]; Rhoshan [ACS]; Sanofi [Lipids, ACS, DM]. All of the relevant financial relationships listed have been mitigated. Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA Consultant/Advisory Boards: Glycardial Diagnostic [Biomarkers]. Speaker's Bureau: Menarini [Angina pectoris]; Servier [Angina pectoris]. All of the relevant financial relationships listed have been mitigated. Sara Swenson, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-of-cardiovascular-disease-events-in-those-with-established-disease-secondary-prevention-or-at-very 25/25

7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation : Robert Phang, MD, FACC, FHRS, Warren J Manning, MD : Bradley P Knight, MD, FACC, Brian Olshansky, MD, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 02, 2022. INTRODUCTION Spontaneous or intended conversion of atrial fibrillation (AF) to sinus rhythm (SR) is associated with a short-term increase from the baseline risk of clinical thromboembolism. This topic will discuss management strategies that attempt to decrease this thromboembolic risk, based on the duration of the AF episode, prior anticoagulant therapy, and the patient s individualized risk of stroke (CHA DS -VASc score ( 2 table 1)). 2 The modalities used to perform cardioversion, long-term anticoagulation in patients with AF, and an overview of the management of AF are presented separately. (See "Atrial fibrillation: Cardioversion" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) EXTREMELY HIGH-RISK PATIENTS Patients with AF and certain types of valvular heart disease (rheumatic mitral stenosis or a mechanical valve), are at extremely high risk of thromboembolic complications at all times, not only at the time of cardioversion. The approach to antithrombotic therapy in such patients is discussed in other UpToDate topics. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism' and "Antithrombotic therapy for mechanical heart valves".) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 1/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate RATIONALE FOR ANTICOAGULATION All patients with AF, whether paroxysmal, persistent, or permanent, have an increased risk of embolization compared with those without AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) At the time of reversion to SR, whether pharmaceutical, electrical, or spontaneous, there is a transient incremental increase from the baseline risk. Most embolic events occur within 10 days of reversion to SR [1-5]. Patients undergoing cardioversion of AF of more than 48 hours duration represent a particularly high-risk group (compared with AF of less than 48 hours duration), with an embolic risk from as low as 1 to as high as 5 percent in the first month after reversion to SR in the absence of anticoagulation [2-4,6-8]. This rate is substantially higher than the rate that would be calculated for the general population of patients with AF, in whom the yearly rate is between 1.3 and 5.1 (or higher) percent, depending on age and additional comorbidities. The most common source of stroke associated with cardioversion in these patients is embolism of a thrombus from the left atrial appendage during or in the first two weeks after the procedure. Possible causes include embolism of a left atrial thrombus that was already present at the time of conversion to SR, embolism of a thrombus that formed after conversion due to depressed left atrial appendage ejection velocity postconversion, or delay in recovery of left atrial mechanical function after conversion, and thrombus formation during subsequent episodes of AF: Precardioversion left atrial thrombus. Embolization after return of synchronous atrial contraction is due to the dislodgement of left atrial thrombi present at the time of cardioversion. This is felt to be the dominant cause of postcardioversion thromboembolism and the rationale for performing transesophageal echocardiogram (TEE) prior to cardioversion. The prevalence of left atrial thrombus in nonanticoagulated patients with AF of less than 72 hours undergoing TEE is 12 and 14 percent [9,10]. This value is similar to that found among AF patients with a duration of unknown or more than two days duration [11,12]. The prevalence of left atrial appendage thrombus is increased in high-risk patients with severe left ventricular systolic dysfunction, left atrial enlargement, depressed left atrial appendage ejection velocity, or left atrial appendage spontaneous echo contrast (a marker of blood stasis). https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 2/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Postcardioversion atrial mechanical dysfunction creates a milieu that promotes new (postcardioversion) thrombus formation. The transient atrial contractile dysfunction after cardioversion is referred to as atrial "stunning" and can occur whether SR is restored spontaneously, by external or internal direct current cardioversion, or by antiarrhythmic medications. The duration of the left atrial contractile dysfunction appears to be related in part to the duration of AF prior to cardioversion. Recovery of atrial mechanical function may be delayed for several weeks [13] for those who have been in AF for a few months prior to cardioversion. In comparison, for those with AF for only a few days, left atrial mechanical recovery occurs within a day (but may still be associated with more pronounced but transient dysfunction immediately after cardioversion). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) In support of the atrial stunning after cardioversion hypothesis, there have been case reports and small series of patients developing TEE evidence for de novo left atrial appendage thrombi (primarily in the setting of no anticoagulation) immediately following cardioversion, when the precardioversion TEE showed no left atrial appendage thrombus [9,14-16]. (See "Role of echocardiography in atrial fibrillation", section on 'Spontaneous echo contrast' and "Mechanisms of thrombogenesis in atrial fibrillation".) Recurrent AF is common during the first month after conversion [17]. Up to 90 percent of these episodes are asymptomatic [18], and asymptomatic episodes lasting more than 48 hours are not uncommon, occurring in 17 percent of patients in a report using continuous monitoring [17]. Anticoagulation during the four weeks postcardioversion thereby provides prophylaxis against new thrombus formation and facilitates early cardioversion without a screening TEE should recurrent AF occur. The rationale and indications for chronic anticoagulation after the period of postconversion anticoagulation are similar to those for the broad population of patients with AF and are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) PATIENTS WITH SPONTANEOUS CONVERSION Some patients with AF have spontaneous conversion prior to planned cardioversion. The risk of thromboembolism after spontaneous conversion or electrical cardioversion is relatively low, but the risk during this time is likely higher than the ambient rate of thromboembolic events associated with AF. There is no evidence that risk of embolization in the first few weeks after https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 3/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate spontaneous conversion differs from that for patients with AF undergoing electrical or chemical cardioversion. In a study of 1041 patients who were anticoagulated prior to and after cardioversion, 16 percent experienced spontaneous conversion (prior to planned electrical cardioversion) [19]. The rate of thromboembolism was similar in patients with spontaneous conversion compared with patients who underwent electrical cardioversion (<1 percent in both groups) although this comparison is limited by the small number of events). Though of unproven efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or via cardioversion) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score ( table 1). The rationale 2 2 for this approach is concern regarding the high likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This approach may be modified in patients at very high bleeding risk. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Management of long-term anticoagulation (after the initial four weeks) including the role of CHA DS -VASc score is discussed separately. (See "Atrial fibrillation in adults: Selection of 2 2 candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) URGENT CARDIOVERSION Patients with new onset AF in whom the ventricular rate is rapid may require urgent (or emergent) cardioversion to prevent adverse clinical consequences such as hemodynamic decompensation. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptom and hemodynamic management'.) The indications for urgent cardioversion of AF are uncommon, but in the setting of hemodynamic instability due to rapid AF that is refractory to pharmacologic support, such as in patients with Wolff-Parkinson-White syndrome, the need for restoration of SR may take precedence over the need for protection from thromboembolism. When possible, the patient should receive precardioversion anticoagulation (eg, bolus of unfractionated heparin or dose of direct oral anticoagulant [DOAC; also referred to as non-vitamin K oral anticoagulant [NOAC]) as soon as possible due to the risk of postcardioversion left atrial appendage stunning. Anticoagulation should be considered for four weeks postcardioversion, unless it is contraindicated [20] (see 'AF duration less than 48 hours' below). Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 4/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION LESS THAN 48 HOURS Anticoagulation prior to cardioversion If conversion to SR (either spontaneous or via cardioversion) occurs within 48 hours of the onset of AF, the thromboembolic risk appears to be very low [21-23]. However, many, and perhaps most, patients cannot accurately define the onset of AF. As a result, we categorize a patient as having AF of less than 48 hours duration only if we have a high level of confidence in the patient s history. Otherwise, we approach the patient as if AF has been present for more than 48 hours. (See 'AF duration uncertain or 48 or more hours' below.) For most patients in whom cardioversion will take place less than 48 hours after the onset of AF, we start a DOAC prior to cardioversion rather than no anticoagulant. Intravenous heparin is a reasonable alternative for hospitalized patients. When a DOAC is used, the specific choice of DOAC should be individualized for each patient. We generally choose the agent that will be given at the time of discharge. Of note, the approach presented here is in contrast to the historical approach of some cardiologists proceeding to early cardioversion without anticoagulation if the duration was less than 24 hours. I(See "Atrial fibrillation in adults: Use of oral anticoagulants".) We generally wait at least three hours after the first dose of a DOAC to cardiovert. For patients at very high bleeding risk, some of our experts suggest cardioversion without anticoagulation if normal SR can be restored within 48 hours of documented onset. Other experts recommend anticoagulation prior to cardioversion even in these high-bleeding-risk patients. If cardioversion needs to take place within three hours, whether for patient instability or convenience (see 'Urgent cardioversion' above), we start intravenous unfractionated heparin (bolus and continuous drip goal partial thromboplastin time 1.5 to 2.0 times control) or a low molecular weight heparin (1 mg/kg subcutaneously every 12 hours); we do not give DOAC and heparin together. However, if warfarin is the agent selected for longer term anticoagulation, warfarin is started while heparin therapy is continued until the international normalized ratio exceeds 2.0. For extremely high-risk patients (eg, those with rheumatic mitral stenosis, mechanical valves, prior thromboembolism, severe left ventricular dysfunction, heart failure, or diabetes), we anticoagulate for at least three weeks or initiate therapeutic anticoagulation (with heparin or DOAC) in combination with TEE prior to an attempt at cardioversion as described above for AF of more than 48 hours duration. (See 'AF duration uncertain or 48 or more hours' below.) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 5/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The 48 hour cut point is based on limited evidence and is somewhat arbitrary. For example, the prevalence of left atrial thrombus on TEE is substantially lower when the duration of AF is less than 48 hours (1.4 percent) [24]. Among patients with a history of AF of less than 48 hours in duration, there is likely a range of risk based on CHA DS -VASc score ( table 1). A retrospective 2 2 study of 3143 patients with AF of less than 48 hours duration demonstrated that patients with heart failure and diabetes were at high risk for clinical thromboembolism (up to 10 percent if both risk factors were present). The absence of both risk factors and age <60 years conveyed a very low risk of 0.2 percent [23]. (See 'AF duration uncertain or 48 or more hours' below and 'Rationale for anticoagulation' above.) No randomized trial has evaluated anticoagulation compared with no anticoagulation in AF patients undergoing cardioversion with a definite duration of AF <48 hours. Observational data suggest that the risk of stroke/thromboembolism is very low (0 to 0.2 percent) in patients with a definite AF duration of <12 hours and a very low stroke risk (CHA DS -VASc 0 in men, 1 in 2 2 women), in whom the benefit of four-week anticoagulation after cardioversion is undefined. The 2020 European Society of Cardiology guidelines for the diagnosis and management of AF suggest that prescription of anticoagulants can be optional, based on an individualized approach [25]. With regard to the question as to whether to anticoagulate these patients or not, there are no studies comparing heparin with no heparin in patients with AF of less than 48 hours duration. However, data regarding the rate of clinical thromboembolization after cardioversion in patients with AF of less than 48 hours duration have raised a concern about the safety of cardioversion without anticoagulation in this population. In an observational study of 2481 such individuals (5116 successful cardioversions) who were not treated with peri- or postprocedural anticoagulant, definite thromboembolic events occurred in 38 (0.7 percent) within 30 days (median of two days); of these, 31 were strokes [23]. Four additional patients suffered a transient ischemic attack. Age greater than 60 years, female sex, heart failure, and diabetes were the strongest predictors of embolization, with nearly 10 percent of those with both heart failure and diabetes experiencing a stroke. The risk of stroke in those without heart failure and age less than 60 years was 0.2 percent. An observational study of 16,274 patients undergoing direct current cardioversion with and without oral anticoagulant therapy also demonstrated that the absence of postcardioversion anticoagulation was associated with a high risk of thromboembolism, regardless of CHA DS -VASc scores [26]. There was a greater-than-twofold 2 2 increased risk of thromboembolism in those not treated with postcardioversion anticoagulation (hazard ratio 2.21; 95% CI 0.79-6.77 and 2.40; 95% CI 1.46-3.95 with CHA DS -VASc score 0 to 1 2 2 and CHA DS -VASc score 2 or more, respectively). The rationale for lack of postcardioversion 2 2 anticoagulation could not be exactly discerned in this trial but was deemed to be multifactorial, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 6/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate including presumed short-duration AF, perceived low thromboembolic risk, and lack of guideline adherence. With regard to the question of which anticoagulant to use, there are no studies comparing differing forms of heparin in patients with AF of short duration nor are there studies comparing a DOAC with heparin. Indirect evidence comparing the two heparins comes from a trial of 496 patients with AF of more than 48 hours duration who were randomly assigned to either low molecular weight heparin or unfractionated heparin followed by oral anticoagulation [27]. Patients were cardioverted after either 21 days of anticoagulation or after a TEE that was negative for thrombus; anticoagulation continued for 28 days after cardioversion. Low molecular weight heparin was noninferior to unfractionated heparin followed by oral anticoagulation in terms of the combined primary end point of ischemic neurologic events, major hemorrhage, or death by the end of study treatment (2.8 versus 4.8 percent). Low molecular weight heparin also has a safety and efficacy profile similar to unfractionated heparin when used as a bridge to oral anticoagulation in patients undergoing TEE-based therapy [28]. Anticoagulation after reversion to sinus rhythm Though of unproven in efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or intended) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score. The rationale for this approach is a concern regarding the high 2 2 likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This decision may be modified in patients at very high bleeding risk. Some of our contributors do not anticoagulate patients with a low CHA DS -VASc score (0 in men 2 2 or 1 in women) after restoration of SR if AF was less than 48 hours duration [23,29]. Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION UNCERTAIN OR 48 OR MORE HOURS Patients with AF of more than 48 hours or of unknown duration should receive at least three weeks of therapeutic anticoagulation prior to cardioversion and four weeks of anticoagulation after cardioversion. In this setting, this treatment regimen can reduce the risk of thromboembolism during the four weeks after cardioversion from 6 percent to less than 1 percent [2-4,6,7,30-32]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 7/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate For patients in whom there is a reason to not wait three weeks, an option for management is precardioversion therapeutic anticoagulation in conjunction with a screening TEE to guide early cardioversion. This strategy can be used for patients in whom cardioversion needs to be performed before at least three weeks of therapeutic anticoagulation have been completed [12]. While the TEE approach shortens the precardioversion duration of anticoagulation, it does not change our recommendation for four weeks of anticoagulation after cardioversion or the need to be therapeutically anticoagulated at the time of the cardioversion due to the risk associated with postcardioversion atrial appendage stunning. (See 'Transesophageal echocardiography- based approach' below.) Prospective studies have shown that the risk of clinical stroke or systemic embolism ranges from 0 to 0.9 percent if preceded by at least three weeks of therapeutic anticoagulation with warfarin (target international normalized ratio [INR] 2.0 to 3.0) or one of the DOACs [2-4,12], or shorter- term anticoagulation with TEE-guided approach discussed directly above. Retrospective data demonstrated that the thromboembolism risk is 4 to 7 percent in nonanticoagulated patients [7,8,33]. Anticoagulant approach Since many patients will require long-term anticoagulation, we prefer the DOACs to warfarin before and after cardioversion (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'). While there has been longer experience with use of warfarin than DOACs prior to cardioversion, we believe there is sufficient evidence that DOACs are as effective and as safe as warfarin in this setting. Advantages of DOAC therapy include convenience (no INR testing required) and the possibility of a shorter duration of precardioversion anticoagulation in reliably adherent patients, since it often takes five or more weeks for a patient to have at least three continuous weeks of therapeutic anticoagulation with warfarin (INR 2.0 to 3.0). In patients in whom adherence to DOAC therapy is questionable, with possible missed doses leading up to the cardioversion, we often obtain precardioversion TEE to exclude an atrial (appendage) thrombus. Routine precardioversion TEE is not recommended for patients who have been therapeutically anticoagulated (INR 2.0 or greater) with warfarin for three weeks or who have been compliant with their daily DOAC. (See 'Transesophageal echocardiography-based approach' below.) Compliance with warfarin can be ascertained with INR monitoring. For patients started on warfarin, the target INR should be 2.5 (range 2.0 to 3.0), and cardioversion should not take place until an INR of 2.0 or greater has been documented for at least three consecutive weeks ( figure 1 and figure 2) [34,35]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 8/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The following data are available for the DOACs: Dabigatran In a post-hoc analysis of the RE-LY trial, which compared dabigatran with warfarin, in which there were 1983 cardioversions in 1270 participants, there was no significant difference in the rate of thromboembolism and stroke within 30 days between those who received at least three weeks of dabigatran 110 or 150 mg twice daily or warfarin (0.8, 0.3, and 0.6 percent, respectively) [2]. Apixaban In a post-hoc analysis of the ARISTOTLE trial, which compared apixaban with warfarin, 743 cardioversions were performed in 540 patients. No strokes or systemic embolism occurred during the 30-day follow-up period of both warfarin and apixaban groups [3]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Rivaroxaban In the X-VeRT study, 1504 patients with AF of unknown or longer than 48 hours duration were randomly assigned in a 2:1 manner to cardioversion after at least three weeks of rivaroxaban or a vitamin K antagonist. There was no significant difference in the rate of the primary efficacy outcome (a composite of stroke, transient ischemic attack, peripheral embolism, myocardial infarction, and cardiovascular death) or the safety outcome of major bleeding (0.51 versus 1.02 percent and 0.6 percent versus 0.8 percent, respectively) [4]. Similarly, in a post-hoc analysis of the ROCKET-AF trial, which compared rivaroxaban with warfarin, 143 patients underwent 181 electric cardioversions, 142 patients underwent 194 pharmacologic cardioversions, and 79 patients underwent 85 catheter ablations. There was no significant difference in the long-term rate of stroke or systemic embolism (hazard ratio 1.38; 95% CI 0.61-3.11) [36]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Edoxaban In the ENSURE-AF trial, 2199 patients were randomly assigned to receive edoxaban or enoxaparin and warfarin with discontinuation of enoxaparin when the INR was >2.0 [5]. There was no significant difference in the primary efficacy end point (0.5 percent in the edoxaban group versus 1 percent in the enoxaparin warfarin group; odds ratio [OR] 0.46, 95% CI 0.12-1.43). The primary safety end point occurred in 1.6 percent of the edoxaban group versus 1.1 percent in the enoxaparin warfarin group (OR 1.48, 95% CI 0.64-3.55). The results were independent of the TEE-guided strategy and anticoagulation status. Therapeutic anticoagulation prior to cardioversion appears to be effective largely due to thrombus resolution, rather than organization and adherence of left atrial thrombi [37,38]. (See https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 9/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 'Rationale for anticoagulation' above.) Transesophageal echocardiography-based approach We suggest a TEE-based approach ( table 2A-B) for symptomatic patients and for patients for whom there is a concern about a three-week (or more) delay to cardioversion. Such a concern might arise from a preference to not have ongoing symptoms of AF or a possible lower likelihood of successful cardioversion with a longer period of AF. Other individuals for whom this strategy may be reasonable include those at high bleeding risk, as the TEE-guided approach shortens the total precardioversion anticoagulation time for those without thrombus; and those at highest risk for a cardioversion- related thromboembolic event, including prior thromboembolism and elderly women with diabetes and heart failure. Patients who require hospitalization are also candidates for this approach [39,40]. This recommendation for a focused use of the TEE-based approach is based on our concerns about cost, the small potential for complications, and the possibility of worse outcomes. We also recommend precardioversion TEE for all patients with a percutaneous left atrial appendage occlusion device in place (eg, Watchman, Lariat, Amulet,) or who have undergone surgical LAA exclusion (eg, by stapling, suture or approved device closure). Following LAA occlusion, adjacent thrombus may occur (with or without incomplete closure) with associated risk of thromboembolism. Limited data are available to guide the anticoagulation strategy in this setting [41]. (See "Atrial fibrillation: Left atrial appendage occlusion".) In a TEE-based approach, the imaging study is performed after therapeutic anticoagulation (of short duration) and prior to anticipated cardioversion. Patients without evidence of left and right atrial (specifically the left atrial appendage, which is the site for the vast majority of thrombi) thrombus proceed to cardioversion. If thrombus is found (or cannot be confidently excluded) on TEE, cardioversion should not be performed, and therapeutic anticoagulation should be continued for at least four weeks after which time we recommend that a TEE be repeated (to screen for residual thrombus, which would be a contraindication to cardioversion) if cardioversion is desired. The TEE approach should include the following sequential steps before cardioversion: For inpatients, the options include using heparin plus warfarin or using an DOAC. With the former, we administer either low molecular weight or unfractionated heparin (bolus and continuous drip with a goal partial thromboplastin time 1.5 to 2 times control) and simultaneously initiate oral warfarin (target INR 2.0 to 3.0). With the latter, we give at least two doses of a DOAC. As the pharmacokinetics of the DOACs are different than warfarin, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 10/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate the combination of a heparin plus DOAC may lead to supratherapeutic anticoagulation. We do not recommend overlap of or combined use of heparin and a DOAC. For most outpatients, we prefer DOAC to warfarin. There are multiple factors that determine whether a DOAC or warfarin would be used, including cost and patient preference, but DOACs have the advantage of faster onset of action and ease of dosing. A strategy of at least two days of DOAC prior to TEE-guided cardioversion can be used. As an alternative, oral warfarin can be started five days before TEE with the target INR 2.0 to 3.0 [12]. A minimal precardioversion INR of 2.0 is acceptable, though 2.5 may be preferred. Obtain a TEE to assess for the presence of atrial thrombi. The use of an endocardial border definition echo contrast agent may help in cases where there is uncertainty about the presence or absence of thrombus [42]. If no thrombus is seen, proceed with cardioversion. Continue therapeutic anticoagulation from the time of TEE through cardioversion and extend for another four weeks. If a thrombus is seen on TEE, the patient should receive a minimum of four weeks of therapeutic anticoagulation and a repeat TEE to document thrombus resolution if cardioversion is desired [37]. If no cardioversion is desired, a follow-up TEE is not needed, as the patient should receive lifelong antithrombotic therapy. If thrombus is absent on repeat TEE, cardioversion may be performed. If thrombus is still evident, the rhythm control strategy may be changed to a rate control strategy, especially when AF-related symptoms are controlled, since there is a high risk of thromboembolism if cardioversion is performed. However, the evidence supporting this latter recommendation of avoidance of cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.)

cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.) The following recommendations apply to patients with AF of clearly less than 48 hours duration (See 'AF duration less than 48 hours' above.): For patients one or more high risk factors for thromboembolism (eg, prior thromboembolism, heart failure, or diabetes mellitus), we suggest deferral of cardioversion to allow for three weeks of effective therapeutic precardioversion anticoagulation rather than early cardioversion (Grade 2C). Anticoagulation with heparin or a direct-acting oral anticoagulant (DOAC) before, during, and after cardioversion along with precardioversion transesophageal echocardiography (TEE) is an alternative approach for these high-risk patients. For patients not at high risk of thromboembolism (listed in the above bulleted recommendation), we anticoagulate most patients with a CHA DS -VASc score 1 2 2 (Grade 2C). We start either DOAC or a combination of heparin and warfarin prior to cardioversion. For patients with low risk of thromboembolism (CHA DS -VASc score 0 in men, 1 in 2 2 women), our experts have differing approaches regarding postcardioversion anticoagulation, with some using four weeks of postcardioversion warfarin or DOAC anticoagulation and others not. The following recommendations apply to patients with AF of more than 48 hours duration or when the duration is unknown (see 'AF duration uncertain or 48 or more https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 14/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate hours' above): We recommend a minimum of three consecutive weeks of therapeutic anticoagulation (warfarin with an international normalized ratio [INR] greater than 2.0 or DOAC) prior to cardioversion, rather than proceeding directly to cardioversion (Grade 1B). We recommend a DOAC prior to elective cardioversion rather than warfarin irrespective of whether the anticoagulant will be given long term (Grade 1B). (See 'Anticoagulant approach' above.) For symptomatic patients in whom there is a strong preference to not delay cardioversion, or in whom there is a concern about bleeding with prolonged oral anticoagulation, or who are not likely to tolerate AF despite adequate rate slowing, a TEE strategy is a reasonable approach using therapeutic anticoagulation with heparin/warfarin or DOAC throughout the pericardioversion period. (See 'Transesophageal echocardiography-based approach' above.) We recommend therapeutic oral anticoagulation (with a DOAC or warfarin with target INR of 2.0 to 3.0) for four weeks after cardioversion in all patients, rather than discontinuing anticoagulation after cardioversion (Grade 1B). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998; 82:1545. 2. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011; 123:131. 3. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014; 63:1082. 4. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014; 35:3346. 5. Goette A, Merino JL, Ezekowitz MD, et al. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 15/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 3b trial. Lancet 2016; 388:1995. 6. Kinch JW, Davidoff R. Prevention of embolic events after cardioversion of atrial fibrillation. Current and evolving strategies. Arch Intern Med 1995; 155:1353. 7. Gentile F, Elhendy A, Khandheria BK, et al. Safety of electrical cardioversion in patients with atrial fibrillation. Mayo Clin Proc 2002; 77:897. 8. Arnold AZ, Mick MJ, Mazurek RP, et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19:851. 9. Stoddard MF, Dawkins PR, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995; 129:1204. 10. Stoddard MF, Dawkins PR, Prince CR, Ammash NM. Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol 1995; 25:452. 11. Weigner MJ, Thomas LR, Patel U, et al. Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year. Am J Med 2001; 110:694. 12. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344:1411. 13. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol 1989; 13:617. 14. Black IW, Hopkins AP, Lee LC, Walsh WF. Evaluation of transesophageal echocardiography before cardioversion of atrial fibrillation and flutter in nonanticoagulated patients. Am Heart J 1993; 126:375. 15. Black IW, Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study. Circulation 1994; 89:2509. 16. Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials. Am Heart J 1995; 129:71. 17. Israel CW, Gr nefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004; 43:47. 18. Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 16/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Circulation 1994; 89:224. 19. Tejan-Sie SA, Murray RD, Black IW, et al. Spontaneous conversion of patients with atrial fibrillation scheduled for electrical cardioversion: an ACUTE trial ancillary study. J Am Coll Cardiol 2003; 42:1638. 20. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 21. Gallagher MM, Hennessy BJ, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002; 40:926. 22. Weigner MJ, Caulfield TA, Danias PG, et al. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997; 126:615. 23. Airaksinen KE, Gr nberg T, Nuotio I, et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013; 62:1187. 24. Kleemann T, Becker T, Strauss M, et al. Prevalence of left atrial thrombus and dense spontaneous echo contrast in patients with short-term atrial fibrillation < 48 hours undergoing cardioversion: value of transesophageal echocardiography to guide cardioversion. J Am Soc Echocardiogr 2009; 22:1403. 25. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 26. Hansen ML, Jepsen RM, Olesen JB, et al. Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy. Europace 2015; 17:18. 27. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109:997. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 17/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 28. Klein AL, Jasper SE, Katz WE, et al. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study. Eur Heart J 2006; 27:2858. 29. Garg A, Khunger M, Seicean S, et al. Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset. JACC Clin Electrophysiol 2016; 2:487. 30. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 31. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139. 32. Botkin SB, Dhanekula LS, Olshansky B. Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs. Am Heart J 2003; 145:233. 33. Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:745. 34. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 35. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 36. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013; 61:1998. 37. Collins LJ, Silverman DI, Douglas PS, Manning WJ. Cardioversion of nonrheumatic atrial fibrillation. Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation 1995; 92:160. 38. Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: A transesophageal echocardiographic study. Am Heart J 2000; 140:150. 39. Silverman DI, Manning WJ. Strategies for cardioversion of atrial fibrillation time for a change? N Engl J Med 2001; 344:1468. 40. Seto TB, Taira DA, Tsevat J, Manning WJ. Cost-effectiveness of transesophageal echocardiographic-guided cardioversion: a decision analytic model for patients admitted to the hospital with atrial fibrillation. J Am Coll Cardiol 1997; 29:122. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 18/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 41. Sharma SP, Turagam MK, Gopinathannair R, et al. Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices. J Am Coll Cardiol 2019; 74:2267. 42. Jung PH, Mueller M, Schuhmann C, et al. Contrast enhanced transesophageal echocardiography in patients with atrial fibrillation referred to electrical cardioversion improves atrial thrombus detection and may reduce associated thromboembolic events. Cardiovasc Ultrasound 2013; 11:1. 43. Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol 2001; 37:691. 44. Manning WJ, Silverman DI, Gordon SP, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750. 45. Manning WJ, Silverman DI, Keighley CS, et al. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995; 25:1354. 46. Klein AL, Grimm RA, Jasper SE, et al. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial. Am Heart J 2006; 151:380. 47. Klein AL, Murray RD, Grimm RA, et al. Bleeding complications in patients with atrial fibrillation undergoing cardioversion randomized to transesophageal echocardiographically guided and conventional anticoagulation therapies. Am J Cardiol 2003; 92:161. 48. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 49. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. Topic 906 Version 62.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 19/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate GRAPHICS Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) 2 2 CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients (n = 73,538) Stroke and thromboembolism event 2 2 rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 20/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 5 8942 15.26 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 21/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 22/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 23/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation. Reproduced with permission from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2011; 123:e269. Copyright 2011 Lippincott Williams & Wilkins. Graphic 87025 Version 4.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 24/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the conventional approach to cardioversion (one month of pretreatment with warfarin) in patients with atrial fibrillation Advantages Disadvantages Use of warfarin for one month before Delaying cardioversion to normal sinus rhythm for one cardioversion may lower the stroke rate month potentially decreases functional capacity. from 5.6 percent to a very low stroke rate of <2 percent. Relatively easy to administer with regular Prolonging treatment for seven to eight weeks one monitoring of INRs. month prior to and one month after cardioversion increases the risk of bleeding complications. Suitable for community hospitals. Not followed by routine clinical practice, especially in the elderly. The conventional approach has withstood the "test of time" since the 1960s. Patients who are at the highest risk for developing systemic embolization who should receive more prolonged or intensive anticoagulation are not routinely identified. Reprinted with permission from the American College of Cardiology. J Am Coll Cardiol 2001; 37:691. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 72971 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 25/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the transesophageal echocardiography- guided approach to cardioversion of patients with atrial fibrillation undergoing cardioversion Advantages Disadvantages Transesophageal echocardiography (TEE) should be able to detect left atrial appendage thrombi, TEE is performed without any definitive guidelines about who should receive the which increase the risk of embolic stroke after procedure (high versus low risk) electrical cardioversion, thus sparing patients with thrombi from undergoing cardioversion In the majority of patients without left atrial Residual thrombus on repeat TEE may diminish appendage thrombi, earlier cardioversion may shorten the period of anticoagulation and lower the cost-effectiveness of the TEE-guided approach the corresponding risk of bleeding complications A TEE-guided approach may prove more cost- effective owing to the reduction in laboratory Transesophageal echocardiography requires a level III-trained physician and availability of monitoring costs and the reduction in bleeding complications expensive echocardiographic machines Earlier cardioversion is believed to increase the Transesophageal echocardiography may miss likelihood of a successful return to and thrombi that may embolize after cardioversion. In maintenance of sinus rhythm contrast, TEE may render false positive results by erroneously identifying spontaneous echocardiographic contrast, sludge, multilobed appendages or pectinate muscles as thrombus. Reprinted with permission from: The American College of Cardiology. J Am Coll of Cardiol 2001; 37:691-704. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 54077 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 26/27 7/6/23, 12:53 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Contributor Disclosures Robert Phang, MD, FACC, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 27/27

7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis : Magdy Selim, MD, PhD : Scott E Kasner, MD, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 07, 2022. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) is often associated with long-term neurologic symptoms, and patients with ICH have an elevated risk of recurrence. Prevention of recurrent ICH (ie, secondary prevention) may reduce accumulating neurologic disability as well as societal burden of ICH. ICH may be categorized as either spontaneous or traumatic. ICH following traumatic brain injury is reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) This topic will review the epidemiology, secondary prevention, and long-term prognosis in adults with spontaneous ICH. Other aspects of ICH are discussed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Cerebral amyloid angiopathy".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) RISK OF RECURRENCE https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 1/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Incidence The incidence of recurrent ICH varies from 2 to 7 percent per year, depending on risk factors [1,2]. Patients with a history of ICH have a risk of recurrent ICH that is higher than the risk of recurrence in patients with ischemic stroke [1-3]. In addition, the rate of recurrent ICH was 6.6-fold higher than for a first ICH in a study of patients with prior ischemic stroke [1]. The risk of ICH recurrence may be highest in the first 12 months after the initial ICH but persists for years after the first event, particularly after lobar ICH [4]. The cumulative risk of ICH recurrence varies from 1.3 to 8.9 percent after one year and ranges from 7.4 to 13.7 percent after five years in different populations [2,3,5,6]. Risk factors Initial ICH location and etiology Deep (nonlobar) ICH involving the basal ganglia, thalamus, cerebellum, or brainstem is associated with a lower risk of recurrence than ICH in lobar locations. The annual risk of ICH recurrence after deep ICH is approximately 2 to 3 percent, versus 7 to 14 percent after lobar ICH [2,7-9]. ICH involving deep nuclei is often attributed to hypertensive microvascular disease and lobar ICH is often attributed to cerebral amyloid angiopathy (CAA), but the risk of recurrence appears to be independent of ICH etiology, at least in part. CAA is a major cause of incident and recurrent lobar ICH [10]. A meta-analysis of 10 prospective cohorts of ICH patients found that the annual risk of ICH recurrence after CAA- related ICH was 7.4 percent (95% CI 3.2-12.6), versus 1.1 percent (95% CI 0.5-1.7) for non- CAA-related ICH [11]. (See "Cerebral amyloid angiopathy".) Other secondary causes of ICH, such as brain arteriovenous malformation, moyamoya syndrome, sickle cell disease, and brain tumors are also associated with elevated risks of recurrent ICH based on the nature of the underlying causes and the presence of specific associated high-risk features. These are discussed separately. (See "Brain arteriovenous malformations" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Prevention of stroke (initial or recurrent) in sickle cell disease" and "Overview of the clinical features and diagnosis of brain tumors in adults".) Other imaging features The presence and number of cerebral microbleeds (CMBs) and/or superficial siderosis on brain magnetic resonance imaging (MRI) identifies patients at high risk for recurrent ICH [11,12]. In one study, the presence of >1 CMB was associated with increased risk of recurrent ICH in patients with CAA-related ICH while a higher threshold, >10 CMBs, identified increased risk of a recurrent event in patients with non- CAA-related ICH [11]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 2/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hyperintensities on diffusion-weighted imaging (DWI) brain MRI sequences found in some patients with ICH may be a marker of severe small-vessel disease associated with the risk of ICH recurrence [13,14]. In one study of 247 patients with ICH, those with DWI hyperintensities had a higher risk of recurrent ICH but not subsequent ischemic stroke at two years [15]. Hypertension Hypertension (HTN) is the most consistent risk factor for ICH recurrence. HTN predisposes to ICH recurrence of both deep and lobar ICH [4]. Inadequate control of HTN is common and increases the risk of recurrent ICH [4,16,17]. In a longitudinal study of 1145 patients with ICH, each 10 mmHg increase in systolic blood pressure was associated with an incremental increase in risk of recurrent lobar ICH (hazard ratio [HR] 1.33, 95% CI 1.02-1.76) and recurrent deep ICH (HR 1.54, 95% CI 1.03-2.30) [18]. The risks of ICH related to inadequate blood pressure control and management to mitigate these risks are discussed below. (See 'Blood pressure management' below.) Age The risk of ICH recurrence with age is based largely on the association of advancing age with the risk of initial ICH [19]. A meta-analysis of more than 8100 patients with ICH assessed the age-related incidence of ICH over a 28-year period [20]. Using the age group of 45 to 54 years as reference, the incidence ratio increased from 0.10 (95% CI 0.06-0.14) for those under 45 years up to 9.6 (95% CI 6.6-13.9) for patients older than 85 years. These findings are likely true for ICH recurrence as well. Older age is also associated with higher prevalence of CAA and higher use of antithrombotic drugs for accumulating cardiovascular comorbidities. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) Medications Antithrombotic medications (including antiplatelet agents and anticoagulants) and statins may be associated with risk of ICH recurrence. In addition, several other substances including selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs have been linked to increased risk of bleeding in general, including ICH and ICH recurrence ( table 1). However, studies examining the associations between these drugs and risk of ICH recurrence have yielded inconsistent results [3,18,21,22]. The potential risks of recurrent ICH due to antithrombotic and statin medications are discussed below. (See 'Management of antithrombotic therapy' below and 'Management of statins' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 3/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other risk factors Race and ethnicity There are racial and ethnic disparities in the risk of ICH recurrence. Black American, Hispanic American, and Asian American patients with a history of ICH seem to be at higher risk for a recurrent event than White American patients [16,23]. The prevalence of HTN in these groups does not fully account for this elevated risk of ICH. In one study, patients remained at higher risk of ICH recurrence after adjusting for blood pressure measurements and variability [16]. Chronic kidney disease Chronic kidney disease can be a marker of atherosclerotic disease and may further contribute to the risk of ICH through renally mediated impairment of cerebral autoregulation [24]. A large population-based study in Denmark evaluated 15,270 patients with ICH and found that patients with kidney failure at the time of the initial ICH were at higher risk for ICH recurrence (relative risk 1.72, 95% CI 1.34-2.17) [3]. Prior ischemic stroke or ICH The risk of a future ICH is higher in patients with history of prior ICH and those with history of a prior ischemic stroke [1]. Genetic features Certain genetic features associated with CAA are associated with increased risk of ICH recurrence [25]. Patients with ICH who are carriers of apolipoprotein-E (APOE) e2 or e4 genotypes, frequently associated with CAA, are at elevated risk of ICH [9]. Additionally, patients with genetic bleeding disorders also are at risk for ICH. These disorders are discussed separately. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Clinical manifestations and diagnosis of hemophilia" and "Rare inherited coagulation disorders".) FOLLOW-UP NEUROIMAGING All patients whose symptoms unexpectedly fail to improve or worsen during the recovery period require neuroimaging to evaluate for a recurrent hemorrhage. In addition, follow-up imaging studies can help to identify or confirm the cause of the ICH, which in turn determines the risk of recurrence and may help guide preventive measures. For some patients, neuroimaging studies performed during the acute hospitalization identify the etiology such that further imaging studies are not required. For other patients, the initial imaging study does not sufficiently exclude other causes of ICH and follow-up studies are required. When acute https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 4/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate bleeding and surrounding edema from the acute ICH shroud and distort underlying brain structures, delayed imaging performed after bleeding and edema have resolved may identify patients who are at high risk for recurrence due to an underlying structural cause ( algorithm 1). (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Patients with suspected hypertensive ICH Patients with ICH attributed to hypertension (HTN) who continue to improve clinically during recovery may not warrant additional imaging. Clinical and imaging features on head computed tomography (CT) or brain magnetic resonance imaging (MRI) suggestive of hemorrhage related to HTN or other atherosclerotic risk factors associated with deep penetrating vasculopathy include: Hematoma or cerebral microbleeds (CMBs) in basal ganglia or thalamus, cerebellar nuclei, or brainstem ( image 1) Known history or new diagnosis of HTN No prior ICH (unless in setting of uncontrolled HTN) No atypical clinical or neuroimaging features ( table 2) Patient age 65 years Clinically stable patients who meet most or all of the criteria listed above likely do not require a follow-up imaging study. For patients with only some of these features, we suggest repeating a brain MRI with gadolinium contrast in 12 to 16 weeks after the ICH to assess for alternative secondary causes. Additional associated imaging features found in some patients with a hypertensive ICH include evidence of prior chronic ischemic stroke attributed to small vessel (penetrating artery) and CMBs located in the basal ganglia or thalamus evident on T2*-weighted brain MRI sequences. Patients with suspected CAA-related ICH Some patients with ICH attributed to cerebral amyloid angiopathy (CAA) whose symptoms continue to improve during recovery may not require additional imaging in the ambulatory setting. Imaging features on brain MRI suggestive of ICH related to CAA include lobar location and evidence of lobar CMBs or cortical superficial siderosis in an older patient ( image 1 and image 2). The approach to confirming that diagnosis is discussed separately. (See "Cerebral amyloid angiopathy", section on 'Diagnostic approach'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 5/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other patients We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause but not identified or excluded during the acute hospitalization ( table 2). Clinical features that raise suspicion for an underlying cause of ICH include: Age <65 years No history or new diagnosis of HTN History of protracted new-onset headaches History of new-onset neurologic symptoms preceding ICH Thunderclap headache at onset of hemorrhage History of prior ICH (unless attributed to uncontrolled HTN or CAA) Imaging features of the hemorrhage on imaging (head CT or brain MRI) raising suspicion for other secondary causes of ICH (such as a vascular lesion, primary or metastatic brain tumor, cerebral venous thrombosis, or hemorrhagic transformation of ischemic infarct) include: Early perihematomal edema out of proportion to the size of the ICH ( image 3) Hemorrhage appears to be in arterial vascular territory suggesting primary ischemic infarction ( image 4) Enhancement of intracranial vessels around ICH ( image 5) Multifocal hemorrhage ( image 6) Isolated intraventricular hemorrhage ( image 7) Specific underlying etiologies of nontraumatic ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Specific etiologies'.) We prefer brain MRI with gadolinium for most patients who undergo post-acute testing to identify underlying cause of ICH. MRI should include T2*-weighted (gradient echo [GRE] or susceptibility-weighted imaging [SWI]) sequences. In an observational study in 400 patients with spontaneous ICH, MRI performed within 30 days improved diagnostic accuracy regarding ICH etiology over CT, changing the diagnostic impression in approximately 14 percent and management in 20 percent of cases [26]. These findings were confirmed in a subsequent study of 123 patients where MRI was most useful for establishing the diagnosis of ICH secondary to cerebral venous sinus thrombosis, hemorrhagic transformation of an ischemic infarct, neoplasms, and vascular malformations [27]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 6/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients who are unable to undergo MRI, head CT with contrast is a reasonable but less sensitive alternative. When an underlying vascular cause is suspected, additional noninvasive vascular imaging with CT or MR angiogram should be performed. Digital subtraction angiography (DSA) is performed when CT or MR angiography is inconclusive or is negative and clinical suspicion for an underlying vascular lesion remains high ( image 5) [28,29]. In addition, we generally obtain DSA to evaluate for a vascular lesion such as an arteriovenous malformation. CT or MR venography is performed for suspected venous lesions, such as cerebral venous thrombosis. (See "Brain arteriovenous malformations" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The optimal time to obtain follow-up imaging depends on the indication and the clinical recovery of the patient. For patients who did not undergo evaluation during the acute hospitalization for potential underlying secondary causes of the ICH, we obtain early imaging in four weeks to identify potential underlying structural sources amenable to early treatment. For other patients with a suspected secondary cause where the acute evaluation did not identify or exclude an underlying source, we obtain imaging after six to eight weeks to allow for better visualization of underlying brain tissue after some resorption of the hematoma. For patients without worrisome clinical or imaging features of the ICH for whom the acute evaluation for underlying causes did not identify the etiology, repeat imaging is indicated to exclude underlying structural sources. For these patients, we typically delay repeat imaging for 12 to 16 weeks after the ICH to promote optimal visualization of underlying brain tissue and reduce the risk of identifying confounding abnormal imaging findings that may be attributed to healing of the ICH in the late subacute time period. BLOOD PRESSURE MANAGEMENT Blood pressure (BP) control is an important aspect of reducing the risk of recurrent ICH. Hypertension (HTN) is one of the single most important modifiable risk factors for initial ICH and ICH recurrence. (See 'Risk factors' above.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 7/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Small improvements in BP control help to reduce the risk of ICH. The relationship between BP control and ICH recurrence has been studied somewhat indirectly in patients with either ischemic stroke or ICH. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, patients with prior stroke (hemorrhage or infarction) were randomly assigned to an angiotensin-converting enzyme inhibitor (perindopril) with or without a diuretic (indapamide) versus placebo. A modest BP reduction rate by 9/4 mmHg in patients assigned to active treatment reduced the risk of ICH from 2.4 to 1.2 percent, corresponding to a 50 percent relative risk reduction (95% CI 26-67 percent) [30]. The relative risk reduction for recurrent stroke was 49 percent (95% CI 18-68 percent) among patients whose qualifying event was ICH [30-32]. Blood pressure goals We suggest aiming for BP <130/80 mmHg as a long-term target to reduce the risk of recurrence after ICH ( table 3) [33]. The risk of ICH is reduced with each incremental reduction in BP, but the benefit may be greatest for patients whose BP reaches intensive BP-lowering targets [18,31]. The benefit for intensive BP reduction has not been demonstrated specifically for ICH recurrence; however, indirect evidence from patients with other cerebrovascular conditions suggests a likely benefit. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, 3020 patients with prior ischemic stroke were assigned either to a systolic BP target of 130 to 149 mmHg or <130 mmHg [34]. During a mean follow-up of 3.7 years, there were fewer ICH events in those assigned to the intensive BP target (6 versus 16), corresponding to a lower rate of ICH at 0.1 percent per patient-year in the intensive group compared with 0.3 percent per patient-year in the higher target. A more intensive BP target was assessed in the Recurrent Stroke Prevention Clinical Outcome (RESPECT) trial, in which 1266 patients with ischemic stroke were randomly assigned to intensive BP control (<120/80 mmHg) or to standard treatment (<140/90 mmHg) [35]. There was a trend toward fewer strokes in patients assigned to the intensive group; however, limitations in this study prevent firm conclusions. The actual mean BP achieved in the intensive group was 127/77, not very different from 133/78 mmHg in the standard group. The trial was stopped early with relatively few (12) ICH events, most in the standard treatment group (11 versus 1). In a meta-analysis of these studies along with two additional trials in patients after ischemic stroke, more intensive BP lowering (variably defined) was associated with a reduced risk of ICH (relative risk [RR] 0.25, 95% CI 0.07-0.90) [35]. Blood pressure lowering has additional benefits in reducing the risk of other vascular events including ischemic stroke, although in the population of patients with prior ICH, the absolute benefits in this regard are likely to be small [35]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 8/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate When to begin antihypertensive therapy The approach to BP control after ICH is stepwise. However, high quality data to specify when to safely implement BP control after ICH are lacking. In the acute (typically hospital) setting, initial steps to control the BP are begun immediately to prevent hematoma expansion. The benefit of acute control of elevated blood pressure must be balanced against the competing risk of cerebral or other organ hypoperfusion. Initial target systolic blood pressure is 140 to 160 mmHg for most patients. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) Further reductions in BP toward normotension are made in a stepwise fashion. For most patients, we aim to achieve the BP target of <130/80 mmHg within 10 to 14 days after the onset of ICH. We also advise close outpatient monitoring to ensure that BP control is maintained. Selection of antihypertensive agent For patients without a clinical indication for a specific agent, we typically start an angiotensin-converting enzyme (ACE) inhibitor. For those unable to tolerate or who prefer an agent other than an ACE inhibitor, we offer an angiotensin receptor blocker, thiazide diuretic, or calcium channel blocker, based on analyses of risk reduction in patients with atherosclerotic disease [36,37]. The choice of agent should be guided by efficacy in achieving target BP. Clinical indications to guide individualized medication selection are discussed elsewhere ( table 4). (See "Choice of drug therapy in primary (essential) hypertension".) The use of combination antihypertensive regimen (ie, multiple antihypertensive drugs, instead of a single drug) may decrease the risk of adverse effects and improves tolerability and compliance [38]. (See "Choice of drug therapy in primary (essential) hypertension".) Education of patients and their caregivers about target BP and their engagement in self- monitoring at home and communications with their medical providers are also key to achieve better BP control and to improve adherence to therapy [39]. Lifestyle modifications and management of obstructive sleep apnea and obesity are fundamental components of BP management. (See 'Lifestyle modifications' below.) MANAGEMENT OF ANTITHROMBOTIC THERAPY Many patients with ICH have comorbid cardiovascular conditions and may have indications for antiplatelet or oral anticoagulant agents. Whether to resume or discontinue these medications after ICH requires weighing the competing risks of thromboembolic events versus ICH recurrence. In the absence of high-quality trial data, observational reports and expert opinion guide risk/benefit assessment and decision-making. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 9/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy Antiplatelet therapy is typically withheld in the acute setting to mitigate the risk of hemorrhage expansion. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) We suggest resuming antiplatelet therapy after ICH for most patients who have a specific indication for such therapy. However, it is important to balance individual risks and benefits. Patients with established atherosclerotic disease We resume antiplatelet therapy for most patients with nonlobar ICH and those with lobar ICH attributed to cerebral amyloid angiopathy (CAA) who have established atherosclerotic disease, in agreement with guidelines from the American Heart Association (AHA) [33]. Such indications may include prior cardiovascular disease, ischemic stroke, or peripheral arterial disease. These indications are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The risks and benefits of resuming antiplatelet medications for patients with CAA are discussed in detail separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) If lobar ICH was attributed to an alternative source, we base decisions on resuming antiplatelet therapy on the individual risks associated with the underlying etiology. We prefer low-dose aspirin (81 mg per day), typically starting a few days after ICH, if neuroimaging confirms stability. Low-dose aspirin has been most studied in relationship to ICH recurrence. Some [4,40-42] but not all [43] small studies have reported no difference in the rates of ICH recurrence among patients with ICH who continued aspirin and those who discontinued it. In the Restart or Stop Antithrombotics Randomized Trial (RESTART), 537 patients who developed ICH while taking antithrombotic therapy were assigned either to continue or discontinue antiplatelet therapy [44]. Most patients (88 percent) were taking antithrombotic therapy for secondary prevention of atherosclerotic disease; 25 percent had atrial fibrillation, either as a comorbid condition or as their primary indication. After a median two years of follow-up, the risk of recurrent ICH was similar (nonsignificantly lower) in patients who continued versus discontinued antiplatelet therapy (4 versus 9 percent; adjusted hazard ratio [aHR] 0.51, 95% CI 0.25-1.03), while rates of major occlusive and thromboembolic events were higher and were similar among treatment groups (15 versus 14 percent; aHR 1.02, 95% CI 0.65-1.60). These findings were sustained in an extended follow-up at a median time of three years (interquartile range two to five years) [45]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 10/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic and thromboembolic outcomes were similar among patients who continued versus those who discontinued antiplatelet therapy, and the rate of recurrent ICH remained lower than the rate of major vascular events (9 versus 30 percent). Primary prevention of atherosclerotic disease For patients with ICH without established atherosclerotic disease, we consider individual risk factors to weigh overall benefits of antiplatelet therapy against the risk of hemorrhage. As examples, we typically would resume aspirin for patients with ICH and hypertension (HTN), hyperlipidemia, and diabetes mellitus or those with carotid atherosclerotic disease. For such patients, ICH may be a marker of atherosclerotic risk. In a Danish cohort study, patients with prior ICH had a higher risk of subsequent cardiovascular events than age- and sex-matched controls, including ischemic stroke (1.5 versus 0.6 per 100 person-years) and major adverse cardiovascular events (4.2 versus 1.4 per 100 person-years) [46]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) For most of these patients in whom antiplatelet therapy is resumed, we prefer low-dose aspirin and restart such therapy several days after the ICH has stabilized. For patients with lobar ICH and suspected CAA without high risk of ischemic stroke or cardiovascular events, we avoid antiplatelet therapy. (See "Cerebral amyloid angiopathy".) Patients with intravascular stents Patients with symptomatic atherosclerotic disease who have undergone intravascular stent placement are typically prescribed antiplatelet therapy for several months to prevent vascular occlusion from thrombosis at the site of the stent. We typically resume these medications in patients with ICH because of the thrombotic risks related to their discontinuation and typically start within a few days after ICH if neuroimaging confirms stability. Whenever feasible, we prefer single antiplatelet therapy over dual antiplatelet therapy. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) Patients taking nonsteroidal antiinflammatory drugs We prefer nonacetylated salicylates (eg, magnesium salicylate) over other nonsteroidal antiinflammatory medications with antithrombotic properties that impair platelet function. Anticoagulation Anticoagulation is typically withheld, and the effects are reversed acutely for patients with ICH, to reduce the risks of hemorrhagic expansion and associated morbidity. (See https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 11/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) Many patients with ICH benefit from resuming anticoagulation when the thromboembolic risk is higher than the risk of recurrent ICH. However, it is important to balance individual risks and benefits. Individualize decision to resume or discontinue We balance the risks of recurrent ICH with the risk of thromboembolism to help make decisions about resuming anticoagulation for individual patients ( algorithm 2). Only limited observational data and expert opinion are available to support clinical decisions regarding resuming or withholding anticoagulation [47-50]. These decisions should be made along with the patient after weighing the individualized risks, benefits, and exploring alternative options whenever possible. Timing of resumption The optimal time for restarting oral anticoagulation after ICH has not been established and may depend on the underlying indication for anticoagulation. Early resumption of anticoagulation within several days after stabilization of the ICH may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve) [33]. (See 'Mechanical prosthetic heart valves' below.) For most other patients who resume anticoagulation, we generally suggest delaying restarting oral anticoagulants for four to eight weeks after onset of the ICH, in agreement with AHA guidelines [33]. We use hemorrhage size and thromboembolic risks to guide the specific timing of resumption for an individual patient. In one study of 177 patients with intracranial hemorrhage and an indication for anticoagulation, the combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir when warfarin was resumed after 10 weeks, suggesting that the optimal timing for resumption of oral anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial

anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial fibrillation associated with valvular heart disease and those with mechanical prosthetic heart valves. (See 'Mechanical prosthetic heart valves' above and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease'.) Warfarin may be preferred by patients previously taking the medication whose international normalized ratio (INR) is well-controlled. Additionally, warfarin may be preferred for other patients, including some with bodyweight <60 kg or age 80 years, and those unable to take a DOAC (eg, drug interaction, creatinine clearance <30 mL/minute). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Settings in which a heparin or vitamin K antagonist may be preferable'.) Left atrial appendage occlusion Percutaneous left atrial appendage occlusion (LAAO) may be a viable treatment option for patients with ICH and nonvalvular atrial fibrillation who are at high risk for recurrent ICH and thromboembolic events and in whom resumption of oral anticoagulation is not resumed or contraindicated [33]. In a meta- analysis of trials comparing LAAO closure with oral anticoagulation, the rates of both systemic embolism and major bleeding were similar after a mean follow-up of 39 months [62]. The risk of ICH was lower for patients assigned to LAAO (0.5 versus 2.4 percent; relative risk 0.22, 95% CI 0.02-0.58). In the Amplatzer Cardiac Plug multicenter registry, the subsequent annual major bleeding rate was 0.7 percent, corresponding to a relative risk reduction of 89 percent in patients with prior intracranial hemorrhage compared with those with other indications for LAAO [63,64]. LAAO is discussed in further detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 15/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy For patients with ICH and atrial fibrillation in whom anticoagulation is not resumed, antiplatelet therapy is used as an alternative. Because the benefit of aspirin to prevent thromboembolism in this population has not been established, we reserve antiplatelet therapy for patients with other indications. (See 'Antiplatelet therapy' above.) Other patients Anticoagulation may be used for patients with selected indications associated with a very high risk of thromboembolism and inadequate alternative choices. In these circumstances, risks and benefits should be discussed with patients and decisions should be individualized based on risk analysis and patient values. Such indications may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired or inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Venous thromboembolism with high risk of recurrence (see "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation") Other forms of cardiovascular disease (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy in patients with heart failure") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Left ventricular thrombus after acute myocardial infarction") Alternatives to intravenous thrombolytic therapy We do not routinely offer intravenous thrombolytic therapy to patients with ICH who develop conditions such as ischemic stroke, myocardial infarction, or pulmonary embolism, consistent with AHA guideline recommendations [65]. Endovascular and mechanical thrombectomy procedures may be an option for such patients. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) MANAGEMENT OF STATINS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 16/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate The decision to resume statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) for patients with ICH requires balancing the benefits of therapy with the potential hemorrhagic risks. We suggest resuming statins in most patients with ICH who have a strong indication for therapy. This includes patients with diabetes and coronary artery disease and those with recent myocardial infarction or baseline severe atherosclerotic arterial disease. We discontinue statins for patients with ICH with less compelling indications such as isolated dyslipidemia and for those with multiple (recurrent) lobar ICHs who are at high risk for ICH recurrence [66]. For patients with ICH who resume statins, we avoid high doses and prefer hydrophilic statins (eg, pravastatin or rosuvastatin). For patients who discontinue statins after ICH, we use the indication for therapy to help select an alternative medication. (See "Statins: Actions, side effects, and administration" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".) Statins appear to increase the propensity for ICH by inhibiting platelets, decreasing thrombus formation, and enhancing fibrinolysis [67,68]. In addition, hyperlipidemia appears to be protective against ICH. In a case-control study including 3492 patients with ICH, a reduced risk of ICH was associated with each increase in serum cholesterol by 5 mg/dL (odds ratio 0.87, 95% CI 0.86-0.88) [69]. Additionally, lower levels of low-density lipoprotein cholesterol are also associated with increased risk for ICH [70,71]. The contribution of statin drugs to the risk of initial ICH is supported by trials and several observational studies [69,72,73]. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, patients with prior transient ischemic attack or ischemic stroke assigned to atorvastatin had fewer major cardiovascular events than those assigned to placebo (3.5 percent absolute risk reduction) [74]. However, the incidence rate of ICH was significantly higher in patients who received atorvastatin 80 mg daily (2.3 versus 1.4 percent; risk ratio [RR] 1.68, 95% CI 1.09-2.5). However, data on the risk of recurrent ICH are less certain [75,76]. Outcomes associated with statin use were evaluated in a 2018 systematic review of 15 studies that included more than 50,000 patients with prior ICH [25]. Among studies reporting ICH recurrence, the risk associated with statin use was similar to controls (RR 1.04, 95% CI 0.86-1.25). However, statin use was associated with improved functional outcome and reduced mortality in patients with prior ICH. These findings may reflect variability of individual risk related to several factors including statin dose or formulation, prescription bias, the burden of atherosclerotic disease, and the cause of the prior ICH. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 17/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Effect of statin dose Statin dose may modify the risk of hemorrhagic complications such as ICH [77]. A meta-analysis of seven randomized controlled trials found that higher doses of statins were associated with increased risk for ICH compared with placebo (RR 1.53, 95% CI 1.16-2.01) [78]. However, a large 10-year nationwide cohort study from Taiwan found no association between statin dose and risk of recurrent ICH [79]. Effect of statin formulation Statins with lipophilic solubility (atorvastatin, lovastatin, simvastatin, cerivastatin, and fluvastatin) have a greater ability to penetrate across blood- brain barrier and have been associated with increased odds of recurrent ICH compared with hydrophilic statins [79]. Cause of incident ICH Some cohorts suggest the hemorrhagic risk with statin use is associated with patients with lobar ICH [80-82]. The protective effect of hyperlipidemia also appears to be higher for patients with lobar versus nonlobar ICH [69]. LIFESTYLE MODIFICATIONS We advise lifestyle modifications based on their association as risk factors of stroke, including ICH [33]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) These include: Regular physical activity (see "The benefits and risks of aerobic exercise") Maintenance of healthy body weight (see "Obesity in adults: Overview of management") Healthy diet (see "Healthy diet in adults") Cessation of smoking and excessive alcohol use (see "Cardiovascular risk of smoking and benefits of smoking cessation") Avoidance of sympathomimetic medications (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors') LONG-TERM PROGNOSIS Prognosis after ICH involves both initial prognosis and long-term prognosis. The clinical and imaging determinants of initial prognosis occur within the acute hospitalization and recovery periods, typically comprising the first 180 days after ICH. Long-term prognosis focuses on sequelae of ICH, which persist beyond 180 days. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 18/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute prognosis in ICH is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) Functional recovery The rate of recovery after ICH may be highest in the first few weeks to months. In one study, recovery was greatest within the first 30 days after ICH [83]. However, recovery after ICH is often delayed and can be slow; many patients report functional improvements for 6 to 12 months [84,85]. In a post-hoc analysis of individual patient data from two clinical trials of patients with intracerebral or intraventricular hemorrhage, poor functional outcome at 30 days was reported in 715 of 999 patients (72 percent) [86]. By one year, 308 of these patients (46 percent) had achieved good functional outcome, including 30 percent who were functionally independent. Older age, larger hemorrhage volumes, and baseline conditions such as diabetes mellitus and severe leukoaraiosis on imaging were associated with poor one- year outcomes. In addition, common complications of acute ICH were also predictors of poor outcome at one year including sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for gastrostomy feeding tube. Aggressive acute treatment to prevent these acute complications may help avoid premature withdrawal of support and improve long-term outcomes. Early rehabilitation and sustained support are recommended to maximize functional recovery [83,87,88]. Educating patients and caregivers regarding secondary prevention strategies and addressing lifestyle changes, depression, and caregiver burden is an important part of post-ICH rehabilitation program. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Initial aggressive care'.) The main clinical determinants associated with reduced functional recovery after ICH include increasing age, baseline comorbidities, and severity of ICH as assessed by Glasgow Coma Scale score at presentation. Key imaging determinants include ICH volume, the presence of intraventricular hemorrhage, and specific ICH locations (including brainstem, posterior limb of internal capsule, or thalamus) [89,90]. Functional outcome may be assessed using varying performance thresholds or clinical scoring tools. The modified Rankin Scale (mRS) is frequently used ( table 7). In several trials, patients with ICH achieving a score of 0 to 3 have been described as having a good functional outcome; poor outcome included those scoring 4 to 6. In a retrospective study of 1499 patients, 51 percent of patients with a first ICH had good functional recovery after 90 days, compared with 31 percent of patients after recurrent ICH [91]. A decline in long-term functional status has been observed among patients after ICH. In a single-center observational study of 560 patients, 23 percent of those with a good functional outcome at six months had declined over a median nine-year follow-up [92]. Advanced age, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 19/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate higher initial ICH volume, lower six-month functional status, and new diagnoses of dementia or stroke during follow-up were predictors of functional decline. Cognitive impairment Cognitive impairment is frequent among patients after ICH [93,94]. A systematic review reported that the prevalence of cognitive impairment ranged between 14 and 88 percent after ICH [95]. Predictive factors were previous stroke, ICH volume and location, and markers of cerebral amyloid angiopathy. Cognitive deficits after ICH were common across multiple domains. The most frequently impaired domains were naming, processing speed, executive functioning, memory, visuospatial abilities, and attention. Long-term mortality In population-based cohorts of patients hospitalized after ICH the 10- year survival rate ranged from 18 to 25 percent [5,96]. Life expectancy among patients after ICH was decreased compared with age- and sex-matched controls in the general population [97-99]. In a cohort of 219 patients with ICH, the major cause of death within five years was cardiovascular disease, largely due to recurrent ICH and its sequelae (10 percent) irrespective of ICH location [5]. The risk of death was similar in patients with lobar versus nonlobar ICH and higher in patients with anticoagulation-associated ICH. A retrospective multicenter 10-year study of 1499 patients with ICH reported recurrent ICH in 9.5 percent of patients and found that 30-day mortality was similar (approximately 14 percent) after first and recurrent ICH [91]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 20/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topic (see "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Risk factors for recurrent ICH Several risk factors have been implicated in the risk of recurrent intracerebral hemorrhage (ICH). These include the location and etiology of the initial ICH, hypertension, older age, several medications ( table 1), race/ethnicity, chronic kidney disease, prior stroke, and specific genetic features. (See 'Risk of recurrence' above.) Follow-up imaging to evaluate for underlying causes We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause ( algorithm 1 and table 2). For most patients, we prefer brain magnetic resonance imaging (MRI) with gadolinium to evaluate for an underlying cause. (See 'Follow-up neuroimaging' above.) Blood pressure management Blood pressure control is an important feature of secondary prevention for all patients with ICH. We suggest a long-term target <130/80 mmHg to lower the risk of ICH recurrence (Grade 2B). (See 'Blood pressure management' above.) Management of antiplatelet therapy We suggest resuming antiplatelet therapy for most patients with ICH who have a specific indication for such therapy (Grade 2C). For patients with ICH in whom antiplatelet therapy is being resumed, we typically start aspirin within a few days after the ICH has stabilized. (See 'Antiplatelet therapy' above.) Management of anticoagulation We balance the risks of recurrent ICH and thromboembolism to help make decisions about resuming anticoagulation for each patient ( algorithm 2). (See 'Anticoagulation' above.) Early resumption of anticoagulation may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve). For most other patients who resume anticoagulation, we generally suggest waiting for at least four weeks after onset of the ICH to restart the anticoagulant (Grade 2C). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 21/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients with atrial fibrillation, prediction models such as the HAS-BLED score may be used to help assess bleeding risk ( table 6) and CHADS2 or CHA2DS2-VASc scores used to help assess thromboembolic risks ( table 5). For many patients with atrial fibrillation, the risk-benefit analysis favors resuming anticoagulation after ICH. For most patients with atrial fibrillation who develop ICH while on warfarin and in whom oral anticoagulation is resumed, we suggest a direct oral anticoagulant (DOAC) over warfarin (Grade 2B). DOACs generally have a lower risk of bleeding, including ICH, than warfarin. Warfarin may be selected for patients with valvular atrial fibrillation, a mechanical heart valve, or an inability to take a DOAC. Management of statins We suggest resuming statins for most patients with lobar and nonlobar ICH who have atherosclerotic disease (Grade 2C). We discontinue statins for most patients with multiple (recurrent) lobar ICHs. (See 'Management of statins' above.) Long-term prognosis The rate of recovery after ICH may be highest in the first few months. However, the greatest extent of recovery may not be evident until 6 to 12 months after ICH. (See 'Functional recovery' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arima H, Tzourio C, Butcher K, et al. Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial. Stroke 2006; 37:1497. 2. Poon MT, Fonville AF, Al-Shahi Salman R. 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23/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 20. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167. 21. Huhtakangas J, L pp nen P, Tetri S, et al. Predictors for recurrent primary intracerebral hemorrhage: a retrospective population-based study. Stroke 2013; 44:585. 22. Kubiszewski P, Sugita L, Kourkoulis C, et al. Association of Selective Serotonin Reuptake Inhibitor Use After Intracerebral Hemorrhage With Hemorrhage Recurrence and Depression Severity. JAMA Neurol 2020. 23. Leasure AC, King ZA, Torres-Lopez V, et al. Racial/ethnic disparities in the risk of intracerebral hemorrhage recurrence. Neurology 2020; 94:e314. 24. Ghoshal S, Freedman BI. Mechanisms of Stroke in Patients with Chronic Kidney Disease. Am J Nephrol 2019; 50:229. 25. Ziff OJ, Banerjee G, Ambler G, Werring DJ. Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2019; 90:75. 26. Chalouhi N, Mouchtouris N, Al Saiegh F, et al. Analysis of the utility of early MRI/MRA in 400 patients with spontaneous intracerebral hemorrhage. J Neurosurg 2019; 132:1865. 27. Wijman CA, Venkatasubramanian C, Bruins S, et al. Utility of early MRI in the diagnosis and management of acute spontaneous intracerebral hemorrhage. Cerebrovasc Dis 2010; 30:456. 28. Wijman CA, Snider RW, Venkatasubramanian C, et al. Diagnostic accuracy of MRI in spontaneous intracerebral hemorrhage (DASH) Final Results. Stroke 2012; 43:A105. 29. van Asch CJ, Velthuis BK, Rinkel GJ, et al. Diagnostic yield and accuracy of CT angiography, MR angiography, and digital subtraction angiography for detection of macrovascular causes of intracerebral haemorrhage: prospective, multicentre cohort study. BMJ 2015; 351:h5762. 30. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033. 31. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006; 24:1201. 32. Zahuranec DB, Wing JJ, Edwards DF, et al. Poor long-term blood pressure control after intracerebral hemorrhage. Stroke 2012; 43:2580. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 24/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 33. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 34. SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382:507. 35. Kitagawa K, Yamamoto Y, Arima H, et al. Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis. JAMA Neurol 2019; 76:1309. 36. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007; :CD002003. 37. Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol 2007; 100:1254. 38. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med 2016; 375:1033. 39. Arima H, Tzourio C, Anderson C, et al. Effects of perindopril-based lowering of blood pressure on intracerebral hemorrhage related to amyloid angiopathy: the PROGRESS trial. Stroke 2010; 41:394. 40. Chong BH, Chan KH, Pong V, et al. Use of aspirin in Chinese after recovery from primary intracranial haemorrhage. Thromb Haemost 2012; 107:241. 41. Flynn RW, MacDonald TM, Murray GD, et al. Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage. Stroke 2010; 41:2606. 42. Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology 2006; 66:206. 43. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010; 75:693. 44. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019; 393:2613. 45. Al-Shahi Salman R, Dennis MS, Sandercock PAG, et al. Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial. JAMA Neurol 2021; 78:1179. 46. Gaist D, Hald SM, Garc a Rodr guez LA, et al. Association of Prior Intracerebral Hemorrhage With Major Adverse Cardiovascular Events. JAMA Netw Open 2022; 5:e2234215. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 25/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 47. Poli D, Antonucci E, Dentali F, et al. Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology 2014; 82:1020. 48. Yung D, Kapral MK, Asllani E, et al. Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study. Can J Cardiol 2012; 28:33. 49. Vestergaard AS, Skj th F, Lip GY, Larsen TB. Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study. Stroke 2016; 47:979. 50. Claassen DO, Kazemi N, Zubkov AY, et al. Restarting anticoagulation therapy after warfarin- associated intracerebral hemorrhage. Arch Neurol 2008; 65:1313. 51. Majeed A, Kim YK, Roberts RS, et al. Optimal timing of resumption of warfarin after intracranial hemorrhage. Stroke 2010; 41:2860. 52. Cannegieter SC, Rosendaal FR, Bri t E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89:635. 53. Murthy SB, Gupta A, Merkler AE, et al. Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke 2017; 48:1594. 54. Biffi A, Kuramatsu JB, Leasure A, et al. Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol 2017; 82:755. 55. Ivany E, Ritchie LA, Lip GYH, et al. Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage: Systematic Review and Meta- Analysis. Stroke 2022; 53:3035. 56. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. 57. Donz J, Rodondi N, Waeber G, et al. Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med 2012; 125:1095. 58. Eckman MH, Rosand J, Knudsen KA, et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 2003; 34:1710. 59. Farmakis D, Davlouros P, Giamouzis G, et al. Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing. Cardiology 2018; 140:126. 60. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 26/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 61. Poli D, Antonucci E, Vignini E, et al. Anticoagulation resumption after intracranial hemorrhage in patients treated with VKA and DOACs. Eur J Intern Med 2020; 80:73. 62. Turagam MK, Osmancik P, Neuzil P, et al. Left Atrial Appendage Closure Versus Oral Anticoagulants in Atrial Fibrillation: A Meta-Analysis of Randomized Trials. J Am Coll Cardiol 2020; 76:2795. 63. Tzikas A, Freixa X, Llull L, et al. Patients with intracranial bleeding and atrial fibrillation treated with left atrial appendage occlusion: Results from the Amplatzer Cardiac Plug registry. Int J Cardiol 2017; 236:232. 64. Tzikas A. Left Atrial Appendage Occlusion with Amplatzer Cardiac Plug and Amplatzer Amulet: a Clinical Trials Update. J Atr Fibrillation 2017; 10:1651. 65. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 66. Shoamanesh A, Selim M. Use of Lipid-Lowering Drugs After Intracerebral Hemorrhage. Stroke 2022; 53:2161. 67. Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000; 31:2442. 68. Asahi M, Huang Z, Thomas S, et al. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab 2005; 25:722. 69. Pezzini A, Grassi M, Iacoviello L, et al. Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy). J Neurol Neurosurg Psychiatry 2016; 87:924. 70. Rist PM, Buring JE, Ridker PM, et al. Lipid levels and the risk of hemorrhagic stroke among women. Neurology 2019; 92:e2286. 71. Ma C, Gurol ME, Huang Z, et al. Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study. Neurology 2019; 93:e445. 72. Woo D, Deka R, Falcone GJ, et al. Apolipoprotein E, statins, and risk of intracerebral hemorrhage. Stroke 2013; 44:3013. 73. Amarenco P, Bogousslavsky J, Callahan A, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006; 3555:549. 74. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 27/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 75. Saliba W, Rennert HS, Barnett-Griness O, et al. Association of statin use with spontaneous intracerebral hemorrhage: A cohort study. Neurology 2018; 91:e400. 76. Ribe AR, Vestergaard CH, Vestergaard M, et al. Statins and Risk of Intracerebral Hemorrhage in Individuals With a History of Stroke. Stroke 2020; 51:1111. 77. Sanz-Cuesta BE, Saver JL. Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors. Stroke 2021; 52:3142. 78. Pandit AK, Kumar P, Kumar A, et al. High-dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis. Acta Neurol Scand 2016; 134:22. 79. Tai SY, Lin FC, Lee CY, et al. Statin use after intracerebral hemorrhage: a 10-year nationwide cohort study. Brain Behav 2016; 6:e00487. 80. Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use following intracerebral hemorrhage: a decision analysis. Arch Neurol 2011; 68:573. 81. Haussen DC, Henninger N, Kumar S, Selim M. Statin use and microbleeds in patients with spontaneous intracerebral hemorrhage. Stroke 2012; 43:2677. 82. Romero JR, Preis SR, Beiser A, et al. Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 2014; 45:1492. 83. Bai Y, Hu Y, Wu Y, et al. A prospective, randomized, single-blinded trial on the effect of early rehabilitation on daily activities and motor function of patients with hemorrhagic stroke. J Clin Neurosci 2012; 19:1376. 84. Selim M, Foster LD, Moy CS, et al. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2019; 18:428. 85. Sreekrishnan A, Leasure AC, Shi FD, et al. Functional Improvement Among Intracerebral Hemorrhage (ICH) Survivors up to 12 Months Post-injury. Neurocrit Care 2017; 27:326. 86. Shah VA, Thompson RE, Yenokyan G, et al. One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability. JAMA Neurol 2022; 79:856. 87. Cumming TB, Thrift AG, Collier JM, et al. Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke 2011; 42:153. 88. Foster L, Robinson L, Yeatts SD, et al. Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial. Stroke 2022; 53:2204. 89. Saulle MF, Schambra HM. Recovery and Rehabilitation after Intracerebral Hemorrhage. Semin Neurol 2016; 36:306. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 28/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 90. Delcourt C, Sato S, Zhang S, et al. Intracerebral hemorrhage location and outcome among INTERACT2 participants. Neurology 2017; 88:1408. 91. Kim KH, Kim HD, Kim YZ. Comparisons of 30-day mortalities and 90-day functional recoveries after first and recurrent primary intracerebral hemorrhage attacks: a multiple- institute retrospective study. World Neurosurg 2013; 79:489. 92. Pasi M, Casolla B, Kyheng M, et al. Long-term functional decline of spontaneous intracerebral haemorrhage survivors. J Neurol Neurosurg Psychiatry 2021; 92:249. 93. Planton M, Saint-Aubert L, Raposo N, et al. High prevalence of cognitive impairment after intracerebral hemorrhage. PLoS One 2017; 12:e0178886. 94. Banerjee G, Summers M, Chan E, et al. Domain-specific characterisation of early cognitive impairment following spontaneous intracerebral haemorrhage. J Neurol Sci 2018; 391:25. 95. Donnellan C, Werring D. Cognitive impairment before and after intracerebral haemorrhage: a systematic review. Neurol Sci 2020; 41:509. 96. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006; 66:1182. 97. Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry 2005; 76:1534. 98. Gonz lez-P rez A, Gaist D, Wallander MA, et al. Mortality after hemorrhagic stroke: data from general practice (The Health Improvement Network). Neurology 2013; 81:559. 99. Hansen BM, Nilsson OG, Anderson H, et al. Long term (13 years) prognosis after primary intracerebral haemorrhage: a prospective population based study of long term mortality, prognostic factors and causes of death. J Neurol Neurosurg Psychiatry 2013; 84:1150. Topic 129071 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 29/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate GRAPHICS Medications and other substances that may increase the risk of bleeding or bruising Drug class or substance Mechanism Anticoagulants Interfere with clot formation (secondary hemostasis) Antiplatelet agents, including NSAIDs Interfere with platelet function (primary hemostasis) Glucocorticoids Interfere with vascular integrity Antibiotics Cause vitamin K deficiency, especially with longer use Some interfere with platelet function SSRIs Interfere with platelet function (primary hemostasis) Alcohol Complications of liver disease may affect clot formation and may cause thrombocytopenia May cause thrombocytopenia due to direct marrow toxicity Vitamin E Interferes with vitamin K metabolism in some individuals Garlic Interferes with platelet function in some individuals Gingko biloba Unknown This is a partial list that does not include drugs used for cancer therapy or drugs that alter the metabolism of anticoagulants. The magnitude of increased bleeding risk depends on many factors including the patient's other bleeding risk factors and the specific drug, dose, and duration of use. Fish oil is often cited, but bleeding risk does not appear to be increased. Refer to drug information monographs and UpToDate topics for further information. NSAIDs: nonsteroidal antiinflammatory drugs; SSRIs: selective serotonin reuptake inhibitors. Graphic 120264 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 30/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Evaluating the underlying etiology of nontraumatic intracerebral hemorrhage This is an algorithm to guide etiologic testing; additional testing may be indicated for patients who develop new or worsening symptoms during recovery period. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. ICH: intracerebral hemorrhage. Refer to the separate UpToDate table on clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes. Lobar or cortical ICH, evidence of multifocal superficial siderosis, age 55 years, and other sources for hemorrhagic features excluded. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 31/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Refer to the UpToDate topic on cerebral amyloid angiopathy for additional details. Graphic 132295 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 32/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2*-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2*-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 33/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 34/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes Alternative Specifying ICH Characteristic Other associated features underlying feature underlying cause causes Basal ganglia or brainstem Deep perforating vasculopathy (HTN) CMBs in basal ganglia, thalamus, pons, cerebellar location nuclei Subcortical white matter lesions on MRI Deep perforating territory ischemic infarcts Clinical history of HTN or diabetes mellitus Lobar location Cerebral amyloid angiopathy Deep penetrating vasculopathy (HTN) Cortico-subcortical CMBs Convexal superficial siderosis Clinical history of cognitive impairment Intraventricular hemorrhage Arteriovenous malformation Deep penetrating vasculopathy (HTN) Flow voids within or adjacent to ICH Calcification within or adjacent to ICH Cavernous malformation Small ICH with adjacent calcification Cavernous malformation Deep penetrating vasculopathy (HTN) T2-weighted image hyperintensity at center on MRI Peripheral rim of T2*- weighted gradient echo image hypointensity on MRI Subarachnoid Ruptured cerebral Perimesencephalic SAH predominates over basal surfaces hemorrhage Basal cisterns aneurysm hemorrhage Clinical history of Non-aneurysmal SAH thunderclap headache Subarachnoid hemorrhage Reversible cerebral vasoconstriction Trauma Hemispheric or cortical ICH Clinical history of recurrent thunderclap headache Cerebral amyloid Convexity syndrome angiopathy Cerebral venous thrombosis https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 35/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Arteriovenous malformation Simultaneous Infective endocarditis Cerebral amyloid CMBs acute infarcts angiopathy Mycotic aneurysms (typically distal arterial locations) Deep penetrating vasculopathy (HTN) Systemic/cutaneous evidence of embolism New heart murmur Cerebral vasculitis Multifocal segmental narrowing on vascular imaging Clinical history of new persistent headaches Progressive cognitive or other neurologic impairment Prominent edema Cerebral sinus thrombosis Subacute ICH of other etiologies Edema/hemorrhage extends to cortical surface Venous flow void (eg, delta and empty-delta signs) Clinical history of seizure or progressive headache Tumor (primary/metastatic) Multifocal lesions Contrast enhancement Clinical history of new persistent headaches Clinical exam findings may be milder than imaging abnormalities Hemorrhagic transformation of (Cytotoxic) Edema appears in distribution of arterial territory infarct Arterial stenosis or occlusion proximal to territory of hemorrhage Clinical history of ischemic risk factors Flow voids Moyamoya Arteriovenous malformation Basal ganglia or hemispheric location Bilateral (but may be asymmetric) narrowing of distal internal carotid or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 36/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate proximal anterior/middle cerebral arteries Clinical history of episodes of transient weakness with vigorous laughing/crying (Prominent cause of ICH and infarcts in children) ICH: intracerebral hemorrhage; HTN: hypertension; CMB: cerebral microbleeds; MRI: magnetic resonance imaging; SAH: subarachnoid hemorrhage. Graphic 132289 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 37/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute and subacute lobar hemorrhage Noncontrast head CT shows acute right parietal ICH (A). T2* susceptibility-weighted sequence on MRI performed one day later shows an acute ICH in the right frontal and parietal hemisphere (B) as well as a subacute hemorrhage in the left occipital lobe (thick arrow) and chronic ICH in right inferior parietal lobule (C; arrow). In addition, multiple microbleeds at cerebral corticomedullary junctions (B, C) are consistent with cerebral amyloid angiopathy. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132283 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 38/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Excessive perihematomal edema in a patient with hemorrhagic lung metastasis Noncontrast head CT showing left frontal ICH surrounded by excessive volume of hypodense vasogenic edema (A, B). MRI performed one day later shows hyperintense vasogenic edema on T2*-weighted gradient echo image (C). Pre- (D) and post-contrast (E) T1-weighted MRI images demonstrate enhancement (arrows) consistent with underlying tumor. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132284 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 39/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic transformation of ischemic infarction Noncontrast head CT (A) shows heterogeneous hyperdensity within hypodense region involving right frontal and insular lobes. On subsequent MRI of the brain, FLAIR (B), T2* gradient recall echo (C), and DWI (D) sequences show hypointense ICH (thin arrows) and hyperintensities consistent with acute infarction in the distribution of the right middle cerebral artery (thick arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132275 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 40/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Enhancing intracranial vessels associated with ICH due to AVM Noncontrast head CT showing right posterior frontal ICH (A, B). T2- weighted MRI images (C, D) and post-contrast T1-weighted MRI image (E) show flow voids and focal enhancement (arrows), both suspicious for AVM nidus. Subsequent digital subtraction angiograms images (F, G) show both pial AVM nidus (thick arrows). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 41/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132285 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 42/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Multifocal intracerebral hemorrhage from thyroid cancer Noncontrast head CT (A) shows multiple hyperdensities (arrows). T2*-weighted gradient echo MRI images show that some but not all lesions are hypointense hemorrhages (B, C). Pre- (D) and post-contrast (E) T1- weighted MRI images show contrast enhancement consistent with metastases. ICH: intracerebral hemorrhage; CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132287 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 43/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 44/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device)* Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 45/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage*? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2

Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage*? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 51/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 52/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 53/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 54/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 55/56 7/6/23, 12:54 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Contributor Disclosures Magdy Selim, MD, PhD Grant/Research/Clinical Trial Support: NIH/NINDS [Intracerebral hemorrhage]. Consultant/Advisory Boards: MedRhythm, Inc [Neurological recovery]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 56/56

7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm : Alejandro A Rabinstein, MD : Lawrence LK Leung, MD, Jos Biller, MD, FACP, FAAN, FAHA : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 20, 2022. INTRODUCTION Unruptured intracranial aneurysms are detected in up to 2 to 3 percent of older adults who undergo high-quality noninvasive intracranial arterial imaging (eg, magnetic resonance angiography, computed tomographic angiography). Subarachnoid hemorrhage from a ruptured intracranial aneurysm is associated with a short-term mortality of 40 percent, with one-half of survivors sustaining permanent neurologic injury. Thus, detection of an asymptomatic unruptured aneurysm creates a management dilemma in patients who have indications for antithrombotic therapy. (See "Unruptured intracranial aneurysms".) This topic review will discuss issues related to anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm. THEORETICAL EFFECTS OF ANTITHROMBOTIC MEDICATION USE Rates of rupture for previously detected unruptured aneurysms vary according to their size (ie, there is a greater risk of rupture in larger aneurysms), specific location (eg, higher rates of rupture with posterior circulation aneurysms) [1], as well as history of prior subarachnoid hemorrhage from a separate aneurysm [2]. This subject is reviewed in depth separately. (See "Unruptured intracranial aneurysms", section on 'Risk factors for aneurysm rupture'.) https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 1/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate It is not known whether antithrombotic therapies influence the rate of rupture of intracranial aneurysms. By reducing thrombus formation in the aneurysmal sac, it is possible that antithrombotic therapy could increase rates of aneurysm rupture. Antithrombotic and antiplatelet therapies also could exacerbate the severity of the hemorrhage in case of rupture, perhaps even converting intramural or minor subarachnoid hemorrhages into major, life- threatening bleeding. Conversely, aspirin could reduce the risk of rupture by inhibiting inflammatory mediators (such as matrix metalloproteinases and tumor necrosis factor-alpha) that might play a role in the evolution and eventual rupture of intracranial aneurysms [3,4]. Clinical data on these points are sparse, as summarized below. EFFECT OF ANTIPLATELET THERAPY Available clinical data are limited and conflicting regarding the influence of aspirin and other antiplatelet agents on rates of aneurysm rupture. Overall, chronic use of antiplatelets appears safe and might even be protective in patients with unruptured, asymptomatic intracranial aneurysms. In the Nurses' Health Study, a large prospective longitudinal cohort study, middle-aged females who used >15 aspirin per week had twice the rate of all-cause subarachnoid hemorrhage compared with nonusers [5]. The excess risk was particularly pronounced among older and hypertensive females and was not observed among those taking lower doses of aspirin. In this study, there were an unduly large number of subarachnoid hemorrhages relative to ischemic strokes and intraparenchymal hemorrhages, although the fraction of subarachnoid hemorrhages that were due to ruptured aneurysms was not reported. Despite multivariate statistical adjustments, imbalances in other vascular risk factors between aspirin users versus nonusers in observational trials leave etiologic associations unproven. In contrast, aspirin use at least three times weekly was associated with a lower risk of aneurysm rupture in a nested case-control study of the untreated cohort of patients in the International Study of Unruptured Intracranial Aneurysms (ISUIA; adjusted odds ratio [OR] 0.27, 95% CI 0.11-0.67) [3]. Aspirin also prevented intracranial aneurysm rupture in an experimental mouse model [6] and this effect is thought to be mediated by cyclooxygenase-2 inhibition [7]. A nationwide case-control study in Denmark found that recent initiation of aspirin, clopidogrel, or both was associated with increased risk of subarachnoid hemorrhage [8]. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 2/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate However, this increased risk was restricted to the first three months after starting antiplatelet therapy and the assessment was based on relatively small numbers of patients. Risk of subarachnoid hemorrhage was not affected by longer-term use of antiplatelet agents. Meanwhile, a population-based Dutch case-control study found no association between use of antiplatelet agents and risk of subarachnoid hemorrhage [9]. Among patients with ischemic stroke, having an intracranial aneurysm did not result in excess risk of adverse outcomes related to antiplatelet therapy [10]. In a retrospective case series of 362 patients, no cases of subarachnoid hemorrhage occurred despite pretreatment with dual antiplatelet therapy for three months before stent-assisted coiling or flow diversion of unruptured (often large) intracranial aneurysm [11]. Regarding the severity of subarachnoid hemorrhage, data from clinical case series have shown no apparent increase in the initial severity of bleeding and no adverse effect on long-term outcome in patients presenting with aneurysmal subarachnoid hemorrhage who were taking aspirin prior to rupture [12-14]. In an analysis of the National Inpatient Sample including 11,549 patients with aneurysmal subarachnoid hemorrhage who were treated with surgical or endovascular aneurysm repair, aspirin use was not associated with in-hospital mortality but was associated with lower rates of cardiac complications and venous thromboembolic events. Furthermore, among patients treated with endovascular repair, the rate of poor outcomes was lower among aspirin users (32 versus 37 percent; OR 0.63, 95% CI 0.42-0.94) [15]. EFFECT OF ANTICOAGULATION No data supporting higher rupture rates following the use of anticoagulants are available from randomized clinical trials or large cohort studies. However, these studies do not convincingly exclude higher rates of aneurysmal subarachnoid hemorrhage in anticoagulated patients due to the infrequency of subarachnoid hemorrhage, which is typically combined with other causes of hemorrhagic strokes in reports of clinical trials. A population-based Dutch study noted an increased risk of subarachnoid hemorrhage in patients taking vitamin K antagonists on a case- crossover analysis (adjusted odds ratio [OR] 2.46, 95% CI 1.04-5.82), but the association was not significant on case-control and case-time-control analyses [9]. A Danish nationwide case-control study found an association between short-term (less than one month) of vitamin K antagonists and subarachnoid hemorrhage, but the association was not sustained with longer-term use of these drugs [8]. Among patients with ischemic stroke, presence of an intracranial aneurysm did not contribute to excess risk of adverse outcomes related to anticoagulation [10]. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 3/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate Anticoagulation might worsen the clinical outcome of aneurysmal subarachnoid hemorrhage. Death or dependency following aneurysmal subarachnoid hemorrhage occurred in 93 percent (14 of 15) of anticoagulated patients versus 49 percent of those not receiving anticoagulants in one reported case series [16]. This was due to the worse clinical status at the time of admission of anticoagulated patients as a consequence of more severe initial bleeding. A study using a large registry of hospitalized patients in the United States (the National Inpatient Sample) found that anticoagulated patients had higher crude rates of in-hospital mortality (19 versus 13 percent) and poor outcome (54 versus 38 percent), but both of these findings were not significant on multivariable analysis [15]. EFFECT OF THROMBOLYSIS Limited data suggest that intravenous thrombolysis with recombinant tissue plasminogen activator (tPA) appears safe in patients with unruptured intracranial aneurysms who have an acute ischemic stroke [17,18]. This argues against an increased risk of rupture from the use of drugs that affect coagulation. MANAGEMENT American Heart Association guidelines [19,20] and major reviews [21] concerning management of unruptured intracranial aneurysms do not address the use of antiplatelet agents or anticoagulants. Given the available information as summarized above, it is not clear that antithrombotic therapies increase the risk of aneurysm rupture. However, the following observations have been made: Aspirin does not appear to be associated with worse clinical outcomes from aneurysmal subarachnoid hemorrhage, but the existing data are meager (see 'Effect of antiplatelet therapy' above). Consequently, at present, detection of an unruptured intracerebral aneurysm should not be regarded as a contraindication to antiplatelet therapy for patients who have a clear indication for such medication. Limited data suggest that anticoagulation with oral vitamin K inhibitors might worsen the severity of initial bleeding if rupture does occur (see 'Effect of anticoagulation' above). The potentially higher rates of death or disability observed after rupture of an intracranial aneurysm in patients taking anticoagulants should be considered in weighing the benefits versus risks of anticoagulation in patients known to harbor an unruptured intracranial aneurysm. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 4/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate As an example, for an older adult patient with atrial fibrillation and prior stroke or transient ischemic attack who has a 10 mm unruptured aneurysm involving the anterior communicating artery, treatment with warfarin would be expected to produce an absolute reduction in the rate of stroke of approximately 6 percent per year (half of which are likely to be fatal or disabling) [22] but would augment the risk of fatal or disabling subarachnoid hemorrhage by approximately 0.25 percent per year [2,16]. In the absence of other risks, this analysis would lead one to favor anticoagulation in this particular patient. For those patients with larger aneurysms or those whose absolute benefits from anticoagulation are smaller, the estimated harm from anticoagulation may substantially mitigate its benefits. Thus, the decision must be individualized according to the best estimates of benefits versus risks. It is unclear how the need for chronic anticoagulation should influence the complex benefit/risk equation regarding repair of unruptured intracranial aneurysms [16,23,24]. Anticoagulation without aneurysm repair is reasonable for patients with a solid indication for anticoagulation who have aneurysms with a low estimated risk of rupture. For patients with aneurysms at higher risk of rupture, and those for whom the absolute benefits from anticoagulation are deemed smaller, the decision regarding the use of anticoagulation must be individualized according to the best estimates of benefits versus risks, accounting for patient values and preferences. Most experts do not consider a requirement for anticoagulation therapy to be an indication for aneurysm repair [25]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Prevalence and complications of intracranial aneurysms Unruptured intracranial aneurysms are detected in 2 to 3 percent of older adults. Subarachnoid hemorrhage from a ruptured intracranial aneurysm is associated with high morbidity and mortality. (See "Unruptured intracranial aneurysms" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Prognosis'.) Antiplatelet therapy Based upon limited evidence, daily use of regular doses of aspirin appears to be safe and there is preliminary evidence that it might even decrease the risk of https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 5/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate aneurysm rupture. The risks associated with other antiplatelet agents or with combination of antiplatelet agents are not known. (See 'Effect of antiplatelet therapy' above.) Anticoagulation Anticoagulation may exacerbate the degree of hemorrhage in case of rupture and may worsen the clinical outcome of aneurysmal subarachnoid hemorrhage. (See 'Effect of anticoagulation' above.) Individualized management Management of a patient with an unruptured intracranial aneurysm who requires treatment with an antiplatelet agent or anticoagulation for another indication requires careful evaluation of multiple factors. General principles Two general principles apply to these patients (see 'Management' above): Detection of an unruptured intracerebral aneurysm should not be regarded as a contraindication to antiplatelet therapy for patients who have a clear indication for such medication. Anticoagulation without treatment of the aneurysm is reasonable for patients with a solid indication for anticoagulation who have aneurysms with a low estimated risk of rupture. For patients with aneurysms at higher risk of rupture, and those for whom the absolute benefits from anticoagulation are deemed smaller, the decision regarding the use of anticoagulation must be individualized according to the best estimates of benefits versus risks, accounting for patient values and preferences. Assessment of individual risks Factors to be considered include the following (see 'Management' above): - - Risk of spontaneous rupture of the aneurysm (eg, size, location) Risk of thrombosis/stroke if antiplatelet/anticoagulant treatment is not given Risk of exacerbated bleeding from an aneurysmal rupture if anticoagulant treatment is given Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 2007; 38:1404. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 6/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate 2. Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362:103. 3. Hasan DM, Mahaney KB, Brown RD Jr, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011; 42:3156. 4. Vergouwen MD, Rinkel GJ, Algra A, et al. Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: Study protocol. Int J Stroke 2018; 13:992. 5. Iso H, Hennekens CH, Stampfer MJ, et al. Prospective study of aspirin use and risk of stroke in women. Stroke 1999; 30:1764. 6. Suzuki T, Kamio Y, Makino H, et al. Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model. Cerebrovasc Dis 2018; 45:180. 7. Starke RM, Chalouhi N, Ding D, Hasan DM. Potential role of aspirin in the prevention of aneurysmal subarachnoid hemorrhage. Cerebrovasc Dis 2015; 39:332. 8. Potteg rd A, Garc a Rodr guez LA, Poulsen FR, et al. Antithrombotic drugs and subarachnoid haemorrhage risk. A nationwide case-control study in Denmark. Thromb Haemost 2015; 114:1064. 9. Risselada R, Straatman H, van Kooten F, et al. Platelet aggregation inhibitors, vitamin K antagonists and risk of subarachnoid hemorrhage. J Thromb Haemost 2011; 9:517. 10. Shono Y, Sugimori H, Matsuo R, et al. Safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysm. Int J Stroke 2018; 13:734. 11. Peret A, Mine B, Bonnet T, et al. Safety and efficacy of a pre-treatment antiplatelet regimen of unruptured intracranial aneurysms: a single-center experience. Neuroradiology 2020; 62:1029. 12. Juvela S. Aspirin and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg 1995; 82:945. 13. Toussaint LG 3rd, Friedman JA, Wijdicks EF, et al. Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage. J Neurosurg 2004; 101:921. 14. Al-Mufti F, Ogulnick J, Feldstein E, et al. Impact of pre-ictal antiplatelet therapy use in aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 2021; 211:107022. 15. Dasenbrock HH, Yan SC, Gross BA, et al. The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis. J Neurosurg 2017; 126:537. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 7/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate 16. Rinkel GJ, Prins NE, Algra A. Outcome of aneurysmal subarachnoid hemorrhage in patients on anticoagulant treatment. Stroke 1997; 28:6. 17. Edwards NJ, Kamel H, Josephson SA. The safety of intravenous thrombolysis for ischemic stroke in patients with pre-existing cerebral aneurysms: a case series and review of the literature. Stroke 2012; 43:412. 18. Chiu WT, Hong CT, Chi NF, et al. The risk of intravenous thrombolysis-induced intracranial hemorrhage in Taiwanese patients with unruptured intracranial aneurysm. PLoS One 2017; 12:e0180021. 19. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012; 43:1711. 20. Thompson BG, Brown RD Jr, Amin-Hanjani S, et al. Guidelines for the Management of Patients With Unruptured Intracranial Aneurysms: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015; 46:2368. 21. Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol 2014; 13:393. 22. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146:857. 23. Wardlaw JM, White PM. The detection and management of unruptured intracranial aneurysms. Brain 2000; 123 ( Pt 2):205. 24. White PM, Wardlaw J. Unruptured intracranial aneurysms: prospective data have arrived. Lancet 2003; 362:90. 25. Etminan N, Beseoglu K, Barrow DL, et al. Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group. Stroke 2014; 45:1523. Topic 1320 Version 15.0 Contributor Disclosures Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 8/9 7/6/23, 12:56 PM Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm - UpToDate Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/anticoagulant-and-antiplatelet-therapy-in-patients-with-an-unruptured-intracranial-aneurysm/print 9/9

7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Selection of candidates for anticoagulation : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 23, 2022. INTRODUCTION Atrial fibrillation (AF) is a major cause of morbidity and mortality in adults. While ischemic stroke due to embolization of left atrial thrombi is the most frequent clinical manifestation of embolization, embolization to other locations in the systemic circulation (and in the pulmonary circulation from right atrial thrombi) also occurs, but is less commonly recognized. Stroke associated with AF tends to be more extensive/larger than stroke related to carotid artery disease. Chronic oral anticoagulation (OAC) is recommended to reduce the risk of thromboembolism for most patients with AF. However, such therapy is associated with an increased risk of bleeding, and recommendations for its use must take both benefit and risk into account through shared decision-making with the patient. (See "Stroke in patients with atrial fibrillation".) This topic will focus on identifying which patients with AF require long-term/chronic OAC with either vitamin K antagonist (VKA; eg, warfarin) or direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]). The discussion here excludes patients with 2 rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ), a bioprosthetic valve (surgical or bioprosthetic) within the first three to six months after implantation, or a mechanical heart valve. Management for patients with these valve conditions is briefly discussed in a section below that provides links to related topics. (See 'Patients with valvular heart disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 1/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Other potentially relevant topics to the reader include: Choice of OAC for AF (see "Atrial fibrillation in adults: Use of oral anticoagulants") (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO DECIDING WHETHER TO ANTICOAGULATE Decision-making based upon risk assessment A first step in deciding which patients with AF should receive long-term oral anticoagulation (OAC) is to assess the individual patient s risks of thromboembolism and bleeding along with patient preferences. Long-term anticoagulation lowers the risk of clinical embolization in patients with AF, but its use is associated with an increased risk of bleeding. The benefits and risks of OAC with respect to reduction in risk of stroke and increment in risk of bleeding must be carefully considered and discussed with each patient. The greater the estimated reduction in absolute stroke risk compared with the increase in absolute risk of life- threatening or severely debilitating bleeding (such as intracranial hemorrhage), the more likely a patient is to benefit from long-term OAC. The benefit generally outweighs the risk for all but those with the lowest risk of thromboembolism. In cases of more balanced stroke reduction and bleeding risks, OAC is less likely to provide a net benefit. Risk scores are commonly used to assess thromboembolic and bleeding risks, although these tools are subject to a number of limitations. (See 'CHA2DS2-VASc score' below and 'Bleeding risk' below.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Our approach to deciding whether to prescribe anticoagulant therapy for patients with AF (without severe or clinically significant rheumatic mitral stenosis [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) is as follows: For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC. For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1), the 2 2 specific nonsex risk factor present and the documented burden of AF influences decision making: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 2/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC. Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score point [1]. 2 2 For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. The frequency and duration of AF episodes vary widely over time and episodes are often asymptomatic. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1)( table 1), 2 2 we suggest against anticoagulant therapy. Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' below) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated, and to flag patients with high bleeding risk for early review and follow-up and to identify potential candidates for left atrial appendage occlusion [2-6]. (See 'Bleeding risk' below and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding'.) Effects of anticoagulation In identifying which patients with AF are likely to benefit from OAC, the relative risk reduction in thromboembolism with OAC identified in randomized trials (see 'General efficacy' below) is combined with estimates of baseline risk using the CHA DS - 2 2 VASc score to estimate the expected absolute risk reduction from OAC (see 'CHA2DS2-VASc score' below). The estimated absolute risk reduction for thromboembolic events is weighed against the estimated increase in absolute risk of intracranial hemorrhage (ICH) and other major bleeding complications. (See 'Bleeding risk' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 3/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate General efficacy For patients with AF, randomized trials have shown that therapeutic OAC (vitamin K antagonist [VKA] or DOAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo irrespective of baseline risk ( figure 1) [7-17]. A meta-analysis included six randomized trials comparing VKA (warfarin) with placebo or no treatment in a total of 2900 participants with AF (mean age at entry 69 years, 20 percent with prior stroke or transient ischemic attack) [14]. The overall rate of stroke was 2.2 percent/patient year in the warfarin group and 6.0 percent/patient year in the control group (relative risk reduction 0.64; 95% CI 0.49-0.74). The absolute risk reduction was 2.7 percent/year for primary prevention and 8.4 percent/year for secondary prevention. With warfarin therapy, all-cause mortality was reduced by 1.6 percent/year (relative risk reduction 0.26; 95% CI 0.03-0.43). While most of the evidence comparing OAC with placebo in patients involved treatment with VKA, a trial comparing edoxaban 15 mg daily with placebo in patients with AF 80 years old with low body weight found a similar relative reduction in risk of stroke or systemic embolism (2.3 versus 6.7 percent/year; hazard ratio 0.34, 95% CI 0.19-0.61) [18]. The possible implications of this study for edoxaban dose are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) CHA2DS2-VASc score Use We use the CHA DS -VASc score (calculator 1) to estimate thromboembolic risk in 2 2 patients with AF, while recognizing its limitations (see 'Potential alternatives' below and 'Limitations' below). This estimation of baseline thromboembolic risk is combined with the above information on relative risk reduction (see 'General efficacy' above) to estimate the expected absolute risk reduction. The annual risk of ischemic stroke in untreated patients is estimated to be 0.2, 0.6, and 2.2 percent for those with CHA DS -VASc scores of 0, 1, and 2 ( table 1) [19]. However, stroke 2 2 rates have varied substantially among studies, which may be due to differences in study populations and methodologies [2,20-24]. As an example, studies examining ischemic stroke rates in patients with a single risk factor have identified risks of <1 to 2.7 percent/year [25-27]. Among patients with AF, ischemic stroke is the dominant type of thromboembolic event. As an example, in a study including data on 39,973 participants in four randomized trials of anticoagulation, the incidence of nonstroke systemic embolic events (SEEs) was 0.23/100 person-years, and the incidence of cerebral embolism was 1.92/100 person-years [28]. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 4/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among those with SEEs, 58 percent occurred in the lower extremities, 31 percent in the visceral-mesenteric system, and 11 percent in the upper extremities. Among patients with AF treated with OAC, annual stroke risk is lowered by approximately two-thirds to <0.1, 0.2, and 0.6 percent, respectively. In addition to the lowering of stroke risk, there is evidence that warfarin, compared with no anticoagulant therapy, leads to less severe stroke episodes and lower 30-day stroke mortality [14,29]. The annual risk of intracranial bleeding with warfarin is 0.2, 0.3, and 0.5 percent, respectively. The risk of ICH with DOAC is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Among adults with AF, females have a modestly higher risk of thromboembolism than males, but female sex is associated with increased risk primarily in patients with at least two CHA DS - 2 2 VASc score non-sex risk score points [1,30]. Thus, we focus on non-sex risk factors when deciding whether OAC is indicated. For CHA DS -VASc score 2 in males or 3 in females (when the risk score points are 2 2 from two or more non-sex risk factors), the benefit from OAC generally exceeds the risks of severe bleeding [19,31-33]. For CHA DS -VASc score of 1 in males or 2 in females (one non-sex risk factor with a 2 2 value of 1), the risk of thromboembolism varies depending upon the non-sex risk factor [1]. Among the risk factors with a one-point value, age 65 to 74 years and the presence of heart failure have the greatest effect on thromboembolic risk [1], and OAC is recommended in patients with any of these risk factors. For CHA DS - VASc score of 0 in males or 1 in females (zero nonsex risk factors), the 2 2 thromboembolic risk is low [27], so no OAC is suggested. (See 'Approach to deciding whether to anticoagulate' above.) The warfarin versus placebo or aspirin trials were reported in the early 1990s, raising concerns that the findings may not be applicable to contemporary clinical practice [31,34,35]. Studies evaluating more contemporary data have found that the absolute risk of stroke in untreated patients has fallen from approximately 8 percent/year to 4 or 5 percent/year ( table 1), but the relative risk reduction attributable to anticoagulant therapy is in the same range as earlier studies [36,37]. A two-thirds risk reduction in thromboembolism using the more contemporary lower absolute risks is clinically important for patients with two or more nonsex risk factors and for selected patients with one nonsex risk factor. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 5/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Comparisons of the effects of VKA and DOAC are presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Potential alternatives A variety of risk scores, imaging methods, and biomarkers have been studied for their potential predictive value for thromboembolic risk in patients with AF [38]. The CHA DS -VASc score has been compared with potential alternatives including the CHADS 2 2 2 and ATRIA risk scores ( table 1 and table 5). The clinical utility of a risk score for individuals with AF hinges primarily on its accuracy in identifying those at lowest risk for thromboembolism, as anticoagulation is generally recommended for individuals with all but the lowest level of risk. Systematic reviews suggest that the CHA DS -VASc score generally performs better than the 2 2 CHADS and ATRIA scores in identifying low-risk patients, although there have been some 2 discrepant results for comparisons of CHA DS -VASc and ATRIA [38]. However, all these risk 2 2 scores are subject to the limitations discussed below. (See 'Limitations' below.) A potential alternative to the risk score approach is to calculate the risk for each patient based upon risk factors including age as a continuous variable using the Calculator of Absolute Stroke Risk (CARS) [1]. For patients with AF, there is no established role for routine cardiac imaging to assess thromboembolic risk. Transesophageal echocardiography (TEE) is used in patients with AF primarily to evaluate left and right atrial appendage anatomy/function to identify individuals who are free of atrial thrombi and are therefore candidates for early cardioversion (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation"). Thromboembolic risk is associated with cardiac imaging findings, including evidence of left atrial thrombus (generally assessed by TEE; less commonly assessed by cardiovascular magnetic resonance [CMR] or cardiac computed tomography [CCT]) and depressed left ventricular ejection fraction (which can be assessed by transthoracic echocardiography, TEE, CMR, CCT, or nuclear methods) [39]. However, imaging findings have not been shown to improve risk stratification in patients with AF [2]. Limitations Risk scores to estimate thromboembolic risk in patients with AF have limited predictive value when applied to individual patients. One limitation is that risk scores utilize point systems that do not reflect differences in risk among included risk factors. Risk factors assigned equal point values are associated with substantially different risks, as illustrated by the following examples for the CHA DS -VASc score 2 2 ( table 1) [1]: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 6/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Age 65 to 74 years is associated with substantially greater stroke risk than other risk factors assigned one point. A history of prior stroke, transient ischemic attack, or thromboembolic event is assigned two points, but the risk associated with this risk factor is more than five times the risk associated with risk factors assigned one point. The continuous risk of age is lumped into categories, so that ages 65 years and 74 years each confer one point, despite the much higher actual risk associated with the older age. Another limitation is that the event rates observed in populations used to generate risk score may differ from those occurring in different clinical settings (eg, community versus hospitalized) and patient populations with differing risk profiles. Also, some clinical features or conditions may impact the risk of thromboembolism but are not included in risk models; these include the duration or frequency of episodes of paroxysmal AF and the presence of conditions such as chronic kidney disease and elevated troponin level. Prediabetes has also been implicated as a possible risk factor for stroke in patients with AF [40]. The potential role of troponin measurement in the assessment of the risk of embolization in patients with AF is discussed separately. (See 'Chronic kidney disease' below and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Atrial fibrillation'.) Bleeding risk When OAC is considered, the major safety concern is the increased risk of bleeding, especially major bleeding, which includes events that require hospitalization, transfusion, or surgery, or that involve particularly sensitive anatomic locations. Thus, bleeding risk and related contraindications to OAC should be reviewed ( table 2). A systematic review comparing various bleeding risk scores in patients with AF found that the HAS-BLED risk score ( table 3) was the best predictor of bleeding risk [2], although all bleeding risk scores provide imprecise estimates for individual patients, do not provide estimates for specific types of major bleeds, and are based upon bleeding risk with warfarin. Two more recent studies confirmed the efficacy of the HAS-BLED score was comparable to or better than ORBIT score in patients treated with DOACs [41,42]. Among patients with AF, the three most important predictors of major bleeding (including ICH) are overanticoagulation with warfarin (defined as an international normalized ratio greater than 3.0), prior stroke, and older patient age [31,43-45]. (See "Risks and prevention of bleeding with oral anticoagulants".) The risk of bleeding was evaluated in a cohort of over 16,000 patients diagnosed with AF between 2005 and 2010 [37]. The incidence of major bleeding with current, recent, past, or no https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 7/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate VKA (warfarin) exposure was 3.8, 4.5, 2.7, and 2.9/100 patient-years, respectively. However, major bleeding includes ICH and extracranial bleeding, particularly gastrointestinal bleeding. ICH is the most serious bleeding complication, since the likelihood of mortality or subsequent major disability is substantially higher than with bleeding at other sites [46]. In this study and others, the annual risk of ICH in patients with AF who are not anticoagulated is estimated to be 0.2 percent/year; that risk approximately doubles with OAC with VKA [34,37]. Randomized trials have shown that the risk of ICH with DOAC (both direct thrombin and factor Xa inhibitors) is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Given differences in morbidity associated with different types of bleeding, we think most patients would weigh the reduction in risk of ischemic stroke primarily against the increase in risk of ICH, with less weight given to the risk of gastrointestinal bleed or other less serious bleeding. While the incremental absolute risk of ICH with VKA (approximately 0.2 percent/year) is not trivial, it is substantially less than the expected absolute reduction in risk of ischemic stroke from OAC for most patients with AF and two or more nonsex CHA DS -VASc risk factors. 2 2 One problem with the bleeding risk scores is that they were developed from studies that included bleeds of differing severity. While any bleed can lead to death or severe disability, most do not; the major exception is ICH. The morbidity associated with ICH is similar to that for ischemic stroke, while the morbidity associated with gastrointestinal bleeding is generally not as severe. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) For patients in the following clinical settings, the bleeding risk is significantly higher: Thrombocytopenia or known coagulation defect associated with bleeding Active bleeding or recent surgery with a concern for ongoing bleeding Prior severe bleeding (including ICH) while on an oral anticoagulant Aortic dissection Malignant hypertension Combined use of anticoagulant and antiplatelet (including regular use of nonsteroidal antiinflammatory) agents SPECIFIC PATIENT GROUPS Patients with valvular heart disease For patients with valvular heart disease (excluding those with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 8/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate implantation, or a mechanical heart valve), the above general approach to deciding on oral anticoagulation (OAC) applies, although the evidence in patients with severe native valve disease is more limited than for the general population of patients with AF [47]. (See 'Approach to deciding whether to anticoagulate' above.) Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with specific valve conditions are discussed separately: 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. (See "Antithrombotic therapy for mechanical heart valves".) Transcatheter bioprosthetic valve. (See "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach'.) AF type and management Paroxysmal AF Our approach to deciding whether to anticoagulate is generally similar for patients with paroxysmal AF (PAF; with or without symptoms) as for persistent, or permanent, AF, as described above (see 'Decision-making based upon risk assessment' above). However, the burden of AF (duration and frequency of episodes) is a factor for decision-making for selected patients in whom the balance of benefit versus risk of anticoagulation is uncertain, recognizing that it may not be possible to accurately estimate AF burden except in patients with cardiac implantable electronic devices that can measure AF burden. We consider the burden of AF in decision-making for patients aged <65 years and who have one nonsex CHA DS -VASc risk 2 2 factor. On the other hand, patients with AF with past history of embolic stroke are at high risk for a recurrent thromboembolic event, so the burden of AF would generally not impact the decision to anticoagulate. (See 'Decision-making based upon risk assessment' above.) As discussed separately, the risk of thromboembolism in patients with PAF appears to be lower than in patients with persistent AF, and thromboembolic risk is higher in those with greater AF burden (percentage of time in AF). (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) There are no definitive data to establish a threshold duration of AF episodes for the initiation of anticoagulant therapy. Some of our experts recommend a single threshold for duration of AF of https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 9/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 30 seconds, and others use a threshold as long as 24 hours [48]. Those experts who do not routinely anticoagulate patients with shorter-duration AF believe that the benefit is small and potentially outweighed by the bleeding risk. However, the AF burden is likely to vary over time, so a patient with 30 seconds of AF in one monitoring period may well have 30 hours of AF in the next monitoring period. While a large proportion of patients with short episodes of AF will go on to experience longer episodes, it is also true that the reverse occurs in a sizable percentage of patients experiencing long episodes of AF [49]. Also, the extent to which thromboembolic risk may continue during periods of sinus rhythm is uncertain. (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) Rhythm versus rate control For patients with AF, the process of deciding whether to anticoagulate is generally the same regardless of the choice between rhythm control or rate control strategies. As discussed separately, the risk of thromboembolism is not reduced by clinical maintenance of sinus rhythm. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Thromboembolic risk'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Older adults For older adults, we follow the general approach described above, including careful assessment the relative benefits and risks of OAC (see 'Decision-making based upon risk assessment' above). The approach to chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) In patients with documented frequent falls but without prior trauma (eg, fracture, subdural), we weight the risks and benefits of OAC versus left atrial appendage occlusion. In this clinical setting, we often recommend OAC and work to reduce the risk of falls. The risk of falls leading to subdural hematomas is increased in older adult patients taking oral anticoagulants independent of the agent chosen. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex' and "Atrial fibrillation: Left atrial appendage occlusion".) A Taiwanese database study compared 15,756 older ( 90 years of age) adults with AF (11,064 receiving no antithrombotic therapy, 4075 receiving antiplatelet therapy, and 617 on warfarin) with 14,658 older adult patients without AF and without antithrombotic therapy [50]: Patients with AF had a greater risk of ischemic stroke (5.75 versus 3.00 percent/year; hazard ratio [HR] 1.93, 95% CI 1.74-2.14) and a similar risk of intracranial hemorrhage (ICH; 0.97 versus 0.54 percent/year; HR 0.85, 95% CI 0.66-1.09) compared with those without AF. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 10/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among patients with AF, warfarin use was associated with a lower stroke risk (3.83 versus 5.75 percent/year; HR 0.69, 95% CI 0.49-0.96) compared with no antithrombotic therapy. There was a nominal but nonsignificant increase in risk of ICH (HR 1.26, 95% CI 0.70-2.25). In a second, later cohort of patients 90 years of age with AF, 768 patients treated with warfarin were compared with 978 patients treated with a direct oral anticoagulant (DOAC) [50]. DOACs were associated with a lower risk of ICH compared with warfarin (0.42 versus 1.63 percent/year; HR 0.32, 95% CI 0.10-0.97) and similar rate of ischemic stroke (4.07 versus 4.59 percent/year; HR 1.16; 95% CI 0.61 2.22). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Older adults'.) Potential use of reduced-dose DOAC (edoxaban) in selected older adults with AF with low body weight is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) Chronic kidney disease For most patients with AF and chronic kidney disease (CKD), we follow the general approach to selection of candidates for OAC described above (see 'Approach to deciding whether to anticoagulate' above). However, some of our authors consider anticoagulation for the very uncommon CKD patient with a CHA DS -VASc score of 0 in males or 2 2 1 in females. For patients with CKD and AF, the following is our approach for deciding whether to anticoagulate ( figure 2): Stages 2, 3, and 4 and 5 (not on dialysis) For patients with estimated glomerular 2 filtration rate (eGFR) of 15 to 89 mL/min/1.73 m , our approach is similar to the general approach described above (see 'Decision-making based upon risk assessment' above), although there are very limited data for patients with end-stage kidney disease. Individualized risk assessment is performed to carefully weigh the benefits and risks of anticoagulation, with special attention to the bleeding risk associated with CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Uremic bleeding'.) Stage 5 on dialysis Among patients with end-stage kidney disease on dialysis, we anticoagulate some higher-risk individuals (based on the CHA DS VASc score) after shared 2 2- decision-making and discussion of risks and benefits between the clinician and the patient. However, it is reasonable to not anticoagulate the following groups of individuals with AF and eGFR <30 mL/min (stages 4 and 5) given our uncertainty of the benefit-to-risk ratio for antithrombotic therapy in these patients: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 11/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to

11/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to OAC with a VKA (target INR 2.0 to 3.0) [79]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because VKA lowered the annual rate of the primary endpoint compared with combined antiplatelet therapy (3.9 versus 5.6 percent; relative risk [RR] 0.69, 95% CI 0.57-0.85). The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin OAC and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [80]. After a median follow- up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined endpoint (6.8 versus 7.8 percent; RR 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent; RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy resulted in a higher rate of major bleeding (2.0 versus 1.3 percent/year; RR 1.57, 95% CI 1.29-1.92). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 14/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Aspirin monotherapy Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. In patients with AF, some but not all meta-analyses of clinical trials comparing aspirin with placebo have found that aspirin reduced the risk of stroke and systemic embolism ( table 6) [14,38,81]. In contrast, clinical trials have demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin ( table 6) [9,14-17,82-84]. Aspirin plus low-dose warfarin In contrast to therapeutic adjusted-dose warfarin (target INR 2.0 to 3.0), low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [17,85,86]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of ischemic stroke and systemic embolism than therapeutic adjusted-dose warfarin ( figure 4A-B) [85]. Aspirin plus full-dose warfarin Limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF. In a post-hoc analysis of the SPORTIF trials in patients with AF, among patients taking aspirin plus warfarin (or aspirin plus the factor Xa inhibitor ximelagatran) experienced similar rates of stroke and systemic embolism as those taking warfarin alone (or ximelagatran alone) [87]. The risk of major bleeding was higher with aspirin plus warfarin compared with warfarin alone (3.9 versus 2.3 percent/year). The management of antithrombotic therapy for patients with AF treated with OAC who have a concurrent indication for antiplatelet therapy is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Concomitant antiplatelet therapy'.) RECOMMENDATIONS OF OTHERS Recommendations for choosing which patients with atrial fibrillation should be anticoagulated are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [38,88-90]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 15/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of oral anticoagulation (OAC) in atrial fibrillation (AF) In patients with AF, OAC reduces the risk of thromboembolism by approximately two-thirds across clinical risk factor profiles but also entails an increased risk of major bleeding. Deciding whether to anticoagulate For each patient, their estimated absolute risk reduction for thromboembolic events is weighed against their estimated increase in absolute risk of intracranial hemorrhage and other life-threatening or severely debilitating bleeding complications. (See 'Approach to deciding whether to anticoagulate' above.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 16/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate CHA DS -VASc risk score Our approach to deciding whether to prescribe anticoagulant 2 2 therapy for patients with AF (excluding those with rheumatic mitral stenosis that is severe 2 or clinically significant [mitral valve area 1.5 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after implantation, or a mechanical heart valve) is as follows (see 'Approach to deciding whether to anticoagulate' above): For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC (Grade 1A). For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1): 2 2 For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC (Grade 1A). Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score 2 2 point. For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1) ( table 1), 2 2 we suggest against OAC (Grade 2C). Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' above) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). Bleeding risk For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). (See 'Bleeding risk' above.) The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated to flag high-bleeding-risk patients for early https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 17/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate review and follow-up. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) Specific patient groups Our approach to OAC for patients with AF who are older, have chronic kidney disease, hyperthyroidism, and hypertrophic cardiomyopathy can sometimes differ for patients who are younger or do not have these conditions. (See 'Specific patient groups' above.) Contraindication to OAC For patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a surgical bioprosthetic valve within the first three to six months after implantation, or a mechanical valve) with an indication for OAC but who have a contraindication for long-term OAC, the primary alternative is left atrial appendage occlusion. For such patients, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic OAC. (See 'Alternatives to anticoagulation' above and "Atrial fibrillation: Left atrial appendage occlusion".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lee CJ, Toft-Petersen AP, Ozenne B, et al. Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach. Eur Heart J Cardiovasc Pharmacother 2021; 7:f3. 2. Borre ED, Goode A, Raitz G, et al. 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Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2

