Optimal antithrombotic therapy for patients with atrial fibrillation (AF) who experience ischemic stroke (IS) and have coexisting atherosclerotic cardiovascular disease (ASCVD) remains uncertain. Balancing the risks of recurrent ischemic events and bleeding is a major challenge in this population. A network meta-analysis published in the Journal of Neurological Sciences evaluated the comparative efficacy and safety of oral anticoagulant (OAC) monotherapy, antiplatelet therapy (APT), and combination therapy for secondary prevention.
Electronic databases were systematically searched through October 2025 for randomized and nonrandomized studies assessing antithrombotic strategies in patients with AF, IS, and ASCVD.

A frequentist network meta-analysis using random-effects models calculated pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Treatment rankings were evaluated using P-scores. The primary outcome was a composite of all-cause mortality, major bleeding, and any ischemic event.

Ten studies including 14,104 patients (one randomized trial and nine observational studies) were analyzed. Compared with 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). For major bleeding, both APT (HR 0.64; 95% CI 0.28–1.46) and OAC monotherapy (HR 0.74; 95% CI 0.35–1.55) showed a trend toward lower major bleeding compared with combination therapy, although results were not statistically significant. Mortality risk was similar between OAC monotherapy and combination therapy (HR 1.11; 95% CI 0.66–1.87), while APT showed a trend toward higher mortality risk.

OAC monotherapy ranked most favorable for efficacy and safety outcomes among the evaluated strategies. However, findings were largely derived from observational data and warrant confirmation in randomized trials.