Response to Letter Regarding Article, “Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation”
We would like to thank Drs Ezekowitz and Nagarakanti for their interesting letter on the advisability and ethics of a superiority trial of a new antithrombotic agent against aspirin in patients with atrial fibrillation at high risk for stroke. They point out the substantial and convincing evidence that warfarin is superior to aspirin at preventing strokes in atrial fibrillation. We agree that, for patients who are willing and able to take warfarin, it is a superior therapy. In these patients, a superiority trial of a new anticoagulant versus aspirin would indeed be unethical. There exists, however, a substantial population of patients who do not receive a vitamin K antagonist both in the United States and beyond. Recent surveys suggest that 40% to 50% of patients with atrial fibrillation do not receive one.1–5 Some of these patients have contraindications for any anticoagulant, and they would be ineligible for a trial of a new anticoagulant versus aspirin. Many others, however, do not receive anticoagulation because of the specific problems of using a vitamin K antagonist and the attendant need for careful, thorough, and ongoing monitoring of the international normalized ratio.
An unmet clinical need exists for an easy-to-use and effective anticoagulant for these patients, and a superiority trial against aspirin is both appropriate and ethical in this group. In addition, it is noteworthy that recent changes to treatment guidelines propose a different approach to patients at moderate risk for stroke, recommending either warfarin or aspirin for most patients who have a CHADS2 score of 1.6 In many of these patients, physicians are choosing aspirin, which, as Ezekowitz and Nagarakanti point out, is only moderately effective. It is likely that a new easy-to-use anticoagulant could be superior to aspirin. These patients are also eligible, therefore, for a superiority trial of a new anticoagulant against aspirin.
We believe that it is important to address the needs of patients who cannot take vitamin K antagonists and patients at moderate risk who may be receiving aspirin on the basis of current guideline recommendations. Several new classes of oral anticoagulant agents are being developed, and some of them may be more effective, safer, and easier to use than warfarin. Noninferiority trials often require very large numbers of patients (eg, 15 000 to 20 000) and are plagued by fundamental uncertainties in interpretation of their results. Therefore, the conduct of superiority trials when feasible is a practical way of reliably assessing the benefits and risks of new agents. Compared with noninferiority trials, this approach will more efficiently and reliably help to address the unmet clinical need for an effective, safe, and simple oral anticoagulant that will help a substantial number of patients with atrial fibrillation.
Drs Connolly and Yusuf have received research grant support from Sanofi Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim for management of the ACTIVE and RELY trials, and both have given lectures and performed other consulting tasks for these companies. Dr Yusuf has served as a consultant/advisory board member for GlaxoSmithKline. The other authors report no conflicts.
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