Factor XI inhibitors reduced major bleeding compared with DOACs (IRR 0.30; 95% CI 0.21-0.45) but were associated with an increased risk of stroke (IRR 1.36; 95% CI 1.04-1.77).
Meta-Analysis (n=16,845)
Do Factor XI inhibitors reduce stroke and major bleeding compared to DOACs in patients with atrial fibrillation?
In patients with atrial fibrillation, Factor XI inhibitors significantly reduce major bleeding compared to DOACs but are associated with a higher risk of stroke.
Relative Risk: 1.36 (95% CI 1.04–1.77)
Abstract Background Direct oral anticoagulants (DOACs) are the anticoagulants of choice in atrial fibrillation (AF), but their use is inevitably associated with an increased risk of bleeding. Factor XI (FXI) has been proposed as a strategy to reduce bleeding while maintaining adequate protection against thrombotic events. However, available trials are inconclusive regarding their antithrombotic efficacy, due to the low statistical power and the use of mixed doses of FXI inhibitors. Purpose Meta-analyses may improve statistical power for underpowered endpoints. We conducted an updated meta-analysis of randomized trials comparing FXI inhibitors vs DOACs in patients with AF. Methods Trials enrolling patients with AF who were randomly assigned to receive a FXI inhibitor or a DOAC and who reported at least one clinical event of interest were included. The primary efficacy endpoint was stroke, and the primary safety endpoint was International Society on Thrombosis and Hemostasis-defined major bleeding. Any bleeding, trial-defined major adverse cardiac event (MACE) and intracranial hemorrhages were the key secondary endpoints. To adjust for varying follow-up durations across trials, incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used. Additionally, to account for differences in FXI inhibitor doses across studies, analyses were conducted within pre-specified subgroups based on the use of high-dose versus low-dose FXI inhibitors. Results A total of 3 trials were included in the analysis (PACIFIC-AF, OCEANIC-AF, and AZALEA-TIMI 71), encompassing a total of 16,845 patients and 9,594.87 patient-year. Mean CHA2DS2-VASc score and follow-up durations were 4.4 and 298.7 days, respectively. Compared with DOACs, FXI inhibitors reduced major bleeding (IRR 0.30; 95% CI 0.21-0.45) but were associated with an increase in stroke (IRR 1.36; 95% CI 1.04-1.77; Figure). Although there was no significant interaction between treatment effect estimates and FXI inhibitor doses, the increase in stroke was numerically higher with the low (IRR 2.41, 95% CI 0.85-6.86) compared with the high doses (IRR 1.30, 95% CI 0.99-1.71; pint=0.25). FXI inhibitors reduced any bleeding (IRR 0.52; 95% CI 0.44-0.61) without significantly affecting MACE (IRR 1.21; 95% CI 0.77-1.91) or intracranial hemorrhages (IRR 0.42; 95% CI 0.13-1.29). No major influence of one trial over another for treatment effect estimates was detected for any of the endpoints. Conclusion This analysis confirms the superior safety profile of FXI inhibitors vs DOACs for any and major bleeding but raises concerns on the antithrombotic efficacy of FXI inhibitors in preventing stroke. Phase 3 trials with adequate statistical power for efficacy, evaluating FXI inhibitors at varying doses or with distinct mechanisms of action, are necessary to establish their role in this clinical setting.Figure
Galli et al. (Sat,) conducted a meta-analysis in atrial fibrillation (n=16,845). Factor XI inhibitors vs. Direct oral anticoagulants (DOACs) was evaluated on Stroke (primary efficacy) (IRR 1.36, 95% CI 1.04-1.77). Factor XI inhibitors reduced major bleeding compared with DOACs (IRR 0.30; 95% CI 0.21-0.45) but were associated with an increased risk of stroke (IRR 1.36; 95% CI 1.04-1.77).