Investigation of age–treatment interaction in the SPACE trial using different statistical approaches

Selection of treatments to fit the specific needs for a certain patient is one major challenge in modern medicine. Personalized treatments rely on established patient–treatment interactions. In recent years, various statistical methods for the identification and estimation of interactions between relevant covariates and treatment were proposed. In this article, different available methods for detection and estimation of a covariate–treatment interaction for a time-to-event outcome, namely the standard Cox regression model assuming a linear interaction, the fractional polynomials approach for interaction, the modified outcome approach, the local partial-likelihood approach, and STEPP (Subpopulation Treatment Effect Pattern Plots) were applied to data from the SPACE trial, a randomized clinical trial comparing stent-protected angioplasty (CAS) to carotid endarterectomy (CEA) in patients with symptomatic stenosis, with the aim to analyse the interaction between age and treatment. Time from primary intervention to the first relevant event (any stroke or death) was considered as outcome parameter. The analyses suggest a qualitative interaction between patient age and treatment indicating a lower risk after treatment with CAS compared to CEA for younger patients, while for elderly patients a lower risk after CEA was observed. Differences in the statistical methods regarding the observed results, applicability, and interpretation are discussed.