Factor XI inhibitors versus direct oral anticoagulants for the prevention of thromboembolic events and safety in patients with atrial fibrillation: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: While DOACs - Direct Oral Anticoagulants are the current standard for stroke prevention, nearly 30-50% of eligible patients remain untreated or undertreated due to perceived or actual bleeding risk. Therefore, evaluating agents that potentially uncouple antithrombotic efficacy from hemostasis is a clinical priority. Factor XI/XIa (FXI/XIa) inhibitors are proposed to reduce bleeding while maintaining antithrombotic efficacy. OBJECTIVES: We aimed to compare the efficacy and safety of FXI/XIa inhibitors versus DOACs in patients with AF. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing FXI/XIa inhibitors with DOACs in adults with AF. Databases including MEDLINE, Embase, and Scopus were searched until February 28, 2025. The study protocol was prospectively registered in PROSPERO (CRD420251045353). The primary outcome was ISTH major bleeding. Secondary outcomes included ischemic stroke, clinically relevant non-major (CRNM) bleeding, and all-cause mortality. Random-effects models were used to pool odds ratios (ORs) and 95% confidence intervals (CIs). Heterogeneity was assessed using I². RESULTS: Four RCTs (OCEANIC-AF, AZALEA-TIMI 71, PACIFIC-AF, and LIBREXIA-AF [design protocol]) involving 16,852 patients were included in the qualitative synthesis, with data from three trials contributing to quantitative meta-analyses. Compared to DOACs, FXI/XIa inhibitors were associated with a significant reduction in ISTH major bleeding (0.40% vs. 1.32%; OR 0.30, 95% CI 0.20-0.43; P < 0.001; I²=0%) and CRNM bleeding (1.53% vs. 3.94%; OR 0.38, 95% CI 0.30-0.47; P < 0.001; I²=0%). However, FXI/XIa inhibitors were associated with a significantly increased risk of ischemic stroke (1.12% vs. 0.35%; OR 3.20, 95% CI 1.85-5.55; P = 0.004; I²=0%). A modest but statistically significant reduction in all-cause mortality was observed (1.37% vs. 1.68%; OR 0.81, 95% CI 0.69-0.95; P = 0.021; I²=0%). CONCLUSIONS: In patients with atrial fibrillation, Factor XI/XIa inhibitors significantly reduce major and clinically relevant non-major bleeding compared to DOACs but are associated with an increased risk of ischemic stroke. While a modest reduction in all-cause mortality was noted, the unfavorable efficacy profile for stroke prevention raises concerns about the net clinical benefit of the currently evaluated FXI/XIa inhibitors in this population. Further data from ongoing large-scale trials are needed to define their ultimate clinical role.