Factor XIa inhibitors show higher stroke risk but lower bleeding risk versus DOACs in atrial fibrillation

This systematic review and meta-analysis pooled data from 3 randomized controlled trials involving 16,845 patients with atrial fibrillation (41% female, mean age 74 years). The analysis compared the efficacy and safety of Factor XIa inhibitors against direct oral anticoagulants (DOACs). The primary outcomes and follow-up duration were not reported in the available data.

For efficacy, Factor XIa inhibitors were associated with a significantly higher risk of ischemic stroke compared to DOACs, with a relative risk of 3.32 (95% CI: 2.24-4.90). Conversely, for safety outcomes, Factor XIa inhibitors showed a significantly lower risk of major or clinically relevant non-major bleeding (RR: 0.41, 95% CI: 0.33-0.49) and minor bleeding (RR: 0.68, 95% CI: 0.49-0.93). No significant differences were found for all-cause mortality, cardiovascular mortality, or hemorrhagic stroke, though specific effect sizes and confidence intervals for these outcomes were not reported.

Safety and tolerability data, including adverse events and discontinuation rates, were not reported. The analysis showed low statistical heterogeneity for the ischemic stroke and major/CRNM bleeding outcomes (I²=0%) but moderate heterogeneity for minor bleeding (I²=64%). Key limitations include the small number of trials (3 RCTs) included in the meta-analysis and the lack of reported data on absolute event numbers, specific patient settings, and long-term outcomes. The funding sources and potential conflicts of interest were also not reported.

For clinical practice, these findings highlight a critical efficacy-safety trade-off: while Factor XIa inhibitors appear to offer a substantial reduction in bleeding risk, this comes at the cost of a more than threefold increase in ischemic stroke risk compared to standard DOAC therapy. The absence of a mortality benefit further complicates the risk-benefit assessment. Clinicians should interpret these results cautiously, recognizing they are derived from a limited evidence base, and await more comprehensive data from larger, longer-term trials before considering any shift in anticoagulation strategy for atrial fibrillation.