Cardiovascular Disease and HRT

The Impact of CVD After Menopause

Statistics show overwhelmingly that CVD – and not cancer – is the leading cause of mortality for postmenopausal women (Figure 6).(43) In fact, 1 in 2 women will eventually die of heart disease or stroke, compared to 1 in 25 women who will die because of breast cancer.(44) The incidence of heart disease, including coronary artery disease and stroke, is rare in premenopausal women.

Figure 6

However, heart disease is the most frequent cause of death in women over the age of 50.(45,46) Despite the impact of CVD, only 35% of women in a recent survey related heart disease to menopause.(47) Although there has been a gradual and pronounced decrease in cardiovascular deaths in this country, thedecrease has not occurred equally among men and women. Since 1984, death rates for men have dropped, while cardiovascular death rates for women have increased (Figure 7).(43) It is possible that estrogen replacement at menopause could have an impact on these mortality curves. Currently, however, only 16% of women receive HRT after natural menopause, and 50% of these stop therapy within a year. Thus, treatment must become widespread before it might have a visible impact on mortality trends.

Figure 7

The Cardioprotective Effects of Estrogen

The fact that estrogen loss and aging are associated with a dramatic increase in cardiovascular disease among women has focused research on the cardioprotective effects of estrogen.(48) The data presented in the RR scale in Figure 8 are based on retrospective observational studies.(49-59) Most of these observational studies show a reduction in relative risk for CVD, and a meta-analysis of these data indicate a risk ratio of 0.5 (a 50% reduction in risk). However, the first, and only, placebo-controlled, retrospective study is the ongoing Women's Health Initiative.

Figure 8

Other studies have examined whether estrogen would confer a protective effect on women with established coronary artery disease (CAD). Several secondary prevention studies show that estrogen use in these women reduces the risk of death and future events by 50% to 90% (Table 9).(56,60-64) This degree of reduction in risk is marked, and is comparable to that observed following successful treatment of LDL cholesterol elevations.

Table 9

The results from the most recent of these studies, the Heart and Estrogen/ Progestin Replacement Study (HERS) trial, are not consistent with the previous studies.(64) In the HERS trial, HRT was evaluated over 4 years in women with established CHD as a treatment for preventing CHD progression, specifically nonfatal myocardial infarction (MI) and death from CHD.

The article reported that in the first year of the study, women treated with HRT experienced an increase in second CHD events compared with placebo (RR 1.52, 1.01-2.29). With continuing treatment, however, this initial increase was reversed, and HRT resulted in a reduction in second CHD events by the fourth and fifth years of treatment (RR 0.67, 0.43-1.04). What does this mean in terms of counseling women about HRT? The HERS study was not designed to evaluate primary prevention in a population of healthy women, who represent the most typical users of HRT. Rather, it looked at a subset of women with an average age of 67 years who have established CHD. Thus, this study should have no impact on the routine use of HRT for cardiovascular benefits in healthy women.

For postmenopausal women with established heart disease, there is no reason to stop their HRT if they have no problems. Those women with established disease who are not currently on HRT need to make individual decisions about the risk/benefit ratio.

Mechanisms of Estrogen's Cardiovascular Effects

Plaque (the basic coronary lesion) development has 2 components, lipid and nonlipid, and estrogen exerts a cardioprotective effect via both of these mechanisms (Figure 9).(65-67) Estrogen reverses the adverse changes in lipid metabolism associated with menopause.(15,68) Roughly a quarter of estrogen's effect is related to this action. But estrogen also exerts a second, lipid-independent effect by directly modifying the function of the endothelium and vascular smooth muscle. These endothelial effects account for the majority of estrogen's cardioprotection.

Figure 9

The PEPI trial confirmed the lipid benefits of HRT.(69) Estrogen, taken alone or in combination with progestin, improves a woman's lipid profile (increases HDL and decreases LDL) and lowers fibrinogen levels (Figure 10).(15,69) In general, the addition of progestin to estrogen slightly reduces, but does not eliminate, the lipid benefits of estrogen alone. Fasting insulin levels decreased slightly, but not significantly, in women taking estrogen, and fasting glucose decreased significantly in all treatment arms compared with placebo.

Estrogen also acts through a second mechanism, directly on the endothelium. The ability of arteries to dilate when they should, rather than to constrict, is one of their most important properties. This function is modulated by the endothelium. If the endothelium is functioning normally, acetylcholine challenge results in dilation of the coronary arteries. But if there is vascular dysfunction, acetylcholine results in constriction. In a classic study, acetylcholine challenge in normal arteries caused a dilation that was associated with increased blood flow.(70) But when diseased arteries were challenged, it resulted in constriction of the arteries and reduced flow. Treatment with estrogen restored their ability to dilate and, thus, to increase blood flow.

Figure10

Options for Cardioprotection

Drug therapy for hypercholesterolemia, particularly for women, has remained controversial mainly because of insufficient clinical evidence that treatment enhances survival. Two recent reports, however, prove there are significant treatment benefits. The Scandinavian Simvastatin Study showed similar benefits for men and women.(73) Both experienced about a 35% decrease in risk for major coronary events when treated with statins (21.7% placebo vs 14.5% simvastatin for women and 29.4% placebo vs 20.5% simvastatin for men). Statin therapy also improved survival in a second study, the Air Force Texas study presented at the American Heart Association.(74) In this study, women had a greater percent reduction in first cardiac events than men (54% for women and 34% for men, P = 0.001).

Antioxidant vitamins are commonly taken by postmenopausal women with the expectation that they may provide some cardioprotection. Whether, and to what extent, they do so is largely based on observational data (Table 10).(75)

Observational studies have suggested that increased intake of vitamins A, C, and E; beta-carotene; flavonoids; and folic acid, by diet or supplement, reduces cardiovascular event rates. For example, Stampfer et al reported a protective effect on the risk of coronary heart disease with vitamin E consumption in the Nurses' Health Study.(76) When subjected to randomized controlled trials, only vitamin E, in doses of 400 to 800 IU daily, significantly reduced the rate of recurrent myocardial infarction. It seems doubtful, however, that a similar beneficial effect is shared by beta-carotene.(77) Folic acid appears to be beneficial, but not as an antioxidant. Its beneficial effect on cardioprotection is by way of lowering plasma concentrations of homocysteine. Aspirin is another option for CVD prevention in postmenopausal women. In a study of high-risk patients, prolonged aspirin treatment (of 1 month or more) offered significant protection against myocardial infarction, stroke, and death. Such therapy reduced vascular events by about 25%. This benefit was seen in those over 65 years of age and was equal in men and women.(78)

Table 10

The SERM raloxifene is being recommended for some postmenopausal women rather than traditional hormone replacement therapy.(31) Because coronary heart disease is the leading cause of death among post-menopausal women, it is important to know how raloxifene compares with traditional therapy in terms of affecting the lipid/lipoprotein profile. Figure 11 shows a comparison of the effects of raloxifene and CEE on the plasma lipid profiles of postmenopausal women.(31,79) Raloxifene is somewhat less effective than CEE in reducing plasma LDL concentrations, and whereas CEE has markedly beneficial effects on increasing HDL concentrations, no such benefit is observed with raloxifene treatment. CEE results in modest increases in plasma triglycerides, which are not seen with raloxifene treatment. However, no adverse effects on coronary heart disease inhibition have beenshown because of these modest increases in plasma triglyceride concentrations.

Figure 11

In summary, the postmenopausal woman has a number of therapeutic options, including HRT, for offsetting the cardiovascular effects of estrogen deprivation. (Other long-term benefits of HRT will be discussed in Monograph 3.)