Who may benefit from oral anticoagulation following an embolic stroke of undetermined source?

Abstract

Embolic stroke of undetermined source (ESUS) represents up to one-sixth of ischemic strokes and is associated with an annual recurrence risk of 4%-5% despite contemporary secondary prevention. The hypothesis that oral anticoagulation would reduce recurrence compared with aspirin has been tested in large randomized trials, yet NAVIGATE-ESUS and RE-SPECT ESUS failed to demonstrate superiority of direct oral anticoagulants in the unselected ESUS population. These neutral findings reflect the heterogeneity of underlying mechanisms captured within the ESUS definition, which includes occult atrial fibrillation, atrial cardiopathy, structural cardiac disease, patent foramen ovale, and supracardiac atherosclerosis. Subgroup analyses, however, generate the hypothesis that anticoagulation may benefit selected patient groups: rivaroxaban reduced recurrence in patients with left atrial enlargement, left ventricular dysfunction and PFO in NAVIGATE-ESUS, and dabigatran was more effective in patients aged 75 years or older in RE-SPECT ESUS. ATTICUS highlighted the importance of atrial high-rate episodes as predictors of future atrial fibrillation, and ARCADIA underscored the need for refined definitions of atrial cardiopathy. Meta-analyses further support anticoagulation in patients with low-risk supracardiac atherosclerosis, atrial cardiopathy, or medically managed patent foramen ovale, although these effects remain inconsistent. Overall, ESUS should not be considered as an indication for anticoagulation. A precision-medicine approach, integrating cardiovascular imaging and biomarkers, is essential to identify subgroups most likely to benefit. Future research needs to refine risk stratification and target pathophysiologically homogeneous cohorts to improve secondary prevention in ESUS.