Targeting Factor XI for Safer Anticoagulation: Emerging Data and Future Directions.
| Title: | Targeting Factor XI for Safer Anticoagulation: Emerging Data and Future Directions. |
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| Authors: | Campanella F; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.; Cardiology Department, Azienda Ospedaliera per l'Emergenza 'Cannizzaro', Catania, Italy.; Barreca F; Department of Cardiology and Cardiac Surgery, Centro Cuore Morgagni, Pedara, CT, Italy.; Giubilato S; Cardiology Department, Azienda Ospedaliera per l'Emergenza 'Cannizzaro', Catania, Italy.; Alagna G; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.; Taverna G; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.; Giamundo DM; Department of Systems Medicine, 'Tor Vergata' University, Rome, Italy.; Ibrahim A; Faculty of Medicine, Alexandria University, Alexandria, Egypt.; Sabouret P; Heart Institute and Action Group, Pitié-Salpétrière, Sorbonne University, 75013, Paris, France.; Amico F; Cardiology Department, Azienda Ospedaliera per l'Emergenza 'Cannizzaro', Catania, Italy.; Andò G; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. giuseppe.ando@unime.it. |
| Source: | American journal of cardiovascular drugs : drugs, devices, and other interventions [Am J Cardiovasc Drugs] 2026 May; Vol. 26 (3), pp. 305-321. Date of Electronic Publication: 2026 Jan 25. |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: Adis, Springer International Country of Publication: New Zealand NLM ID: 100967755 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-187X (Electronic) Linking ISSN: 11753277 NLM ISO Abbreviation: Am J Cardiovasc Drugs Subsets: MEDLINE; In Process |
| Imprint Name(s): | Publication: Auckland : Adis, Springer International; Original Publication: Auckland, New Zealand : Adis International, c2001- |
| Abstract: | Despite major advances with direct oral anticoagulants (DOACs), the clinical challenge of minimizing bleeding without losing efficacy remains unresolved. Factor XI (FXI) plays a pivotal role in thrombosis with limited contribution to hemostasis, making it an attractive target for novel anticoagulant therapy. Inhibition of FXI or its active form, FXIa, may therefore achieve effective antithrombotic protection while reducing the risk of bleeding. This review summarizes the biological rationale for targeting FXI, key pharmacological features of different inhibitor classes, and the main results from phase I-II trials of antisense oligonucleotides, monoclonal antibodies, and small-molecule FXIa inhibitors. It also discusses the ongoing phase III programs evaluating these agents across clinical settings, including atrial fibrillation, venous thromboembolism, and secondary prevention after acute coronary syndromes. Early phase studies have demonstrated robust and reproducible benefits in preventing venous thromboembolism after major orthopedic surgery, whereas efficacy in atrial fibrillation and secondary stroke prevention has been more variable. Key uncertainties persist regarding the most suitable indications, patient selection criteria, and how FXI inhibitors should be positioned alongside existing DOACs, particularly in high-bleeding-risk groups unsuitable for oral therapy, such as those with severe kidney failure, on dialysis, or facing cancer-related thrombosis.; (© 2026. The Author(s), under exclusive licence to Springer Nature Switzerland AG.) |
| Competing Interests: | Declarations. Conflict of interest: Francesca Campanella, Francesco Barreca, Simona Giubilato, Giulia Alagna, Giovanni Taverna, Domenico Mario Giamundo, Ahmed Ibrahim, Pierre Sabouret, Francesco Amico, and Giuseppe Andò declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Author contributions: Francesca Campanella, Francesco Barreca, and Giuseppe Andò conceived and designed the study and wrote the first draft of the manuscript. Simona Giubilato, Giulia Alagna, Giovanni Taverna, Ahmed Ibrahim, Pierre Sabouret, and Domenico Mario Giamundo contributed to content development. All authors contributed to the revision of the manuscript and approved the final version. Francesco Amico and Giuseppe Andò critically revised the manuscript and acted as institutional supervisors, taking responsibility for the integrity of the work as a whole. Data availability statement: Data sharing not applicable to this article as no datasets were generated for it. Ethics approval: Not applicable. Code availability: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. |
