Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I² = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I² = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I² = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I² = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I² = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I² = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I² = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I² = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I² = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.