63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 26/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 27/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia (platelet count <50,000/microL) Absolute platelet count, platelet count trend, and platelet function (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or planned) Type of procedure and associated bleeding risk, interval between procedure and anticoagulation Previous intracranial hemorrhage Time interval since hemorrhage and underlying cause (eg, trauma or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled hypertension Absolute blood pressure and blood pressure trend This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 28/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 29/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 30/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Benefit of warfarin in chronic atrial fibrillation Efficacy of anticoagulation with warfarin to prevent ischemic stroke and other thromboemboli in 4 major studies. An intention to treat approach was used, and transient ischemic attack and hemorrhage were excluded. The numbers at the top represent the risk reduction with warfarin therapy, which ranged from 45 to 82%. SPAF: Stroke Prevention in Atrial Fibrillation; AFASAK: Copenhagen AFASAK Study; BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation Study. The data in the warfarin group in the SPAF assumes that half of the events were attributable to warfarin toxicity. Data from: Connolly SJ, Laupacis AN, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349. Graphic 79839 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 31/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 32/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 33/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 34/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ATRIA stroke risk model point scoring system Points without prior Risk factor Points with prior stroke stroke Age, y 85 6 9 75 to 84 5 7 65 to 74 3 7 <65 0 8 Female 1 1 Diabetes 1 1 CHF 1 1 Hypertension 1 1 Proteinuria 1 1 eGFR <45 or ESRD 1 1 Possible point scores range from 0 to 12 for those without a prior stroke and from 7 to 15 for those with a prior stroke. ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease. Reprinted with permission. J Am Heart Assoc 2013; 2:e000250. Copyright 2013 American Heart Association, Inc. Graphic 90032 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 35/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 36/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Prevalence of atrial fibrillation in chronic kidney disease patients The prevalence (percent) of atrial fibrillation in the general population and different cohorts of patients with CKD are shown: While patients with peritoneal dialysis appear to suffer less frequently from atrial fibrillation, in those on hemodialysis, the prevalence was observed to be 10- to 20-fold higher than in the general population. Age was in all groups a key factor. CKD: chronic kidney disease. Reproduced with permission from: Reinecke H, Brand E, Mesters R, et al. Dilemmas in the management of atrial brillation in chronic kidney disease. J Am Soc Nephrol 2009; 20:705. Copyright 2009 American Society of Nephrology. Graphic 55373 Version 6.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 37/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Meta-analysis of randomized controlled trials of warfarin and aspirin for primary prevention of stroke in atrial fibrillation Stroke Major bleeding Comparison Odds ratio, p Odds ratio, 95 p 95% CI value percent CI value Conventional dose warfarin versus placebo 0.31 (0.19 to 0.50) <0.001 1.88 (0.88 to 4.0) 0.10 Aspirin versus placebo 0.68 (0.46 to 0.06 0.82 (0.37 to 1.78) >0.2 1.02) Conventional dose warfarin versus aspirin 0.66 (0.45 to 0.04 1.61 (0.75 to 3.44) >0.2 0.99) Conventional dose warfarin versus low dose warfarin 0.52 (0.25 to 1.08) 0.08 2.21 (0.67 to 7.25) 0.19 Conventional dose warfarin versus low dose warfarin plus aspirin 0.44 (0.14 to 1.39) 0.16 1.14 (0.55 to 2.36) >0.2 Low dose warfarin versus aspirin 1.01 (0.49 to 2.06) >0.2 1.04 (0.43 to 2.48) >0.2 NOTE: The data in this table cannot be directly applied to clinical practice (an individual patient) since the decision to use warfarin or aspirin is importantly related to a patient's estimated risk of embolic events. Adapted from McNamara RL, Tamariz LJ, Segal JB, Bass EB. Ann Intern Med 2004; 139:1018. Graphic 66736 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 38/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Low-dose warfarin plus aspirin is not optimal in high-risk AF Cumulative event rate of patients with AF at high risk for thromboembolism in the SPAF III trial. High risk was defined as the presence of at least 1 of the following: previous thromboembolism, female older than 75 years of age, heart failure or severe left ventricular systolic dysfunction, and systolic pressure >160 mmHg. There was a much lower incidence of events with standard adjusted- dose warfarin therapy (INR 2 to 3) compared with treatment with aspirin and low-dose warfarin (INR 1.2 to 1.5; p<0.0001). AF: atrial fibrillation; INR: international normalized ratio. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 72790 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 39/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Increased stroke risk with low-dose warfarin plus aspirin in AF Results from the SPAF III trial of high-risk patients showing significantly higher event rates for intracranial hemorrhage and ischemic stroke in patients treated with fixed low-dose warfarin plus aspirin compared with standard adjusted-dose warfarin. The risk was greater in those with a previous thromboembolic event. AF: atrial fibrillation. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 62833 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 40/41 7/6/23, 12:57 PM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 41/41

7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Use of oral anticoagulants : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Most patients with atrial fibrillation (AF) should receive long-term oral anticoagulation to decrease the risk of ischemic stroke and other embolic events. For most patients, the benefit from anticoagulation outweighs the associated increase in the risk of bleeding. The use of anticoagulant therapy for patients with AF who are not pregnant (excluding those 2 with rheumatic mitral stenosis that is moderate or severe [mitral valve area 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve) will be reviewed here. Management for patients with valve disease is briefly discussed in a section below that provides links to related topics on these specific valve conditions. (See 'Patients with valvular heart disease' below.) Related topics include: (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation for atrial fibrillation during pregnancy. (See "Supraventricular arrhythmias during pregnancy", section on 'Atrial fibrillation and flutter' and "Use of anticoagulants during pregnancy and postpartum".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 1/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO ANTICOAGULATION Choice of anticoagulant For patients with AF, we suggest the following sequential steps (related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation): Determine if anticoagulation is indicated. The identification of patients who should receive long-term oral anticoagulation is discussed separately. Prior to initiation of anticoagulant therapy, possible contraindications should be weighed ( table 1). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Select an anticoagulant. The following discussion applies to patients who are not pregnant. Selection of anticoagulant for use during pregnancy is discussed separately. (See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation' and "Use of anticoagulants during pregnancy and postpartum".) For most patients with AF with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than vitamin K antagonist (VKA; eg, warfarin). For most patients with AF who have been treated with warfarin with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to a DOAC. However, it is reasonable to continue VKA in these patients for financial or other preferences. Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include: Clinical settings in which VKA (eg, warfarin; target international normalized ratio [INR] 2.0 to 3.0; TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' below): Patients with a mechanical heart valve of any type and location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 2/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) ( table 2A-C) [1]. (See 'Drug interactions' below and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose creatinine clearance (CrCl by Cockcroft-Gault equation) is less than 25 to 30 mL/min. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting, as described below. (See 'Chronic kidney disease' below.) Evidence supporting this approach comes from randomized trials in patients with nonvalvular AF in which DOAC use resulted in similar or lower rates of both ischemic stroke and major bleeding compared with treatment with adjusted-dose warfarin (INR of 2.0 to 3.0) ( table 3) [2-8]. Important additional advantages of the DOAC agents include a high relative but small absolute reduction in the risk of intracranial hemorrhage (ICH), convenience (no requirement for routine testing of the INR), lack of susceptibility to dietary interactions, and markedly reduced susceptibility to drug interactions [3-6]. Disadvantages of DOAC include lack of efficacy and safety data in patients with severe chronic kidney disease, lack of easily available monitoring of blood levels and compliance, and higher patient cost in some health care settings. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) A meta-analysis including the RE-LY (dabigatran) [3,9], ARISTOTLE (apixaban) [5], ROCKET AF (rivaroxaban) [4], and ENGAGE AF-TIMI 48 (edoxaban) [10] trials supports the broad conclusion that DOAC agents are preferable to adjusted-dose VKA for most patients [2]. Compared with VKA (warfarin), DOAC reduced rates of mortality, stroke or systemic embolic event, and hemorrhagic stroke ( table 3). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 3/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Regarding the relative efficacy and safety of the DOAC agents, no randomized controlled trials (RCTs) directly comparing the DOACs have been published. Published observational studies have many limitations and are no substitute for head to head RCTs [11-16]. Initiation DOAC For patients with AF starting DOAC, effective anticoagulation is achieved within a few hours. We do not use heparin to bridge patients starting DOAC. For patients prescribed one of the DOACs, we suggest that clinicians review dosing recommendations from regulatory agencies and available in drug information compendia such as Lexicomp. (See 'Dosing' below.) Vitamin K antagonist Protocols for initiating VKA (eg, warfarin) are discussed separately. All patients should have an INR measured before starting therapy. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and 'Dosing' below.) For patients with AF starting VKA (eg, warfarin): With no intracardiac thrombus or prior history of thromboembolism, the risk of a thromboembolic event during the several days typically required to achieve therapeutic anticoagulation with warfarin is generally very low. Thus, it is reasonable for outpatients to initiate warfarin without low molecular weight heparin bridging. (See "Warfarin and other VKAs: Dosing and adverse effects".) With high risk of thromboembolism (eg, prior cerebrovascular event/transient ischemic attack or current intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen may be reasonable in some clinical settings (eg, patient who is hospitalized for another condition such as heart failure and has no acute stroke) although there is no high quality evidence to support this approach. Management for patients with acute stroke is discussed below. (See 'Acute stroke' below.) Dosing DOACs Dosing recommendations for DOACs are largely derived from the doses tested in the randomized clinical trials ( table 3) [3-5,10,17,18]. Given differences in the characteristics and availability of DOACs, it is important for practitioners to develop familiarity with the clinical use of multiple DOAC agents. DOACs are generally administered at fixed doses without laboratory monitoring. Use in patients with chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 4/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Use of these agents including drug interactions ( table 2A-C) and dosing in patients with chronic renal insufficiency is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.): Apixaban The dose of apixaban is 5 mg twice daily (approximately 12 hours apart) unless the patient has two or more of the following: age 80 years, body weight 60 kg, or serum creatinine level 1.5 mg/dL [133 micromol/L]). Then the dose of apixaban is 2.5 mg twice daily. This dose adjustment is for moderate renal impairment. Data are lacking to inform use in patients with CrCL <15 mL/min or on dialysis. (See 'Chronic kidney disease' below.) Dabigatran For patients with CrCl >30 mL/min, the dose is 150 mg twice daily (approximately 12 hours apart). For most patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, based upon the results of the RE-LY trial. Where available, the 110 mg twice daily dose may be preferred in patients assessed to be at increased risk of bleeding or who are particularly concerned about the risk of bleeding. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For patients with CrCL 15 to 30 mL/min, the dose is 75 mg orally, twice daily. Concomitant use of a P-gp inhibitor or antiviral should be avoided. We generally avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) For patients with CrCl <15 mL/min or on dialysis, no dosing recommendations are available. We avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) Edoxaban dosing varies according to the estimated glomerular filtration rate: For patients with a Cockcroft-Gault equation CrCl >95 mL/min, edoxaban should not be used due to lesser efficacy compared with warfarin in preventing stroke in this group due to high renal clearance. For such patients, another DOAC is an alternative. For patients with a CrCl of >50 to 95 mL/min, an edoxaban dose of 60 mg once daily is used. For patients with a CrCl of 15 to 50 mL/min, the dose is 30 mg once daily. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 5/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For patients with a CrCl of <15 mL/min, there are limited data, so edoxaban is avoided in these patients. For patients 65 years of age and with at least one of the following characteristics, the dose is 30 mg once daily: weight 60 kg or concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine). For patients with advanced age ( 80 years) and low body weight (ie, 45 kg or 60 kg plus an additional risk factor), a lower dose of edoxaban (15 mg once daily) may be safe and effective. This approach is supported by the results of the ELDERCARE-AF trial in which 984 Japanese patients age 80 years or older were randomly assigned to receive edoxaban 15 mg or placebo daily [19]. The mean body weight of participants was low (50.6 11 kg). All patients were considered inappropriate candidates for standard oral anticoagulant regimens due to one or more of the following concerns: a low CrCL ( 15 and <30 mL/min), a history of bleeding, low body weight ( 45 kg), or use of a nonsteroidal antiinflammatory drug or an antiplatelet drug. The annualized rate of stroke or systemic embolism was 2.3 and 6.7 percent in the two groups, respectively (hazard ratio [HR] 0.34, 95% CI 0.19-0.61), and the rate of major bleeding was 3.3 and 1.8 percent, respectively (HR 1.87, 95% CI 0.90-3.89). ICH was rare in both groups (0.3 and 0.6 percent). In a prespecified subanalysis of this trial, findings were largely similar across different categories of renal dysfunction (ie, mild, moderate, and severe) [20]. (See 'Older adults' below.) Rivaroxaban If the CrCl is >50 mL/min, the rivaroxaban dose is 20 mg once daily with the largest meal of the day (>500 calories), usually the evening meal. If the CrCl is 15 to 50 mL/min, the rivaroxaban dose is 15 mg once daily with the largest meal of the day (>500 calories). If the CrCl <15 mL/min, avoid use of rivaroxaban. (See 'Chronic kidney disease' below.) Vitamin K antagonist For patients with AF treated with VKA (eg, warfarin), an INR between 2.0 and 3.0 is recommended with an average annual TTR >70 percent [21,22]. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1) [23-27]. Dosing of warfarin is discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 6/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation as well as a risk factor for stroke. However, we recommend an INR between 2.0 and 3.0 for these patients as well [27]. Temporary interruption of anticoagulation Temporary interruption of oral anticoagulation for reasons of bleeding or urgent/elective surgery/invasive procedure results in an increased risk of thromboembolism after the period of effective anticoagulation has ended [28]. The optimal approach to such patients is unclear and likely depends on issues such as baseline thromboembolic risk, duration of anticoagulant interruption, and bleeding risk. These issues are discussed in detail separately. (See "Perioperative management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Use of anticoagulants during pregnancy and postpartum" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'.) The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found separately [29,30]. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The reversal of the anticoagulant effect of warfarin and DOAC agents is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) Anticoagulant failure Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'): Transesophageal echocardiographic (TEE) evidence of dense spontaneous echo contrast and low left atrial appendage ejection velocity [31]. TEE evidence of complex aortic plaque [31]. TEE-detected thrombi can be related to clinical risk factors [32]. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.) Subtherapeutic INR on VKA [33] or noncompliance in patients taking DOAC agents. Elevated D-dimer levels. In a single-center, prospective, observational study of 269 patients, D-dimer levels were elevated (at least 0.5 mcg/mL) in 23 percent, and elevated levels were significantly associated with a higher rate of thromboembolism (HR 15.8, 95% CI 3.33-75.5) [34]. Similarly, in a study of 829 patients with AF, elevated von Willebrand factor levels were associated with risk of thrombotic events [35]. However, we do not recommend routine https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 7/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate testing of D-dimer or von Willebrand factor in patients with AF, as incorporating such testing in anticoagulation decision-making has not been shown to alter outcomes in this setting. There are no studies of the optimal anticoagulation strategy for those experiencing a thromboembolic event. For those patients with a subtherapeutic INR with warfarin at the time of the event, an attempt should be made to identify the cause (compliance, drug/food interaction) and to consider switching to a DOAC if the annual TTR has been less than 70 percent [36]. For those on a twice-a-day DOAC, consideration of a once-a-day DOAC should be made if noncompliance is an issue. For those on a once-a-day DOAC, a different once-daily agent may be considered (eg, another once-daily DOAC or possibly warfarin because the INR can be followed). Though reasonable, none of these approaches is of proven benefit. Ischemic strokes with nonembolic causes occur in patients with AF as in patients without AF. These are not the target of anticoagulants. Occurrence of such a stroke is not a "failure" of anticoagulation. Other reasons for switching agents Some patients with AF may need to be switched from DOAC agent to VKA, from VKA to DOAC, or between DOAC agents for reasons other than anticoagulant failure (which is discussed above). (See 'Anticoagulant failure' above.) Reasons for switching from VKA to DOAC: As discussed above, most patients with AF treated with VKA should be switched to DOAC. (See 'Choice of anticoagulant' above.) Need for repeated invasive procedures, annual TTR <70 percent, convenience. Possible reasons for switching from DOAC to VKA: Out-of-pocket cost Development of severe kidney disease (see 'Chronic kidney disease' below) Development of a contraindication to DOAC use, as discussed above (see 'Choice of anticoagulant' above) Information on switching oral agents is provided separately ( table 4). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.) Recommendations for transitioning between DOACs and parenteral anticoagulants, including unfractionated heparin and low molecular weight heparin, are available in the individual drug https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 8/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate monographs for each DOAC. Drug interactions The individual DOACs are in varying degrees eliminated by CYP3A4 metabolism or are substrates of P-glycoprotein (P-gp) efflux pump and subject to pharmacokinetic drug interactions, although fewer in number than warfarin interactions. Drugs that inhibit CYP3A4 metabolism or P-gp efflux can increase DOAC levels (ie, greater anticoagulant effect and bleeding), whereas drugs that are inducers can decrease DOAC effect, which can lead to therapeutic failure. A detailed review of the different drug interactions can be found in tables ( table 2A-C) and the Lexicomp drug interaction program within UpToDate. Additional related content is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) SPECIFIC PATIENT GROUPS Patients with valvular heart disease The above general considerations regarding choice of anticoagulant (DOAC versus VKA) apply to patients with valvular heart disease (excluding patients with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 2 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve in any location), although the evidence in patients with severe native valve disease is more limited than for the general population of AF patients [37]. (See 'Choice of anticoagulant' above.) Some patients with valvular lesions (without heart failure), such as mitral valve prolapse, nonrheumatic moderate or severe mitral regurgitation, mitral valve repair (except for the first three to six months postoperatively), or moderate or less aortic valvular conditions, have been enrolled in clinical trials of the DOACs. These trials also included a few patients (with or without heart failure) with severe native valvular conditions who were not scheduled to undergo valve replacement. As an example, in the ARISTOTLE trial, which compared apixaban with warfarin ( table 3), approximately 26 percent of the patients had a history of moderate or severe valvular heart disease or previous valve surgery (not including placement of a mechanical heart valve) [38]. While these patients had higher rates of stroke and systemic embolism than those without, the benefits of a lower rate of stroke/systemic embolism and major bleeding with apixaban (compared with warfarin) were similar to those without valvular heart disease. Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with the following specific valve conditions are discussed separately: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 9/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Antithrombotic therapy for mechanical heart valves" and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve in any location. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. The choice of anticoagulant after surgical valve procedures is discussed separately. (See "Antithrombotic therapy for mechanical heart valves" and 'Choice of anticoagulant' above.) Transcatheter bioprosthetic valve. The choice of anticoagulant after transcatheter valve procedures is discussed separately. (See 'Choice of anticoagulant' above and "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach' and "Transcatheter mitral valve repair", section on 'Antithrombotic therapy'.) Older adults For most older patients, including those over the age of 75 years, we prefer DOACs (also referred to as non-vitamin K oral anticoagulants [NOACs]) to warfarin because of the reduced risk of intracranial hemorrhage versus warfarin. Since there are no head to head randomized trials comparing DOACs in this patient group, we do not have a preference for a specific DOAC. Dose adjustment should be made if the patient meets relevant criteria such as renal function for the DOAC. The results of the ELDERCARE-AF trial are discussed separately. (See 'Dosing' above and 'Chronic kidney disease' below.) Chronic kidney disease Who to anticoagulate Our approach to deciding which AF patients with chronic kidney disease (CKD) to anticoagulate is presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) Choice of anticoagulant For patients with AF and CKD stage G2 or G3 ( figure 2) treated with oral anticoagulation, most of our contributors choose a DOAC rather than VKA. However, the evidence to support this choice in patients with CKD is limited [39-43]. One contributor prefers VKA in this setting given wider clinical experience. For patients with AF and severe kidney disease (stage G4 or G5; estimated glomerular filtration 2 rate <30 mL/min/1.73 m ), on dialysis, or with acute renal injury, DOAC is generally avoided and VKA is generally the preferred long-term anticoagulant. Patients with stage 4 and 5 CKD are at higher risk of having unpredictable sudden deterioration in renal function than patients with https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 10/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate normal renal function, and such deterioration could cause an abrupt reduction in clearance of a DOAC that depends on renal metabolism. In such a setting, use of an agent such as warfarin that allows for therapeutic drug monitoring may be preferred. An annual time in the therapeutic range of >70 percent is desirable. (See "Direct oral anticoagulants (DOACs) and parenteral direct- acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) If a DOAC is chosen for a patient with stage 4 or 5 CKD or on dialysis, our contributors prefer apixaban, in part because apixaban is less dependent on kidney function for clearance than other DOACs available in the US ( table 2A). The support for use of apixaban in these patients is largely based upon our clinical experience and observational studies [40,41]. In a subgroup analysis of the ARISTOTLE trial in patients with creatinine clearance (CrCl) 25 to 30 mL/min, the risk of major bleeding was significantly less with apixaban compared with warfarin (hazard ratio [HR] 0.34, 95% CI 0.14-0.80) [41]. We avoid dabigatran in patients with stage 4 or 5 CKD because a high percentage of the drug is renally cleared. These issues are discussed further separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Based upon pharmacokinetic modeling, the US Food and Drug Administration approved DOAC dosing for use in selected patients with CKD based upon Cockcroft-Gault CrCl as described above (see 'Dosing' above). Patients at risk for gastrointestinal bleeding Risk factors for gastrointestinal bleeding in patients on oral anticoagulants have been identified. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastrointestinal'.) Choosing apixaban or dabigatran over rivaroxaban or warfarin may be prudent to prevent major bleeding outcomes in AF patients at high risk of gastrointestinal bleeding. In a subgroup analysis of the ARISTOPHANES observational study, 381,054 individuals anticoagulated for nonvalvular AF and who were at high risk of gastrointestinal bleeding were followed for major bleeding outcomes [44]. Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major bleeding (apixaban: HR 0.59, 95% CI 0.56-0.63; dabigatran: HR 0.78, 95% CI 0.70-0.86), whereas rivaroxaban was associated with a higher gastrointestinal bleeding risk (HR 1.11, 95% CI 1.05-1.16). Acute stroke Recommendations for the management (including the role of antithrombotic therapy) of patients with AF with an acute stroke are presented separately. Patients with AF for whom anticoagulant therapy is being considered and who have had an ischemic stroke within 30 days should be referred to a neurologist or other clinician who is experienced in managing https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 11/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate antithrombotic care in such patients. Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke is generally avoided as studies have shown that such treatment causes more harm than good (See "Stroke in patients with atrial fibrillation" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Concomitant antiplatelet therapy For patients with indications for both anticoagulant for AF and for antiplatelet therapy (for a concurrent condition), any potential benefit must take into account an increased risk of bleeding with concomitant antiplatelet and anticoagulant therapy. The combination of antiplatelet and anticoagulant increases the risk of bleeding compared with either alone [45]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) The potential use of both anticoagulant and antiplatelet therapies in patients with AF is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients" and "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The issue of whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF is discussed in detail separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The impact of antiplatelet therapy on bleeding (and efficacy) outcomes in patients taking either warfarin or dabigatran was evaluated in a post-hoc subgroup analysis of the RE-LY trial (see 'Choice of anticoagulant' above) in which approximately 40 percent of patients were taking concomitant aspirin or clopidogrel at some point during the study [46]. Very few patients were taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct

taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct factor Xa inhibitors (eg, apixaban, edoxaban, and rivaroxaban). DOACs are generally https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 15/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate administered at fixed doses without laboratory monitoring. Given differences in the characteristics and availability of DOACs, it is important for clinicians to be familiar with the clinical use of multiple DOAC agents ( table 2A and table 3). (See 'DOACs' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.) Target INR For patients with AF treated with VKA (eg, warfarin), the target INR is between 2.0 and 3.0 with an average annual TTR 70 percent. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1). (See 'Vitamin K antagonist' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bellesini M, Bianchin M, Corradi C, et al. Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review. Clin Drug Investig 2020; 40:1001. 2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. 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Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke 2018; 49:2933. 13. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019; 132:596. 14. Andersson NW, Svanstr m H, Lund M, et al. Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation. Int J Cardiol 2018; 268:113. 15. Fralick M. Effectiveness and safety of apixaban. Ann Intern Med 2020; :463. 16. Ray WA, Chung CP, Stein CM, et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA 2021; 326:2395. 17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 18. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013; 128:237. 19. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 20. Yoshida T, Nakamura A, Funada J, et al. Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial. Circulation 2022; 145:718. 21. Fuster V, Ryd n LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 17/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001; 104:2118. 22. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. 23. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S. 24. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540. 25. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 26. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 27. Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. 28. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 129:1850. 29. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011; 106:572. 30. Huber K, Airaksinen KJ, Cuisset T, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe. Thromb Haemost 2011; 106:569. 31. Bernhardt P, Schmidt H, Hammerstingl C, et al. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol 2005; 45:1807. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 18/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 32. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-VASc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011; 105:1107. 33. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004; 126:1938. 34. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010; 55:2225. 35. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 36. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 37. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 38. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015; 132:624. 39. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. 40. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation 2018; 138:1519. 41. Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020; 141:1384. 42. Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020; 223:3. 43. Su X, Yan B, Wang L, et al. Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis. Am J Kidney Dis 2021; 78:678. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 19/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 44. Lip GYH, Keshishian AV, Zhang Y, et al. Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 2021; 4:e2120064. 45. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185. 46. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. 49. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 50. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1031 Version 139.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 20/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate GRAPHICS Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (platelet count <50,000/microL) (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or Type of procedure and associated bleeding risk, interval between procedure and anticoagulation planned) Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma hemorrhage or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled Absolute blood pressure and blood pressure trend hypertension This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 21/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic Anticoagulant Bioavailability and Half-life drug clearance* interactions* Dabigatran 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase (Pradaxa) kidney dabigatran effect Unaffected by Prolonged food P-gp with kidney P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact and requires adults effect gastric acidity for absorption Avoidance of some combinations or dose adjustment may be needed Apixaban (Eliquis) 50% bioavailable 27% cleared by the kidney 12 hours Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect Prolonged in older adults Unaffected by food Metabolized, primarily by CYP3A4 Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase (Savaysa, Lixiana) edoxaban effect Unaffected by Reduced Prolonged in food efficacy in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 22/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate and CrCl >95 dose adjustment mL/minute may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% bioavailable Prolonged to 11 to 13 inhibitors can increase Metabolized, primarily by CYP3A4 hours in older adults Unaffected rivaroxaban effect by food P-gp substrate* 20 mg dose: Strong CYP3A4 66% inducers and/or P-gp inducers can decrease rivaroxaban bioavailable if taken when fasting; increased if taken with food effect Avoidance of some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 23/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown. [1] Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 24/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate Strong inducers Moderate inducers inhibitors Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone therapy pack Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- Netupitant Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 25/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]).

Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 30/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 31/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 32/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 33/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Switching between oral anticoagulants Switching from a DOAC to warfarin Dabigatran Overlap warfarin with dabigatran for 3 days (normal renal function); 2 days (CrCl 30 to 50 mL/min); or 1 day (CrCl 15 to 30 mL/min); note that dabigatran can contribute to INR elevation. or- Overlap warfarin with dabigatran until the INR is therapeutic on warfarin (ASH).* Apixaban If continuous anticoagulation is needed, discontinue apixaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that apixaban can contribute to INR elevation. or- Overlap warfarin with apixaban until the INR is therapeutic on warfarin, testing right before the next apixaban dose to minimize the effect of apixaban on INR elevation (ASH).* Edoxaban Reduce dose by half (eg, from 60 to 30 mg daily or from 30 to 15 mg daily) and begin warfarin concurrently (PI). Discontinue edoxaban when the INR is 2; note that edoxaban can contribute to INR elevation. or- Discontinue edoxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). or- Overlap warfarin with edoxaban until the INR is therapeutic on warfarin, testing right before the next edoxaban dose to minimize the effect of edoxaban on INR elevation (ASH).* Rivaroxaban Discontinue rivaroxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that rivaroxaban can contribute to INR elevation. or- Overlap warfarin with rivaroxaban until the INR is therapeutic on warfarin, testing right before the next rivaroxaban dose to minimize the effect of rivaroxaban on INR elevation (ASH).* Switching from warfarin to a DOAC Dabigatran Stop warfarin, monitor the PT/INR, and start dabigatran when the INR https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 34/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate is <2 (PI). Apixaban Stop warfarin, monitor the PT/INR, and start apixaban when the INR is <2 (PI). Edoxaban Stop warfarin, monitor the PT/INR, and start edoxaban when the INR is 2.5 (PI). Rivaroxaban Stop warfarin, monitor the PT/INR, and start rivaroxaban when the INR is <3 (PI). Switching from one DOAC to a different DOAC Any DOAC Start the second DOAC when the next dose of the first DOAC would have been due; do not overlap. This table presents a reasonable approach to switching between oral anticoagulants. It does not substitute for clinical judgment regarding individual patient risks of thrombosis and bleeding. Individuals switching from a DOAC to warfarin are more likely to require continuous anticoagulation if they have had a recent thromboembolic event or if they are at especially high risk of thromboembolism. Refer to UpToDate topics on specific indications, perioperative management, and the use of DOACs and warfarin for further details. DOAC: direct oral anticoagulant; CrCl: creatinine clearance; INR: international normalized ratio; ASH: American Society of Hematology clinical practice guideline; PI: package insert; PT: prothrombin time. Two to three days of overlap after the INR becomes therapeutic may be needed in individuals with higher thrombosis risk, because the PT/INR will enter the therapeutic range before full anticoagulation occurs. In individuals overlapping warfarin and a DOAC, the DOAC may contribute to INR elevation. Prepared with information from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. PRADAXA (dabigatran etexilate mesylate) capsules. US FDA approval 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf (Accessed on April 25, 2019). 3. ELIQUIS (apixaban) tablets. US FDA approval 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s020lbl.pdf (Accessed on April 25, 2019). 4. SAVAYSA (edoxaban) tablets. US FDA approval 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206316s012lbl.pdf (Accessed on April 25, 2019). 5. XARELTO (rivaroxaban) tablets. US FDA approval 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022406s030s032lbledt.pdf (Accessed on April 25, 2019). Graphic 120639 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 35/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 36/37 7/6/23, 12:58 PM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 37/37

7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation : Robert Phang, MD, FACC, FHRS, Warren J Manning, MD : Bradley P Knight, MD, FACC, Brian Olshansky, MD, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 02, 2022. INTRODUCTION Spontaneous or intended conversion of atrial fibrillation (AF) to sinus rhythm (SR) is associated with a short-term increase from the baseline risk of clinical thromboembolism. This topic will discuss management strategies that attempt to decrease this thromboembolic risk, based on the duration of the AF episode, prior anticoagulant therapy, and the patient s individualized risk of stroke (CHA DS -VASc score ( 2 table 1)). 2 The modalities used to perform cardioversion, long-term anticoagulation in patients with AF, and an overview of the management of AF are presented separately. (See "Atrial fibrillation: Cardioversion" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) EXTREMELY HIGH-RISK PATIENTS Patients with AF and certain types of valvular heart disease (rheumatic mitral stenosis or a mechanical valve), are at extremely high risk of thromboembolic complications at all times, not only at the time of cardioversion. The approach to antithrombotic therapy in such patients is discussed in other UpToDate topics. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism' and "Antithrombotic therapy for mechanical heart valves".) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 1/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate RATIONALE FOR ANTICOAGULATION All patients with AF, whether paroxysmal, persistent, or permanent, have an increased risk of embolization compared with those without AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) At the time of reversion to SR, whether pharmaceutical, electrical, or spontaneous, there is a transient incremental increase from the baseline risk. Most embolic events occur within 10 days of reversion to SR [1-5]. Patients undergoing cardioversion of AF of more than 48 hours duration represent a particularly high-risk group (compared with AF of less than 48 hours duration), with an embolic risk from as low as 1 to as high as 5 percent in the first month after reversion to SR in the absence of anticoagulation [2-4,6-8]. This rate is substantially higher than the rate that would be calculated for the general population of patients with AF, in whom the yearly rate is between 1.3 and 5.1 (or higher) percent, depending on age and additional comorbidities. The most common source of stroke associated with cardioversion in these patients is embolism of a thrombus from the left atrial appendage during or in the first two weeks after the procedure. Possible causes include embolism of a left atrial thrombus that was already present at the time of conversion to SR, embolism of a thrombus that formed after conversion due to depressed left atrial appendage ejection velocity postconversion, or delay in recovery of left atrial mechanical function after conversion, and thrombus formation during subsequent episodes of AF: Precardioversion left atrial thrombus. Embolization after return of synchronous atrial contraction is due to the dislodgement of left atrial thrombi present at the time of cardioversion. This is felt to be the dominant cause of postcardioversion thromboembolism and the rationale for performing transesophageal echocardiogram (TEE) prior to cardioversion. The prevalence of left atrial thrombus in nonanticoagulated patients with AF of less than 72 hours undergoing TEE is 12 and 14 percent [9,10]. This value is similar to that found among AF patients with a duration of unknown or more than two days duration [11,12]. The prevalence of left atrial appendage thrombus is increased in high-risk patients with severe left ventricular systolic dysfunction, left atrial enlargement, depressed left atrial appendage ejection velocity, or left atrial appendage spontaneous echo contrast (a marker of blood stasis). https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 2/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Postcardioversion atrial mechanical dysfunction creates a milieu that promotes new (postcardioversion) thrombus formation. The transient atrial contractile dysfunction after cardioversion is referred to as atrial "stunning" and can occur whether SR is restored spontaneously, by external or internal direct current cardioversion, or by antiarrhythmic medications. The duration of the left atrial contractile dysfunction appears to be related in part to the duration of AF prior to cardioversion. Recovery of atrial mechanical function may be delayed for several weeks [13] for those who have been in AF for a few months prior to cardioversion. In comparison, for those with AF for only a few days, left atrial mechanical recovery occurs within a day (but may still be associated with more pronounced but transient dysfunction immediately after cardioversion). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) In support of the atrial stunning after cardioversion hypothesis, there have been case reports and small series of patients developing TEE evidence for de novo left atrial appendage thrombi (primarily in the setting of no anticoagulation) immediately following cardioversion, when the precardioversion TEE showed no left atrial appendage thrombus [9,14-16]. (See "Role of echocardiography in atrial fibrillation", section on 'Spontaneous echo contrast' and "Mechanisms of thrombogenesis in atrial fibrillation".) Recurrent AF is common during the first month after conversion [17]. Up to 90 percent of these episodes are asymptomatic [18], and asymptomatic episodes lasting more than 48 hours are not uncommon, occurring in 17 percent of patients in a report using continuous monitoring [17]. Anticoagulation during the four weeks postcardioversion thereby provides prophylaxis against new thrombus formation and facilitates early cardioversion without a screening TEE should recurrent AF occur. The rationale and indications for chronic anticoagulation after the period of postconversion anticoagulation are similar to those for the broad population of patients with AF and are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) PATIENTS WITH SPONTANEOUS CONVERSION Some patients with AF have spontaneous conversion prior to planned cardioversion. The risk of thromboembolism after spontaneous conversion or electrical cardioversion is relatively low, but the risk during this time is likely higher than the ambient rate of thromboembolic events associated with AF. There is no evidence that risk of embolization in the first few weeks after https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 3/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate spontaneous conversion differs from that for patients with AF undergoing electrical or chemical cardioversion. In a study of 1041 patients who were anticoagulated prior to and after cardioversion, 16 percent experienced spontaneous conversion (prior to planned electrical cardioversion) [19]. The rate of thromboembolism was similar in patients with spontaneous conversion compared with patients who underwent electrical cardioversion (<1 percent in both groups) although this comparison is limited by the small number of events). Though of unproven efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or via cardioversion) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score ( table 1). The rationale 2 2 for this approach is concern regarding the high likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This approach may be modified in patients at very high bleeding risk. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Management of long-term anticoagulation (after the initial four weeks) including the role of CHA DS -VASc score is discussed separately. (See "Atrial fibrillation in adults: Selection of 2 2 candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) URGENT CARDIOVERSION Patients with new onset AF in whom the ventricular rate is rapid may require urgent (or emergent) cardioversion to prevent adverse clinical consequences such as hemodynamic decompensation. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptom and hemodynamic management'.) The indications for urgent cardioversion of AF are uncommon, but in the setting of hemodynamic instability due to rapid AF that is refractory to pharmacologic support, such as in patients with Wolff-Parkinson-White syndrome, the need for restoration of SR may take precedence over the need for protection from thromboembolism. When possible, the patient should receive precardioversion anticoagulation (eg, bolus of unfractionated heparin or dose of direct oral anticoagulant [DOAC; also referred to as non-vitamin K oral anticoagulant [NOAC]) as soon as possible due to the risk of postcardioversion left atrial appendage stunning. Anticoagulation should be considered for four weeks postcardioversion, unless it is contraindicated [20] (see 'AF duration less than 48 hours' below). Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 4/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION LESS THAN 48 HOURS Anticoagulation prior to cardioversion If conversion to SR (either spontaneous or via cardioversion) occurs within 48 hours of the onset of AF, the thromboembolic risk appears to be very low [21-23]. However, many, and perhaps most, patients cannot accurately define the onset of AF. As a result, we categorize a patient as having AF of less than 48 hours duration only if we have a high level of confidence in the patient s history. Otherwise, we approach the patient as if AF has been present for more than 48 hours. (See 'AF duration uncertain or 48 or more hours' below.) For most patients in whom cardioversion will take place less than 48 hours after the onset of AF, we start a DOAC prior to cardioversion rather than no anticoagulant. Intravenous heparin is a reasonable alternative for hospitalized patients. When a DOAC is used, the specific choice of DOAC should be individualized for each patient. We generally choose the agent that will be given at the time of discharge. Of note, the approach presented here is in contrast to the historical approach of some cardiologists proceeding to early cardioversion without anticoagulation if the duration was less than 24 hours. I(See "Atrial fibrillation in adults: Use of oral anticoagulants".) We generally wait at least three hours after the first dose of a DOAC to cardiovert. For patients at very high bleeding risk, some of our experts suggest cardioversion without anticoagulation if normal SR can be restored within 48 hours of documented onset. Other experts recommend anticoagulation prior to cardioversion even in these high-bleeding-risk patients. If cardioversion needs to take place within three hours, whether for patient instability or convenience (see 'Urgent cardioversion' above), we start intravenous unfractionated heparin (bolus and continuous drip goal partial thromboplastin time 1.5 to 2.0 times control) or a low molecular weight heparin (1 mg/kg subcutaneously every 12 hours); we do not give DOAC and heparin together. However, if warfarin is the agent selected for longer term anticoagulation, warfarin is started while heparin therapy is continued until the international normalized ratio exceeds 2.0. For extremely high-risk patients (eg, those with rheumatic mitral stenosis, mechanical valves, prior thromboembolism, severe left ventricular dysfunction, heart failure, or diabetes), we anticoagulate for at least three weeks or initiate therapeutic anticoagulation (with heparin or DOAC) in combination with TEE prior to an attempt at cardioversion as described above for AF of more than 48 hours duration. (See 'AF duration uncertain or 48 or more hours' below.) https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 5/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The 48 hour cut point is based on limited evidence and is somewhat arbitrary. For example, the prevalence of left atrial thrombus on TEE is substantially lower when the duration of AF is less than 48 hours (1.4 percent) [24]. Among patients with a history of AF of less than 48 hours in duration, there is likely a range of risk based on CHA DS -VASc score ( table 1). A retrospective 2 2 study of 3143 patients with AF of less than 48 hours duration demonstrated that patients with heart failure and diabetes were at high risk for clinical thromboembolism (up to 10 percent if both risk factors were present). The absence of both risk factors and age <60 years conveyed a very low risk of 0.2 percent [23]. (See 'AF duration uncertain or 48 or more hours' below and 'Rationale for anticoagulation' above.) No randomized trial has evaluated anticoagulation compared with no anticoagulation in AF patients undergoing cardioversion with a definite duration of AF <48 hours. Observational data suggest that the risk of stroke/thromboembolism is very low (0 to 0.2 percent) in patients with a definite AF duration of <12 hours and a very low stroke risk (CHA DS -VASc 0 in men, 1 in 2 2 women), in whom the benefit of four-week anticoagulation after cardioversion is undefined. The 2020 European Society of Cardiology guidelines for the diagnosis and management of AF suggest that prescription of anticoagulants can be optional, based on an individualized approach [25]. With regard to the question as to whether to anticoagulate these patients or not, there are no studies comparing heparin with no heparin in patients with AF of less than 48 hours duration. However, data regarding the rate of clinical thromboembolization after cardioversion in patients with AF of less than 48 hours duration have raised a concern about the safety of cardioversion without anticoagulation in this population. In an observational study of 2481 such individuals (5116 successful cardioversions) who were not treated with peri- or postprocedural anticoagulant, definite thromboembolic events occurred in 38 (0.7 percent) within 30 days (median of two days); of these, 31 were strokes [23]. Four additional patients suffered a transient ischemic attack. Age greater than 60 years, female sex, heart failure, and diabetes were the strongest predictors of embolization, with nearly 10 percent of those with both heart failure and diabetes experiencing a stroke. The risk of stroke in those without heart failure and age less than 60 years was 0.2 percent. An observational study of 16,274 patients undergoing direct current cardioversion with and without oral anticoagulant therapy also demonstrated that the absence of postcardioversion anticoagulation was associated with a high risk of thromboembolism, regardless of CHA DS -VASc scores [26]. There was a greater-than-twofold 2 2 increased risk of thromboembolism in those not treated with postcardioversion anticoagulation (hazard ratio 2.21; 95% CI 0.79-6.77 and 2.40; 95% CI 1.46-3.95 with CHA DS -VASc score 0 to 1 2 2 and CHA DS -VASc score 2 or more, respectively). The rationale for lack of postcardioversion 2 2 anticoagulation could not be exactly discerned in this trial but was deemed to be multifactorial, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 6/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate including presumed short-duration AF, perceived low thromboembolic risk, and lack of guideline adherence. With regard to the question of which anticoagulant to use, there are no studies comparing differing forms of heparin in patients with AF of short duration nor are there studies comparing a DOAC with heparin. Indirect evidence comparing the two heparins comes from a trial of 496 patients with AF of more than 48 hours duration who were randomly assigned to either low molecular weight heparin or unfractionated heparin followed by oral anticoagulation [27]. Patients were cardioverted after either 21 days of anticoagulation or after a TEE that was negative for thrombus; anticoagulation continued for 28 days after cardioversion. Low molecular weight heparin was noninferior to unfractionated heparin followed by oral anticoagulation in terms of the combined primary end point of ischemic neurologic events, major hemorrhage, or death by the end of study treatment (2.8 versus 4.8 percent). Low molecular weight heparin also has a safety and efficacy profile similar to unfractionated heparin when used as a bridge to oral anticoagulation in patients undergoing TEE-based therapy [28]. Anticoagulation after reversion to sinus rhythm Though of unproven in efficacy, some of our contributors recommend anticoagulation for four weeks after reversion to SR (either spontaneous or intended) for patients with AF of less than 48 hours duration, even for those with a low CHA DS -VASc score. The rationale for this approach is a concern regarding the high 2 2 likelihood of AF recurrence in the first month after reversion to SR, as well as transient postcardioversion atrial stunning in the immediate pericardioversion period. This decision may be modified in patients at very high bleeding risk. Some of our contributors do not anticoagulate patients with a low CHA DS -VASc score (0 in men 2 2 or 1 in women) after restoration of SR if AF was less than 48 hours duration [23,29]. Management of long-term anticoagulation (after the initial four weeks) is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) AF DURATION UNCERTAIN OR 48 OR MORE HOURS Patients with AF of more than 48 hours or of unknown duration should receive at least three weeks of therapeutic anticoagulation prior to cardioversion and four weeks of anticoagulation after cardioversion. In this setting, this treatment regimen can reduce the risk of thromboembolism during the four weeks after cardioversion from 6 percent to less than 1 percent [2-4,6,7,30-32]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 7/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate For patients in whom there is a reason to not wait three weeks, an option for management is precardioversion therapeutic anticoagulation in conjunction with a screening TEE to guide early cardioversion. This strategy can be used for patients in whom cardioversion needs to be performed before at least three weeks of therapeutic anticoagulation have been completed [12]. While the TEE approach shortens the precardioversion duration of anticoagulation, it does not change our recommendation for four weeks of anticoagulation after cardioversion or the need to be therapeutically anticoagulated at the time of the cardioversion due to the risk associated with postcardioversion atrial appendage stunning. (See 'Transesophageal echocardiography- based approach' below.) Prospective studies have shown that the risk of clinical stroke or systemic embolism ranges from 0 to 0.9 percent if preceded by at least three weeks of therapeutic anticoagulation with warfarin (target international normalized ratio [INR] 2.0 to 3.0) or one of the DOACs [2-4,12], or shorter- term anticoagulation with TEE-guided approach discussed directly above. Retrospective data demonstrated that the thromboembolism risk is 4 to 7 percent in nonanticoagulated patients [7,8,33]. Anticoagulant approach Since many patients will require long-term anticoagulation, we prefer the DOACs to warfarin before and after cardioversion (see "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'). While there has been longer experience with use of warfarin than DOACs prior to cardioversion, we believe there is sufficient evidence that DOACs are as effective and as safe as warfarin in this setting. Advantages of DOAC therapy include convenience (no INR testing required) and the possibility of a shorter duration of precardioversion anticoagulation in reliably adherent patients, since it often takes five or more weeks for a patient to have at least three continuous weeks of therapeutic anticoagulation with warfarin (INR 2.0 to 3.0). In patients in whom adherence to DOAC therapy is questionable, with possible missed doses leading up to the cardioversion, we often obtain precardioversion TEE to exclude an atrial (appendage) thrombus. Routine precardioversion TEE is not recommended for patients who have been therapeutically anticoagulated (INR 2.0 or greater) with warfarin for three weeks or who have been compliant with their daily DOAC. (See 'Transesophageal echocardiography-based approach' below.) Compliance with warfarin can be ascertained with INR monitoring. For patients started on warfarin, the target INR should be 2.5 (range 2.0 to 3.0), and cardioversion should not take place until an INR of 2.0 or greater has been documented for at least three consecutive weeks ( figure 1 and figure 2) [34,35]. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 8/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The following data are available for the DOACs: Dabigatran In a post-hoc analysis of the RE-LY trial, which compared dabigatran with warfarin, in which there were 1983 cardioversions in 1270 participants, there was no significant difference in the rate of thromboembolism and stroke within 30 days between those who received at least three weeks of dabigatran 110 or 150 mg twice daily or warfarin (0.8, 0.3, and 0.6 percent, respectively) [2]. Apixaban In a post-hoc analysis of the ARISTOTLE trial, which compared apixaban with warfarin, 743 cardioversions were performed in 540 patients. No strokes or systemic embolism occurred during the 30-day follow-up period of both warfarin and apixaban groups [3]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Rivaroxaban In the X-VeRT study, 1504 patients with AF of unknown or longer than 48 hours duration were randomly assigned in a 2:1 manner to cardioversion after at least three weeks of rivaroxaban or a vitamin K antagonist. There was no significant difference in the rate of the primary efficacy outcome (a composite of stroke, transient ischemic attack, peripheral embolism, myocardial infarction, and cardiovascular death) or the safety outcome of major bleeding (0.51 versus 1.02 percent and 0.6 percent versus 0.8 percent, respectively) [4]. Similarly, in a post-hoc analysis of the ROCKET-AF trial, which compared rivaroxaban with warfarin, 143 patients underwent 181 electric cardioversions, 142 patients underwent 194 pharmacologic cardioversions, and 79 patients underwent 85 catheter ablations. There was no significant difference in the long-term rate of stroke or systemic embolism (hazard ratio 1.38; 95% CI 0.61-3.11) [36]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Edoxaban In the ENSURE-AF trial, 2199 patients were randomly assigned to receive edoxaban or enoxaparin and warfarin with discontinuation of enoxaparin when the INR was >2.0 [5]. There was no significant difference in the primary efficacy end point (0.5 percent in the edoxaban group versus 1 percent in the enoxaparin warfarin group; odds ratio [OR] 0.46, 95% CI 0.12-1.43). The primary safety end point occurred in 1.6 percent of the edoxaban group versus 1.1 percent in the enoxaparin warfarin group (OR 1.48, 95% CI 0.64-3.55). The results were independent of the TEE-guided strategy and anticoagulation status. Therapeutic anticoagulation prior to cardioversion appears to be effective largely due to thrombus resolution, rather than organization and adherence of left atrial thrombi [37,38]. (See https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 9/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 'Rationale for anticoagulation' above.) Transesophageal echocardiography-based approach We suggest a TEE-based approach ( table 2A-B) for symptomatic patients and for patients for whom there is a concern about a three-week (or more) delay to cardioversion. Such a concern might arise from a preference to not have ongoing symptoms of AF or a possible lower likelihood of successful cardioversion with a longer period of AF. Other individuals for whom this strategy may be reasonable include those at high bleeding risk, as the TEE-guided approach shortens the total precardioversion anticoagulation time for those without thrombus; and those at highest risk for a cardioversion- related thromboembolic event, including prior thromboembolism and elderly women with diabetes and heart failure. Patients who require hospitalization are also candidates for this approach [39,40]. This recommendation for a focused use of the TEE-based approach is based on our concerns about cost, the small potential for complications, and the possibility of worse outcomes. We also recommend precardioversion TEE for all patients with a percutaneous left atrial appendage occlusion device in place (eg, Watchman, Lariat, Amulet,) or who have undergone surgical LAA exclusion (eg, by stapling, suture or approved device closure). Following LAA occlusion, adjacent thrombus may occur (with or without incomplete closure) with associated risk of thromboembolism. Limited data are available to guide the anticoagulation strategy in this setting [41]. (See "Atrial fibrillation: Left atrial appendage occlusion".) In a TEE-based approach, the imaging study is performed after therapeutic anticoagulation (of short duration) and prior to anticipated cardioversion. Patients without evidence of left and right atrial (specifically the left atrial appendage, which is the site for the vast majority of thrombi) thrombus proceed to cardioversion. If thrombus is found (or cannot be confidently excluded) on TEE, cardioversion should not be performed, and therapeutic anticoagulation should be continued for at least four weeks after which time we recommend that a TEE be repeated (to screen for residual thrombus, which would be a contraindication to cardioversion) if cardioversion is desired. The TEE approach should include the following sequential steps before cardioversion: For inpatients, the options include using heparin plus warfarin or using an DOAC. With the former, we administer either low molecular weight or unfractionated heparin (bolus and continuous drip with a goal partial thromboplastin time 1.5 to 2 times control) and simultaneously initiate oral warfarin (target INR 2.0 to 3.0). With the latter, we give at least two doses of a DOAC. As the pharmacokinetics of the DOACs are different than warfarin, https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 10/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate the combination of a heparin plus DOAC may lead to supratherapeutic anticoagulation. We do not recommend overlap of or combined use of heparin and a DOAC. For most outpatients, we prefer DOAC to warfarin. There are multiple factors that determine whether a DOAC or warfarin would be used, including cost and patient preference, but DOACs have the advantage of faster onset of action and ease of dosing. A strategy of at least two days of DOAC prior to TEE-guided cardioversion can be used. As an alternative, oral warfarin can be started five days before TEE with the target INR 2.0 to 3.0 [12]. A minimal precardioversion INR of 2.0 is acceptable, though 2.5 may be preferred. Obtain a TEE to assess for the presence of atrial thrombi. The use of an endocardial border definition echo contrast agent may help in cases where there is uncertainty about the presence or absence of thrombus [42]. If no thrombus is seen, proceed with cardioversion. Continue therapeutic anticoagulation from the time of TEE through cardioversion and extend for another four weeks. If a thrombus is seen on TEE, the patient should receive a minimum of four weeks of therapeutic anticoagulation and a repeat TEE to document thrombus resolution if cardioversion is desired [37]. If no cardioversion is desired, a follow-up TEE is not needed, as the patient should receive lifelong antithrombotic therapy. If thrombus is absent on repeat TEE, cardioversion may be performed. If thrombus is still evident, the rhythm control strategy may be changed to a rate control strategy, especially when AF-related symptoms are controlled, since there is a high risk of thromboembolism if cardioversion is performed. However, the evidence supporting this latter recommendation of avoidance of cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.)

