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Menopause Matters

Cardiovascular Disease

David M. Herrington, MD, MHS

In the United States, cardiovascular disease (CVD) is the leading cause of mortality in both men and women. Among US women, the mortality rate from CVD exceeds the next 14 causes of death combined.¹ While rare in premenopausal women, rates of CVD increase sharply in women over age 50. Thus, it appears that premenopausal women have a protective factor that is lost after age 50, approximately the average age of menopause, suggesting that estrogen provides some cardioprotective benefits. This concept was supported by numerous observational studies that have shown lower rates of heart disease in women who use postmenopausal estrogen replacement therapy (ERT) or hormone replacement therapy (estrogen plus a progestogen, HRT) compared with nonusers, as well as the favorable effects of estrogen in studies of various cardiovascular risk factors and animal models of atherosclerosis.

However, a series of randomized clinical trial results has dramatically altered our understanding of the relationship between hormone therapy and risk of CVD-moving from a presumption of benefit to evidence of harm, at least for the most commonly prescribed form of HRT. This transformation in our understanding of hormone therapy highlights the complexity of sex steroid hormones in human biology and clinical medicine, and underscores the value of randomized clinical trials to verify presumed benefits of therapeutic interventions and ensure that these benefits are not offset by other, unanticipated adverse effects. Despite the new data summarized below, there remain many questions about hormone therapy and cardiovascular risk whose answers may ultimately lead to new strategies for primary and secondary prevention of heart disease.

SECONDARY PREVENTION
Coronary disease is one of the most common serious chronic conditions in postmenopausal women, and leads to extremely high risk for recurrent myocardial infarction and coronary heart disease (CHD) death. Thus, even a small risk reduction with ERT/HRT in this group would have a major impact on public health. Furthermore, some evidence suggested that ERT/HRT might be especially effective in women who already had established atherosclerosis.² However, a series of randomized clinical trials of ERT/HRT for secondary prevention of CVD has failed to demonstrate a benefit on clinical or anatomic progression of atherosclerosis.^3-7 Several of these negative trials used conjugated equine estrogen⁵ combined with medroxyprogesterone acetate, while others examined oral or 17b-estradiol or unopposed ERT regimens, with similar negative results. In the Heart and Estrogen/progestin Replacement Study (HERS), a pattern of early increase in risk for CHD events in women on HRT appeared to be offset by an emerging pattern of benefit in the latter years of the trial; however, this suggestion of long-term benefit was not substantiated with additional long-term follow-up of the HERS participants.⁸ There did remain a significant increase in risk for venous thromboembolic events and gallbladder surgery in these women with CHD. The position of NAMS and the American Heart Association (AHA)⁹ is that ERT/ HRT should not be used for secondary prevention of CHD, and use for other indications should take into account both the known benefits and risks, and patient preference.

PRIMARY PREVENTION
Despite the absence of benefit of ERT/HRT for secondary prevention, there remained reasons to be hopeful that those regimens might still be useful for primary prevention of CHD. However, in the Women's Health Initiative, the largest clinical trial of ERT/HRT in mostly healthy normal women, there were early indications that these expectations would not be met. During the first few years of this trial, the investigators announced that there was a pattern of increased risk for CHD and venous thromboembolic events in both the ERT and HRT arms that resembled the pattern of early risk observed in HERS. The trial was allowed to continue because these trends were not yet statistically significant, and because of the possibility that other, noncoronary benefits might produce an overall net clinical benefit. However, most recently, the HRT arm of the trial was stopped prematurely after a mean of 5.2 years of follow-up because of a significant increase in risk for CHD events, stroke, venous thromboembolic events, and breast cancer that outweighed the significant reductions in hip fracture and colorectal cancer.¹⁰ The ERT arm was allowed to continue and is still scheduled to be completed in 2005.

Currently, NAMS and the AHA are revising their recommendations for use of ERT/HRT for primary prevention. However, it seems clear that the most commonly used form of HRT in the US can no longer be recommended for most healthy postmenopausal women, except for short-term relief of perimenopausal symptoms and unusual cases of severe osteoporosis not adequately treated with other, safer forms of therapy.

FUTURE DIRECTIONS
The final word on unopposed estrogen regimens for primary prevention is not yet known. In the meantime, ongoing studies are attempting to identify subgroups of postmenopausal women in whom HRT could be more efficacious (eg, because of estrogen-receptor polymorphisms that confer enhanced lipid effects with ERT/HRT¹¹) or deleterious (eg, because of abnormalities such as Factor V Leiden¹² or the prothrombin 20210 A/G¹³ gene polymorphisms that confer a propensity for venous thromboembolic events). Future work will certainly center on evaluating the safety and efficacy of other hormone replacement regimens, such as selective estrogen receptor modulators (SERMs).¹⁴

David M. Herrington, MD, MHS, is a professor of internal medicine/cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. He is a member of the 2001-2002 NAMS Professional Education Committee.

REFERENCES

1. American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association, 2001.
2. Sullivan JM, VanderZwaag R, Hughes JP, et al. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med 1990;150:2557-2562.
3. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 289:695-613.
4. Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529.
5. Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. A randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262-268.
6. Clarke S, Kelleher J, Lloyd-Jones H, et al. Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women (abstr). Eur Heart J 2000;21:212.
7. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-1249.
8. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
9. Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 2001;104: 499-503.
10. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.
11. Herrington DM, Howard TD, Hawkins GA, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967-974.
12. Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002; 22:1012-1017.
13. Psaty BM, Smith NL, Lemaitre RN, et al. Hormone replacement therapy, prothrombotic mutations and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001; 285:906-913.
14. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847-857.

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