Abstract DP007: Individual Participant Data Meta-Analysis of Randomized Trials of Direct Oral Anticoagulants compared with Aspirin in Patients with Embolic Strokes of Undetermined Source

Background: Anticoagulation did not reduce the risk of stroke recurrence compared with antiplatelet therapy in randomized controlled trial (RCT) participants with embolic stroke of undetermined source (ESUS). Subsequent analyses of individual RCTs suggested a benefit of anticoagulation in particular subgroups, but these findings have not been consistently replicated. We aimed to determine the effect of anticoagulation in ESUS patients and pre-specified subgroups using pooled RCT data. Methods: We performed an individual participant data meta-analysis (IPD-MA) of published RCTs comparing anticoagulation with antiplatelet therapy after ESUS on the primary outcomes of stroke recurrence and major bleeding, in addition to other secondary cardiovascular endpoints. The effect of anticoagulation on the risk for stroke recurrence compared with aspirin was further explored in subgroups predefined by baseline demographics, medical comorbidities, concomitant medication use, and echocardiographic and electrocardiographic parameters. Databases from individual RCTs were obtained and hazard ratios (HRs) with corresponding 95% confidence intervals (95%CIs) in the overall trial population and subgroups were estimated following adjustment for predefined covariates, using Cox proportional hazard models. Adjusted HRs were then combined into pooled estimates using the random-effects model. Differences between subgroups were assessed using Cochran's Q test of heterogeneity. The protocol of the IPD-MA is published in PROSPERO (CRD42025644724). Results: We included 4 RCTs with a total of 13,970 participants (mean age 66 years; 39% female). Baseline characteristics were well balanced between the treatment groups (Figure 1). Participants allocated to anticoagulant therapy (n=6,989) had comparable risks of stroke recurrence (adjusted HR=0.94, 95%CI: 0.78-1.14) and major bleeding (adjusted HR=1.21, 95%CI: 0.52-2.80) compared with participants allocated to antiplatelet therapy (n=6,981). We identified no significant difference in secondary efficacy or safety cardiovascular endpoints (Figure 2). We did not identify any predefined subgroup in which the effect of anticoagulation significantly differed from antiplatelet therapy (Figure 3). Conclusion: Anticoagulation did not reduce the risk for stroke recurrence or other cardiovascular events after ESUS when compared with antiplatelet therapy. None of the predefined subgroups benefitted from anticoagulation.