Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis With First-Line Therapy–Extended Treatment - AMPLIFY-EXT

Dec 09, 2012
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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:
01/01/2012
Date Updated:
12/09/2012
Original Posted Date:
12/09/2012
References

Description:

The goal of the trial was to evaluate treatment with apixaban, a factor Xa inhibitor, compared with placebo among patients with venous thromboembolism who had completed 6-12 months of anticoagulation therapy.

Hypothesis:

Apixaban will prevent recurrent venous thromboembolism or death.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel
  • Blinded
  • Stratified

Patient Populations:

  • Patients at least 18 years of age with prior venous thromboembolism (deep vein thrombosis or pulmonary embolism) who had completed 6-12 months of anticoagulation therapy

    Number of enrollees: 2,482
    Duration of follow-up: 1 year
    Mean patient age: 57 years
    Percentage female: 42%

Exclusions:

  • Contraindication to anticoagulation or antiplatelet therapy
  • Hemoglobin <9 g/dl
  • Platelet count <100,000 per mm3
  • Serum creatinine >2.5 mg/dl (or creatinine clearance <25 ml/min)
  • AST or ALT >2 times the upper limit of normal
  • Total bilirubin >1.5 times the upper limit of normal

Primary Endpoints:

  • Symptomatic recurrent venous thromboembolism or death
  • Major bleeding

Secondary Endpoints:

  • Clinically relevant nonmajor bleeding
  • Major or clinically relevant nonmajor bleeding

Drug/Procedures Used:

Patients with venous thromboembolism who had completed 6-12 months of anticoagulation therapy were randomized to apixaban 2.5 mg twice daily (n = 840), apixaban 5 mg twice daily (n = 813), versus placebo twice daily (n = 829). Study drugs were administered for 12 months.

Principal Findings:

Overall 2,482 patients were randomized. The mean age was 57 years, 42% were women, mean weight was 86 kg, and initial diagnosis was deep vein thrombosis in 65% and pulmonary embolism in 35%.

The primary efficacy outcome, symptomatic recurrent venous thromboembolism or all-cause mortality, occurred in 3.8% of the apixaban 2.5 mg twice daily group, 4.2% of the apixaban 5 mg twice daily group, versus 11.6% of the placebo group (p < 0.001 for both comparisons).

All-cause mortality occurred in 0.8% of the apixaban 2.5 mg twice daily group, 0.5% of the apixaban 5 mg twice daily group, versus 1.7% of the placebo group.

The primary safety outcome, major bleeding, occurred in 0.2% of the apixaban 2.5 mg twice daily group, 0.1% of the apixaban 5 mg twice daily group, versus 0.5% of the placebo group (p = not significant [NS] for both comparisons).

Clinically relevant nonmajor bleeding occurred in 3.0% of the apixaban 2.5 mg twice daily group, 4.2% of the apixaban 5 mg twice daily group, versus 2.3% of the placebo group (p = NS for apixaban 2.5 mg vs. placebo; p < 0.05 for apixaban 5 mg vs. placebo).

Major or clinically relevant nonmajor bleeding occurred in 3.2% of the apixaban 2.5 mg twice daily group, 4.3% of the apixaban 5 mg twice daily group, versus 2.7% of the placebo group (p = NS for both comparisons).

Interpretation:

Among patients with venous thromboembolism who had completed 6-12 months of anticoagulation therapy, extended therapy with apixaban (2.5 mg or 5 mg twice daily) reduced symptomatic recurrent venous thromboembolism or death. Clinical benefit was accomplished without an increase in major bleeding; however, clinically relevant nonmajor bleeding was increased with apixaban 5 mg compared with placebo. Future research will need to examine an even longer duration of treatment.

References:

Agnelli G, Buller HR, Cohen A, et al., on behalf of the AMPLIFY-EXT Investigators. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2012;Dec 8:[Epub ahead of print].

Keywords: Pulmonary Embolism, Venous Thromboembolism, Venous Thrombosis, Pyrazoles, Factor Xa, Pyridones


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