cardioversion with a residual thrombus is minimal. It is best to be conservative with at least three weeks of precardioversion oral anticoagulant if an atrial thrombus cannot be confidently excluded on TEE. Continuous oral anticoagulation (warfarin INR 2.0 to 3.0 or full-dose DOAC) for at least four weeks after cardioversion in all eligible patients, regardless of the cardioversion method, CHA DS -VASc score, or apparent maintenance of SR. In patients who have not achieved 2 2 therapeutic anticoagulation with warfarin at the time of cardioversion, unfractionated or low molecular weight heparin should be continued until the INR is therapeutic. Observational studies have suggested that patients with AF of more than 48 hours duration can be acutely anticoagulated with heparin/oral anticoagulant and proceed directly to cardioversion without prolonged anticoagulation if no atrial thrombus is seen on precardioversion TEE ( table 2A-B) [11,43-45]. The ACUTE trial compared a TEE-guided strategy with a conventional https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 11/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate strategy (including therapeutic warfarin [INR 2.0 to 3.0] anticoagulation for at least three weeks prior to electrical cardioversion) in 1222 patients with AF of more than two days duration (median duration 13 days) who were undergoing electrical cardioversion [12,46]. Patients assigned to the TEE-guided strategy were anticoagulated with heparin before TEE if they were inpatients or with oral warfarin for five days (target INR 2.0 to 3.0) before TEE if they were outpatients. TEE was then followed by cardioversion if no atrial thrombi were identified. With both approaches, warfarin therapy was continued for four weeks after cardioversion. If the initial TEE demonstrated thrombus (which was present in 12 percent), cardioversion was postponed and patients received therapeutic (INR 2.0 to 3.0) anticoagulation for three weeks, at which time a repeat TEE was performed. Patients assigned to conventional strategy received three weeks of therapeutic anticoagulation before cardioversion. The following findings were noted: Within the eight weeks after study enrollment, there was no significant difference between the TEE and conventional groups in the incidence of ischemic stroke (0.6 versus 0.3 percent, respectively; relative risk [RR] 1.95, 95% CI 0.36-10.60) or all embolic events, including stroke, transient ischemic attack, and peripheral embolism (0.8 versus 0.5 percent, respectively; RR 1.62, 95% CI 0.39-6.76). One important difference is that the majority of thromboembolic events in the TEE arm occurred in patients who had reverted back to AF and/or had a subtherapeutic INR at the time of the event, while the thromboembolic events in the warfarin arm occurred in patients with SR with a therapeutic INR. There were significantly fewer hemorrhagic events with the TEE strategy (2.9 versus 5.5 percent), but no significant difference in the incidence of major bleeding (0.8 versus 1.5 percent) [12,47]; in addition, there was no significant difference in all-cause mortality (2.4 versus 1 percent) or cardiac deaths (1.3 versus 0.7). The TEE strategy led to a shorter mean time to cardioversion (3 versus 31 days) and a greater incidence of successful restoration of SR (71 versus 65 percent). Thromboembolism has been reported after a negative precardioversion TEE in some patients who were not therapeutically anticoagulated at the time of TEE and continuing for one month after cardioversion [9,14,15]. These adverse events may be related to the limited sensitivity of TEE for small thrombi, or to new thrombus formation that has been reported during the period between TEE and cardioversion or after cardioversion [9,14,15]. Thus, we recommend therapeutic anticoagulation for all patients undergoing a TEE-based approach to cardioversion. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 12/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate The development of impaired left atrial mechanical function and of new thrombi after cardioversion provides the rationale for four weeks of therapeutic anticoagulation after cardioversion (INR 2.0 to 3.0 or daily DOAC), even when the precardioversion TEE shows no thrombus [15,16]. There is suggestive evidence that such an approach reduces the incidence of embolic events [16]. (See 'Rationale for anticoagulation' above.) Although the results of the ACUTE study discussed above raise concerns about possible worse outcomes in patients treated with this strategy [39], some experts have suggested that the TEE strategy is a reasonable alternative to a conventional approach in some patients, such as those with a strong preference for early cardioversion, those with AF of less than three to four weeks duration who would benefit most from left atrial mechanical recovery, and those at increased risk of hemorrhagic complications (as the duration of precardioversion anticoagulation may be shortened). Another potential reason to consider this strategy is that a shorter period of AF may increase the likelihood of successful cardioversion and long-term maintenance of SR. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) RECOMMENDATIONS OF OTHERS Our recommendations are in broad agreement with those from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the European Heart Rhythm Association [20,25,48,49]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 13/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Conversion of atrial fibrillation (AF) to sinus rhythm (SR), either spontaneously or intended, is associated with a clinically important transient increase in the risk of thromboembolism, particularly stroke. This risk increases significantly after 48 hours of AF and can be lowered by therapeutic anticoagulation before cardioversion. (See 'Rationale for anticoagulation' above.) The following recommendations apply to patients with AF of clearly less than 48 hours duration (See 'AF duration less than 48 hours' above.): For patients one or more high risk factors for thromboembolism (eg, prior thromboembolism, heart failure, or diabetes mellitus), we suggest deferral of cardioversion to allow for three weeks of effective therapeutic precardioversion anticoagulation rather than early cardioversion (Grade 2C). Anticoagulation with heparin or a direct-acting oral anticoagulant (DOAC) before, during, and after cardioversion along with precardioversion transesophageal echocardiography (TEE) is an alternative approach for these high-risk patients. For patients not at high risk of thromboembolism (listed in the above bulleted recommendation), we anticoagulate most patients with a CHA DS -VASc score 1 2 2 (Grade 2C). We start either DOAC or a combination of heparin and warfarin prior to cardioversion. For patients with low risk of thromboembolism (CHA DS -VASc score 0 in men, 1 in 2 2 women), our experts have differing approaches regarding postcardioversion anticoagulation, with some using four weeks of postcardioversion warfarin or DOAC anticoagulation and others not. The following recommendations apply to patients with AF of more than 48 hours duration or when the duration is unknown (see 'AF duration uncertain or 48 or more https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 14/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate hours' above): We recommend a minimum of three consecutive weeks of therapeutic anticoagulation (warfarin with an international normalized ratio [INR] greater than 2.0 or DOAC) prior to cardioversion, rather than proceeding directly to cardioversion (Grade 1B). We recommend a DOAC prior to elective cardioversion rather than warfarin irrespective of whether the anticoagulant will be given long term (Grade 1B). (See 'Anticoagulant approach' above.) For symptomatic patients in whom there is a strong preference to not delay cardioversion, or in whom there is a concern about bleeding with prolonged oral anticoagulation, or who are not likely to tolerate AF despite adequate rate slowing, a TEE strategy is a reasonable approach using therapeutic anticoagulation with heparin/warfarin or DOAC throughout the pericardioversion period. (See 'Transesophageal echocardiography-based approach' above.) We recommend therapeutic oral anticoagulation (with a DOAC or warfarin with target INR of 2.0 to 3.0) for four weeks after cardioversion in all patients, rather than discontinuing anticoagulation after cardioversion (Grade 1B). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998; 82:1545. 2. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. 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January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 21. Gallagher MM, Hennessy BJ, Edvardsson N, et al. Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion. J Am Coll Cardiol 2002; 40:926. 22. Weigner MJ, Caulfield TA, Danias PG, et al. Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours. Ann Intern Med 1997; 126:615. 23. Airaksinen KE, Gr nberg T, Nuotio I, et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013; 62:1187. 24. Kleemann T, Becker T, Strauss M, et al. Prevalence of left atrial thrombus and dense spontaneous echo contrast in patients with short-term atrial fibrillation < 48 hours undergoing cardioversion: value of transesophageal echocardiography to guide cardioversion. J Am Soc Echocardiogr 2009; 22:1403. 25. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 26. Hansen ML, Jepsen RM, Olesen JB, et al. Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy. Europace 2015; 17:18. 27. Stellbrink C, Nixdorff U, Hofmann T, et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109:997. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 17/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 28. Klein AL, Jasper SE, Katz WE, et al. The use of enoxaparin compared with unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study. Eur Heart J 2006; 27:2858. 29. Garg A, Khunger M, Seicean S, et al. Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset. JACC Clin Electrophysiol 2016; 2:487. 30. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 31. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139. 32. Botkin SB, Dhanekula LS, Olshansky B. Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs. Am Heart J 2003; 145:233. 33. Weinberg DM, Mancini J. Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:745. 34. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 35. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 36. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013; 61:1998. 37. Collins LJ, Silverman DI, Douglas PS, Manning WJ. Cardioversion of nonrheumatic atrial fibrillation. Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation 1995; 92:160. 38. Jaber WA, Prior DL, Thamilarasan M, et al. Efficacy of anticoagulation in resolving left atrial and left atrial appendage thrombi: A transesophageal echocardiographic study. Am Heart J 2000; 140:150. 39. Silverman DI, Manning WJ. Strategies for cardioversion of atrial fibrillation time for a change? N Engl J Med 2001; 344:1468. 40. Seto TB, Taira DA, Tsevat J, Manning WJ. Cost-effectiveness of transesophageal echocardiographic-guided cardioversion: a decision analytic model for patients admitted to the hospital with atrial fibrillation. J Am Coll Cardiol 1997; 29:122. https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 18/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 41. Sharma SP, Turagam MK, Gopinathannair R, et al. Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices. J Am Coll Cardiol 2019; 74:2267. 42. Jung PH, Mueller M, Schuhmann C, et al. Contrast enhanced transesophageal echocardiography in patients with atrial fibrillation referred to electrical cardioversion improves atrial thrombus detection and may reduce associated thromboembolic events. Cardiovasc Ultrasound 2013; 11:1. 43. Klein AL, Murray RD, Grimm RA. Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation. J Am Coll Cardiol 2001; 37:691. 44. Manning WJ, Silverman DI, Gordon SP, et al. Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 1993; 328:750. 45. Manning WJ, Silverman DI, Keighley CS, et al. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5-year study. J Am Coll Cardiol 1995; 25:1354. 46. Klein AL, Grimm RA, Jasper SE, et al. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial. Am Heart J 2006; 151:380. 47. Klein AL, Murray RD, Grimm RA, et al. Bleeding complications in patients with atrial fibrillation undergoing cardioversion randomized to transesophageal echocardiographically guided and conventional anticoagulation therapies. Am J Cardiol 2003; 92:161. 48. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 49. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. Topic 906 Version 62.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 19/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate GRAPHICS Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) 2 2 CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients (n = 73,538) Stroke and thromboembolism event 2 2 rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 20/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 5 8942 15.26 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 21/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 22/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 23/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation. Reproduced with permission from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2011; 123:e269. Copyright 2011 Lippincott Williams & Wilkins. Graphic 87025 Version 4.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 24/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the conventional approach to cardioversion (one month of pretreatment with warfarin) in patients with atrial fibrillation Advantages Disadvantages Use of warfarin for one month before Delaying cardioversion to normal sinus rhythm for one cardioversion may lower the stroke rate month potentially decreases functional capacity. from 5.6 percent to a very low stroke rate of <2 percent. Relatively easy to administer with regular Prolonging treatment for seven to eight weeks one monitoring of INRs. month prior to and one month after cardioversion increases the risk of bleeding complications. Suitable for community hospitals. Not followed by routine clinical practice, especially in the elderly. The conventional approach has withstood the "test of time" since the 1960s. Patients who are at the highest risk for developing systemic embolization who should receive more prolonged or intensive anticoagulation are not routinely identified. Reprinted with permission from the American College of Cardiology. J Am Coll Cardiol 2001; 37:691. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 72971 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 25/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Advantages and disadvantages of the transesophageal echocardiography- guided approach to cardioversion of patients with atrial fibrillation undergoing cardioversion Advantages Disadvantages Transesophageal echocardiography (TEE) should be able to detect left atrial appendage thrombi, TEE is performed without any definitive guidelines about who should receive the which increase the risk of embolic stroke after procedure (high versus low risk) electrical cardioversion, thus sparing patients with thrombi from undergoing cardioversion In the majority of patients without left atrial Residual thrombus on repeat TEE may diminish appendage thrombi, earlier cardioversion may shorten the period of anticoagulation and lower the cost-effectiveness of the TEE-guided approach the corresponding risk of bleeding complications A TEE-guided approach may prove more cost- effective owing to the reduction in laboratory Transesophageal echocardiography requires a level III-trained physician and availability of monitoring costs and the reduction in bleeding complications expensive echocardiographic machines Earlier cardioversion is believed to increase the Transesophageal echocardiography may miss likelihood of a successful return to and thrombi that may embolize after cardioversion. In maintenance of sinus rhythm contrast, TEE may render false positive results by erroneously identifying spontaneous echocardiographic contrast, sludge, multilobed appendages or pectinate muscles as thrombus. Reprinted with permission from: The American College of Cardiology. J Am Coll of Cardiol 2001; 37:691-704. https://www.journals.elsevier.com/journal-of-the-american-college-of-cardiology. Graphic 54077 Version 6.0 https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 26/27 7/6/23, 1:00 PM Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation - UpToDate Contributor Disclosures Robert Phang, MD, FACC, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-of-embolization-prior-to-and-after-restoration-of-sinus-rhythm-in-atrial-fibrillation/print 27/27

7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis : Magdy Selim, MD, PhD : Scott E Kasner, MD, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 07, 2022. INTRODUCTION Spontaneous intracerebral hemorrhage (ICH) is often associated with long-term neurologic symptoms, and patients with ICH have an elevated risk of recurrence. Prevention of recurrent ICH (ie, secondary prevention) may reduce accumulating neurologic disability as well as societal burden of ICH. ICH may be categorized as either spontaneous or traumatic. ICH following traumatic brain injury is reviewed separately. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) This topic will review the epidemiology, secondary prevention, and long-term prognosis in adults with spontaneous ICH. Other aspects of ICH are discussed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Cerebral amyloid angiopathy".) (See "Hemorrhagic stroke in children".) (See "Stroke in the newborn: Management and prognosis".) RISK OF RECURRENCE https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 1/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Incidence The incidence of recurrent ICH varies from 2 to 7 percent per year, depending on risk factors [1,2]. Patients with a history of ICH have a risk of recurrent ICH that is higher than the risk of recurrence in patients with ischemic stroke [1-3]. In addition, the rate of recurrent ICH was 6.6-fold higher than for a first ICH in a study of patients with prior ischemic stroke [1]. The risk of ICH recurrence may be highest in the first 12 months after the initial ICH but persists for years after the first event, particularly after lobar ICH [4]. The cumulative risk of ICH recurrence varies from 1.3 to 8.9 percent after one year and ranges from 7.4 to 13.7 percent after five years in different populations [2,3,5,6]. Risk factors Initial ICH location and etiology Deep (nonlobar) ICH involving the basal ganglia, thalamus, cerebellum, or brainstem is associated with a lower risk of recurrence than ICH in lobar locations. The annual risk of ICH recurrence after deep ICH is approximately 2 to 3 percent, versus 7 to 14 percent after lobar ICH [2,7-9]. ICH involving deep nuclei is often attributed to hypertensive microvascular disease and lobar ICH is often attributed to cerebral amyloid angiopathy (CAA), but the risk of recurrence appears to be independent of ICH etiology, at least in part. CAA is a major cause of incident and recurrent lobar ICH [10]. A meta-analysis of 10 prospective cohorts of ICH patients found that the annual risk of ICH recurrence after CAA- related ICH was 7.4 percent (95% CI 3.2-12.6), versus 1.1 percent (95% CI 0.5-1.7) for non- CAA-related ICH [11]. (See "Cerebral amyloid angiopathy".) Other secondary causes of ICH, such as brain arteriovenous malformation, moyamoya syndrome, sickle cell disease, and brain tumors are also associated with elevated risks of recurrent ICH based on the nature of the underlying causes and the presence of specific associated high-risk features. These are discussed separately. (See "Brain arteriovenous malformations" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Prevention of stroke (initial or recurrent) in sickle cell disease" and "Overview of the clinical features and diagnosis of brain tumors in adults".) Other imaging features The presence and number of cerebral microbleeds (CMBs) and/or superficial siderosis on brain magnetic resonance imaging (MRI) identifies patients at high risk for recurrent ICH [11,12]. In one study, the presence of >1 CMB was associated with increased risk of recurrent ICH in patients with CAA-related ICH while a higher threshold, >10 CMBs, identified increased risk of a recurrent event in patients with non- CAA-related ICH [11]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 2/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hyperintensities on diffusion-weighted imaging (DWI) brain MRI sequences found in some patients with ICH may be a marker of severe small-vessel disease associated with the risk of ICH recurrence [13,14]. In one study of 247 patients with ICH, those with DWI hyperintensities had a higher risk of recurrent ICH but not subsequent ischemic stroke at two years [15]. Hypertension Hypertension (HTN) is the most consistent risk factor for ICH recurrence. HTN predisposes to ICH recurrence of both deep and lobar ICH [4]. Inadequate control of HTN is common and increases the risk of recurrent ICH [4,16,17]. In a longitudinal study of 1145 patients with ICH, each 10 mmHg increase in systolic blood pressure was associated with an incremental increase in risk of recurrent lobar ICH (hazard ratio [HR] 1.33, 95% CI 1.02-1.76) and recurrent deep ICH (HR 1.54, 95% CI 1.03-2.30) [18]. The risks of ICH related to inadequate blood pressure control and management to mitigate these risks are discussed below. (See 'Blood pressure management' below.) Age The risk of ICH recurrence with age is based largely on the association of advancing age with the risk of initial ICH [19]. A meta-analysis of more than 8100 patients with ICH assessed the age-related incidence of ICH over a 28-year period [20]. Using the age group of 45 to 54 years as reference, the incidence ratio increased from 0.10 (95% CI 0.06-0.14) for those under 45 years up to 9.6 (95% CI 6.6-13.9) for patients older than 85 years. These findings are likely true for ICH recurrence as well. Older age is also associated with higher prevalence of CAA and higher use of antithrombotic drugs for accumulating cardiovascular comorbidities. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) Medications Antithrombotic medications (including antiplatelet agents and anticoagulants) and statins may be associated with risk of ICH recurrence. In addition, several other substances including selective serotonin reuptake inhibitors and nonsteroidal anti-inflammatory drugs have been linked to increased risk of bleeding in general, including ICH and ICH recurrence ( table 1). However, studies examining the associations between these drugs and risk of ICH recurrence have yielded inconsistent results [3,18,21,22]. The potential risks of recurrent ICH due to antithrombotic and statin medications are discussed below. (See 'Management of antithrombotic therapy' below and 'Management of statins' below.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 3/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other risk factors Race and ethnicity There are racial and ethnic disparities in the risk of ICH recurrence. Black American, Hispanic American, and Asian American patients with a history of ICH seem to be at higher risk for a recurrent event than White American patients [16,23]. The prevalence of HTN in these groups does not fully account for this elevated risk of ICH. In one study, patients remained at higher risk of ICH recurrence after adjusting for blood pressure measurements and variability [16]. Chronic kidney disease Chronic kidney disease can be a marker of atherosclerotic disease and may further contribute to the risk of ICH through renally mediated impairment of cerebral autoregulation [24]. A large population-based study in Denmark evaluated 15,270 patients with ICH and found that patients with kidney failure at the time of the initial ICH were at higher risk for ICH recurrence (relative risk 1.72, 95% CI 1.34-2.17) [3]. Prior ischemic stroke or ICH The risk of a future ICH is higher in patients with history of prior ICH and those with history of a prior ischemic stroke [1]. Genetic features Certain genetic features associated with CAA are associated with increased risk of ICH recurrence [25]. Patients with ICH who are carriers of apolipoprotein-E (APOE) e2 or e4 genotypes, frequently associated with CAA, are at elevated risk of ICH [9]. Additionally, patients with genetic bleeding disorders also are at risk for ICH. These disorders are discussed separately. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Clinical manifestations and diagnosis of hemophilia" and "Rare inherited coagulation disorders".) FOLLOW-UP NEUROIMAGING All patients whose symptoms unexpectedly fail to improve or worsen during the recovery period require neuroimaging to evaluate for a recurrent hemorrhage. In addition, follow-up imaging studies can help to identify or confirm the cause of the ICH, which in turn determines the risk of recurrence and may help guide preventive measures. For some patients, neuroimaging studies performed during the acute hospitalization identify the etiology such that further imaging studies are not required. For other patients, the initial imaging study does not sufficiently exclude other causes of ICH and follow-up studies are required. When acute https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 4/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate bleeding and surrounding edema from the acute ICH shroud and distort underlying brain structures, delayed imaging performed after bleeding and edema have resolved may identify patients who are at high risk for recurrence due to an underlying structural cause ( algorithm 1). (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) Patients with suspected hypertensive ICH Patients with ICH attributed to hypertension (HTN) who continue to improve clinically during recovery may not warrant additional imaging. Clinical and imaging features on head computed tomography (CT) or brain magnetic resonance imaging (MRI) suggestive of hemorrhage related to HTN or other atherosclerotic risk factors associated with deep penetrating vasculopathy include: Hematoma or cerebral microbleeds (CMBs) in basal ganglia or thalamus, cerebellar nuclei, or brainstem ( image 1) Known history or new diagnosis of HTN No prior ICH (unless in setting of uncontrolled HTN) No atypical clinical or neuroimaging features ( table 2) Patient age 65 years Clinically stable patients who meet most or all of the criteria listed above likely do not require a follow-up imaging study. For patients with only some of these features, we suggest repeating a brain MRI with gadolinium contrast in 12 to 16 weeks after the ICH to assess for alternative secondary causes. Additional associated imaging features found in some patients with a hypertensive ICH include evidence of prior chronic ischemic stroke attributed to small vessel (penetrating artery) and CMBs located in the basal ganglia or thalamus evident on T2*-weighted brain MRI sequences. Patients with suspected CAA-related ICH Some patients with ICH attributed to cerebral amyloid angiopathy (CAA) whose symptoms continue to improve during recovery may not require additional imaging in the ambulatory setting. Imaging features on brain MRI suggestive of ICH related to CAA include lobar location and evidence of lobar CMBs or cortical superficial siderosis in an older patient ( image 1 and image 2). The approach to confirming that diagnosis is discussed separately. (See "Cerebral amyloid angiopathy", section on 'Diagnostic approach'.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 5/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Other patients We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause but not identified or excluded during the acute hospitalization ( table 2). Clinical features that raise suspicion for an underlying cause of ICH include: Age <65 years No history or new diagnosis of HTN History of protracted new-onset headaches History of new-onset neurologic symptoms preceding ICH Thunderclap headache at onset of hemorrhage History of prior ICH (unless attributed to uncontrolled HTN or CAA) Imaging features of the hemorrhage on imaging (head CT or brain MRI) raising suspicion for other secondary causes of ICH (such as a vascular lesion, primary or metastatic brain tumor, cerebral venous thrombosis, or hemorrhagic transformation of ischemic infarct) include: Early perihematomal edema out of proportion to the size of the ICH ( image 3) Hemorrhage appears to be in arterial vascular territory suggesting primary ischemic infarction ( image 4) Enhancement of intracranial vessels around ICH ( image 5) Multifocal hemorrhage ( image 6) Isolated intraventricular hemorrhage ( image 7) Specific underlying etiologies of nontraumatic ICH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Specific etiologies'.) We prefer brain MRI with gadolinium for most patients who undergo post-acute testing to identify underlying cause of ICH. MRI should include T2*-weighted (gradient echo [GRE] or susceptibility-weighted imaging [SWI]) sequences. In an observational study in 400 patients with spontaneous ICH, MRI performed within 30 days improved diagnostic accuracy regarding ICH etiology over CT, changing the diagnostic impression in approximately 14 percent and management in 20 percent of cases [26]. These findings were confirmed in a subsequent study of 123 patients where MRI was most useful for establishing the diagnosis of ICH secondary to cerebral venous sinus thrombosis, hemorrhagic transformation of an ischemic infarct, neoplasms, and vascular malformations [27]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 6/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients who are unable to undergo MRI, head CT with contrast is a reasonable but less sensitive alternative. When an underlying vascular cause is suspected, additional noninvasive vascular imaging with CT or MR angiogram should be performed. Digital subtraction angiography (DSA) is performed when CT or MR angiography is inconclusive or is negative and clinical suspicion for an underlying vascular lesion remains high ( image 5) [28,29]. In addition, we generally obtain DSA to evaluate for a vascular lesion such as an arteriovenous malformation. CT or MR venography is performed for suspected venous lesions, such as cerebral venous thrombosis. (See "Brain arteriovenous malformations" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The optimal time to obtain follow-up imaging depends on the indication and the clinical recovery of the patient. For patients who did not undergo evaluation during the acute hospitalization for potential underlying secondary causes of the ICH, we obtain early imaging in four weeks to identify potential underlying structural sources amenable to early treatment. For other patients with a suspected secondary cause where the acute evaluation did not identify or exclude an underlying source, we obtain imaging after six to eight weeks to allow for better visualization of underlying brain tissue after some resorption of the hematoma. For patients without worrisome clinical or imaging features of the ICH for whom the acute evaluation for underlying causes did not identify the etiology, repeat imaging is indicated to exclude underlying structural sources. For these patients, we typically delay repeat imaging for 12 to 16 weeks after the ICH to promote optimal visualization of underlying brain tissue and reduce the risk of identifying confounding abnormal imaging findings that may be attributed to healing of the ICH in the late subacute time period. BLOOD PRESSURE MANAGEMENT Blood pressure (BP) control is an important aspect of reducing the risk of recurrent ICH. Hypertension (HTN) is one of the single most important modifiable risk factors for initial ICH and ICH recurrence. (See 'Risk factors' above.) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 7/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Small improvements in BP control help to reduce the risk of ICH. The relationship between BP control and ICH recurrence has been studied somewhat indirectly in patients with either ischemic stroke or ICH. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, patients with prior stroke (hemorrhage or infarction) were randomly assigned to an angiotensin-converting enzyme inhibitor (perindopril) with or without a diuretic (indapamide) versus placebo. A modest BP reduction rate by 9/4 mmHg in patients assigned to active treatment reduced the risk of ICH from 2.4 to 1.2 percent, corresponding to a 50 percent relative risk reduction (95% CI 26-67 percent) [30]. The relative risk reduction for recurrent stroke was 49 percent (95% CI 18-68 percent) among patients whose qualifying event was ICH [30-32]. Blood pressure goals We suggest aiming for BP <130/80 mmHg as a long-term target to reduce the risk of recurrence after ICH ( table 3) [33]. The risk of ICH is reduced with each incremental reduction in BP, but the benefit may be greatest for patients whose BP reaches intensive BP-lowering targets [18,31]. The benefit for intensive BP reduction has not been demonstrated specifically for ICH recurrence; however, indirect evidence from patients with other cerebrovascular conditions suggests a likely benefit. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, 3020 patients with prior ischemic stroke were assigned either to a systolic BP target of 130 to 149 mmHg or <130 mmHg [34]. During a mean follow-up of 3.7 years, there were fewer ICH events in those assigned to the intensive BP target (6 versus 16), corresponding to a lower rate of ICH at 0.1 percent per patient-year in the intensive group compared with 0.3 percent per patient-year in the higher target. A more intensive BP target was assessed in the Recurrent Stroke Prevention Clinical Outcome (RESPECT) trial, in which 1266 patients with ischemic stroke were randomly assigned to intensive BP control (<120/80 mmHg) or to standard treatment (<140/90 mmHg) [35]. There was a trend toward fewer strokes in patients assigned to the intensive group; however, limitations in this study prevent firm conclusions. The actual mean BP achieved in the intensive group was 127/77, not very different from 133/78 mmHg in the standard group. The trial was stopped early with relatively few (12) ICH events, most in the standard treatment group (11 versus 1). In a meta-analysis of these studies along with two additional trials in patients after ischemic stroke, more intensive BP lowering (variably defined) was associated with a reduced risk of ICH (relative risk [RR] 0.25, 95% CI 0.07-0.90) [35]. Blood pressure lowering has additional benefits in reducing the risk of other vascular events including ischemic stroke, although in the population of patients with prior ICH, the absolute benefits in this regard are likely to be small [35]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 8/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate When to begin antihypertensive therapy The approach to BP control after ICH is stepwise. However, high quality data to specify when to safely implement BP control after ICH are lacking. In the acute (typically hospital) setting, initial steps to control the BP are begun immediately to prevent hematoma expansion. The benefit of acute control of elevated blood pressure must be balanced against the competing risk of cerebral or other organ hypoperfusion. Initial target systolic blood pressure is 140 to 160 mmHg for most patients. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) Further reductions in BP toward normotension are made in a stepwise fashion. For most patients, we aim to achieve the BP target of <130/80 mmHg within 10 to 14 days after the onset of ICH. We also advise close outpatient monitoring to ensure that BP control is maintained. Selection of antihypertensive agent For patients without a clinical indication for a specific agent, we typically start an angiotensin-converting enzyme (ACE) inhibitor. For those unable to tolerate or who prefer an agent other than an ACE inhibitor, we offer an angiotensin receptor blocker, thiazide diuretic, or calcium channel blocker, based on analyses of risk reduction in patients with atherosclerotic disease [36,37]. The choice of agent should be guided by efficacy in achieving target BP. Clinical indications to guide individualized medication selection are discussed elsewhere ( table 4). (See "Choice of drug therapy in primary (essential) hypertension".) The use of combination antihypertensive regimen (ie, multiple antihypertensive drugs, instead of a single drug) may decrease the risk of adverse effects and improves tolerability and compliance [38]. (See "Choice of drug therapy in primary (essential) hypertension".) Education of patients and their caregivers about target BP and their engagement in self- monitoring at home and communications with their medical providers are also key to achieve better BP control and to improve adherence to therapy [39]. Lifestyle modifications and management of obstructive sleep apnea and obesity are fundamental components of BP management. (See 'Lifestyle modifications' below.) MANAGEMENT OF ANTITHROMBOTIC THERAPY Many patients with ICH have comorbid cardiovascular conditions and may have indications for antiplatelet or oral anticoagulant agents. Whether to resume or discontinue these medications after ICH requires weighing the competing risks of thromboembolic events versus ICH recurrence. In the absence of high-quality trial data, observational reports and expert opinion guide risk/benefit assessment and decision-making. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 9/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy Antiplatelet therapy is typically withheld in the acute setting to mitigate the risk of hemorrhage expansion. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) We suggest resuming antiplatelet therapy after ICH for most patients who have a specific indication for such therapy. However, it is important to balance individual risks and benefits. Patients with established atherosclerotic disease We resume antiplatelet therapy for most patients with nonlobar ICH and those with lobar ICH attributed to cerebral amyloid angiopathy (CAA) who have established atherosclerotic disease, in agreement with guidelines from the American Heart Association (AHA) [33]. Such indications may include prior cardiovascular disease, ischemic stroke, or peripheral arterial disease. These indications are discussed separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The risks and benefits of resuming antiplatelet medications for patients with CAA are discussed in detail separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) If lobar ICH was attributed to an alternative source, we base decisions on resuming antiplatelet therapy on the individual risks associated with the underlying etiology. We prefer low-dose aspirin (81 mg per day), typically starting a few days after ICH, if neuroimaging confirms stability. Low-dose aspirin has been most studied in relationship to ICH recurrence. Some [4,40-42] but not all [43] small studies have reported no difference in the rates of ICH recurrence among patients with ICH who continued aspirin and those who discontinued it. In the Restart or Stop Antithrombotics Randomized Trial (RESTART), 537 patients who developed ICH while taking antithrombotic therapy were assigned either to continue or discontinue antiplatelet therapy [44]. Most patients (88 percent) were taking antithrombotic therapy for secondary prevention of atherosclerotic disease; 25 percent had atrial fibrillation, either as a comorbid condition or as their primary indication. After a median two years of follow-up, the risk of recurrent ICH was similar (nonsignificantly lower) in patients who continued versus discontinued antiplatelet therapy (4 versus 9 percent; adjusted hazard ratio [aHR] 0.51, 95% CI 0.25-1.03), while rates of major occlusive and thromboembolic events were higher and were similar among treatment groups (15 versus 14 percent; aHR 1.02, 95% CI 0.65-1.60). These findings were sustained in an extended follow-up at a median time of three years (interquartile range two to five years) [45]. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 10/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic and thromboembolic outcomes were similar among patients who continued versus those who discontinued antiplatelet therapy, and the rate of recurrent ICH remained lower than the rate of major vascular events (9 versus 30 percent). Primary prevention of atherosclerotic disease For patients with ICH without established atherosclerotic disease, we consider individual risk factors to weigh overall benefits of antiplatelet therapy against the risk of hemorrhage. As examples, we typically would resume aspirin for patients with ICH and hypertension (HTN), hyperlipidemia, and diabetes mellitus or those with carotid atherosclerotic disease. For such patients, ICH may be a marker of atherosclerotic risk. In a Danish cohort study, patients with prior ICH had a higher risk of subsequent cardiovascular events than age- and sex-matched controls, including ischemic stroke (1.5 versus 0.6 per 100 person-years) and major adverse cardiovascular events (4.2 versus 1.4 per 100 person-years) [46]. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".) For most of these patients in whom antiplatelet therapy is resumed, we prefer low-dose aspirin and restart such therapy several days after the ICH has stabilized. For patients with lobar ICH and suspected CAA without high risk of ischemic stroke or cardiovascular events, we avoid antiplatelet therapy. (See "Cerebral amyloid angiopathy".) Patients with intravascular stents Patients with symptomatic atherosclerotic disease who have undergone intravascular stent placement are typically prescribed antiplatelet therapy for several months to prevent vascular occlusion from thrombosis at the site of the stent. We typically resume these medications in patients with ICH because of the thrombotic risks related to their discontinuation and typically start within a few days after ICH if neuroimaging confirms stability. Whenever feasible, we prefer single antiplatelet therapy over dual antiplatelet therapy. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) Patients taking nonsteroidal antiinflammatory drugs We prefer nonacetylated salicylates (eg, magnesium salicylate) over other nonsteroidal antiinflammatory medications with antithrombotic properties that impair platelet function. Anticoagulation Anticoagulation is typically withheld, and the effects are reversed acutely for patients with ICH, to reduce the risks of hemorrhagic expansion and associated morbidity. (See https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 11/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) Many patients with ICH benefit from resuming anticoagulation when the thromboembolic risk is higher than the risk of recurrent ICH. However, it is important to balance individual risks and benefits. Individualize decision to resume or discontinue We balance the risks of recurrent ICH with the risk of thromboembolism to help make decisions about resuming anticoagulation for individual patients ( algorithm 2). Only limited observational data and expert opinion are available to support clinical decisions regarding resuming or withholding anticoagulation [47-50]. These decisions should be made along with the patient after weighing the individualized risks, benefits, and exploring alternative options whenever possible. Timing of resumption The optimal time for restarting oral anticoagulation after ICH has not been established and may depend on the underlying indication for anticoagulation. Early resumption of anticoagulation within several days after stabilization of the ICH may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve) [33]. (See 'Mechanical prosthetic heart valves' below.) For most other patients who resume anticoagulation, we generally suggest delaying restarting oral anticoagulants for four to eight weeks after onset of the ICH, in agreement with AHA guidelines [33]. We use hemorrhage size and thromboembolic risks to guide the specific timing of resumption for an individual patient. In one study of 177 patients with intracranial hemorrhage and an indication for anticoagulation, the combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir when warfarin was resumed after 10 weeks, suggesting that the optimal timing for resumption of oral anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial

anticoagulation is after 10 weeks [51]. The risk of ischemic stroke was lowest and the risk of recurrent hemorrhage was highest within the first five weeks after the initial hemorrhage, suggesting anticoagulation may be delayed during this time interval. Mechanical prosthetic heart valves Resumption of warfarin is recommended for most patients with mechanical prosthetic valves who develop ICH while taking warfarin because the ongoing risk of thromboembolic events is higher than the risk of recurrent ICH, regardless of hemorrhage etiology. In a meta-analysis of more than 13,000 patients with mechanical heart valves, the incidence of major embolism was four times higher among those not on antithrombotic therapy versus those taking warfarin (4 versus 1 per 100 patient-years) [52]. A https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 12/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prosthesis in the mitral position increased the thromboembolic risk almost twice as compared with the aortic position. (See "Antithrombotic therapy for mechanical heart valves".) CAA-related ICH Many patients with lobar ICH do not resume anticoagulation because of the associated risk of recurrent ICH attributed to CAA outside a compelling indication such as a mechanical heart valve. The specific risks of future ICH for individual patients with CAA should be weighed against the benefits of resuming anticoagulation. These risks and benefits of anticoagulation for patients with CAA are discussed separately. (See "Cerebral amyloid angiopathy", section on 'Prevention of recurrent hemorrhage'.) Atrial fibrillation In the absence of high-quality trial data, the decision to resume or withhold anticoagulation in patients with ICH and atrial fibrillation requires balancing future hemorrhagic and thromboembolic risks at an individual level. For many patients with atrial fibrillation, ischemic stroke is more common than recurrent ICH and the risk-benefit analysis favors resuming anticoagulation after ICH [6]. In a 2017 meta- analysis of eight studies including 5306 patients with anticoagulation-associated ICH, restarting anticoagulation after ICH was associated with a lower risk of thromboembolic complications and no excess risk of ICH recurrence [53]. Most patients resumed warfarin and atrial fibrillation was the most common indication for restarting anticoagulation. Resumption of oral anticoagulation was also associated with reduced risk of all-cause stroke and mortality at 12 months in an analysis of 1012 patients with warfarin-associated lobar and nonlobar ICH [54]. Another meta- analysis of 50,470 patients with spontaneous or anticoagulation-associated intracranial hemorrhage and atrial fibrillation also found that resuming anticoagulation was associated with lower risk of subsequent thromboembolism without excess risk of recurrent intracranial hemorrhage [55]. However, interpretation of these meta-analyses is limited by heterogeneity of included studies, their retrospective and observational nature, and inherent selection, indication, and prescription biases. Estimating bleeding and thromboembolic risks Several clinical prediction scores have been developed to help quantify individual risks of future bleeding and thromboembolism. The CHADS2 or CHA2DS2-VASc scores to assess thromboembolic risks are used widely ( table 5 and algorithm 2). Other scores have been developed to help estimate bleeding risk. Among these, the HAS-BLED score incorporates clinical risk factors associated with bleeding to help to assess initial hemorrhagic risk (scored 1 to 9) in patients with atrial fibrillation ( table 6) [56]. However, its generalizability is limited by the small number of patients with risks who scored 5 to 9 and may also be restricted to the assessment of initial ICH risk among patients taking warfarin. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 13/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Additionally, subjective clinical assessment of bleeding risk may have a similar predictive accuracy to bleeding scores [57]. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) As examples: For a typical patient with nonlobar ICH attributed to HTN without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may resume anticoagulation once HTN is controlled. For a typical patient with lobar ICH attributed to CAA without additional hemorrhagic risk factors who has atrial fibrillation and a CHA2DS2-VASc score 2, we may pursue alternatives to anticoagulation. For a typical patient with non-lobar ICH of undetermined source who has atrial fibrillation a CHA2DS2-VASc score 2, we would exclude underlying sources prior to considering resuming anticoagulation. One study using a decision-analysis model to compare warfarin resumption versus discontinuation after ICH found that resumption improves quality-adjusted life (QoL) expectancy in some patients. For patients with lobar ICH, warfarin discontinuation improves QoL expectancy by 1.9 years and is therefore preferred unless the rate of ICH recurrence is estimated to be <1.4 percent per year [58]. By contrast, for patients with deep ICH, resumption of warfarin may be preferred if the rate of recurrent ICH is low (eg, <1.6 percent per year) and the rate of ischemic stroke is high (eg, >7 percent per year). This analysis was limited to patients taking warfarin. Therapeutic options Therapeutic options for patients with ICH and atrial fibrillation include: Resumption of anticoagulation For patients with ICH who have atrial fibrillation, anticoagulation may be resumed when the associated risk of thromboembolism is higher than the future hemorrhagic risk. (See 'Estimating bleeding and thromboembolic risks' above.) For long-term anticoagulation, options include a direct oral anticoagulant (DOAC) or a vitamin K antagonist, such as warfarin. For most patients with atrial fibrillation who develop ICH while on an oral anticoagulant and in whom oral anticoagulation is resumed, we suggest a DOAC over warfarin because of a favorable hemorrhagic risk profile. For select patients, warfarin may be preferred for specific indications, described immediately below. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 14/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Direct oral anticoagulants DOACs are at least as effective as warfarin for prevention of thromboembolic events in patients with atrial fibrillation [59]. Because they are associated with a lower risk for ICH, they are an appealing option to help reduce the risk of recurrent ICH [60]. In a study of patients with atrial fibrillation or venous thromboembolism resuming anticoagulation, there was a trend toward fewer ICH recurrences in those taking a DOAC [61]. The incidence rate of recurrent ICH was 2.5 per 100 patient-years with warfarin and 1.3 per 100-patient years with a DOAC (risk ratio 1.9, 95% CI 0.6-7.4) [61]. There were too few recurrent events to assess a difference among specific DOACs. Warfarin Much of the experience with resumption of anticoagulation has been from patients taking warfarin [48,50,51]. Warfarin may be chosen based on cost or availability and is indicated for patients with specific indications, including some patients with atrial fibrillation associated with valvular heart disease and those with mechanical prosthetic heart valves. (See 'Mechanical prosthetic heart valves' above and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease'.) Warfarin may be preferred by patients previously taking the medication whose international normalized ratio (INR) is well-controlled. Additionally, warfarin may be preferred for other patients, including some with bodyweight <60 kg or age 80 years, and those unable to take a DOAC (eg, drug interaction, creatinine clearance <30 mL/minute). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Settings in which a heparin or vitamin K antagonist may be preferable'.) Left atrial appendage occlusion Percutaneous left atrial appendage occlusion (LAAO) may be a viable treatment option for patients with ICH and nonvalvular atrial fibrillation who are at high risk for recurrent ICH and thromboembolic events and in whom resumption of oral anticoagulation is not resumed or contraindicated [33]. In a meta- analysis of trials comparing LAAO closure with oral anticoagulation, the rates of both systemic embolism and major bleeding were similar after a mean follow-up of 39 months [62]. The risk of ICH was lower for patients assigned to LAAO (0.5 versus 2.4 percent; relative risk 0.22, 95% CI 0.02-0.58). In the Amplatzer Cardiac Plug multicenter registry, the subsequent annual major bleeding rate was 0.7 percent, corresponding to a relative risk reduction of 89 percent in patients with prior intracranial hemorrhage compared with those with other indications for LAAO [63,64]. LAAO is discussed in further detail separately. (See "Risks and prevention of bleeding with oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 15/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Antiplatelet therapy For patients with ICH and atrial fibrillation in whom anticoagulation is not resumed, antiplatelet therapy is used as an alternative. Because the benefit of aspirin to prevent thromboembolism in this population has not been established, we reserve antiplatelet therapy for patients with other indications. (See 'Antiplatelet therapy' above.) Other patients Anticoagulation may be used for patients with selected indications associated with a very high risk of thromboembolism and inadequate alternative choices. In these circumstances, risks and benefits should be discussed with patients and decisions should be individualized based on risk analysis and patient values. Such indications may include: Cancer-related thrombophilia with high risk of or prior venous thromboembolism (see "Risk and prevention of venous thromboembolism in adults with cancer") Hypercoagulable (acquired or inherited) conditions (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors") Venous thromboembolism with high risk of recurrence (see "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation") Other forms of cardiovascular disease (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy in patients with heart failure") Other temporary high-risk indications for anticoagulation (see "Atrial fibrillation: Left atrial appendage occlusion", section on 'Postprocedure management' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" and "Left ventricular thrombus after acute myocardial infarction") Alternatives to intravenous thrombolytic therapy We do not routinely offer intravenous thrombolytic therapy to patients with ICH who develop conditions such as ischemic stroke, myocardial infarction, or pulmonary embolism, consistent with AHA guideline recommendations [65]. Endovascular and mechanical thrombectomy procedures may be an option for such patients. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) MANAGEMENT OF STATINS https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 16/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate The decision to resume statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) for patients with ICH requires balancing the benefits of therapy with the potential hemorrhagic risks. We suggest resuming statins in most patients with ICH who have a strong indication for therapy. This includes patients with diabetes and coronary artery disease and those with recent myocardial infarction or baseline severe atherosclerotic arterial disease. We discontinue statins for patients with ICH with less compelling indications such as isolated dyslipidemia and for those with multiple (recurrent) lobar ICHs who are at high risk for ICH recurrence [66]. For patients with ICH who resume statins, we avoid high doses and prefer hydrophilic statins (eg, pravastatin or rosuvastatin). For patients who discontinue statins after ICH, we use the indication for therapy to help select an alternative medication. (See "Statins: Actions, side effects, and administration" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".) Statins appear to increase the propensity for ICH by inhibiting platelets, decreasing thrombus formation, and enhancing fibrinolysis [67,68]. In addition, hyperlipidemia appears to be protective against ICH. In a case-control study including 3492 patients with ICH, a reduced risk of ICH was associated with each increase in serum cholesterol by 5 mg/dL (odds ratio 0.87, 95% CI 0.86-0.88) [69]. Additionally, lower levels of low-density lipoprotein cholesterol are also associated with increased risk for ICH [70,71]. The contribution of statin drugs to the risk of initial ICH is supported by trials and several observational studies [69,72,73]. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, patients with prior transient ischemic attack or ischemic stroke assigned to atorvastatin had fewer major cardiovascular events than those assigned to placebo (3.5 percent absolute risk reduction) [74]. However, the incidence rate of ICH was significantly higher in patients who received atorvastatin 80 mg daily (2.3 versus 1.4 percent; risk ratio [RR] 1.68, 95% CI 1.09-2.5). However, data on the risk of recurrent ICH are less certain [75,76]. Outcomes associated with statin use were evaluated in a 2018 systematic review of 15 studies that included more than 50,000 patients with prior ICH [25]. Among studies reporting ICH recurrence, the risk associated with statin use was similar to controls (RR 1.04, 95% CI 0.86-1.25). However, statin use was associated with improved functional outcome and reduced mortality in patients with prior ICH. These findings may reflect variability of individual risk related to several factors including statin dose or formulation, prescription bias, the burden of atherosclerotic disease, and the cause of the prior ICH. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 17/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Effect of statin dose Statin dose may modify the risk of hemorrhagic complications such as ICH [77]. A meta-analysis of seven randomized controlled trials found that higher doses of statins were associated with increased risk for ICH compared with placebo (RR 1.53, 95% CI 1.16-2.01) [78]. However, a large 10-year nationwide cohort study from Taiwan found no association between statin dose and risk of recurrent ICH [79]. Effect of statin formulation Statins with lipophilic solubility (atorvastatin, lovastatin, simvastatin, cerivastatin, and fluvastatin) have a greater ability to penetrate across blood- brain barrier and have been associated with increased odds of recurrent ICH compared with hydrophilic statins [79]. Cause of incident ICH Some cohorts suggest the hemorrhagic risk with statin use is associated with patients with lobar ICH [80-82]. The protective effect of hyperlipidemia also appears to be higher for patients with lobar versus nonlobar ICH [69]. LIFESTYLE MODIFICATIONS We advise lifestyle modifications based on their association as risk factors of stroke, including ICH [33]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) These include: Regular physical activity (see "The benefits and risks of aerobic exercise") Maintenance of healthy body weight (see "Obesity in adults: Overview of management") Healthy diet (see "Healthy diet in adults") Cessation of smoking and excessive alcohol use (see "Cardiovascular risk of smoking and benefits of smoking cessation") Avoidance of sympathomimetic medications (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors') LONG-TERM PROGNOSIS Prognosis after ICH involves both initial prognosis and long-term prognosis. The clinical and imaging determinants of initial prognosis occur within the acute hospitalization and recovery periods, typically comprising the first 180 days after ICH. Long-term prognosis focuses on sequelae of ICH, which persist beyond 180 days. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 18/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute prognosis in ICH is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) Functional recovery The rate of recovery after ICH may be highest in the first few weeks to months. In one study, recovery was greatest within the first 30 days after ICH [83]. However, recovery after ICH is often delayed and can be slow; many patients report functional improvements for 6 to 12 months [84,85]. In a post-hoc analysis of individual patient data from two clinical trials of patients with intracerebral or intraventricular hemorrhage, poor functional outcome at 30 days was reported in 715 of 999 patients (72 percent) [86]. By one year, 308 of these patients (46 percent) had achieved good functional outcome, including 30 percent who were functionally independent. Older age, larger hemorrhage volumes, and baseline conditions such as diabetes mellitus and severe leukoaraiosis on imaging were associated with poor one- year outcomes. In addition, common complications of acute ICH were also predictors of poor outcome at one year including sepsis, new ischemic stroke, prolonged mechanical ventilation, hydrocephalus, and the need for gastrostomy feeding tube. Aggressive acute treatment to prevent these acute complications may help avoid premature withdrawal of support and improve long-term outcomes. Early rehabilitation and sustained support are recommended to maximize functional recovery [83,87,88]. Educating patients and caregivers regarding secondary prevention strategies and addressing lifestyle changes, depression, and caregiver burden is an important part of post-ICH rehabilitation program. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Initial aggressive care'.) The main clinical determinants associated with reduced functional recovery after ICH include increasing age, baseline comorbidities, and severity of ICH as assessed by Glasgow Coma Scale score at presentation. Key imaging determinants include ICH volume, the presence of intraventricular hemorrhage, and specific ICH locations (including brainstem, posterior limb of internal capsule, or thalamus) [89,90]. Functional outcome may be assessed using varying performance thresholds or clinical scoring tools. The modified Rankin Scale (mRS) is frequently used ( table 7). In several trials, patients with ICH achieving a score of 0 to 3 have been described as having a good functional outcome; poor outcome included those scoring 4 to 6. In a retrospective study of 1499 patients, 51 percent of patients with a first ICH had good functional recovery after 90 days, compared with 31 percent of patients after recurrent ICH [91]. A decline in long-term functional status has been observed among patients after ICH. In a single-center observational study of 560 patients, 23 percent of those with a good functional outcome at six months had declined over a median nine-year follow-up [92]. Advanced age, https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 19/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate higher initial ICH volume, lower six-month functional status, and new diagnoses of dementia or stroke during follow-up were predictors of functional decline. Cognitive impairment Cognitive impairment is frequent among patients after ICH [93,94]. A systematic review reported that the prevalence of cognitive impairment ranged between 14 and 88 percent after ICH [95]. Predictive factors were previous stroke, ICH volume and location, and markers of cerebral amyloid angiopathy. Cognitive deficits after ICH were common across multiple domains. The most frequently impaired domains were naming, processing speed, executive functioning, memory, visuospatial abilities, and attention. Long-term mortality In population-based cohorts of patients hospitalized after ICH the 10- year survival rate ranged from 18 to 25 percent [5,96]. Life expectancy among patients after ICH was decreased compared with age- and sex-matched controls in the general population [97-99]. In a cohort of 219 patients with ICH, the major cause of death within five years was cardiovascular disease, largely due to recurrent ICH and its sequelae (10 percent) irrespective of ICH location [5]. The risk of death was similar in patients with lobar versus nonlobar ICH and higher in patients with anticoagulation-associated ICH. A retrospective multicenter 10-year study of 1499 patients with ICH reported recurrent ICH in 9.5 percent of patients and found that 30-day mortality was similar (approximately 14 percent) after first and recurrent ICH [91]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 20/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topic (see "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Risk factors for recurrent ICH Several risk factors have been implicated in the risk of recurrent intracerebral hemorrhage (ICH). These include the location and etiology of the initial ICH, hypertension, older age, several medications ( table 1), race/ethnicity, chronic kidney disease, prior stroke, and specific genetic features. (See 'Risk of recurrence' above.) Follow-up imaging to evaluate for underlying causes We obtain follow-up imaging for patients with clinical or imaging features of the ICH suggestive of an underlying cause ( algorithm 1 and table 2). For most patients, we prefer brain magnetic resonance imaging (MRI) with gadolinium to evaluate for an underlying cause. (See 'Follow-up neuroimaging' above.) Blood pressure management Blood pressure control is an important feature of secondary prevention for all patients with ICH. We suggest a long-term target <130/80 mmHg to lower the risk of ICH recurrence (Grade 2B). (See 'Blood pressure management' above.) Management of antiplatelet therapy We suggest resuming antiplatelet therapy for most patients with ICH who have a specific indication for such therapy (Grade 2C). For patients with ICH in whom antiplatelet therapy is being resumed, we typically start aspirin within a few days after the ICH has stabilized. (See 'Antiplatelet therapy' above.) Management of anticoagulation We balance the risks of recurrent ICH and thromboembolism to help make decisions about resuming anticoagulation for each patient ( algorithm 2). (See 'Anticoagulation' above.) Early resumption of anticoagulation may be indicated for select patients with a compelling indication (eg, mechanical prosthetic heart valve). For most other patients who resume anticoagulation, we generally suggest waiting for at least four weeks after onset of the ICH to restart the anticoagulant (Grade 2C). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 21/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate For patients with atrial fibrillation, prediction models such as the HAS-BLED score may be used to help assess bleeding risk ( table 6) and CHADS2 or CHA2DS2-VASc scores used to help assess thromboembolic risks ( table 5). For many patients with atrial fibrillation, the risk-benefit analysis favors resuming anticoagulation after ICH. For most patients with atrial fibrillation who develop ICH while on warfarin and in whom oral anticoagulation is resumed, we suggest a direct oral anticoagulant (DOAC) over warfarin (Grade 2B). DOACs generally have a lower risk of bleeding, including ICH, than warfarin. Warfarin may be selected for patients with valvular atrial fibrillation, a mechanical heart valve, or an inability to take a DOAC. Management of statins We suggest resuming statins for most patients with lobar and nonlobar ICH who have atherosclerotic disease (Grade 2C). We discontinue statins for most patients with multiple (recurrent) lobar ICHs. (See 'Management of statins' above.) Long-term prognosis The rate of recovery after ICH may be highest in the first few months. However, the greatest extent of recovery may not be evident until 6 to 12 months after ICH. (See 'Functional recovery' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arima H, Tzourio C, Butcher K, et al. Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial. Stroke 2006; 37:1497. 2. Poon MT, Fonville AF, Al-Shahi Salman R. 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Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167. 21. Huhtakangas J, L pp nen P, Tetri S, et al. Predictors for recurrent primary intracerebral hemorrhage: a retrospective population-based study. Stroke 2013; 44:585. 22. Kubiszewski P, Sugita L, Kourkoulis C, et al. Association of Selective Serotonin Reuptake Inhibitor Use After Intracerebral Hemorrhage With Hemorrhage Recurrence and Depression Severity. JAMA Neurol 2020. 23. Leasure AC, King ZA, Torres-Lopez V, et al. Racial/ethnic disparities in the risk of intracerebral hemorrhage recurrence. Neurology 2020; 94:e314. 24. Ghoshal S, Freedman BI. Mechanisms of Stroke in Patients with Chronic Kidney Disease. Am J Nephrol 2019; 50:229. 25. Ziff OJ, Banerjee G, Ambler G, Werring DJ. Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2019; 90:75. 26. Chalouhi N, Mouchtouris N, Al Saiegh F, et al. Analysis of the utility of early MRI/MRA in 400 patients with spontaneous intracerebral hemorrhage. J Neurosurg 2019; 132:1865. 27. Wijman CA, Venkatasubramanian C, Bruins S, et al. Utility of early MRI in the diagnosis and management of acute spontaneous intracerebral hemorrhage. Cerebrovasc Dis 2010; 30:456. 28. Wijman CA, Snider RW, Venkatasubramanian C, et al. Diagnostic accuracy of MRI in spontaneous intracerebral hemorrhage (DASH) Final Results. Stroke 2012; 43:A105. 29. van Asch CJ, Velthuis BK, Rinkel GJ, et al. Diagnostic yield and accuracy of CT angiography, MR angiography, and digital subtraction angiography for detection of macrovascular causes of intracerebral haemorrhage: prospective, multicentre cohort study. BMJ 2015; 351:h5762. 30. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033. 31. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006; 24:1201. 32. Zahuranec DB, Wing JJ, Edwards DF, et al. Poor long-term blood pressure control after intracerebral hemorrhage. Stroke 2012; 43:2580. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 24/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 33. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 34. SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382:507. 35. Kitagawa K, Yamamoto Y, Arima H, et al. Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis. JAMA Neurol 2019; 76:1309. 36. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007; :CD002003. 37. Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol 2007; 100:1254. 38. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med 2016; 375:1033. 39. Arima H, Tzourio C, Anderson C, et al. Effects of perindopril-based lowering of blood pressure on intracerebral hemorrhage related to amyloid angiopathy: the PROGRESS trial. Stroke 2010; 41:394. 40. Chong BH, Chan KH, Pong V, et al. Use of aspirin in Chinese after recovery from primary intracranial haemorrhage. Thromb Haemost 2012; 107:241. 41. Flynn RW, MacDonald TM, Murray GD, et al. Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage. Stroke 2010; 41:2606. 42. Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology 2006; 66:206. 43. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010; 75:693. 44. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019; 393:2613. 45. Al-Shahi Salman R, Dennis MS, Sandercock PAG, et al. Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial. JAMA Neurol 2021; 78:1179. 46. Gaist D, Hald SM, Garc a Rodr guez LA, et al. Association of Prior Intracerebral Hemorrhage With Major Adverse Cardiovascular Events. JAMA Netw Open 2022; 5:e2234215. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 25/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 47. Poli D, Antonucci E, Dentali F, et al. Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology 2014; 82:1020. 48. Yung D, Kapral MK, Asllani E, et al. Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study. Can J Cardiol 2012; 28:33. 49. Vestergaard AS, Skj th F, Lip GY, Larsen TB. Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study. Stroke 2016; 47:979. 50. Claassen DO, Kazemi N, Zubkov AY, et al. Restarting anticoagulation therapy after warfarin- associated intracerebral hemorrhage. Arch Neurol 2008; 65:1313. 51. Majeed A, Kim YK, Roberts RS, et al. Optimal timing of resumption of warfarin after intracranial hemorrhage. Stroke 2010; 41:2860. 52. Cannegieter SC, Rosendaal FR, Bri t E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89:635. 53. Murthy SB, Gupta A, Merkler AE, et al. Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke 2017; 48:1594. 54. Biffi A, Kuramatsu JB, Leasure A, et al. Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol 2017; 82:755. 55. Ivany E, Ritchie LA, Lip GYH, et al. Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage: Systematic Review and Meta- Analysis. Stroke 2022; 53:3035. 56. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. 57. Donz J, Rodondi N, Waeber G, et al. Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med 2012; 125:1095. 58. Eckman MH, Rosand J, Knudsen KA, et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 2003; 34:1710. 59. Farmakis D, Davlouros P, Giamouzis G, et al. Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing. Cardiology 2018; 140:126.

