Elsevier

Atherosclerosis

Volume 207, Issue 2, December 2009, Pages 336-340
Atherosclerosis

Review
Coronary heart disease and menopause management: The swinging pendulum of HRT

https://doi.org/10.1016/j.atherosclerosis.2009.05.033Get rights and content

Abstract

The Women's Health Initiative comprised a randomized placebo-controlled clinical trial of therapeutic and dietary interventions influencing postmenopausal women's health. One arm evaluated hormone replacement therapy and its effects on major health outcomes. Initial publication of the preliminary results suggested overall harm from hormone replacement therapy, leading to a dramatic worldwide decrease in its use, and concerns from clinicians and regulatory authorities. Subsequent publications with more detailed analyses appear to have countermanded these initial concerns. Analyses of the studies have not been adherent to those specified in the original published protocol. Nominal confidence intervals should have been used only for the primary outcome, which was coronary heart disease. Initially reported as showing a significant increase in events with hormone replacement therapy, in a subsequent analysis of the full data the increase was no longer significant. Adjusted confidence intervals showed no significant increase for breast cancer, the primary adverse outcome. A major difference in the effects of hormones between younger and older women has emerged but this important finding has been minimized. For women under age 60 years or within 10 years of menopause, the final findings for all outcomes closely resemble those from observational cohorts. The raw data must be made available for independent assessment to obtain valid conclusions which may again change clinical practice.

Introduction

Although clinical medicine tends to be an evolving process, one field in which there has been a dramatic change in prescribing patterns is the treatment of the postmenopausal woman. In the past 5 years, so much confusion and fear about hormone replacement therapy has emerged that patients and physicians have abandoned hormone replacement therapy or avoided this option, even in the most symptomatic healthy women at the onset of menopause [1]. Yet societies representing various medical groups are agreed that treatment of healthy women at the onset of menopause is appropriate [2], [3]. Why has there been so much confusion? We herewith provide an historical perspective regarding the reporting of the results of the Women's Health Initiative studies, and offer evidence that in the final analysis, the “final” results of the Women's Health Initiative are not different from data from the many observational studies that were available prior to Women's Health Initiative.

Section snippets

Women's Health Initiative trial designs

The Women's Health Initiative consisted of both a clinical trial and an observational study. The clinical trial consisted of three parts, hormone replacement therapy (estrogen and estrogen plus progestin arms comprising women randomized to active treatment or placebo), calcium and vitamin D supplementation, and low fat dietary modification. The Women's Health Initiative clinical trial was designed in 1991–1992 [4]. The results of the observational studies of the Women's Health Initiative, which

Coronary heart disease

The National Institutes of Health reported that “the adverse effects of estrogen plus progestin applied to all women irrespective of age, ethnicity, or prior disease state” [7]. They reported a statistically significant increase in heart attacks both in their press release and in the initial publication (Table 1) [4], [7]. This publication reported no trend with time and no noteworthy interaction with age on the coronary heart disease effects of hormone replacement therapy [4]. It was not

Breast cancer

In the initial report from the Women's Health Initiative estrogen plus progestin arm in 2002, breast cancers were confirmed by pathology reports “when available” and at the time of the initial publication at least 98% were available [4]. The incidence of breast cancer was initially reported as being statistically increased in the nominal but not the adjusted statistic (Table 3) [4]. In June 2003, the Women's Health Initiative presented the “centrally adjudicated” breast cancer data from the

Other clinical outcomes

Interestingly, in the Women's Health Initiative publication on gynecological cancers from the estrogen plus progestin arm, the authors concluded that estrogen plus progestin may increase the risk of ovarian cancer, yet they describe the endometrial cancer rates as similar to placebo, not as possibly decreased [24]. The differences between groups for both ovarian and endometrial cancer were not statistically significant [24].

The combined data on stroke showed an overall increase with hormones

Conclusions

In conclusion, the initial publication of the Women's Health Initiative hormone trial results has had a major impact on the management of postmenopausal women. Hormone replacement therapy has been vilified, both by prescribers and by regulatory authorities who appear to have accepted these results without question. Subsequent publications from the Women's Health Initiative with more complete results and analyses have cast doubt on the initial interpretation of the data. One of the most striking

Conflicts of interest

JCS has received research grants from Eli Lilly, Janssen-Cilag, Novo Nordisk, Organon, Schering, Shire, Solvay, Wyeth and the UK Medical Research Council, and has served on Advisory Boards and/or received honoraria for lectures from AstraZeneca, Bayer-Schering, Novo Nordisk, Orion, Proctor & Gamble, Servier, Solvay, Theramex and Wyeth. HNH is the Principal Investigator of the Early versus Late Intervention Trial with Estradiol (ELITE) funded by the NIH, R01AG-024154, and has served in the past

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