Daily doses of ≥100 mg of milvexian were superior to enoxaparin for preventing venous thromboembolism (VTE) while maintaining a low risk of bleeding in patients undergoing knee arthroplasty, according to the results of a phase II trial published in The New England Journal of Medicine.
Anticoagulants are used to prevent VTE, but they carry a bleeding risk that causes some patients to underuse them. Factor XIa inhibitors like milvexian may be a viable option to prevent and treat venous and arterial thromboembolism with a lower risk of bleeding.
In a parallel-group phase II trial led by Jeffrey I. Weitz, MD, of the Thrombosis and Atherosclerosis Research Institute, researchers examined the safety and efficacy of milvexian in patients ages 50 and older who were undergoing elective knee arthroplasty at 118 centers in 18 countries.
“Evaluation of new anticoagulants often starts in patients undergoing elective knee arthroplasty because such patients are at risk of postoperative deep vein thrombosis (DVT), which can be efficiently detected by venography,” Dr. Weitz told ASH Clinical News.
To be included in the study, patients were required to be candidates for anticoagulant prophylaxis and medically stable. Patients (n=1,242) were randomized to one of eight treatment regimens after surgery. Those assigned to take milvexian twice daily were given either 25 mg, 50 mg, 100 mg, or 200 mg. Those given once-daily regimens took either 25 mg, 50 mg, or 200 mg of milvexian. The final treatment group received 40 mg of enoxaparin once per day.
The primary composite endpoint of VTE included any asymptomatic and confirmed symptomatic DVT, as well as death from any cause. The principal safety outcome was defined as bleeding of any severity.
Investigators discovered a significant dose-response relationship between milvexian and VTE. In the group taking twice-daily doses, VTE occurrence was as follows:
- 25 mg: 21% (27 out of 129)
- 50 mg: 11% (14 out of 124)
- 100 mg: 9% (12 of 134)
- 200 mg: 8% (10 of 131)
A similar significant dose-response relationship with VTE occurrence was noted in those taking milvexian once per day:
- 25 mg: 25% (7 of 28)
- 50 mg: 24% (30 of 127)
- 200 mg: 7% (8 of 123)
In the treatment arm taking enoxaparin, 21% (54 of 252) developed VTE.
“Whether given twice or once daily, milvexian reduced the risk of postoperative VTE in a dose-dependent manner, and with daily doses of 100 mg or more, milvexian was superior to enoxaparin for VTE prevention,” Dr. Weitz said.
The bleeding outcomes for those taking milvexian were also favorable, with 38 of 923 patients (4%) developing bleeding of any severity compared to 12 of 296 patients (4%) who were taking enoxaparin. Only one major bleeding incident occurred in the enoxaparin group, while investigators reported no major bleeding in the milvexian group.
A major limitation of the study was that the assignment to enoxaparin or milvexian was not blinded, opening the possibility of bias in assessing bleeding events. Also, conclusions drawn regarding the rate of clinically meaningful bleeding events associated with milvexian are limited due to the study size.
“An ongoing phase II study is evaluating milvexian on top of antiplatelet drugs for secondary stroke prevention,” Dr. Weitz said. “The phase II studies will pave the way for phase III studies evaluating milvexian for stroke prevention in patients with atrial fibrillation and for secondary prevention in patients with stroke or acute coronary syndrome.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Weitz J, Strony J, Ageno W, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med. 2021;385:2161-2172.
