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

Mattia Galli; Renzo Laborante; Luis Ortega-Paz; Francesco Franchi; Fabiana Rollini; Domenico D'Amario; Davide Capodanno; Elena Tremoli; Charles Micheal Gibson; Roxana Mehran; Dominick J. Angiolillo

doi:10.1055/a-2043-0346

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2023; 123(06): 576-584
DOI: 10.1055/a-2043-0346

Coagulation and Fibrinolysis

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

Mattia Galli

¹Catholic University of the Sacred Heart, Rome, Italy

²Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy

,

Renzo Laborante

¹Catholic University of the Sacred Heart, Rome, Italy

,

Luis Ortega-Paz

³Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States

,

Francesco Franchi

³Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States

,

Fabiana Rollini

³Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States

,

Domenico D'Amario

⁴Dipartimento Universitario di Medicina Traslazionale, Università Piemonte Orientale, Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara, Novara, Italy

,

Davide Capodanno

⁵Division of Cardiology, Azienda Ospedaliero Universitaria Policlinico “G. Rodolico-San Marco,” University of Catania, Catania, Italy

,

Elena Tremoli

²Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy

,

Charles Micheal Gibson

⁶Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

,

Roxana Mehran

⁷Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, United States

,

Dominick J. Angiolillo

³Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States

› Author Affiliations

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 (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).

Keywords

FXI inhibitors - low-molecular-weight heparin - direct oral anticoagulant - placebo - bleeding

Full Text

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Supplementary Material

Supplementary Material