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

Nananda F. Col, MD, MPP, MPH; and Stephen G. Pauker, MD
[+] Article and Author 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@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.


Ann Intern Med. 2003;139(11):923-929. doi:10.7326/0003-4819-139-11-200312020-00011
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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.

Figures

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Figure 1.
Pairwise comparison of the relative risk for various neoplastic and vascular clinical outcomes associated with menopausal hormone therapy use reported in the Nurses' Health Study (NHS) and the Women's Health Initiative (WHI) trial.
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Figure 2.
Effect of excluding silent myocardial infarction.NHSWHIMIs

The differences in nonfatal cardiac events between the observational Nurses' Health Study ( ) and the randomized Women's Health Initiative ( ) trial are shown. Unlike the WHI trial, the NHS excluded silent (unrecognized) myocardial infarctions ( ) from its definition of coronary heart disease, thereby missing all MIs that were asymptomatic or that presented with atypical symptoms not attributed to cardiac ischemia at the time.

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Figure 3.
Sensitivity analyses on the effect of misclassifying silent myocardial infarctions (MIs) and coronary heart disease (CHD) deaths on the observed relative risk for CHD.

The top panel shows the effect of excluding silent MIs on the observed relative risk for CHD, according to the percentage reduction in recognition of silent events between hormone therapy users and nonusers and the prevalence of silent events. The middle panel shows the effect of misclassifying a variable proportion of CHD deaths on the observed relative risk for CHD, according to the underlying CHD death rate, which was varied from 0.0016 to 0.006 during the 5.2-year simulation. The bottom panel shows the combined effect of excluding silent infarctions and misclassifying CHD deaths on the observed relative risk for CHD. The difference in the percentage of infarctions that are recognized according to hormone therapy use varied (assuming that 34% of infarctions are silent), as did the percentage of misclassified CHD deaths.

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Figure 4.
Three-way sensitivity analysis: combined effect of 2 reporting biases in an observational study (with and without adjustment for differences in socioeconomic status).MIsCHDsolid lineAB

Each line represents the combination of missing silent myocardial infarctions ( ) and misclassified coronary heart disease ( ) deaths needed to produce a reported event rate equivalent to the rate observed in the observational Nurses' Health Study (relative risk, 0.6), given that the actual event rates correspond to those in the randomized Women's Health Initiative trial. The solid line does not adjust for differences in socioeconomic status, while the dotted line does. At the extremes, without adjustment for socioeconomic status ( ), if the percentage reduction in recognition of silent MIs according to hormone therapy use were 50%, 63% of CHD deaths have to be misclassified to bring the relative risk to 0.6 ( ). On the other hand, if the percentage reduction in recognition of silent MIs were 20%, every CHD death (100%) would need to be misclassified ( ). Combinations of missed and misclassified events falling above a line in the Nurses' Health Study would have an observed risk below 0.6; combinations falling below a line would have a risk more than 0.6.

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