Commentary: Observation versus intervention—what's different?

Elizabeth Barrett-Connor

Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, La Jolla, CA 92093–0607, USA. E-mail: ebarrettconnor{at}ucsd.edu

Women have coronary heart disease (CHD) later than men in every country.1 This universal sex difference has been attributed to a cardioprotective effect of premenopausal oestrogen levels. Many other lines of evidence including laboratory studies support this thesis. Belief in the preventive power of endogenous oestrogen was transformed to action mainly by meta-analyses of epidemiological studies of ‘oestrogen replacement therapy’ and heart disease.

Meta-analyses pool data from separate studies weighted for sample size, thereby increasing the total number of events, increasing power, and potentially providing statistically significant results (and narrow CI) not observed in individual studies. One of the first meta-analyses of hormone therapy and CHD is the 1991 paper by Stampfer and Colditz2 reproduced here. The authors reported an overall relative risk (RR) of 0.56 (95% CI: 0.50, 0.61) based on pooled data from all 31 publications reviewed, and an RR of 0.50 (95% CI: 0.43, 0.56) based on pooled data from 13 prospective cohort studies and 3 cross-sectional angiographic studies. They concluded that these results were ‘unlikely to be explained by confounding factors.’ Other than the authors, few noted that the results for individual studies were inconsistent (test for heterogeneity P <0.001), and that more than half of the associations were not statistically significant. The Nurses Health Study,3 being the largest study, carried considerable weight in this and subsequent meta-analyses.

The promotion of hormone therapy for the prevention of heart disease for nearly all postmenopausal women came from a meta-analysis suggesting that the expected CHD risk reduction exceeded any expected increased risk for cancer.4 Within 10 years many leading US medical organizations had endorsed the concept that all postmenopausal women should be offered hormone therapy to prevent heart disease.

By 2002, however, publications from two large, randomized, placebo-controlled clinical trials5,6 and several smaller trials7 failed to show a reduced risk of CHD in women assigned to oral oestrogen therapy, and some suggested an early excess risk.

Can we explain such diametrically opposed results? This could happen if trial participants differ in important ways from the populations in observational studies, or if the trial treatment differs from the regimen(s) found to be useful in observational studies.


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Age
One popular thesis is that the women in the trials were too old. Many of the epidemiological studies reviewed by Stampfer and Colditz included relatively young postmenopausal women; in the Nurse's Health Study, by far the largest prospective study in their meta-analysis, postmenopausal women 30–55 years of age taking oestrogen at baseline had a 70% reduction in the relative risk of CHD (RR = 0.30).3

Women in the two large clinical trials were older, with an average age of 67 (Heart and Estrogen/progestin Replacement Study, HERS) or 64 (Women's Health Initiative, WHI) years. Nevertheless, the RR of CHD in the more than 5000 WHI women who were aged 50–60 years at baseline did not differ significantly from the RR observed in the older WHI women.8 Although it is possible that oestrogen is no longer cardioprotective once atherosclerotic plaque is in place, in studies using electron beam computed tomography, many women aged 50–65 have no significant plaque burden based on coronary artery calcification.9

Health
Participants in clinical outcome trials are often healthier than the general population, because they must be well enough to participate, and must not be expected to die of another condition during the trial period. This limited generalizability is also true to some degree for epidemiological studies; for example the 40% who refused an invitation to join the original Framingham Study were more likely to smoke cigarettes and more likely to die within a few years than those who agreed to participate.

In the era of the older observational studies reviewed by Stampfer and Colditz, the most common reason to initiate hormone treatment was to relieve menopause symptoms. Women with severe menopause symptoms are usually excluded from clinical trials to reduce unblinding and dropouts. There is no evidence that women who are highly symptomatic have the lowest oestrogen levels, and are therefore most in need of hormone replacement for cardioprotection. Stratified analyses in the WHI failed to show any difference in CHD risk by vasomotor symptoms in women aged 50–59 assigned to placebo versus oestrogen plus progestogen.8

Women who have a hysterectomy before their menopause tend to have more severe menopause symptoms than intact women. The cardiovascular effects of unopposed oestrogen treatment for women who have had a hysterectomy, not yet reported from WHI, will be of interest.

Stampfer and Colditz do an excellent job of critiquing the studies they review in their meta-analysis. They consider the potential effect of common and obscure biases. Similarly, many subgroups, defined by baseline disease or risk factor status, have been examined in clinical trials. HERS, which examined more than 170 subgroups,7,10 and WHI, which examined more than 30 subgroups,8 found few interactions, and none seem likely to explain the absent cardiovascular benefit in these clinical trials.

