Interpretation of Outcomes of Antiarrhythmic Clinical Trials

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Abstract
The results of the Cardiac Arrhythmia Suppression Trials (CAST and CAST II) were a watershed in attitudes about management of cardiac arrhythmias.1 2 3 On the basis of the then-prevailing assumption that premature ventricular contractions (PVCs) in the presence of recent myocardial infarction identified a risk for life-threatening arrhythmias and that they also served as the trigger for fatal arrhythmias, it was logical to determine whether suppression of ambient arrhythmias would protect against fatal events.4 Despite the outcomes of these trials, ambient arrhythmias are still viewed as a marker of risk (perhaps somewhat lower than previously thought) and as pathophysiological triggers under proper conditions.5 However, the concept that suppression of asymptomatic PVCs is an appropriate preventive strategy has fallen under the weight of evidence from those studies.6 In addition, new concepts of proarrhythmia emerged from CAST and other sources of information.7 After CAST, a variety of trials testing therapy with other drugs and with implantable devices were implemented, some of which are now completed. The various trials differ in regard to therapeutic strategies, designs, and patient populations. With the flow of new information that has been forthcoming and is anticipated to continue during the next few years, it is important to keep the strengths and limitations of clinical trial designs in perspective and to consider the extent to which the results of any one trial or group of trials can be generalized. This review is intended to analyze general features of trial design that influence their interpretation, application, and clinical impact. It is not intended as a critique of individual trials. The factors discussed include (1) specific outcomes measures; (2) the type of controls used; (3) intention-to-treat versus on-therapy analysis; (4) comparison of therapeutic efficacy, efficiency, and equilibrium; (5) significant negative outcomes; and (6) population …