Milvexian For Prevention of Venous Thromboembolism After Elective Knee Arthroplasty: The AXIOMATRIC-TKR Study

Presented at the American Heart Association’s Scientific Sessions 2021 by: Jeffrey Weitz, MD - McMaster University, Hamilton, ON, Canada.

Introduction and methods

Background

Milvexian is potent and specific small molecular inhibitor of factor XIa. It is rapidly absorbed after oral administration and has a half-life of ~12 hours in healthy volunteers. Factor XIa is an exciting target for novel anticoagulant therapy, because there is increasing evidence that factor XI is important in thrombosis, but mostly dispensable in hemostasis. Factor XI inhibitors could therefore be safer than inhibitors of downstream targets. Previous studies have shown that parental factor XI inhibitors prevent thrombosis after elective knee surgery.

This study investigated whether oral milvexian reduces the incidence of postoperative VTE.

Study design

AXIOMATIC-TKR trial was a phase 2, dose-ranging, open-label study in which oral milvexian was compared with subcutaneous enoxaparin for thromboprophylaxis after elective knee arthroplasty. Events were adjudicated by a blinded committee. 1242 subjects undergoing unilateral knee replacement surgery were randomized to 6 different doses of milvexian (from 25 mg to 200 mg once daily or twice daily) or to enoxaparin, starting 12-24 hours after surgery until mandatory venography of the operative leg at day 10-14. Enrollment in the milvexian 25 mg once daily arm was stopped early due to futility and a milvexian 50 mg once daily arm was started.

Primary outcome

The primary efficacy outcome was venous thromboembolism or death from any cause and the principal safety outcome was any bleeding (a composite of ISTH major bleeding, clinically relevant nonmajor, and minor bleeding). Follow-up was 30 days.

Main results

• Rate of VTE was with the combined twice daily doses was 12.2% (P<0.0001 vs. a prespecified 30% benchmark).
• There was a dose-response with both twice-daily and once-daily milvexian.
• VTE rate was significantly lower with milvexian ≥100 mg per day than enoxaparin.
• Rate of any bleeding was similar with milvexian and enoxaparin. Rate of serious adverse events or adverse events leading to discontinuation of treatment was similar between patients on milvexian and patients on enoxaparin.
• aPTT ratio was prolonged with milvexian, in a dose-dependent manner, but there was no increase in major or clinically relevant nonmajor bleeding across the range of milvexian 25 mg to 400 mg per day.

Conclusion

Postoperative FXIa inhibition with oral milvexian reduces VTE events after 30 days in patients undergoing elective knee replacement when compared to enoxaparin, and is associated with a low risk of bleeding. Jeffrey Weitz said that milvexian is currently evaluated in a study for secondary stroke prevention.

Discussion

The discussant Tracy Wang, MD (Duke University, Durham, NC, USA) listed some strengths and questions raised by this study. The strengths included the blinded exploration of a range of doses and dose frequency. Questions raised concerned the mandated venogram, symptomatic vs. asymptomatic VTE events, and proximal vs. distal location of VTE.

In the end she wondered what is next with regard to factor XIa inhibitors. The options will vary in appeal to different patients and healthcare setting, the orthopedic surgeons need to be convinced (aspirin is still often used, and DOACs may be preferred over enoxaparin), and the question of the bleeding advantage needs to be answered.

- Our reporting is based on the information provided at the American Heart Association’s Scientific Sessions 2021 -

The findings of this study were simultaneously published in the New Engl J Med