In atrial fibrillation patients, dabigatran (Pradaxa) administered at 110 mg was associated with similar rates of stroke and systemic embolism as with warfarin, as well as lower rates of major hemorrhage, based on the RE-LY trial presented Sunday at the European Society of Cardiology (ESC) Congress in Barcelona, Spain. Yet, dabigatran administered at 150 mg, compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.
In this noninferiority trial, Stuart J. Connolly, MD, and colleagues from the Population Health Research Institute in Hamilton, Ontario, and colleagues randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of the oral direct thrombin inhibitor dabigatran—110 mg or 150 mg twice daily—or, in an unblinded fashion, adjusted-dose warfarin.
The investigators of RE-LY (Randomized Evaluation of Long-term anticoagulation therapY), which was simultaneously published online in the New England Journal of Medicine, said the median duration of the follow-up period was two years. The primary outcome was stroke or systemic embolism.
According to the researchers, rates of the primary outcome were 1.69 percent per year in the warfarin group, compared with 1.53 percent per year in the group that received 110 mg of dabigatran, and 1.11 percent per year in the group that received 150 mg of dabigatran (from Boehringer Ingelheim).
For adverse events, the rate of major bleeding was 3.36 percent annually in the warfarin group, compared with 2.71 percent per year in the group receiving 110 mg of dabigatran, and 3.11 percent per year in the group receiving 150 mg of dabigatran. The rate of hemorrhagic stroke was 0.38 percent per year in the warfarin group, compared with 0.12 percent per year with 110 mg of dabigatran and 0.1 percent per year with 150 mg of dabigatran.
The mortality rate was 4.13 percent per year in the warfarin group, compared with 3.75 percent per year with 110 mg of dabigatran and 3.64 percent per year with 150 mg of dabigatran, Connolly and colleagues reported.
However, the authors reported that the rate of MI was higher with both doses of dabigatran than with warfarin. They said an “explanation might be that warfarin provides better protection against coronary ischemic events than dabigatran, and warfarin is known to reduce the risk of MI. However, rates of MI were similar between patients with atrial fibrillation who were receiving warfarin and those who were receiving ximelagatran [Exanta from the London-based AstraZeneca], another direct thrombin inhibitor. The explanation for this finding is therefore uncertain.”
Based on their findings, Connolly and colleagues said that the net clinical benefit outcome was similar between the two doses of dabigatran, owing to the lower risk of ischemia with the 150 mg dose and the lower risk of hemorrhage with the 110 mg dose. “These findings suggest that the dose of dabigatran could potentially be tailored to take into consideration the risk characteristics of a specific patient, although this concept was not specifically tested in our trial,” the authors wrote.
In an accompanying NEJM commentary, Brian F. Gage, MD, wrote that warfarin is prescribed to only two-thirds of appropriate candidates, suggesting that “new oral anticoagulants are needed.” He said that dabigatran etexilate “appears to be an anticoagulant that could fill this niche.”
However, Gage acknowledges that dabigatran is not without important drug interactions. P-glycoprotein inhibitors—including verapamil, amiodarone and especially quinidine—raise dabigatran serum concentrations considerably. He noted that while the interaction may have contributed toward “greater efficacy of dabigatran in the subgroup of patients taking amiodarone, it could elevate the risk of hemorrhage in such patients.”
The study was supported by a grant from Boehringer Ingelheim of Ingelheim, Germany.