Continuing treatment of either low- or high-dose apixaban reduces the risk of recurrent venous thromboembolism (VTE), according to results of the AMPLIFY-EXT trial. Patients given extended anticoagulation also were at no higher risk of major bleeding than the placebo group. The results were published online Dec. 8 in the New England Journal of Medicine.
Giancarlo Agnelli, MD, of the department of internal and cardiovascular medicine–stroke unit at the University of Perugia in Perugia, Italy, and colleagues evaluated the efficacy and safety of 2.5 mg and 5 mg apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) as an extended treatment for patients with recurrent VTE. All of the 2,486 patients enrolled in the AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) study had finished six to 12 months of anticoagulation therapy and were at clinical equipoise; their physicians were uncertain about the benefits or risks of continuing treatment.
Apixaban, an oral factor Xa inhibitor, is an alternative to warfarin for the prevention of recurrent venous thromboembolism in some countries. It was approved in 2011 for the prevention of VTE events in adults who have undergone elective hip or knee replacement surgery in 27 European Union countries. The European Commission extended approval in November for prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation with one or more risk factors, and Canada Health gave it thumbs up in December for the prevention of stroke and systemic embolism in atrial fibrillation patients.
Apixaban is not approved for any indication in the U.S. The FDA has changed the date to review its New Drug Application several times, with the goal date now set for March 17, 2013.
AMPLIFY-EXT investigators designed the double-blind study and randomized patients enrolled between 2008 and 2011 to a 2.5 mg apixaban group (840 patients), a 5 mg apixaban group (813 patients) or a placebo group (829 patients). All patients received doses twice daily for 12 months and were assessed monthly during the one-year study plus 30 days after it ended.
The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism (fatal and nonfatal pulmonary embolism and deep vein thrombosis) or death from any cause. The prespecified secondary efficacy outcome was symptomatic recurrent venous thromboembolism or death related to venous thromboembolism.
The primary safety outcome was major bleeding and the secondary safety outcome was the composite of major or clinically relevant nonmajor bleeding.
Patient characteristics were similar for all three groups. In their intention-to-treat analysis, Agnelli and colleagues found that both doses compared with placebo reduced the risk of recurrent VTE without an increased risk of bleeding. Results for the primary efficacy outcome showed that 8.8 percent of the placebo group experienced symptomatic recurrent VTE or death from venous thromboembolism compared with 1.7 percent of the 2.5 mg apixaban group and 1.7 percent of 5 mg group.
The rates of major bleeding were 0.5 percent in the placebo group, 0.2 percent in the 2.5 mg group and 0.1 percent in the 5 mg group. Nonmajor bleeding rates were 2.3 percent, 3 percent and 4.2 percent, respectively, while rates of death from any cause were 1.7 percent, 0.8 percent and 0.5 percent, respectively.
Agnelli and colleagues emphasized that the study included only patients who had already received anticoagulation therapy whose physicians were uncertain about continuing therapy. “Furthermore, patients who required continued anticoagulation, such as those with atrial fibrillation or the antiphospholipid syndrome, were excluded,” they wrote. “Given that the proportion of patients with recurrent thromboembolism (fatal or nonfatal) in the placebo group was 8.8 percent, it is evident that these entry criteria identified patients with an appreciable risk of recurrence.”
The results showed that apixaban in either low or high doses was effective and safe, the study authors wrote, and provide physicians with evidence for extending therapy for another year. “The number of patients who would need to be treated to prevent one episode of recurrent venous thromboembolism (fatal or nonfatal) during the one-year active study period was only 14, whereas the number needed for treatment to cause one episode of major or clinically relevant nonmajor bleeding was 200,” they pointed out.
They added that few patients in the study were older than 75, frail or had renal impairment. They recommended more research to better determine the risks and benefits for these patients as well as more studies to assess the net benefits and risks of extended treatment.
The study was funded by Bristol-Myers Squibb and Pfizer.