Direct Oral Anticoagulants versus Aspirin for Secondary Stroke Prevention in Patients with Embolic Stroke of Undetermined Source: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract Embolic stroke of undetermined source (ESUS) accounts for around 20% of ischemic strokes. The ideal treatment for secondary prevention in ESUS remains unclear. This study aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the safety and efficacy of direct oral anticoagulants (DOACs) versus aspirin in patients with ESUS. A systematic search of PubMed, Embase, Cochrane, and Web of Science databases was conducted for eligible trials until March 2024. The primary outcome was recurrent stroke, while safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for analysis. Four RCTs were included, involving 13,970 patients, half of whom were randomized to the DOACs group. Over a mean follow-up of 16 months, DOACs did not significantly reduce recurrent stroke (HR: 0.95; 95% CI: 0.81-1.09; p=0.44), ischemic stroke (HR: 0.91; 95% CI: 0.79-1.06; p=0.23), all-cause mortality (HR: 1.11; 95% CI: 0.87-1.42; p=0.40), or major bleeding (HR: 1.56; 95% CI: 0.85%-2.86; p=0.15) compared to aspirin. However, DOACs were associated with a significantly higher risk of CRNMB (HR: 1.54; 95% CI: 1.23-1.92; p=0.0002). Subgroup analysis revealed no significant differences in stroke recurrence among patients with low or high CHA2-DS2-VASc scores. DOACs did not demonstrate superior efficacy over aspirin in preventing recurrent stroke among ESUS patients and were linked to an increased risk of CRNMB.