Lessons from hormone replacement therapy trials for primary prevention of cardiovascular disease

PURPOSE OF REVIEW: Coronary heart disease in women is a common cause of morbidity and mortality, particularly after menopause. It was thought that estrogen and progesterone protected women from coronary heart disease. The recommendations of the recent Women's Health Initiative, however, are that hormone replacement therapy should not be used for primary prevention of coronary heart disease in women. Here, we have made a comprehensive review of major studies and comment on the validity of this recommendation. We have also analyzed the importance of dietary modification in primary prevention. In addition, we have delineated the important predictors of cardiovascular disease in women from prior observational and clinical studies. RECENT FINDINGS: Recent major studies, including the Women's Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS), studied the role of hormone replacement therapy in protecting women from coronary heart disease. These studies showed no significant reduction in coronary heart disease events. In addition, the dietary modification component of the Women's Health Initiative did not show any significant reduction in the incidence of coronary heart disease. SUMMARY: It can be summarized that hormone replacement is not generally recommended in postmenopausal women for primary prevention of coronary heart disease. Although the dietary modification trials did not show any significant reduction in the incidence of coronary heart disease, it is currently recommended to continue using a heart-healthy diet.     

Hormone replacement therapy in ischemic heart disease prevention in women. Arguments against

Hormone replacement therapy is one of the most difficult issues women and their doctors face. Epidemiological studies have consistently found that women using hormone replacement therapy are at a substantially lower risk of developing coronary heart disease. Observational data are supported by findings demonstrating that hormone replacement therapy improves several risk factors o coronary heart disease, specially the favourable changes in lipid profile. However, no study has clearly established hormones help prevent heart disease. In women without heart disease, the benefits of hormone replacement therapy are unclear. However, recent clinical trials have sown that the use of hormone replacement therapy does not provide cardiovascular benefits in women with established heart disease.     

雌性激素替代治疗与女性冠状动脉性心脏病预防

近年来,一些大规模临床研究显示,激素替代治疗无益于女性冠状动脉性心脏病预防。然而深入分析现有资料,可以发现雌性激素替代治疗的心血管保护作用与患者年龄以及开始治疗的时机和治疗持续时间密切相关。长期雌性激素治疗可以降低较年轻的围绝经期女性人群的总病死率和冠状动脉性心脏病风险,并且治疗相关性风险并不高于冠状动脉性心脏病的其他一级预防措施。     

Hormone therapy to prevent disease and prolong life in postmenopausal women.

PURPOSE: To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong life. DATA SOURCES: Review of the English-language literature since 1970 on the effect of estrogen therapy and estrogen plus progestin therapy on endometrial cancer, breast cancer, coronary heart disease, osteoporosis, and stroke. We used standard meta-analytic statistical methods to pool estimates from studies to determine summary relative risks for these diseases in hormone users and modified lifetable methods to estimate changes in lifetime probability and life expectancy due to use of hormone regimens. RESULTS: There is evidence that estrogen therapy decreases risk for coronary heart disease and for hip fracture, but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase in risk for breast cancer. The increase in endometrial cancer risk can probably be avoided by adding a progestin to the estrogen regimen for women who have a uterus, but the effects of combination hormones on risk for other diseases has not been adequately studied. We present estimates for changes in lifetime probabilities of disease and life expectancy due to hormone therapy in women who have had a hysterectomy; with coronary heart disease; and at increased risk for coronary heart disease, hip fracture, and breast cancer. CONCLUSIONS: Hormone therapy should probably be recommended for women who have had a hysterectomy and for those with coronary heart disease or at high risk for coronary heart disease. For other women, the best course of action is unclear.     

Hormone replacement therapy and coronary heart disease: results of randomized trials

A number of lines of evidence have suggested that postmenopausal hormone replacement therapy might be useful in the primary and secondary prevention of coronary heart disease (CHD). Data from recent randomized trials are consistent in showing no overall benefit of hormone replacement therapy as a continuous combined regimen of estrogen and a progestin (PERT) in preventing the development of CHD or preventing recurrent events or progression of atherosclerosis. The randomized trials also raise questions about hormone replacement therapy in the form of estrogen alone (ERT) for prevention of CHD and CHD recurrence. Other interventions to prevent CHD and decrease morbidity and mortality in women with established disease have a strong evidence base. Hormone replacement therapy should not be recommended to prevent CHD or CHD recurrence until and unless data from randomized trials establish this as a benefit.     

