Apixaban Noninferior to Standard Therapy for Acute Venous Thromboembolism

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The factor Xa inhibitor apixaban is noninferior to conventional therapy with enoxaparin and a vitamin K antagonist in patients with acute venous thromboembolism (VTE). The study, published online July 1, 2013, ahead of print in the New England Journal of Medicine, also found that apixaban resulted in a 69% reduction in major bleeding events.

For the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, researchers led by Giancarlo Agnelli, MD, of the University of Perugia (Perugia, Italy), randomized 5,395 patients with acute VTE and/or pulmonary embolism to apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months (n = 2,691) or subcutaneous enoxaparin for at least 5 days plus warfarin for 6 months (n = 2,704). The warfarin dose was adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0. Enoxaparin or placebo was discontinued when a blinded INR of 2.0 or more was achieved.

Patients were enrolled at 358 centers in 28 countries from August 2008 through August 2012.

Apixaban Noninferior for VTE Recurrence, Superior for Bleeding

At 6 months, the incidence of recurrent symptomatic VTE or death related to VTE, the primary efficacy endpoint, was similar in the apixaban and conventional-therapy groups, meeting the prespecified criteria for noninferiority. However, apixaban resulted in a marked reduction in relative risk for the primary safety endpoint of major bleeding. This reduction was paralleled by a decrease in clinically relevant nonmajor bleeding (table 1).

Table 1. Outcomes at 6 Months

^a P for noninferiority.

Other P values are for superiority.

Similarly, when patients were categorized according to whether they had VTE or pulmonary embolism, rates of the primary efficacy endpoint for apixaban vs. conventional theapy were 2.2% vs. 2.7% and 2.3% vs. 2.6%, respectively.

Results Likely Generalizable

According to the investigators, the current data add to those of their own recent study, which found similar results for extended use of apixaban in patients who have completed 6 to 12 months of anticoagulant therapy for acute VTE (Agnelli G, et al. N Engl J Med. 2013;368:699-708).

Additionally, they say the new study answers concerns about the efficacy and safety of new agents relative to well-controlled warfarin therapy, since even in centers where the mean time in the therapeutic range with warfarin exceeded 68%, the efficacy and the reduction in major bleeding with apixaban were consistent with the overall findings.

Dr. Agnelli and colleagues say the results are “likely to be generalizable” to the VTE population but note that additional information is needed on the efficacy and safety of apixaban in those with cancer, low body weight, or a creatinine clearance < 50 mL per minute. 

No Nail in the Coffin for Vitamin K Antagonists

But in an editorial accompanying the paper, Mary Cushman, MD, of the University of Vermont (Burlington, VT), notes that new anticoagulants such as apixaban are not for every patient, and that ongoing research aims “to optimize the use of vitamin K antagonists, so it is unlikely that these will disappear from practice.”

Among the ongoing research she cites are:

• Prothrombin-time self-testing
• Anticoagulation clinics
• Diminished frequency of monitoring for selected patients
• Basing dosing decisions on genetic information

Dr. Cushman also cautions that translating knowledge gleaned from years of using vitamin K antagonists to newer agents like apixaban is complex. For example, she notes that information is still needed regarding “reversal strategies, monitoring (eg, in the presence of interacting drugs, extremes of patient weight, or bleeding or thrombosis complications), approaches to treatment failure, comparisons of adherence to treatment among new drugs and warfarin, and formal cost-effectiveness analyses.”

 

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Sources:
1. Agnelli G, Buller, HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;Epub ahead of print.

2. Cushman C. Treating acute venous thromboembolism: Shift with care [editorial]. N Engl J Med. 2013;Epub ahead of print.

 

 

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