Antithrombotic Treatment With Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events in Total Knee Replacement - AXIOMATIC-TKR

Contribution To Literature:

The AXIOMATIC-TKR trial showed that milvexian was beneficial at preventing venous thromboembolism after knee arthroplasty compared with enoxaparin.


The goal of the trial was to evaluate oral milvexian compared with subcutaneous enoxaparin among patients undergoing elective knee arthroplasty. Milvexian is a potent inhibitor of factor XIa, which is absorbed 2-4 hours after oral administration and has a half-life of 8-14 hours.

Study Design

  • Randomization
  • Parallel
  • Open-label

Participants undergoing elective knee arthroplasty were randomized to: milvexian 25 mg daily (n = 34) vs. milvexian 50 mg daily (n = 150) vs. milvexian 200 mg daily (n = 149) vs. milvexian 25 mg twice daily (n = 153) vs. milvexian 50 mg twice daily (n = 150) vs. milvexian 100 mg twice daily (n = 152) vs. milvexian 200 mg twice daily (n = 153) vs. enoxaparin 40 mg daily (n = 301).

  • Total number of enrollees: 1,242
  • Duration of follow-up: 14 days
  • Mean patient age: 69 years
  • Percentage female: 71%

Inclusion criteria:

  • Patients ≥18 years of age undergoing elective knee arthroplasty

Principal Findings:

The primary efficacy outcome, venous thromboembolism (asymptomatic deep vein thrombosis on mandatory unilateral venogram on days 10-14, symptomatic venous thromboembolism, or death), occurred at a rate of:

  • 25.0% in the milvexian 25 mg daily group
  • 23.6% in the milvexian 50 mg daily group
  • 6.5% in the milvexian 200 mg daily group

(p = 0.0003 for combined daily group vs. enoxaparin)

  • 20.9% in the milvexian 25 mg twice daily group
  • 11.3% in the milvexian 50 mg twice daily group
  • 9.0% in the milvexian 100 mg twice daily group
  • 7.6% in the milvexian 200 mg twice daily group

(p = 0.0004 for combined twice daily group vs. enoxaparin)

  • 21.4% in the enoxaparin 40 mg daily group

The primary safety outcome, any bleeding (composite of major [ISTH criteria], clinically relevant nonmajor, and minor bleeding), occurred at a rate of 4.1% in the milvexian group vs. 4.1% in the enoxaparin group.


Among patients undergoing elective knee arthroplasty, the factor XIa inhibitor milvexian was effective at preventing venous thromboembolism compared with enoxaparin in this phase 2 randomized clinical trial. Milvexian was associated with a low rate of any bleeding, which was similar to the enoxaparin group.


Weitz JI, Strony J, Ageno W, et al., on behalf of the AXIOMATIC-TKR Investigators. Milvexian for the Prevention of Venous Thromboembolism. N Engl J Med 2021;Nov 15:[Epub ahead of print].

Presented by Dr. Jeffrey I. Weitz at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 15, 2021.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Novel Agents

Keywords: AHA Annual Scientific Sessions, AHA21, Anticoagulants, Arthroplasty, Replacement, Knee, Elective Surgical Procedures, Enoxaparin, Factor XIa, Hemorrhage, Primary Prevention, Vascular Diseases, Venous Thromboembolism, Venous Thrombosis

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