| References: | Ingrasciotta Y, Crisafulli S, Pizzimenti V, Marciano I, Mancuso A, Ando G, et al. Pharmacokinetics of new oral anticoagulants: implications for use in routine care. Expert Opin Drug Metab Toxicol. 2018;14(10):1057–69. https://doi.org/10.1080/17425255.2018.1530213 . (PMID: 10.1080/17425255.2018.153021330277082); Muscente F, De Caterina R. The new in anticoagulation: factor XI inhibitors. Eur Heart J Suppl. 2023;25(Suppl B):B65–8. https://doi.org/10.1093/eurheartjsupp/suad070 . (PMID: 10.1093/eurheartjsupp/suad0703709165210120978); Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost. 2013;39(6):621–31. https://doi.org/10.1055/s-0033-1353420 . (PMID: 10.1055/s-0033-135342023929304); Angiolillo DJ, Capodanno D. Uncoupling thrombosis and hemostasis by inhibiting factor XI. N Engl J Med. 2025;392(4):400–3. https://doi.org/10.1056/NEJMe2414209 . (PMID: 10.1056/NEJMe241420939842017); Cohen O, Santagata D, Ageno W. Novel horizons in anticoagulation: the emerging role of factor XI inhibitors across different settings. Haematologica. 2024;109(10):3110–24. https://doi.org/10.3324/haematol.2023.283682 . (PMID: 10.3324/haematol.2023.2836823877974411443408); Ali AE, Becker RC. Factor XI: structure, function and therapeutic inhibition. J Thromb Thrombolysis. 2024;57(8):1315–28. https://doi.org/10.1007/s11239-024-02972-5 . (PMID: 10.1007/s11239-024-02972-53862227711645426); Greco A, Laudani C, Spagnolo M, Agnello F, Faro DC, Finocchiaro S, et al. Pharmacology and clinical development of factor XI inhibitors. Circulation. 2023;147(11):897–913. https://doi.org/10.1161/CIRCULATIONAHA.122.062353 . (PMID: 10.1161/CIRCULATIONAHA.122.06235336913497); Gragnano F, van Klaveren D, Heg D, Raber L, Krucoff MW, Raposeiras-Roubin S, et al. Derivation and validation of the PRECISE-HBR score to predict bleeding after percutaneous coronary intervention. Circulation. 2025;151(6):343–55. https://doi.org/10.1161/CIRCULATIONAHA.124.072009 . (PMID: 10.1161/CIRCULATIONAHA.124.07200939462482); Liang J, Nilsson S, Wikstrom J, Cao H, Zheng S, Xu Q, et al. Inhibition of factor XI using RBD4059: a novel GalNAc-siRNA with potent and durable antithrombotic effects. JACC Basic Transl Sci. 2025;10(6):786–97. https://doi.org/10.1016/j.jacbts.2024.12.005 . (PMID: 10.1016/j.jacbts.2024.12.0054056249112230477); Ali AE, Becker RC. The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease. J Thromb Thrombolysis. 2024;57(8):1283–96. https://doi.org/10.1007/s11239-024-02985-0 . (PMID: 10.1007/s11239-024-02985-03866211411645312); Donkor DA, Bhakta V, Eltringham-Smith LJ, Stafford AR, Weitz JI, Sheffield WP. Selection and characterization of a DNA aptamer inhibiting coagulation factor XIa. Sci Rep. 2017;7(1):2102. https://doi.org/10.1038/s41598-017-02055-x . (PMID: 10.1038/s41598-017-02055-x285228125437010); Woodruff RS, Ivanov I, Verhamme IM, Sun MF, Gailani D, Sullenger BA. Generation and characterization of aptamers targeting factor XIa. Thromb Res. 2017;156:134–41. https://doi.org/10.1016/j.thromres.2017.06.015 . (PMID: 10.1016/j.thromres.2017.06.015286449595697752); Liu M, Zaman K, Fortenberry YM. Overview of the therapeutic potential of aptamers targeting coagulation factors. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22083897 . (PMID: 10.3390/ijms22083897350088958745296); Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Jones WS, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399(10333):1383–90. https://doi.org/10.1016/S0140-6736(22)00456-1 . (PMID: 10.1016/S0140-6736(22)00456-135385695); Shoamanesh A, Mundl H, Smith EE, Masjuan J, Milanov I, Hirano T, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet. 2022;400(10357):997–1007. https://doi.org/10.1016/S0140-6736(22)01588-4 . (PMID: 10.1016/S0140-6736(22)01588-436063821); Rao SV, Kirsch B, Bhatt DL, Budaj A, Coppolecchia R, Eikelboom J, et al. A multicenter, phase 2, randomized, placebo-controlled, double-blind, parallel-group, dose-finding trial of the oral factor XIa inhibitor asundexian to prevent adverse cardiovascular outcomes after acute myocardial infarction. Circulation. 