The AMPLIFY trial: Apixaban for treatment of venous thromboembolism [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Apixaban was found to be non-inferior to conventional therapy (i.e., enoxaparin followed by warfarin) in the treatment of acute venous thromboembolism.

2. Major bleeding was found to be significantly less common in patients treated with apixaban as compared with conventional therapy.

Original Date of Publication: August 2013

Study Rundown: New oral anticoagulants are being increasingly used for a number of different indications, including stroke prophylaxis in patients with atrial fibrillation and treatment of venous thromboembolic disease. The purpose of the Apixiban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial was to determine if apixaban, an oral factor Xa inhibitor, would be non-inferior to conventional therapy (i.e., enoxaparin followed by warfarin) for the treatment of acute venous thromboembolic disease. In summary, apixaban was found to be non-inferior to conventional therapy in preventing recurrent venous thromboembolism or death from venous thromboembolism. The rate of major bleeding was found to be significantly lower in patients treated with apixaban as compared with conventional therapy. Of note, the study was funded Bristol-Myers Squibb and Pfizer, and employees of Pfizer were involved in numerous stages of the study’s design and conduct.

Click to read study in NEJM

In-Depth [randomized controlled trial]: This randomized, non-inferiority trial was conducted at 358 centres in 28 countries. A total of 5,400 patients were enrolled and randomized to treatment with apixaban or conventional therapy (i.e., enoxaparin for 5 days and warfarin for 6 months with target INR between 2-3). Patients were included in the trial if they were >18 years of age, had objectively confirmed proximal deep-vein thrombosis (DVT) and/or pulmonary embolism. Exclusion criteria included active bleeding, a high risk of bleeding, other contraindications to anticoagulation, cancer, provoked venous thromboembolic disease, dual antiplatelet therapy, and creatinine clearance <25 mL/min. The primary efficacy outcome was a composite of recurrent symptomatic venous thromboembolism or death from venous thromboembolism. Secondary outcomes included each component of the primary outcome, in addition to cardiovascular mortality and all-cause mortality. The primary safety outcome was major bleeding. Notably, the trial was sponsored by Bristol-Myers Squibb and Pfizer. Moreover, the steering committee included employees of Pfizer, who were involved in study design, study oversight, data verification and analysis, and manuscript writing.

There was no difference in the rate of the primary outcome in the two groups (RR 0.84; 95%CI 0.60-1.18) and the findings met criteria for non-inferiority. Moreover, there were no significant differences between the groups in terms of the risk of cardiovascular or all-cause mortality. Major bleeding occurred significantly less frequently in patients treated with apixaban compared to those on conventional therapy (RR 0.31; 95%CI 0.17-0.55).

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