AXIOMATIC-TKR

In Review

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

Clinical Question

In patients who underwent total knee arthroplasty, does milvexian, an oral Factor XIa inhibitor, reduce the risk of postoperative venous thromboembolism?

Bottom Line

Certain dosing regimens of milvexian were superior to enoxaparin for prevention of postoperative venous thromboembolism and were associated with a comparatively similar 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. Therefore, factor XI inhibition may reduce thrombosis risk without increasing bleeding risk as compared to other anticoagulants. This theory is further supported by patients with genetic factor XI deficiencies, who have a lower risk of VTE and stroke, but maintain hemostasis similar to the general population. 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. Notably, the 25 mg daily group was closed to randomization after an a priori analysis revealed a VTE incidence of 25%, which met the study's pre-specified criteria of insufficient efficacy. This group was subsequently replaced with a 50 mg daily group.

Milvexian, in a dose-related fashion, was found to be superior compared to enoxaparin in terms of reducing the risk of postoperative venous thromboembolism. The primary composite outcome of symptomatic VTE, asymptomatic DVT, or death from any cause was driven entirely by reductions in asymptomatic distal DVTs. Twice daily dosing appeared more efficacious across several doses compared to daily dosing, consistent with the drug's 12-hour half-life. Although the was not powered for its safety outcome, there was no significant difference in bleeding rates between milvexian and enoxaparin, and bleeding events did not increase as the dose of milvexian increased. Overall, the results of this phase II trial are promising and show that oral factor XI inhibitors may be efficacious anticoagulants. Based on the coagulation cascade and milvexian's mechanism, these agents should result in 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.

Guidelines

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

Design

• 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: Modified intention-to-treat, including all patients who received at least one dose of trial medication and underwent a venogram
• 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

Population

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
• Use of long-term antithrombotic therapy other than aspirin
• Unable to undergo venography

Baseline Characteristics

'Enoxaparin group'

• Median age: 68
• Race
  • White: 88%
  • Asian: 11%
  • Black: 1%
• Median time after surgery to anticoagulation: 22 hours
• Median duration of anticoagulation: 12 days

Interventions

• 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

Outcomes

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% (RR 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 nonmajor bleeding

1% vs 2%

Criticisms

• 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
• No comparisons between milvexian and DOACs, such as rivaroxaban or apixaban, which are more clinically relevant in the postoperative outpatient setting and may have been a more appropriate comparator than enoxaparin. This would have also compared two oral therapies and allowed for a blinded trial.

Funding

Bristol Myers Squibb Janssen Research and Development