Factor XI Inhibitors in Early Clinical Trials: A Meta-analysis.

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 (risk ratio [RR]: 0.49, 95% confidence interval [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 toward 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 toward 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).
Conclusion:  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.
Study Registration:  This study is registered in PROSPERO (CRD42022367706).
Competing Interests: M.G. declares that he has received consulting fees or honoraria from Terumo, outside the present work. F.F. declares that he has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer, and Sanofi, and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. D.C. declares that he has received consulting and speaker's fee from Amgen, Daiichi Sankyo, Sanofi, and Terumo outside the present work. C.M.G. has received research grant support from Angel Medical Corporation, Bayer Corp, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and Portola Pharmaceuticals, and has received modest consulting monies from Amarin Pharma, Amgen, Arena Pharmaceuticals, Bayer Corporation, Boehringer Ingelheim, Boston Clinical Research Institute, Cardiovascular Research Foundation, Chiesi, CSL Behring, Eli Lilly, Gilead Sciences, Inc, Janssen Pharmaceuticals, Johnson & Johnson Corporation, The Medicines Company, Merk & Co, Inc., Novo Nordisk, Pfizer, Pharma Mar, Portola Pharmaceuticals, Sanofi, Somahlution, St. Francis Hospital, Verson Corporation, and Web MD. R.M. reports the following outside of the submitted work: institutional research payments from Abbott, Abiomed, Alleviant Medical, AM‐Pharma, Amgen, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol‐Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi‐Cardia, RenalPro, Shockwave, Vivasure, and Zoll; personal fees from Cine‐Med Research and WebMD; equity <1% in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); Scientific Advisory Board for American Medical Association, American College of Cardiology (Board of Trustees Member), Society for Cardiovascular Angiography and Interventions (Women in Innovations Committee Member), and JAMA Associate Editor; and Faculty Cardiovascular Research Foundation (no fee). D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi and Ventura, outside the present work. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and Scott R. MacKenzie Foundation. The remaining authors report no disclosures.
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