Direct Oral Anticoagulants Versus Aspirin for Stroke Prevention After Embolic Stroke of Undetermined Source: An Updated Meta-Analysis of Randomized Controlled Trials

Background: Four randomized controlled trials (RCTs) did not show a benefit of direct oral anticoagulant (DOAC) treatment compared with antiplatelet therapy for the prevention of recurrent strokes in patients with embolic stroke of undetermined source (ESUS). However, the balance between efficacy and safety in subgroups needs to be better defined. We aimed to assess the relative benefits of DOACs in key subgroups of adult patients with ESUS. Methods: We searched major databases (PubMed, Embase, CENTRAL, and Web of Science) for RCTs published from inception to 16 June 2024. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed the risk of bias using the Cochrane Risk of Bias tool 2. Results: We identified four RCTs, involving a total of 13,970 patients with ESUS. Compared to antiplatelet therapy, treatment with DOAC did not reduce the risk of recurrent stroke (RR 0.95, 95% CI 0.83-1.08, p = 0.45) or ischemic stroke (RR 0.92, 95% CI 0.80-1.05, p = 0.22) or increase major bleeding (RR 1.57, 95% CI 0.87-2.83; p = 0.14). DOAC treatment was associated with a significantly higher risk of CRNMB compared to aspirin (RR 1.52, 95% CI: 1.22-1.90; p = 0.0002). The subgroup analysis demonstrated that use of DOACs was associated with a significant protective effect in patients aged 75 or older (RR 0.76, 95% CI 0.60-0.97, p = 0.03) and when the time from index stroke to randomization was >= 8 days (RR 0.80, 95% CI 0.66-0.97, p = 0.02) in preventing recurrency of any type of stroke. Conclusions: Our meta-analysis showed lack of overall benefit of anticoagulation with DOAC compared to antiplatelet therapy for recurrent stroke prevention in adult patients with ESUS. However, the subgroup analyses suggest the possibility of interactions between age and timing of randomization since stroke and treatment with an DOAC in terms of recurrent stroke prevention. Further research toward tailoring the antithrombotic strategy according to patient characteristics is needed.