Dose‐Response Efficacy and Safety of Factor XI/XIa Inhibitors in Atrial Fibrillation; a Systematic Review and Meta‐Analysis With Subgroup Exploration and Trial Sequential Validation

BACKGROUND: Factor XI/XIa inhibitors are emerging anticoagulants with potential to reduce bleeding complications in atrial fibrillation (AF) patients. This meta-analysis evaluated their efficacy and safety compared to direct oral anticoagulants (DOACs) and explored dose optimization. METHODS: A systematic search of PubMed, Cochrane, and Embase was conducted through March 2025 following PRISMA guidelines. Randomized controlled trials (RCTs) comparing Factor XI/XIa inhibitors with DOACs in AF patients were included. Outcomes assessed were major bleeding, stroke, systemic embolism, all-cause and cardiovascular mortality and serious adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a Mantel-Haenszel random-effects model. Heterogeneity was evaluated with the I² statistic, and evidence certainty assessed by the GRADE approach. Trial Sequential Analysis (TSA) was performed. RESULTS: Three RCTs including 16,772 patients (mean age 73 years, CHA₂DS₂-VASc 3.9-5) were analyzed. Factor XI/XIa inhibitors significantly reduced major bleeding (RR: 0.41, 95% CI: 0.36-0.46, I² = 0%) compared to DOACs. However, stroke risk was increased (RR: 3.42, 95% CI: 2.62-4.46), particularly with asundexian 50 mg (RR: 4.02). No significant differences were observed in all-cause mortality (RR: 0.82) or cardiovascular death (RR: 1.05). Systemic embolism risk was higher (RR: 4.26), while serious adverse events were comparable (RR: 0.95). TSA indicated encouraging safety outcomes but highlighted the need for further large-scale studies. CONCLUSION: Factor XI/XIa inhibitors lower major bleeding risk in AF patients but increase stroke and systemic embolism rates without impacting mortality.