23/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 20. van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010; 9:167. 21. Huhtakangas J, L pp nen P, Tetri S, et al. Predictors for recurrent primary intracerebral hemorrhage: a retrospective population-based study. Stroke 2013; 44:585. 22. Kubiszewski P, Sugita L, Kourkoulis C, et al. Association of Selective Serotonin Reuptake Inhibitor Use After Intracerebral Hemorrhage With Hemorrhage Recurrence and Depression Severity. JAMA Neurol 2020. 23. Leasure AC, King ZA, Torres-Lopez V, et al. Racial/ethnic disparities in the risk of intracerebral hemorrhage recurrence. Neurology 2020; 94:e314. 24. Ghoshal S, Freedman BI. Mechanisms of Stroke in Patients with Chronic Kidney Disease. Am J Nephrol 2019; 50:229. 25. Ziff OJ, Banerjee G, Ambler G, Werring DJ. Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2019; 90:75. 26. Chalouhi N, Mouchtouris N, Al Saiegh F, et al. Analysis of the utility of early MRI/MRA in 400 patients with spontaneous intracerebral hemorrhage. J Neurosurg 2019; 132:1865. 27. Wijman CA, Venkatasubramanian C, Bruins S, et al. Utility of early MRI in the diagnosis and management of acute spontaneous intracerebral hemorrhage. Cerebrovasc Dis 2010; 30:456. 28. Wijman CA, Snider RW, Venkatasubramanian C, et al. Diagnostic accuracy of MRI in spontaneous intracerebral hemorrhage (DASH) Final Results. Stroke 2012; 43:A105. 29. van Asch CJ, Velthuis BK, Rinkel GJ, et al. Diagnostic yield and accuracy of CT angiography, MR angiography, and digital subtraction angiography for detection of macrovascular causes of intracerebral haemorrhage: prospective, multicentre cohort study. BMJ 2015; 351:h5762. 30. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033. 31. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens 2006; 24:1201. 32. Zahuranec DB, Wing JJ, Edwards DF, et al. Poor long-term blood pressure control after intracerebral hemorrhage. Stroke 2012; 43:2580. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 24/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 33. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 34. SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382:507. 35. Kitagawa K, Yamamoto Y, Arima H, et al. Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis. JAMA Neurol 2019; 76:1309. 36. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007; :CD002003. 37. Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol 2007; 100:1254. 38. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med 2016; 375:1033. 39. Arima H, Tzourio C, Anderson C, et al. Effects of perindopril-based lowering of blood pressure on intracerebral hemorrhage related to amyloid angiopathy: the PROGRESS trial. Stroke 2010; 41:394. 40. Chong BH, Chan KH, Pong V, et al. Use of aspirin in Chinese after recovery from primary intracranial haemorrhage. Thromb Haemost 2012; 107:241. 41. Flynn RW, MacDonald TM, Murray GD, et al. Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage. Stroke 2010; 41:2606. 42. Viswanathan A, Rakich SM, Engel C, et al. Antiplatelet use after intracerebral hemorrhage. Neurology 2006; 66:206. 43. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology 2010; 75:693. 44. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019; 393:2613. 45. Al-Shahi Salman R, Dennis MS, Sandercock PAG, et al. Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage: Extended Follow-up of the RESTART Randomized Clinical Trial. JAMA Neurol 2021; 78:1179. 46. Gaist D, Hald SM, Garc a Rodr guez LA, et al. Association of Prior Intracerebral Hemorrhage With Major Adverse Cardiovascular Events. JAMA Netw Open 2022; 5:e2234215. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 25/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 47. Poli D, Antonucci E, Dentali F, et al. Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology 2014; 82:1020. 48. Yung D, Kapral MK, Asllani E, et al. Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study. Can J Cardiol 2012; 28:33. 49. Vestergaard AS, Skj th F, Lip GY, Larsen TB. Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study. Stroke 2016; 47:979. 50. Claassen DO, Kazemi N, Zubkov AY, et al. Restarting anticoagulation therapy after warfarin- associated intracerebral hemorrhage. Arch Neurol 2008; 65:1313. 51. Majeed A, Kim YK, Roberts RS, et al. Optimal timing of resumption of warfarin after intracranial hemorrhage. Stroke 2010; 41:2860. 52. Cannegieter SC, Rosendaal FR, Bri t E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89:635. 53. Murthy SB, Gupta A, Merkler AE, et al. Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke 2017; 48:1594. 54. Biffi A, Kuramatsu JB, Leasure A, et al. Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol 2017; 82:755. 55. Ivany E, Ritchie LA, Lip GYH, et al. Effectiveness and Safety of Antithrombotic Medication in Patients With Atrial Fibrillation and Intracranial Hemorrhage: Systematic Review and Meta- Analysis. Stroke 2022; 53:3035. 56. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. 57. Donz J, Rodondi N, Waeber G, et al. Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study. Am J Med 2012; 125:1095. 58. Eckman MH, Rosand J, Knudsen KA, et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 2003; 34:1710. 59. Farmakis D, Davlouros P, Giamouzis G, et al. Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing. Cardiology 2018; 140:126. 60. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 26/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 61. Poli D, Antonucci E, Vignini E, et al. Anticoagulation resumption after intracranial hemorrhage in patients treated with VKA and DOACs. Eur J Intern Med 2020; 80:73. 62. Turagam MK, Osmancik P, Neuzil P, et al. Left Atrial Appendage Closure Versus Oral Anticoagulants in Atrial Fibrillation: A Meta-Analysis of Randomized Trials. J Am Coll Cardiol 2020; 76:2795. 63. Tzikas A, Freixa X, Llull L, et al. Patients with intracranial bleeding and atrial fibrillation treated with left atrial appendage occlusion: Results from the Amplatzer Cardiac Plug registry. Int J Cardiol 2017; 236:232. 64. Tzikas A. Left Atrial Appendage Occlusion with Amplatzer Cardiac Plug and Amplatzer Amulet: a Clinical Trials Update. J Atr Fibrillation 2017; 10:1651. 65. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 66. Shoamanesh A, Selim M. Use of Lipid-Lowering Drugs After Intracerebral Hemorrhage. Stroke 2022; 53:2161. 67. Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000; 31:2442. 68. Asahi M, Huang Z, Thomas S, et al. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab 2005; 25:722. 69. Pezzini A, Grassi M, Iacoviello L, et al. Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy). J Neurol Neurosurg Psychiatry 2016; 87:924. 70. Rist PM, Buring JE, Ridker PM, et al. Lipid levels and the risk of hemorrhagic stroke among women. Neurology 2019; 92:e2286. 71. Ma C, Gurol ME, Huang Z, et al. Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study. Neurology 2019; 93:e445. 72. Woo D, Deka R, Falcone GJ, et al. Apolipoprotein E, statins, and risk of intracerebral hemorrhage. Stroke 2013; 44:3013. 73. Amarenco P, Bogousslavsky J, Callahan A, et al. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med 2006; 3555:549. 74. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 27/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 75. Saliba W, Rennert HS, Barnett-Griness O, et al. Association of statin use with spontaneous intracerebral hemorrhage: A cohort study. Neurology 2018; 91:e400. 76. Ribe AR, Vestergaard CH, Vestergaard M, et al. Statins and Risk of Intracerebral Hemorrhage in Individuals With a History of Stroke. Stroke 2020; 51:1111. 77. Sanz-Cuesta BE, Saver JL. Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors. Stroke 2021; 52:3142. 78. Pandit AK, Kumar P, Kumar A, et al. High-dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis. Acta Neurol Scand 2016; 134:22. 79. Tai SY, Lin FC, Lee CY, et al. Statin use after intracerebral hemorrhage: a 10-year nationwide cohort study. Brain Behav 2016; 6:e00487. 80. Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use following intracerebral hemorrhage: a decision analysis. Arch Neurol 2011; 68:573. 81. Haussen DC, Henninger N, Kumar S, Selim M. Statin use and microbleeds in patients with spontaneous intracerebral hemorrhage. Stroke 2012; 43:2677. 82. Romero JR, Preis SR, Beiser A, et al. Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 2014; 45:1492. 83. Bai Y, Hu Y, Wu Y, et al. A prospective, randomized, single-blinded trial on the effect of early rehabilitation on daily activities and motor function of patients with hemorrhagic stroke. J Clin Neurosci 2012; 19:1376. 84. Selim M, Foster LD, Moy CS, et al. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2019; 18:428. 85. Sreekrishnan A, Leasure AC, Shi FD, et al. Functional Improvement Among Intracerebral Hemorrhage (ICH) Survivors up to 12 Months Post-injury. Neurocrit Care 2017; 27:326. 86. Shah VA, Thompson RE, Yenokyan G, et al. One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability. JAMA Neurol 2022; 79:856. 87. Cumming TB, Thrift AG, Collier JM, et al. Very early mobilization after stroke fast-tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke 2011; 42:153. 88. Foster L, Robinson L, Yeatts SD, et al. Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial. Stroke 2022; 53:2204. 89. Saulle MF, Schambra HM. Recovery and Rehabilitation after Intracerebral Hemorrhage. Semin Neurol 2016; 36:306. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 28/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate 90. Delcourt C, Sato S, Zhang S, et al. Intracerebral hemorrhage location and outcome among INTERACT2 participants. Neurology 2017; 88:1408. 91. Kim KH, Kim HD, Kim YZ. Comparisons of 30-day mortalities and 90-day functional recoveries after first and recurrent primary intracerebral hemorrhage attacks: a multiple- institute retrospective study. World Neurosurg 2013; 79:489. 92. Pasi M, Casolla B, Kyheng M, et al. Long-term functional decline of spontaneous intracerebral haemorrhage survivors. J Neurol Neurosurg Psychiatry 2021; 92:249. 93. Planton M, Saint-Aubert L, Raposo N, et al. High prevalence of cognitive impairment after intracerebral hemorrhage. PLoS One 2017; 12:e0178886. 94. Banerjee G, Summers M, Chan E, et al. Domain-specific characterisation of early cognitive impairment following spontaneous intracerebral haemorrhage. J Neurol Sci 2018; 391:25. 95. Donnellan C, Werring D. Cognitive impairment before and after intracerebral haemorrhage: a systematic review. Neurol Sci 2020; 41:509. 96. Flaherty ML, Haverbusch M, Sekar P, et al. Long-term mortality after intracerebral hemorrhage. Neurology 2006; 66:1182. 97. Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry 2005; 76:1534. 98. Gonz lez-P rez A, Gaist D, Wallander MA, et al. Mortality after hemorrhagic stroke: data from general practice (The Health Improvement Network). Neurology 2013; 81:559. 99. Hansen BM, Nilsson OG, Anderson H, et al. Long term (13 years) prognosis after primary intracerebral haemorrhage: a prospective population based study of long term mortality, prognostic factors and causes of death. J Neurol Neurosurg Psychiatry 2013; 84:1150. Topic 129071 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 29/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate GRAPHICS Medications and other substances that may increase the risk of bleeding or bruising Drug class or substance Mechanism Anticoagulants Interfere with clot formation (secondary hemostasis) Antiplatelet agents, including NSAIDs Interfere with platelet function (primary hemostasis) Glucocorticoids Interfere with vascular integrity Antibiotics Cause vitamin K deficiency, especially with longer use Some interfere with platelet function SSRIs Interfere with platelet function (primary hemostasis) Alcohol Complications of liver disease may affect clot formation and may cause thrombocytopenia May cause thrombocytopenia due to direct marrow toxicity Vitamin E Interferes with vitamin K metabolism in some individuals Garlic Interferes with platelet function in some individuals Gingko biloba Unknown This is a partial list that does not include drugs used for cancer therapy or drugs that alter the metabolism of anticoagulants. The magnitude of increased bleeding risk depends on many factors including the patient's other bleeding risk factors and the specific drug, dose, and duration of use. Fish oil is often cited, but bleeding risk does not appear to be increased. Refer to drug information monographs and UpToDate topics for further information. NSAIDs: nonsteroidal antiinflammatory drugs; SSRIs: selective serotonin reuptake inhibitors. Graphic 120264 Version 2.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 30/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Evaluating the underlying etiology of nontraumatic intracerebral hemorrhage This is an algorithm to guide etiologic testing; additional testing may be indicated for patients who develop new or worsening symptoms during recovery period. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. ICH: intracerebral hemorrhage. Refer to the separate UpToDate table on clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes. Lobar or cortical ICH, evidence of multifocal superficial siderosis, age 55 years, and other sources for hemorrhagic features excluded. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 31/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Refer to the UpToDate topic on cerebral amyloid angiopathy for additional details. Graphic 132295 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 32/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Distinctive distribution of cerebral microbleeds (A-C) CMBs on T2*-weighted gradient echo MRI sequences suggestive of deep penetrating (hypertensive) vasculopathy. CMBs predominate in bilateral thalami (A), brainstem (B), and dentate nucleus of cerebellum (C). (D-F) CMBs on T2*-weighted gradient echo MRI sequences suggestive of cerebral amyloid angiopathy. CMBs predominate in cerebral hemispheres (D, E). Associated findings include lobar hemorrhage (D; arrow and thick arrow) and superficial siderosis (F; circles). CMB: cerebral microbleeds; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 33/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Graphic 132282 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 34/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical and neuroimaging features of intracerebral hemorrhage associated with underlying causes Alternative Specifying ICH Characteristic Other associated features underlying feature underlying cause causes Basal ganglia or brainstem Deep perforating vasculopathy (HTN) CMBs in basal ganglia, thalamus, pons, cerebellar location nuclei Subcortical white matter lesions on MRI Deep perforating territory ischemic infarcts Clinical history of HTN or diabetes mellitus Lobar location Cerebral amyloid angiopathy Deep penetrating vasculopathy (HTN) Cortico-subcortical CMBs Convexal superficial siderosis Clinical history of cognitive impairment Intraventricular hemorrhage Arteriovenous malformation Deep penetrating vasculopathy (HTN) Flow voids within or adjacent to ICH Calcification within or adjacent to ICH Cavernous malformation Small ICH with adjacent calcification Cavernous malformation Deep penetrating vasculopathy (HTN) T2-weighted image hyperintensity at center on MRI Peripheral rim of T2*- weighted gradient echo image hypointensity on MRI Subarachnoid Ruptured cerebral Perimesencephalic SAH predominates over basal surfaces hemorrhage Basal cisterns aneurysm hemorrhage Clinical history of Non-aneurysmal SAH thunderclap headache Subarachnoid hemorrhage Reversible cerebral vasoconstriction Trauma Hemispheric or cortical ICH Clinical history of recurrent thunderclap headache Cerebral amyloid Convexity syndrome angiopathy Cerebral venous thrombosis https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 35/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Arteriovenous malformation Simultaneous Infective endocarditis Cerebral amyloid CMBs acute infarcts angiopathy Mycotic aneurysms (typically distal arterial locations) Deep penetrating vasculopathy (HTN) Systemic/cutaneous evidence of embolism New heart murmur Cerebral vasculitis Multifocal segmental narrowing on vascular imaging Clinical history of new persistent headaches Progressive cognitive or other neurologic impairment Prominent edema Cerebral sinus thrombosis Subacute ICH of other etiologies Edema/hemorrhage extends to cortical surface Venous flow void (eg, delta and empty-delta signs) Clinical history of seizure or progressive headache Tumor (primary/metastatic) Multifocal lesions Contrast enhancement Clinical history of new persistent headaches Clinical exam findings may be milder than imaging abnormalities Hemorrhagic transformation of (Cytotoxic) Edema appears in distribution of arterial territory infarct Arterial stenosis or occlusion proximal to territory of hemorrhage Clinical history of ischemic risk factors Flow voids Moyamoya Arteriovenous malformation Basal ganglia or hemispheric location Bilateral (but may be asymmetric) narrowing of distal internal carotid or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 36/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate proximal anterior/middle cerebral arteries Clinical history of episodes of transient weakness with vigorous laughing/crying (Prominent cause of ICH and infarcts in children) ICH: intracerebral hemorrhage; HTN: hypertension; CMB: cerebral microbleeds; MRI: magnetic resonance imaging; SAH: subarachnoid hemorrhage. Graphic 132289 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 37/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Acute and subacute lobar hemorrhage Noncontrast head CT shows acute right parietal ICH (A). T2* susceptibility-weighted sequence on MRI performed one day later shows an acute ICH in the right frontal and parietal hemisphere (B) as well as a subacute hemorrhage in the left occipital lobe (thick arrow) and chronic ICH in right inferior parietal lobule (C; arrow). In addition, multiple microbleeds at cerebral corticomedullary junctions (B, C) are consistent with cerebral amyloid angiopathy. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132283 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 38/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Excessive perihematomal edema in a patient with hemorrhagic lung metastasis Noncontrast head CT showing left frontal ICH surrounded by excessive volume of hypodense vasogenic edema (A, B). MRI performed one day later shows hyperintense vasogenic edema on T2*-weighted gradient echo image (C). Pre- (D) and post-contrast (E) T1-weighted MRI images demonstrate enhancement (arrows) consistent with underlying tumor. CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132284 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 39/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Hemorrhagic transformation of ischemic infarction Noncontrast head CT (A) shows heterogeneous hyperdensity within hypodense region involving right frontal and insular lobes. On subsequent MRI of the brain, FLAIR (B), T2* gradient recall echo (C), and DWI (D) sequences show hypointense ICH (thin arrows) and hyperintensities consistent with acute infarction in the distribution of the right middle cerebral artery (thick arrows). CT: computed tomography; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ICH: intracerebral hemorrhage. Courtesy of Glenn A Tung, MD, FACR. Graphic 132275 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 40/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Enhancing intracranial vessels associated with ICH due to AVM Noncontrast head CT showing right posterior frontal ICH (A, B). T2- weighted MRI images (C, D) and post-contrast T1-weighted MRI image (E) show flow voids and focal enhancement (arrows), both suspicious for AVM nidus. Subsequent digital subtraction angiograms images (F, G) show both pial AVM nidus (thick arrows). https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 41/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate CT: computed tomography; ICH: intracerebral hemorrhage; MRI: magnetic resonance imaging; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132285 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 42/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Multifocal intracerebral hemorrhage from thyroid cancer Noncontrast head CT (A) shows multiple hyperdensities (arrows). T2*-weighted gradient echo MRI images show that some but not all lesions are hypointense hemorrhages (B, C). Pre- (D) and post-contrast (E) T1- weighted MRI images show contrast enhancement consistent with metastases. ICH: intracerebral hemorrhage; CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132287 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 43/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 44/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device)* Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 45/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage*? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6

Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 46/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Considerations for individualizing antihypertensive therapy Indication or Antihypertensive drugs contraindication Compelling indications (major improvement in outcome independent of blood pressure) Heart failure with reduced ejection fraction ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* Postmyocardial infarction ACE inhibitor or ARB, beta blocker, aldosterone antagonist Proteinuric chronic kidney ACE inhibitor or ARB disease Angina pectoris Beta blocker, calcium channel blocker Atrial fibrillation rate control Beta blocker, nondihydropyridine calcium channel blocker Atrial flutter rate control Beta blocker, nondihydropyridine calcium channel blocker Likely to have a favorable effect on symptoms in comorbid conditions Benign prostatic hyperplasia Alpha blocker Essential tremor Beta blocker (noncardioselective) Hyperthyroidism Beta blocker Migraine Beta blocker, calcium channel blocker Osteoporosis Thiazide diuretic Raynaud phenomenon Dihydropyridine calcium channel blocker Contraindications Angioedema Do not use an ACE inhibitor Bronchospastic disease Do not use a non-selective beta blocker Liver disease Do not use methyldopa Pregnancy (or at risk for) Do not use an ACE inhibitor, ARB, or renin inhibitor (eg, aliskiren) Second- or third-degree heart block Do not use a beta blocker, nondihydropyridine calcium channel blocker unless a functioning ventricular pacemaker Drug classes that may have adverse effects on comorbid conditions Depression Generally avoid beta blocker, central alpha-2 agonist Gout Generally avoid loop or thiazide diuretic Hyperkalemia Generally avoid aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor Hyponatremia Generally avoid thiazide diuretic https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 47/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Renovascular disease Generally avoid ACE inhibitor, ARB, or renin inhibitor ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker. A benefit from an aldosterone antagonist has been demonstrated in patients with NYHA class III-IV heart failure or decreased left ventricular ejection fraction after a myocardial infarction. Adapted from: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003; 289:2560. Graphic 63628 Version 15.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 48/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Can anticoagulation be resumed after intracerebral hemorrhage*? ICH: intracerebral hemorrhage. Applicable only for patients with a persistent thromboembolic indication for anticoagulation. Timing of initiating/resuming medication depends on strength of indication and ICH features. Refer to the UpToDate topic on secondary prevention and long-term prognosis of spontaneous intracerebral hemorrhage for additional details. Cerebral vascular malformation, ruptured cerebral aneurysm or intracranial dissection, primary or metastatic tumor, cerebral venous thrombosis, cerebral vasculitis, or other cerebral vasculopathy. Refer to the UpToDate topic on secondary prevention and long-term https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 49/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate prognosis of spontaneous intracerebral hemorrhage for additional details. Examples include recurrent deep venous thrombosis or pulmonary embolus. Known bleeding diathesis, severe thrombocytopenia (<50,000/microL), abnormal liver or kidney function, or uncontrolled hypertension; patient prioritizes prevention of hemorrhagic over thromboembolic complications. Graphic 132293 Version 1.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 50/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 51/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 52/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 53/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 54/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 55/56 7/6/23, 1:00 PM Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis - UpToDate Contributor Disclosures Magdy Selim, MD, PhD Grant/Research/Clinical Trial Support: NIH/NINDS [Intracerebral hemorrhage]. Consultant/Advisory Boards: MedRhythm, Inc [Neurological recovery]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spontaneous-intracerebral-hemorrhage-secondary-prevention-and-long-term-prognosis/print 56/56

7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment and prevention of venous thromboembolism in patients with brain tumors : Eudocia Quant Lee, MD, MPH, Patrick Y Wen, MD : Lawrence LK Leung, MD : April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 27, 2023. INTRODUCTION Treatment and prevention of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors is complicated by two conflicting issues. Patients with brain tumors have a substantial risk for developing VTE due to a hypercoagulable state, neurosurgical procedures, and often leg paresis. However, there is concern that antithrombotic agents can precipitate hemorrhage into the tumor with neurologic worsening. The balance between these issues is discussed here. The overall risk, diagnosis, and treatment of VTE in patients with malignancy, as well as risk and treatment of anticoagulant-associated intracerebral hemorrhage, are reviewed separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and "Risks and prevention of bleeding with oral anticoagulants" and "Reversal of anticoagulation in intracranial hemorrhage".) PRE-ANTICOAGULATION RISK ASSESSMENT General principles The principles of managing acute VTE in patients with brain tumors are the same as in other patients with and without cancer. Anticoagulation is the cornerstone of treatment, and treatment decisions balance the risk of bleeding complications due to anticoagulation with the risks of untreated and recurrent VTE. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 1/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate The risks of untreated VTE are substantial. Mortality associated with untreated pulmonary embolism is approximately 30 percent, usually due to recurrent embolism. Untreated, symptomatic deep vein thrombosis (DVT) carries a 50 percent risk of pulmonary embolism. (See "Overview of acute pulmonary embolism in adults", section on 'Prognosis' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Patients at low risk of bleeding'.) Patients with cancer have higher than usual rates of recurrent VTE as well as a higher risk of bleeding with anticoagulant therapy compared with the general population. Therapy can be further complicated by comorbidities, procedures, and medication interactions ( table 1). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) For patients with brain tumors, an individual assessment of bleeding risk with anticoagulant therapy takes into account the following: General risk factors for bleeding at any site ( table 2). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Assessing bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) Risk factors for intracranial bleeding specifically, which may be influenced by the type of brain tumor, history of prior intracranial hemorrhage, recent craniotomy, and certain therapies. Each of these factors is discussed individually below. Evidence-based guidelines on the treatment of acute VTE in cancer patients provide variable amounts of detail and specificity regarding brain tumors [1-4]. Our approach is generally consistent with these guidelines except as noted in the topic. Our recommendations for anticoagulation assume that treatment is in accordance with patient preferences with regard to goals of care and life expectancy. Type of brain tumor Brain tumors have varying propensities to hemorrhage spontaneously. In general, malignant tumors are more likely to bleed than benign tumors, and certain cancer types are associated with higher risk than others. Primary brain tumors The rate of symptomatic bleeding into high-grade gliomas (eg, glioblastoma) is estimated at approximately 1 to 12 percent in the absence of antithrombotic therapy [5-9]. In observational studies, the risk of hemorrhage is several percentage points higher in patients receiving anticoagulation. (See 'Safety' below.) https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 2/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Spontaneous bleeding into benign or low-grade primary brain tumors occurs less commonly, although studies are lacking to provide precise estimates of the frequency of symptomatic intracranial hemorrhage. Among benign or low-grade tumors, pituitary adenomas may be especially prone to spontaneous intratumoral hemorrhage [7]. Brain metastases Brain metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma have particularly high propensities for spontaneous hemorrhage [10], while brain metastases from certain other primary tumors (eg, breast) generally do not bleed spontaneously. In one study, the risk of measurable intracranial hemorrhage over a one-year interval was fourfold higher in patients with brain metastases from renal cell carcinoma or melanoma compared with lung cancer [11]. The cumulative incidence of significant hemorrhage (defined as size >10 mL, symptomatic, or requiring surgical intervention) in the absence of anticoagulation was 37 percent in patients with melanoma or renal cell cancer and 19 percent in patients with non-small cell lung cancer. Prior intracranial hemorrhage In the general adult population, patients with a history of spontaneous intracranial hemorrhage are at increased risk for recurrent hemorrhage. The annual risk is estimated at 1 to 7 percent, and recurrence is most common within the first year following hemorrhage [12]. The most important risk factors for recurrent intracranial hemorrhage are uncontrolled hypertension, lobar location of the initial hemorrhage (as opposed to deep), and older age. In patients who require anticoagulation, guidelines suggest delaying anticoagulants for at least four weeks after onset of hemorrhage [13]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Anticoagulation'.) Patients with a history of tumor-associated intracranial hemorrhage are likely to be at increased risk of recurrent hemorrhage as well, although this has not been well studied, and the population is more heterogeneous. In the absence of better data, it is reasonable to consider recurrence risk estimates from patients with spontaneous intracranial hemorrhage when making risk/benefit decisions in patients with brain tumors. Estimates of risk may be further individualized based on the status of the residual tumor, if present, and the clinical circumstances at the time of the index hemorrhage, including the presence or absence of additional risk factors for bleeding (eg, thrombocytopenia, antithrombotic therapy). Microhemorrhage within tumor Evidence of microhemorrhage within tumors on susceptibility-weighted or proton density magnetic resonance imaging (MRI) sequences, without signal change on T1- or T2-weighted imaging, is common in patients with high-grade gliomas and brain metastases, especially melanoma. Susceptibility sequences are highly sensitive to the paramagnetic properties of hemosiderin, a breakdown product of blood. The changes may be https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 3/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate variably described in radiology reports as susceptibility artifact, microhemorrhage, or chronic hemorrhage. The significance of isolated susceptibility artifact within a tumor with regard to risk of clinical hemorrhage with or without anticoagulation has not been established in patients with brain tumors. While intuitively it raises concern that anticoagulation may pose a higher risk of tumor- related hemorrhage, this has not been well studied. In our clinical experience, the presence of microhemorrhage in isolation does not appear to be a contraindication in a patient who is otherwise deemed a candidate for anticoagulation. Treatment with antiangiogenic therapy Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor and is used in the treatment of recurrent malignant glioma as well as other cancers. (See "Management of recurrent high-grade gliomas", section on 'Bevacizumab'.) Bevacizumab is associated with both an increased risk of VTE and an increased risk of bleeding complications. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial and venous thromboembolism' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Bleeding'.) Limited data in patients with malignant glioma who are treated with bevacizumab and anticoagulation suggest that although the risk of intracerebral hemorrhage is increased in patients receiving anticoagulants compared with those who are not, the risk-to-benefit ratio favors concurrent therapy in many cases [14,15]. (See "Management of recurrent high-grade gliomas", section on 'Side effects'.) In a retrospective review of 38 malignant glioma patients treated with bevacizumab, VTE developed in five patients (13 percent) and was preceded four weeks before the onset of symptoms by D-dimer elevation above 865 ng/mL [16]. An existing hemiparesis conferred the highest risk for thrombotic complication. In patients with brain metastases, there does not appear to be a significant increase in the risk of hemorrhage with use of bevacizumab. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Intracranial bleeding'.) THERAPEUTIC ANTICOAGULATION Anticoagulation is the cornerstone of treatment for acute VTE for patients with and without cancer, including most patients with intracranial tumors. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 4/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Historically, patients with primary or metastatic brain tumors and VTE were often managed with the placement of inferior vena cava (IVC) filters rather than with anticoagulation because of concern over an increased risk of symptomatic intratumoral hemorrhage [17-20]. However, practice has evolved, and anticoagulation is now generally preferred in many cases because the incidence of complications with IVC filters is higher than originally thought, and the risk of intracranial hemorrhage secondary to anticoagulation, although elevated overall compared with no anticoagulation [21,22], is not as high as once feared. Absolute contraindications Absolute contraindications to anticoagulation include acute (<48 hours) intracranial hemorrhage, uncontrolled malignant hypertension, severe coagulopathy, severe platelet dysfunction, severe thrombocytopenia, inherited bleeding disorder, and high-risk invasive intracranial procedure within the last 7 to 14 days [1]. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Patients at high risk of bleeding'.) Relative contraindications Most brain tumors do not pose a prohibitive risk of hemorrhage in patients with VTE who are otherwise appropriate candidates for anticoagulation, and the treatment approach is the same as in other patients with cancer. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) The primary exceptions are patients with a history of intratumoral hemorrhage and those with tumors that have a high rate of spontaneous intracranial hemorrhage (ie, metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma). In such patients, decisions must be individualized, as each of these factors represents a relative contraindication to anticoagulation that must be weighed against the risk of untreated VTE. (See 'Pre- anticoagulation risk assessment' above.) Selected patients may be reasonable candidates for anticoagulation, such as those with surgically resected disease or otherwise effectively treated brain metastases [11]. Anticoagulation can also be considered even in patients with cancers that have a greater propensity for hemorrhage (ie, melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma), provided that there is no evidence of acute intracranial hemorrhage on imaging and the potential benefits outweigh the risks. In a meta-analysis of retrospective studies, the risk of intracerebral hemorrhage was not significantly elevated in patients with brain metastases from melanoma or renal cell carcinoma who were treated with warfarin and/or low molecular weight (LMW) heparin [21]. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 5/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate We generally avoid anticoagulation in patients with intratumoral hemorrhage within the past four weeks or a remote history of a clinically significant intracranial hemorrhage. We do not consider the presence of microhemorrhage on MRI to be a contraindication to anticoagulation for VTE, in the absence of additional risk factors for bleeding. (See 'Prior intracranial hemorrhage' above and 'Microhemorrhage within tumor' above.) Agent selection Based on accumulating safety data in brain tumor patients as well as convenience, our approach to agent selection in patients who require anticoagulation for VTE is as follows: For most patients, we suggest use of a direct oral anticoagulant (DOAC) rather than LMW heparin or warfarin. (See 'Direct oral anticoagulants' below.) For patients who cannot take a DOAC due to reasons such as cost, we suggest LMW heparin rather than warfarin for maintenance. (See 'Low molecular weight heparin' below.) For patients with severe renal insufficiency (eg, creatinine clearance <30 mL/minute), options include either renally-dosed LMW heparin with monitoring of anti-factor Xa activity or warfarin. (See 'Low molecular weight heparin' below and 'Warfarin' below.) Thrombolysis is contraindicated in patients with an intracranial malignancy. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration".) For most patients, a DOAC or LMW heparin are appropriate for both immediate (ie, first five days) and continued anticoagulation. We prefer to use unfractionated heparin initially in patients who are clinically unstable and in patients at very high risk of bleeding, based on the short half- life of heparin and the ability to reverse rapidly with protamine sulfate. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.) There are no randomized trials directly comparing DOACs, LMW heparin, and/or warfarin anticoagulation specifically in patients with brain tumors. However, a growing body of observational data in these patients suggests that DOACs have similar efficacy and lower major bleeding risk compared with LMW heparin (see 'Direct oral anticoagulants' below). In addition, indirect evidence drawn from randomized trials in cancer patients (mostly without brain metastases) suggests that DOACs are associated with similar or lower VTE recurrence rates and similar or slightly increased major bleeding rates compared with LMW heparin, and that LMW heparin is more effective for recurrent VTE than warfarin with similar rates of bleeding. These data are reviewed in detail separately. (See "Anticoagulation therapy for venous https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 6/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) Safety Direct oral anticoagulants The available data and our accumulating clinical experience suggest that DOACs are an effective, convenient, and probably safer alternative to LMW heparin for brain tumor patients who require anticoagulation [23-29]. Nonetheless, all of the data on comparative risk of intracranial hemorrhage in this patient population are retrospective, and in the absence of randomized trials, we acknowledge ongoing uncertainty for this endpoint. Evidence in patients with glioblastoma includes a single-center retrospective cohort study of 121 patients diagnosed with VTE who were treated with a DOAC (n = 33) or LMW heparin (n = 88) [27]. At 30 days, the incidence of clinically relevant intracranial hemorrhage was nonsignificantly lower in patients treated with a DOAC compared with LMW heparin (0 versus 9 percent, p = 0.11). At six months, among 107 patients who were maintained on their initial anticoagulant, the cumulative incidence of clinically relevant intracranial hemorrhage was significantly lower in the DOAC group (0 versus 24 percent, p = 0.001), with four fatal hemorrhages in the LMW heparin group. Rates of recurrent VTE were similar between groups (0 and 4 percent for DOACs and LMW heparin, respectively, p = 0.55). Patient characteristics appeared balanced between groups with the exception of time since most recent surgery, which was shorter in the LMW heparin group, and concurrent use of an antiplatelet agent, which was nonsignificantly higher in the DOAC group. Other retrospective data in patients with brain metastases and various primary brain tumors have shown similar results favoring DOACs. In a retrospective study of patients with primary (n = 67) or metastatic (n = 105) brain tumors with VTE who were anticoagulated with either a DOAC or LMW heparin, the 12-month incidence of major intracranial hemorrhage was lower with DOACs in patients with primary brain tumors (0 versus 18 percent) as well as brain metastases (11 versus 18 percent), although the difference was not statistically significant for brain metastases [24]. In both the primary and metastatic brain tumor comparisons, patients in the DOAC group were more likely to have baseline hypertension, chronic kidney disease, and concomitant aspirin use. In a second retrospective study that included 96 patients with brain metastases treated with either a DOAC or LMW heparin, the adjusted risk of any intracranial hemorrhage was similar between DOAC- and LMW heparin-treated patients (HR 0.98, 95% CI 0.28-3.40) [25]. In a third study that included 52 brain tumor patients treated with a DOAC, the risk of any major bleeding was higher in association with LMW heparin, and the risk of intracranial hemorrhage was nonsignificantly lower with DOACs [26]. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 7/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate In trials comparing DOACs with LMW heparin for initial treatment of cancer-associated VTE, most or all patients did not have brain metastases at baseline. Available data on intracranial hemorrhage and brain metastases in these trials are reviewed below: Edoxaban, an oral factor Xa inhibitor, was compared with dalteparin in 1050 patients with active cancer and VTE, of which 74 patients had a primary or metastatic brain tumor [30]. The trial showed a nonsignificant reduction in the rate of recurrent thrombosis in the edoxaban arm but a higher rate of major bleeding, mostly from gastrointestinal bleeding and predominantly in patients with primary gastrointestinal malignancies. The rate of serious bleeding, which included intracranial hemorrhage, was equal between the groups. Rivaroxaban, an oral factor Xa inhibitor, was compared with dalteparin in 406 patients with active cancer and VTE, but only three patients had a brain tumor [31]. Rivaroxaban was associated with relatively low VTE recurrence but higher clinically relevant nonmajor bleeding compared with dalteparin. No central nervous system (CNS) bleeds were reported on study. Apixaban, another oral factor Xa inhibitor, was compared with dalteparin in 287 cancer patients with acute symptomatic or incidental VTE [32]. This trial enrolled eight patients with brain tumors, but the number of patients with brain metastases was not explicitly reported. VTE recurrence rate was significantly lower in the apixaban arm, and the rate of major bleeding was similar in the two treatment groups. In a larger trial comparing apixaban versus dalteparin, there were no brain tumor patients, and major bleeding rates were similar between groups [33]. There was one fatal intracranial hemorrhage in the dalteparin group. DOACs are convenient because they do not require injections or drug level monitoring. US Food and Drug Administration (FDA)-approved antidotes or specific reversal agents for the DOACs are now available, though routine coagulation tests cannot be used to determine the degree of anticoagulation. (See "Management of bleeding in patients receiving direct oral anticoagulants" and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) Low molecular weight heparin The best available estimate of the risk of major hemorrhage in brain tumor patients treated with LMW heparin is derived from a retrospective case control study of 364 patients with cancer-associated VTE, half of whom had a primary or metastatic brain tumor [34]. Anticoagulation consisted of extended-duration therapeutic LMW heparin in approximately 90 percent of patients. With a median follow-up of 6.7 months, the incidence of major bleeding was similar in patients with and without brain tumors (8.6 versus 5.0 per 100 https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 8/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate patient-years). The rate of intracranial hemorrhage in patients with brain tumors was 4.4 percent; seven of nine hemorrhages were symptomatic and none were fatal. There were no intracranial hemorrhages in the control group. Most but not all smaller studies have found similar results: In a retrospective matched cohort study of 293 patients with brain metastases in which approximately one-third of the patients received therapeutic enoxaparin, there was no significant difference in the cumulative incidence of intracranial hemorrhage at one year in patients treated with enoxaparin compared with controls who were not (19 versus 21 percent for measurable hemorrhage, 21 versus 22 percent for significant hemorrhage, and 44 versus 37 percent for total hemorrhages) [11]. The risk of hemorrhage was fourfold higher in patients with melanoma or renal cell carcinoma compared with lung cancer (adjusted hazard ratio [HR] 3.98, 95% CI 2.41-6.57), but the risk was not affected by anticoagulation status. In a retrospective study of 64 patients with glioblastoma who were diagnosed with VTE, 93 percent of patients were treated with anticoagulation, mostly LMW heparin [35]. The majority of patients were treated for >6 months. Ten patients (16 percent) developed complications due to anticoagulation, including three patients with brain hemorrhage (4.7 percent) and three with extracranial bleeding. A retrospective cohort study that included 50 patients with a primary brain tumor (mostly glioblastoma) treated with enoxaparin for VTE identified a higher rate of intracranial hemorrhage (14.7 versus 2.5 percent not treated with anticoagulation) [36]. Neither hypertension nor use of an antiangiogenic agent were risk factors for hemorrhage; older age at diagnosis approached statistical significance. A larger retrospective study in 220 patients with high-grade glioma found a similarly high risk of measurable intracranial hemorrhage in patients treated with LMW heparin for VTE (17 percent one-year cumulative incidence), which was not statistically different than the cumulative incidence in patients not receiving anticoagulation, both with VTE (9 percent) and without VTE (13 percent) [9]. Approximately two-thirds of the hemorrhages were associated with symptoms. Warfarin Studies of warfarin in patients with brain tumors also indicate that the risk of tumor-associated intracranial hemorrhage may not be significantly increased in patients with primary or metastatic brain tumors if the degree of anticoagulation with warfarin is carefully monitored [6,17,18,37-40]. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 9/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Dosing Dosing for DOACs, LMW heparin, unfractionated heparin, and fondaparinux in the treatment of VTE is discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation".) Duration of therapy Patients with acute VTE should be treated for at least three to six months. Extended or lifelong therapy is suggested in most patients with glioblastoma and other forms of active cancer, including those receiving antitumor therapy, as well as in patients with recurrent VTE, provided the bleeding risk is low and no clinically relevant complications from anticoagulation have occurred. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) Duration of therapy in patients without active malignancy (eg, patients with low-grade gliomas or benign brain tumors such as meningioma) should be individualized based on an assessment of risk of recurrence, risk of bleeding, and patient values and preferences. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Role of inferior vena cava filter While IVC filters should not be routinely inserted in patients with acute deep vein thrombosis (DVT), they remain in use for patients deemed to have a prohibitive risk of bleeding with anticoagulation and life-threatening thrombus burden [1]. The efficacy of IVC filters for prevention of recurrent pulmonary embolism in patients with brain tumors is not well characterized. In the general population, observational data indicate that rates of recurrent pulmonary embolism are low (<5 percent in most series). (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter'.) In small studies, the use of IVC filters in patients with brain tumors has been associated with higher risk of recurrent VTE and variable complication rates [17,37]. In an older series of 42 such patients, 12 percent had recurrent pulmonary emboli and 57 percent developed IVC or filter thrombosis, recurrent DVT, or post-thrombotic syndrome [17]. A more modern series reported a 30 percent rate of recurrent VTE in 60 patients with glioblastoma who had an IVC filter placed, some of whom also received anticoagulation [41]. (See "Placement of vena cava filters and their complications".) PRIMARY PREVENTION (VTE PROPHYLAXIS) https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 10/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Incidence and risk factors Patients with primary or metastatic brain tumors, as well as malignancies at other sites, have a latent hypercoagulable state that predisposes to thromboembolism, particularly in the postoperative period [42-44]. (See "Risk and prevention of venous thromboembolism in adults with cancer" and "Cancer-associated hypercoagulable state: Causes and mechanisms".) Estimates of the incidence of VTE consistently show increased relative risk among patients with cancer compared with the general population, particularly in patients with glioblastoma [45]. In prospective studies of patients with malignant glioma, the observed incidence of symptomatic VTE ranges from 17 to 26 percent [5,46-48]. Although there is clustering of VTE events in the postoperative period following craniotomy and during intensive chemotherapy, the risk persists throughout the clinical course [44]. Risk factors for VTE in brain tumor patients include [16,35,43,44,49-51]: Older age ( 60 years) Obesity Glioblastoma histology and absence of an isocitrate dehydrogenase type 1 or 2 (IDH1/2) mutation Large tumor size and subtotal resection Use of steroids and/or chemotherapy Recent neurosurgery (within the past two months) Leg paresis or plegia A or AB blood type For adults with diffuse gliomas, a VTE prediction tool has been developed based on a cohort of 258 adults with newly-diagnosed grade 2 to 4 diffuse glioma, in which the incidence of VTE was 18 percent [52]. Multivariable modeling verified many of the above risk factors and was used to generate a 10-item tool, which predicted high versus low VTE risk with moderate accuracy in validation cohorts (areas under the curve [AUCs] ranging from 0.63 to 0.84). A web-based version of the tool is available [53]. However, since it is based on relatively low AUCs and has not been prospectively validated, it should not be used as a stand-alone tool to make clinical decisions about preventive treatment. Inpatients and postoperative patients Perioperatively, the frequency of VTE in brain tumor patients is approximately 10 to 15 percent [43,54,55]. The use of pneumatic compression stockings combined with low molecular weight (LMW) heparin or unfractionated subcutaneous heparin started preoperatively and resumed 24 to 48 hours after surgery is effective and https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 11/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate relatively safe in neurosurgical patients [56-60]. These measures are generally continued until the patient resumes ambulation. Outpatients Primary prophylaxis with anticoagulants is not generally recommended in patients with brain tumors except in the perioperative period [61]. The extended use of LMW heparin (dalteparin) as primary prophylaxis of VTE in patients with newly diagnosed malignant glioma was assessed in the PRODIGE trial [5]. The trial was terminated prematurely because of the unavailability of placebo. Overall, 186 patients were randomly assigned to six months of treatment with dalteparin or placebo, with an option to continue on study medication for up to 12 months. The incidence of clinically evident VTE at six months was lower among those receiving dalteparin (11 versus 17 percent with placebo), but the difference was not statistically significant. Intracranial hemorrhages were more common in patients treated with dalteparin (5 versus 1 percent with placebo at 12 months; hazard ratio [HR] 4.2, 95% CI 0.48-36). The PRODIGE trial confirmed the substantial risk of VTE in patients with malignant gliomas. Although there were trends toward reduction of VTE and increase in intracranial hemorrhage, the trial did not have adequate statistic power at the time of termination to draw definitive conclusions about the benefits versus risks of long-term anticoagulation. A small phase II trial involving 40 patients with malignant gliomas treated with the LMW heparin tinzaparin 4500 international units subcutaneously daily for a median of approximately five months reported symptomatic central nervous system (CNS) hemorrhage in one patient (2.5 percent) and deep vein thrombosis (DVT) in one patient (2.5 percent) [62]. For the prevention of VTE in at-risk patients with brain tumors, long-term treatment with daily aspirin (eg, 325 mg/day orally) may offer partial protection and is easy to administer, although neither the safety nor efficacy of this approach has been well defined in this population [40]. For general VTE prevention, aspirin appears to have some activity, but it is clearly less than that afforded by anticoagulation [63]. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Aspirin therapy may be considered for primary prevention of VTE in brain tumor patients who are 60 years old, have large tumors or substantial leg weakness, or are undergoing chemotherapy. However, the effect of aspirin in inhibiting platelet function in patients at risk for chemotherapy-induced thrombocytopenia must be weighed against the limited evidence of benefit in preventing VTE. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 12/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Primary brain tumors".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Warfarin (Beyond the Basics)" and "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General principles The general principles of managing acute venous thromboembolism (VTE) in patients with brain tumors are the same as in other patients with and without cancer. Anticoagulation is the cornerstone of treatment, and treatment decisions balance the risk of bleeding complications due to anticoagulation with the risks of untreated and recurrent VTE. (See 'Introduction' above.) Pretreatment risk assessment The risk of bleeding in patients with brain tumors is determined by considering both general risk factors for bleeding with anticoagulant therapy ( table 2 and table 1) and risk of intracranial hemorrhage related to the tumor and any antitumor therapies. (See 'Pre-anticoagulation risk assessment' above.) https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 13/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Absolute contraindications to anticoagulation in patients with and without brain tumors include acute intracranial hemorrhage (<48 hours), uncontrolled malignant hypertension, severe coagulopathy, severe platelet dysfunction or thrombocytopenia, inherited bleeding disorder, and recent intracranial surgery. (See 'Absolute contraindications' above.) Therapeutic anticoagulation Most brain tumors do not pose a prohibitive risk of hemorrhage in patients with VTE who are otherwise appropriate candidates for anticoagulation. Potential exceptions include brain metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma, which have a higher rate of spontaneous intratumoral hemorrhage than other tumor types, and patients with a history of intratumoral hemorrhage. Decisions in these patients should be individualized. (See 'Relative contraindications' above.) Agent selection In patients with brain tumors who are selected to receive anticoagulation for VTE, we suggest a direct oral anticoagulant (DOAC) rather than low molecular weight (LMW) heparin or warfarin (Grade 2C). For patients who cannot take a DOAC due to cost, we suggest LMW heparin rather than warfarin for maintenance (Grade 2C). For patients with severe renal insufficiency, options include renally-dosed LMW heparin with monitoring of anti-factor Xa activity or warfarin. (See 'Agent selection' above.) Duration VTE in low-grade glioma and benign tumors should be treated for three to six months, whereas long-term anticoagulation is generally indicated for patients with glioblastoma and other active malignancies. (See 'Duration of therapy' above.) Role of inferior vena cava (IVC) filter IVC filters should not be routinely inserted in brain tumor patients with acute deep vein thrombosis (DVT). However, they remain in use for patients deemed to have a prohibitive risk of bleeding with anticoagulation and life- threatening thrombus burden. (See 'Role of inferior vena cava filter' above.) Prophylactic anticoagulation Although patients with primary or metastatic brain tumors are at relatively high risk for the development of VTE, we suggest that these patients not be anticoagulated prophylactically, except in the postoperative period (Grade 2B). (See 'Primary prevention (VTE prophylaxis)' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 14/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate 1. Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020; 38:496. 2. Farge D, Debourdeau P, Beckers M, et al. International clinical practice guidelines for the

newly diagnosed malignant glioma was assessed in the PRODIGE trial [5]. The trial was terminated prematurely because of the unavailability of placebo. Overall, 186 patients were randomly assigned to six months of treatment with dalteparin or placebo, with an option to continue on study medication for up to 12 months. The incidence of clinically evident VTE at six months was lower among those receiving dalteparin (11 versus 17 percent with placebo), but the difference was not statistically significant. Intracranial hemorrhages were more common in patients treated with dalteparin (5 versus 1 percent with placebo at 12 months; hazard ratio [HR] 4.2, 95% CI 0.48-36). The PRODIGE trial confirmed the substantial risk of VTE in patients with malignant gliomas. Although there were trends toward reduction of VTE and increase in intracranial hemorrhage, the trial did not have adequate statistic power at the time of termination to draw definitive conclusions about the benefits versus risks of long-term anticoagulation. A small phase II trial involving 40 patients with malignant gliomas treated with the LMW heparin tinzaparin 4500 international units subcutaneously daily for a median of approximately five months reported symptomatic central nervous system (CNS) hemorrhage in one patient (2.5 percent) and deep vein thrombosis (DVT) in one patient (2.5 percent) [62]. For the prevention of VTE in at-risk patients with brain tumors, long-term treatment with daily aspirin (eg, 325 mg/day orally) may offer partial protection and is easy to administer, although neither the safety nor efficacy of this approach has been well defined in this population [40]. For general VTE prevention, aspirin appears to have some activity, but it is clearly less than that afforded by anticoagulation [63]. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Aspirin therapy may be considered for primary prevention of VTE in brain tumor patients who are 60 years old, have large tumors or substantial leg weakness, or are undergoing chemotherapy. However, the effect of aspirin in inhibiting platelet function in patients at risk for chemotherapy-induced thrombocytopenia must be weighed against the limited evidence of benefit in preventing VTE. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 12/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Primary brain tumors".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Warfarin (Beyond the Basics)" and "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS General principles The general principles of managing acute venous thromboembolism (VTE) in patients with brain tumors are the same as in other patients with and without cancer. Anticoagulation is the cornerstone of treatment, and treatment decisions balance the risk of bleeding complications due to anticoagulation with the risks of untreated and recurrent VTE. (See 'Introduction' above.) Pretreatment risk assessment The risk of bleeding in patients with brain tumors is determined by considering both general risk factors for bleeding with anticoagulant therapy ( table 2 and table 1) and risk of intracranial hemorrhage related to the tumor and any antitumor therapies. (See 'Pre-anticoagulation risk assessment' above.) https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 13/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Absolute contraindications to anticoagulation in patients with and without brain tumors include acute intracranial hemorrhage (<48 hours), uncontrolled malignant hypertension, severe coagulopathy, severe platelet dysfunction or thrombocytopenia, inherited bleeding disorder, and recent intracranial surgery. (See 'Absolute contraindications' above.) Therapeutic anticoagulation Most brain tumors do not pose a prohibitive risk of hemorrhage in patients with VTE who are otherwise appropriate candidates for anticoagulation. Potential exceptions include brain metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma, which have a higher rate of spontaneous intratumoral hemorrhage than other tumor types, and patients with a history of intratumoral hemorrhage. Decisions in these patients should be individualized. (See 'Relative contraindications' above.) Agent selection In patients with brain tumors who are selected to receive anticoagulation for VTE, we suggest a direct oral anticoagulant (DOAC) rather than low molecular weight (LMW) heparin or warfarin (Grade 2C). For patients who cannot take a DOAC due to cost, we suggest LMW heparin rather than warfarin for maintenance (Grade 2C). For patients with severe renal insufficiency, options include renally-dosed LMW heparin with monitoring of anti-factor Xa activity or warfarin. (See 'Agent selection' above.) Duration VTE in low-grade glioma and benign tumors should be treated for three to six months, whereas long-term anticoagulation is generally indicated for patients with glioblastoma and other active malignancies. (See 'Duration of therapy' above.) Role of inferior vena cava (IVC) filter IVC filters should not be routinely inserted in brain tumor patients with acute deep vein thrombosis (DVT). However, they remain in use for patients deemed to have a prohibitive risk of bleeding with anticoagulation and life- threatening thrombus burden. (See 'Role of inferior vena cava filter' above.) Prophylactic anticoagulation Although patients with primary or metastatic brain tumors are at relatively high risk for the development of VTE, we suggest that these patients not be anticoagulated prophylactically, except in the postoperative period (Grade 2B). (See 'Primary prevention (VTE prophylaxis)' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 14/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate 1. Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2020; 38:496. 2. Farge D, Debourdeau P, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11:56. 3. Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16:1891. 4. NCCN guidelines on cancer-associated venous thromboembolic disease. https://www.nccn.o rg/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pd f/vte.pdf. 5. Perry JR, Julian JA, Laperriere NJ, et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost 2010; 8:1959. 6. Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983; 13:334. 7. Wakai S, Yamakawa K, Manaka S, Takakura K. Spontaneous intracranial hemorrhage caused by brain tumor: its incidence and clinical significance. Neurosurgery 1982; 10:437. 8. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370:709. 9. Jo J, Donahue J, Sarai G, et al. Management of venous thromboembolism in high-grade glioma: Does low molecular weight heparin increase intracranial bleeding risk? Neuro Oncol 2022; 24:455. 10. Mandybur TI. Intracranial hemorrhage caused by metastatic tumors. Neurology 1977; 27:650. 11. Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood 2015; 126:494. 12. Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014; 85:660. 13. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 15/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate American Heart Association/American Stroke Association. Stroke 2015; 46:2032. 14. Nghiemphu PL, Green RM, Pope WB, et al. Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol 2008; 10:355. 15. Norden AD, Bartolomeo J, Tanaka S, et al. Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients. J Neurooncol 2012; 106:121. 16. Misch M, Czabanka M, Dengler J, et al. D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma. Anticancer Res 2013; 33:2093. 17. Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology 1993; 43:1111. 18. Olin JW, Young JR, Graor RA, et al. Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors. Anticoagulants or inferior vena cava filter? Arch Intern Med 1987; 147:2177. 19. Wen PY, Marks PW. Medical management of patients with brain tumors. Curr Opin Oncol 2002; 14:299. 20. Norris LK, Grossman SA. Treatment of thromboembolic complications in patients with brain tumors. J Neurooncol 1994; 22:127. 21. Zwicker JI, Karp Leaf R, Carrier M. A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation. J Thromb Haemost 2016; 14:1736. 22. Wood P, Boyer G, Mehanna E, et al. Intracerebral haemorrhage in patients with brain metastases receiving therapeutic anticoagulation. J Neurol Neurosurg Psychiatry 2021. 23. Riedl J, Ay C. Venous Thromboembolism in Brain Tumors: Risk Factors, Molecular Mechanisms, and Clinical Challenges. Semin Thromb Hemost 2019; 45:334. 24. Carney BJ, Uhlmann EJ, Puligandla M, et al. Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors. J Thromb Haemost 2019; 17:72. 25. Leader A, Hamuly k EN, Carney BJ, et al. Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases. Blood Adv 2020; 4:6291. 26. Swartz AW, Drappatz J. Safety of Direct Oral Anticoagulants in Central Nervous System Malignancies. Oncologist 2021; 26:427. 27. Reed-Guy L, Desai AS, Phillips RE, et al. Risk of intracranial hemorrhage with direct oral anticoagulants vs low molecular weight heparin in glioblastoma: A retrospective cohort study. Neuro Oncol 2022; 24:2172. 28. Giustozzi M, Proietti G, Becattini C, et al. ICH in primary or metastatic brain cancer patients with or without anticoagulant treatment: a systematic review and meta-analysis. Blood Adv https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 16/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate 2022; 6:4873. 29. Giustozzi M, Becattini C, Roila F, et al. DOACs in patients with brain cancers: promising but still a long way to go. Blood Adv 2023; 7:283. 30. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med 2018; 378:615. 31. Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol 2018; 36:2017. 32. McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. J Thromb Haemost 2020; 18:411. 33. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med 2020; 382:1599. 34. Chai-Adisaksopha C, Linkins LA, ALKindi SY, et al. Outcomes of low-molecular-weight heparin treatment for venous thromboembolism in patients with primary and metastatic brain tumours. Thromb Haemost 2017; 117:589. 35. Yust-Katz S, Mandel JJ, Wu J, et al. Venous thromboembolism (VTE) and glioblastoma. J Neurooncol 2015; 124:87. 36. Mantia C, Uhlmann EJ, Puligandla M, et al. Predicting the higher rate of intracranial hemorrhage in glioma patients receiving therapeutic enoxaparin. Blood 2017; 129:3379. 37. Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer 1994; 73:493. 38. Choucair AK, Silver P, Levin VA. Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism. J Neurosurg 1987; 66:357. 39. Altschuler E, Moosa H, Selker RG, Vertosick FT Jr. The risk and efficacy of anticoagulant therapy in the treatment of thromboembolic complications in patients with primary malignant brain tumors. Neurosurgery 1990; 27:74. 40. Quevedo JF, Buckner JC, Schmidt JL, et al. Thromboembolism in patients with high-grade glioma. Mayo Clin Proc 1994; 69:329. 41. Edwin NC, Khoury MN, Sohal D, et al. Recurrent venous thromboembolism in glioblastoma. Thromb Res 2016; 137:184. 42. Gerber DE, Grossman SA, Streiff MB. Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 2006; 24:1310. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 17/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate 43. Semrad TJ, O'Donnell R, Wun T, et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 2007; 106:601. 44. Jenkins EO, Schiff D, Mackman N, Key NS. Venous thromboembolism in malignant gliomas. J Thromb Haemost 2010; 8:221. 45. Perry JR. Thromboembolic disease in patients with high-grade glioma. Neuro Oncol 2012; 14 Suppl 4:iv73. 46. Ay C, Vormittag R, Dunkler D, et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27:4124. 47. Brandes AA, Scelzi E, Salmistraro G, et al. Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer 1997; 33:1592. 48. Streiff MB, Ye X, Kickler TS, et al. A prospective multicenter study of venous thromboembolism in patients with newly-diagnosed high-grade glioma: hazard rate and risk factors. J Neurooncol 2015; 124:299. 49. Streiff MB, Segal J, Grossman SA, et al. ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 2004; 100:1717. 50. Mir Seyed Nazari P, Riedl J, Preusser M, et al. Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism. J Thromb Haemost 2018; 16:1121. 51. Diaz M, Jo J, Smolkin M, et al. Risk of Venous Thromboembolism in Grade II-IV Gliomas as a Function of Molecular Subtype. Neurology 2021; 96:e1063. 52. Burdett KB, Unruh D, Drumm M, et al. Determining venous thromboembolism risk in patients with adult-type diffuse glioma. Blood 2023; 141:1322. 53. Burdett, Kristen Bell. VTE Prediction for Patients with Glioma. 2022. Available at: https://kbell burdett.shinyapps.io/GliomaPredictVTE/ (Accessed on May 04, 2023). 54. Chan AT, Atiemo A, Diran LK, et al. Venous thromboembolism occurs frequently in patients undergoing brain tumor surgery despite prophylaxis. J Thromb Thrombolysis 1999; 8:139. 55. Smith TR, Lall RR, Graham RB, et al. Venous thromboembolism in high grade glioma among surgical patients: results from a single center over a 10 year period. J Neurooncol 2014; 120:347. 56. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998; 339:80. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 18/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate 57. Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis. Arch Intern Med 2000; 160:2327. 58. Constantini S, Kanner A, Friedman A, et al. Safety of perioperative minidose heparin in patients undergoing brain tumor surgery: a prospective, randomized, double-blind study. J Neurosurg 2001; 94:918. 59. Alshehri N, Cote DJ, Hulou MM, et al. Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-analysis. J Neurooncol 2016; 130:561. 60. Khan NR, Patel PG, Sharpe JP, et al. Chemical venous thromboembolism prophylaxis in neurosurgical patients: an updated systematic review and meta-analysis. J Neurosurg 2018; 129:906. 61. Schmidt F, Faul C, Dichgans J, Weller M. Low molecular weight heparin for deep vein thrombosis in glioma patients. J Neurol 2002; 249:1409. 62. Perry SL, Bohlin C, Reardon DA, et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. J Neurooncol 2009; 95:129. 63. Hovens MM, Snoep JD, Tamsma JT, Huisman MV. Aspirin in the prevention and treatment of venous thromboembolism. J Thromb Haemost 2006; 4:1470. Topic 5201 Version 45.0 https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 19/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate GRAPHICS Issues to be considered when making decisions concerning the use or non- use of anticoagulation in patients with malignancy Overall treatment plan and prognosis Therapeutic goal (eg, palliation of symptoms related to VTE, planned oncologic intervention, immediate prognosis, hospice care) Planned chemotherapy Stage of the malignancy, overall prognosis Other causes for hypercoagulability (eg, bedridden, pathologic fracture, recent surgery or invasive procedures, use of hormonal agents or other medications with a high incidence of thrombotic side effects, presence of a central venous access line) Patient preferences, logistic, and financial issues Inpatient or outpatient care planned Who will supervise medication's use and required monitoring, if any? Patient preferences (eg, oral versus injectable agent, need for frequent monitoring of coagulation status) Treatment costs; Will the patient's insurance pay for the medication? Relative contraindications to anticoagulation Presence of central nervous system involvement Central nervous system primary or metastases Prior intracerebral hemorrhage Thrombocytopenia or bleeding diathesis present? Are risk factors for bleeding after use of warfarin present? (eg, impaired liver function, hepatic metastases, concomitant medication, poor nutrition) Selection of appropriate dosing (eg, impaired renal function, obesity, advanced age) Need for monitoring of treatment (eg, INR for treatment with warfarin) Ability or inability to reverse anticoagulation if bleeding occurs VTE: venous thromboembolism; INR: international normalized ratio. Graphic 81646 Version 7.0 https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 20/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Risk factors for bleeding with anticoagulant therapy and estimated risk of major bleeding in low, moderate, and high risk categories Risk factors* Age >65 years Age >75 years Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery Frequent falls Alcohol abuse Estimated absolute risk of major bleeding (%) Categorization Low risk Moderate risk High risk ( 2 risk factors) of risk of bleeding (0 risk factors) (1 risk factor) Anticoagulation 0 to 3 months Baseline risk (%) 0.6 1.2 4.8 Increased risk (%) 1 2 8 Total risk (%) 1.6 3.2 12.8 Anticoagulation after first 3 months 2.5 Baseline risk (%/years) 0.3 0.6 4 Increased risk (%/years) 0.5 1 6.5 Total risk (%/years) 0.8** 1.6** GI: gastrointestinal; UFH: unfractionated heparin; LMWH: low molecular weight heparin; VKA: vitamin K-dependent antagonist (ie, warfarin); VTE: venous thromboembolism. https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 21/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, location and extent of metastatic disease, platelet count), (2) temporal relationships (eg, interval from surgery or a previous bleeding episode), and (3) how effectively a previous cause of bleeding was corrected (eg, upper-GI bleeding). Important for parenteral anticoagulation (eg, first 10 days), but less important for long-term or extended anticoagulation. Although there is evidence that risk of bleeding increases with the prevalence of risk factors, this categorization scheme has not been validated. Furthermore, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past 2 days, severe thrombocytopenia). Compared with low-risk patients, moderate-risk patients are assumed to have a 2-fold risk and high-risk patients an 8-fold risk of major bleeding. The 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy. We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with anticoagulation (refer to footnote ). [1] Consistent with frequency of major bleeding observed by Hull et al in high-risk patients . We estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no extended anticoagulation. The relative risk of major bleeding during the first 3 months of therapy may be greater than during extended VKA therapy because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA therapy; (2) anticoagulant control will be less stable during the first 3 months; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the first 3 months of therapy. However, studies of patients with acute coronary syndromes do not suggest a 2.6 relative risk of major bleeding with parenteral anticoagulation (eg, UFH or LMWH) compared with control. Our estimated baseline risk of major bleeding for low-risk patients (and adjusted up for moderate- and high-risk groups as per footnote ). * Consistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE. Reference: 1. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322:1260. Reproduced from: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 97160 Version 5.0 https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 22/23 7/6/23, 1:01 PM Treatment and prevention of venous thromboembolism in patients with brain tumors - UpToDate Contributor Disclosures Eudocia Quant Lee, MD, MPH Consultant/Advisory Boards: Medscape [Brain tumors]. Other Financial Interest: MedLink [Neurologic complications of cancer therapy]. All of the relevant financial relationships listed have been mitigated. Patrick Y Wen, MD Grant/Research/Clinical Trial Support: Agios Pharmaceuticals [Brain tumor]; AstraZeneca/MedImmune [Brain tumor]; Bayer [Brain tumor]; BeiGene [Brain tumor]; Bristol Meyers Squibb [Brain tumor]; Celgene [Brain tumor]; Chimerix [Brain tumor]; Eli Lilly [Brain tumor]; Kazia [Brain tumor]; MediciNova [Brain tumor]; Merck [Brain tumor]; Novartis [Brain tumor]; Nuvation Bio [Brain tumor]; Oncoceutics [Brain tumor]; Puma [Brain tumor]; Servier [Brain tumor]; Vascular Biogenics [Brain tumor]; VBI Vaccines [Brain tumor]. Consultant/Advisory Boards: AstraZeneca [Brain tumor]; Bayer [Brain tumor]; Black Diamond [Brain tumor]; Boston Pharmaceuticals [Brain tumor]; Celularity [Brain tumor]; Chimerix [Brain tumor]; Day One Bio [Brain tumor]; Genenta [Brain tumor]; Glaxo Smith Kline [Brain tumor]; Karyopharm [Brain tumor]; Merck [Brain tumor]; Mundipharma [Brain tumor]; Novartis [Brain tumor]; Novocure [Brain tumor]; Nuvation Bio [Brain tumor]; Prelude Therapeutics [Brain tumor]; Sagimet [Brain tumor]; Sapience [Brain tumor]; Servier [Brain tumor]; Vascular Biogenics [Brain tumor]; VBI Vaccines [Brain tumor]; Voyager [Brain tumor]. Other Financial Interest: Elsevier [Editor]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. April F Eichler, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/treatment-and-prevention-of-venous-thromboembolism-in-patients-with-brain-tumors/print 23/23

