Factor XIa Inhibitors Versus Direct Oral Anticoagulants for Atrial Fibrillation: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

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.