American Journal of Epidemiology, kwaa033, https://doi.org/10.1093/aje/kwaa033
Dual outcome intention-to-treat hazard rate analyses have potential to complement single outcome analyses for the evaluation of treatments or exposures in relation to multivariate time-to-response outcomes. Here we consider pairs formed from important clinical outcomes for further insight into menopausal hormone therapy influences on chronic disease. The Women’s Health Initiative randomized, placebo controlled, hormone therapy trials (1993 to present, at 40 U.S. clinical centers) of conjugated equine estrogens (CEE) among post-hysterectomy participants, and of these same estrogens plus medroxyprogesterone acetate (CEE+MPA) among participants with uterus, provides the context for analyses over the trial intervention periods, and over a nearly 20-year (median) cumulative follow-up. The rates of multiple outcome pairs were significantly influenced by hormone therapy, especially over cumulative follow-up, providing potential clinical and mechanistic insights. For example, hazard ratios for pairs defined by fracture during intervention followed by death from any cause were reduced, and by gallbladder disease followed by death were increased, among women randomized to either regimen, though these may primarily reflect single outcome associations. In comparison, hazard ratios for diabetes followed by death were reduced with CEE but not with CEE+MPA, and for hypertension followed by death were increased with CEE+MPA but not with CEE.