7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD, Jonathan A Edlow, MD, FACEP : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 12, 2022. INTRODUCTION In the United States, the proportion of stroke due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage (SAH) is approximately 87, 10, and 3 percent, respectively. Most nontraumatic SAHs are caused by ruptured saccular aneurysms. This is often a devastating clinical event with substantial mortality, and high morbidity among survivors. The epidemiology, etiology, clinical manifestations, and diagnosis of aneurysmal SAH are reviewed here. Other aspects are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Unruptured intracranial aneurysms" and "Overview of infected (mycotic) arterial aneurysm" and "Nonaneurysmal subarachnoid hemorrhage" and "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) CLINICAL PRESENTATION Headache characteristics The classic presentation of patients with aneurysmal SAH is a sudden-onset, severe headache typically described as the "worst headache of my life" [1]. Every patient with this kind of headache, often referred to as a "thunderclap headache" (see "Overview of thunderclap headache"), should be evaluated for SAH. Headache is often an isolated finding. In neurologically intact patients with a severe-onset headache peaking https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 1/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate within one hour, three large sequential studies with a total of 5283 patients found that 329 patients (6 percent) had SAH [2-5]. Importantly, the headache onset in SAH is not always noted as instantaneous, either because the patient does not perceive it that way or because the physician does not elicit that information. In a study that included 132 patients with SAH, the time to peak intensity was one hour in six (5 percent), and the physician interobserver agreement for sudden onset was only moderate (kappa = 0.49) [2]. Location is not useful since the headache can be localized or generalized. Associated symptoms In addition to headache, common associated symptoms of SAH include a brief loss of consciousness, vomiting, and neck pain or stiffness [6]. In one series, these occurred in 9, 61, and 75 percent of patients, respectively, and each of these symptoms was more common in patients with SAH compared with patients without SAH [3]. Meningismus, often accompanied by lower back pain, may develop several hours after the bleed, since they are caused by the breakdown of blood products within the cerebrospinal fluid (CSF), which lead to an aseptic meningitis [7]. While many patients have an altered level of consciousness, coma is unusual. Seizures occur during the first 24 hours in less than 10 percent of patients but are a predictor of poor outcome [8]. SAH may also present as sudden death; as many as 22 percent of patients die before reaching the hospital [9]. Prodromal symptoms Some patients report a history of a sudden and severe headache (the sentinel headache) that precedes a major SAH, occurring days to weeks prior to aneurysm rupture. Sentinel headache may represent either a minor hemorrhage (a "warning leak") or physical changes within the aneurysm wall (eg, acute dissection, thrombosis, or expansion), but supporting data are weak. A systematic literature review of mainly retrospective studies through September 2002 found that 10 to 43 percent of patients with aneurysmal SAH reported a history of a sentinel or warning headache [10]. However, retrospective data may be confounded by recall bias, and a number of reports question the existence of "warning leaks" as the cause of sentinel headaches, as reviewed separately. (See "Overview of thunderclap headache", section on 'Sentinel headache'.) Clinical settings While the onset of symptoms in the setting of physical exertion, activities associated with a Valsalva maneuver, or emotional stress suggest SAH, aneurysmal SAH occurs most often during nonstrenuous activity, rest, or sleep [11,12]. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Pathogenesis'.) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 2/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Examination findings Physical examination often shows hypertension and may show meningismus. Terson syndrome (preretinal hemorrhages) may be seen and implies a poorer prognosis. In a systematic review, patients with Terson syndrome had higher Hunt and Hess grades ( table 1) and significantly higher mortality than those without [13]. The preretinal hemorrhages of Terson syndrome may indicate a more abrupt increase in intracranial pressure and must be distinguished from the more benign retinal hemorrhages sometimes associated with SAH [14]. Nearly any neurologic sign may be present ( table 2) and will depend on the location of the hemorrhage, presence or absence of hydrocephalus, elevated intracranial pressure, ischemia, infarction, or hematoma [15]. Although a pupil-involving third nerve palsy is often cited as a finding of SAH, it is more common with an expanding but unruptured aneurysm of the posterior communicating artery or superior cerebellar artery, which is located close to where the third nerve exits the brainstem [16,17]. If present, this finding mandates a work-up for an aneurysm including some form of cerebral angiography, but its absence does not decrease the likelihood of SAH in patients with acute headache. Grading severity A number of grading systems are used in practice to standardize the clinical classification of patients with SAH at the time of initial presentation. However, clinical grade assessment at the time of nadir, or after neurologic resuscitation, appears to be more predictive of outcome [18,19]. The grading system proposed by Hunt and Hess ( table 1) and that of the World Federation of Neurological Surgeons (WFNS) ( table 3) are among the most widely used. The WFNS system incorporates the Glasgow Coma Scale ( table 4) combined with the presence of motor deficit. The Fisher scale is an index of vasospasm risk based upon a computed tomography (CT)- defined hemorrhage pattern ( table 5), and the modified Fisher scale (also known as the Claassen scale) is a similar index of the risk of delayed cerebral ischemia due to vasospasm ( table 6). A system proposed by Ogilvy and Carter stratifies patients based upon age, Hunt and Hess grade, Fisher grade, and aneurysm size ( table 7). In addition to predicting outcome, this scale more accurately substratifies patients for therapy. Grading scales for SAH are discussed in greater detail separately. (See "Subarachnoid hemorrhage grading scales".) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 3/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate EVALUATION AND DIAGNOSIS When to suspect SAH The complaint of the sudden or rapid onset of severe headache is sufficiently characteristic that SAH should always be considered in the evaluation. All patients with this complaint should undergo immediate evaluation for SAH beginning with head computed tomography (CT), even those who are alert and neurologically intact at the time of initial presentation [2,20]. Additional clues to the diagnosis of SAH, such as preretinal hemorrhages, neck pain, or meningismus, may or may not be present. In a systematic review and meta-analysis that included 22 diagnostic studies of emergency department patients evaluated for spontaneous SAH, the presence of meningismus on physical examination had a positive likelihood ratio of 6.6 [21]. Ottawa Subarachnoid Hemorrhage Rule In neurologically intact patients presenting with acute nontraumatic headache that reached maximal intensity within one hour, a clinical decision rule (the Ottawa Subarachnoid Hemorrhage Rule) that included any of the following features had a sensitivity of 100 percent and a specificity of 15 percent for the diagnosis of SAH [2]: Age 40 years Neck pain or stiffness Limited neck flexion on examination Witnessed loss of consciousness Onset during exertion Thunderclap headache (instantly peaking pain) Subsequent validation studies, most from the same investigators, reported similar findings [3,22,23]. Moreover, application of this rule would have eliminated the need for evaluation in only 14 percent of patients [24]. Misdiagnosis and delayed diagnosis Misdiagnosis and delayed diagnosis of SAH are common and can lead to delays in treatment and worse outcomes [25,26]. Missed or delayed diagnosis of SAH usually results from three errors ( table 8) [6,17]: Failure to appreciate the spectrum of clinical presentation associated with SAH Failure to obtain a head CT scan or to understand its limitations in diagnosing SAH Failure to perform a lumbar puncture or correctly interpret the results Perhaps the most important source of misdiagnosis results from the misconception that patients with aneurysmal SAH always appear "sick" or have neurologic findings or altered https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 4/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate mental status when in fact nearly 40 percent of patients are awake, alert, and neurologically intact [17]. Practitioners with the misconception may not perform CT scans in such patients. From a practice perspective, the vast majority of patients will be correctly diagnosed if all patients with thunderclap headache undergo head CT (and lumbar puncture if the CT is done after six hours from headache onset). Only an extremely small minority whose thunderclap headache is from a symptomatic but unruptured aneurysm would be missed by this approach [27-29]. The frequency of SAH misdiagnosis may be decreasing but remains a problem. In four studies of patients hospitalized with SAH published from 1980 to 1997, initial misdiagnosis rates ranged from 23 to 51 percent [1]. In contrast, a 2017 systematic review identified three studies published from 1996 to 2007 in emergency department populations with a pooled misdiagnosis rate of 7 percent [30]. Included the systematic review was a report of 482 patients admitted with SAH; initial misdiagnosis was independently associated with small SAH volume, normal mental status at presentation, and right-sided aneurysm location [25]. Failure to obtain a head CT scan at initial contact was the most common error, occurring in 73 percent of misdiagnosed patients. Among patients with SAH and normal mental status at first contact (45 percent), the misdiagnosis rate rose to 20 percent and was associated with a nearly fourfold increase in mortality at 12 months as well as increased morbidity among survivors. Standard diagnostic approach The first step in the diagnosis of SAH is noncontrast head CT [20]. A lumbar puncture should be done if the head CT is negative [20]. If both tests are negative, they effectively eliminate the diagnosis of SAH as long as both tests are performed within two weeks of the event [27,31]. In cases presenting more than two weeks after headache onset (at such time when even xanthochromia may have disappeared), additional testing with noninvasive CT angiography (CTA) or magnetic resonance angiography (MRA) should be done. If diagnostic doubt remains, especially if the clinical context suggests other causes of acute-onset severe headache, magnetic resonance imaging (MRI), catheter cerebral angiography, or cerebral venography may be necessary ( table 9) [20]. (See "Overview of thunderclap headache".) The sensitivity of all diagnostic tests for SAH is time-dependent, measuring time from onset of the bleed. This is due to the physiologic brisk flow of cerebrospinal fluid (CSF). Normally, there is approximately 150 mL of CSF in a person's subarachnoid space at any point in time, but 450 to 500 mL are manufactured per 24 hours. This is why CT scans and red blood cell (RBC) counts are very sensitive early after bleeding onset but lose sensitivity with the passage of time. RBCs present in the CSF undergo lysis, resulting in breakdown products such as bilirubin and https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 5/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate oxyhemoglobin, a process that takes time, accounting for the fact that xanthochromia is not sensitive early but becomes increasingly sensitive after a few hours. Head CT scan The cornerstone of SAH diagnosis is the noncontrast head CT scan [32,33]. The head CT scan should be performed with thin cuts through the base of the brain to increase the sensitivity to small amounts of blood [34]. Sensitivity for SAH The sensitivity of modern head CT for detecting SAH is highest in the first six hours after SAH (nearly 100 percent when interpreted by expert reviewers), and then progressively declines over time to approximately 58 percent at day 5 [28,33,35-37]. In the largest study of the relation of time and CT sensitivity, the expert reviewers were attending-level general radiologists [38]. Clot is seen in the subarachnoid space in 92 percent of cases if the scan is performed within 24 hours of the bleed [33,38]. The sensitivity of head CT may be reduced with low-volume bleeds. In one study, for example, a minor SAH was not diagnosed by CT scan in 55 percent of patients; lumbar puncture was positive in all cases [39] However, the time from SAH onset to head CT was not reported. Anemia with hematocrits of 30 percent or less and poor scan quality due to patient movement are other causes of ambiguous or false-negative CT results. However, the most important factor that affects CT sensitivity is time from onset. Location of blood Blood in SAH is generally found in the basal cisterns. Additional locations may include the sylvian fissures, interhemispheric fissure, interpeduncular fossa, and suprasellar, ambient, and quadrigeminal cisterns [15]. Intracerebral extension is present in 20 to 40 percent of patients and intraventricular and subdural blood may be seen in 15 to 35 and 2 to 5 percent, respectively. The distribution of blood on CT (performed within 72 hours after the bleed) is a poor predictor of the site of an aneurysm except in patients with ruptured anterior cerebral artery or anterior communicating artery aneurysms and in patients with a parenchymal hematoma [40]. However, the distribution of blood does have implications about whether or not the cause of the SAH is aneurysmal ( image 1). Blood restricted to the subarachnoid space in front of the brainstem suggests a nonaneurysmal perimesencephalic (also called pretruncal) SAH. Convexal SAH suggests reversible cerebral vasoconstriction syndrome (RCVS) in younger patients or cerebral amyloid angiopathy in older patients, whereas blood adjacent to bone in the anterior or middle cranial fossae suggests traumatic SAH. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 6/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Lumbar puncture Lumbar puncture is mandatory if there is a strong suspicion of SAH despite a normal head CT [32,41]. Although controversial, one possible exception involves select patients with isolated headache, a normal examination, and a negative CT scan performed within six hours from onset of headache and interpreted by an expert reviewer, as discussed below. (See 'Need for LP when early CT is negative' below.) Lumbar puncture should include measurement of opening pressure, routine CSF analyses including RBC and white blood cell (WBC) counts, and visual inspection for xanthochromia. The classic lumbar puncture findings of SAH are an elevated opening pressure, an elevated RBC count that does not diminish from CSF tube 1 to tube 4, and xanthochromia. Accidental trauma to a capillary or venule may occur during performance of a lumbar puncture, increasing the number of both RBCs and WBCs in the CSF. The differential of RBC counts between tubes 1 and 4, and immediate centrifugation of the CSF, can help differentiate bleeding in SAH from that due to a traumatic spinal tap: Clearing of blood Clearing of blood (a declining RBC count with successive collection tubes) is purported to be a useful way of distinguishing a traumatic lumbar puncture from SAH. However, this is an unreliable sign of a traumatic tap, since a decrease in the number of RBCs in later tubes can also occur in SAH [42]. This method can reliably exclude SAH only if there is substantial RBC count in the first tube, and the late or final collection tube is normal. One study found that the percent change in RBC count between the first and last tubes was more useful than the absolute difference as a test for distinguishing traumatic tap from SAH; the optimal test threshold based on this sample was a 63 percent reduction in the RBC count [43]. These findings require independent confirmation. If the CSF is visibly bloody, one practical method to increase the likelihood that the last tube of CSF will contain close to zero RBCs is to discard CSF between the first and last tubes with a goal of visual clearing [20]. Given the brisk flow of CSF (approximately 20 to 25 mL is produced every hour), even discarding 10 mL will take only 30 minutes for the body to replace [44]. RBC count The greater the RBC count in the last tube, the more likely SAH is the cause. In one study examining CSF results in 1739 patients with acute nontraumatic headache, fewer than 2000 RBCs/microL in addition to no xanthochromia excluded aneurysmal SAH with a sensitivity of 100 percent [45]. In a retrospective report of over 4400 adults who had lumbar puncture in the emergency department, finding fewer than 100 RBCs/microL in the CSF greatly decreased the likelihood of a SAH [43]. These results require independent prospective confirmation. Xanthochromia Xanthochromia (pink or yellow tint) represents hemoglobin degradation products. An otherwise unexplained xanthochromic supernatant in CSF is highly suggestive https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 7/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate of SAH. Xanthochromia determined by visual inspection Xanthochromia may be visually detected by comparing a vial of CSF with a vial of plain water held side by side against a white background in bright light [46]. The presence of xanthochromia indicates that blood has been in the CSF for at least two hours. Therefore, if the CSF is analyzed quickly after a traumatic lumbar puncture or SAH, there will not be xanthochromia; the absence of xanthochromia cannot be used as evidence of a traumatic tap if a lumbar puncture is performed in a SAH of less than two hours duration. Over the course of the ensuing hours, more patients will have xanthochromia, and by 12 hours post SAH, 100 percent of patients will have xanthochromia, even when measured visually [47]. Xanthochromia lasts for two weeks or more [48,49]. One retrospective study identified 117 adults with no known history of aneurysm or previous SAH who presented to the emergency room with thunderclap headache [50]. All had a negative noncontrast head CT followed by lumbar puncture. Xanthochromic CSF was found by visual inspection in 18 patients (15 percent). Those patients then had four-vessel catheter angiography, which detected a ruptured cerebral aneurysm in 13 (72 percent). One patient with no xanthochromia had an elevated RBC count ( 20,000 RBC/microL) in four successive collection tubes and a ruptured aneurysm by angiography. In this series, xanthochromia for the detection of cerebral aneurysms had a sensitivity and specificity of 93 and 95 percent. Other conditions that can produce xanthochromia include increased CSF concentrations of protein (150 mg/dL), systemic hyperbilirubinemia (serum bilirubin >10 to 15 mg/dL), and traumatic lumbar puncture with more than 100,000 RBCs/microL. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Xanthochromia'.) Xanthochromia determined by spectrophotometry Spectrophotometry detects blood breakdown products as they progress from oxyhemoglobin to methemoglobin and finally to bilirubin [48,51,52]. Bilirubin concentration peaks about 48 hours after SAH onset, and may last as long as four weeks after extensive, large-volume SAH [53]. While CSF spectrophotometry is more sensitive than visual inspection for xanthochromia, it is not universally recommended. As a practical matter, spectrophotometry of CSF is rarely available in North American hospitals [54]. The sample of CSF to be tested by spectrophotometry should be the one that contains the least amount of bloodstain. It should be protected from light and sent immediately https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 8/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate to the laboratory for analysis [48,53]. Spectrophotometry for detection of bilirubin is highly sensitive (>95 percent) when lumbar puncture is done at least 12 hours after SAH [49]. Although xanthochromia is generally identified by visual inspection, laboratory confirmation with CSF spectrophotometry is more sensitive and is recommended by some experts, if available [48,53,55-57]. In one study, 11 analysts compared xanthochromic CSF samples using visual and spectrophotometric analysis [56]. The spectrophotometric detection of bilirubin was significantly higher than visual detection in conditions where CSF samples were contaminated by presence of hemolyzed blood, or when CSF samples contained low levels of bilirubin. However, in a study comparing visual inspection with spectrophotometry, CSF that was considered colorless by visual inspection was not compatible with a diagnosis of SAH [58]. Despite a higher sensitivity than visual inspection for the detection of xanthochromia, CSF spectrophotometry has only a low to moderate specificity for the diagnosis of SAH [59]. Alternative approaches One alternative approach to the diagnosis of aneurysmal SAH is to follow a negative head CT with CTA rather than lumbar puncture (LP). Another involves omitting the LP for select patients who have a negative head CT performed within six hours of headache onset. The utility of MRI in place of head CT for detecting SAH is supported by limited data. CT followed by CTA As CTA has become more available, some physicians have advocated the use of CTA (rather than LP) after a negative head CT for the diagnosis of aneurysmal SAH [60,61]. Chief among the various potential downstream implications is finding an asymptomatic aneurysm, which occurs in approximately 3 percent of the population [62,63]. Two cost- effectiveness studies concluded that the standard approach with CT followed by LP approach is equivalent or better than a CT/CTA approach [64,65]. Therefore, we recommend the standard approach using CT, followed by LP if CT is negative, reserving CTA for patients with a positive noncontrast CT or CSF analysis. Need for LP when early CT is negative Because the consequences of missing SAH are potentially dire, we recommend a LP when the CT scan is negative for blood, as do most guidelines [41,61]. In contrast, some experts have argued that the sensitivity of CT when performed within six hours of the onset of symptoms is sufficiently sensitive (95.5 to 100 percent) to make a follow-up LP unnecessary [22,38,66,67]. In a prospective study that reported 95.5 percent sensitivity, there were five missed SAH cases, which included two false positives (attributed to a traumatic LP), one CT scan misinterpreted initially as negative for blood, one https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 9/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate case of nonaneurysmal SAH, and one case of SAH that was not detected on CT due to anemia [22]. A meta-analysis published in 2016 found that less than 1.5 in 1000 patients with SAH would be missed if no LP was done in patients who met the following conditions: a normal head CT using a modern scanner within six hours of headache onset (with a clear time of onset); CT interpretation by an experienced radiologist; a normal neurologic examination; and presentation with an isolated thunderclap headache [28]. There are important caveats ( table 10) that suggest that this approach must be applied carefully and cautiously [20]. One is that such studies are performed in centers where CT scans are generally interpreted by expert reviewers (eg, at least the level of an attending radiologist). A second is that the sensitivity of CT may be reduced when symptoms are atypical, such as isolated neck pain. A third is that detection of blood on CT is unreliable when there is significant anemia (ie, hemoglobin <10g/dL [<100 g/l] or hematocrit <30 percent [<0.30]) [22,68]. Other experts have questioned whether LP is ever needed after a negative head CT in the diagnosis of SAH, based upon both Bayesian analysis (the post-test likelihood after a negative CT is sufficiently low to rule out SAH) and empiric data [21,69,70]. However, in a prospective study of patients with acute severe headache, the diagnosis of SAH was missed by CT in 17 of 119 patients (14 percent) with SAH who had initial CT performed more than six hours after the onset of headache [38]. We therefore continue to recommend LP after a negative CT, while other experts advise omitting the LP for select patients who meet all the criteria outlined in the table ( table 10). Brain MRI Limited data suggest that proton density and fluid-attenuated inversion recovery (FLAIR) sequences on brain MRI may be as sensitive as head CT for the acute detection of SAH [71]. In addition, FLAIR and T2* sequences on MRI have a high sensitivity in patients with a subacute presentation of SAH (ie, 4 to 14 days from the onset of hemorrhage) [72]. However, MRI is seldom obtained as the first study for suspected SAH because it is typically less readily available than CT [15]. As with a negative CT scan, LP should follow a negative MRI if a patient is suspected to have SAH [41,73]. DIFFERENTIAL DIAGNOSIS Aneurysmal SAH is always the primary consideration when a patient presents with an abrupt onset headache. However, a number of other conditions listed in the table can cause a similar presentation ( table 9). These are discussed in detail separately. (See "Overview of thunderclap headache".) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 10/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate IDENTIFYING THE SOURCE OF BLEEDING Choosing initial angiography Once a diagnosis of SAH has been made, the etiology of the hemorrhage must be determined with angiographic studies. We prefer conventional digital subtraction angiography (DSA) because it has the best resolution for the detection of aneurysms and can facilitate endovascular treatment as part of the same procedure. However, many centers use noninvasive imaging with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) as the initial study, reserving DSA for cases when noninvasive imaging does not identify the cause of the SAH. A major advantage of CTA over DSA is the speed and ease by which it can be obtained, often immediately after the diagnosis of SAH is made by head computed tomography (CT) when the patient is still in the scanner. CTA is increasingly used as an alternative to DSA in many patients with SAH, thereby avoiding the need for DSA in some cases during the pre-interventional phase of management [74,75]. CTA is particularly useful in the acute setting in a rapidly declining patient who needs emergent craniotomy for hematoma evacuation. Furthermore, CTA offers a more practical approach to acute diagnosis than MRA, given the constraints of acute patient management. However, DSA will often be needed after CTA, as primary treatment when feasible should involve endovascular approaches. (See "Treatment of cerebral aneurysms".) Digital subtraction angiography Of the available tests, DSA is believed to have the highest resolution to detect intracranial aneurysms and define their anatomic features and remains the gold standard test for this indication [41,76]. Most ruptured aneurysms can be readily identified using standard cross-sectional imaging techniques coupled with DSA that includes injections of bilateral vertebral and internal carotid arteries, as well as the external carotid circulation and deep cervical branches, all of which may supply a cryptic dural arteriovenous fistula. Angiographic demonstration of key branch points, including the proximal posterior circulation, is essential to definitively rule out aneurysm. As an increasing number of aneurysms are treated endovascularly, another advantage of DSA is the ability to both diagnose and then definitively treat the aneurysm in the same sitting. (See "Treatment of cerebral aneurysms".) The morbidity of DSA in patients with SAH is relatively low. In a meta-analysis of three prospective studies, for example, the combined risk of permanent and transient neurologic complications was significantly lower in patients with SAH compared with those with a transient ischemic attack (TIA) or stroke (1.8 versus 3.7 percent) [77]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 11/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate CT and MR angiography CTA and MRA are noninvasive tests that are useful for screening and presurgical planning. Both CTA and MRA can identify aneurysms 3 mm with a high degree of sensitivity [78], but they do not achieve the resolution of conventional angiography (ie, DSA). The sensitivity of CTA for the detection of ruptured aneurysms, using DSA as the gold standard, is 83 to 98 percent [79-85]. Small aneurysms (especially 2 mm) may not be reliably identified. Although small aneurysms rupture less frequently than large aneurysms [86], they are more common, and rupture of small aneurysms (approximately 5 mm or less) accounts for nearly one- half of SAH cases [87-89]. Therefore, DSA should be performed if CTA does not reveal an aneurysm in a patient with SAH [41]. As technology improves, the sensitivity and specificity of noninvasive imaging is also likely to improve [90]. A 2011 meta-analysis of CTA diagnosis of intracranial aneurysms found that, compared with single-detector CTA, use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms 4 mm in diameter [91]. Another systematic review and meta-analysis restricted to patients with SAH had similar findings [92]. While a "spot sign" (ie, contrast extravasation) on CTA is associated with risk of hemorrhage expansion or rebleeding in patients with intracerebral hemorrhage, this is not the case for SAH [93,94]. It is likely that this sign, while appearing similar, actually reflects different processes when observed in SAH versus intracerebral hemorrhage. Patients with negative angiography Repeat angiography No angiographic cause of SAH is evident in 14 to 22 percent of cases. It is critical to repeat the angiogram in 4 to 14 days if the initial angiogram is negative. The recommended follow-up test in this setting is usually DSA. Up to 24 percent of all SAH patients with initial negative angiography have an aneurysm found on repeat angiography [95-99]. This may increase to as much as 49 percent if patients with perimesencephalic SAH and patients with normal CT scans are excluded [96]. Reasons for an initial false-negative angiogram include technical or reading errors, small aneurysm size, and obscuration of the aneurysm because of vasospasm, hematoma, or thrombosis within the aneurysm [95,96,100,101]. A third angiogram (DSA) at a period of two to three months is advocated by some, but is probably not necessary if the initial two studies are felt to be well-performed and expertly reviewed (see "Nonaneurysmal subarachnoid hemorrhage"). However, patients with SAH and a second negative angiogram should have a brain and spine MRI to look for possible vascular malformation of the brain or spinal cord [15]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 12/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Nonaneurysmal SAH An estimated 15 to 20 percent of SAH cases are nonaneurysmal. The causes of nonaneurysmal SAH are potentially diverse, and include perimesencephalic hemorrhage, vascular malformations, intracranial arterial dissection, and a variety of other etiologies. The mechanism of bleeding in these cases is often not identified. (See "Nonaneurysmal subarachnoid hemorrhage".) Some patients with an initially negative angiogram have blood in the cisterns around the midbrain on head CT, which reflects a perimesencephalic pattern of hemorrhage ( image 2). Perimesencephalic hemorrhage accounts for about 10 percent of all cases of SAH and a majority of patients with nonaneurysmal SAH. Most patients with perimesencephalic hemorrhage do not have an aneurysm or other defined etiology. The need for repeat angiography in patients with perimesencephalic hemorrhage is discussed in detail separately. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage", section on 'The role of repeat angiography' and "Nonaneurysmal subarachnoid hemorrhage", section on 'The role of repeat cerebral angiography'.) COMPLICATIONS A variety of early complications can occur with SAH, including rebleeding, hydrocephalus, cerebral edema, vasospasm and delayed cerebral ischemia, seizures, hyponatremia, cardiopulmonary abnormalities, and neuroendocrine dysfunction. These are discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Early complications'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 13/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Brain aneurysm (The Basics)" and "Patient education: Subarachnoid hemorrhage (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Clinical presentation The overwhelming majority of patients with aneurysmal subarachnoid hemorrhage (SAH) present with a sudden-onset severe headache, which may be associated with brief loss of consciousness, seizures, nausea or vomiting, or meningismus. (See 'Clinical presentation' above.) Evaluation and diagnosis Sudden onset of headache, regardless of severity or prior headache history, should raise the clinical suspicion for SAH and compel a diagnostic evaluation. (See 'Evaluation and diagnosis' above.) Imaging Noncontrast head computed tomography (CT) reveals the diagnosis in more than 90 percent of cases if performed within 24 hours of bleeding onset. (See 'Head CT scan' above.) Lumbar puncture Lumbar puncture is mandatory if there is a strong suspicion of SAH despite a normal head CT, with the disputed exception of select patients with isolated headache and normal examination presenting early and scanned within six hours of headache onset. (See 'Lumbar puncture' above.) The classic findings are an elevated opening pressure, an elevated red blood cell count that does not diminish from cerebrospinal fluid (CSF) tube 1 to tube 4, and xanthochromia. Immediate centrifugation of the CSF can help differentiate bleeding in SAH from that due to a traumatic spinal tap. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 14/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Identifying the source of bleeding Once a diagnosis of SAH has been made, the etiology of the hemorrhage must be determined with vascular imaging. Of the available tests, digital subtraction angiography (DSA) has the highest resolution to detect intracranial aneurysms and define their anatomic features and remains the gold standard test for this,

is 83 to 98 percent [79-85]. Small aneurysms (especially 2 mm) may not be reliably identified. Although small aneurysms rupture less frequently than large aneurysms [86], they are more common, and rupture of small aneurysms (approximately 5 mm or less) accounts for nearly one- half of SAH cases [87-89]. Therefore, DSA should be performed if CTA does not reveal an aneurysm in a patient with SAH [41]. As technology improves, the sensitivity and specificity of noninvasive imaging is also likely to improve [90]. A 2011 meta-analysis of CTA diagnosis of intracranial aneurysms found that, compared with single-detector CTA, use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms 4 mm in diameter [91]. Another systematic review and meta-analysis restricted to patients with SAH had similar findings [92]. While a "spot sign" (ie, contrast extravasation) on CTA is associated with risk of hemorrhage expansion or rebleeding in patients with intracerebral hemorrhage, this is not the case for SAH [93,94]. It is likely that this sign, while appearing similar, actually reflects different processes when observed in SAH versus intracerebral hemorrhage. Patients with negative angiography Repeat angiography No angiographic cause of SAH is evident in 14 to 22 percent of cases. It is critical to repeat the angiogram in 4 to 14 days if the initial angiogram is negative. The recommended follow-up test in this setting is usually DSA. Up to 24 percent of all SAH patients with initial negative angiography have an aneurysm found on repeat angiography [95-99]. This may increase to as much as 49 percent if patients with perimesencephalic SAH and patients with normal CT scans are excluded [96]. Reasons for an initial false-negative angiogram include technical or reading errors, small aneurysm size, and obscuration of the aneurysm because of vasospasm, hematoma, or thrombosis within the aneurysm [95,96,100,101]. A third angiogram (DSA) at a period of two to three months is advocated by some, but is probably not necessary if the initial two studies are felt to be well-performed and expertly reviewed (see "Nonaneurysmal subarachnoid hemorrhage"). However, patients with SAH and a second negative angiogram should have a brain and spine MRI to look for possible vascular malformation of the brain or spinal cord [15]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 12/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Nonaneurysmal SAH An estimated 15 to 20 percent of SAH cases are nonaneurysmal. The causes of nonaneurysmal SAH are potentially diverse, and include perimesencephalic hemorrhage, vascular malformations, intracranial arterial dissection, and a variety of other etiologies. The mechanism of bleeding in these cases is often not identified. (See "Nonaneurysmal subarachnoid hemorrhage".) Some patients with an initially negative angiogram have blood in the cisterns around the midbrain on head CT, which reflects a perimesencephalic pattern of hemorrhage ( image 2). Perimesencephalic hemorrhage accounts for about 10 percent of all cases of SAH and a majority of patients with nonaneurysmal SAH. Most patients with perimesencephalic hemorrhage do not have an aneurysm or other defined etiology. The need for repeat angiography in patients with perimesencephalic hemorrhage is discussed in detail separately. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage", section on 'The role of repeat angiography' and "Nonaneurysmal subarachnoid hemorrhage", section on 'The role of repeat cerebral angiography'.) COMPLICATIONS A variety of early complications can occur with SAH, including rebleeding, hydrocephalus, cerebral edema, vasospasm and delayed cerebral ischemia, seizures, hyponatremia, cardiopulmonary abnormalities, and neuroendocrine dysfunction. These are discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Early complications'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 13/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Brain aneurysm (The Basics)" and "Patient education: Subarachnoid hemorrhage (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Clinical presentation The overwhelming majority of patients with aneurysmal subarachnoid hemorrhage (SAH) present with a sudden-onset severe headache, which may be associated with brief loss of consciousness, seizures, nausea or vomiting, or meningismus. (See 'Clinical presentation' above.) Evaluation and diagnosis Sudden onset of headache, regardless of severity or prior headache history, should raise the clinical suspicion for SAH and compel a diagnostic evaluation. (See 'Evaluation and diagnosis' above.) Imaging Noncontrast head computed tomography (CT) reveals the diagnosis in more than 90 percent of cases if performed within 24 hours of bleeding onset. (See 'Head CT scan' above.) Lumbar puncture Lumbar puncture is mandatory if there is a strong suspicion of SAH despite a normal head CT, with the disputed exception of select patients with isolated headache and normal examination presenting early and scanned within six hours of headache onset. (See 'Lumbar puncture' above.) The classic findings are an elevated opening pressure, an elevated red blood cell count that does not diminish from cerebrospinal fluid (CSF) tube 1 to tube 4, and xanthochromia. Immediate centrifugation of the CSF can help differentiate bleeding in SAH from that due to a traumatic spinal tap. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 14/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Identifying the source of bleeding Once a diagnosis of SAH has been made, the etiology of the hemorrhage must be determined with vascular imaging. Of the available tests, digital subtraction angiography (DSA) has the highest resolution to detect intracranial aneurysms and define their anatomic features and remains the gold standard test for this, but CT angiography is being increasingly used as a first-line vascular test. (See 'Identifying the source of bleeding' above.) Repeat angiography is necessary if the initial study is negative, unless the pattern of hemorrhage is perimesencephalic, in which a repeat angiography may be considered optional. Additional testing is required for SAH that is nonaneurysmal. (See 'Patients with negative angiography' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000; 342:29. 2. Perry JJ, Stiell IG, Sivilotti ML, et al. Clinical decision rules to rule out subarachnoid hemorrhage for acute headache. JAMA 2013; 310:1248. 3. Perry JJ, Sivilotti MLA, Sutherland J, et al. Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache. CMAJ 2017; 189:E1379. 4. Perry JJ, Stiell IG, Sivilotti ML, et al. High risk clinical characteristics for subarachnoid haemorrhage in patients with acute headache: prospective cohort study. BMJ 2010; 341:c5204. 5. Perry DC, Bruce C. Evaluating the child who presents with an acute limp. BMJ 2010; 341:c4250. 6. Claassen J, Park S. Spontaneous subarachnoid haemorrhage. Lancet 2022; 400:846. 7. Schievink WI. Intracranial aneurysms. N Engl J Med 1997; 336:28. 8. Butzkueven H, Evans AH, Pitman A, et al. Onset seizures independently predict poor outcome after subarachnoid hemorrhage. Neurology 2000; 55:1315. 9. Lindbohm JV, Kaprio J, Jousilahti P, et al. Risk Factors of Sudden Death From Subarachnoid Hemorrhage. Stroke 2017; 48:2399. 10. Polmear A. Sentinel headaches in aneurysmal subarachnoid haemorrhage: what is the true incidence? A systematic review. Cephalalgia 2003; 23:935. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 15/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate 11. Schievink WI, Karemaker JM, Hageman LM, van der Werf DJ. Circumstances surrounding aneurysmal subarachnoid hemorrhage. Surg Neurol 1989; 32:266. 12. Matsuda M, Watanabe K, Saito A, et al. Circumstances, activities, and events precipitating aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 2007; 16:25. 13. McCarron MO, Alberts MJ, McCarron P. A systematic review of Terson's syndrome: frequency and prognosis after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2004; 75:491. 14. Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006; 354:387. 15. Suarez JI. Diagnosis and Management of Subarachnoid Hemorrhage. Continuum (Minneap Minn) 2015; 21:1263. 16. Woodruff MM, Edlow JA. Evaluation of third nerve palsy in the emergency department. J Emerg Med 2008; 35:239. 17. Edlow JA, Malek AM, Ogilvy CS. Aneurysmal subarachnoid hemorrhage: update for emergency physicians. J Emerg Med 2008; 34:237. 18. Giraldo EA, Mandrekar JN, Rubin MN, et al. Timing of clinical grade assessment and poor outcome in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2012; 117:15. 19. van Donkelaar CE, Bakker NA, Veeger NJ, et al. Prediction of outcome after subarachnoid hemorrhage: timing of clinical assessment. J Neurosurg 2017; 126:52. 20. Edlow JA. 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Can computed tomography angiography of the brain replace lumbar puncture in the evaluation of acute-onset headache after a negative noncontrast cranial computed tomography scan? Acad Emerg Med 2010; 17:444. 61. Meurer WJ, Walsh B, Vilke GM, Coyne CJ. Clinical Guidelines for the Emergency Department Evaluation of Subarachnoid Hemorrhage. J Emerg Med 2016; 50:696. 62. Edlow JA. What are the unintended consequences of changing the diagnostic paradigm for subarachnoid hemorrhage after brain computed tomography to computed tomographic angiography in place of lumbar puncture? Acad Emerg Med 2010; 17:991. 63. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10:626. 64. Alons IM, van den Wijngaard IR, Verheul RJ, et al. The value of CT angiography in patients with acute severe headache. Acta Neurol Scand 2015; 131:164. 65. 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Topic 1130 Version 27.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 22/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate GRAPHICS Hunt and Hess grading system for patients with subarachnoid hemorrhage Grade Neurologic status 1 Asymptomatic or mild headache and slight nuchal rigidity 2 Severe headache, stiff neck, no neurologic deficit except cranial nerve palsy 3 Drowsy or confused, mild focal neurologic deficit 4 Stuporous, moderate or severe hemiparesis 5 Coma, decerebrate posturing Based upon initial neurologic examination. Adapted from: Hunt W, Hess R. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968; 28:14. Graphic 69179 Version 5.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 23/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Focal physical findings in patients with subarachnoid hemorrhage Findings Likely cause Third nerve palsy Usually posterior communicating aneurysm; also posterior cerebral artery and superior cerebellar artery aneurysms Sixth nerve palsy Elevated intracranial pressure (false localizing sign) Combination of hemiparesis and aphasia or visuospatial neglect Middle cerebral artery aneurysm, thick subarachnoid clots, or parenchymal hematomas Bilateral leg weakness and abulia Anterior communicating artery aneurysm Ophthalmoplegia Internal carotid artery aneurysm impinging upon the cavernous sinus Unilateral visual loss or bitemporal hemianopia Internal carotid artery aneurysm compressing optic nerve or optic chiasm Impaired level of consciousness and impaired Pressure on the dorsal midbrain due to upward gaze hydrocephalus Brainstem signs Brainstem compression by basilar artery aneurysm Neck stiffness Meningeal irritation by the presence of subarachnoid blood Retinal and subhyaloid hemorrhages Sudden increase of intracranial pressure Preretinal hemorrhages (Terson syndrome) Vitreous hemorrhage due to severe elevations of intracranial pressure From: Suarez JI. Diagnosis and Management of Subarachnoid Hemorrhage. Continuum (Minneap Minn) 2015; 21:1263. DOI: 10.1212/CON.0000000000000217. Copyright 2015 American Academy of Neurology. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121321 Version 2.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 24/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate World Federation of Neurological Surgeons subarachnoid hemorrhage grading scale Grade GCS score Motor deficit 1 15 Absent 2 13 to 14 Absent 3 13 to 14 Present 4 7 to 12 Present or absent 5 3 to 6 Present or absent GCS: Glasgow Coma Scale. Data from: Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988; 68:985. Graphic 65468 Version 3.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 25/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 26/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate [1] Fisher grade of cerebral vasospasm risk in subarachnoid hemorrhage Group Appearance of blood on head CT scan 1 No blood detected 2 Diffuse deposition or thin layer with all vertical layers (in interhemispheric fissure, insular cistern, ambient cistern) less than 1 mm thick 3 Localized clot and/or vertical layers 1 mm or more in thickness 4 Intracerebral or intraventricular clot with diffuse or no subarachnoid blood CT: computed tomography. Reference: 1. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980; 6:1. Graphic 81122 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 27/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Modified Fisher (Claassen) subarachnoid hemorrhage CT rating scale Grade Head CT criteria 0 No SAH or IVH 1 Minimal SAH and no IVH 2 Minimal SAH with bilateral IVH 3 Thick SAH (completely filling one or more cistern or fissure) without bilateral IVH 4 Thick SAH (completely filling one or more cistern or fissure) with bilateral IVH CT: computed tomography; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. From: Claassen J, Bernardini GL, Kreiter K, et al. E ect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001; 32:2012. Graphic 57558 Version 5.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 28/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Ogilvy and Carter grading system to predict outcome for surgical management of intracranial aneurysms Criteria Points Age 50 or less 0 Age greater than 50 1 Hunt and Hess grade 0 to 3 (no coma) 0 Hunt and Hess grade 4 and 5 (in coma) 1 Fisher scale score 0 to 2 0 Fisher scale score 3 and 4 1 Aneurysm size 10 mm or less 0 Aneurysm size greater than 10 mm 1 Giant posterior circulation aneurysm size 25 mm or more 1 The total score ranges from 0 to 5, corresponding to grades 0 to 5 Adapted from: Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict outcome for surgical management of intracranial aneurysms. Neurosurgery 1998; 42:959. Graphic 70705 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 29/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate [1] Reasons for misdiagnosis of subarachnoid hemorrhage Failure to recognize spectrum of presentation of subarachnoid hemorrhage Not obtaining complete history from patients with unusual (for the patient) headaches Is the onset abrupt? Is the quality different and severity greater than prior headaches? Failure to appreciate that the headache can improve spontaneously or with non-narcotic analgesics Focusing on the secondary head injury resulting from syncope and fall or motor vehicle collision Focusing on ECG abnormalities Focusing on elevated blood pressure Overreliance on the classic presentation Misdiagnosis of other disorders (eg, viral syndrome, viral meningitis, migraine, tension-type headache, sinus-related headache, psychiatric disorder) Failure to understand the limitations of head CT scanning Sensitivity decreases as onset of headache increases False-negative results with small-volume bleeds Scan interpreted by inexperienced physician Motion artifacts or lack of thin cuts of posterior fossa False-negative results due to hematocrit of less than 30% Failure to perform lumbar puncture or interpret the CSF findings correctly Failure to perform lumbar puncture in patients with negative or inconclusive CT scans Failure to distinguish a traumatic tap from true subarachnoid hemorrhage Failure to recognize that xanthochromia may be absent very early (less than 12 hours) and very late (more than 2 weeks) ECG: electrocardiogram; CT: computed tomography; CSF: cerebrospinal fluid. Reference: 1. Suarez JI. Diagnosis and Management of Subarachnoid Hemorrhage. Continuum (Minneap Minn) 2015; 21:1263. Original gure modi ed for this publication. From: Edlow JA, Malek AM, Ogilvy CS. Aneurysmal subarachnoid hemorrhage: update for emergency physicians. J Emerg Med 2008; 34:237. Table used with the permission of Elsevier Inc. All rights https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 30/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate reserved. Graphic 121322 Version 1.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 31/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 32/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 33/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Various radiologic patterns of subarachnoid hemorrhage on noncontrast compu tomography (CT) of the head (A) Obvious large SAH: hyperdense blood in all the basal cisterns, with some dilatation of the temporal horn the lateral ventricles, suggesting early hydrocephalus. (B) More subtle, smaller SAH: small hyperdense collection of blood in the basal cistern adjacent to the left p and suprasellar cistern (short solid arrow). (C) Perimesencephalic SAH: the long solid arrows indicate a perimesencephalic (sometimes called a pretrun SAH. These hemorrhages represent approximately 10% of nontraumatic SAHs. They are thought to be caused venous bleeding, will have a negative CTA result, and usually have an excellent outcome. However, the radiographic pattern is also observed with posterior circulation aneurysms, so all of these patients require neurosurgical consultation and vascular imaging. (D) Convexal SAH: the arrowheads indicate a high convexal SAH. This pattern is observed in two groups of

26/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate [1] Fisher grade of cerebral vasospasm risk in subarachnoid hemorrhage Group Appearance of blood on head CT scan 1 No blood detected 2 Diffuse deposition or thin layer with all vertical layers (in interhemispheric fissure, insular cistern, ambient cistern) less than 1 mm thick 3 Localized clot and/or vertical layers 1 mm or more in thickness 4 Intracerebral or intraventricular clot with diffuse or no subarachnoid blood CT: computed tomography. Reference: 1. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980; 6:1. Graphic 81122 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 27/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Modified Fisher (Claassen) subarachnoid hemorrhage CT rating scale Grade Head CT criteria 0 No SAH or IVH 1 Minimal SAH and no IVH 2 Minimal SAH with bilateral IVH 3 Thick SAH (completely filling one or more cistern or fissure) without bilateral IVH 4 Thick SAH (completely filling one or more cistern or fissure) with bilateral IVH CT: computed tomography; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. From: Claassen J, Bernardini GL, Kreiter K, et al. E ect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001; 32:2012. Graphic 57558 Version 5.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 28/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Ogilvy and Carter grading system to predict outcome for surgical management of intracranial aneurysms Criteria Points Age 50 or less 0 Age greater than 50 1 Hunt and Hess grade 0 to 3 (no coma) 0 Hunt and Hess grade 4 and 5 (in coma) 1 Fisher scale score 0 to 2 0 Fisher scale score 3 and 4 1 Aneurysm size 10 mm or less 0 Aneurysm size greater than 10 mm 1 Giant posterior circulation aneurysm size 25 mm or more 1 The total score ranges from 0 to 5, corresponding to grades 0 to 5 Adapted from: Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict outcome for surgical management of intracranial aneurysms. Neurosurgery 1998; 42:959. Graphic 70705 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 29/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate [1] Reasons for misdiagnosis of subarachnoid hemorrhage Failure to recognize spectrum of presentation of subarachnoid hemorrhage Not obtaining complete history from patients with unusual (for the patient) headaches Is the onset abrupt? Is the quality different and severity greater than prior headaches? Failure to appreciate that the headache can improve spontaneously or with non-narcotic analgesics Focusing on the secondary head injury resulting from syncope and fall or motor vehicle collision Focusing on ECG abnormalities Focusing on elevated blood pressure Overreliance on the classic presentation Misdiagnosis of other disorders (eg, viral syndrome, viral meningitis, migraine, tension-type headache, sinus-related headache, psychiatric disorder) Failure to understand the limitations of head CT scanning Sensitivity decreases as onset of headache increases False-negative results with small-volume bleeds Scan interpreted by inexperienced physician Motion artifacts or lack of thin cuts of posterior fossa False-negative results due to hematocrit of less than 30% Failure to perform lumbar puncture or interpret the CSF findings correctly Failure to perform lumbar puncture in patients with negative or inconclusive CT scans Failure to distinguish a traumatic tap from true subarachnoid hemorrhage Failure to recognize that xanthochromia may be absent very early (less than 12 hours) and very late (more than 2 weeks) ECG: electrocardiogram; CT: computed tomography; CSF: cerebrospinal fluid. Reference: 1. Suarez JI. Diagnosis and Management of Subarachnoid Hemorrhage. Continuum (Minneap Minn) 2015; 21:1263. Original gure modi ed for this publication. From: Edlow JA, Malek AM, Ogilvy CS. Aneurysmal subarachnoid hemorrhage: update for emergency physicians. J Emerg Med 2008; 34:237. Table used with the permission of Elsevier Inc. All rights https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 30/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate reserved. Graphic 121322 Version 1.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 31/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 32/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 33/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Various radiologic patterns of subarachnoid hemorrhage on noncontrast compu tomography (CT) of the head (A) Obvious large SAH: hyperdense blood in all the basal cisterns, with some dilatation of the temporal horn the lateral ventricles, suggesting early hydrocephalus. (B) More subtle, smaller SAH: small hyperdense collection of blood in the basal cistern adjacent to the left p and suprasellar cistern (short solid arrow). (C) Perimesencephalic SAH: the long solid arrows indicate a perimesencephalic (sometimes called a pretrun SAH. These hemorrhages represent approximately 10% of nontraumatic SAHs. They are thought to be caused venous bleeding, will have a negative CTA result, and usually have an excellent outcome. However, the radiographic pattern is also observed with posterior circulation aneurysms, so all of these patients require neurosurgical consultation and vascular imaging. (D) Convexal SAH: the arrowheads indicate a high convexal SAH. This pattern is observed in two groups of patients. In younger patients, it is usually due to RCVS, but in older ones, it often indicates amyloid angiopath a patient presenting with a severe rapid-onset headache, RCVS would be the likely diagnosis. (E) Traumatic SAH: the history usually suggests a traumatic SAH (the most common cause). However, if this pattern (dashed arrows indicate small amounts of SAH abutting bone, often in the anterior frontal and temp bones) is observed in a patient without a clear history of trauma, the likely cause is a traumatic SAH. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 34/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate SAH: subarachnoid hemorrhage; CTA: computed tomography angiography; RCVS: reversible cerebral vasoconstriction syndrome. Reproduced from: Edlow JA. Managing Patients With Nontraumatic, Severe, Rapid-Onset Headache. Ann Emerg Med 2018; 71:400. Illus used with the permission of Elsevier Inc. All rights reserved. Graphic 121315 Version 1.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 35/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Considerations for omitting the lumbar puncture in patients who have a negative CT within six hours of headache onset in the evaluation for subarachnoid hemorrhage Patient factors The time of onset of the headache is clearly defined. The CT is performed within six hours of headache onset. The presentation is an isolated severe rapid-onset headache (no primary neck pain, seizure, or syncope at onset, or other atypical presentations). There is no meningismus and the neurologic examination result is normal. Radiologic factors The CT scanner is a modern, third-generation or newer machine with thin cuts through the brain. The CT is technically adequate, without significant motion artifact. The hematocrit level is >30%. The physician interpreting the scan is an attending-level radiologist (or has equivalent experience in reading brain CT scans). Radiologists should specifically examine the brain CTs for subtle hydrocephalus, small amounts of blood in the dependent portions of the ventricles, and small amounts of isodense or hyperdense material in the basal cisterns. Communication factors The clinician should communicate the specific concern to the radiologist (eg, "severe acute headache; rule out SAH"). After a negative CT result, the clinician should communicate the posttest risk of SAH that persists (1 to 2 per 1000). CT: computed tomography; SAH: subarachnoid hemorrhage. Reproduced from: Edlow JA. Managing Patients With Nontraumatic, Severe, Rapid-Onset Headache. Ann Emerg Med 2018; 71:400. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 121294 Version 1.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 36/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Perimesencephalic subarachnoid hemorrhage CT scan demonstrates the typical findings of a nonaneurysmal perimesencephalic subarachnoid hemorrhage. Note the predominance of hemorrhage in the interpeduncular fossa (arrow). CT: computed tomography. Courtesy of Guy Rordorf, MD. Graphic 72476 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 37/38 7/7/23, 11:26 AM Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis - UpToDate Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-clinical-manifestations-and-diagnosis/print 38/38

7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 08, 2023. INTRODUCTION Twenty percent of strokes are hemorrhagic, with subarachnoid hemorrhage (SAH) and intracerebral hemorrhage, each accounting for 10 percent. Most spontaneous SAHs are caused by ruptured saccular aneurysms. Other causes include occult trauma, arteriovenous malformations/fistulae, vasculitides, intracranial arterial dissections, amyloid angiopathy, bleeding diatheses, and illicit drug use (especially cocaine and amphetamines). The epidemiology and risk factors of aneurysmal SAH are reviewed here. Other aspects of intracranial aneurysms and aneurysmal SAH are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) (See "Unruptured intracranial aneurysms".) Mycotic aneurysms and nonaneurysmal subarachnoid hemorrhage are discussed elsewhere. (See "Overview of infected (mycotic) arterial aneurysm".) (See "Nonaneurysmal subarachnoid hemorrhage".) (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) EPIDEMIOLOGY https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 1/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate In a systematic review and meta-analysis, the overall crude global incidence of aneurysmal SAH across all study periods was 7.9 per 100,000 person-years [1]. By time trends, the SAH incidence for 2010 was 6.1 per 100,000 person-years in 2010, having declined from 1980 when the incidence was 10.2 per 100,000 person-years. The incidence of aneurysmal SAH varies by geographic region [1]. For 2010, the incidence in North America was 6.9 per 100,000 person-years, and the rate was similar in Australia/New Zealand (7.4). A much higher rate was reported in Japan (28), while lower rates were reported in Asia excluding Japan (3.7), and in South and Central America (5.1). In a Swiss national database of patients admitted between 2009 and 2014, the incidence of SAH was 3.7 per 100,000 person- years [2]. The mean age of aneurysmal rupture is in the range of 50 to 55 years [3]. While most aneurysmal SAH occur between 40 and 60 years of age, young children and older adults can be affected [4-6]. Black Americans appear to be at higher risk than White Americans [7-9]. There is a slightly higher incidence of aneurysmal SAH in females, which may relate to hormonal status [4,9,10]. In a meta-analysis of nine prospective studies that assessed the risk factors for and rupture rates of 9940 patients' intracranial aneurysms, the rupture rate was higher for females than males (1 versus 0.7 percent, hazard ratio 1.43, 95% CI 1.1-1.9) [11]. The higher rupture rate for females persisted even after adjustment for other risk factors associated with aneurysm rupture. (See 'Estrogen deficiency' below.) RISK FACTORS Risk factors for SAH relate to anatomic features of the aneurysm and patient-level factors. Hypertension, cigarette smoking, and family history are among the most consistently observed risk factors [6,12,13]. Many risk factors for aneurysmal SAH are modifiable. Aneurysm size and location Most SAHs are due to the rupture of intracranial aneurysms. Both aneurysm size and location influence its risk of rupture. This is discussed in detail separately. (See "Unruptured intracranial aneurysms", section on 'Risk factors for aneurysm rupture'.) Cigarette smoking Cigarette smoking appears to be the most important preventable risk factor for SAH [12,14-20]. Among various longitudinal and case control studies the reported relative risk associated with current smoking ranges from 2 to 7. Heavy smokers have a higher risk than lighter smokers, and individuals who stop smoking have a risk of SAH that decreases over time [15,19,20]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 2/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate In one cohort study, the analysis suggested that smoking is a stronger risk factor for female individuals than males and that the risk factors of hypertension and smoking interact to create a joint risk that is stronger than the sum of the independent effects [21,22]. Hypertension Hypertension is also a major risk factor for SAH [12,16-18,23,24]. In a systematic review that included 3936 patients with SAH, hypertension was significantly associated with SAH risk in both the longitudinal (relative risk 2.5, 95% CI 2.0-3.1) and case- control studies (odds ratio 2.6, 95% CI 2.0-3.1) [16]. Genetic risk Most aneurysmal SAHs are not predominantly determined by genetic factors [25]. However, a number of relatively rare inherited conditions are associated with increased risk of cerebral aneurysm and SAH. These include autosomal dominant polycystic kidney disease, glucocorticoid-remediable aldosteronism, and Ehlers-Danlos syndrome. The risk of aneurysmal SAH associated with these conditions is discussed separately. (See "Screening for intracranial aneurysm", section on 'Hereditary syndromes associated with aneurysm formation'.) A family history of SAH also increases the risk of SAH in individuals without one of these conditions [12,26]. As an example, one case-control study found that patients with a family history of SAH had an odds ratio of 4.0 (95% CI 2.0-8.0) for SAH compared with controls [27]. Similarly, another study found that first-degree relatives of patients with SAH have a three- to fivefold increased risk of SAH compared with the general population [28]. Unruptured aneurysms in families with cerebral aneurysms are more likely to rupture than those found in individuals without a family history [29]. It may be reasonable to screen some family members for the presence of cerebral aneurysm. This issue is discussed in detail separately. (See "Screening for intracranial aneurysm", section on 'Relatives of patients with cerebral aneurysm'.) The genetic susceptibility to SAH appears to be heterogeneous; many genes on multiple chromosomes have been implicated in various families [30-41] . Some familial SAH pedigrees are most consistent with autosomal dominant inheritance, while others are more consistent with autosomal recessive or multifactorial transmission [42,43]. One study found evidence of anticipation in two successive generations of familial SAH, with affected parents significantly older than affected children (55.2 versus 35.4 years, respectively) [44]. Familial susceptibility to SAH can also be nongenetic and attributable to environmental and other shared risk factors [25]. Alcohol Moderate to heavy alcohol consumption appears to increase the risk of SAH [16,45]. In a systematic review, excessive alcohol intake was a significant risk factor for SAH in both the longitudinal (relative risk 2.1, 95% CI 1.5-2.8) and case-control studies (odds ratio 1.5, 95% CI 1.3- https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 3/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate 1.8) [16]. This association was confirmed in a subsequent meta-analysis which also found evidence of a linear dose-response [46]. Sympathomimetic drugs In case-control studies, phenylpropanolamine in appetite suppressants, and possibly cold remedies, appeared to be an independent risk factor for hemorrhagic stroke (including intracerebral hemorrhage and subarachnoid hemorrhage) in females [47,48]. Caffeine containing medications have also been associated with SAH [49]. Methamphetamine and cocaine abuse have also been associated with both aneurysmal and nonaneurysmal SAH [50-54]. In one study, methamphetamine use was associated with a more severe clinical presentation and worse outcome [55]. Similarly, acute cocaine use was associated with higher rates of rebleeding and in hospital mortality in one study [56]. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Other associated conditions'.) Estrogen deficiency There is a female preponderance for aneurysms ranging from 54 to 61 percent [10]. Because the sex discrepancy is present in older (>50 years) but not younger individuals, hormonal influences have been suggested to play a role in the risk of SAH. In one case-control study of patients without a history of smoking or hypertension, premenopausal females were at reduced risk of SAH compared with age-matched postmenopausal females (odds ratio 0.24) [57]. In an analysis of data from the Nurses' Health Study, shorter reproductive life span and early menopause (<45 years of age) were associated with an elevated risk of SAH [58]. Furthermore, the use of estrogen replacement therapy was associated with a reduced risk of SAH in postmenopausal females (odds ratio 0.47). Risk reduction with the use of estrogen replacement therapy has also been seen in other observational studies [16,59,60]; however, in the Women's Health Initiative Study, which included more than 90 thousand participants, SAH risk was higher among those who reported active use of hormone replacement therapy (relative risk 1.6) [61]. Hormonal effects may also explain the association between risk of SAH and repeated childbirth that was observed in one case-control study; each additional parity increased the risk with an odds ratio of 1.34 [62]. However, this association is not consistently observed, and physical and environmental factors during pregnancy and delivery are also likely factors [60]. Studies examining a relationship between risk of SAH and hormonal contraceptive use have had mixed results. Antithrombotic therapy Data are limited and conflicting as to whether anticoagulant or antiplatelet therapy increase the risk of aneurysm rupture. Most of the observational data suggest that there is a modestly increased risk of SAH with anticoagulant and antiplatelet therapy [63-65]; however, one study found that long-term aspirin use was protective (odds ratio https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 4/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate 0.63) [64]. A systematic review of seven studies found that short-term (less than three months) use of aspirin was associated with risk of SAH, but no association was found for risk of SAH and longer durations of aspirin use [66]. Anticoagulation therapy does appear to increase the severity of a SAH. (See "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm".) Cholesterol status and statin therapy The relationship between cholesterol status, statin use, and the risk of ischemic versus hemorrhagic cerebrovascular events is complex. Statin use is associated with an overall lower risk of total and ischemic cerebrovascular events, but there is some concern that low cholesterol levels and perhaps statin use may increase the risk of intracerebral hemorrhage [12]. One systematic review suggested that elevated total cholesterol levels may raise the risk for SAH in males (relative risk 1.33) [67]. (See "Overview of secondary prevention of ischemic stroke".) One case control study found that current statin use was not significantly associated with SAH risk, but recent statin drug withdrawal was associated with increased risk of SAH [68]. However, the effect of statin withdrawal was highest in patients who had also stopped taking antihypertensive drugs. PATHOGENESIS A rupture of a saccular aneurysm is the cause of most aneurysmal SAH. Saccular aneurysms are acquired rather than congenital lesions; the pathogenesis of their formation is discussed separately. (See "Unruptured intracranial aneurysms", section on 'Aneurysm formation'.) Epidemiologic studies suggest that most aneurysms do not rupture. The overall prevalence of intracranial saccular aneurysms is approximately 3 to 5 percent [69,70], while aneurysmal SAH occurs at an estimated rate of 3 to 25 per 100,000 population, or, in North America, approximately 30,000 affected persons per year [71-73]. An acute trigger event preceding SAH occurs in some cases, but most cases occur without an identifiable trigger; some aneurysmal ruptures occur during sleep [52,74]. One trigger is physical exertion. A case-crossover study in 338 patients with SAH found that patients were more likely to have engaged in moderate or greater exertion in the two hours prior to SAH than in the same two-hour period on the previous day (odds ratio 2.7, 95% CI 1.6-4.6) [75]. Acute elevation in blood pressure may be the mechanism by which physical exertion acts as a trigger for SAH and may also play a role in the observed associations between caffeine consumption, acute anger or startling, and sexual exertion as triggers for SAH [76]. Emotionally stressful life events have not been convincingly shown to be a trigger for SAH [77,78]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 5/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. The blood often spreads into the intraventricular space, but can also spread into the brain parenchyma or rarely, the subdural space, depending on the location of the aneurysm [79,80]. The bleeding usually lasts only a few seconds, but rebleeding is common and occurs most often within the first day. In addition to rebleeding, secondary events after aneurysmal rupture contribute to brain injury and outcome: Hydrocephalus after SAH is thought to be caused by obstruction of CSF flow by blood products or adhesions, or by a reduction of CSF absorption at the arachnoid granulations [81]. The former occurs as an acute complication; the latter tends to occur two weeks or later, and is more likely to be associated with shunt dependence. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Vasospasm is believed to be produced by spasmogenic substances generated during the lysis of subarachnoid blood clots which cause endothelial damage and smooth muscle contraction [82]. The vascular endothelium produces nitric oxide, which tonically dilates the cerebral vasculature; endothelial damage may interfere with nitric oxide production, leading to vasoconstriction and an impaired response to vasodilators [83]. In addition, increased release of the potent vasoconstrictor endothelin may play a major role in the induction of cerebral vasospasm after SAH [82]. Vasospasm, in turn, can cause regional cerebral hypoperfusion and delayed cerebral ischemia and infarction [84]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.) Increased intracranial pressure results from a number of factors, including hemorrhage volume, acute hydrocephalus, reactive hyperemia after hemorrhage or ischemia, and distal cerebral arteriolar vasodilation [85-88]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Elevated intracranial pressure'.) Spreading depolarization has also been hypothesized to mediate brain injury after SAH [89]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 6/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate SUMMARY Epidemiology Aneurysmal SAH occurs at an estimated rate of 3 to 25 per 100,000 population; the incidence appears to vary geographically. Most aneurysmal SAH occur in individuals between 40 and 60 years of age; however young children and older adults can be affected. There is a preponderance of aneurysmal SAH in female individuals. (See 'Epidemiology' above.) Major risk factors Risk factors for aneurysmal rupture relate to anatomic features of the aneurysm and patient-level factors. (See 'Risk factors' above.) Aneurysm size and location influence the risk of aneurysmal SAH. (See "Unruptured intracranial aneurysms", section on 'Risk factors for aneurysm rupture'.) Cigarette smoking (see 'Cigarette smoking' above) Hypertension (see 'Hypertension' above) Genetic predisposition (see 'Genetic risk' above) Moderate to heavy alcohol consumption (see 'Alcohol' above) Sympathomimetic drug use (see 'Sympathomimetic drugs' above) Others (see 'Estrogen deficiency' above and 'Antithrombotic therapy' above and 'Cholesterol status and statin therapy' above) Pathogenesis Physical exertion may trigger some aneurysmal ruptures, perhaps by precipitating an acute rise in blood pressure. Most aneurysmal SAH occur without an identifiable trigger. (See 'Pathogenesis' above.) Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. Rebleeding is common, especially within the first 24 hours. Blood spreads throughout the CSF space and leads to secondary complications of increased intracranial pressure, vasospasm, and hydrocephalus. (See 'Pathogenesis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Etminan N, Chang HS, Hackenberg K, et al. Worldwide Incidence of Aneurysmal Subarachnoid Hemorrhage According to Region, Time Period, Blood Pressure, and Smoking Prevalence in the Population: A Systematic Review and Meta-analysis. JAMA Neurol 2019; 76:588. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 7/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate 2. Schatlo B, Fung C, Stienen MN, et al. 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Clusters of spreading depolarizations are associated with disturbed cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage. Stroke 2013; 44:220. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 13/14 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis - UpToDate Topic 90075 Version 16.0 Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-epidemiology-risk-factors-and-pathogenesis/print 14/14

