AMPLIFY-EXT: Extra Year of Apixaban Safely Cuts Long-Term Recurrent-VTE Risk

December 10, 2012

ATLANTA — Twelve months of treatment with apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) at either of two dosages, given after six to 12 months of anticoagulation to treat venous thromboembolism (VTE), significantly lowered the risk of recurrent VTE compared with placebo, suggests a randomized trial with almost 2500 patients [1].

Patients who took the oral anticoagulant, a factor-Xa inhibitor increasingly used as a warfarin alternative around the world, showed a significant reduction in the primary end point of recurrent VTE or death from any cause without raising the risk of major bleeding or the composite of major bleeding or clinically important minor bleeds.

"For patients with VTE for whom there is uncertainty about the benefits and risks of continued therapy, the results of this study provide a rationale for continuing anticoagulation therapy for an additional 12 months," write the investigators in a report published today in the New England Journal of Medicine. What's more, apixaban at a dosage of either 2.5 mg or 5 mg twice daily was "effective, safe, and simple to use," they add.

During that extra year, the number needed to treat with apixaban to prevent one VTE recurrence was 14, yet it was 200 to cause one major or clinically relevant minor bleed, according to the authors, led by Dr Giancarlo Agnelli (University of Perugia, Italy).

The results of the Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment (AMPLIFY-EXT) study were also presented to reporters here today at the American Society of Hematology (ASH) 2012 Annual Meeting.

AMPLIFY-EXT randomized 2482 patients with venous thromboembolism who had remained asymptomatic while completing six to 12 months of anticoagulation therapy to receive one of two dosages of apixaban, 2.5 mg or 5.0 mg twice daily, or placebo in double-blind fashion for 12 months. Dual antiplatelet therapy wasn't allowed.

Patients were eligible if they had completed six to 12 months of anticoagulation therapy for confirmed symptomatic deep-venous thrombosis (DVT) or pulmonary embolism with or without DVT and "if there was clinical equipoise about the continuation or cessation of anticoagulant therapy."

The study was conducted at 328 sites in 26 countries in Europe, Asia, and North and South America, plus Australia, Israel, and South Africa.

During the one year of randomized therapy, the primary end point was reached by 3.8% of the 840 patients who received twice-daily apixaban at 2.5 mg and by 4.2% of the 813 who received it at 5.0 mg; the rate was 11.6% for the 829 in the placebo group (p<0.001 compared with both apixaban dosages). The primary-event rates by intention to treat included the 13, 19, and 20 patients in the three groups, respectively, who had been lost to follow-up.

Relative Risk (95% CI) for Efficacy and Safety End Points by Apixaban Dosage

End point Apixaban 2.5 mg vs placebo Apixaban 5 mg vs placebo Apixaban 2.5 mg vs 5 mg
Recurrent VTE or death from any cause (primary end point) 0.33 (0.22–0.48) 0.36 (0.25–0.53) NA
Non-VTE-related CV death, MI, or stroke 0.36 (0.11–1.12) 0.47 (0.16–1.33) 0.77 (0.21–2.88)
Recurrent VTE, VTE-related death, MI, stroke, or CV death 0.21 (0.13–0.35) 0.23 (0.14–0.38) 0.92 (0.48–1.74)
Major bleeding 0.49 (0.09–2.64) 0.25 (0.03–2.24) 1.93 (0.18–21.25)
Major or clinically relevant nonmajor bleeding 1.20 (0.69–2.10) 1.62 (0.96–2.73) 0.74 (0.46–1.22)
VTE, VTE-related death, MI, stroke, CV death, or major bleeding (net clinical benefit) 0.23 (0.14–0.37) 0.24 (0.15–0.38) 0.97 (0.52–1.79)

VTE=venous thromboembolism

A subgroup analysis suggested that the efficacy of apixaban in the trial was mostly independent of sex, age, weight, and renal function and whether anticoagulation was originally for VTE or pulmonary embolism.

The authors caution that only 15% of the study's patients were older than 75 years and few weighed less than 60 kg, so "more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients."

AMPLIFY-EXT was supported by Bristol-Myers Squibb and Pfizer. Agnelli discloses receiving honoraria or consulting fees, reimbursement for travel expenses, and payments for manuscript writing or reviewing, all related to the study, from Pfizer; and consulting for Bayer Healthcare, Boehringer Ingelheim, and Daiichi Sankyo and receiving payments for lecturing or serving on speaker's bureaus from Bayer Healthcare, Bristol-Myers Squibb, and Sanofi for purposes unrelated to the current study. Disclosures for the other authors are at www.nejm.org .

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