The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: dabigatran vs. warfarin.

Atrial fibrillation is an increasingly common arrhythmia, now said to stand at epidemic proportion in Western societies: .2.3 million people in the USA and .4.5 million people in Western Europe. It is an expression of underlying heart disease and a threat to life and living. In particular it is associated with 4.5-fold risk of stroke, predominantly ischaemic in nature, largely due to embolization of a left atrial clot. Over the last several decades a formidable evidence base has been developed for the use of anticoagulant therapy, mostly warfarin/coumadin, and antiplatelet therapy, predominantly aspirin and more recently clopidogrel plus aspirin. Although warfarin is undoubtedly an effective anticoagulant therapy, its application is associated with a highly significant risk of bleeding such that it has been necessary to provide regular and sometimes intense monitoring of coagulation parameters, and stringent control of diet, alcohol, and co-medications. Recently it has been suggested that it might be necessary to apply modern pharmacogenomic principles of personalized medicine to warfarin recipients to optimize the safety of anticoagulant control. Despite all this, warfarin therapy remains problematic, especially in the elderly because of nonadherence to medication, falls, and polypharmacy. The alternative approach is aspirin, the efficacy of which is doubted unless combined with clopidogrel, although the bleeding risk when used alone is not negligible, and is considerable in combination with clopidogrel. As a result, neither physicians nor patients have been confident about anticoagulant/antithrombotic therapy, and its utilization for atrial fibrillation has been inconsistent and often inappropriate. There has been a very determined effort on the part of basic scientists, clinical researchers, and the Pharma industry to find a better anticoagulant. Two main avenues of research emerged: direct thrombin inhibitors (e.g. ximelagatran and dabigatran) and factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxaban, etc.). Ximelagatran was compared against warfarin in patients with atrial fibrillation and, although probably as effective as warfarin, it appeared to be unsafe, predominantly because of liver toxicity. Large-scale clinical trials of the factor Xa inhibitors against warfarin, and in one case (apixaban) against aspirin, are underway. The trial of dabigatran vs. warfarin has been reported at the 2009 ESC Annual Congress in Barcelona and has been published in the New England Journal of Medicine. The RE-LY study is a trial of .18 000 patients with atrial fibrillation who were randomized between warfarin or one of two doses of dabigatran etexilate (110 mg b.i.d. or 150 mg b.i.d.), a direct thrombin inhibitor which has already been proven valuable for the prophylactic treatment of venous thromboembolism. A previous pilot study in patients with atrial fibrillation had been used to define the appropriate dosing schedule. The trial population consisted of typical patients with atrial fibrillation and cardiovascular/thromboembolic risk: average age 72 years, mean CHADS score 2.1, and history of myocardial infarction (17%), stroke (20%), and heart failure (32%). Half the patients had no previous exposure to warfarin treatment. The trial design was prospective, randomized, and open, with blinded adjudication of events (PROBE). Patients were treated for an average of 2 years with practically complete follow-up. Those on warfarin were in the therapeutic range for 64% of visits. At the 2-year time point 15% of warfarin patients and 20% of those taking dabigatran had discontinued therapy, usually for adverse gastrointestinal events in all three limbs of the trial. The primary endpoint was stroke or systemic embolism, and the results were remarkable: warfarin, 198 patients (1.7% per annum); dabigatran 110 mg b.i.d., 182 patients (1.55% per annum, P 1⁄4 0.37 for superiority and P ,0.001 for non-inferiority); and dabigatran 150 mg b.i.d., 133 patients (1.11% per annum, P ,0.001 for superiority). Compared with warfarin (3.46), major bleeds were less for dabigatran 110 mg b.i.d. (2.74, P 1⁄4 0.002) but similar for 150 mg b.i.d. (3.22, P 1⁄4 0.32). Importantly, intracranial bleeds were significantly less with both doses of dabigatran than with warfarin. The