Forbidden Fruit: On the Analysis of Recurrent Events in Randomized Clinical Trials

The conventional analysis of a typical clinical trial focuses on the time to occurrence of the first among a composite set of alternative events such as death or nonfatal myocardial infarction. Subsequent recurrent events are thereby excluded from consideration to ensure that all the observations were mutually exclusive of each other. Thus, not all events occurring during follow-up will be analyzed. Consequently, some investigators are now reporting additional analyses of previously published trials based on a naive comparison of the total number of events—first events plus recurrent events—and are recommending that these additional analyses be routinely conducted in future trials. We have summarized the potential limitations of this proposal and suggest other methods to analyze recurrent events, with a particular focus on kinetic modeling. The application of this approach to several previously published trials illustrates its facility to help elucidate the causal mechanisms underlying empirical demonstrations of safety and efficacy.