Principal stratification analysis of noncompliance with time-to-event outcomes.

ABSTRACT

Post-randomization events, also known as intercurrent events, such as treatment noncompliance and censoring due to a terminal event, are common in clinical trials. Principal stratification is a framework for causal inference in the presence of intercurrent events. The existing literature on principal stratification lacks generally applicable and accessible methods for time-to-event outcomes. In this paper, we focus on the noncompliance setting. We specify 2 causal estimands for time-to-event outcomes in principal stratification and provide a nonparametric identification formula. For estimation, we adopt the latent mixture modeling approach and illustrate the general strategy with a mixture of Bayesian parametric Weibull-Cox proportional hazards model for the outcome. We utilize the Stan programming language to obtain automatic posterior sampling of the model parameters. We provide analytical forms of the causal estimands as functions of the model parameters and an alternative numerical method when analytical forms are not available. We apply the proposed method to the ADAPTABLE (Aspirin Dosing A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial to evaluate the causal effect of taking 81 versus 325 mg aspirin on the risk of major adverse cardiovascular events. We develop the corresponding R package PStrata.