Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy - AMPLIFY

Jul 01, 2013
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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:
Bristol-Myers Squibb and Pfizer
Date Published:
01/01/2013
Date Updated:
07/01/2013
Original Posted Date:
07/01/2013
References

Description:

Apixaban is a novel oral anti-Xa antagonist, with demonstrated safety and efficacy as compared with agents such as warfarin in patients with atrial fibrillation and enoxaparin in patients undergoing orthopedic surgery. Recently, in the AMPLIFY-EXT trial, apixaban demonstrated superiority over placebo for reducing recurrent thromboembolic events in patients with established venous thromboembolism (VTE). The current trial sought to study the safety and efficacy of apixaban as compared with conventional anticoagulant therapy for patients with acute symptomatic VTE.

Hypothesis:

Apixaban would be noninferior to conventional anticoagulation for the primary efficacy outcome.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Age ≥18 years
  • Objectively confirmed symptomatic proximal DVT or PE

    Number of enrollees: 5,395
    Duration of follow-up: 1 year
    Mean patient age: 57 years
    Percentage female: 41%

Exclusions:

  • Contraindications for enoxaparin or warfarin
  • Active bleeding or high risk for serious bleeding
  • Short life expectancy
  • Uncontrolled high blood pressure
  • Significantly impaired kidney (glomerular filtration rate <25 or creatinine >2.5 mg/dl) or liver function
  • Known cancer, with planned long-term use of a LMWH
  • DVT/PE in the absence of a persistent risk factor for recurrence
  • Treatment for <6 months
  • Another indication for long-term anticoagulation
  • Dual antiplatelet therapy
  • Use of aspirin >165 mg daily
  • Treatment with potent inhibitors of CYP 3A4
  • >36 hours of continuous UFH
  • Hemoglobin <9 mg/dl
  • Platelet count <100,000/mm3

Primary Endpoints:

  • Efficacy: Recurrent symptomatic VTE or death related to VTE
  • Safety: Major bleeding

Secondary Endpoints:

  • Efficacy:
    - Recurrent symptomatic VTE
    - Death related to VTE
    - Cardiovascular (CV) death
    - All-cause mortality
    - Composite of symptomatic recurrent VTE with CV death, all-cause mortality or death related to VTE + major bleeding

  • Safety:
    - Major bleeding + clinically relevant nonmajor bleeding

Drug/Procedures Used:

Patients with acute symptomatic VTE (proximal deep-vein thrombosis [DVT] or pulmonary embolism [PE]) were randomized to receive either apixaban (10 mg BID for 7 days, followed by 5 mg BID for 6 months) or enoxaparin (1 mg/kg BID for ≥5 days) and concomitant warfarin (international normalized ratio [INR] goal 2.0-3.0).

Principal Findings:

A total of 5,395 patients were randomized, 2,691 to apixaban and 2,704 to conventional anticoagulation. Baseline characteristics were fairly similar between the two arms. The qualifying diagnosis was DVT in two-thirds of the patients, PE in one-fourth, and a combination in the others. Of the DVTs, 25% were in the popliteal vein, 33% in the femoral vein, and 43% in the iliofemoral veins. Similarly, thrombus burden in PE was noted to be intermediate in 43% and extensive in 37%. The VTE event was unprovoked in the majority (90%) of patients. Risk factors included: previous VTE (16%), cancer (3%), and known thrombophilia (2.5%). Nearly two-thirds of the patients had received treatment with unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux for 12-36 hours prior to randomization. In the conventional therapy arm, enoxaparin was given for a median of 6.5 days, and the time in therapeutic range for warfarin was 61%.

The primary efficacy endpoint of recurrent symptomatic VTE or VTE-related death was similar between the apixaban and conventional therapy arms (2.3% vs. 2.7%; hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.60-1.18; p for noninferiority < 0.001). The majority of recurrent events were nonfatal PE with or without DVT. Outcomes were similar in patients with DVT only and PE only at baseline. All-cause mortality was similar (1.5% vs. 1.9%, p > 0.05).

The primary safety outcome of major bleeding was significantly lower in the apixaban arm (0.6% vs. 1.8%, HR 0.31, 95% CI 0.17-0.55; p < 0.001 for superiority). A reduction in bleeding at most sites including gastrointestinal (0.3% vs. 0.7%), intracranial (0.1% vs. 0.2%), and major bleeding at a critical site (0.1% vs. 0.5%) were all lower in the apixaban arm. The composite outcome of major bleeding or clinically relevant nonmajor bleeding was significantly lower with apixaban as well (4.3% vs. 9.7%, p < 0.001).

Serious adverse events were similar between the two arms (15.6% vs. 15.2%).

Interpretation:

The results of the AMPLIFY trial indicate that apixaban (as a loading dose for 7 days, followed by standard dose for 6 months) is noninferior to conventional therapy with subcutaneous enoxaparin and concomitant warfarin for the acute management of patients with symptomatic VTE. These results are fairly similar to those noted in the recent EINSTEIN PE and EINSTEIN DVT trials with rivaroxaban, and the RE-COVER trial with dabigatran. All of these agents have the potential to significantly simply the management of patients with acute VTE. Although length of stay is not reported in the current trial, it is conceivable that such a strategy may significantly lower length of stay for acute VTE, and perhaps even lend itself to outpatient management in selected patients. Cost-effectiveness analyses are eagerly awaited.

A couple of caveats regarding the current study warrant mention. Patients with transient risk factors, such as perioperative period, were excluded from the study. Only 3% of all patients had cancer. Adherence with twice daily dosing of apixaban was >80% in the trial, which may not be true in a real-world scenario, potentially reducing the efficacy of this medication.

References:

Agnelli G, Buller HR, Cohen A, et al., on behalf of the AMPLIFY Investigators. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013;369:799-808. 

Keywords: Polysaccharides, Neoplasms, Morpholines, Pulmonary Embolism, Heparin, Low-Molecular-Weight, Warfarin, Heparin, Venous Thromboembolism, Femoral Vein, Pyrazoles, Orthopedics, Length of Stay, beta-Alanine, Benzimidazoles, Thrombophilia, Enoxaparin, Popliteal Vein, Pyridones


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