Our analysis of the WHI randomized trial found no suggestion of a reduced risk of CHD during the first 2 years of estrogen-plus-progestin therapy in subgroups of women defined by years since menopause (). A cardioprotective effect of estrogen-plus-progestin among women within 10 years of menopause was only apparent after approximately 6 years of use.
Table 1 Hazard ratios (95% confidence intervals) of coronary heart disease for continuous use of estrogen-plus-progestin therapy versus no hormone therapy use by years since baseline, the Women's Health Initiative (WHI) randomized trial and the Nurses' Health (more ...)
These findings are consistent with those of a recent re-analysis of the observational Nurses' Health Study (3
). compares the randomized and observational estimates of the effect of continuous use of estrogen-plus-progestin. These adherence-adjusted estimates need to be compared after stratification by follow-up period and by time since menopause because women in the WHI and in the re-analysis of the Nurses' Health Study (after excluding women <50 years old) differ with respect to level of nonadherence (42% in hormone arm and 38% in placebo arm in the WHI vs. 61% for hormone initiators and 19% for non-initiators in the Nurses' Health Study), average length of follow-up (5.6 vs. 9.3 years), age distribution (67% vs. 61% aged 60 years or older) and proportion of women within 10 years of menopause (33% vs. 40%). When taken together, the findings from the WHI and the Nurses' Health Study suggest a 29% increase in CHD risk during the first 2 years of use in women within 10 years of menopause (). This result does not attain traditional statistical significance. Though we need to be cautious when drawing conclusions, it is important to note that our pooled WHI and Nurses' Health Study estimates are, and will probably be for a long time, the best available evidence on this topic. Randomized trial and observational data from the WHI have been previously combined (8
), but the WHI observational data contributed few events during the first 2 years after initiation of hormone therapy. One of the strengths of our pooled analysis is the large number of early events when the adverse effect of estrogen-plus-progestin use on CHD is most strikingly manifested.
Pooled hazard ratios (95% confidence intervals) of coronary heart disease for continuous use of estrogen-plus-progestin therapy versus no hormone therapy use, the Women's Health Initiative randomized trial and the Nurses' Health Study
The CHD-free survival curves for continuous use versus no use () showed no indication of a protective effect of estrogen-plus-progestin therapy during the first 6 years of use among women within 10 years of menopause. In the Nurses' Health Study, there was no evidence for a protective effect during the first 3 years of use (3
). This difference in the estimated crossover time may be due to random variability (the estimates from both studies are based on relatively few cases), different patient characteristics, failure to include all the joint determinants of hormone use and CHD in either or both of the studies, a misspecified dose-response model in our analysis, or a shorter average time since menopause in the observational study compared with the randomized trial.
This paper does not address the complex clinical and public health issues related to hormone therapy, including risk-benefit considerations. Rather, we focus on the effect of one common formulation of estrogen-plus-progestin therapy (conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d) on CHD. The evidence summarized above suggests that cardioprotection from this therapy does not occur during the first 3-6 years of use in women within 10 years of menopause. Since most newly menopausal women use this therapy for a short period (2
), an expected reduction of CHD risk should not be a consideration for initiation or continuation of hormone therapy in this group.
Though most of the current guidelines do not recommend the use of postmenopausal estrogen-plus-progestin for the prevention of CHD (16
), a recent report of the International Menopause Society ruled out an early harm of hormone therapy on CHD in newly postmenopausal women (19
). This conclusion was based in part on previously published data from the WHI estrogen-only trial (20
), which may not be relevant to estrogen-plus-progestin therapy, and from 2 small trials (22
) which, when combined, totaled 1 CHD case. Because of the uncertainty surrounding the estimates and the low baseline risk of CHD in younger women, our findings are consistent with current guidelines that recommend short-term use of postmenopausal hormone only for relief of vasomotor symptoms (16
The WHI findings reported here provide some support for the debated timing hypothesis (4
), which argues that the effect of postmenopausal hormone therapy varies by the stage of coronary atherosclerosis (4
). According to this hypothesis, estrogen may reduce the risk of CHD (through, for example, its effects on lipid profile or endothelial function) among younger women who do not yet have advanced atherosclerotic plaque in their coronary arteries, but trigger CHD (through, for example, its effects on coagulation and inflammatory factors) in the presence of advanced lesions. If the timing hypothesis were true, however, one would also expect a lower relative risk of CHD for hormone users compared with non users in women aged 50-59 years. We did not find a decreased risk in this age group, however. One could try to explain this finding by arguing that time from menopause is a better indicator of stage of coronary atherosclerosis than age, or that the addition of progestin modified the effects of estrogen. Further research on the role of age versus time since menopause is warranted, especially since the Nurses' Health Study found a suggestion of lower relative risk in women under age 60.
In summary, the available evidence suggests that estrogen-plus-progestin therapy does not reduce the CHD risk during the first 3-6 years of use in women who initiated therapy close to menopause. Because the typical duration of use of hormone therapy is short, most women contemplating estrogen-plus-progestin therapy for the relief of menopausal symptoms should not expect protection against CHD.