Optimal antithrombotic therapy for post-ischemic stroke patients with atrial fibrillation and atherosclerotic cardiovascular disease: A frequentist network meta-analysis

Background The optimal antithrombotic strategy for secondary prevention in patients with atrial fibrillation (AF) and concomitant atherosclerotic cardiovascular disease (ASCVD) following acute ischemic stroke (IS) remains undefined. This network meta-analysis compared the efficacy and safety of oral anticoagulant (OAC) monotherapy, antiplatelet therapy (APT), and their combination in this population. Methods We systematically searched major electronic databases through October 2025 for relevant randomized and non-randomized studies. A frequentist network meta-analysis was performed using random-effects models to calculate pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Treatment hierarchies were ranked using P-scores. The primary outcome was a composite of all-cause mortality, major bleeding, and any ischemic event. Results Ten studies (1 randomized trial, 9 observational) involving 14,104 patients were included. Compared to combination therapy, OAC monotherapy ranked most favorable for the primary composite endpoint (HR 0.82, 95% CI: 0.53–1.27; P-score: 0.90) and for recurrent IS (HR 0.77, 95% CI: 0.50–1.20; P-score: 0.88). Regarding major bleeding, both APT (HR 0.64, 95% CI: 0.28–1.46; P-score: 0.75) and OAC monotherapy (HR 0.74, 95% CI: 0.35–1.55; P-score: 0.57) ranked superior to combination therapy, respectively. For mortality, OAC monotherapy was comparable to combination therapy (HR 1.11, 95% CI: 0.66–1.87), whereas APT suggested a higher risk (HR 1.78, 95% CI: 0.97–3.29; P-score: 0.05). Conclusion In patients with IS, AF, and ASCVD, OAC monotherapy appears to be the most favorable strategy for secondary prevention, offering an optimal balance between efficacy and safety. Adding APT confers no additional clinical benefit while introducing a concerning increase in bleeding risk. However, given the predominance of observational data, these findings should be interpreted with caution and confirmed through dedicated randomized controlled trials.