Sample size estimation for recurrent event data using multifrailty and multilevel survival models.

In epidemiology and clinical research, recurrent events refer to individuals who are likely to experience transient clinical events repeatedly over an observation period. Examples include hospitalizations in patients with heart failure, fractures in osteoporosis studies and the occurrence of new lesions in oncology. We provided an in-depth analysis of the sample size required for the analysis of recurrent time-to-event data using multifrailty or multilevel survival models. We covered the topic from the simple shared frailty model to models with hierarchical or joint frailties. We relied on a Wald-type test statistic to estimate the sample size assuming either a single or multiple endpoints. Simulations revealed that the sample size increased as heterogeneity increased. We also observed that it was more attractive to include more patients and reduce the duration of follow-up than to include fewer patients and increase the duration of follow-up to obtain the number of events required. Each model investigated can address the question of the number of subjects for recurrent events. However, depending on the research question, one model will be more suitable than another. We illustrated our methodology with the AFFIRM-AHF trial investigating the effect of intravenous ferric carboxymaltose in patients hospitalised for acute heart failure.