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Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial
Study Questions:
How do the risks of bleeding associated with dabigatran compare at 150 mg versus 110 mg twice daily in the RE-LY trial of patients with atrial fibrillation?
Methods:
The RE-LY trial randomized 18,113 patients to receive dabigatran 110 or 150 mg twice a day or warfarin dose adjusted to an international normalized ratio of 2.0-3.0 for a median follow-up of 2.0 years. The main safety outcome was major bleeding, and the primary efficacy outcome was stroke or systemic embolism.
Results:
There was no difference between groups for the following: mean age 71.5 years, 64% male, mean blood pressure 131/77 mm Hg, aspirin use ~39%, history of warfarin use ~50%, and CHADS2 score of 2.1 ± 1.1. Compared with warfarin, dabigatran 110 mg twice a day was associated with a lower risk of major bleeding (2.87% vs. 3.57%; p = 0.002), whereas dabigatran 150 mg twice a day was associated with a similar risk of major bleeding (3.31% vs. 3.57%; p = 0.32). There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients ages <75 years (1.89% vs. 3.04%; p < 0.001) and a similar risk in those ages ≥75 years (4.43% vs. 4.37%; p = 0.89; p for interaction < 0.001), whereas dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those ages <75 years (2.12% vs. 3.04%; p < 0.001) and a trend toward higher risk of major bleeding in those ages ≥75 years (5.10% vs. 4.37%; p = 0.07; p for interaction < 0.001). The interaction with age was evident for extracranial bleeding, but not for intracranial bleeding, with the risk of the latter being consistently reduced with dabigatran compared with warfarin irrespective of age.
Conclusions:
In patients with atrial fibrillation at risk for stroke, both doses of dabigatran compared with warfarin have lower risks of both intracranial and extracranial bleeding in patients ages <75 years. In those ages >75 years, intracranial bleeding risk is lower, but extracranial bleeding risk is similar or higher with both doses of dabigatran compared with warfarin.
Perspective:
The Food and Drug Administration approved only the higher dose of dabigatran, because while it had less bleeding, the lower dose was associated with a 12% increase in ischemic strokes compared to warfarin. There was a twofold higher risk of major bleeding with dabigatran or warfarin in patients with a creatinine clearance <50 ml/min compared with those who had a clearance >80 ml/min, which is consistent with reports that renal function is a powerful predictor of bleeding risk in patients treated with warfarin. They approved a 75 mg twice daily schedule for persons with a creatinine clearance of 15-30 ml/min and 150 mg twice daily for those with a creatinine clearance >30 ml/min.
Keywords: Follow-Up Studies, United States Food and Drug Administration, Benzimidazoles, Warfarin, Blood Pressure, Embolism, United States
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