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Original ArticleFree Preview


MILVEXIAN FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM

List of authors.
 * Jeffrey I. Weitz, M.D.,
 * John Strony, M.D.,
 * Walter Ageno, M.D.,
 * David Gailani, M.D.,
 * Elaine M. Hylek, M.D.,
 * Michael R. Lassen, M.D.,
 * Kenneth W. Mahaffey, M.D.,
 * Ravi S. Notani, M.B.A.,
 * Robin Roberts, M.S.,
 * Annelise Segers, M.D.,
 * and Gary E. Raskob, Ph.D.
 * et al.,
 * for the AXIOMATIC-TKR Investigators*

The investigators in the AXIOMATIC-TKR trial and the members of the trial
committees are listed in the Supplementary Appendix, available at NEJM.org.



November 15, 2021
DOI: 10.1056/NEJMoa2113194



ABSTRACT


BACKGROUND

Factor 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.


METHODS

In 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.


RESULTS

Among 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.


CONCLUSIONS

Postoperative 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. opens in new tab.)


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FUNDING AND DISCLOSURES

Supported by Bristol Myers Squibb and Janssen Research and Development.

Disclosure forms provided by the authors are available with the full text of
this article at NEJM.org.

This article was published on November 15, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text
of this article at NEJM.org.


AUTHOR AFFILIATIONS

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.).

Dr. Weitz can be contacted at weitzj@taari.ca or at the Thrombosis and
Atherosclerosis Research Institute, 237 Barton St. East, Hamilton, ON, Canada
L8L 2X2.

The investigators in the AXIOMATIC-TKR trial and the members of the trial
committees are listed in the Supplementary Appendix, available at NEJM.org.



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November 15, 2021
DOI: 10.1056/NEJMoa2113194




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