The RE-LY trial: Dabigatran non-inferior to warfarin in preventing strokes in patients with atrial fibrillation [Classics Series]

Classics Series, Landmark Trials in Medicine

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1. High-dose dabigatran is superior to warfarin in the prevention of strokes in patients with atrial fibrillation, while low-dose dabigatran is non-inferior to warfarin in preventing strokes in this population

2. There is lower risk of major hemorrhage on low-dose dabigatran compared to warfarin, while there is similar rate of major hemorrhage on high-dose dabigatran as compared to warfarin

Original Date of Publication: September 17, 2009

Study Rundown: Dabigatran is non-inferior to warfarin in the prevention of stroke in at-risk patients with atrial fibrillation, and is associated with an overall lower risk of major bleeding and intracranial hemorrhage. For those at-risk patients requiring anticoagulation for the prevention of stroke in the context of atrial fibrillation, dabigatran could be considered as an alternative to warfarin in those patients with a creatinine clearance >30ml/min, as dabigatran is renally cleared. A major criticism of the RE-LY trial is the high risk of bias created by the unblinded administration of warfarin. Moreover, it has been noted that the incidence of intracranial hemorrhage with warfarin observed in this study was much higher than previously reported rates and reasons for this are unclear.

Please click to read the study in NEJM

Primer: Anticoaguation with warfarin, a vitamin K antagonist, has long been the standard of care for preventing thromboembolic strokes in high-risk patients with atrial fibrillation. Warfarin, however, is limited by the need for frequent monitoring due to its narrow therapeutic window, as well as its variable pharmacokinetics and drug interactions. Furthermore, its use is associated with a significant risk of major bleeding.

Dabigatran, a direct thrombin inhibitor, is one of the new oral anticoagulants introduced within the last decade as a possible alternative to warfarin. There is evidence for its use for venous thromboembolism (VTE) prophylaxis after total knee or hip arthroplasty, as well as in the treatment of acute VTE. No evidence, however, existed for the use of dabgitran in the context of atrial fibrillation in the prevention of stroke.

The RE-LY trial was published in the New England Journal of Medicine in 2009. In the era of the new anticoagulants, this landmark RCT compared low- (110 mg PO BID) and high-dose (150 mg PO BID) dabigatran with dose-adjusted warfarin in preventing stroke in at risk patients with atrial fibrillation. The risk of major bleeding on dabigatran as compared to warfarin was also investigated.

Relevant Reading:

  1. Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty: A meta-analysis. Thromb Haemost 2009;101(1):77-85.
  2. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-2352.

In-Depth [randomized, controlled study]: This large, randomized, double-blinded, controlled trial included 18,113 patients from 951 clinical centers in 44 countries. Patients were randomized to 3 groups: 1) dose-adjusted warfarin titrated to INR of 2.0-3.0, 2) low-dose dabigatran (110 mg PO BID), or 3) high-dose dabigatran (150 mg PO BID). Notably, dabigatran administration was blinded, while warfarin administration was unblinded. The primary outcome studied was stroke or systemic embolism. The primary safety outcome was major hemorrhage. The trial lasted a total of 2 years.

Results revealed that the rate of stroke was significantly less in patients that received high-dose dabigatran as compared to warfarin, and there was no significant difference in major bleeding between these two groups. Furthermore, low-dose dabigatran was non-inferior to warfarin in preventing strokes, but it was associated with a significant reduction in risk of major bleeding. Intracranial hemorrhage was significantly less common in both dabigatran groups compared to warfarin. Rate of major gastrointestinal bleeding was significantly higher for patients receiving high-dose dabigatran as compared to the warfarin group. There was no significant difference in mortality between all three groups. Dyspepsia was the only adverse effect that was significantly more common with dabigatran.

By Aimee Li, M.D.; Andrew Cheung, M.D.

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