The following are key points to remember from this review on embolic stroke of undetermined source (ESUS):

1. About 17% of ischemic stroke patients have ESUS (i.e., strokes manifesting with infarcts >1.5 cm [nonlacunar infarcts]) without a known etiology such as carotid disease, atrial fibrillation, infective endocarditis, drug use, etc.
2. The rate of recurrent stroke after ESUS may be as high as 5% per year.
3. Based on observational data, covert atrial fibrillation cannot be assumed to be the leading cause of ESUS.
4. Patients <60 years old with patent foramen ovale (PFO) should not be included under the ESUS umbrella given evidence from two randomized controlled trials (REDUCE and CLOSE) that PFO closure is superior to antithrombotic therapy in this age group.
5. Two large randomized controlled trials, NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) and RE-SPECT (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source), tested whether empiric anticoagulation with rivaroxaban or dabigatran, respectively, would reduce the risk of recurrent stroke in ESUS patients when compared to aspirin. These studies found that empiric anticoagulation was not associated with lower rates of stroke recurrence than aspirin. Practically speaking, these studies reduced enthusiasm among stroke providers for using empiric anticoagulation in nonlacunar stroke and cryptogenic recurrent stroke.
6. One potential reason NAVIGATE ESUS and RE-SPECT ESUS were negative is heterogeneity of stroke etiology, including etiologies that may not respond well to anticoagulation such as atherosclerotic vessel disease (of the aortic arch, carotid and vertebral arteries, and/or intracranial vessels). The authors propose a role for a randomized controlled trial to test the hypothesis that the combination of low-dose oral anticoagulation and aspirin could decrease the risk of stroke recurrence in patients with ESUS and atherosclerotic vessel disease.
7. Thrombi may form in a diseased left atrium, even in the absence of atrial fibrillation, and lead to embolic stroke. The ongoing ARCADIA (AtRial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke) trial will test whether ESUS patients with atrial cardiopathy have less stroke recurrence with apixaban versus with aspirin.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Prevention, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias

Keywords: Anticoagulants, Aspirin, Atherosclerosis, Atrial Fibrillation, Brain Ischemia, Embolism, Endocarditis, Fibrinolytic Agents, Foramen Ovale, Patent, Infarction, Myocardial Ischemia, Secondary Prevention, Stroke, Thrombosis, Vascular Diseases

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