Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned

Abstract

Background: The Heart and Estrogen/Progestin Replacement Study (HERS) showed no overall benefit of postmenopausal hormone treatment in women with coronary heart disease (CHD). We analyzed the HERS data to determine whether there were specific subgroups of women who responded differently to treatment, either during the first year or in the overall study.

Methods and results: In the search for significant treatment interactions, we analyzed a total of 86 subgroups defined by baseline characteristics. These included demographics and lifestyle factors, laboratory and physical examination variables, medical history and symptoms by self-report, medication use, and prior CHD history by chart review. We examined within-subgroup treatment effects for baseline variables that significantly interacted with treatment assignment. Under the null hypothesis, 4 (5%) of the 86 interactions would be expected to be nominally significant (P<0.05) by chance alone at each time point. Six of the interaction values were P<0.05 at 1 year, and 3 were P<0.05 at trial completion. The findings are discussed in the context of known mechanisms of action and prior scientific knowledge. Use of digitalis and history of myocardial infarction emerged as 2 possible modifiers of the effect of hormone therapy during the first year, and lipoprotein(a) emerged as a possible modifier during the overall study.

Conclusions: Extensive post hoc analyses did not identify any subgroup of HERS participants in which postmenopausal hormone treatment was clearly beneficial or harmful, but several possibilities emerged for testing in future trials.