The Discrepancy between Observational Studies and Randomized Trials of Menopausal Hormone Therapy: Did Expectations Shape Experience?

2 December 2003 | Volume 139 Issue 11 | Pages 923-929

Differences between observational and randomized studies of the effects of menopausal hormone therapy (HT) on coronary heart disease (CHD) have been attributed to the fact that women who choose to use HT tend to be healthier than those who do not. Although this bias should affect all clinical outcomes with modifiable risk factors, estimates for stroke and pulmonary embolism were unaffected. The authors sought possible explanations for this isolated discrepancy in CHD findings.

Unlike the randomized Women's Health Initiative (WHI) trial, the observational Nurses' Health Study (NHS) did not try to detect silent myocardial infarctions. Many women present with atypical ischemic symptoms. Hormone therapy users who believe that HT reduces CHD risks might not interpret ischemic symptoms as related to CHD, might not seek medical attention, and might present differently to their physicians, all of which could lead to more unrecognized myocardial infarctions among HT users in the NHS. In addition, persons completing death certificates and NHS physicians interpreting death certificates were not blinded to the use of HT. If persons assigning cause of death knew the patient had used HT and believed that HT prevented CHD, they might have been more likely to assign a condition other than CHD as the cause of death. If HT users were 20% less likely to have their infarctions recognized and their deaths attributed to CHD, a true increase in CHD due to HT use would appear to be a reduction in CHD. Combining these reporting biases with socioeconomic differences between users and nonusers could explain discrepancies. Beliefs held by patients, clinicians, and investigators might have affected the ascertainment of CHD outcomes in observational studies.

Author and Article Information

From Brigham and Women's Hospital, Harvard Medical School, and Tufts-New England Medical Center, Boston, Massachusetts.

Acknowledgments: The authors thank Drs. Avrum Bluming, Robert Goldberg, Robert Greenes, Paula Johnson, Anthony Komaroff, JoAnn Manson, and Douglas Rosendale and Ms. Jennifer Fortin for their insightful comments that contributed to the development of the manuscript.

Grant Support: In part by the American Cancer Society Breast Cancer Prevention Forum, the Robert Wood Johnson Foundation Generalist Physician Faculty Scholars Award (#033958), and the Agency for Healthcare Research and Quality (RO1 HS01332901).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Nananda F. Col, MD, Department of Medicine, Division of Women's Health, Brigham and Women's Hospital-Harvard Medical School, 1620 Tremont Street, Boston, MA 02120; e-mail, ncol{at}partners.org.

Current Author Addresses: Dr. Col: Department of Medicine, Division of Women's Health, Brigham and Women's Hospital-Harvard Medical School, 1620 Tremont Street, Boston, MA 02120.

Dr. Pauker: Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111.