Hormone Therapy and Heart Disease

More than two decades of accumulated evidence suggested that women taking estrogen plus progesterone hormone therapy (HT) and estrogen therapy (ET) alone gained protection against coronary heart disease (CHD). Notably criticized, these largely observational studies were confounded by superior cardiovascular health profiles among participants electing to use HT or ET. To assess fully the role of HT and ET for CHD protection among menopausal women, large-scale randomized, controlled clinical trials were begun. Recent evidence suggesting cardioprotective effects of HT and ET has sparked debate regarding the possibility of a “timing hypothesis” (ie, women who recently experienced menopause may be more likely to benefit from HT than women who have been menopausal for a longer period) (1, 2).

Among menopausal women with known CHD, the Heart and Estrogen/Progestin Replacement Study (HERS) examined whether conjugated equine estrogen and medroxyprogesterone acetate altered CHD risk (3). After 4 years of follow-up, the study did not demonstrate an overall reduction in CHD risk. Those receiving conjugated equine estrogen and medroxyprogesterone acetate exhibited a 52% increase in CHD and a 3–4-fold increase in venous thromboembolic events during the first and second years of use.

In 2002, the Women's Health Initiative (WHI), a CHD prevention trial among predominantly healthy menopausal women, published its initial results after 5.2 years of follow-up (4). The study was prematurely terminated because of reports of adverse cardiovascular effects and a worsened global index. Not only did conjugated equine estrogen and medroxyprogesterone acetate not provide protection against CHD, but its use also imparted a 29% increase in CHD-related events (37 versus 30 per 10,000 woman-years) that developed soon after randomization. Notably, most CHD events attributed to conjugated equine estrogen and medroxyprogesterone acetate use were nonfatal myocardial infarctions, and there were no significant differences in overall CHD deaths (hazard ratio (HR): 1.18; 95% CI, 0.70–1.97). Unlike prior randomized studies (5, 6), WHI associated conjugated equine estrogen and medroxyprogesterone acetate use with a 41% increased stroke risk, mostly nonfatal events (29 versus 21 per 10,000 woman-years) that became apparent between the first and second year of use. Consistent with the HERS trial, WHI provided further evidence that conjugated equine estrogen and medroxyprogesterone acetate increased venous thromboembolism and pulmonary embolism risks twofold (venous thromboembolism: 34 versus 16 per 10,000 woman-years; pulmonary embolism: 16 versus 8 per 10,000 woman-years). Time-trend analyses suggested that the risk of CHD and pulmonary embolism began to occur immediately following the initiation of HT. Similar to HERS, the conjugated equine estrogen and medroxyprogesterone acetate arm of the WHI indicated that there was a 26% increase in invasive breast cancer (38 versus 30 per 10,000 woman-years). Benefits associated with conjugated equine estrogen and medroxyprogesterone acetate use in the WHI trial included a 37% reduction in colorectal carcinoma rates (10 versus 16 per 10,000 woman-years) and reduced incidence of hip (10 versus 15 per 10,000 woman-years) and vertebral fractures (9 versus 15 per 10,000 woman-years).

Nearly 2 years later, the conjugated equine estrogen alone study of the WHI was published after a mean of 6.8 years of follow-up, in advance of its designed observation period because of a lack of improvement in CHD risk (the primary outcome) and an increased rate of stroke (7). This conjugated equine estrogen alone trial revealed several notable differences from the initial WHI study publications. No differences in CHD incidence were observed among those receiving conjugated equine estrogen compared with placebo. Although not statistically significant, another notable finding was that invasive breast cancer occurred 23% less frequently in the conjugated equine estrogen alone group compared with the control group (HR=0.77; 95% CI, 0.59–1.01; P=.06). Moreover, no differences were seen in colorectal carcinoma rates. In line with the conjugated equine estrogen and medroxyprogesterone acetate arm of the WHI trial, conjugated equine estrogen alone increased stroke rates by 39% and reduced both hip and vertebral fractures. Although deep vein thrombosis risk was increased (21 versus 15 per 10,000 woman-years), increases in venous thromboembolism and pulmonary embolism risk failed to reach statistical significance. Time-trend analyses demonstrated an increased stroke risk immediately after randomization, but no risk differences could be elucidated for pulmonary embolism or CHD.

