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Human Reproduction, Vol. 19, No. 1, 8-13, January 2004
© 2004 European Society of Human Reproduction and Embryology

Issues to debate on the Women’s Health Initiative (WHI) study

Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies

E. Garbe1 and S. Suissa2,3

1 Institute of Clinical Pharmacology, Charité, Humboldt-University, Berlin and Institute of Pharmacoepidemiology and Technology Assessment, Schumanstrasse 20/21, D-10117 Berlin, Germany and 2 Department of Epidemiology and Biostatistics,McGill University, Pharmacoepidemiology Research Unit, Division of Clinical Epidemiology, Royal Victoria Hospital, Montréal, Québec, Canada H3A 1A1

3 To whom correspondence should be addressed. e-mail: samy.suissa{at}clinepi.mcgill.ca

A large number of observational studies, supported by animal and basic research studies, have shown a protective effect of hormone replacement therapy (HRT) on acute coronary outcomes. The recent large randomized Women’s Health Initiative (WHI) study reported the opposite result, i.e. a small risk increase of 29% for acute coronary outcomes under estrogen–progestin treatment. Possible methodological reasons for these discrepancies are discussed. Despite randomization, the reported small increase in risk in the WHI study could be spurious because of differential unblinding of HRT users, which could have resulted in higher detection rates of otherwise clinically unrecognized acute myocardial infarction in these women. We show that altering diagnostic patterns because of unblinding could lower the crude rate ratio of 1.28 to 1.02. In the observational studies, the protective effect may have been exaggerated due to a healthy user bias and to the inappropriate choice of the reference group. Using an alternative reference group, the combined rate ratio of 0.67 was increased to 0.82. The diametrical effects of HRT on acute coronary outcomes found between the observational studies and the WHI Study may be a result not only of bias in the observational studies, but also of bias in the WHI Study.

Key words: acute myocardial infarction/detection bias/healthy user bias/observational studies/Women’s Health Initiative study


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