Statistics in Biosciences

, Volume 5, Issue 2, pp 361–368 | Cite as

Menopausal Hormone Therapy and Coronary Heart Disease: Reconciling Divergent Findings from Observational Studies and Clinical Trials

  • Jacques E. RossouwEmail author


Randomized clinical trials of menopausal hormone therapy have shown increased risks of coronary heart disease in the first few years after randomization, and neutral or increased risk over the full trial period. These results diverge substantially from the protective associations of menopausal hormone use with coronary heart disease found in observational studies. In common with many other studies, conventional analyses in the Women’s Health Initiative Observational Study cohort of estrogen plus progestin users showed an association with reduced risk of coronary heart disease even after adjustment for potential confounders. However, upon allowing risk to vary by time since initiation, the hazard ratios did not differ significantly from those observed in the clinical trial. In analyses combining clinical trial and observational data the hazard ratios were 1.58 (1.12, 2.24) within the first 2 years after initiation, 1.19 (0.87, 1.63) between 2 and 5 years, and 0.63 (0.59, 1.26) after 5 years. Similar analyses for estrogen alone also reconciled trial and observational data. These findings were confirmed in novel re-analyses of the Nurses’ Health Study when investigators for the first time included outcomes occurring in the interval between the biennial study cycles. The key towards understanding the underestimation of coronary heart disease in observational studies of menopausal hormone therapy appears to lie in the time-dependent nature of coronary heart disease risk rather than differences in study populations. Observational studies typically do not capture early events in current users and the data mostly reflect the experience of long-term users who have survived the early risk, while clinical trials by design capture early events very efficiently and mainly reflect short-term use.


Menopausal hormone therapy Estrogen Progestogen Coronary heart disease Epidemiology Clinical trials 


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.National Heart, Lung, and Blood InstituteBethesdaUSA

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