Factor XI/XIa inhibitors are emerging anticoagulants designed to potentially reduce bleeding risk in patients with atrial fibrillation (AF). A systematic review and meta-analysis published in the Clinical Cardiology evaluated their efficacy and safety compared with direct oral anticoagulants (DOACs), and explored dose-related effects.

Following PRISMA guidelines, investigators searched PubMed, Cochrane, and Embase through March 2025. Three randomized controlled trials comprising 16,772 patients (mean age 73 years; CHA₂DS₂-VASc score 3.9–5) were included. Outcomes were pooled using a Mantel-Haenszel random-effects model, with heterogeneity assessed by I² and evidence certainty evaluated using GRADE. Trial Sequential Analysis (TSA) was also performed.

Factor XI/XIa inhibitors significantly reduced major bleeding compared with DOACs (RR 0.41; 95% CI 0.36–0.46; I²=0%). However, stroke risk was higher (RR 3.42; 95% CI 2.62–4.46), particularly with asundexian 50 mg (RR 4.02). Systemic embolism was also increased (RR 4.26). No significant differences were observed for all-cause mortality (RR 0.82) or cardiovascular mortality (RR 1.05), and serious adverse events were comparable (RR 0.95). TSA suggested favorable bleeding outcomes but indicated the need for further large-scale studies.

Factor XI/XIa inhibitors were associated with lower major bleeding but higher stroke and systemic embolism rates compared with DOACs. Mortality outcomes were not significantly different.

This meta-analysis included only three randomized trials with heterogeneous populations and follow-up durations (12–46 weeks), which may limit statistical power and generalizability. Participants had relatively high CHA₂DS₂-VASc scores, and potential bias from missing data and selective reporting cannot be excluded.