Commentary: Hormones and heart disease: do trials and observational studies address different questions?

Meir Stampfer

Harvard School of Public Health, Department of Epidemiology, 677 Huntington Avenue, Kresge 904, Boston, MA 02115. USA. E-mail: mstampfe{at}hsph.harvard.edu

By 1990, the number of epidemiological studies of postmenopausal hormone use and coronary heart disease (CHD) was sufficient to justify a quantitative assessment of the evidence. Divergent views of the potential effect of postmenopausal hormones on cardiovascular risk were common. On the one hand, the observation that premenopausal women had substantially lower risk for cardiovascular disease led many to suspect that oestrogens might be protective. On the other hand, the experience of higher risk for cardiovascular disease (though not coronary atherosclerosis) with the early oral contraceptive agents, combined with the adverse experience of oestrogen in men in the Coronary Drug Project, led many to believe that it was harmful. The drug labelling for postmenopausal hormones carried warnings of risk for an increase in cardiovascular disease.

Observational data from epidemiological studies were remarkably consistent in showing that postmenopausal hormone users tended to be at lower cardiovascular disease risk than non-users. The epidemiological studies summarized in the review at the time were augmented by additional observational studies that followed.1 In the review, we recognized the possibility that this association might not represent cause and effect but could perhaps be due to confounding or biased ascertainment of endpoints. However, the latter explanation seemed implausible. Since women taking hormones were under closer medical scrutiny, it seemed likely that borderline cases would be more rather than less likely to be diagnosed. The potential for confounding seemed more plausible because oestrogen users tended to be healthier (i.e. at lower cardiovascular risk) in several studies. However, this was not universally true, and depended on the population under study. Moreover, adjustment for a wide array of known confounders had only a modest impact on the relative risk estimates, suggesting that residual confounding would have to be quite substantial to account for the remaining association.

The studies included in this review, along with other data from a variety of sources, provided some of the impetus for the Women's Health Study Initiative trial of postmenopausal hormones.

Presumably, this review was chosen for retrospective scrutiny and reflection because of the apparent differences in the results of the Women's Health Initiative (WHI) Trial2 and the observational studies of postmenopausal hormones and CHD. A variety of explanations for these apparent differences have been offered many of which we considered in the review. The most speculative suggestion (which we did not consider in the review) was suggested by Col and Pauker;3 without providing any evidence, they hypothesize that misdiagnosis of CHD endpoints in a biased manner led to an apparent protective effect of hormone therapy. According to this scenario, silent infarctions would be preferentially diagnosed among non-users of oestrogen, and epidemiological investigators would systematically code CHD less often among oestrogen users because of the expectation that it would be protective. Such an explanation defies logic. Only 3% of non-fatal infarctions in the WHI were silent infarctions so even systematic misdiagnosis in observational studies could not have yielded findings of the magnitude observed. Moreover, the expectation of lower risk among oestrogen users followed rather than preceded the results of the observational studies. At the time most of those studies were conducted, that expectation was absent. Moreover, most of the epidemiological studies had strict criteria for endpoints such that systematic miscoding, of the magnitude required, would be virtually impossible.

Another unlikely explanation is that the differences are due to confounding by socio-economic status between hormone users and non-users.4 This suggestion ignores the findings from studies that did adjust for differences in socio-economic status. Typically, such adjustment had little impact.5 Moreover, several of the influential observational studies were conducted in relatively homogeneous strata of socio-economic status or employment category, such as the Leisure World Study and the Nurses' Health Study.

As mentioned above, the possibility for confounding by known or suspected coronary risk factors was discussed at some length in the review. At that time, we concluded that, although in general, hormone users tended to be healthier, the differences were insufficient to explain the magnitude of the reduction in subsequent disease incidence for hormone users. Specifically, adjustment for numerous coronary risk factors in observational studies resulted in only modest changes in the point estimates for the relative risk. Some have argued that subtle differences, such as willingness to take medication, would define a particularly healthy subgroup. While the possibility of such confounding cannot be ruled out, such logic would suggest that compliance to any medication would identify a group at low risk for heart disease. However, the observational studies that found lower risk for hormone use did not uniformly find low risk for all manner of medications.

A second line of evidence also suggests that confounding factors are unlikely to provide the whole explanation for findings from observational studies compared with trials. Observational studies actually have found results virtually identical to the WHI trial for all other endpoints. For example, when the Nurses' Health Study and other observational studies reported a lower risk for colon cancer among oestrogen users,6 the findings were greeted with intense skepticism and disbelief. However, a protective effect was confirmed in the WHI, and the relative risk estimates were nearly identical. More important, the Nurses' Health Study reported an increase in risk of stroke7 of almost identical magnitude as later observed in the trial. Stroke shares many risk factors with CHD and is also closely linked with a variety of socio-economic status indicators. Hence, if confounding were present to the extent that would explain the apparent divergence for CHD, how could one account for the consistent relative risk estimates for stroke?

These observations, and other data, suggest an alternative explanation for the different results. Specifically, the observational studies reflected common clinical practice whereby women were typically initiated on postmenopausal hormones at the time of menopausal symptoms. Thus, the vast majority of hormone use began at a relatively young age, close to the time of menopause. In contrast, two-thirds of the participants in the WHI began the trial at age ≥60. Do the differences in age matter? Experimental data suggests that they do.8 Monkeys randomized to postmenopausal hormones at the time of oophorectomy had substantially reduced coronary atherosclerosis compared with those given placebo. In contrast, however, when hormone use was begun 2 years after surgical menopause (equivalent to about 6 human years) no such protection was observed.9 In a rabbit model, oestrogens had either a beneficial or adverse effect depending on the state of the arteries. Animals with healthy arteries showed a protective effect of oestrogen, but in those with damaged arteries, the effect was adverse.10 Data in humans support these differences. The effect of oestrogen on acetylcholine-induced vasodilatation differs markedly according to the presence or absence of coronary atherosclerosis.11 Randomized trials of women with CHD did not show any benefit of oestrogen (indeed, they tended to show harm), but a trial in younger postmenopausal women demonstrated a reduction in progression of atherosclerosis in the treated group compared with those given placebo.11 Thus, perhaps the differing results from the observational studies and the WHI trial may be attributed to the differences in populations. The results of the WHI trial themselves support such an explanation. The WHI found a trend toward lower risk with decreasing time since menopause; among women <10 years since menopause (65 total cases), the relative risk of CHD with hormone therapy versus placebo was 0.89 (95% CI: 0.55, 1.46); for 10–19 years since menopause, it was 1.22, and for 20+ years, 1.71.1 This trend is statistically significant (P = 0.036).

An important limitation of most observational studies was the inability to capture possible acute effects of postmenopausal hormones.7 The increase in CHD events in WHI was concentrated in the initial year after starting hormones. This short-term effect would tend to be missed in observational studies, even with fairly frequent updating of exposure. This effect probably led to a modest overestimate of the apparent benefit of hormones for CHD in the observational studies.

Although biological differences offer a plausible explanation for the apparently divergent findings from the observation findings and WHI, from a clinical prospective, this may not matter. For the oestrogen-progestin combination, the increased risk of breast cancer is now well established from observational studies12 and the WHI trial. Thus, even if such therapy were proven to be protective for women at a young age, it still would not balance the excess risk due to breast cancer. In particular, many safe options are available for reducing risk of CHD, but few are available for breast cancer prevention. Overall, from a clinical perspective, it would not make sense to employ long-term oestrogen with progestin for chronic disease prevention.


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