Milvexian for the Prevention of Venous Thromboembolism

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.).

Figure 1.. Enrollment, Randomization, and Populations for Analyses.

Enrollment in the group receiving 25 mg of milvexian once daily was stopped early by the trial operations committee after an ad hoc analysis showed insufficient efficacy. A regimen of 50 mg of milvexian once daily was then added to the trial regimens. One patient who was assigned to receive 100 mg of milvexian twice daily received 50 mg twice daily, and another patient who was assigned to receive 200 mg of milvexian twice daily received 25 mg once daily. For the safety analyses, these patients were included in the actual treatment group, whereas for the efficacy analyses, they were included in the planned treatment group.

Figure 2.. Activated Partial-Thromboplastin Time (aPTT) Ratios and Bleeding Incidences.

Panel A shows box plots of aPTT ratios with the various doses of milvexian and with enoxaparin. The median is indicated by the horizontal line in the box; the top and bottom of the box indicate the upper and lower limits, respectively, of the interquartile range; and the vertical lines above and below the box indicate the maximum and minimum values, respectively. Panel B shows the incidences of any bleeding and clinically relevant bleeding (defined as the composite of major bleeding and clinically relevant nonmajor bleeding) according to trial group.