AXIOMATIC-TKR: Milvexian a Success for Prevention of Venous Thromboembolism after Elective Knee Arthroplasty

Key Points:

•  Milvexian is a first-in-class rapidly absorbed oral Factor XIa inhibitor being tested for safety and efficacy for prevention and treatment of venous thromboembolism (VTE)
• Across a 16-fold range of milvexian doses, there was a significant reduction in VTE events with milvexian 100mg total a day or more compared with enoxaparin; a dose-response relationship was established
• There were similar bleeding events in the milvexian arm at all doses compared with enoxaparin, establishing the safety of the drug
•  In combination with the trial evaluating milvexian for secondary stroke prevention (AXIOMATIC-SSP), milvexian may prove to be a safer, more effective option for oral anticoagulation

Medical providers struggle with choosing appropriate oral anticoagulants that adequately balance prevention and treatment of thromboembolism with risk of bleeding. There is a well-established clinical need for safer oral anticoagulant options. Factor XI inhibitors are a new class of antithrombotic medication that have a unique physiologic role in that they promote thrombus formation but have a dispensable role in the clotting cascade. Milvexian, a first-in-class oral Factor XIa inhibitor, has been developed by the Bristol Myers Squibb-Janssen Collaboration for this reason. In an exclusive interview the primary investigator of the AXIOMATIC-TKR trial, Dr. Jeffrey Weitz (McMaster University, Ontario, Canada) points out, “patients with factor XI deficiency can bleed with major surgery or trauma but this does not occur regularly”. In doing so he highlights a key potential advantage to Milvexian amongst the anticoagulant class.

AXIOMATIC-TKR (Antithrombotic Treatment with Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events in Total Knee Replacement) was a proof-of-principle, randomized, prospective phase 2 trial comparing the efficacy and safety of milvexian and enoxaparin in patients undergoing elective knee arthroplasty. Though it was open label for treatment assignment to milvexian or enoxaparin providers were blinded to milvexian dose. Similar to other oral anticoagulant phase 2 trials, knee replacement surgery was chosen as a platform for safety evaluation because of the efficacy of objectively assessing patients using venography to find proof of venous thromboembolism (VTE). It is important to note that the AXIOMATIC-TKR trial (NCT03891524) was coupled with another Phase 2 clinical trial evaluating milvexian in secondary stroke prevention (SSP) called AXIOMATIC-SSP (NCT03766581), the results of which have not yet been released.

The AXIOMATIC-TKR trial, presented at the 2021 American Heart Association virtual Scientific Sessions with simultaneous publication in the New England Journal of Medicine, included patients 50 years of age or older who were medically stable and appropriate candidates for anticoagulant prophylaxis while undergoing unilateral total knee arthroplasty. Exclusion criteria included contraindications to enoxaparin (due to renal function), history of severe hepatic impairment or previous VTE, use of long-term antithrombotic therapy other than aspirin, or inability to undergo venography. This prospective parallel group study compared a total of 7 different doses of milvexian once or twice daily with enoxaparin for thromboprophylaxis after TKR. Due to the adaptive design of the study, the 25mg once daily milvexian dose arm was changed to 50mg once daily because this group met the prespecified criteria for insufficient efficacy. All patients were followed for 30 days and none were lost to follow-up in this study.

The primary efficacy outcome of the study was VTE, which was a composite of asymptomatic deep-vein thrombosis (DVT) (detected by mandatory unilateral venography 10-14 days after surgery), confirmed symptomatic VTE (symptomatic DVT or pulmonary embolism), or death from any cause. Amongst 1,242 subjects randomized from 118 centers in 18 countries, the rate of total VTE in the milvexian arm at any dose was 12.2% which was significantly lower than the prespecified safety benchmark of 30% (considered the baseline rate of VTE amongst patients undergoing TKR with no thromboprophylaxis). There was also a significant dose response with both once and twice daily milvexian dosing compared to enoxaparin (p=0.0003 and p=0.0004, respectively). In his AHA presentation Dr. Weitz points out that with total daily doses of 100mg milvexian or greater there were significantly lower rates of VTE with milvexian than with enoxaparin (which had 21.4% total VTE rate). Therefore, both pre-established proof-of-efficacy criteria were met.

The principal safety outcome of bleeding of any severity occurred in 4% of patients in both the milvexian and enoxaparin groups, with no major bleeding episodes seen with milvexian.

This landmark trial of a novel Factor-XIa inhibitor therefore established that milvexian is a safe and effective antithrombotic agent. Since a 16-fold range of milvexian doses was being tested the investigators were able to establish a firm dose-response with both daily and twice daily dosing. Rates of adverse events were also notably similar between two groups with no dose response of bleeding events despite higher milvexian doses. In an interview Dr. Weitz concludes that milvexian is effective for reducing post-operative TKR VTE and associated with lower bleeding than enoxaparin. When asked about next steps he points out that these results, combined with the AXIOMATIC-SSP trial, could lead to Phase 3 studies evaluating milvexian for additional clinical antithrombotic uses. He also points out that there are several potential reversal agent options though the drug’s relatively short half life of 12 hours makes such options unlikely to be necessary.