RE-LY (Dabigatran versus warfarin in atrial fibrillation)

Warfarin had been the standard anticoagulant for stroke prevention in atrial fibrillation since the late 1980s and early 1990s, when trials such as AFASAK and SPAF 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. An earlier oral direct thrombin inhibitor, ximelagatran, had been compared with warfarin in 3,410 patients in the SPORTIF III trial in 2003. By the late 2000s, dabigatran, another 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. Hemorrhagic stroke occurred at 0.10% per year with the 150 mg dose and 0.38% per year with warfarin. 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 for stroke prevention in nonvalvular atrial fibrillation on October 19, 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 made direct oral anticoagulants an established alternative to warfarin for most patients with atrial fibrillation who needed anticoagulation.

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. Dabigatran later drew controversy over bleeding and over whether some patients would benefit from measuring drug levels, which fixed dosing had been promoted as making unnecessary.