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Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism
Study Questions:
What is the efficacy and safety of dabigatran during long-term prophylaxis after venous thromboembolism, compared with warfarin and placebo?
Methods:
The active-control study in which dabigatran at a dose of 150 mg twice daily was compared with warfarin and was designated RE-MEDY. The placebo-control study was designated RE-SONATE. Both studies were randomized, double-blind, multicenter, international trials that enrolled patients who had completed at least 3 months of treatment for venous thromboembolism. Patients were eligible if they had objectively confirmed, symptomatic, proximal deep-vein thrombosis or pulmonary embolism that had already been treated with an approved anticoagulant, or if they had received dabigatran in one of two previous clinical trials of short-term venous thromboembolism (i.e., RE-COVER and RE-COVER II). The required duration of initial treatment before trial enrollment was 3-12 months for the active-control study and 6-18 months for the placebo-control study. In both studies, the primary efficacy outcome was recurrent symptomatic and objectively verified venous thromboembolism or death associated with venous thromboembolism. Safety outcomes included major bleeding and clinically relevant nonmajor bleeding.
Results:
Recurrent venous thromboembolism occurred in 26 of 1,430 patients in the dabigatran group (1.8%), and 18 of 1,426 patients in the warfarin group (1.3%) (hazard ratio [HR] with dabigatran, 1.44; 95% confidence [CI], 0.78-2.64; p = 0.01 for noninferiority). Major or clinically relevant bleeding was less frequent with dabigatran (HR, 0.54; 95% CI, 0.41-0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and three patients in the warfarin group (0.2%) (p = 0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (HR, 0.08; 95% CI, 0.02-0.25; p < 0.001). Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (HR, 2.92; 95% CI, 1.52-5.60).
Conclusions:
Dabigatran at 150 mg twice daily was as effective as warfarin for the extended maintenance therapy of venous thromboembolism, and compared to placebo, dabigatran significantly reduced the rate of recurrent venous thromboembolism. Dabigatran was associated with a lower risk of major or clinically relevant bleeding than warfarin; however, compared to placebo, clinically relevant bleeding was three times more likely in those taking dabigatran.
Perspective:
In two related randomized trials, the authors evaluated the use of fixed-dose dabigatran for the long-term treatment of venous thromboembolism. Results from the active-control RE-MEDY study demonstrated dabigatran was both noninferior to warfarin and associated with a lower risk of bleeding, adding to the very scant literature on the safety and efficacy of the novel oral anticoagulants in the ‘extension phase’ of treatment for venous thromboembolism. Of note, there were more acute coronary syndrome (ACS) events in the dabigatran group, compared to those in the warfarin group, findings that parallel those in the RE-LY study, where an increased risk of myocardial infarction was seen with dabigatran compared with warfarin in the trial of stroke prevention in atrial fibrillation. There were baseline differences in the dabigatran and warfarin treatment groups that could have contributed to the higher incidence of ACS in those taking dabigatran (e.g., 120 patients in the dabigatran group having coronary artery disease compared with 87 in the warfarin group, p = 0.02). Overall, the novel oral anticoagulants may have a role for extended anticoagulation of idiopathic or unprovoked venous thromboembolism.
Keywords: Acute Coronary Syndrome, Benzimidazoles, Warfarin, Venous Thromboembolism
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