Hormone replacement therapy in clinical cardiology

The relationship between coronary heart disease (CHD) and menopause remains controversial, but observational studies of hormone replacement therapy among postmenopausal women have found a lower risk of CHD among women taking postmenopausal estrogens or estrogen/progestin combination therapy. In contrast, the Heart and Estrogen/progestin Replacement Study (HERS) did not show any overall benefit of estrogen/progestin therapy over 4.1 years of follow-up in a sample of women with established CHD, despite the expected favorable changes in the participants' lipid profiles. There appeared to be an initial increase in CHD risk, but benefit with increasing duration of hormone use. More research on the relative benefits and risks of hormone replacement therapy in postmenopausal women is needed. For now, a cautionary approach to hormone replacement therapy appears warranted, at least among postmenopausal women with established coronary artery disease.     

The lost promise of hormone replacement therapy and heart disease

Since the first secondary prevention trials were published in 1998, the prospect of hormone replacement therapy to prevent atherosclerotic heart disease in postmenopausal women has changed dramatically. Early harmful effects of hormone replacement therapy and lack of beneficial effects on coronary heart disease event rates in high-risk women have challenged the beneficial results gleaned from observational studies in the past. In this article, the effects of estrogens on lipids, hemostatic parameters, inflammation, and the vascular wall are described. The discrepancies that have arisen between the previous observational studies and recent randomized clinical trials are discussed: The current available data indicate that estrogens are beneficial to healthy endothelium but are harmful once atherosclerotic disease has developed.     

Hormone replacement therapy and cardiovascular risk

We are reexamining the role of hormone replacement therapy in cardiovascular risk in light of the results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. Prior to this trial, the wealth of evidence in the laboratory and in observational trials suggested that estrogen replacement was associated with significant cardioprotection. The HERS trial was the first randomized trial of this therapy in postmenopausal women with coronary artery disease, and it did not demonstrate a reduction in cardiovascular events in women taking hormone replacement therapy. These findings have made us rethink some of the basic science underlying the cardiovascular effects of hormone replacement therapy. Recent evidence regarding thromboembolic risk, inflammation, and types of hormone replacement therapy is discussed.     

Role of hormone-replacement therapy for prevention of coronary artery disease in women

The postmenopausal increase in the incidence of coronary artery disease implied a protective effect of estrogens. Nonrandomized, clinical and experimental studies have supported this notion. In the first randomized study (HERS 1998) no protective effect on prognosis of postmenopausal women with coronary artery disease was demonstrated. Also, in healthy postmenopausal women no beneficial effect of a hormone-replacement therapy on coronary events was shown (WHI-Study 2002, 2004). Therefore, hormone-replacement therapy is not recommended for prophylaxis of cardiovascular disease in healthy women or in women with documented coronary artery disease (Recommendation class I, evidence-level A). The continuation or the start of a hormone- replacement therapy is only justified for therapy of severe menopausal symptoms. Women should be informed that changes in lifestyle including not smoking, a heart healthy diet, and regular exercise are the most important measures to prevent cardiovascular diseases.     

Hormone replacement therapy trials: An update

Recent randomized trials of hormone replacement therapy (HRT) in postmenopausal women are not consistent with the decrease in cardiovascular risk seen in observational studies of hormone therapy users compared with nonusers. Emerging evidence indicates that HRT use in some women with established coronary heart disease may be associated with prothrombotic effects or proinflammatory effects leading to adverse events. In healthy women, the decision to use HRT should be based primarily on non-cardiac factors until more data becomes available that is relevant to this population. Several alternatives to HRT, including phytoestrogens and selective estrogen receptor modulators, have favorable effects on cardiovascular risk factors, but their impact on clinical outcomes remains to be determined.     

Hormone replacement therapy for prevention of coronary heart disease: current evidence

Postmenopausal estrogen replacement, with or without progestin therapy, has a generally favorable impact on lipids, improves endothelial function, and has anti-inflammatory and antioxidant effects. These properties should favorably impact coronary risk; indeed, epidemiologic studies have consistently associated hormone replacement therapy with reduced coronary risk. Nonetheless, the Heart & Estrogen/progestin Replacement Study (HERS), a randomized, placebo-controlled, secondary prevention trial of conjugated estrogen with progestin, found no overall reduction in coronary events among women assigned to active hormone treatment. This review explores the role of estrogen replacement among interventions intended to prevent coronary heart disease in the post-HERS era.     