Subsequent to the aforementioned studies, the WHI investigators have published several follow-up studies. Consistent with previous reports, analysis directed at extricating the HT effect on CHD risk found superior lipid, insulin, and glucose profiles with conjugated equine estrogen and medroxyprogesterone acetate (8). Subsequent data from the conjugated equine estrogen alone arm suggested an attenuation of venous thromboembolism risk by the exclusion of progestin, yet venous thromboembolism risks were increased with HT use in both the conjugated equine estrogen and conjugated equine estrogen and medroxyprogesterone acetate arms of the study after a longer mean follow-up period (conjugated equine estrogen: 7.1 years; conjugated equine estrogen and medroxyprogesterone acetate: 5.6 years) (9, 10). Likewise, HT increased the risk of ischemic stroke in both the conjugated equine estrogen and conjugated equine estrogen and medroxyprogesterone acetate arms (11, 12). Overall, the risks associated with long-term primary preventive therapy appeared to outweigh the beneficial effects.

The mean participant age of the WHI trial exceeded 60 years and it has been suggested that the results may not apply to women who recently experienced menopause and for whom treatment would likely be initiated. In an attempt to delineate the impact of age on CHD risk with HT use, WHI data was stratified according to participant age and duration of menopause (13). This study found that the effects of either conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate on CHD risk might depend, in part, on age at the start of treatment. When analyzed according to treatment type, a trend toward reduced total mortality with conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate use was noted among those women aged 50–59 years (see Table 1). When individual treatment type data were pooled, total mortality decreased by 30% with conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate use (95% CI, 0.51–0.96). Whether conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate administration improves the cardiovascular health of women who recently experienced menopause remains to be determined. Presently, there is insufficient evidence to suggest that long-term conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate use improves cardiovascular outcomes (1). Nevertheless, recent evidence suggests that women in early menopause who are in good cardiovascular health are at low risk of adverse cardiovascular outcomes and as such should be considered candidates for the use of conjugated equine estrogen or conjugated equine estrogen and medroxyprogesterone acetate for relief of menopausal vasomotor symptoms (2). Ongoing studies, including the Kronos Early Estrogen Prevention Study (KEEPS) are evaluating alterations in surrogate CHD risk markers, including carotid intimal thickness and the accrual of coronary calcium deposition induced by HT, in this case conjugated equine estrogen or transdermal estradiol patches combined with cyclic oral, micronized progesterone.

The WHI Coronary-Artery Calcium Study (WHI-CACS) recently evaluated 1,064 women aged 50–59 years who were previously enrolled in the conjugated equine estrogen arm of WHI (14). Because coronary atherosclerotic plaques have been associated with future CHD risk, the investigators used computed tomography heart imaging to determine the degree of coronary-artery calcium burden. The study results indicated that the overall distribution of coronary-artery calcification scores were lower among those receiving conjugated equine estrogen compared with those receiving placebo (P=.03). Furthermore, for those who adhered to the study medication regimen (80% medication adherence for 5 or more years), conjugated equine estrogen use was associated with a significant reduction in the coronary-artery calcification (OR=0.64; 95% CI, 0.46-0.91; P=.01). This preliminary evidence, using surrogate outcome markers, needs confirmation of its clinical significance and correlation with clinical outcomes. Nevertheless, it suggests that conjugated equine estrogen therapy may reduce CHD risk factors and may provide cardiovascular protection for select populations of women who experienced menopause recently.

Conclusion

Menopausal HT should not be used for the primary or secondary prevention of CHD at the present. Recent analyses suggest that HT may not increase CHD risk for select populations of women who have experienced menopause recently. Hormone therapy use should be limited to the treatment of menopausal symptoms at the lowest effective dosage over the shortest duration possible and continued use should be reevaluated on a periodic basis. Some women may require extended therapy because of persistent symptoms.

References

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