• Jeffrey I Weitz, John Strony, Walter Ageno, David Gailani, Elaine M Hylek, Michael R Lassen, Kenneth W Mahaffey, Ravi S Notani, Robin Roberts, Annelise Segers, Gary E Raskob, and AXIOMATIC-TKR Investigators.
• From the Thrombosis and Atherosclerosis Research Institute and McMaster University (J.I.W., R.R.) - both in Hamilton, ON, Canada; Janssen Research and Development, Raritan, NJ (J.S., R.S.N.); the University of Insubria, Varese, Italy (W.A.); Vanderbilt University Medical Center, Nashville (D.G.); Boston University School of Medicine, Boston (E.M.H.); Gildhøj Private Hospital, Copenhagen (M.R.L.); Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.); International Trial Expertise Advisory and Services, Amsterdam (A.S.); and Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City (G.E.R.).
• N. Engl. J. Med. 2021 Dec 2; 385 (23): 2161-2172.

BackgroundFactor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor.MethodsIn this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding.ResultsAmong the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively.ConclusionsPostoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).Copyright © 2021 Massachusetts Medical Society.

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