The current state of hormonal prevention of coronary heart disease in menopausal women

The increased incidence and prevalence of coronary heart disease among older women, coupled with the less favorable prognosis for women who sustain coronary events than for men, has resulted in the medical community's attention to the potential beneficial effects of hormone therapy in menopausal women. Much biological evidence supports a protective mechanism of estrogen; nevertheless, some aspects are contradictory. Although observational studies have shown a clear cardiovascular benefit associated with hormone therapy, the significant skew inherent in these data has resulted in overestimation of benefits and underestimation of risks. Recent reanalysis of these observational data controlling for confounding variables failed to show cardiovascular benefit. Several randomized, double-blind, placebo-controlled studies have failed to show improvement in clinical cardiovascular outcomes with menopausal hormone therapy both in healthy women and in women with established coronary heart disease. Current research has also focused on pharmacologic agents that selectively modulate estrogen receptors, such as raloxifene, which are useful for the prevention and treatment of osteoporosis without increasing the risk of breast cancer. A clinical trial is now underway to evaluate the effects of raloxifene on coronary events and on the incidence of invasive breast cancer in menopausal women both with established coronary heart disease and at increased risk for coronary events. Current recommendations do not advocate the initiation of menopausal hormone therapy for the primary or secondary prevention of coronary events. The proven lifestyle interventions of smoking cessation, heart healthy diet, weight control, and physical activity should be undertaken, with statin use for control of elevated LDL cholesterol levels and pharmacologic blood pressure control when appropriate.     

The role of hormone replacement therapy in the prevention of postmenopausal heart disease

Coronary heart disease is the single leading cause of death in women and a significant cause of disability. Menopause adversely affects several risk factors for coronary heart disease, suggesting that hormones influence the risk of coronary heart disease in postmenopausal women. This article reviews the observational and clinical trial data evaluating the relation between cardiovascular disease and hormone replacement therapy. Biological mechanisms of estrogen and the impact of adding progestins are emphasized. Potential risks and benefits of therapy are discussed. The relative effects of other estrogen and lipid-lowering therapies for preventing coronary heart disease in postmenopausal women are highlighted.     

Effects of hormone replacement therapy on the sympathetic nervous system and blood pressure

Hypertension is a major health problem that significantly contributes to heart disease and stroke. While most studies of hypertension have focused on men, women also experience significant hypertension-related morbidity and mortality. However, the incidence of hypertension and cardiovascular disease is significantly lower in premenopausal women compared with men until the onset of menopause, at which time cardiovascular disease incidence increases dramatically in women and eventually approaches that in men. These observations indicate that the loss of estrogen contributes to menopause-related increases in blood pressure and cardiovascular disease, and suggest that the use of estrogen hormone replacement therapy could decrease the incidence of cardiovascular disease in postmenopausal women. However, new findings from the Women’s Health Initiative study suggest that estrogen therapy has few positive benefits and some significant negative effects on the health of postmenopausal women, and these data have caused many to abandon long-term estrogen replacement therapy. Conversely, numerous clinical and basic research studies indicate that estrogen replacement therapy beneficially reduces blood pressure, thereby decreasing the incidence of hypertension and cardiovascular disease. Further, several of these studies suggest that one means by which estrogen lowers blood pressure is by decreasing sympathetic nervous system activity. This review examines the evidence supporting estrogen’s ability to modulate sympathetic nervous system tone and thereby decrease arterial pressure.     

Menopausal hormone therapy and cardiovascular disease

Despite biologically plausible mechanisms for cardiac protection and compelling evidence from observational studies suggesting that menopausal hormone therapy confers cardiovascular benefit, results of well-designed and conducted randomized clinical trials in healthy women and in women with established coronary heart disease displayed that menopausal hormone therapy failed to prevent clinical cardiovascular events and rather was associated with harms. Clinical trial of the SERM raloxifene also did not demonstrate a decrease in coronary events. It is unknown whether the earlier initiation of such therapies, i.e., at menopause, would result in favorable outcomes; or whether different hormonal preparations, lower doses, or alternate routes of administration would confer benefit. At present, proved coronary risk reduction strategies are requisite (albeit underutilized) for menopausal women; these include lifestyle and pharmacologic coronary preventive interventions. The baseline characteristics of menopausal women with coronary heart disease who were participants in cardiovascular outcome trials of menopausal hormone therapy or raloxifene were remarkably similar; globally, cardiovascular risk factors were not optimally controlled at entry into these trials, suggesting that more aggressive cardiovascular risk interventions are appropriate to achieve optimal target goals for menopausal women with documented coronary heart disease.     

