INTRODUCTION: Direct oral anticoagulants (DOACs) are the standard treatment for reducing thromboembolic risk in patients with atrial fibrillation (AF); however, bleeding remains a major concern. Factor XIa inhibitors have emerged as a potential alternative, but evidence about their therapeutic potential remains unclear. We performed a systematic review and meta-analysis to evaluate the comparative efficacy and safety of Factor XIa inhibitors versus DOACs for AF.

METHODS: PubMed, Embase, and Cochrane Library were systematically searched until February 15, 2025, to identify RCTs comparing Factor XIa inhibitors with DOACs in AF patients. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random-effects model. Statistical analysis was performed in RevMan 5.4 with p-value < 0.05 considered significant, and meta-analyses were conducted using a bivariate random-effects model. Study heterogeneity was measured using I² statistics, and study quality was assessed using the revised Cochrane risk-of-bias (RoB 2) tool.

RESULTS: Three RCTs comprising 16,845 patients (41% females) were included. The mean age of the participants was 74 years. Factor XIa inhibitors were associated with a significantly higher risk of ischemic stroke (RR: 3.32; 95% CI: 2.24-4.90, I²: 0%, p < 0.00001) but a lower risk of major or clinically relevant non-major (CRNM) bleeding (RR: 0.41; 95% CI: 0.33-0.49, I²: 0%, p < 0.00001) and minor bleeding (RR: 0.68; 95% CI: 0.49-0.93, I²: 64%, p = 0.02) compared to DOACs. However, there was no significant difference in the risk of all-cause mortality, cardiovascular mortality, or hemorrhagic stroke between the two groups.

CONCLUSION: Factor XIa inhibitors are associated with a reduced risk of major, minor, and clinically relevant non-major bleeding than DOACs but simultaneously increase the risk of ischemic stroke. No significant differences were found in the risk of hemorrhagic stroke or overall mortality rates compared to DOACs.