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  • Review Article
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Factor XI inhibitors for the prevention and treatment of venous and arterial thromboembolism

Nature Reviews Cardiology volume 22, pages 896–912 (2025)Cite this article

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Abstract

Therapeutic anticoagulation is essential to prevent and treat venous and arterial thromboembolism. The available agents target coagulation factors involved in thrombus formation but are associated with an increased risk of bleeding. Factor XI plays a minor role in haemostasis but contributes substantially to thrombus expansion, making it an attractive target to mitigate bleeding while maintaining antithrombotic efficacy. Various novel inhibitors, including antisense oligonucleotides, monoclonal antibodies and small molecules, have been developed. Phase II trials in orthopaedic surgery showed dose-dependent reductions in venous thromboembolism without significantly increasing bleeding compared with enoxaparin. In the first phase III trial of a small-molecule inhibitor of activated factor XI in patients with atrial fibrillation, asundexian was associated with a reduction in bleeding but also a higher risk of stroke, compared with apixaban. Factor XI inhibitors appear safe and hold promise for secondary prevention in myocardial infarction and ischaemic stroke, with ongoing phase III trials assessing their broader efficacy and safety. This Review discusses the rationale, pharmacology, evidence and future directions of factor XI inhibitors across various clinical settings.

Key points

  • Factor XI (FXI) inhibitors aim to uncouple haemostasis from thrombosis, presenting a novel approach to anticoagulation, with a reduced risk of bleeding compared with that associated with traditional anticoagulant agents.

  • Several phase II studies indicate that FXI inhibitors decrease thrombotic complications dose-dependently, without corresponding increases in bleeding, suggesting a favourable safety profile.

  • FXI inhibitors showed non-inferiority and potential superiority to low-molecular-weight heparin for the prevention of venous thromboembolism in patients undergoing orthopaedic surgery, with minimal bleeding risks observed at therapeutic doses.

  • Milvexian and abelacimab are theoretically promising for reducing the risk of bleeding associated with thromboprophylaxis in patients with atrial fibrillation; phase III clinical trials of safety and efficacy are ongoing.

  • In phase II trials involving patients with non-cardioembolic ischaemic stroke, no significant benefit of FXI inhibitors was found in terms of the primary ischaemic end points, but future phase III trials might find benefits in selected patients with large-vessel atherosclerosis.

  • The ongoing LIBREXIA-ACS trial will assess the use of milvexian in 16,000 patients with recent acute coronary syndrome.

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Fig. 1: Contribution of factor XI to haemostasis and thrombosis.
Fig. 2: Mechanisms of action of anticoagulant drugs.
Fig. 3: Classification and mechanisms of action of factor XI inhibitors.

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Authors and Affiliations

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

    Davide Capodanno

  2. Duke University Medical Center, Durham, NC, USA

    John H. Alexander, Renato D. Lopes, Manesh R. Patel & Jonathan P. Piccini

  3. INECO Neurociencias, Rosario, Argentina

    M. Cecilia Bahit

  4. BAIM Institute for Clinical Research, Boston, MA, USA

    M. Cecilia Bahit

  5. Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

    John W. Eikelboom, Shamir R. Mehta & Jeffrey I. Weitz

  6. Hamilton Health Sciences, Hamilton, Ontario, Canada

    John W. Eikelboom, Shamir R. Mehta & Jeffrey I. Weitz

  7. Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    C. Michael Gibson

  8. St. Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, Canada

    Shaun G. Goodman

  9. Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Shaun G. Goodman

  10. Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada

    Shaun G. Goodman

  11. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, UK

    Vijay Kunadian

  12. Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK

    Gregory Y. H. Lip

  13. Liverpool John Moores University, Liverpool, UK

    Gregory Y. H. Lip

  14. Liverpool Heart and Chest Hospital, Liverpool, UK

    Gregory Y. H. Lip

  15. Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Gregory Y. H. Lip

  16. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Roxana Mehran

  17. New York University School of Medicine, New York, NY, USA

    Sunil V. Rao

  18. TIMI Study Group, Division of Cardiovascular Medicine, Brigham & Women’s Hospital, Boston, MA, USA

    Christian T. Ruff

  19. Harvard Medical School, Boston, MA, USA

    Christian T. Ruff

  20. Université Paris-Cité, INSERM-UMR1148, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, French Alliance for Cardiovascular Trials, Paris, France

    P. Gabriel Steg

  21. Institut Universitaire de France, Paris, France

    P. Gabriel Steg

  22. Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA

    Dominick J. Angiolillo

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  1. Davide Capodanno
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  2. John H. Alexander
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  3. M. Cecilia Bahit
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  18. Dominick J. Angiolillo
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Contributions

D.C. and D.J.A. researched data for the article and wrote the manuscript. All the authors discussed its content and reviewed/edited it before submission.

Corresponding author

Correspondence to Dominick J. Angiolillo.

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Competing interests

D.C. has received consulting fees or honoraria from Bristol Myers Squibb, Daiichi Sankyo, Novo Nordisk, Sanofi and Terumo. J.H.A. reports research grants through Duke University from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring and Humacyte; and honoraria or consulting payments from AbbVie, AtriCure, Artivion/CryoLife, Bayer, Bristol Myers Squibb, Curis, Eli Lilly, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Theravance and Veralox. M.C.B. has received consulting fees or honoraria from Anthos, Bristol Myers Squibb, CSL Behring, Johnson & Johnson, MSD and Pfizer. J.W.E. has received payments and/or grant support from Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Johnson & Johnson, Merck, Pfizer, PhaseBio and Servier. C.M.G. has received grants from CSL Behring, Janssen, Johnson & Johnson and SCAD Alliance; has received personal fees from AMAG Pharmaceuticals, Amarin, Angel Medical Corporation, Anthos Therapeutics, AstraZeneca (during the conduct of the study), Bayer, Bioclinica, Boston Clinical Research Institute, Boston Scientific, Bristol Myers Squibb, Caladrius Biosciences, Cardiovascular Clinical Science Foundation, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, CytoSorbents, Duke Clinical Research Institute, Dyad Medical, Eidos Therapeutics, EXCITE International ($0 received), Gilead Sciences, Inari, Janssen, Johnson & Johnson, MD Magazine, MedImmune, Medtelligence, MedTrace, Merck, Microdrop, Microport, Novo Nordisk, Paratek, PERT Consortium, Pfizer, PhaseBio, PHRI, PLx Pharma, Revance Therapeutics, SmartMedics, Society for Cardiovascular Angiography and Interventions, Somahlution, UpToDate in Cardiovascular Medicine and WebMD; has received non-financial support from the Baim Institute; and has equity from Absolutys and Dyad Medical. S.G.G. has received research grant support (for work on steering committees or data and safety monitoring committees) and/or speaker or consulting honoraria (such as advisory boards) from Alnylam, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk, Pendopharm/Pharmascience, Pfizer, Regeneron, Roche, Sanofi, Servier, Tolmar Pharmaceuticals and Valeo Pharma; and salary support/honoraria from the Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital/CIUSSS Centre-Ouest-de-l’Ile-de-Montreal, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, Ted Rogers Centre for Heart Research and TIMI Study Group (Brigham Health). R.D.L. reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Daiichi Sankyo, Novo Nordisk and Pfizer; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb and Novo Nordisk. M.R.P. reports research grants with Bayer, Idorsia, Medtronic, NHBLI and Novartis, and has received honoraria for scientific advisory boards and consulting from Bayer, Esperion and Novartis. J.P.P. is supported by a grant (R01AG074185) from the National Institutes of Aging; receives grants for clinical research from Abbott, American Heart Association, Boston Scientific, iRhythm and Philips; and serves as a consultant to Abbott, Boston Scientific, Kardium, Medtronic, Milestone Pharmaceuticals, Philips, Sanofi and Up-to-Date. S.V.R. reports research grants from American College of Cardiology and NHLBI. C.T.R. reports research grants through Brigham and Women’s Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis; has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer; and is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Saghmos Therapeutics, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, Verve Therapeutics and Zora Biosciences. P.G.S. has received research grants from Bayer; is a consultant for Amarin, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Sanofi and Servier; and is Chief Medical Officer for Bioquantis. D.J.A. has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer and Sanofi; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Company, Merck, Novartis and the Scott R. MacKenzie Foundation. The other authors declare no competing interests.

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Capodanno, D., Alexander, J.H., Bahit, M.C. et al. Factor XI inhibitors for the prevention and treatment of venous and arterial thromboembolism. Nat Rev Cardiol 22, 896–912 (2025). https://doi.org/10.1038/s41569-025-01144-z

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