Apixaban Dosed Orally Versus Anticoagulation With Injectable Enoxaparin to Prevent Venous Thromboembolism 3 - ADVANCE-3

Dec 22, 2010
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb and Pfizer
Date Published:
01/01/2010
Date Updated:
12/22/2010
Original Posted Date:
12/22/2010
References

Description:

The goal of this trial was to compare treatment with the specific factor Xa inhibitor apixaban versus enoxaparin after hip replacement.

Hypothesis:

Apixaban would be superior for thromboprophylaxis.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Stratified

Patient Populations:

  • Patients undergoing hip replacement

Patients screened: 5,765
Patients enrolled: 5,407
Mean follow-up: 95 days
Mean patient age: 61 years
Female: 53%

Exclusions:

  • Active bleeding
  • Unable to tolerate anticoagulant prophylaxis
  • Need for ongoing anticoagulant or antiplatelet therapy

Primary Endpoints:

  • Composite of asymptomatic or symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, or all-cause mortality

Secondary Endpoints:

  • Composite of asymptomatic or symptomatic proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death due to thromboembolism
  • Major bleeding, minor bleeding, clinically relevant nonmajor bleeding, and a composite of major or clinically relevant nonmajor bleeding

Drug/Procedures Used:

Patients undergoing hip replacement were randomized to apixaban 2.5 mg orally twice daily initiated 12-24 hours after surgery (n = 2,708) versus enoxaparin 40 mg subcutaneously daily initiated 12 hours before surgery (n = 2,699). In both groups, prophylaxis was continued for 35 days after surgery. Bilateral venography was performed after the treatment period.

Principal Findings:

Overall, 5,407 patients were randomized. In the apixaban group, the mean age was 61 years, 53% were women, mean body mass index was 28.2 kg/m2, 61% received spinal anesthesia, and mean hospital duration was 9.3 days. Apixaban was administered a mean of 19.0 hours after surgery, whereas enoxaparin was administered a mean of 13.6 hours before surgery.

The primary efficacy outcome occurred in 1.4% of the apixaban group versus 3.9% of the enoxaparin group (p < 0.001 for noninferiority and superiority). Major venous thromboembolism occurred in 0.5% versus 1.1% (p < 0.001), symptomatic venous thromboembolism and death from venous thromboembolism occurred in 0.1% versus 0.4% (p = 0.11), and death occurred in 0.1% versus <0.1%, respectively.

Major bleeding events occurred in 0.8% of the apixaban group versus 0.7% of the enoxaparin group (p = 0.54). Clinically relevant nonmajor bleeding occurred in 4.1% versus 4.5% (p = 0.43), and the composite of major or clinically relevant nonmajor bleeding occurred in 4.8% versus 5.0% (p = 0.72), respectively. Aminotransferases >3 x upper limit of normal occurred in 1.3% versus 1.5%, respectively.

Interpretation:

Among patients undergoing hip replacement, the use of the specific factor Xa inhibitor apixaban was beneficial. The initiation of this oral agent after surgery reduced venous thromboembolism more effectively than subcutaneous enoxaparin initiated before surgery. Bleeding and adverse events were similar between treatment groups. In addition to apixaban, other new options for thromboprophylaxis after orthopedic surgery include dabigatran and rivaroxaban.

References:

Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM, on behalf of the ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-98.

Keywords: Morpholines, Thiophenes, Venous Thromboembolism, Pyrazoles, Body Mass Index, beta-Alanine, Benzimidazoles, Enoxaparin, Phlebography, Transaminases, Factor Xa, Pyridones


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