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Weitz et al.. "Milvexian for the Prevention of Venous Thromboembolism". New England Journal of Medicine. 2021. 385(23):2161-72.

Clinical Question

In patients undergoing knee arthroplasty, does milvexian, an oral Factor XIa inhibitor, reduce the risk of venous thromboembolism?

Bottom Line

Milvexian was superior to enoxaparin for prevention of venous thromboembolism and was associated with a low risk of bleeding.

Major Points

Patients undergoing knee arthroplasty are at high risk of postoperative venous thromboembolism, and therefore they are a useful population to study the efficacy of new anticoagulants. Factor XI inhibitors are promising anticoagulation research agents because factor XI is important for thrombus growth, but has a smaller role in hemostasis.[1] Therefore factor XI inhibition may reduce thrombosis risk without increasing bleeding risk as compared to other anticoagulants. While there are have been previous studies investigating intravenous and subcutaneous factor XI inhibitors, Milvexian is a promising oral factor XIa inhibitor.

The AXIOMATIC-TKR study randomized patients undergoing total knee replacement to post-operative milvexian vs enoxaparin. To evaluate dose-response, patient were randomized 1:1:1:1:1:1:2 to milvexian 25 mg twice daily, 100 mg twice daily, 200 mg twice daily, 25 mg daily, 200 mg daily, or enoxaprin 40 mg daily for 10-14 days after surgery. Milvexian, in a dose-related fashion, was found to be superior compared to enoxaparin in terms of reducing the risk of venous thromboembolism. Twice daily dosing appeared more efficaciouss across several doses compared to daily dosing, consistent with the drugs half-life of 12 hours. There was no significant difference in bleeding rates, although the trial was not powered to detect a clinically significant difference in bleeding. Overall the results of this phase II trial are promising that oral factor XI inhibitors may be efficacious anticoagulants. Based on pathophysiology, these agents should have a lower risk of bleeding compared to other anticoagulants, although this trial was underpowered to evaluate that outcome. Future trials will need to have increased power to detect potential differences in bleeding rates.


As of December 2021, no guidelines have been updated to reflect the results of this trial.


  • Multicenter, parallel-group, randomized, open-label trial
  • Blinded outcome adjudication
  • N=1242
    • Milvexian (n=941)
    • Enoxaparin (n=301)
  • Setting: 118 centers in 18 countries
  • Enrollment: June 27, 2019 to February 25, 2021
  • Mean follow-up: 30 days
  • Analysis: Intention-to-treat, including all patients receiving at least one dose of trial medication
  • Primary outcome: composite of asymptomatic deep-vein thrombosis by unilateral venography 10-14 days after surgery, confirmed symptomatic venous thromboembolism, or death from any cause


Inclusion Criteria

  • undergoing elective unilateral total knee arthroplasty
  • Age 50 years or older
  • Candidate for anticoagulation

Exclusion Criteria

  • contraindications to enoxaparin
  • Creatine clearance <30 mL/min
  • history of severe hepatic impairment
  • history of previous venous thromboembolism
  • long-term antithrombotic therapy other than aspirin

Baseline Characteristics

'Enoxaparin group'

  • Median age: 69
  • Race
    • White: 89%
    • Black: 1%
  • Median time after surgery to anticoagulation: 22 hours
  • Median duration of anticoagulation: 12 days


  • Randomized 1:1:1:1:1:1:2 to Milvexian 25 mg BID, Milvexian 50 mg BID, Milvexian 100 mg BID, Milvexian 200 mg BID, Milvexian 25 mg daily, Milvexian 200 mg daily, and Enoxaparin 40 mg daily
    • Milvexian groups received total of four pills daily of either study medication or placebo; enoxaparin group received subcutaneous dosing


Comparisons are Milvexian 100 mg BID vs enoxaparin 40 mg daily

Primary Outcomes

Composite of death, pulmonary embolism, or deep-vein thrombosis
9% vs 21% (HR 0.42; 95% CI 0.23-0.76)

Secondary Outcomes

Death from any cause
0 vs 1
Nonfatal pulmonary embolism
1 vs 1

Adverse Events

Milvexian (all-doses) vs Enoxaparin
4% vs 4%
Major bleeding
0 vs 1
Clinically relevant bleeding
1% vs 2%


  • Trial not adequately powered to detect differences in bleeding events
  • Open label trial, so participants and treating physicians not blinded to treatment assignment
  • Operations committee was not blinded and performed an ad hoc analysis


Bristol Myers Squibb Janssen Research and Development

Further Reading