|The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) was a randomized trial designed to compare two fixed doses of dabigatran, each administered in a blinded manner, with open-label use of warfarin in patients who had atrial fibrillation and were at increased risk for stroke…
Advertisement The study compared two fixed-dose regimens of dabigatran (110 mg twice daily and 150 mg twice daily), administered in a blinded fashion, with adjusted-dose warfarin, administered in an unblinded fashion, in patients who had atrial fibrillation and were at risk for stroke. Both dabigatran doses were noninferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. In addition, the 150-mg dose of dabigatran was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg dose was superior to warfarin with respect to major bleeding.
Previous studies seeking to identify a safe and effective alternative to warfarin for patients with atrial fibrillation have all had specific limitations. The combination of clopidogrel and aspirin was more effective than aspirin alone but less effective than warfarin. Subcutaneous idraparinux was more effective than warfarin but was associated with a substantially higher risk of bleeding. Ximelagatran, an earlier direct thrombin inhibitor, appeared to be similar to warfarin with respect to efficacy and safety but was found to be hepatotoxic. In our serial measurement of liver function, they did not find evidence of hepatotoxicity with dabigatran.
The rate of myocardial infarction was higher with both doses of dabigatran than with warfarin. An explanation might be that warfarin provides better protection against coronary ischemic events than dabigatran, and warfarin is known to reduce the risk of myocardial infarction. However, rates of myocardial infarction were similar between patients with atrial fibrillation who were receiving warfarin and those who were receiving ximelagatran, another direct thrombin inhibitor. The explanation for this finding is therefore uncertain.
The most devastating complication of warfarin therapy is intracranial hemorrhage, especially hemorrhagic stroke. As compared with aspirin, warfarin doubles the risk of intracranial hemorrhage. Thus, our finding that the rate of this complication with both doses of dabigatran was less than one third the rate with warfarin, without a reduction in the efficacy against ischemic stroke, suggests an important advantage of dabigatran. The rate of major bleeding with warfarin was higher in our study than in some previous trials. This is partly explained by the more inclusive definition of major bleeding in our study. There was an increase in the rate of gastrointestinal bleeding with the higher dabigatran dose, despite the overall lower rates of bleeding at other sites. To enhance absorption of dabigatran, a low pH is required. Therefore, dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core. This acidity may partly explain the increased incidence of dyspeptic symptoms with both dabigatran doses and the increased risk of gastrointestinal bleeding with the 150-mg dose.
The benefit of dabigatran may be explained in part by the twice-daily dosing regimen. Since dabigatran has an elimination half-life of 12 to 17 hours, twice-daily dosing reduces variability in the anticoagulation effect, especially as compared with the anticoagulation effect of warfarin, which is difficult to control. Warfarin broadly inhibits coagulation (inhibiting factors II, VII, IX, and X and proteins C and S). By selectively inhibiting only thrombin, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding.
The net clinical benefit outcome, which is a measure of the overall benefit and risk, 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.
|In conclusion, we compared two doses of dabigatran with warfarin in patients who had atrial fibrillation and who were at risk for stroke. As compared with warfarin, the 110-mg dose of dabigatran was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage; the 150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage.