Milvexian prevents VTE without raising bleeding after knee arthroplasty
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In patients who underwent knee arthroplasty, oral milvexian, a novel factor XIa inhibitor, was effective at preventing venous thromboembolism and was linked to a low rate of bleeding, researchers reported.
For the phase 2 AXIOMATIC-TKR trial presented at the American Heart Association Scientific Sessions and published in The New England Journal of Medicine, the researchers randomly assigned 1,242 patients scheduled for knee arthroplasty to one of seven regimens of oral milvexian (Bristol Myers Squibb/Janssen) or once-daily subcutaneous enoxaparin after the procedure.
“Development of new anticoagulants usually starts with dose-finding studies in patients undergoing elective knee arthroplasty because efficacy can be objectively and efficiently assessed by using venography to determine the rate of deep vein thrombosis after surgery,” presenter Jeffrey I. Weitz, MD, professor of medicine and biochemistry and biosciences at McMaster University in Hamilton, Ontario, Canada, and executive director of the Thrombosis and Atherosclerosis Research Institute, told Healio.
The primary efficacy outcome was VTE, defined as asymptomatic DVT on venography 10 to 14 days after the procedure, confirmed symptomatic VTE or death. The primary safety outcome was major, clinically relevant nonmajor or minor bleeding using the International Society on Thrombosis and Haemostasis criteria.
“Factor XIa is an important driver of postoperative VTE,” Weitz said during the presentation.
VTE occurred in 21% of patients assigned enoxaparin and at the following rates in patients assigned the milvexian regimens:
- 25 mg twice daily, 21%;
- 50 mg twice daily, 11% (P vs. enoxaparin < .01);
- 100 mg twice daily, 9% (P vs. enoxaparin < .002);
- 200 mg twice daily, 8% (P vs. enoxaparin < .0001);
- 25 mg once daily, 25%;
- 50 mg once daily, 24%; and
- 200 mg once daily, 7% (P vs. enoxaparin < .0001).
There was a significant dose-response relationship with twice-daily and once-daily milvexian (P < .001), and the 12.2% rate of VTE in the pooled twice-daily milvexian cohort was lower than the prespecified benchmark of 30% (P < .001), according to the researchers.
Bleeding occurred in 4% of patients assigned milvexian and 4% of patients assigned enoxaparin, whereas major or clinically relevant nonmajor bleeding occurred in 1% of the pooled milvexian group and 2% of the enoxaparin group, and serious adverse events occurred in 2% of the pooled milvexian group and 4% of the enoxaparin group, Weitz and colleagues found.
The rate of adverse events leading to discontinuation of treatment was 3% in both groups, Weitz said during the presentation.
“Postoperative factor XIa inhibition with oral milvexian was effective for prevention of venous thromboembolism and was associated with a low risk of bleeding,” Weitz told Healio. “Although milvexian reduced the incidence of postoperative venous thromboembolism in a dose-dependent manner, there was no increase in the incidence of clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) over a 16-fold range of milvexian doses.”
More research on milvexian is in progress, Weitz told Healio.
“The safety of milvexian when given on top of dual or single antiplatelet therapy is under investigation in the ongoing AXIOMATIC SSP trial,” he said. “Further studies are needed to determine whether oral anticoagulants targeting factor XIa can dissociate thrombosis from hemostasis.”
Reference:
Perspective
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This phase 2a study was the first time analyzing preoperative Factor XIa inhibition for VTE prophylaxis. The researchers did great work on proof of efficacy. The trial design included large numbers of patients with multiple different doses of milvexian twice daily or once daily compared with the current standard of enoxaparin 40 mg once daily.
Factor XIa is an important driver of postoperative VTE. Milvexian was tremendously effective, particularly the twice-daily dosing, even at low doses. Most importantly, the safety profile was excellent, which means patients got the prophylactic benefit without increased bleeding.
These results pave the way for a prospective, randomized, large-scale study. If the large-scale studies are successful, then we hope to see these in clinical use. Large-scale phase 3 programs will be underway for different indications to evaluate safety and efficacy of this Factor XIa inhibitor.
The findings of this study are extremely promising, as it is very important to balance ischemic and bleeding risk. This compound could be a promising next therapy for balancing these risks for important clinical indications.
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Weitz JI, et al. LBS.07. New Drugs and New Drug Indications in Cardiovascular Disease. Presented at: American Heart Association Scientific Sessions; Nov. 13-15, 2021 (virtual meeting).
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