Challenges of establishing new antithrombotic therapies in atrial fibrillation.

Warfarin is the single most effective treatment to prevent stroke in patients with atrial fibrillation (AF) in that it reduces the risk by about two thirds compared with placebo.1 Despite its effectiveness, however, warfarin is difficult to use and its uptake into clinical practice has been constrained.2 Warfarin has a slow onset and offset of action, it exhibits considerable variability in dose response among individuals, it is subject to multiple food and drug interactions, it has a narrow therapeutic window, and considerable risk of hemorrhage exists. The slow offset of action of warfarin can be beneficial if a patient misses a dose but complicates temporary discontinuation of warfarin for surgery. Thus, warfarin requires careful laboratory monitoring and dose adjustment to maintain the international normalized ratio (INR) in the target therapeutic range. Even with careful laboratory monitoring, major bleeding occurs in 1% to 3% of AF patients on warfarin per year. Consequently, many clinicians and patients are reluctant to use warfarin. Some patients have contraindications to anticoagulation, but others choose not to use it.2 Such patients typically use aspirin. Educational and support programs have been shown to improve knowledge of disease and treatment, INR control, and physician management of AF.3–5 Nonetheless, there have been intensive efforts to find a replacement for warfarin. Several new drugs with the potential to overcome the limitations of warfarin have been evaluated in randomized trials but appeared to be less effective or less safe than warfarin. The experience from these trials has highlighted the methodological challenges of finding a replacement for warfarin, which include a number of difficulties in design and in interpretation of results from noninferiority trials, the widespread use of warfarin in the community, availability of warfarin-naïve patients, and low event rates on warfarin. The present article will review the results of recent phase III randomized trials that evaluated new antithrombotic agents in AF, and it will focus on the methodological challenges in the evaluation of a new antithrombotic therapy.