While-alive regression analysis of composite survival endpoints

Composite endpoints, which combine two or more distinct outcomes, are frequently used in clinical trials to enhance the event rate and improve the statistical power. In the recent literature, the while-alive cumulative frequency measure offers a strong alternative to define composite survival outcomes, by relating the average event rate to the survival time. Although non-parametric methods have been proposed for two-sample comparisons between cumulative frequency measures in clinical trials, limited attention has been given to regression methods that directly address time-varying effects in while-alive measures for composite survival outcomes. Motivated by an individually randomized trial (HF-ACTION) and a cluster randomized trial (STRIDE), we address this gap by developing a regression framework for while-alive measures for composite survival outcomes that include a terminal component event. Our regression approach uses splines to model time-varying association between covariates and a while-alive loss rate of all component events, and can be applied to both independent and clustered data. We derive the asymptotic properties of the regression estimator in each setting and evaluate its performance through simulations. Finally, we apply our regression method to analyze data from the HF-ACTION individually randomized trial and the STRIDE cluster randomized trial. The proposed methods are implemented in the WAreg R package.