7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Aneurysmal subarachnoid hemorrhage: Treatment and prognosis : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 18, 2023. INTRODUCTION Aneurysmal subarachnoid hemorrhage (SAH) is often a devastating event. The treatment of aneurysmal SAH and its complications are reviewed here. Other aspects of this illness are discussed separately. (See "Treatment of cerebral aneurysms" and "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) CRITICAL CARE MANAGEMENT Stabilization Initial care of patients with SAH is directed at reversing or stabilizing life- threatening conditions, particularly for comatose patients. Important steps include ensuring a secure airway, normalizing cardiovascular function, and treating seizures [1,2]. Indications for endotracheal intubation include a Glasgow Coma Scale (GCS) score 8 ( table 1), elevated intracranial pressure (ICP), poor oxygenation or hypoventilation, hemodynamic instability, and requirement for heavy sedation or paralysis. Grading severity of SAH The degree of neurologic impairment and the extent of subarachnoid bleeding at the time of admission are the most important predictors of neurologic https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 1/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate complications and outcome [1,3]. Therefore, it is imperative to grade the severity of SAH as soon as feasible after presentation and stabilization of patients with SAH. A number of grading systems are used in practice to standardize the clinical classification of patients with SAH based upon the initial evaluation. The grading system proposed by Hunt and Hess ( table 2) and that of the World Federation of Neurological Surgeons (WFNS) ( table 3) are among the most widely used. The WFNS system incorporates the Glasgow Coma Scale ( table 1) combined with the presence of motor deficit. The Fisher grade is an index of vasospasm risk based upon a computed tomography (CT)- defined hemorrhage pattern ( table 4), and the Claassen grading system (also known as modified Fisher scale) is a similar index of the risk of delayed cerebral ischemia due to vasospasm ( table 5). A system proposed by Ogilvy and Carter stratifies patients based upon age, Hunt and Hess grade, Fisher grade, and aneurysm size ( table 6). In addition to predicting outcome, this scale more accurately substratifies patients for therapy. Grading scales for SAH are discussed in greater detail separately. (See "Subarachnoid hemorrhage grading scales".) Admit or transfer to expert center Patients with aneurysmal SAH are most appropriately cared for in high-volume centers with dedicated neurocritical care units and experienced staff that includes neurovascular surgeons, endovascular specialists, and neurologic intensive care specialists [2-4]. Observational data suggest that such centers have improved outcomes with lower mortality [5-9]. Acute care The most important goal of SAH management is the prevention of rebleeding by early repair of the unsecured aneurysm with surgical clipping or endovascular coiling. (See 'Aneurysm treatment' below.) Additional measures to reduce the risk of neurologic and systemic complications, particularly vasospasm and delayed cerebral ischemia, involve blood pressure control, maintenance of euvolemia, treatment with nimodipine, and continuous monitoring for hemodynamic and neurologic complications. Additional acute measures include bedrest, analgesia, venous thromboembolism prophylaxis, and discontinuation of antithrombotics (plus reversal of anticoagulation when present). Hypoxemia, hyperglycemia, fever, and cardiovascular instability are common complications associated with poor outcome and should be prevented and promptly treated. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 2/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Blood pressure control The optimal therapy of hypertension in SAH is not clear. For most patients with acute SAH, the goal is to maintain systolic blood pressure (SBP) <160 mmHg or mean arterial pressure (MAP) <110 mmHg, as recommended by guidelines [3,4]. It is reasonable to use premorbid baseline blood pressure to refine these targets [4]. Hypotension should be avoided. When blood pressure control is necessary, intravenous labetalol, nicardipine, clevidipine, or enalapril are preferred. The use of vasodilators such as nitroprusside or nitroglycerin should be avoided because of their propensity to increase cerebral blood volume and therefore ICP. While lowering blood pressure may decrease the risk of rebleeding in a patient with an unsecured aneurysm, this benefit may be offset by an increased risk of infarction. Cerebral perfusion pressure (CPP) equals the MAP minus the ICP. Thus, with increased ICP, cerebral perfusion may be impaired, and increases in MAP may be the only means to maintain CPP at a level necessary to prevent infarction. Results from one study suggest that this CPP threshold may be 70 mmHg [10]. In another report of 134 patients with SAH, 80 received antihypertensive therapy to lower the diastolic pressure below 100 mmHg [11]. The patients given antihypertensive therapy had a lower incidence of rebleeding (15 versus 33 percent) that was offset by a higher incidence of infarction (43 versus 22 percent). In the absence of ICP measurement, antihypertensive therapy is often withheld unless there is a severe elevation in blood pressure [12]. The patient's cognitive status may be a useful guide. If the patient is alert, CPP is adequate and lowering the blood pressure may decrease the risk of rerupture; we typically keep the systolic blood pressure in such patients below 140 mmHg. In contrast, antihypertensive therapy is generally withheld in those with a severely impaired level of consciousness since the impairment may be due to a reduced CPP. Antithrombotic reversal In general agreement with the 2015 guidelines from the Neurocritical Care Society (NCS) and Society of Critical Care Medicine (SCCM) [13], we recommend discontinuation of all antithrombotic agents and reversal of all anticoagulation for acute SAH until the aneurysm is definitively repaired by surgery or coiling. Antiplatelets We pretreat SAH patients with platelet transfusion (1 apheresis unit) prior to surgery if they had received antiplatelet agents or are thrombocytopenic (platelet count <100,000/microL) [13]. Otherwise, the role of platelet transfusion in intracranial hemorrhage is not established, even for patients on concomitant antiplatelet therapy. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Limited role of platelet transfusions'.) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 3/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate In addition, a single intravenous dose of desmopressin (DDAVP) at 0.4 mcg/kg over 30 minutes can be given to patients who have received antiplatelet agents, but this is based on weak evidence and is not part of our routine practice. Warfarin Any vitamin K antagonist effect should be reversed immediately with 4-factor prothrombin complex concentrate (PCC) and intravenous vitamin K; if a PCC is not available, a plasma product such as fresh frozen plasma (FFP) or thawed plasma may be used. Warfarin reversal is discussed in detail elsewhere. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Warfarin'.) Direct oral anticoagulants (DOACs) Available strategies for reversing the anticoagulant effect of DOACs include the following: A specific reversal agent/antidote (for dabigatran, idarucizumab; for the oral direct factor Xa inhibitors, andexanet alfa) ( table 7) Nonspecific agents such as prothrombin complex concentrates Desmopressin Drug removal from the circulation and/or gastrointestinal tract These options are discussed in detail separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Dabigatran' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'Apixaban, edoxaban, and rivaroxaban'.) Antifibrinolytic therapy Antifibrinolytic agents (eg, tranexamic acid, aminocaproic acid) should not be used routinely in the management of aneurysmal SAH. A 2022 meta-analysis of 11 trials (2717 patients) found that antifibrinolytic therapy did not reduce the risk of poor outcome, defined as death, vegetative state, or severe disability [14]. In this analysis, antifibrinolytic treatment was associated with a reduced risk of rebleeding (odds ratio [OR] 0.65, 95% CI 0.47- 0.91), but substantial heterogeneity between trials limits the certainty of these results. In addition, one large trial of 955 patients included in the analysis that assessed the effect of early administration of tranexamic acid (median 185 minutes) when risk of rebleeding may be highest found similar rates of rebleeding, functional improvement, and mortality for tranexamic acid or placebo [15]. DVT prophylaxis Deep venous thrombosis (DVT) prophylaxis with intermittent pneumatic compression devices is started prior to aneurysm treatment [16]. Chemoprophylaxis with subcutaneous unfractionated heparin or low molecular weight heparin can be added once the aneurysm is secured. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach in subarachnoid hemorrhage'.) https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 4/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Seizure prophylaxis The prophylactic use of antiseizure medications in patients with SAH is controversial [3,17,18]. Many experts believe that seizure prophylaxis in the setting of an unsecured aneurysm is reasonable, given the relatively low risk associated with antiseizure medication administration versus the potential deleterious effects of seizures on an already dysautoregulated brain [19,20]. However, evidence from a large case series suggests that antiseizure medication exposure to phenytoin may be associated with worse neurologic and cognitive outcome after SAH [21]. Therefore, the use of antiseizure medications for seizure prophylaxis after SAH should probably be minimized whenever possible, and phenytoin is generally avoided. The decision to treat with antiseizure medications may be based in part upon the distribution of blood on axial imaging studies. A higher threshold to start antiseizure medications is warranted in the setting of perimesencephalic blood without cortical layering, since this pattern of hemorrhage is associated with a particularly good prognosis. In contrast, initiation of antiseizure medications in higher risk patients with poor neurologic grade, unsecured aneurysm, and associated intracerebral hemorrhage may be reasonable [3]. In the absence of acute seizures, antiseizure medication therapy should be discontinued in most patients after the aneurysm is secured [22]. Euvolemia maintenance Hypovolemia is a risk factor for ischemic complications and should be avoided [23,24]. Euvolemia is the goal of intravenous fluid administration, usually with normal saline, which should be monitored by documentation of fluid input and output. Fluid administration should also target normal electrolyte balance. Hyponatremia, in particular, is common, and sodium levels should be checked at least daily. (See 'Hyponatremia' below.) There is no clear consensus about the optimal methods to determine euvolemia [1]. Combinations of methods are often used, including replacing urine output and strict monitoring of fluid balance, central venous pressure, and echocardiography. Some experts treat patients with significant diuresis using fludrocortisone or hydrocortisone [1]. Monitoring A patient presenting with aneurysmal SAH is admitted to an intensive care setting for constant hemodynamic, cardiac, and neurologic monitoring [25,26]. Transcranial Doppler Transcranial Doppler (TCD) sonography is useful for detecting and monitoring vasospasm in SAH [3,4,27-29]. Velocity changes detected by TCD typically precede the clinical sequelae of vasospasm. Daily recordings offer a window of opportunity to treat patients prior to clinical decline. However, it is an operator-dependent technology that has imperfect sensitivity and specificity. In general, digital subtraction angiography is https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 5/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate required to diagnose vasospasm and institute treatment. (See 'Vasospasm and delayed cerebral ischemia' below.) Brain and vascular imaging Accumulating data suggest that arterial narrowing on CT angiography (CTA) and brain perfusion asymmetry demonstrated on CT perfusion (CTP) scanning in the acute stage of SAH may be useful and sensitive methods for predicting delayed cerebral ischemia [30-33]. The use of this technique as a monitoring tool may be limited by risks of recurrent dye loads and radiation exposure [3]. A finding of perfusion- diffusion mismatch on magnetic resonance imaging may be another method of detecting brain areas at risk of infarction in this setting [34]. The clinical utility of either of these methods remains to be established. Continuous electroencephalography (EEG) Continuous EEG can be useful to detect subclinical seizures or nonconvulsive status epilepticus, particularly for patients with poor- grade SAH who develop unexplained neurologic deterioration or fail to improve [4]. Frequency of neuro checks and monitoring studies Patients with acute SAH should be carefully examined every one to two hours, especially during the high-risk period for delayed cerebral ischemia [1,26]. Symptomatic vasospasm and delayed cerebral ischemia are manifested clinically by neurologic decline, including the onset of focal neurologic abnormalities. (See 'Vasospasm and delayed cerebral ischemia' below.) A change in neurologic status (eg, development or worsening of inattention and confusion, new focal neurologic deficit, reduced level of consciousness, seizure) should be evaluated with an urgent head CT scan (to identify rebleeding, cerebral infarction, hydrocephalus), angiography (to identify symptomatic vasospasm), and/or EEG (to detect subclinical seizures). Medical complications can also contribute to a change in neurologic status. Even in the absence of clinical change, it may be important to identify cerebral vasospasm and decreased cerebral perfusion. Therefore, some centers monitor all patients with aneurysmal SAH with TCD sonography daily and head CT, CTA, and CT perfusion on admission and between days 3 to 5 and days 7 to 10 to screen for evidence of decreased cerebral perfusion or vasospasm [1]. Digital subtraction angiography can be used in place of CTA/CTP. Additional monitoring may be employed for high-risk patients with poor neurologic status, including EEG, and invasive monitoring of brain tissue oxygenation and cerebral blood flow [35]. Cardiac studies Troponin levels and electrocardiogram should be checked on admission [4]. Echocardiography is also recommended, particularly for patients with suspected myocardial dysfunction. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 6/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Intracranial pressure monitoring We generally place a ventriculostomy in patients with enlarged ventricles on CT or with WFNS scale score 3 ( table 3); this allows direct measurement of ICP and also allows treatment by drainage of cerebrospinal fluid (CSF) when appropriate. While some concern has been raised about precipitating rebleeding with abrupt lowering of ICP, this has not been substantiated in clinical studies [36]. (See "Intraventricular hemorrhage", section on 'External ventricular drain' and "Evaluation and management of elevated intracranial pressure in adults", section on 'ICP monitoring'.) Nimodipine Nimodipine 60 mg every four hours is administered to all patients with aneurysmal SAH starting within 48 hours of symptom onset, or sooner once the patient is stabilized. Nimodipine must be given orally or by nasogastric tube because inadvertent intravenous administration has been associated with serious adverse events, including death. Treatment is continued for 21 days. The calcium channel blocker nimodipine was initially studied in patients with SAH as a means to prevent vasospasm. However, despite the vasodilatory effects of nimodipine on cerebral vessels, there is no convincing evidence that nimodipine affects the incidence of either angiographic or symptomatic vasospasm [37-42]. Nevertheless, nimodipine has been demonstrated to improve outcomes in SAH and is the standard of care in these patients [37-40,43-46]. Meta-analyses of randomized trials of prophylactic nimodipine administered for SAH have consistently noted a benefit [41,42,47]: Nimodipine treatment compared with placebo improved the odds of a good outcome after SAH by 1.86 (99% CI 1.07-3.25) [41]. Nimodipine reduced the odds of deficit, mortality, or both attributed to vasospasm by 0.46, and it reduced the rate of delayed cerebral ischemia by 0.53 (95% CI 0.39-0.72) [41,46]. Overall mortality was lower with nimodipine than placebo (OR 0.73, 95% CI 0.53-1.00) [46]. The number needed to treat (NNT) with nimodipine to prevent one poor outcome was 13 (95% CI 8-30) [42]. Blood pressure fluctuations and hypotension are common after administration of nimodipine. Thus, blood pressure monitoring is essential to avoid hypotension and decreased cerebral perfusion pressure. The mechanism of benefit of nimodipine in SAH is unknown. Putative mechanisms include neuroprotection via dilation of small arteries not visible on angiograms, reduction of calcium- https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 7/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate dependent excitotoxicity, diminished platelet aggregation, inhibition of ischemia triggered by red blood cell products, or some combination of these actions. Pain control For pain control of headache, neck pain, and other sources of pain, short-acting opiates (eg, morphine sulfate) are typically used [22]. European guidelines recommend starting with acetaminophen (paracetamol) 500 mg every three to four hours, avoiding aspirin before aneurysm is secured [4]. For more severe pain, the guidelines suggest opiates (eg, codeine, tramadol by suppository or intravenous administration) or piritramide (a mu opioid receptor agonist marketed in certain European countries) as a last resort. General care Patients with acute SAH are given stool softeners and kept at bedrest to diminish hemodynamic fluctuations and lower the risk of rebleeding prior to securing the aneurysm. The administration of stress ulcer prophylaxis is an area of controversy, as discussed separately. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'Prophylaxis'.) ANEURYSM TREATMENT After aneurysmal SAH, the patient is at substantial risk of rebleeding (see 'Rebleeding' below). Aneurysm repair with surgical clipping or endovascular coiling is the only effective treatment to prevent this occurrence and should be performed as early as feasible, preferably within 24 hours [3]; some expert centers report a median time to aneurysm repair of 7 hours from admission [1]. Patients in whom aneurysm treatment is not possible or must be delayed may be candidates for antifibrinolytic therapy (tranexamic acid or aminocaproic acid), but these agents should not be used for more than 72 hours. (See 'Antifibrinolytic therapy' above.) Aneurysm treatment is discussed in more detail separately. (See "Treatment of cerebral aneurysms".) EARLY COMPLICATIONS Medical and neurologic complications are common after SAH and contribute substantially to the overall morbidity and mortality. Patients with SAH are at risk for hemodynamic instability and neurologic deterioration. In one study, neurologic worsening occurred in 35 percent of patients within the first 24 hours of admission and heralded the onset of complications and poor outcomes [48]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 8/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Rebleeding After aneurysmal SAH, the patient is at substantial risk of early rebleeding (4 to 14 percent in the first 24 hours, with maximal risk in the first 2 to 12 hours) [3,49-52]. Rerupture is associated with a high mortality. Factors identified as predictors of rebleeding include [3,50,51,53-55]: Longer time to aneurysm treatment Worse neurologic status on admission Larger aneurysm size High systolic blood pressure Presence of intracerebral or intraventricular blood Acute hydrocephalus While most rebleeding is into the subarachnoid space, bleeding can also occur into the intraparenchymal, intraventricular, or subdural compartments. Rebleeding is usually diagnosed based on an acute deterioration of neurologic status accompanied by appearance of new hemorrhage on head computed tomography (CT) scan. Lumbar puncture is harder to evaluate because xanthochromia from the initial bleeding can persist for two weeks or more. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Lumbar puncture'.) Aneurysm treatment is the only effective treatment for the prevention of rebleeding. Therefore, patients with rebleeding should have emergency aneurysm repair. (See 'Aneurysm treatment' above.) Rebleeding is associated with a higher rate of other complications and worse outcomes [56]. The mortality associated with rebleeding is reported to be as high as 70 percent. Vasospasm and delayed cerebral ischemia Delayed cerebral ischemia is a frequent complication of SAH; it contributes substantially to morbidity and mortality after SAH [57-59]. Delayed cerebral ischemia Delayed cerebral ischemia occurs in approximately 30 percent of patients with aneurysmal SAH, typically between 4 and 14 days after symptom onset [1,60]. The definition of delayed cerebral ischemia requires the occurrence of focal neurologic impairment (such as hemiparesis, aphasia, apraxia, hemianopia, or neglect) or a decrease of at least two points on the Glasgow Coma Scale that lasts for at least one hour, was not apparent immediately after aneurysm occlusion, and cannot be attributed to other causes after appropriate clinical assessment, brain imaging, and laboratory studies [61]. However, in patients with poor clinical grade (ie, already stuporous or comatose), delayed cerebral ischemia may not be clinically discernable [62]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 9/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate In one case series of 56 patients with delayed cerebral ischemia, the two most common patterns of infarction were single cortical infarcts, typically located near the site of the ruptured aneurysm, and multiple widespread infarcts, often involving bilateral and subcortical regions and frequently located distal to the ruptured aneurysm, seen in 40 and 50 percent of patients, respectively [63]. Hypodense lesions on CT consistent with infarction appear to be more likely with larger volume SAH and poor initial clinical condition [64-70]. Younger patients (<55 years) and those who smoke appear to be at higher risk of delayed cerebral ischemia. Mechanisms and risk factors The most common cause of delayed cerebral ischemia after SAH is assumed to be vasospasm [71]. The severity of symptoms depends upon the artery affected and the degree of collateral circulation. Vasospasm typically begins no earlier than day 3 after hemorrhage, reaching a peak at days 7 to 8. However, vasospasm can occur earlier, even at the time of hospital admission [72-75]. Vasospasm is believed to be produced by spasmogenic substances generated during the lysis of subarachnoid blood. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Pathogenesis'.) Risk factors for vasospasm include the severity of bleeding and its proximity to the major intracerebral blood vessels. The location and extent of blood on CT scan can help predict the likelihood of complicating cerebral vasospasm [76-78]. Radiologic grading scales including those of Fisher ( table 4) and Claassen ( table 5) are often used to predict the likelihood of vasospasm and cerebral ischemia. (See "Subarachnoid hemorrhage grading scales".) Other factors that may increase the risk of vasospasm include age less than 50 years and hyperglycemia [79,80]. Most [81-83] but not all [79] studies have found that poor clinical grade (eg, Hunt and Hess grade 4 or 5, or Glasgow Coma Scale score <14) is associated with an increased risk of vasospasm. It is unclear whether the type of aneurysm treatment (surgical clipping versus endovascular coiling) influences the risk of vasospasm. Observational data from several studies suggest that endovascular coiling is associated with a reduced risk of vasospasm [84-87], while other studies suggest that clipping and coiling have a similar risk [88,89], and still others suggest that coiling is associated with more severe vasospasm [90]. Mechanisms other than vasospasm may contribute to delayed cerebral ischemia. These include microcirculatory dysfunction with loss of autoregulation, microthrombosis, cortical spreading depression, and delayed cellular apoptosis [91,92]. There is also experimental evidence implicating early brain injury beginning at the time of aneurysm rupture and https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 10/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate triggered by increased intracranial pressure (ICP) and global hypoperfusion that leads to glial activation, endothelial dysfunction, diffuse neuroinflammation, and subsequent ischemia [93]. Prevention and treatment To reduce the risk of poor outcomes from delayed cerebral ischemia, all patients should receive nimodipine, and euvolemia should be maintained. (See 'Euvolemia maintenance' above and 'Nimodipine' above.) An important distinction must be made between angiographic vasospasm, which is seen in 30 to 70 percent of angiograms performed at day 7 after SAH, and clinical or symptomatic vasospasm, which is seen in 20 to 30 percent of patients [94-96]. Symptomatic vasospasm is associated with a clinical decline and portends a poorer prognosis. We generally do noninvasive angiography with CT angiography (CTA) to confirm vasospasm for patients with elevated velocities on transcranial Doppler ultrasound (see 'Monitoring' above). Isolated, asymptomatic angiographic vasospasm traditionally has not been treated, but some experts will treat if the vasospasm is severe. Angiography is used to identify patients with symptomatic vasospasm who might benefit from treatment. In one series in which angiograms were performed systematically in 381 patients at 9 2 days after aneurysmal SAH, the presence and severity of vasospasm correlated with the presence of cerebral infarction on CT [97]. However, even symptomatic vasospasm may not be identifiable on cerebral angiography as spasm in small arteries defies the resolution of even state-of-the-art angiography. Aggressive therapy of vasospasm can only be pursued after the aneurysm has been treated with surgical clipping or endovascular coiling. Following aneurysmal occlusion, treatment options include: Hemodynamic augmentation is considered first-line therapy for the treatment of new- onset delayed cerebral ischemia [35]. This approach is intended to raise the mean arterial pressure and thereby increase cerebral perfusion. The treatment involves induced hypertension with vasopressor agents such as phenylephrine, norepinephrine, or dopamine and maintenance of euvolemia using crystalloid or colloid solution [3,4]. Blood pressure augmentation should progress in a stepwise fashion with assessment of clinical status at each mean arterial pressure level [4]. The addition of inotropic support with agents such as dobutamine or milrinone has been reported to be helpful in patients who do not appear to respond to pressors alone https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 11/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate [4]. Patients treated with hemodynamic augmentation need to be monitored for complications such as pulmonary or cerebral edema and volume overload. Earlier versions of this therapy included hypervolemia along with hemodilution and hypertension, so-called "triple-H" therapy, but subsequent studies revealed that hypervolemia was not beneficial and might be harmful [35,98]. Balloon angioplasty has become the mainstay of treatment at many centers for symptomatic focal vasospasm of the larger cerebral arteries that is refractory to hemodynamic augmentation, again despite an absence of clinical trial data [99,100]. Intra-arterial administration of vasodilators are generally used for diffuse vasospasm involving smaller arterial branches. Agents reported as effective for improving vasospasm in case series include intra-arterial nicardipine [101], milrinone [102], papaverine [103-105], nimodipine [106], verapamil [107], and intrathecal nitroprusside [108]. Intra-arterial vasodilator therapy and angioplasty also may be used in combination [104,107]. Elevated intracranial pressure Patients with SAH may develop elevated intracranial pressure (ICP) due to a number of factors, including hemorrhage volume, acute hydrocephalus (see 'Hydrocephalus' below), reactive hyperemia after hemorrhage and/or ischemia, and distal cerebral arteriolar vasodilation [59,109-112]. In a series of 234 patients with SAH who had ICP monitoring, increased ICP occurred during the hospital stay in 54 percent, including 49 percent of those considered to have a good clinical grade (Hunt and Hess grades I to III) [113]. Hydrocephalus Hydrocephalus affects 20 to 30 percent of patients with SAH. It usually presents within the first few minutes to hours after SAH [22]. It can also be a later complication. Hydrocephalus after SAH is thought to be caused by obstruction of cerebrospinal fluid (CSF) flow by blood products or adhesions or by a reduction of CSF absorption at the arachnoid granulations [114]. The former occurs as an acute complication; the latter tends to occur two weeks after or later and is more likely to be associated with shunt dependence. The clinical presentation of hydrocephalus in this setting is progressive deterioration in level of consciousness, accompanied by ventricular dilation on head CT scan. Ocular signs of elevated ICP (miosis, downward eye deviation, or restricted upgaze) occur in many but not all patients [115]. Spontaneous improvement occurs in approximately 30 percent of patients with acute hydrocephalus and impaired consciousness, usually within 24 hours [22,116]. In the remainder, acute hydrocephalus is associated with increased morbidity and mortality secondary to rebleeding and cerebral infarction [117]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 12/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Factors associated with an increased risk for hydrocephalus include older age, intraventricular hemorrhage, posterior circulation aneurysms, treatment with antifibrinolytic agents, and a low Glasgow Coma Scale score on presentation [118,119]. The incidence had also been reported to be increased in patients with hyponatremia or a history of hypertension. Management of elevated ICP CSF diversion Immediate CSF diversion with an external ventricular drain (EVD) or lumbar drainage is indicated for patients who have a deteriorating level of consciousness and evidence of elevated ICP and/or hydrocephalus [117]. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Removal of CSF'.) EVD placement is always indicated if the hydrocephalus is deemed noncommunicating (ie, from obstruction of CSF flow, typically at the level of the aqueduct). EVD placement ( figure 1) can improve the clinical grade of patients presenting with SAH [3]. Lumbar drainage is an alternative for patients with communicating hydrocephalus but is contraindicated with obstructive hydrocephalus or intraparenchymal hematoma [2]. There is controversy regarding the preferred mode of CSF drainage through an EVD [120]. Some experts recommend a rapid weaning of the EVD after the aneurysm is secured, or within 48 hours of EVD placement, for patients who are neurologically stable [22,121]. Other experts prefer to avoid weaning the EVD during the first week or longer after the onset of SAH, a time when the risk of vasospasm reaches its peak. An intermittent CSF drainage with rapid EVD wean approach has been associated with fewer ventriculoperitoneal (VP) shunt placements, fewer complications, and shorter length of stay compared with a continuous CSF drainage with gradual EVD wean approach [122]. However, premature EVD wean resulting in increased ICP could exacerbate cerebral hypoperfusion, a particularly hazardous problem if the patient is also having vasospasm [123]. In one study, the number of failed clamping trials (ie, clamping the EVD catheter and stopping external drainage of CSF to determine if EVD removal can be tolerated) increased the likelihood that the patient would require a shunt [124]. Thus, more research is necessary to define the optimal strategy for CSF drainage and EVD wean in patients with aneurysmal SAH. EVD placement may be complicated by infection (eg, ventriculitis/meningitis), particularly when drainage is continued for more than three days [116,125], and bleeding (eg, hemorrhage along the catheter tract), with a risk of approximately 8 percent for each [126]. There are few high-quality data to guide optimal EVD placement and management to minimize these risks [121]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 13/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Osmotic therapy and diuresis Patients without a ventriculostomy can be managed medically with osmotic therapy and diuresis. Hyperventilation is generally avoided because it may precipitate or exacerbate vasospasm. The use of hypertonic saline has been evaluated in patients with elevated ICP related to traumatic brain injury and appears to lower ICP and may improve cerebral perfusion. A small observational study in 16 patients with poor-grade SAH suggests that it may also be useful in this setting, but further study is required [127]. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis'.) Hemicraniectomy In some cases, decompressive craniectomy may be needed for ICP control in the setting of intracerebral hemorrhage and/or severe cerebral edema. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Decompressive craniectomy'.) Shunt-dependent hydrocephalus The need for long-term CSF diversion is assessed in the subacute period by attempts at weaning ventricular drainage hydrocephalus [1,22]. Some patients who had EVD removed in the hospital after passing a clamping trial may subsequently require placement of a ventricular shunt to treat delayed recurrence of symptomatic hydrocephalus that develops after hospital discharge [128,129]. In a systematic analysis including 23 studies and more than 22,000 patients with SAH, 22 percent developed shunt-dependent hydrocephalus [130]. Notable predictors of developing shunt dependency included acute hydrocephalus at presentation, poor clinical grade (elevated Hunt and Hess score) at admission, vasospasm, intraventricular bleeding, and female gender. Shunt rates were similar between patients undergoing surgical clipping and endovascular coiling [1,22,128,129,131,132]. Other studies have reported similar results [128,133,134]. Hyponatremia Hyponatremia develops in up to 30 percent of patients with SAH [1,3,135] and is probably mediated by hypothalamic injury [22]. The water retention that leads to hyponatremia following SAH may result from either the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or from cerebral salt wasting. These are physiologically distinct: Patients with SIADH are euvolemic. In other settings, therapy of asymptomatic hyponatremia in SIADH usually consists of water restriction, but fluid restriction is not desirable in patients with SAH as it increases the risk of intravascular volume contraction and consequently vasospasm-related ischemic injury. Thus, hyponatremia in patients with SAH is treated with hypertonic saline. (See "Treatment of hyponatremia: Syndrome of https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 14/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Subarachnoid hemorrhage'.) Cerebral salt wasting is caused by excessive secretion of natriuretic peptides that diminish central sympathetic activity. It is characterized by volume depletion, which leads to the release of antidiuretic hormone (ADH). Cerebral salt wasting can be treated with fluid administration using infusions of isotonic saline if serum sodium is normal but may require infusions of hypertonic saline and fludrocortisone to counteract diuresis and natriuresis when these conditions impede maintenance of euvolemia. Restoration of euvolemia will suppress the release of ADH. (See "Cerebral salt wasting".) SIADH and cerebral salt wasting can be difficult to differentiate since the laboratory findings are similar in both, including hyponatremia (<134 mEq/L), low serum osmolality (<274 mosmol/kg), high urine sodium (>40 mEq/L), and high urine osmolality (>100 mosmol/kg) [22]. The major

by blood products or adhesions or by a reduction of CSF absorption at the arachnoid granulations [114]. The former occurs as an acute complication; the latter tends to occur two weeks after or later and is more likely to be associated with shunt dependence. The clinical presentation of hydrocephalus in this setting is progressive deterioration in level of consciousness, accompanied by ventricular dilation on head CT scan. Ocular signs of elevated ICP (miosis, downward eye deviation, or restricted upgaze) occur in many but not all patients [115]. Spontaneous improvement occurs in approximately 30 percent of patients with acute hydrocephalus and impaired consciousness, usually within 24 hours [22,116]. In the remainder, acute hydrocephalus is associated with increased morbidity and mortality secondary to rebleeding and cerebral infarction [117]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 12/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Factors associated with an increased risk for hydrocephalus include older age, intraventricular hemorrhage, posterior circulation aneurysms, treatment with antifibrinolytic agents, and a low Glasgow Coma Scale score on presentation [118,119]. The incidence had also been reported to be increased in patients with hyponatremia or a history of hypertension. Management of elevated ICP CSF diversion Immediate CSF diversion with an external ventricular drain (EVD) or lumbar drainage is indicated for patients who have a deteriorating level of consciousness and evidence of elevated ICP and/or hydrocephalus [117]. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Removal of CSF'.) EVD placement is always indicated if the hydrocephalus is deemed noncommunicating (ie, from obstruction of CSF flow, typically at the level of the aqueduct). EVD placement ( figure 1) can improve the clinical grade of patients presenting with SAH [3]. Lumbar drainage is an alternative for patients with communicating hydrocephalus but is contraindicated with obstructive hydrocephalus or intraparenchymal hematoma [2]. There is controversy regarding the preferred mode of CSF drainage through an EVD [120]. Some experts recommend a rapid weaning of the EVD after the aneurysm is secured, or within 48 hours of EVD placement, for patients who are neurologically stable [22,121]. Other experts prefer to avoid weaning the EVD during the first week or longer after the onset of SAH, a time when the risk of vasospasm reaches its peak. An intermittent CSF drainage with rapid EVD wean approach has been associated with fewer ventriculoperitoneal (VP) shunt placements, fewer complications, and shorter length of stay compared with a continuous CSF drainage with gradual EVD wean approach [122]. However, premature EVD wean resulting in increased ICP could exacerbate cerebral hypoperfusion, a particularly hazardous problem if the patient is also having vasospasm [123]. In one study, the number of failed clamping trials (ie, clamping the EVD catheter and stopping external drainage of CSF to determine if EVD removal can be tolerated) increased the likelihood that the patient would require a shunt [124]. Thus, more research is necessary to define the optimal strategy for CSF drainage and EVD wean in patients with aneurysmal SAH. EVD placement may be complicated by infection (eg, ventriculitis/meningitis), particularly when drainage is continued for more than three days [116,125], and bleeding (eg, hemorrhage along the catheter tract), with a risk of approximately 8 percent for each [126]. There are few high-quality data to guide optimal EVD placement and management to minimize these risks [121]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 13/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Osmotic therapy and diuresis Patients without a ventriculostomy can be managed medically with osmotic therapy and diuresis. Hyperventilation is generally avoided because it may precipitate or exacerbate vasospasm. The use of hypertonic saline has been evaluated in patients with elevated ICP related to traumatic brain injury and appears to lower ICP and may improve cerebral perfusion. A small observational study in 16 patients with poor-grade SAH suggests that it may also be useful in this setting, but further study is required [127]. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Osmotic therapy and diuresis'.) Hemicraniectomy In some cases, decompressive craniectomy may be needed for ICP control in the setting of intracerebral hemorrhage and/or severe cerebral edema. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Decompressive craniectomy'.) Shunt-dependent hydrocephalus The need for long-term CSF diversion is assessed in the subacute period by attempts at weaning ventricular drainage hydrocephalus [1,22]. Some patients who had EVD removed in the hospital after passing a clamping trial may subsequently require placement of a ventricular shunt to treat delayed recurrence of symptomatic hydrocephalus that develops after hospital discharge [128,129]. In a systematic analysis including 23 studies and more than 22,000 patients with SAH, 22 percent developed shunt-dependent hydrocephalus [130]. Notable predictors of developing shunt dependency included acute hydrocephalus at presentation, poor clinical grade (elevated Hunt and Hess score) at admission, vasospasm, intraventricular bleeding, and female gender. Shunt rates were similar between patients undergoing surgical clipping and endovascular coiling [1,22,128,129,131,132]. Other studies have reported similar results [128,133,134]. Hyponatremia Hyponatremia develops in up to 30 percent of patients with SAH [1,3,135] and is probably mediated by hypothalamic injury [22]. The water retention that leads to hyponatremia following SAH may result from either the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or from cerebral salt wasting. These are physiologically distinct: Patients with SIADH are euvolemic. In other settings, therapy of asymptomatic hyponatremia in SIADH usually consists of water restriction, but fluid restriction is not desirable in patients with SAH as it increases the risk of intravascular volume contraction and consequently vasospasm-related ischemic injury. Thus, hyponatremia in patients with SAH is treated with hypertonic saline. (See "Treatment of hyponatremia: Syndrome of https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 14/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Subarachnoid hemorrhage'.) Cerebral salt wasting is caused by excessive secretion of natriuretic peptides that diminish central sympathetic activity. It is characterized by volume depletion, which leads to the release of antidiuretic hormone (ADH). Cerebral salt wasting can be treated with fluid administration using infusions of isotonic saline if serum sodium is normal but may require infusions of hypertonic saline and fludrocortisone to counteract diuresis and natriuresis when these conditions impede maintenance of euvolemia. Restoration of euvolemia will suppress the release of ADH. (See "Cerebral salt wasting".) SIADH and cerebral salt wasting can be difficult to differentiate since the laboratory findings are similar in both, including hyponatremia (<134 mEq/L), low serum osmolality (<274 mosmol/kg), high urine sodium (>40 mEq/L), and high urine osmolality (>100 mosmol/kg) [22]. The major distinguishing feature is intravascular volume status; patients with SIADH are euvolemic or even hypervolemic, while patients with cerebral salt wasting are hypovolemic. A protocol for managing hyponatremia using 3 percent sodium chloride (NaCl) solutions in patients with SAH is presented in the table ( table 8). Seizures Acute seizures occur in 6 to 18 percent of patients with SAH [3]. Risk factors include thick subarachnoid clot, intracerebral hemorrhage, delayed infarction, and aneurysm in the middle cerebral artery. Seizures that occur prior to aneurysm treatment are often a sign of early rebleeding [22]. (See 'Neurologic morbidity' below.) Patients with acute seizures after SAH are treated with antiseizure medications to prevent recurrence. Agents with favorable side effect profile, such as levetiracetam, are typically used. It is advisable to avoid phenytoin because its use has been associated with worse cognitive outcomes in patients with aneurysmal SAH [21]. (See "Initial treatment of epilepsy in adults".) Antiseizure medications are usually continued for a few months in patients who have experienced an acute seizure following SAH, although there are no strict guidelines. While acute seizures are a risk factor for developing epilepsy, most patients do not require long-term antiseizure medications. (See 'Neurologic morbidity' below.) Generalized convulsive status epilepticus is unusual after SAH, occurring in 0.2 percent of patients in one study [136]. However, with increased use of continuous electroencephalography (EEG) monitoring, nonconvulsive status epilepticus and subclinical seizures have been recognized as a potential contributor to prolonged impairment of consciousness in patients after SAH. In one series, subclinical seizures were documented by continuous recording in 7 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 15/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate percent of patients after SAH [137,138]. Even when documented, the clinical correlates of nonconvulsive seizures can be subtle and nonspecific and may be limited to changes in heart rate, blood pressure, and/or ICP [139]. The management of status epilepticus is discussed separately. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".) Nonconvulsive status epilepticus (NCSE) and subclinical seizures are increasingly recognized as a potential contributor to prolonged impairment of consciousness in patients after SAH. Diagnosis of NCSE and subclinical seizures requires a high index of suspicion as patients with NCSE are often those with poor neurologic grade and other neurologic complications of SAH, making it difficult to detect subclinical seizures; continuous EEG monitoring is often required. NCSE is associated with worse outcomes after SAH [139]. The diagnosis and management of NCSE is discussed separately. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".) Anemia Anemia is common after SAH, occurring in 18 percent of patients during their hospital stay in one report [140]. Most studies suggest that anemia is associated with worse outcomes, while higher hemoglobin levels are associated with fewer cerebral infarctions and improved outcomes [141-144]. A goal hemoglobin for transfusion has not been defined in patients with SAH [3]; some experts recommend a target above 8 to 10 g/dL [4] and one randomized trial found that a higher transfusion goal (11.5 g/dL versus 10 g/dL) appeared to be safe [145]. Yet, red blood cell transfusion has been independently associated with worse outcomes in observational studies of patients with SAH, particularly among patients without delayed cerebral ischemia [146,147]. Therefore, larger randomized trials are necessary to determine the optimal transfusion strategy in SAH [148]. Cardiopulmonary complications Pulmonary edema and cardiac arrhythmias complicate 23 and 35 percent of SAH cases respectively [149]. (See "Complications of stroke: An overview", section on 'Cardiac complications' and "Complications of stroke: An overview", section on 'Pulmonary complications'.) A number of cardiac changes occur after SAH, including electrocardiography (ECG) changes, structural changes on echocardiography, and acute troponin elevations. These appear to be more common and more severe in those with more severe SAH [150,151]. Occasionally, focus on these findings can result in misdiagnosis. ECG abnormalities The most frequent ECG abnormalities are ST segment depression, QT interval prolongation, deep symmetric T-wave inversions, and prominent U waves [152]. Life-threatening rhythm disturbances such as torsades de pointes have also been https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 16/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate described, as well as atrial fibrillation and flutter. ST-T wave abnormalities along with bradycardia and relative tachycardia were found in one large series to be independently associated with mortality [153]. Another study reported an association between QT prolongation and angiographic vasospasm [154]. The ECG changes are predominantly reflective of ischemic changes in the subendocardium of the left ventricle. The development of actual myocardial injury (in as many as 20 percent of patients) can be established by elevations of creatine kinase-MB (CK-MB) or serum troponin I (>0.1 mcg/L), which is a specific and more sensitive marker of myocardial necrosis [151,155]. Patients with elevated troponin I concentrations are more likely to have ECG abnormalities and clinical evidence of left ventricular dysfunction. Subendocardial ischemia is an independent predictor of poor outcome in patients with SAH and must be managed aggressively (although without the use of aspirin) [150]. (See "Troponin testing: Clinical use" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) Left ventricular dysfunction Echocardiographic abnormalities may be found in approximately 21 percent of patients with acute SAH [156]. A wide spectrum of regional left ventricular wall motion abnormalities can occur with SAH; these are typically but not always reversible [151,157,158]. Heart failure and pulmonary edema can result [159]. Some patients develop a pattern of transient apical left ventricular dysfunction that mimics myocardial infarction (but in the absence of significant coronary artery disease), a condition known as takotsubo cardiomyopathy, or transient left ventricular apical ballooning syndrome [158,160]. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".) Troponin release Acute troponin elevation after SAH appears to be associated with increased risk of cardiopulmonary and cerebrovascular complications [150,161]. Elevated peak troponin levels have been associated with an increased risk of left ventricular dysfunction, pulmonary edema, and hypotension requiring pressors as well as with increased mortality and worse functional outcome [150]. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Acute stroke'.) Other complications Hyperglycemia has been associated with a poor outcome after SAH in many studies [162- 166]. One study found that the use of an aggressive hyperglycemia management protocol appeared to improve glycemic control and neurologic outcomes; however, the use of a historical control group limits the validity of this study [167]. No blood glucose targets have https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 17/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate been specifically identified for intervention. The 2012 American Stroke Association guidelines suggest careful glucose management with strict avoidance of hypoglycemia [3]. Fever of infectious and noninfectious origin is a common complication of SAH, particularly in those with a higher neurologic grade, and is associated with a poor prognosis [168,169]. Body temperature should be monitored and infection should be ruled out or treated. We treat fever with antipyretics and cooling blankets. While high-quality evidence of benefit with this approach is lacking, one nonrandomized study found that the use of external cooling devices in patients with fever after SAH was associated with improved outcomes [170]. Hypothalamic-pituitary dysfunction is common after SAH, but the clinical implications and appropriate treatment is uncertain [171]. Routine administration of glucocorticoids is not recommended after SAH but may be considered in patients who are unresponsive to vasopressor therapy for vasospasm [4]. PROGNOSIS Outcome after treatment of aneurysmal SAH is affected by potential brain injury from the SAH and subsequent complications as well as by risks related to neurosurgery. (See "Treatment of cerebral aneurysms".) Mortality Early mortality SAH is associated with a high early mortality rate [172]. Population-based studies found that 18 to 24 percent of patients with SAH died suddenly prior to even being evaluated in a hospital [173,174]. Among patients who reach the hospital alive, much of the subsequent early mortality is caused by the common complications of aneurysmal SAH related to initial bleeding, rebleeding, vasospasm and delayed cerebral ischemia, hydrocephalus, increased intracranial pressure, seizures, and cardiac complications [175- 177]. While early mortality due to SAH remains high, it is decreasing over time [174,178-184]. Historical case-fatality rates for SAH reached 50 percent [185], but they have declined to approximately 30 percent from 1988 to 2010 [178]. In a Finnish study of patients hospitalized with SAH, the 30-day case-fatality rate declined an average of nearly 2 percent each year between 1998 and 2017 with an overall rate of 20 percent during the study period [174]. Improved diagnostic accuracy over time and therapeutic advances in https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 18/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate neurocritical care are plausible but unproven reasons for the reduction in mortality [22,184]. Long-term mortality Survivors of aneurysmal SAH have an increased mortality rate compared with the general population (standardized mortality ratio [SMR] 1.6) [186-190]. In a Swiss national registry of 1787 patients with SAH, the one-year mortality rate was 22 percent [191]. In the International Subarachnoid Aneurysm Trial (ISAT), the risk of death at five years was lower in the endovascular therapy group than in the surgical group [186]. In one cohort study, the excess mortality risk appeared to be attributed to cerebrovascular events [189]. The risk of nonfatal vascular events (eg, stroke, myocardial infarction) was also increased (relative risk [RR] 1.5) in survivors of aneurysmal SAH [188]. Neurologic morbidity Long-term complications of SAH include neurocognitive dysfunction, epilepsy, and other focal neurologic deficits. In one registry, more than 10 percent of patients with SAH remained moderately or severely disabled [191]. Several studies suggest that SAH survivors have high rates of memory and neurocognitive impairment [3,192-198]. The largest prospective evaluation of neuropsychological function evaluated 873 survivors of SAH [196]. At three months after aneurysmal clipping, global impairment was present in approximately 20 percent of all survivors and in 16 percent of those with excellent preoperative condition. Detailed neuropsychological testing of patients after surgically treated SAH has commonly shown cognitive deficits, even among patients making an otherwise good neurologic recovery [199]. The importance of these neuropsychological deficits to long-term morbidity is controversial, but they are often permanent [58,200]. The location of the aneurysm responsible for SAH does not appear to influence cognitive outcome [192], but the occurrence of vasospasm, delayed cerebral infarction, and other complications does [58,201]. Treatment modality does not compellingly influence outcome. In the ISAT, the proportions of survivors who reached independent status were similar in those treated with endovascular therapy versus surgical clipping [186]. However, among the group that was not otherwise disabled (modified Rankin Scale [mRS] >2), the proportion of those with cognitive impairment at 12 months was higher in those treated surgically than with endovascular coiling [193]. By contrast, in a follow-up study of the ISAT, health-related quality of life was higher after endovascular coiling compared with neurosurgical clipping, which contributed to the quality-adjusted life years gained over a 10-year period [202]. Depression, anxiety, and sleep disturbances are also common and contribute to decreased quality of life; these may be more amenable to treatment [195,197,203]. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 19/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate The incidence of late epilepsy after SAH is unclear. In a retrospective report of 472 patients with aneurysmal SAH who had undergone surgical clipping of the aneurysm between 1994 and 2000 and were followed for at least 12 months, late epilepsy occurred in 23 (5 percent) [204]. Patients presenting with a poor grade had a higher incidence of epilepsy (9.6 and 12.5 percent of those grades 3 and 4, respectively), as did those with associated cerebral infarction or subdural hematoma. In the ISAT, 25 of 612 patients (4 percent) had a diagnosis of epilepsy at a 12-month assessment; the rate was lower in patients treated with endovascular coiling as compared with surgical clipping [193]. Patients who have had acute seizures after SAH are somewhat more likely to develop epilepsy than those who do not. The management of epilepsy is discussed separately. (See "Initial treatment of epilepsy in adults" and "Overview of the management of epilepsy in adults".) Anosmia may complicate SAH. Studies suggest that this is a more frequent complication in patients who undergo aneurysm clipping (one in three patients) than in those who undergo endovascular coiling (one in six patients) and that recovery is more likely in patients who also have endovascular therapy [205,206]. Intraventricular hemorrhage is a risk factor for this complication. Anosmia is a less frequent complication of nonaneurysmal perimesencephalic hemorrhage [207]. Aneurysm recurrence and late rebleeding Patients who survive aneurysmal SAH have a small but enduring risk of recurrent SAH, which can occur despite successful endovascular or surgical treatment of the ruptured aneurysm. Recurrent SAH may result from recurrence of the treated aneurysm, rupture of another pre-existing aneurysm in a patient with multiple aneurysms, and de novo aneurysm formation. The risk of these events and recommendations for monitoring and treatment are discussed separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) Predictive factors The most important predictive factors for acute prognosis after SAH include [19,26,57,78]: Level of consciousness and neurologic grade on admission Patient age (inverse correlation) Amount of blood on initial head computed tomography scan (inverse correlation) Other studies have noted that hypoxemia, hyperglycemia, renal insufficiency, fever, and anemia are also common after SAH and are associated with poor outcomes [149,162,208-210]. Correction of these physiologic derangements in patients with SAH is suggested [16], although no studies have confirmed the benefit of such treatments. Seizures at the onset of SAH appear https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 20/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate to be an independent risk factor for late seizures (epilepsy) and a predictor of poor outcome [139,211,212]. Screening of family members First-degree relatives of patients with SAH have a two- to fivefold increased risk of SAH compared with the general population [213,214]. It may be reasonable to screen some family members for the presence of cerebral aneurysm. The risk is much higher when there are two or more first-degree family members with ruptured aneurysms [214]. This issue is discussed in detail separately. (See "Screening for intracranial aneurysm".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Subarachnoid hemorrhage (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Hemorrhagic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 21/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Acute care Patients with aneurysmal subarachnoid hemorrhage (SAH) should be admitted to an intensive care setting for constant hemodynamic, cardiac, and neurologic monitoring. Additional initial measures to reduce the risk of neurologic and systemic complications include: Blood pressure should be titrated to a target systolic blood pressure (SBP) <160 mmHg or mean arterial pressure (MAP) <110 mmHg for most patients with SAH. (See 'Blood pressure control' above.) All antithrombotic agents should be discontinued and anticoagulation reversed until the aneurysm is repaired by surgery or coiling. (See 'Antithrombotic reversal' above.) The use of antiseizure medications for seizure prophylaxis after SAH is controversial. Antiseizure prophylaxis prior to aneurysm repair may be reasonable for some patients with poor neurologic grade, unsecured aneurysm, and associated intracerebral hemorrhage. (See 'Seizure prophylaxis' above.) Euvolemia should be maintained and monitored by documentation of fluid input and output to decrease the risk of ischemic complications. (See 'Euvolemia maintenance' above.) Nimodipine 60 mg every four hours is administered for 21 days to improve outcomes for patients aneurysmal SAH. (See 'Nimodipine' above.) Other general measures for all patients with acute aneurysmal SAH include includes bedrest, analgesia for pain control, and venous thromboembolism prophylaxis. Hypoxemia, hyperglycemia, and fever should be prevented and promptly treated. (See 'Acute care' above.) Treatment of aneurysm Aneurysm repair with surgical clipping or endovascular coiling is the only effective treatment to prevent rebleeding and should be performed as early as feasible, preferably within 24 hours, and immediately if rebleeding does occur. (See 'Aneurysm treatment' above and "Treatment of cerebral aneurysms".) Early complications Medical and neurologic complications are common after SAH. In addition to rebleeding, major concerns include vasospasm and delayed cerebral ischemia, elevated intracranial pressure (ICP) related to hydrocephalus or other causes, hyponatremia, and seizures. (See 'Early complications' above.) Vasospasm and delayed cerebral ischemia Following treatment of the aneurysms, neurologic deterioration due to vasospasm may be treated with hemodynamic https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 22/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate augmentation via induced hypertension, balloon angioplasty, and/or intra-arterial administration of vasodilators. (See 'Vasospasm and delayed cerebral ischemia' above.) Elevated intracranial pressure Immediate CSF diversion with an external ventricular drain (EVD) is indicated for patients who have a deteriorating level of consciousness and evidence of elevated ICP and/or hydrocephalus. Additional options for some patients include osmotic diuresis and hemicraniectomy. (See 'Elevated intracranial pressure' above.) Seizures Seizures should be treated promptly and antiseizure medications are usually discontinued in a few months following SAH unless seizures recur. If prophylactic antiseizure medications were administered acutely, therapy may be discontinued after the aneurysm is secured. (See 'Seizures' above and 'Seizure prophylaxis' above.) Hyponatremia Hyponatremia after SAH is usually due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and rarely due to cerebral salt wasting. A protocol for managing hyponatremia in this setting is presented in the table ( table 8). (See 'Hyponatremia' above.) Prognosis Mortality within the first 30 days after SAH approaches 30 percent and is attributed largely to the effects of initial and recurrent bleeding. Long-term complications of SAH include neurocognitive dysfunction, epilepsy, other focal neurologic deficits, and late rebleeding from aneurysm recurrence. 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https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 35/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate 173. Lindbohm JV, Kaprio J, Jousilahti P, et al. Risk Factors of Sudden Death From Subarachnoid Hemorrhage. Stroke 2017; 48:2399. 174. Asikainen A, Korja M, Kaprio J, Rautalin I. Case Fatality in Patients With Aneurysmal Subarachnoid Hemorrhage in Finland: A Nationwide Register-Based Study. Neurology 2023; 100:e348. 175. Abulhasan YB, Alabdulraheem N, Simoneau G, et al. Mortality after Spontaneous Subarachnoid Hemorrhage: Causality and Validation of a Prediction Model. World Neurosurg 2018; 112:e799. 176. Vergouwen MD, Jong-Tjien-Fa AV, Algra A, Rinkel GJ. Time trends in causes of death after aneurysmal subarachnoid hemorrhage: A hospital-based study. Neurology 2016; 86:59. 177. Roos YB, de Haan RJ, Beenen LF, et al. 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Stroke incidence rates were unchanged, while fatality rates declined, during 1971-1987 in G teborg, Sweden. Stroke 1992; 23:1410. 183. Chan V, Lindsay P, McQuiggan J, et al. Declining Admission and Mortality Rates for Subarachnoid Hemorrhage in Canada Between 2004 and 2015. Stroke 2018; :STROKEAHA118022332. 184. Nieuwkamp DJ, Setz LE, Algra A, et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 2009; 8:635. 185. Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997; 28:660. 186. Molyneux AJ, Kerr RS, Birks J, et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 36/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 2009; 8:427. 187. Wermer MJ, Greebe P, Algra A, Rinkel GJ. Long-term mortality and vascular event risk after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2009; 80:1399. 188. Nieuwkamp DJ, Algra A, Blomqvist P, et al. Excess mortality and cardiovascular events in patients surviving subarachnoid hemorrhage: a nationwide study in Sweden. Stroke 2011; 42:902. 189. Korja M, Silventoinen K, Laatikainen T, et al. Cause-specific mortality of 1-year survivors of subarachnoid hemorrhage. Neurology 2013; 80:481. 190. Koroknay-P l P, Laakso A, Lehto H, et al. Long-term excess mortality in pediatric patients with cerebral aneurysms. Stroke 2012; 43:2091. 191. Schatlo B, Fung C, Stienen MN, et al. Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS). Stroke 2021; 52:344. 192. Tidswell P, Dias PS, Sagar HJ, et al. Cognitive outcome after aneurysm rupture: relationship to aneurysm site and perioperative complications. Neurology 1995; 45:875. 193. Scott RB, Eccles F, Molyneux AJ, et al. Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the International Subarachnoid Aneurysm Trial (ISAT). Stroke 2010; 41:1743. 194. Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 2002; 59:1750. 195. Hackett ML, Anderson CS. Health outcomes 1 year after subarachnoid hemorrhage: An international population-based study. The Australian Cooperative Research on Subarachnoid Hemorrhage Study Group. Neurology 2000; 55:658. 196. Anderson SW, Todd MM, Hindman BJ, et al. Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery. Ann Neurol 2006; 60:518. 197. Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010; 41:e519. 198. Wong GK, Lam S, Ngai K, et al. Evaluation of cognitive impairment by the Montreal cognitive assessment in patients with aneurysmal subarachnoid haemorrhage: prevalence, risk factors and correlations with 3 month outcomes. J Neurol Neurosurg Psychiatry 2012; 83:1112. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 37/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate 199. Ljunggren B, Sonesson B, S veland H, Brandt L. Cognitive impairment and adjustment in patients without neurological deficits after aneurysmal SAH and early operation. J Neurosurg 1985; 62:673. 200. Stenhouse LM, Knight RG, Longmore BE, Bishara SN. Long-term cognitive deficits in patients after surgery on aneurysms of the anterior communicating artery. J Neurol Neurosurg Psychiatry 1991; 54:909. 201. Wong GK, Lam SW, Ngai K, et al. Cognitive domain deficits in patients with aneurysmal subarachnoid haemorrhage at 1 year. J Neurol Neurosurg Psychiatry 2013; 84:1054. 202. Hua X, Gray A, Wolstenholme J, et al. Survival, Dependency, and Health-Related Quality of Life in Patients With Ruptured Intracranial Aneurysm: 10-Year Follow-up of the United Kingdom Cohort of the International Subarachnoid Aneurysm Trial. Neurosurgery 2021; 88:252. 203. Visser-Meily JM, Rhebergen ML, Rinkel GJ, et al. Long-term health-related quality of life after aneurysmal subarachnoid hemorrhage: relationship with psychological symptoms and personality characteristics. Stroke 2009; 40:1526. 204. Buczacki SJ, Kirkpatrick PJ, Seeley HM, Hutchinson PJ. Late epilepsy following open surgery for aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2004; 75:1620. 205. Wermer MJ, Donswijk M, Greebe P, et al. Anosmia after aneurysmal subarachnoid hemorrhage. Neurosurgery 2007; 61:918. 206. Bor AS, Niemansburg SL, Wermer MJ, Rinkel GJ. Anosmia after coiling of ruptured aneurysms: prevalence, prognosis, and risk factors. Stroke 2009; 40:2226. 207. Greebe P, Rinkel GJ, Algra A. Anosmia after perimesencephalic nonaneurysmal hemorrhage. Stroke 2009; 40:2885. 208. Zacharia BE, Ducruet AF, Hickman ZL, et al. Renal dysfunction as an independent predictor of outcome after aneurysmal subarachnoid hemorrhage: a single-center cohort study. Stroke 2009; 40:2375. 209. Wartenberg KE, Mayer SA. Medical complications after subarachnoid hemorrhage. Neurosurg Clin N Am 2010; 21:325. 210. Ayling OGS, Ibrahim GM, Alotaibi NM, et al. Anemia After Aneurysmal Subarachnoid Hemorrhage Is Associated With Poor Outcome and Death. Stroke 2018; 49:1859. 211. Butzkueven H, Evans AH, Pitman A, et al. Onset seizures independently predict poor outcome after subarachnoid hemorrhage. Neurology 2000; 55:1315. 212. Claassen J, Peery S, Kreiter KT, et al. Predictors and clinical impact of epilepsy after subarachnoid hemorrhage. Neurology 2003; 60:208. https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 38/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate 213. Gaist D, Vaeth M, Tsiropoulos I, et al. Risk of subarachnoid haemorrhage in first degree relatives of patients with subarachnoid haemorrhage: follow up study based on national registries in Denmark. BMJ 2000; 320:141. 214. Bor AS, Rinkel GJ, Adami J, et al. Risk of subarachnoid haemorrhage according to number of affected relatives: a population based case-control study. Brain 2008; 131:2662. Topic 1127 Version 39.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 39/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate GRAPHICS Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 40/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Hunt and Hess grading system for patients with subarachnoid hemorrhage Grade Neurologic status 1 Asymptomatic or mild headache and slight nuchal rigidity 2 Severe headache, stiff neck, no neurologic deficit except cranial nerve palsy 3 Drowsy or confused, mild focal neurologic deficit 4 Stuporous, moderate or severe hemiparesis 5 Coma, decerebrate posturing Based upon initial neurologic examination. Adapted from: Hunt W, Hess R. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968; 28:14. Graphic 69179 Version 5.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 41/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate World Federation of Neurological Surgeons subarachnoid hemorrhage grading scale Grade GCS score Motor deficit 1 15 Absent 2 13 to 14 Absent 3 13 to 14 Present 4 7 to 12 Present or absent 5 3 to 6 Present or absent GCS: Glasgow Coma Scale. Data from: Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988; 68:985. Graphic 65468 Version 3.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 42/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate [1] Fisher grade of cerebral vasospasm risk in subarachnoid hemorrhage Group Appearance of blood on head CT scan 1 No blood detected 2 Diffuse deposition or thin layer with all vertical layers (in interhemispheric fissure, insular cistern, ambient cistern) less than 1 mm thick 3 Localized clot and/or vertical layers 1 mm or more in thickness 4 Intracerebral or intraventricular clot with diffuse or no subarachnoid blood CT: computed tomography. Reference: 1. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980; 6:1. Graphic 81122 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 43/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Modified Fisher (Claassen) subarachnoid hemorrhage CT rating scale Grade Head CT criteria 0 No SAH or IVH 1 Minimal SAH and no IVH 2 Minimal SAH with bilateral IVH 3 Thick SAH (completely filling one or more cistern or fissure) without bilateral IVH 4 Thick SAH (completely filling one or more cistern or fissure) with bilateral IVH CT: computed tomography; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. From: Claassen J, Bernardini GL, Kreiter K, et al. E ect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001; 32:2012. Graphic 57558 Version 5.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 44/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Ogilvy and Carter grading system to predict outcome for surgical management of intracranial aneurysms Criteria Points Age 50 or less 0 Age greater than 50 1 Hunt and Hess grade 0 to 3 (no coma) 0 Hunt and Hess grade 4 and 5 (in coma) 1 Fisher scale score 0 to 2 0 Fisher scale score 3 and 4 1 Aneurysm size 10 mm or less 0 Aneurysm size greater than 10 mm 1 Giant posterior circulation aneurysm size 25 mm or more 1 The total score ranges from 0 to 5, corresponding to grades 0 to 5 Adapted from: Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict outcome for surgical management of intracranial aneurysms. Neurosurgery 1998; 42:959. Graphic 70705 Version 4.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 45/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 46/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate External ventricular drain An external ventricular drain (EVD) is a small catheter inserted through the skull usually into the lateral ventricle, which is typically connected to a closed collecting device to allow for drainage of cerebrospinal fluid. The EVD can also be connected to a transducer that records intracranial pressure. Graphic 56391 Version 2.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 47/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Protocol for management of hyponatremia in patients with subarachnoid hemorrage For Na level <133 mEq/L or a decrease of 6 mEq/L in 24 to 48 hours: 1. NaCl tabs 3 g PO/NGT every 6 hours 2. Initiate 3 percent NaCl infusion at 20 mL/hour IV 3. Check serum Na every 6 hours a. If Na <130 mEq/L: Increase rate by 20 mL/hour (max rate = 80 mL/hour) If on hold at present, initiate 3 percent NaCl infusion at 20 mL/hour IV b. If Na = 130 to 135 mEq/L: Increase rate by 10 mL/hour (max rate = 80 mL/hour) If on hold at present, initiate 3 percent NaCl infusion at 10 mL/hour IV c. If Na = 136 to 140 mEq/L: No change d. If Na 140 mEq/L: Hold infusion NaCl: sodium chloride; PO: by mouth; NGT: nasogastric tube; IV: intravenously. Reproduced from: Woo CH, Roa VA, Sheridan W, Flint A. Performance characteristics of a sliding-scale hypertonic saline infusion protocol for the treatment of acute neurologic hyponatremia. Neurocrit Care 2009; 11:228, with kind permission from Springer Science + Business Media B.V. Copyright 2009. Graphic 65772 Version 15.0 https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 48/49 7/7/23, 11:27 AM Aneurysmal subarachnoid hemorrhage: Treatment and prognosis - UpToDate Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/aneurysmal-subarachnoid-hemorrhage-treatment-and-prognosis/print 49/49

