RE-LY: Dabigatran superior to warfarin for stroke prevention in atrial fibrillation

The 110-mg dose of the anticoagulation also had lower rates of major hemorrhage.

Compared with warfarin, dabigatran given at a 110-mg dose was associated with a similar risk for stroke and systemic embolism in patients with atrial fibrillation, but also a lower risk for major hemmorhage. Given at a 150-mg dose, dabigatran was associated with a lower risk for stroke and systemic embolism compared with warfarin, but also a similar risk for major hemmorhage, according to non-inferiority data from the Randomized Evaluation of Long-Term Anticoagulation Therapy trial.

Although recommended for patients with atrial fibrillation who are at risk for stroke, warfarin increases the risk for bleeding and is difficult to use, according to the researchers. The oral thrombin inhibitor dabigatran, however, was shown to prevent venous thromboembolism among patients with atrial fibrillation in a pilot study. Based on those results, the current study examined the use of 110 mg or 150 mg dabigatran twice daily vs. warfarin for the prevention of stroke in patients with atrial fibrillation. The results were presented at the European Society of Cardiology Congress 2009 in Barcelona, Spain, and published in The New England Journal of Medicine.

Between Dec. 22, 2005, and Dec. 15, 2007, the RE-LY trial accrued 18,113 patients from 951 clinical centers in 44 countries. Patients were randomly assigned to 110 mg dabigatran twice daily (n=6,015); 150 mg dabigatran twice daily (n=6,076) or 1 mg, 3 mg or 5 mg warfarin (n=6,022). Follow-up occurred 14 days after, one month after and three months after randomization, and every three months thereafter during the first year and every four months until the study’s end.

The primary endpoint was stroke or systemic embolism; the primary safety outcome was major hemorrhage. Secondary outcomes included stroke, systemic embolism and death. According to the researchers, the primary net clinical benefit was the composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death or major hemorrhage.

The follow-up period lasted for a median duration of two years; 99.9% of participants completed follow-up.

Demonstrated superiority

Compared with warfarin, dabigatran 110 mg and 150 mg were associated with fewer strokes or systemic embolisms (199 patients vs. 182 patients and 134 patients); neither dose was inferior to warfarin (P<.001). Dabigatran 150 mg was superior to warfarin (relative risk=0.66; 95% CI, 0.53-0.82); the 110-mg dose was non-inferior to warfarin (RR=0.91; 95% CI, 0.74-1.11). Hemorraghic stroke rates were also lower with both doses of dabigatran compared with warfarin (0.12% for 110 mg dabigatran, 0.10% for 150 mg and 0.38% for warfarin; P<.001).

Death from any cause occurred at a rate of 4.13% per year with warfarin vs. 3.75% per year with 110 mg dabigatran (RR=0.91; 95% CI, 0.80-1.03) and 3.64% per year with 150 mg dabigatran (RR=0.88; 95% CI, 0.77-1.00). The rate of myocardial infarction was higher with both doses of dabigatran compared with warfarin.

Although the rate of major bleeding was lower in the 110-mg group compared with warfarin (2.71% vs. 3.36%; RR=0.80; 95% CI, 0.69-0.93), the rate was similar between the 150-mg group (3.11% per year; RR=0.93; 95% CI, 0.81-1.07) and warfarin. However, rates of life-threatening bleeding, intracranial bleeding and major or minor bleeding were higher with warfarin compared with the 110-mg dose or the 150-mg dose. The 150-mg dose of dabigatran was associated with a significantly higher rate of gastrointestinal bleeding compared with warfarin.

The rate of major vascular events, major bleeding and death combined were lower in the dabigatran group compared with warfarin: 7.09% per year for 110 mg (RR=0.92; 95% CI, 0.84-1.02), 6.91% per year for 150 mg (RR=0.91; 95% CI, 0.82-1.00) vs. 7.64% per year.

When both doses of dabigatran were compared, the researchers reported that the 150-mg dose was associated with a lower risk for stroke and systemic embolism (P=.005).

“This difference was driven mostly by a decrease in the rate of stroke with ischemic or unspecific cause, whereas rates of hemorrhagic stroke were similar in the two dabigatran groups,” the researchers wrote. “There was no significant difference in the rates of death from either vascular causes or any cause between the two doses.”

However, the 150-mg dose was associated with a trend toward a higher risk for major bleeding (P=.052) and increased risks for gastrointestinal, minor and any bleeding compared with the 110-mg dose.

According to Brian F. Gage, MD, MSc, internist at Washington University School of Medicine, and author of an accompanying editorial, despite the qualifications associated with the current study, the RE-LY trial is a reliable one.

“Because of dabigatran’s twice-daily dosing and greater risk of nonhemorrhagic side effects, patients already taking warfarin with excellent INR control have little to gain by switching to dabigatran,” he wrote. “In contrast, many other patients who have atrial fibrillation and at least one additional risk factor for stroke could benefit from dabigatran.”

Gage BF. N Engl J Med. 2009;doi:10.1056/NEJMe0906886.

Connolly S J. N Engl J Med. 2009;doi:10.1056/NEJMoa0905561.