2022;146(16):1196–206. https://doi.org/10.1161/CIRCULATIONAHA.122.061612 . (PMID: 10.1161/CIRCULATIONAHA.122.06161236030390); Piccini JP, Patel MR, Steffel J, Ferdinand K, Van Gelder IC, Russo AM, et al. Asundexian versus apixaban in patients with atrial fibrillation. N Engl J Med. 2025;392(1):23–32. https://doi.org/10.1056/NEJMoa2407105 . (PMID: 10.1056/NEJMoa240710539225267); Alexander JH, Lydon EJ, Piccini JP, Viethen T, Oldgren J, Goodman SG, et al. Asundexian or apixaban in patients with atrial fibrillation according to prior oral anticoagulant use: a subgroup analysis of the OCEANIC-AF randomized clinical trial. JAMA Cardiol. 2025;10(6):555–63. https://doi.org/10.1001/jamacardio.2025.0277 . (PMID: 10.1001/jamacardio.2025.02774013630911947966); Perera V, Wang Z, Luettgen J, Li D, DeSouza M, Cerra M, et al. First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor. Clin Transl Sci. 2022;15(2):330–42. https://doi.org/10.1111/cts.13148 . (PMID: 10.1111/cts.1314834558200); Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med. 2021;385(23):2161–72. https://doi.org/10.1056/NEJMoa2113194 . (PMID: 10.1056/NEJMoa2113194347806839540352); Sharma M, Molina CA, Toyoda K, Bereczki D, Bangdiwala SI, Kasner SE, et al. Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2024;23(1):46–59. https://doi.org/10.1016/S1474-4422(23)00403-9 . (PMID: 10.1016/S1474-4422(23)00403-93810190210822143); Jain SS, Mahaffey KW, Pieper KS, Shimizu W, Potpara T, Ruff CT, et al. Milvexian vs apixaban for stroke prevention in atrial fibrillation: the LIBREXIA atrial fibrillation trial rationale and design. Am Heart J. 2024;277:145–58. https://doi.org/10.1016/j.ahj.2024.08.011 . (PMID: 10.1016/j.ahj.2024.08.01139214801); Gibson CM, Bahit MC, Mehran R, Mehta SR, Lamee RA, Goto S, et al. Oral factor xia inhibitor milvexian after a recent acute coronary syndrome: rationale and design of the phase 3 (Librexia ACS). Am Heart J. 2025;285:21–8. https://doi.org/10.1016/j.ahj.2025.02.011 . (PMID: 10.1016/j.ahj.2025.02.01139986336); Verhamme P, Yi BA, Segers A, Salter J, Bloomfield D, Buller HR, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385(7):609–17. https://doi.org/10.1056/NEJMoa2105872 . (PMID: 10.1056/NEJMoa210587234297496); Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. Abelacimab versus rivaroxaban in patients with atrial fibrillation. N Engl J Med. 2025;392(4):361–71. https://doi.org/10.1056/NEJMoa2406674 . (PMID: 10.1056/NEJMoa240667439842011); Weitz JI, Bauersachs R, Becker B, Berkowitz SD, Freitas MCS, Lassen MR, et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA. 2020;323(2):130–9. https://doi.org/10.1001/jama.2019.20687 . (PMID: 10.1001/jama.2019.20687319350286990695); Weitz JI, Tanko LB, Floege J, Fox KAA, Bhatt DL, Thadhani R, et al. Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial. Nat Med. 2024;30(2):435–42. https://doi.org/10.1038/s41591-023-02794-7 . (PMID: 10.1038/s41591-023-02794-73836595210878964); Lorentz CU, Tucker EI, Verbout NG, Shatzel JJ, Olson SR, Markway BD, et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood. 2021;138(22):2173–84. https://doi.org/10.1182/blood.2021011725 . (PMID: 10.1182/blood.2021011725340868808641100); Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–40. https://doi.org/10.1056/NEJMoa1405760 . (PMID: 10.1056/NEJMoa140576025482425); Walsh M, Bethune C, Smyth A, Tyrwhitt J, Jung SW, Yu RZ, et al. Phase 2 study of the factor XI antisense inhibitor IONIS-FXI(Rx) in patients with ESRD. Kidney Int Rep. 2022;7(2):200–9. https://doi.org/10.1016/j.ekir.2021.11.011 . (PMID: 10.1016/j.ekir.2021.11.01135155859); Winkelmayer WC, Lensing AWA, Thadhani RI, Mahaffey KW, Walsh M, Pap AF, et al. A phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis. Kidney Int. 2024;106(1):145–53. https://doi.org/10.1016/j.kint.2024.02.024 . (PMID: 10.1016/j.kint.2024.02.02438537676); Gabrielsen A, Feng Z, Fu J, Ueckert S, Egnell L, Wikstrom J, et al. First-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of RBD4059, a GalNAc-siRNA drug targeting coagulation factor XI (FXI), in healthy subjects. Eur Heart J. 2024;45(Supplement_1):ehae666.3327. https://doi.org/10.1093/eurheartj/ehae666.3327 . (PMID: 10.1093/eurheartj/ehae666.3327); Ando G, Capranzano P. Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with chronic kidney disease: a systematic review and network meta-analysis. Int J Cardiol. 2017;231:162–9. https://doi.org/10.1016/j.ijcard.2016.11.303 . (PMID: 10.1016/j.ijcard.2016.11.30328007305) |
| Entry Date(s): | Date Created: 20260125 Latest Revision: 20260422 |
| Update Code: | 20260422 |
| DOI: | 10.1007/s40256-025-00787-0 |
| PMID: | 41581095 |
| Database: | MEDLINE |
Journal Article; Review