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

ABSTRACT

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.

KEYWORDS:

• Covariate–treatment interaction
• predictive covariate
• non-linear interaction
• individualized medicine
• qualitative interaction

Data availability statement

The R code used for data analysis is provided as electronic supplementary material. The file includes code for random generation of data with properties similar to the SPACE data used in the manuscript, in order to test application of the presented methods.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Funding for conduction of the SPACE trial was provided by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) (01GI9918), the German Research Foundation (Deutsche Forschungsgemeinschaft; HA 1394/4-2 and 1397/4-3), the German Society of Neurology, German Society of Neuroradiology, German Radiological Society, Boston Scientific, Guidant, and Sanofi-Aventis.