ANT-005 Total Knee Arthroplasty - ANT-005 TKA

Aug 24, 2021
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Anthos Therapeutics
Date Published:
08/11/2021
Date Updated:
08/24/2021
Original Posted Date:
08/24/2021
References

Contribution To Literature:

The ANT-005 TKA trial showed that, among patients undergoing total knee arthroplasty, a single IV abelacimab infusion was noninferior for the primary efficacy endpoint of VTE at all 3 tested doses (30 mg, 75 mg, 150 mg) compared with subcutaneous enoxaparin administered daily for 9 days; the higher 2 doses were superior compared with enoxaparin for this endpoint.

Description:

The goal of this phase II trial was to assess the safety and efficacy of abelacimab compared with enoxaparin in patients undergoing total knee arthroplasty (TKA).

Study Design

Patients undergoing total knee replacement were randomized in 1:1:1:1 fashion to either abelacimab 30 mg, 75 mg, 150 mg, or enoxaparin. Abelacimab was administered in a single intravenous (IV) infusion over a period of 30-60 minutes and was started 4-8 hours after surgery. Enoxaparin 40 mg was administered subcutaneously once daily and was started either the evening before or approximately 12 hours after surgery and was to be continued until venography was performed (median duration, 9 days). The randomization to abelacimab vs. enoxaparin was done in an open-label fashion.

  • Total screened: 554
  • Total number of enrollees: 412
  • Duration of follow-up: 30 days
  • Median patient age: 67 years
  • Percentage female: 82%

Inclusion criteria:

  • Age 18-80 years
  • Undergoing elective primary unilateral total knee arthroplasty
  • Body weight of 50-130 kg
  • Willing to adhere to the trial procedures

Exclusion criteria:

  • Active bleeding or a high risk of bleeding
  • History of venous thromboembolism (VTE)
  • Estimated glomerular filtration rate <60 ml/min/1.73 m2 (amended to a rate <45 ml/min/1.73 m2)
  • Clinically significant liver disease

Other salient features/characteristics:

  • Median body weight: 90 kg
  • Anesthesia: spinal (89%), epidural (10%)
  • Median time to ambulation: 1 day

Principal Findings:

The primary efficacy endpoint, VTE at 30 days for abelacimab 30 mg vs. 75 mg vs. 150 mg vs. enoxaparin, was 13% vs. 5% vs. 4% vs. 22% (p < 0.05 for noninferiority of all abelacimab regimens vs. enoxaparin; p < 0.001 for abelacimab 75 mg and 150 mg vs. enoxaparin, respectively).

  • Primary safety endpoint, major or clinically relevant nonmajor bleeding (randomization till venography): 2% vs. 2% vs. 0% vs. 0%
  • Primary safety endpoint, major or clinically relevant nonmajor bleeding (randomization till day 30): 2% vs. 2% vs. 0% vs. 0%

Secondary outcomes (for abelacimab 30 mg vs. 75 mg vs. 150 mg vs. enoxaparin):

  • Symptomatic VTE: 0% vs. 0% vs. 0% vs. 1%
  • Proximal deep-vein thrombosis (DVT): 1% vs. 0% vs. 0% vs. 2%
  • No antidrug antibodies were detected with abelacimab infusion

Interpretation:

The results of this partially open-label phase II trial indicate that among patients undergoing TKA, a single IV abelacimab infusion was noninferior for the primary efficacy endpoint of VTE at all 3 tested doses (30 mg, 75 mg, 150 mg) compared with subcutaneous enoxaparin administered daily for 9 days; the higher 2 doses were superior compared with enoxaparin for this endpoint. The vast majority of VTE events were asymptomatic and distal DVTs. Bleeding rates were similar.

Abelacimab is a monoclonal antibody that rapidly binds to factor XI and prevents its activation by locking it in the inactive precursor conformation. This suggests that factor XI inhibition may be an alternate target for thromboprophylaxis, and potentially for venous and arterial thrombosis, although this needs to be tested in future studies. A comparison of abelacimab to novel oral anticoagulants for thromboprophylaxis and cost-effectiveness analyses will also be important.

References:

Verhamme P, Yi A, Segers A, et al., on behalf of the ANT-005 TKA Investigators. Abelacimab for Prevention of Venous Thromboembolism. N Engl J Med 2021;385:609-17.

Clinical Topics: Anticoagulation Management, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Novel Agents, Angiography, Nuclear Imaging

Keywords: Antibodies, Monoclonal, Anticoagulants, Arthroplasty, Replacement, Knee, Enoxaparin, Factor XI, Glomerular Filtration Rate, Hemorrhage, Knee Prosthesis, Phlebography, Secondary Prevention, Elective Surgical Procedures, Vascular Diseases, Venous Thromboembolism, Venous Thrombosis


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