Interpretation of subgroup analyses in randomized trials: heterogeneity versus secondary interventions

In randomized trials with subgroup analyses, the primary treatment or intervention of interest is randomized, but the secondary factors defining subgroups are not. This article clarifies when confounding is an issue in subgroup analyses. If investigators are interested simply in targeting subpopulations for intervention, control for confounding is not needed. If investigators are interested in intervening on the secondary factors that define the subgroups to increase the treatment effect or in attributing the subgroup differences to the secondary factors themselves, then confounding is relevant and must be controlled for. The authors demonstrate this point by using examples from published randomized trials.