Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis

Lina Palaiodimou; Georgia Papagiannopoulou; Aristeidis H Katsanos; Andreas Eleftheriou; Theodore Karapanayiotides; Panayiotis D Mitsias; Robin Lemmens; Carlos A Molina; Andrei Alexandrov; Valeria Caso; Ashkan Shoamanesh; Mukul Sharma; Georgios Tsivgoulis

doi:10.3390/jcm12175562

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis

J Clin Med. 2023 Aug 26;12(17):5562. doi: 10.3390/jcm12175562.

Authors

Affiliations

¹ Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.
² Division of Neurology, McMaster University/Population Health Research Institute, Hamilton, ON L8L2X2, Canada.
³ Second Department of Neurology, School of Medicine, Faculty of Health Sciences, AHEPA University General Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.
⁴ Neurology Department, University General Hospital of Heraklion, 71500 Heraklion, Greece.
⁵ Experimental Neurology, Department of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
⁶ VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3001 Leuven, Belgium.
⁷ Department of Neurology, University Hospitals Leuven, 3000 Leuven, Belgium.
⁸ Vall d'Hebron Stroke Center, Department of Neurology, Hospital Universitari Vall d'Hebron, Departament de Medicina, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
⁹ Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
¹⁰ Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, 06129 Perugia, Italy.

Abstract

Introduction: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention.

Methods: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding.

Results: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90).

Conclusion: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.

Keywords: anticoagulation; antithrombotic treatment; factor Xia inhibitors; ischemic stroke; meta-analysis; randomized-controlled clinical trials; stroke prevention.

Publication types

Review

Grants and funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.