Apixaban and Dabigatran Found Effective, Safe for Extended Venous Thromboembolism Therapy

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism in three industry-sponsored, randomized clinical trials published in the February 21 issue of the New England Journal of Medicine. Both medications also reduced the risk of bleeding complications, the investigators said.

Apixaban Results From AMPLIFY-EXT
In one trial, two doses of apixaban were compared against placebo in 2,486 patients with venous thromboembolism who had finished six to 12 months of standard anticoagulation therapy and whose physicians were uncertain whether to stop or continue anticoagulation treatment, said Giancarlo Agnelli, MD, and colleagues in the Apixaban after the Initial Management of Pulmonary Embolism and DVT with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) study.

Apixaban is an oral factor Xa inhibitor that is administered in fixed doses and does not require laboratory monitoring. The 5-mg (treatment) dose of apixaban has been proven effective at preventing stroke in patients with atrial fibrillation, and the 2.5-mg (maintenance) dose has been proven effective for thromboprophylaxis after major orthopedic surgery, said Dr. Agnelli of the Department of Internal and Cardiovascular Medicine-Stroke Unit at the University of Perugia, Italy, and colleagues.

The study subjects were enrolled during a three-year period at 328 medical centers in 28 countries. They were randomly assigned in double-blind fashion to receive the 2.5-mg dose (840 subjects), the 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for one year.

The primary efficacy outcome measure was a composite of symptomatic recurrent venous thromboembolism or death from any cause. This occurred in 3.8% of the maintenance-dose group and in 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). Thus, both doses of apixaban significantly decreased the incidence of recurrent venous thromboembolism, Dr. Agnelli's group stated.

The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and in 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Thus, both doses of apixaban were comparable to placebo in rates of major bleeding.

Clinically relevant nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and in 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo.

The number of patients who would need to be treated with apixaban to prevent a single episode of recurrent venous thromboembolism was 14. In contrast, the number who would need to be treated to cause an episode of major or clinically relevant nonmajor bleeding was 200, the investigators noted.

"For patients with venous thromboembolism 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," they said.

"It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment. Consequently, more data are needed to better determine the benefit-to-risk profile of apixaban with respect to bleeding in such patients," the researchers said.

Further research also is needed to determine the risks and benefits of extending anticoagulation therapy beyond the 12-month mark examined in this study, they added.

Dabigatran Results From RE-MEDY AND RE-SONATE
In a separate report, Sam Schulman, MD, PhD, and colleagues, in the RE-MEDY and RE-SONATE studies, examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. These trials were extensions of two previous studies of short-term anticoagulation after venous thromboembolism.

In RE-MEDY, 2,866 patients with venous thromboembolism who had completed at least three months of anticoagulation therapy and were considered to have an increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute in Hamilton, Ontario, Canada, and his colleagues.

The RE-SONATE trial, in contrast, involved 1,343 patients with venous thromboembolism who had completed at least three months of anticoagulation therapy but were not considered to be at increased risk of recurrence. So it was ethical to assess the effect of dabigatran versus placebo in these patients, noted the researchers. The subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries.

In both RE-SONATE and RE-MEDY, the primary efficacy outcome measure was recurrent symptomatic venous thromboembolism or venous thromboembolism–related death.