Atrial fibrosis and its implications on a revised ESUS concept

Embolic stroke of undetermined source (ESUS) accounts for up to 25% of all stroke cases, which, together with the high risk of stroke recurrence despite antiplatelet therapy (5%–14.5% per year), underlines the importance of optimizing secondary prevention in this population.1 Given past experience with vitamin k antagonists2 and the improved safety profile of direct oral anticoagulants (DOACs), these agents provide an attractive choice. The most pragmatic approach was to treat all patients with ESUS with a DOAC after a typically relatively brief, unsophisticated, and thus easily available diagnostic assessment, comprising only basic brain and vessel imaging, precordial echography, and cardiac monitoring for at least 24 hours. Unfortunately, this strategy failed in 2 most recent phase III randomized controlled trials (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source [NAVIGATE-ESUS] and Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source [RE-SPECT ESUS]) that compared rivaroxaban and dabigatran, respectively, with aspirin for secondary prevention after ESUS.3,4 Neutral main results but tendencies for a better outcome in older patients or after prolonged follow-up in RE-SPECT ESUS and in patients with enlarged left atrium in NAVIGATE-ESUS imply the necessity of addressing the heterogeneity of suspected embolic pathways in patients with ESUS, which range from occult atrial fibrillation (AF) to structural abnormalities of the heart and atherogenic emboli.1