Socioeconomic status
Curiously absent from the Stampfer and Colditz discussion of their meta-analysis is the potential impact of education and occupation on the hormone therapy-cardiovascular risk data they reviewed, although lower social class is a strong determinant of CHD risk. In the Lipid Research Clinics Prevalence Study, for example, women with a college education had half the risk of CHD compared with women with less education (T Bush, personal communication). Most of the epidemiological studies were conducted in the US, which has no universal health care, and where women with less education and/or income less often seek medication. In the influential Nurse's Health Study,3 it was inferred that social class was similar because all women were nurses, yet women's social class is often determined by the presence of a husband and his occupation. In a recent meta-analysis by Humphrey and colleagues,11 pooled data from the five observational studies of CHD incidence that adjusted for socioeconomic status showed no protective effect of hormone therapy.


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The advantage of the properly done clinical trial is that randomization controls for known and unknown heart disease risk factors permit an estimate of risk free of the health-related biases including measured and unmeasured consequences of socioeconomic status. But randomization does not ensure that the optimal treatment was tested.

The oestrogen
Specific oestrogens were not described in most papers reviewed by Stampfer and Colditz, but are presumed to be mainly oral conjugated equine oestrogen, the most commonly prescribed postmenopausal oestrogen where and when the majority of observational studies were conducted. This was the basis for selecting this oestrogen for the HERS and WHI trials. Conjugated equine oestrogen is not the most popular regimen in most of Europe, however, and the European Menopause Society has made a strong plea that other oestrogens, particularly oral and transdermal oestradiol, be studied for prevention of CHD (H Rosenblum, personal communication, European Menopause Society Consensus Jury Guidelines). Some of the small trials7 have studied other oestrogens, however, including oral and transdermal oestradiol, without showing cardiovascular benefit.

The progestogen
Some propose that the failure to show cardioprotection in HERS and WHI was due to the progestogen, concordant with results from the non-human primate model.12 Most of the women included in the prospective observational studies reviewed by Stampfer and Colditz probably used oestrogen without a progestogen. Although only a few observational studies have reported the risk of CHD associated with the use of oestrogen plus a progestogen, these studies showed a similar cardioprotective effect to that observed with unopposed oestrogen.13 Medroxyprogesteone was the most commonly used progestogen in these studies, and was chosen as the progestogen for HERS and WHI.

The regimen chosen for HERS and WHI differed in one potentially significant way from the usual combined hormone regimen in observational studies. Previously medroxyprogeserone was prescribed to women with a uterus in a dose of 10 mg/day taken for 10–12 days each month, a regimen designed to prevent endometrial hyperplasia. This cyclic regimen was not chosen for HERS or WHI because the attendant monthly bleeding would have eliminated the double blind, and could have led to selective dropout as well. There are no published epidemiological data on the association of continuous combined conjugated equine oestrogen and 2.5 mg of daily medroxyprogesterone acetate with CHD, and it could be argued that the different or uninterrupted dose of progestogen explains the discordance between the observational studies and the clinical trials. It can also be postulated that another progestogen, or progesterone itself, would have allowed oestrogen to be cardioprotective.

Speculation on the appropriate oestrogen and progestogen will continue, but it seems unlikely that other oestrogens with or without other progestogens, or other doses or routes of delivery, would be better than statins for the prevention of heart disease. Statins, unlike oestrogen, have been shown in clinical trials to reduce the risk of heart disease in women.14 At present, we can use the HERS and WHI clinical trial data to advise our patients who have bothersome menopause symptoms that the treatment regimen chosen for HERS and WHI carries a small increased risk and even smaller benefits. Other untested treatments may provide a better or worse outcome.


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1 Kalin MF, Zumof B. Sex hormones and coronary disease: a review of the clinical studies. Steroids 1990;55:330–52.[CrossRef][ISI][Medline]

2 Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47–63. (Reprinted Int J Epidemiol 2004;33:445–53.)[ISI][Medline]

3 Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044–49.[Abstract]

4 Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37.[ISI][Medline]

5 Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.[Abstract/Free Full Text]

6 Rossouw JE, Anderson GL, Prentice RL et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.[Abstract/Free Full Text]

7 Barrett-Connor E. Clinical Review 162 Cardiovascular Endocrinology 3. An epidemiologist looks at hormones and heart disease in women. J Clin Endocrionol Metab 2003;88:4031–42.[Free Full Text]

8 Manson JE, Hsia J, Johnson KC et al. Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–34.[Abstract/Free Full Text]

9 Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr. Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol 1993;72:247–54.[ISI][Medline]

10 Furberg CD, Vittinghoff E, Davidson M et al. Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned. Circulation 2002;105:917–22.[Abstract/Free Full Text]

11 Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137:273–84.[Abstract/Free Full Text]

12 Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 2002;53:605–19.[CrossRef][ISI][Medline]

13 Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55–72.[CrossRef][ISI][Medline]

14 LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999;282:2340–46.[Abstract/Free Full Text]