Extended treatment of venous thromboembolism.

Patients with provoked venous thromboembolism caused by transient risk factors can generally stop anticoagulation after 3 months of treatment. For patients with unprovoked venous thromboembolism, for which the risk of recurrence is as high as 40% at 5 years,1 it may be appropriate to consider a longer course of therapy. However, deciding how to balance the risks and benefits of extended anticoagulation is difficult. Warfarin has greater than 90% efficacy in preventing recurrences but carries an associated risk of major bleeding of 1 to 2% per year.2 Warfarin is also a burdensome long-term treatment, with many food and drug interactions and the need for frequent monitoring. Three studies reported in two articles in this issue of the Journal3,4 examine the efficacy and safety of two new oral anticoagulants for extended treatment of unprovoked venous thromboembolism after initial anticoagulation therapy. In the double-blind RE-MEDY trial,3 Schulman and colleagues randomly assigned 2866 patients designated by investigators to be at increased risk for recurrence of venous thromboembolism to receive dabigatran, a direct thrombin inhibitor, at dose of 150 mg twice daily, or warfarin (international normalized ratio, 2.0 to 3.0). Two other trials focused on patients whose treating physicians were uncertain about the need for continued anticoagulation. In the RE-SONATE trial,3 1353 patients were randomly assigned to receive dabigatran (150 mg twice daily) or placebo for 6 months. In the AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment) study4 by Agnelli and colleagues, 2486 patients were randomly assigned to receive apixaban, a direct factor Xa inhibitor, at a dose of 2.5 mg twice daily or 5 mg twice daily, or placebo for 12 months. Results of all three studies are summarized in Table 1, along with results of a trial of extended treatment of venous thromboembolism with rivaroxaban, a direct factor Xa inhibitor.5 Dabigatran met the investigators’ noninferiority criteria for efficacy as compared with warfarin, with less major or clinically relevant nonmajor bleeding. Both drugs showed significantly greater efficacy than placebo. Bleeding was increased with dabigatran as compared with placebo. Surprisingly, the rates of recurrent venous thromboembolism were the same for both doses of apixaban, with bleeding rates that were not significantly different from the rate with placebo. Dabigatran and apixaban have not been approved for short-term or extended treatment of venous thromboembolism, but rivaroxaban recently became the first new anticoagulant approved for this indication in the United States and Europe. Rivaroxaban was more effective than placebo for extended treatment of venous thromboembolism (82% reduction in relative risk), albeit with an increase in bleeding.5 Recently published studies have also examined the role of aspirin in this context.6,7 In a pooled analysis of two similarly designed trials with carefully selected patient populations, 100 mg per day of aspirin reduced the risk of recurrent venous thromboembolism by 32%, with no increase in bleeding, as compared with placebo. Although aspirin may be safer than the newer agents, it appears to have less efficacy in reducing recurrent events. With the potential for lower bleeding rates, easier administration, and similar efficacy, the new targeted anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favor of extended treatment for this