Background and knowledge gap
In a phase II trial, patients with proximal DVT were randomized to a 3-month course of treatment with apixaban or to conventional anticoagulant therapy with LMWH or fondaparinux followed by a vitamin K antagonist. The composite of recurrent VTE and increased thrombus burden with apixaban were similar to conventional treatment, with no increase in clinically relevant non-major bleeding. Based on these results, the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial was designed to compare apixaban with conventional anticoagulant therapy in patients with acute symptomatic venous thromboembolism.
Aim of the Study
The objectives of the study are summarised as follows:
a) Primary efficacy outcome: incidence of the composite of recurrent symptomatic VTE or death related to VTE
b) Secondary efficacy outcomes:
-each component of the primary efficacy outcome (recurrent symptomatic VTE or death related to VTE)
– Death from cardiovascular causes
– Death from any cause
– Composite of symptomatic recurrent VTE with death from cardiovascular causes, with death from any cause, or with death related to venous thromboembolism plus major bleeding.
c) Primary safety outcome: major bleeding.
d) Secondary safety outcome: composite of major bleeding and clinically relevant non-major bleeding..
This multicentric, double blind trial randomized 5395 VTE patients to receive apixaban (10 mg twice daily during seven days, followed by 5mg twice daily) or conventional treatment (parenteral enoxaparin and warfarin during 7 days, followed by warfarin) during a six-month period.
Regarding efficacy endpoint, apixaban showed non-inferiority compared to conventional therapy. The primary endpoint occurred in 59 patients in the apixaban group (2.3%) and 71 patients (2.7%) in the conventional treatment group (RR 0.84%; 95% CI, 0.60-1.18; P Apixaban was proved superior to conventional therapy in the safety endpoint (major bleeding), which accounted for 0.6% of patients receiving apixaban and 1.8% in those receiving conventional treatment (RR 0.31%; 95% CI, 0.17-0.55; P The composite of major bleeding and clinically relevant non-major bleeding presented in 4.3% of the patients in the apixaban group compared to 9.7% of the patients in the conventional group (RR 0.44; 95% CI, 0.36- 0.55).
Rates of other adverse events were similar in both groups.
In this phase III trial, the administration of apixaban during a six-month period reached the primary efficacy endpoint of non-inferiority when compared to conventional treatment (reduction the composite of symptomatic recurrent VTE or death related to VTE).
In addition, apixaban showed superiority in the safety endpoint (69% reduction in major bleeding compared to conventional treatment).
With this trial, apixaban proved its potential to obviate the need for parenteral anticoagulant therapy for initial VTE management and the combination with warfarin. With fixed dosing, no need for coagulation monitoring, and less bleeding, apixaban could be more convenient than conventional therapy and may expand the indications for long-term anticoagulation in patients with unprovoked VTE.
Corresponding author from original paper
Dr. Giancarlo Agnelli
University of Perugia, Piazzale Menghini 1, 06100 Perugia, Italy
Electronic address: email@example.com.
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Citation: Giancarlo Agnelli, Harry R. Buller, Alexander Cohen, Madelyn Curto, Alexander S. Gallus, Margot Johnson, Urszula Masiukiewicz, Raphael Pak, John Thompson, Gary E. Raskob, et al. N Engl J Med. 2013 August 29; 369(9): 799–808.