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KHANDEKAR et al. presented a retrospective analysis of hydroxocobalamin use in cardiac surgical patients. 1 The authors theorized that intraoperative administration of the drug might be more effective because nitric oxide-mediated vasoplegia is possibly more intense during and shortly after bypass. The authors’ question was in the category of treatment effect heterogeneity, that is, the extent to which responses differ across a study population. In this case, the subgroups of interest were patients given hydroxocobalamin intraoperatively versus postoperatively. A related question is whether there were definable subgroups that do and do not respond to hydroxocobalamin.

Treatment-effect heterogeneity is an underappreciated aspect of study interpretation. Consider, for example, a robust, well-conducted trial that demonstrates clinically meaningful benefits from a particular intervention. Technically, the results apply to …