7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral and cervical artery dissection: Treatment and prognosis : David S Liebeskind, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2022. INTRODUCTION Arterial dissections are a common cause of stroke in the young but may occur at any age. Dissection occurs when structural integrity of the arterial wall is compromised, allowing blood to collect between layers as an intramural hematoma. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. The optimal treatment of dissection remains a challenge due to limitations in rapidly establishing a definitive diagnosis, the overall low incidence, low recurrence rate, and marked variation in patient characteristics [1]. This topic will review the treatment and prognosis of cerebral and cervical artery dissection. Other aspects of this disorder are reviewed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".) ACUTE ISCHEMIC STROKE OR TIA DUE TO DISSECTION General management For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to management should be rigorously followed including blood pressure regulation, fluid administration, control of hyperglycemia and other metabolic derangements, and airway management. These issues are discussed in detail separately. (See "Initial assessment and management of acute stroke" https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 1/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see 'Reperfusion therapy for eligible patients' below). Reperfusion therapy for eligible patients The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis with alteplase or tenecteplase, and mechanical thrombectomy. Since the ischemic stroke mechanism is often unknown or unconfirmed at the time of decision-making for intravenous thrombolysis, and since cervical or cerebral artery dissection is not a contraindication, patients with suspected cervical or intracranial dissection should receive intravenous thrombolysis if otherwise eligible. Intravenous thrombolysis Intravenous thrombolysis with alteplase (tPA) or tenecteplase is indicated for eligible patients ( table 1) with acute ischemic stroke, including those with isolated extracranial or intracranial cervical artery dissection. Extension of aortic dissection, however, is a known complication of thrombolysis. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) The major randomized trials of intravenous thrombolysis for acute ischemic stroke did not exclude patients with cervicocephalic arterial dissection. While thrombolysis in the setting of dissection may theoretically cause enlargement of the intramural hematoma, accumulating evidence suggests that the effectiveness and safety of thrombolysis for patients with ischemic stroke related to cervical artery dissection are similar to its effectiveness and safety for patients with ischemic stroke from other causes [2-7]. Perhaps the strongest evidence, although indirect, comes from a 2011 meta-analysis of individual patient data from 14 retrospective series and 22 case reports involving 180 patients with cervical artery dissection who were treated with thrombolysis and followed for a median of three months [4]. When these patients were compared with matched historic controls from the observational SITS-ISTR registry of patients treated with intravenous alteplase for acute ischemic stroke, there were no major differences between groups for rates of symptomatic intracranial hemorrhage, mortality, excellent outcome, or favorable outcome. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 2/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate There is controversy regarding the use of thrombolysis for ischemic symptoms in patients with isolated intracranial dissection alone or intracranial extension of extracranial dissection because of a presumed increased risk of subarachnoid or symptomatic intracranial hemorrhage. Limited observational data suggest this risk is minimal, but efficacy and safety are still uncertain [8]. Mechanical thrombectomy For select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, early treatment with mechanical thrombectomy is indicated when performed at stroke centers with appropriate expertise, whether or not the patient received treatment with intravenous thrombolysis. This includes patients with extracranial carotid dissection who have a tandem proximal intracranial artery occlusion amenable to mechanical thrombectomy [9-13]. The efficacy of mechanical thrombectomy for vertebral and basilar artery occlusions is unproven. (See "Mechanical thrombectomy for acute ischemic stroke".) Emergency stenting In addition to mechanical thrombectomy, angioplasty and stenting of arterial dissection may be treatment options for acute stroke at expert centers [14-17]. Choosing between antiplatelet and anticoagulation therapy Antithrombotic therapy is often used for the prevention of new or recurrent ischemic symptoms caused by arterial dissection, but the approach may differ for extracranial versus intracranial dissection. Extracranial dissection For patients with extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended [18-24]. However, there is no clear consensus about which of these is optimal. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy [25], while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by shared decision making that incorporates patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests, but does not establish, that there is no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection. In an open-label, assessor-blind pilot trial (CADISS), 250 subjects with extracranial carotid and vertebral dissection were randomly assigned to antiplatelet or anticoagulant treatment for three months [26]. At the end of this period, there was no significant difference between the two treatment groups; ipsilateral ischemic stroke occurred in 3 of 126 (2 percent) in the antiplatelet group and 1 of 124 (1 percent) in the anticoagulant group (odds https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 3/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate ratio 0.34, 95% CI 0.01-4.23). There were no deaths in either group. There was one major bleeding event, a subarachnoid hemorrhage, in a patient assigned to the anticoagulation group who had a vertebral artery dissection with intracranial extension. At 12 months of follow-up, the rate of recurrent stroke remained low (approximately 2.5 percent) in both treatment groups with no difference between groups for any outcome, including no difference in the angiographic recanalization rate among patients with confirmed dissection [27]. Because of the low stroke rate and rarity of outcome events, the CADISS trial was unable to establish which treatment is superior or safer when used to treat cervical artery dissection [1]. The investigators estimated that a definitive trial would require approximately 10,000 participants, making such a trial unfeasible given the slow enrollment rate of the CADISS trial. However, it is highly likely that anticoagulation is associated with a higher risk of hemorrhagic events, since anticoagulation is a known risk factor for bleeding. (See "Risks and prevention of bleeding with oral anticoagulants".) The subsequent TREAT-CAD trial was an open-label, assessor-blind trial that enrolled 194 adult patients who presented with symptomatic extracranial dissection within two weeks of enrollment and were randomly assigned to aspirin monotherapy (300 mg daily) or to anticoagulation with a vitamin K antagonist (target INR 2.0 to 3.0) for 90 days [28]. The trial was designed to test the noninferiority of aspirin compared with vitamin K antagonist anticoagulants. The trialists chose a composite primary endpoint of clinical events (stroke, major hemorrhage, or death) and magnetic resonance imaging findings (new silent ischemic or hemorrhagic brain lesions) in order to achieve sufficient power, and performed a per-protocol analysis of 173 patients who received the allocated treatment and completed the assessment period. The composite endpoint occurred more often in the aspirin group compared with the vitamin K antagonist group (23 versus 15 percent, absolute difference 8 percent, 95% CI -4 to 21 percent); while the difference was not statistically significant, aspirin failed to meet noninferiority criteria because the upper limit of the 95% CI (21 percent) exceeded the predefined noninferiority margin of 12 percent. Ischemic stroke was also more frequent in the aspirin group (8 versus 0 percent), and all ischemic stroke occurred within seven days of trial enrollment. There were no deaths in either group. There was one major extracranial hemorrhage (a gastrointestinal bleed) in a patient from the vitamin K antagonist group and none in the aspirin group. The risk of ischemic stroke in the TREAT-CAD aspirin group (8 percent) was greater than that in the CADISS antiplatelet group (2 percent); one possible explanation for the difference is that TREAT-CAD used aspirin monotherapy, whereas CADISS permitted the use of other antiplatelet agents and dual antiplatelet therapy [29]. However, this is speculative, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 4/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate as indirect cross-trial comparisons may be confounded by various issues and lead to erroneous conclusions. A 2012 meta-analysis of nonrandomized studies with over 1600 patients with cervical artery dissection reported no significant difference in recurrent stroke risk or mortality comparing anticoagulation with antiplatelet agents [30]. Similarly, a 2015 meta-analysis of nonrandomized studies with over 1300 patients who had acute carotid artery dissection found no differences in outcome or complication rates comparing anticoagulation with antiplatelet therapy [31]. Intracranial dissection For patients who have ischemic neurologic symptoms caused by intracranial arterial dissection, we suggest antiplatelet therapy rather than anticoagulation [24]. Anticoagulation is generally avoided in the setting of intracranial dissection due to the risk of subarachnoid hemorrhage, although limited evidence suggests that anticoagulation can be used safely for some patients who have intracranial dissection without subarachnoid hemorrhage [32]. Starting antiplatelet therapy For patients selected for antiplatelet therapy (rather than anticoagulation), initiation should be delayed for 24 hours after infusion of intravenous thrombolytic therapy. Otherwise, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) 2 For patients with a low-risk TIA, defined by an ABCD score <4 ( table 2), or moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3), we start treatment with aspirin (162 to 325 mg daily) alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4 ( table 2), or minor ischemic stroke, defined by a NIHSS score 5 ( table 3), we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Most reports of antiplatelet therapy for acute cervical artery dissection have employed daily aspirin at various doses; there are few data regarding other antiplatelet agents such as clopidogrel, dipyridamole, or combinations of these agents. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 5/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Starting anticoagulation therapy For patients selected for anticoagulation rather than antiplatelet therapy, the initiation of therapy is affected by a number of factors. For medically stable patients with a small- or moderate-sized infarct, anticoagulation using heparin or low molecular weight heparin (as a bridge to warfarin) can be started as soon as 24 hours after symptom onset, or at least 24 hours after infusion of thrombolytic therapy, with minimal risk of transformation to hemorrhagic stroke; anticoagulation with a direct oral anticoagulant (DOAC) can be started as soon as 48 hours after stroke onset, as DOACs have a more rapid anticoagulant effect. However, the role of DOACs for treating dissection is uncertain and data are limited [21]. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended. In such cases, we start aspirin if there are no significant bleeding complications; anticoagulation can be started (and aspirin stopped) after one to two weeks if the patient is stable. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of long-term anticoagulation'.) Anticoagulation can be started immediately for patients with a TIA due to dissection. Acute anticoagulation may be achieved with either subcutaneous low molecular weight heparin such as enoxaparin (1 mg/kg twice daily) or dalteparin (100 units/kg twice daily) or with intravenous unfractionated heparin (dose-adjusted to achieve a goal activated partial thromboplastin time of 1.5 to 2 times control). Transition to warfarin (dose adjusted for a goal international normalized ratio [INR] of 2.5 with an acceptable range of 2 to 3) can be pursued in the subacute period for clinically stable patients. Vessel monitoring and repeat imaging After three to six months from symptom onset or diagnosis of dissection, repeat neurovascular imaging is suggested to assess the status of artery or arteries affected by dissection and guide the need for ongoing treatment, particularly if the patient is being treated with anticoagulation. We use transcranial Doppler, carotid duplex, computed tomography angiography (CTA), and/or magnetic resonance angiography (MRA) to help us decide the status of the arterial system prior to discontinuing anticoagulation therapy. Further treatment is tailored to imaging findings. (See 'Duration of antithrombotic therapy' below.) In most cases, arteries with stenosis or luminal irregularities caused by dissection undergo recanalization and healing in the first months after the initial event. In a report of 61 patients with acute vertebral artery dissection who presented with symptoms of vertebrobasilar territory ischemia, complete recanalization of the vertebral artery was observed at six months in 62 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 6/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate percent [33]. In another study that followed 76 patients with cervical artery dissection involving 105 vessels with a mean follow-up of 58 months, complete recanalization was noted in 51 percent of vessels, nearly all occurring within the first nine months, and hemodynamically significant recanalization in 20 percent [34]. Data from the prospective CADISS study suggest that dissecting aneurysms are inconstant and can either resolve or develop for the first time in the months following the clinical diagnosis of extracranial cervical artery dissection [35]. Residual headache may indicate persistent vascular abnormalities [36]. Duration of antithrombotic therapy For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed on repeat imaging at three to six months. For patients with persistent vascular luminal stenosis, irregularity, or dissecting aneurysm, it is reasonable to continue anticoagulation. For patients treated with antiplatelet therapy in the acute phase, long-term antiplatelet therapy is recommended using aspirin, clopidogrel, aspirin-extended-release dipyridamole, or cilostazol for secondary prevention of stroke. However, there are no concrete data regarding optimal duration of antithrombotic therapy. The time course of healing of the vessel wall or resolution of vascular abnormalities may be used to guide duration of initial treatment. Most arterial abnormalities stabilize in appearance or resolve by three months, and vessels that fail to reconstitute a normal lumen by six months are highly unlikely to recover at later time points [37]. Recurrent ischemia Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes with a history and examination, brain and vessel imaging, and cardiac and laboratory testing. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Neuroimaging of acute stroke".) Due to dissection In various reports, the rate of recurrent ischemic symptoms (stroke and transient ischemic attack) after dissection ranges from 0 to 13 percent [38,39], but it is likely that the actual rate of recurrent ischemic stroke caused by dissection is at the lower end of this range. The prospective CADISS trial found that the rate of recurrent ischemic stroke at three months was approximately 2 percent, and all recurrences were within 10 days of randomization, suggesting that the risk beyond the first two weeks is extremely low https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 7/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate [26]. Prospective data from the CADISS study also suggest that extracranial cervical dissecting aneurysms have a benign prognosis, with a low rate (1 of 48, or approximately 2 percent) of ischemic stroke during 12 months of follow-up, similar to the rate observed in dissections without aneurysm formation [35]. Another study evaluated 432 surviving patients with carotid or vertebral dissection who were followed for a mean time of 31 months [40]. Recurrent ischemic stroke due to initial or recurrent dissection was observed in four patients (0.9 percent), giving an annual incidence of 0.3 percent. Transient ischemic attack was observed in eight patients (1.8 percent), for an annual incidence of 0.6 percent. Endovascular and surgical repair for dissection Endovascular techniques or surgical repair have been used to treat dissection, mainly for patients who have recurrent ischemia despite antithrombotic therapy [23]. Endovascular techniques for the treatment of dissection and dissecting aneurysm include angioplasty, stent placement, embolization with various materials, and combinations of such approaches [23,41]. Angioplasty and stenting may occlude the false lumen and restore true arterial lumen patency. However, data regarding endovascular treatment of dissection is limited to case reports and case series [41-48]. There are no randomized trial data comparing endovascular techniques with medical therapies, and the long-term safety and durability of these methods are unknown. In isolated cases, accessible lesions may be treated by surgical vessel reconstruction or bypass around a dissecting aneurysm [49,50]. Other surgical revascularization procedures include extracranial-intracranial bypass, endarterectomy, thrombectomy, and proximal vessel ligation. SUBARACHNOID HEMORRHAGE DUE TO INTRACRANIAL DISSECTION Subarachnoid hemorrhage is an uncommon complication of intracranial dissection. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Intracranial arterial dissection'.) It is managed according to the same principles as subarachnoid hemorrhage caused by rupture of a saccular aneurysm (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis"), with the exception that the surgical or endovascular treatment of dissecting aneurysm itself may differ from that of a saccular aneurysm because of morphologic differences between the two types of aneurysms. The risk of rebleeding from an intracranial dissecting https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 8/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate aneurysm is as high as 40 percent in the first week or so after the event [51-54]. Thus, early repair is typically recommended [51]. The morphology of most dissecting aneurysms limits standard surgical clipping. Management is individualized according to location and other anatomic features, and can include proximal occlusion of the artery, trapping or wrapping of the pseudoaneurysm, bypass, embolization, or stenting [52,54]. These are complicated procedures that can incur additional morbidity. NONISCHEMIC LOCAL SYMPTOMS For patients with nonischemic symptoms caused by extracranial or intracranial carotid or vertebral artery dissection, we suggest antiplatelet therapy for prevention of ischemic stroke. Headache and neck pain associated with dissection can usually be managed with simple analgesics such as acetaminophen. Anecdotally, gabapentin may be helpful. Nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen sodium, ibuprofen) are generally avoided in patients receiving anticoagulation because of the increased risk of bleeding. There is no specific treatment for other local symptoms of dissection such as Horner syndrome, lower cranial nerve palsy, audible bruit, or tinnitus, but these may improve with time and vessel healing. MEASURES TO REDUCE RISK OF DISSECTION There are no proven methods that reduce the risk of recurrent cervicocephalic arterial dissection. Nevertheless, some experts suggest that patients with dissection should avoid contact sports, chiropractic neck manipulation, and any activity that involves abrupt rotation and flexion-extension of the neck [55,56]. In addition, estrogen-containing compounds should be discontinued, as estrogen may induce proliferation of intimal and fibromuscular arterial tissue. All vascular risk factors including hypertension should be addressed. (See "Overview of secondary prevention of ischemic stroke".) PROGNOSIS Neurologic outcome The prognosis of cerebral and cervical artery dissection is related primarily to the severity of associated ischemic stroke or subarachnoid hemorrhage. Morbidity and mortality of acute cervicocephalic arterial dissection varies according to the specific arteries involved and location of the lesion. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 9/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate In the CADISP study of 982 patients with extracranial cervical artery dissection, an unfavorable outcome at three months among patients with ischemic stroke, defined as a modified Rankin Scale ( table 4) score >2, was more likely with stroke due to internal carotid artery dissection compared with stroke due to vertebral artery dissection (25 versus 8 percent) [57]. This result was largely driven by stroke severity at onset, which was greater for patients with internal carotid dissection compared with those who had vertebral dissection by mean National Institutes of Health Stroke Scale (NIHSS) score on admission (8 versus 3). Only limited systematic data are available regarding long-term outcomes of dissection. Complete or excellent recovery occurs in 70 to 85 percent of patients with extracranial dissection, with major disabling deficits in 10 to 25 percent, and death in 5 to 10 percent of cases [38,58]. In observational studies, factors associated with poor functional outcome after cervical artery dissection include a high NIHSS score at onset, arterial occlusion, and older age [58-61]. Quality of life may be impaired in almost half of long-term survivors after dissection [62]. Recurrence of dissection The recurrence rate of cervical and intracranial artery dissection, with or without symptoms, is uncertain, and available data are inconsistent. In the CADISP study, which retrospectively and prospectively recruited 982 patients with cervical artery dissection, the recurrence rate for extracranial cervical dissection at three months was 2 percent [57]. Even higher rates were reported by a single-center study of 232 patients with cervical artery dissection who were followed clinically and with serial imaging for at least one year. Over the course of the study, there were 46 new dissections affecting 39 patients (16 percent). Recurrent dissection was detected within one month of the initial event in 9 percent, and beyond one month until up to eight years after the initial event in another 7 percent [63]. Most initial dissections were linked to ischemic stroke, but the majority of recurrent dissections were either asymptomatic or associated with purely local symptoms. Recurrent dissection may affect several vessels at once, even when preceded by initial dissection isolated to one artery [63,64]. Although data are limited, rare patients with familial dissection tend to be young (mean age 36 years) and are probably at high risk for recurrent or multiple dissection [65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 10/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute management of TIA or ischemic stroke For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to stroke management should be rigorously followed. All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. (See 'General management' above and 'Reperfusion therapy for eligible patients' above and "Approach to reperfusion therapy for acute ischemic stroke".) Choice of antithrombotic therapy for secondary ischemic stroke prevention Beyond the hyperacute period of acute stroke, antithrombotic therapy with either anticoagulation or antiplatelet drugs is accepted treatment for prevention of new or recurrent ischemic symptoms due to extracranial artery dissection, although there is controversy regarding the choice between the two. (See 'Choosing between antiplatelet and anticoagulation therapy' above.) Ischemia due to extracranial dissection For patients with acute ischemic stroke or TIA caused by extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy, while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests (but does not establish) that there no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection, although it is likely that anticoagulation is associated with a higher risk of hemorrhagic events. (See 'Extracranial dissection' above.) Nonischemic local symptoms due to extracranial dissection For patients with nonischemic local symptoms caused by extracranial cervical dissection, we suggest antiplatelet therapy for prevention of ischemic stroke (Grade 2C). (See 'Nonischemic local symptoms' above.) Ischemia due to intracranial dissection For patients who have ischemic stroke or TIA caused by intracranial dissection, we suggest antiplatelet therapy rather than https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 11/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate anticoagulation (Grade 2C). (See 'Intracranial dissection' above.) Initiating therapy The timing and suggested dosing for starting antiplatelet or anticoagulant therapy is detailed in the sections above. (See 'Starting antiplatelet therapy' above and 'Starting anticoagulation therapy' above.) Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361.

Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361. 27. Markus HS, Levi C, King A, et al. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results. JAMA Neurol 2019; 76:657. 28. Engelter ST, Traenka C, Gensicke H, et al. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol 2021; 20:341. 29. Kasner SE. Antithrombotic therapy for cervical arterial dissection. Lancet Neurol 2021; 20:328. 30. Kennedy F, Lanfranconi S, Hicks C, et al. Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. Neurology 2012; 79:686. 31. Chowdhury MM, Sabbagh CN, Jackson D, et al. Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. Eur J Vasc Endovasc Surg 2015; 50:148. 32. Metso TM, Metso AJ, Helenius J, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke 2007; 38:1837. 33. Arauz A, M rquez JM, Artigas C, et al. Recanalization of vertebral artery dissection. Stroke 2010; 41:717. 34. Baracchini C, Tonello S, Meneghetti G, Ballotta E. Neurosonographic monitoring of 105 spontaneous cervical artery dissections: a prospective study. Neurology 2010; 75:1864. 35. Larsson SC, King A, Madigan J, et al. Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review. Neurology 2017; 88:646. 36. Manabe H, Yonezawa K, Kato T, et al. Incidence of intracranial arterial dissection in non- emergency outpatients complaining of headache: preliminary investigation with MRI/MRA examinations. Acta Neurochir Suppl 2010; 107:41. 37. Nedeltchev K, Bickel S, Arnold M, et al. R2-recanalization of spontaneous carotid artery dissection. Stroke 2009; 40:499. 38. Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol 2009; 8:668. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 15/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 39. Arauz A, Hoyos L, Espinoza C, et al. Dissection of cervical arteries: Long-term follow-up study of 130 consecutive cases. Cerebrovasc Dis 2006; 22:150. 40. Touz E, Gauvrit JY, Moulin T, et al. Risk of stroke and recurrent dissection after a cervical artery dissection: a multicenter study. Neurology 2003; 61:1347. 41. Donas KP, Mayer D, Guber I, et al. Endovascular repair of extracranial carotid artery dissection: current status and level of evidence. J Vasc Interv Radiol 2008; 19:1693. 42. Ansari SA, Thompson BG, Gemmete JJ, Gandhi D. Endovascular treatment of distal cervical and intracranial dissections with the neuroform stent. Neurosurgery 2008; 62:636. 43. Ecker RD, Levy EI, Hopkins LN. Acute neuroform stenting of a symptomatic petrous dissection. J Invasive Cardiol 2007; 19:E137. 44. Cohen JE, Leker RR, Gotkine M, et al. Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making. Stroke 2003; 34:e254. 45. Biondi A, Katz JM, Vallabh J, et al. Progressive symptomatic carotid dissection treated with multiple stents. Stroke 2005; 36:e80. 46. Kadkhodayan Y, Jeck DT, Moran CJ, et al. Angioplasty and stenting in carotid dissection with or without associated pseudoaneurysm. AJNR Am J Neuroradiol 2005; 26:2328. 47. Edgell RC, Abou-Chebl A, Yadav JS. Endovascular management of spontaneous carotid artery dissection. J Vasc Surg 2005; 42:854. 48. Kim BM, Shin YS, Kim SH, et al. Incidence and risk factors of recurrence after endovascular treatment of intracranial vertebrobasilar dissecting aneurysms. Stroke 2011; 42:2425. 49. M ller BT, Luther B, Hort W, et al. Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980. 50. Chiche L, Praquin B, Koskas F, Kieffer E. Spontaneous dissection of the extracranial vertebral artery: indications and long-term outcome of surgical treatment. Ann Vasc Surg 2005; 19:5. 51. Ono H, Nakatomi H, Tsutsumi K, et al. Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation. Stroke 2013; 44:126. 52. Debette S, Compter A, Labeyrie MA, et al. Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection. Lancet Neurol 2015; 14:640. 53. Mizutani T, Aruga T, Kirino T, et al. Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 1995; 36:905. 54. Bond KM, Krings T, Lanzino G, Brinjikji W. Intracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history. J Neuroradiol 2021; 48:176. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 16/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 55. Paciaroni M, Bogousslavsky J. Cerebrovascular complications of neck manipulation. Eur Neurol 2009; 61:112. 56. Reuter U, H mling M, Kavuk I, et al. Vertebral artery dissections after chiropractic neck manipulation in Germany over three years. J Neurol 2006; 253:724. 57. Debette S, Grond-Ginsbach C, Bodenant M, et al. Differential features of carotid and vertebral artery dissections: the CADISP study. Neurology 2011; 77:1174. 58. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006; 37:2499. 59. 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Familial cervical artery dissections: clinical, morphologic, and genetic studies. Stroke 2006; 37:2924. Topic 16649 Version 30.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 17/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 18/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: tissue plasminogen activator (alteplase or tenecteplase); TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous thrombolysis despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with intravenous thrombolysis in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous thrombolysis if glucose level is subsequently normalized. The potential risks of bleeding with tPA from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 19/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate The increased risk of surgical site bleeding with tPA should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with tPA in the setting of past gastrointestinal or genitourinary bleeding. However, tPA administration within 21 days of gastrointestinal bleeding is not recommended. Intravenous thrombolysis is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * tPA can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering tPA is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous tPA appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 27.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 20/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 21/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial _____ answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes and then to grip and release the non-paretic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. 2 = Performs neither task correctly. made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 22/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. maneuver. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or raise eyebrows and close eyes. Score 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 23/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice 2 = Some effort against gravity; limb and pantomime, but not noxious cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency period but does not hit bed. 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is UN = Amputation or joint fusion, explain:________________ scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 24/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. Comprehension is judged from responses conversation about provided materials difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is hand, repeat, and produce speech. The through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 25/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so articulation of spontaneous speech can be _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify 1 = Visual, tactile, auditory, spatial, or neglect may be obtained during the prior testing. If the patient has a severe visual loss personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; does not recognize own hand or orients to has aphasia but does appear to attend to both sides, the score is normal. The only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 26/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 27/28 7/7/23, 11:28 AM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Contributor Disclosures David S Liebeskind, MD Consultant/Advisory Boards: Cerenovus [Stroke]; Genentech [Stroke]; Medtronic [Stroke]; Stryker [Stroke]. Speaker's Bureau: Astra-Zeneca [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 28/28

7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hemorrhagic stroke in children : Evelyn K Shih, MD, PhD, Lauren A Beslow, MD, MSCE : Scott E Kasner, MD, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 17, 2022. INTRODUCTION Although less common than in adults, hemorrhagic stroke can affect children, resulting in significant morbidity and mortality. An overview of hemorrhagic stroke in children beyond the newborn period is provided here. Other clinical aspects of stroke in neonates and children are reviewed elsewhere: (See "Stroke in the newborn: Classification, manifestations, and diagnosis".) (See "Stroke in the newborn: Management and prognosis".) (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".) (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".) (See "Ischemic stroke in children: Management and prognosis".) (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".) (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) CLASSIFICATION https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 1/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Hemorrhagic stroke encompasses spontaneous intracerebral hemorrhage (ICH), isolated intraventricular hemorrhage, and nontraumatic subarachnoid hemorrhage [1]. ICH is defined by intraparenchymal hemorrhage or a combination of intraparenchymal and intraventricular hemorrhage ( image 1). Despite its common usage, the term hemorrhagic stroke remains confusing. It has also been used to denote hemorrhagic transformation of arterial ischemic stroke or of cerebral venous sinus thrombosis, but it does not encompass those entities, strictly speaking. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) EPIDEMIOLOGY Although stroke in children is relatively rare compared with adults, it is a significant cause of childhood death and lifelong disability. A stroke suffered within the first decade may cause functional sequelae for multiple decades to follow. Hemorrhagic stroke is a notable contributor to childhood morbidity and mortality, as it accounts for about half of all childhood strokes, compared with <20 percent of adult strokes [2,3]. The estimated incidence of all types of stroke (ischemic and hemorrhagic) in children ranges 2 to 13 per 100,000 children per year in the developed world [4,5]. A study of a California-wide hospital discharge database for first stroke admission for children ages 1 month through 19 years found an annual incidence rate of 1.1 per 100,000 children for hemorrhagic stroke and 1.2 per 100,000 children for ischemic stroke [4]. Similarly, a retrospective cohort study of 2.3 million children (age <20 years) followed for more than a decade revealed an average annual incidence rate of 1.4 per 100,000 children for hemorrhagic stroke [6]. Among hemorrhagic stroke subtypes, the estimated annual incidence of intracerebral hemorrhage in developed countries ranges from 1.1 to 5.2 per 100,000 children [4,5], while the estimated annual incidence of subarachnoid hemorrhage is 0.4 per 100,000 children [4]. ETIOLOGY AND RISK FACTORS Ruptured vascular malformations are the most common cause of intracerebral hemorrhage (ICH) in children. In contrast, hypertension and amyloid angiopathy are the most frequent causes of ICH in adults. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 2/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Aneurysms are the most common cause of nontraumatic subarachnoid hemorrhage in both adults and children. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) The etiology and risk factors of perinatal hemorrhagic stroke are reviewed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Hemorrhagic stroke'.) Vascular malformations Depending on the series, vascular malformations are responsible for 18 to 90 percent of childhood ICH cases [3,7-9], with arteriovenous malformations (AVMs) being the most common type and cavernous malformations and aneurysms found less frequently ( image 2) [10]. AVMs consist of abnormal direct connections between arteries and veins without intervening capillaries that give rise to high-flow lesions extremely prone to rupture (see "Brain arteriovenous malformations"). The incidence of cerebral AVMs in adults has been estimated to be 1 per 100,000 person-years [11]. Many AVM lesions are thought to be congenital, so this estimate may reflect the incidence in children as well; however, only a small percentage of AVMs (estimated 8 to 20 percent) become symptomatic under the age of 15 years [12,13]. The risk of hemorrhage from a cerebral AVM in children has been estimated at 2 percent per year [14]. AVMs account for 14 to 46 percent of ICH in children and nearly 50 percent of intraparenchymal hemorrhage [15-17]. Although most AVMs are isolated developmental lesions, there are genetic causes that predispose to multiple AVMs. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder of vascular dysplasia associated with mucocutaneous telangiectasias and AVMs. AVMs in patients with HHT most often occur in the pulmonary, hepatic, and cerebral circulations [18,19]. Multiplicity of brain AVMs is highly predictive of the diagnosis of HHT [20]. Incidence of HHT is reported to be 1 in 5000 to 8000 individuals per year [21], although this is likely to be an underestimate due to the variability in clinical manifestations. Approximately 20 percent of adults with HHT have cerebrovascular malformations [22]. The prevalence of cerebrovascular malformations in children with HHT is unknown but believed to approximate that of adult [23]. In one of the largest case series of pediatric patients with confirmed HHT, 11 of 115 children had cerebral AVMs and >50 percent developed symptomatic ICH [19]. Arteriovenous fistulas differ from AVMs because there is an absence of a discrete nidus between the arterial feeder and draining vein. Arteriovenous fistulas are worth noting as these also carry a significant risk of hemorrhage of 1.5 percent per year. However, arteriovenous fistulas are much rarer, comprising only 4 percent of pediatric cerebral vascular malformations [24,25]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 3/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Cavernous malformations (cavernomas or cavernous angiomas) have an estimated annual incidence of 0.56 per 100,000 people, which is approximately one-half that of AVMs [26]. Cavernous malformations consist of dilated sinusoidal vessels lined by endothelium without intervening neural parenchyma. "Leaking" of blood into surrounding tissue can occur due to dysfunctional endothelial cell connections. These are considered to be low-flow lesions. Cavernous malformations have been found to have a prevalence of 0.5 percent in autopsy studies [27,28] and are estimated to account for 20 to 25 percent of pediatric intraparenchymal hemorrhage [3,16,29]. While symptoms may manifest in all age groups, affected children tend to cluster in two age groups: infants and toddlers under the age of 3 years and children in early puberty, ages 12 to 16 years [30,31] While aneurysms are one of the most common vascular anomalies of the central nervous system, they are far less common in children than in adults, with a reported prevalence ranging from 0.5 to 5 percent of the total prevalence of intracranial aneurysms in the general population [32-39]. Aneurysms in children are felt to be different from those in adults in the following respects [33,39-41]: Pediatric aneurysms tend to be larger in size There is a higher incidence of giant aneurysms in children There tends to be a male predominance in children The most common cause of nontraumatic subarachnoid hemorrhage in children and adolescents is rupture of a cerebral aneurysm [6]. Ruptured aneurysms can also cause intraparenchymal hemorrhage or can present with nonhemorrhagic symptoms like headaches or seizures. Hematologic In reports from developed countries, hematologic abnormalities (including thrombocytopenia or platelet dysfunction, hemophilia and other congenital or acquired coagulopathies, and sickle cell disease) were the major risk factor for pediatric hemorrhagic stroke, found in 10 to 30 percent of cases [42]. In resource-limited countries, ICH secondary to underlying hematologic disorders occurs more frequently than hemorrhage due to vascular malformations. A retrospective study of 50 children with ICH at a single institution in Pakistan demonstrated that 52 percent had bleeding disorders compared with 14 percent with vascular malformations [43]. Similarly, a retrospective analysis of 94 children with hemorrhagic stroke in China found that 88 percent of patients had a bleeding diathesis compared with 14 percent with AVM [44]. Special populations with hematologic abnormalities include children with immune thrombocytopenia (ITP), hemophilia, and sickle cell disease: https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 4/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate With ITP, intracranial hemorrhage is estimated to occur in up to 1 percent. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Intracranial hemorrhage'.) With hemophilia, the reported ICH prevalence in children is 3 to 12 percent [45-47]. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Intracranial bleeding'.) With sickle cell disease (SCD), affected individuals are at risk for ischemic and hemorrhagic stroke. One report suggested that children with SCD had a >200-fold higher risk of hemorrhagic stroke compared with children without SCD [48]. In other reports, specific factors associated with hemorrhage in children with SCD included premorbid hypertension, transfusion within the last 14 days, treatment with glucocorticoids, low steady-state hemoglobin concentration, high steady-state leukocyte count, and late effects of moyamoya-type vasculopathy [49-51]. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Cancer A smaller proportion of hemorrhagic stroke in children is attributable to cancer. In one case series of 69 children with intraparenchymal hemorrhage, brain tumors accounted for 13 percent cases [7]. In another case series from a tertiary cancer center, ICH occurred in 3 percent of over 1000 children with brain tumors and in 1 percent of nearly 1600 children with acute leukemia [52]. [53,54] Other Although much less common than in the adult population, hypertension has also been associated with ICH in children. In one small retrospective cohort study, 45 percent of children th with ICH had elevated blood pressure above the 90 percentile at presentation; however, only 14 percent continued to have persistently elevated blood pressure on follow-up, and none required antihypertensive treatment [55]. Another cause of hemorrhagic stroke in childhood is moyamoya disease. Ischemic cerebrovascular events, either transient ischemic attack or infarction, are more prevalent than hemorrhagic events in children with moyamoya, while hemorrhagic stroke is more common in adults. However, moyamoya can cause either ICH or subarachnoid hemorrhage in children. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Drugs of abuse, coagulopathies secondary to liver dysfunction, and porphyria are rare causes of hemorrhagic stroke in children. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 5/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Cohort studies have shown that 9 to 23 percent of childhood ICH remains cryptogenic without a definitive risk factor identified despite extensive evaluation [8,56,57]. However, some proportion of these cryptogenic cases may be due to vascular malformations that have self-obliterated at the time of the incident hemorrhage [58]. CLINICAL FEATURES AND PRESENTATION Among all children who present outside the perinatal period, headache is the most common symptom of hemorrhagic stroke, affecting 46 to 80 percent [7,8,10,17]. Other common presenting symptoms in children include: Nausea and emesis in nearly 60 percent [8] Seizures (either generalized or focal) in 20 to 40 percent [7,8,59] Focal neurologic deficits such as hemiparesis or aphasia, which range in frequency from 13 to 50 percent [8,17,55,58] Neck pain Altered level of consciousness in 50 percent or more [7,8,56,58] The clinical presentation of hemorrhagic stroke can vary based upon the age of the child; younger children are most likely to present with only nonspecific features (eg, altered mentation, seizures, vomiting) while older children are more likely to present with headache, mental status change, and focal neurologic deficits. There is overlap between symptoms in pediatric hemorrhagic stroke, pediatric arterial ischemic stroke, and pediatric cerebral sinovenous thrombosis. All can present with headache, altered mental status, focal neurologic deficits, and seizures. Therefore, neuroimaging is required to differentiate among these entities. However, severe sudden headache with rapid alteration in level of consciousness may be more indicative of a hemorrhage. In a retrospective review of 85 children with nontraumatic intracerebral hemorrhage (ICH) at a tertiary pediatric hospital, the most common clinical signs in young children (<6 years of age) were mental status change, seizures, or vomiting [55]. In contrast, older children ( 6 years of age) often presented with headache and focal neurologic deficits in addition to symptoms of mental status change and nausea/vomiting, allowing clinicians to quickly narrow the differential diagnosis. Another cohort study found that children younger than three years of age at time of hemorrhage onset (n = 9) presented with vague symptoms of general deterioration, increased crying and sleepiness, irritability, feeding difficulty, vomiting, and sepsis-like symptoms with cold extremities [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 6/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate The onset of clinical symptoms due to hemorrhagic stroke is variable and ranges from rapid occurrence over minutes to insidious progression over several hours to days. In a cohort study of 22 children with ICH, the median time to hospital presentation was 70 minutes, but 23 percent of children presented after 24 hours [8]. A prospective study of 53 children with ICH found that acute symptomatic seizures, defined as those occurring from presentation to seven days after onset, occurred in 36 percent [59]. Thus, acute symptomatic seizures with ICH may be more common in children than in adults, where the corresponding rate is estimated to range from 5 to 30 percent (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'). Further, children with ICH may present with seizures more commonly than children with arterial ischemic stroke, in whom seizures at stroke onset have been reported in 22 percent [60]. Cortical involvement of ICH, which is an important predictor of acute symptomatic seizures in adults [61,62], was not related to acute symptomatic seizures in the pediatric ICH cohort [59]. The pace of symptom onset may be related to the underlying etiology, with aneurysm rupture expected to correlate with sudden onset, while other mechanisms may allow for subacute onset, at least in some cases. However, data are sparse. In a small cohort study of children with spontaneous ICH, approximately half had acute onset of symptoms while the other half had a subacute course [17]. Among children with a known onset, there were four with aneurysms, and the presentation was acute in three; among 16 children with arteriovenous malformation and known onset, an acute presentation occurred in 10 cases (63 percent). Other factors that could affect the rapidity of symptom development are size and location of hemorrhage, intraventricular extension, and presence of hydrocephalus. INITIAL EVALUATION AND DIAGNOSIS The diagnosis of hemorrhagic stroke requires confirmation by brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) [63]. Therefore, clinical suspicion for hemorrhage in the setting of a compatible presentation (eg, headache, mental status changes, seizure, vomiting, or focal neurologic deficits) as described above should prompt urgent imaging. (See 'Clinical features and presentation' above.) For children of school age or older, the acute onset of headache, particularly when severe, (eg, sometimes reported as the "worst headache of life") should prompt evaluation for intracerebral or subarachnoid hemorrhage. However, the diagnosis of hemorrhagic stroke in children can be difficult because the presentation is often nonspecific and subacute. In one small study, most cases with delayed diagnosis (7 of 11) had subacute onset [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 7/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate The initial evaluation should center on rapid diagnosis of the hemorrhage, assessment for presence of elevated intracranial pressure, and identification of easily correctible risk factors such as thrombocytopenia or coagulopathy. Children with hemorrhagic stroke are also at increased risk of subsequent ischemic stroke due to compression of blood vessels from mass effect from the intracerebral hemorrhage, vasospasm after subarachnoid hemorrhage, or underlying vasculopathy (such as moyamoya or cocaine-induced vasculopathy) [64]. Urgent neuroimaging Neuroimaging with CT or MRI as the initial study is necessary to determine the cause, to distinguish hemorrhagic stroke from ischemic stroke, and to distinguish stroke from stroke mimics. In a stable patient, MRI is preferred because of the lack of radiation and the better resolution of the parenchyma. MRI with gradient echo and/or susceptibility- weighted sequences is equally sensitive for acute hemorrhage and more sensitive for chronic hemorrhage than CT [65]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) However, MRI is not universally available and may require sedation [65]. Noncontrast head CT should be performed if a patient with suspected hemorrhage is unstable or if obtaining an MRI might delay diagnosis. CT is quick, widely available, does not require sedation in most cases, and is highly sensitive for acute hemorrhage. Noncontrast head CT reveals the diagnosis of subarachnoid hemorrhage in more than 90 percent of cases if performed within 24 hours of bleeding onset; the sensitivity of modern head CT for detecting SAH is highest in the first six hours after subarachnoid hemorrhage (nearly 100 percent when interpreted by expert reviewers). Limited data suggest that proton density and fluid-attenuated inversion recovery (FLAIR) sequences on brain MRI may be as sensitive as head CT for the detection of acute subarachnoid hemorrhage. If neuroimaging is negative for blood and there is high clinical concern for subarachnoid hemorrhage, lumbar puncture should be performed to detect red blood cells or xanthochromia if there are no contraindications (eg, large hemorrhage with significant edema causing impending herniation). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Laboratory studies First-line laboratory studies should include electrolytes, blood urea nitrogen and creatinine, glucose, complete blood count with platelets, coagulation studies (prothrombin time, international normalized ratio, and activated partial thromboplastin time) [63]. Type and screen should be sent for any child who will undergo surgery. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 8/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate DIFFERENTIAL DIAGNOSIS Hemorrhagic stroke must first be differentiated from other types of acute intracerebral vascular events, such as arterial ischemic stroke and cerebral sinovenous thrombosis, both of which may have concomitant hemorrhagic transformation [66]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The differential diagnosis for hemorrhagic stroke ( table 1) also includes a broad list of diagnoses that can mimic stroke syndromes. The most common childhood stroke mimics are: Migraine syndromes (see "Types of migraine and related syndromes in children" and "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Forms of migraine with aura') Postictal (Todd) paralysis (see "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Transient neurologic events') Other conditions that may mimic stroke include the following: Brain tumors (see "Clinical manifestations and diagnosis of central nervous system tumors in children") Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (see "Reversible posterior leukoencephalopathy syndrome") Intracranial infections including abscess, encephalitis, and meningitis White matter diseases ( algorithm 1) including multiple sclerosis, acute disseminated encephalomyelitis, and leukodystrophies (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Differential diagnosis of acute central nervous system demyelination in children") Metabolic derangements such as hypoglycemia (see "Approach to hypoglycemia in infants and children") Organic or amino acidurias (see "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features") https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 9/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Mitochondrial diseases such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') Methotrexate and other chemotherapeutic agent neurotoxicity (see "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy") Bell's palsy (see "Facial nerve palsy in children") Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)") Conversion disorders Musculoskeletal conditions Neuroimaging is required to diagnose hemorrhagic stroke and to distinguish stroke from mimics. (See 'Initial evaluation and diagnosis' above.) MANAGEMENT Once diagnosis of hemorrhagic stroke is confirmed (see 'Initial evaluation and diagnosis' above), the focus should shift to stabilization of the patient, treatment of elevated intracranial pressure (if present), and close monitoring for brain herniation. There are currently no established evidence-based diagnostic or management guidelines for children with hemorrhagic stroke. The American Heart Association (AHA) scientific statement for the management of stroke in infants and children includes recommendations for children with hemorrhagic stroke [67], which are mostly extrapolated from adult guidelines or are based on expert opinion derived from small retrospective pediatric studies. Immediate consultations Immediate consultations should be obtained from neurosurgery and neurology; hematology should also be consulted if hematologic abnormalities are present on laboratory studies (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR], complete blood count [CBC]) or are suspected. Platelet transfusion may be required if there is thrombocytopenia or concern for platelet dysfunction. Coagulopathy may require intravenous vitamin K and/or fresh frozen plasma, and children with factor VIII or IX deficiency typically require urgent factor replacement. Any child on an anticoagulant medication who presents with hemorrhage should receive blood products, https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 10/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate protamine, or vitamin K as warranted. (See "Reversal of anticoagulation in intracranial hemorrhage".) Potential need for decompressive hemicraniectomy and hematoma evacuation should be discussed with neurosurgery. (See 'Surgical management' below.) Supportive measures Subsequent supportive medical management of children with hemorrhagic stroke centers on preventing the progression of brain injury, with primary goals of reducing metabolic demand on brain tissue and avoiding hematoma expansion [63]. Isotonic fluids without glucose should be immediately started to maintain euvolemia, and normothermia should be maintained with acetaminophen and cooling blankets, as temperature elevation >37.5 C increased the likelihood of poor outcome in adult intraparenchymal hemorrhage [68]. Children who present with seizures should be treated with appropriate antiseizure medication (see "Seizures and epilepsy in children: Initial treatment and monitoring"). Prophylactic antiseizure medication treatment is unproven, though there are no high-quality studies of prophylactic antiseizure medication administration in pediatric hemorrhagic stroke. The AHA pediatric stroke guidelines make no recommendations regarding prophylactic antiseizure medication treatment in intracerebral hemorrhage (ICH) [67]. We agree with the AHA guidelines for management of ICH, which recommend against prophylactic antiseizure medications [69]. While treatment of hypertension is a mainstay of hemorrhagic stroke management in adults [63], no clear evidence for managing hypertension after ICH exists in children. It may be a th reasonable goal to lower a child's blood pressure to the 95 percentile for age and sex if elevated after hemorrhage to help prevent hematoma expansion. However, this is not evidence based and may cause a reduction in cerebral perfusion, thereby exacerbating secondary brain injury, particularly if there is elevated intracranial pressure. Any use of antihypertensive medication should be used cautiously. Intracranial pressure Medical management General measures for children with increased intracranial pressure include: Rapid treatment of hypoxia, hypercarbia, and hypotension Elevation of the head of the bed to at least 30 degrees Maintenance of the head and neck midline to facilitate venous drainage Aggressive treatment of fever with antipyretics and cooling blankets Control of shivering in intubated patients with muscle relaxants (eg, vecuronium, rocuronium) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 11/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate Maintenance of adequate analgesia to blunt the response to noxious stimuli Intracranial pressure (ICP) may become precipitously elevated in hemorrhagic stroke due to mass effect from the hemorrhage or from obstructive or communicating hydrocephalus from intraventricular hemorrhage. This contrasts with acute ischemic stroke, in which increased ICP typically develops several days after the incident event as infarcted brain tissue become edematous. To help reduce or prevent elevated ICP, the head of the bed should be elevated to at least 30 degrees, and the neck should be maintained in a midline position to promote venous drainage. Signs and symptoms of elevated ICP should be frequently reassessed, including presence of positional headache, vomiting, irritability or combativeness, declining mental status, sixth nerve palsies, and papilledema. While Cushing's triad (ie, hypertension, bradycardia, and respiratory depression) is highly suggestive of elevated ICP, this is typically a late finding. For any neurologic deterioration, a head computed tomography (CT) should be obtained promptly to assess for worsening hemorrhage, hydrocephalus, edema, or herniation. Direct ongoing measurement of ICP may require placement of an intraventricular catheter, which can also aid in ICP reduction via direct cerebrospinal fluid drainage, or a subdural bolt if an intraventricular catheter is not technically feasible due to small size of a child's ventricles or other reasons. Nonsurgical interventions for management of increased ICP include hyperventilation to PCO of 2 25 to 30 mmHg (if the child is intubated) and hyperosmolar therapy with intravenous mannitol (bolus 1 g/kg, given as an intravenous infusion through an in-line filter over 20 to 30 minutes, followed by infusions of 0.25 to 0.5 g/kg as needed, generally every six to eight hours) or hypertonic saline to promote osmotic diuresis (see "Elevated intracranial pressure (ICP) in children: Management", section on 'Hyperosmolar therapy'). If hyperosmolar therapy is administered, close monitoring of plasma osmoles and electrolytes is required to avoid hypovolemia, hypotension, and renal failure. Glucocorticoids should be avoided because they did not improve outcomes in randomized controlled trials of adults with ICH [70,71], and the resultant hyperglycemia may lead to worse outcomes [72,73]. Surgical management Ultimately, medical interventions for elevated ICP are only temporizing measures, and surgical evacuation of a parenchymal hematoma or decompressive craniectomy may be necessary to control refractory elevations in ICP and/or mass effect. Surgical hemorrhage evacuation for supratentorial ICH is controversial, and no high-quality studies in children have evaluated early surgical hematoma evacuation or hemicraniectomy. In adults, randomized trials have not conclusively demonstrated benefit. (See "Spontaneous https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 12/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients'.) As children typically lack the baseline cerebral atrophy found in older adults that permits expansion of the hematoma without consequent compression of the surrounding parenchyma, it is biologically plausible that children may benefit from hematoma evacuation to reduce ICP. If a child is undergoing resection of an underlying vascular malformation that is at high risk for acute rebleeding, it may be optimal to concurrently evacuate the hematoma. Surgical evaluation also might be warranted if a child is comatose, has elevated intracranial pressure that is refractory to medical management, or a worsening neurological examination. As in adults, cerebellar hemorrhages >3 cm in diameter in a child who is deteriorating or in whom brainstem compression and/or hydrocephalus is developing due to compression on the ventricular system should also be considered for surgical evacuation. If a cerebellar hemorrhage is evacuated, suboccipital craniectomy is typically performed at the same time. While hemicraniectomy has not been studied in the setting of pediatric hemorrhagic stroke, there are some series in which hemicraniectomy was associated with improved function and survival in pediatric arterial ischemic stroke [74,75]. In a child who undergoes surgical hematoma evacuation due to a supratentorial hemorrhage causing elevated intracranial pressure that is refractory to medical management, the surgeon may elect to perform a concomitant hemicraniectomy, particularly if the intracranial pressure remains elevated after hematoma evacuation or if there is herniation out of the craniotomy defect. Identifying the etiology Obtaining dedicated cerebrovascular imaging in the acute setting is critical to guide appropriate interventions given the high rate of vascular malformations underlying hemorrhagic stroke in children. Cerebral angiography is a minimally invasive modality that may be used for diagnosis and treatment of vascular causes of ICH [76]. While conventional cerebral angiography remains the gold standard, many institutions opt to first use noninvasive modalities. One retrospective study found that a combination of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) images accurately identified the cause of ICH in 66 percent of subjects, which was statistically equivalent to the diagnostic yield of conventional cerebral angiography alone (61 percent) [77]. However, another retrospective case series of children with nontraumatic ICH reported identification of the cause of bleeding in 97 percent of children who underwent conventional cerebral angiography compared with 80 percent of children who did not have angiography [7]. Another alternative is CT angiography (CTA), which can be rapidly obtained without the need for sedation in some children, is more widely available than MRA, and may offer superior https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 13/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate angioarchitectural visualization compared with MRA [78]. CTA also has a higher sensitivity for detecting aneurysms up to 2 mm in size. However, CTA exposes the child to both ionizing radiation and an iodinated contrast agent, requires a large bore intravenous line, and may be nondiagnostic if the child moves during the study. For children with hemorrhagic stroke and no identified cause despite a thorough evaluation, including appropriate noninvasive vascular imaging, we suggest conventional cerebral angiography. As an acute hemorrhage with large hematoma and significant cerebral edema can obscure visualization of an underlying vascular malformation, vascular studies that are initially nondiagnostic should be repeated weeks to months later once the clot has been reabsorbed if no other cause for the hemorrhage (eg, tumor, coagulopathy) is found [76]. The yield of an extensive evaluation for a bleeding diathesis in children with hemorrhagic stroke is not well-studied. A rational approach is to obtain the screening laboratory studies suggested above (see 'Laboratory studies' above) (ie, a complete blood count with platelets, coagulation studies, prothrombin time, international normalized ratio, and activated partial thromboplastin time) and to pursue additional testing if the screening studies are abnormal or if an underlying vascular lesion or tumor is not found. Higher-level studies may include factor VIII, IX, and XIII levels and von Willebrand disease studies and should be ordered in consultation with a hematologist. (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".) Treatment of vascular lesions Endovascular and/or surgical management of vascular malformations may be required in the acute setting depending on the location and vascular anatomy of the lesion in conjunction with the clinical status of the child. Multidisciplinary consultation with neurosurgery, interventional radiology, and neurology is advised to choose the optimal approach to treatment of these lesions [67]. Vascular malformations other than aneurysm typically have a low risk of acute rebleeding (although they may rebleed at later times) [79-81]. Therefore, many centers will await hematoma resolution prior to definitive treatment so that the full extent of the vascular malformation can be elucidated. However, if hematoma evacuation is needed, a vascular malformation may be addressed at the same time. Some arteriovenous malformations that cannot be treated with endovascular or surgical techniques may be amenable to gamma knife or proton beam therapy once the hematoma has retracted. Aneurysms have a higher rate of acute rebleeding [82]. Therefore, aneurysm repair typically occurs in the acute setting. AVMs with an aneurysmal component that may cause acute https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 14/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate rebleeding also may require earlier intervention. Follow-up imaging Due to the high risk of recurrence, we suggest follow-up imaging for most children with hemorrhagic stroke due to a vascular malformation. In addition, we suggest follow-up imaging in cases where a vascular cause is not found but is suspected. Even when complete resection of an arteriovenous malformation is achieved, there is a substantial risk of recurrence. In one retrospective report of 28 children who underwent surgical resection of arteriovenous malformations, 4 had recurrence leading to repeat resections [83]. Of note, two of the children in this cohort had arteriovenous malformations that were not detected until 17.7 and 25 months after the incident hemorrhage. While the frequency and modality of follow-up imaging is center-dependent, our suggested protocol is to obtain brain MRI with MRA at three to six months after the first hemorrhage, and/or a conventional angiogram between three and six months. Additional follow-up imaging at later points is typically necessary. In children with an unresected cavernous malformation, periodic imaging with MRI is suggested if the child is having frequent symptoms such as headaches or seizures. Genetic screening Genetic screening may be reasonable if multiple vascular malformations are found on imaging or if there is a suggestive family history [67]. The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. (See