Factor XI inhibitors in early clinical trials: a meta-analysis

Abstract Background Phase II randomized controlled trials (RCTs) on factor(F)XI inhibitors have shown promising results but they were burdened by low statistical power for clinical outcomes. Methods We performed a systematic review and meta-analysis of RCT comparing FXI inhibitors versus other anticoagulants (enoxaparin or direct oral anticoagulants, DOACs) or versus placebo on top of antiplatelet therapy. Results Eight RCTs testing FXI inhibitors (ISIS 416858, osocimab, abelacimab, milvexian, asundexian) and enrolling 9,216 patients were included. Compared with enoxaparin, FXI inhibitors were associated with reduced any-bleeding (RR 0.49, 95% CI 0.31-0.77), no difference in major bleeding (RR 0.96, 95% CI 0.41-2.28) and reduced trial-defined efficacy endpoint (RR 0.62, 95% CI 0.49-0.79), the latter driven by the high dose regimens. Compared with DOACs, FXI inhibitors were associated with a trend towards reduced any-bleeding (RR 0.66, 95% CI 0.31-1.38) and no difference in major bleeding (RR 1.03, 95% CI 0.22-4.78) or in trial-defined efficacy endpoint (RR 1.23, 95% CI 0.88-1.70). Compared with placebo, FXI inhibitors were associated with increased any-bleeding (RR 1.25, 95% CI 1.08-1.43) and a trend towards increased major bleeding (RR 1.21, 95% CI 0.75-1.93), both driven by high dose regimens, with no difference in trial-defined efficacy endpoint (RR 1.02, 95% CI 0.92-1.13). Conclusions Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy.