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

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