A Systematic Review of Safety and Efficacy of Factor XI/XIa Inhibitors in Patients With ESKD on Hemodialysis.

Introduction: Factor XI/XIa (FXI/XIa) has emerged as a potential target for antithrombotic therapy, driven by preclinical evidence showing the role of FXI/XIa inhibition for preventing thrombosis without impeding hemostasis. This is particularly promising for patients at high risk of both thromboembolic events and bleeding, such as patients with end-stage kidney disease (ESKD) on hemodialysis (HD).

Methods: We systematically searched Embase, MEDLINE, and ClinicalTrials.gov for randomized controlled trials evaluating FXI/XIa inhibitors in patients with ESKD on HD, without restricting inclusion to specific comparators or indications. Interventional treatment arms were pooled, and study results were synthesized by fitting random-effects models, calculating odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Five phases 2 studies encompassing 1270 participants were identified, investigating gruticibart, IONIS-FXI osocimab, or fesomersen in the general HD population and using placebo as a comparator. Four studies were fully published and included in the meta-analysis. Use of FXI/XIa inhibitors was associated with an OR of 0.80 (95% CI = 0.47-1.35) for clinically relevant bleeding, 0.51 (95% CI = 0.21-1.28) for major bleeding, and 0.90 (95% CI = 0.49-1.68) for clinically relevant nonmajor bleeding. The ORs for thromboembolic events and all-cause mortality were 0.66 (95% CI = 0.28-1.56) and 0.46 (95% CI = 0.15-1.40), respectively.

Conclusion: Currently available evidence does not indicate a significantly increased bleeding risk of FXI/XIa inhibitors in patients with ESKD on HD compared to placebo. Their efficacy and their association with all-cause mortality need to be investigated in sufficiently powered, randomized controlled phase 3 trials.