Statistical models for composite endpoints of death and non-fatal events: a review.

The proper analysis of composite endpoints consisting of both death and non-fatal events is an intriguing and sometimes contentious topic. The current practice of analyzing time to the first event often draws criticisms for ignoring the unequal importance between component events and for leaving recurrent-event data unused. Novel methods that address these limitations have recently been proposed. To compare the novel versus traditional approaches, we review three typical models for composite endpoints based on time to the first event, composite event process, and pairwise hierarchical comparisons. The pros and cons of these models are discussed with reference to the relevant regulatory guidelines, such as the recently released ICH-E9(R1) Addendum "Estimands and Sensitivity Analysis in Clinical Trials". We also discuss the impact of censoring when the model assumptions are violated and explore sensitivity analysis strategies. Simulation studies are conducted to assess the performance of the reviewed methods under different settings. As demonstration, we use publicly available R-packages to analyze real data from a major cardiovascular trial.