Cardiology · 2009
RE-LY (Dabigatran versus warfarin in atrial fibrillation)
Randomized Evaluation of Long-Term Anticoagulation Therapy
Warfarin had been the standard anticoagulant for stroke prevention in atrial fibrillation since the late 1980s, when the SPAF and AFASAK trials first established its efficacy. Its clinical shortcomings were well known: a narrow therapeutic window, food and drug interactions, the need for regular INR monitoring, and a risk of intracranial hemorrhage that made physicians and patients reluctant to initiate or maintain it. By the 2000s, dabigatran, a direct thrombin inhibitor, had been developed as an alternative that required no coagulation monitoring and could be given at a fixed dose.
RE-LY randomized 18,113 patients with atrial fibrillation and at least one additional stroke risk factor across 951 centers in 44 countries. Stuart Connolly of McMaster University led the trial design and execution. The study used an unusual design: the two dabigatran doses were blinded, while warfarin was open-label, maintained at an INR of 2 to 3. Michael Ezekowitz contributed to the trial's design and conduct.
The 150 mg twice-daily dose of dabigatran reduced the combined outcome of stroke and systemic embolism from 1.69% per year on warfarin to 1.11% per year, a relative risk reduction of approximately 34%, with similar rates of major bleeding overall. Intracranial hemorrhage was 0.38% per year with the 150 mg dose versus 0.60% per year with warfarin, a difference with significant clinical importance given warfarin's intracranial bleeding risk. The 110 mg dose was non-inferior to warfarin on stroke prevention and produced less major bleeding, offering an option for patients at higher bleeding risk.
Publication in the New England Journal of Medicine in 2009 was followed quickly by FDA approval of dabigatran 150 mg for stroke prevention in nonvalvular atrial fibrillation in October 2010. ROCKET-AF reported rivaroxaban data in 2011 and ARISTOTLE reported apixaban data in 2011, both confirming the pattern of non-inferiority or superiority on stroke prevention with better intracranial hemorrhage profiles than warfarin. Together, the three trials established direct oral anticoagulants as the first-line choice for most patients with atrial fibrillation who required anticoagulation.
The shift in practice that followed was large and rapid. By the mid-2010s, new prescriptions for anticoagulation in atrial fibrillation in most high-income countries were predominantly DOACs rather than warfarin. Anticoagulation clinics designed around INR monitoring experienced declining referral volumes. The practical consequence for outpatient medicine was that patients who previously went without anticoagulation because of the monitoring burden, or who had poorly controlled INRs, could be offered a fixed-dose regimen without routine laboratory follow-up.
Key People
- Stuart Connolly — Principal investigator; led RE-LY trial design and execution
- Michael Ezekowitz — Co-investigator; contributed to trial design and conduct
- Salim Yusuf — McMaster University; senior oversight of the RE-LY program
- Lars Wallentin — Uppsala University; co-investigator and contributor to DOAC trial program
N Engl J Med. 2009;361(12):1139-1151.
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