Plasma fibrinogen in women: relationships with oral contraception, the menopause and hormone replacement therapy

Summary. Plasma fibrinogen was measured in 4837 women aged 25-64 years as part of the Scottish Heart Health Study and Scottish MONICA population surveys. The relationships of oral contraceptive use, the menopause and hormone replacement therapy were examined.
Univariate analyses found that women with a history of oral contraceptive use, premenopausal women and those on hormone replacement therapy all had significantly lower fibrinogen levels than women who had never used oral contraceptives, postmenopausal women and non-hormone replacement users respectively. These differences persisted after age standardization.
On multivariate analysis, menopausal status and hormone replacement therapy had independent effects on fibrinogen levels. Together with the common risk factors, 9.9% of the total variation in plasma fibrinogen levels was explained. However, less than 1% of this was from the combined menopausal and hormonal factors.
These results confirm a postmenopausal rise in fibrinogen level which may be relevant to an increased risk of coronary heart disease. In addition, a protective effect with hormone replacement therapy is noted, although this was probably due to selection bias.     

Perspectives on dyslipidemia and coronary heart disease in women.

Coronary heart disease (CHD) remains the leading cause of death among American women. Numerous differences exist between younger and older women and between women and men with respect to the pathology of CHD and its incidence and prevalence over the life cycle. Differences in lipoprotein levels and lipid fractions play an important role in CHD risk. Hormonal influences on lipoprotein levels in women are complex, change throughout the life span, and are influenced by the administration of oral contraceptives and hormone replacement therapy. Women with obesity, metabolic syndrome, or diabetes have lipid profiles that adversely affect CHD risk. To date, no randomized trials testing the impact of lifestyle changes on lipoprotein levels and subsequent CHD events in non-institutionalized women have been performed, and women have not been well represented in clinical end point trials of pharmacologic lipid-lowering therapy. Available evidence suggests that lipid-lowering therapy with statins does provide benefit in reducing the risk of coronary events in women; however, women remain undertreated, and more data are needed to determine optimal cardiovascular prevention and treatment in this population.     

Perspectives on dyslipidemia and coronary heart disease in women

Coronary heart disease (CHD) remains the leading cause of death among American women. Numerous differences exist between younger and older women and between women and men with respect to the pathology of CHD and its incidence and prevalence over the life cycle. Differences in lipoprotein levels and lipid fractions play an important role in CHD risk. Hormonal influences on lipoprotein levels in women are complex, change throughout the life span, and are influenced by the administration of oral contraceptives and hormone replacement therapy. Women with obesity, metabolic syndrome, or diabetes have lipid profiles that adversely affect CHD risk. To date, no randomized trials testing the impact of lifestyle changes on lipoprotein levels and subsequent CHD events in non-institutionalized women have been performed, and women have not been well represented in clinical end point trials of pharmacologic lipid-lowering therapy. Available evidence suggests that lipid-lowering therapy with statins does provide benefit in reducing the risk of coronary events in women; however, women remain undertreated, and more data are needed to determine optimal cardiovascular prevention and treatment in this population.     

Cell adhesion molecules in relation to simvastatin and hormone replacement therapy in coronary artery disease.

AIMS: To assess the effect of simvastatin, hormone replacement therapy and their combination on soluble cell adhesion molecules and plasma lipids, in hypercholesterolaemic post-menopausal women with coronary artery disease. METHODS: We studied 16 post-menopausal women with coronary artery disease and hypercholesterolaemia (total cholesterol >200mg x dl(-1) and LDL cholesterol >130 mg x dl(-1)). We compared simvastatin (20 mg daily) with hormone replacement therapy (0.625 mg conjugated oestrogen and 2.5 mg medroxyprogesterone acetate daily) and their combination, in a randomized, crossover, placebo controlled study. Each treatment period was 8 weeks long with a 4 week washout interval between treatments. Circulating cell adhesion molecules and plasma lipids were evaluated at the end of each treatment period. RESULTS: All three active treatments--simvastatin, hormone replacement therapy and the combination therapy--significantly reduced total and LDL cholesterol, compared to placebo (P<0.001). Only hormone replacement therapy, alone and in combination with simvastatin, significantly decreased lipoprotein(a) when compared to placebo (P<0.05), whereas simvastatin had no significant effect. Likewise, hormone replacement therapy and the combination therapy significantly reduced the intercellular adhesion molecule (ICAM-1) plasma levels (P=0.03 and P=0.02, respectively), while simvastatin, which was superior to hormone replacement therapy in lowering total and LDL cholesterol, did not modify ICAM-1 levels; the combination therapy was not more effective than hormone replacement therapy alone in ICAM-1 reduction. Neither the effect, on any treatment when compared to placebo, of VCAM-1 nor E-selectin levels differed significantly. CONCLUSIONS: Hormone replacement therapy may limit the inflammatory response to injury by modulating the expression of cell adhesion molecules from the endothelial cells, possibly in association with lipoprotein (a) reduction.