Speaker
Description
Introduction:
In clinical trials time to event endpoints like time to death, time to hospitalization or time to myocardial infarction are often or primary interest. Although multiple events might be observed per individual, only the time to the first occurring event is considered in primary analysis. One reason for this could be that guidelines recommend analyzing the data using the same method that was used to calculate the sample size. In most cases, sample size calculation in time to event settings is based on methods where only the time to first event is considered. However, there can be a gain in power if all events that might occur per patient are analyzed. Hence, sample size calculation for multiple time to events are of interest. The associated methods may not be as familiar to applied researchers. We therefore aim to give an overview of methods that were described in the literature for planning a study where multiple event times are of interest. Advantages and disadvantages of the methods are described. We further aim to illustrate the method using data from a cardiovascular trial.
Methods:
We started a first literature search in PubMed, Embase, the Cochrane Library, and Google Scholar with the following search terms: “multiple events”, “sample size calculation”, “recurrent events”, “composite endpoints”, “power calculation”, and “multiple time-to-event”.
Results:
So far 29 publications were screened and 11 selected for further review. Different approaches are described: methods for recurrent events using time to event approaches (e.g. Andersen-Gill model) or event counts (e.g. negative binomial model), approaches using additive models or frailty models, and methods for the win ratio. Furthermore, approaches that consider adaptive designs are also described. Some of the methods found involve quite complex formulas which are not easy to implement. Advantages and disadvantages depend on the primary research aim.
Discussion:
Planning a clinical trial with multiple time to event endpoints can be difficult. Therefore, we try to give a comprehensive overview of methods that were described in the literature for planning such studies. Since quite different approaches were found that can also lead to different sample sizes, the researcher should be very clear about his/her primary study aim to select the appropriate method for e.g. sample size calculation.
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