Prof. Skaia Nikol
The suspected benefit for the course of cardiovascular disease based on observational studies led to the wide spread use of hormone replacement therapy. However, the conclusion from data now available from randomised, placebo-controlled trials is, that there is no net benefit from hormone replacement therapy regarding primary prevention, secondary prevention or angiographic endpoints of cardiovascular disease, except for the young post-menopausal woman. Results of a controlled trial with cardiovascular events as primary endpoints for hormone replacement therapy using selective estrogen receptor modulators are awaited.
Until recently, approximately 38 % of post-menopausal women received hormone replacement therapy in the USA. Particularly, the suspected benefit for the course of cardiovascular disease based on initial observational studies led to the wide spread use of hormone replacement therapy. Observational studies supported the hypothesis that hormone replacement therapy may provide cardiovascular protection via reduction of atherosclerosis. However, these early studies also reported an increased risk for the development of breast cancer and venous thromboembolism. Randomised placebo-controlled studies to investigate the role of hormone replacement therapy in the primary and secondary prevention of atherosclerotic disease were urgently needed. Results of most of these hormone replacement therapy trials are now published and allow for a new evaluation of the use of hormone replacement therapy, at least for the use of estrogens and gestagens.
The conclusion from the data now available from those randomised placebo-controlled trials is, that there is no net benefit for hormone replacement therapy regarding primary prevention (WHI, 1,2,3), secondary prevention (HERS, 4; HERS II, 5,6; ESPRIT, 7; WEST, 8) or angiographic endpoints (WAVE, 9; ERA, 10) of cardiovascular disease. This also accounts for women on higher risk due to risk factors, known atherosclerosis, previous myocardial infarction or stroke. Recommendations of the American Heart Association were published in 2001 (11).
Those almost consistently negative results were only slightly put into perspective by a recent meta-analysis of data from 30 randomised, placebo-controlled hormone replacement therapy trials between 1966 and September 2002 (12). Overall mortality associated with hormone replacement therapy remained unchanged, however, mortality in the age group under 60 years was significantly reduced. Thus, at best hormone replacement therapy can be recommended as early as possible following menopause. Also, hormone replacement therapy should only be temporarily used and terminated before the more critical higher age has been reached.
A potential alternative to estrogens and gestagens for hormone replacement therapy are the selective estrogen receptor modulators (SERMs), such as raloxifene. Placebo-controlled data are available for raloxifene in a larger cohort of patients from the MORE study (13). Primary endpoint of this study was the influence of raloxifene on osteoporosis. In a secondary analysis of women with multiple cardiovascular risk factors also coronary and cerebrovascular endpoints were investigated. No significant change of cardiovascular events was observed in the overall cohort, however, a significant reduction of events was found in women with increased cardiovascular risk. Moreover, a reduction of risk for breast cancer is expected in the currently conducted placebo-controlled RUTH trial with cardiovascular events as primary endpoints (14).
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG; Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839-54
2. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34
3. Grady D. Postmenopausal hormones--therapy for symptoms only. N Engl J Med 2003;348:1835-7
4. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13
5. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med 2002;113:543-8
6. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake D; HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66
7. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M, Buckley H; ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:2001-8
8. 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;345:1243-9
9. Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higginson L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 2002;288:2432-40
10. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, Waters D. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-9
11. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC Jr, Taubert KA, Wenger NK; American Heart Association. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499-503
12. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791-804
13. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD; MORE Investigators (Multiple Outcomes of Raloxifene Evaluation). Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847-57
14. Mosca L, Barrett-Connor E, Wenger NK, Collins P, Grady D, Kornitzer M, Moscarelli E, Paul S, Wright TJ, Helterbrand JD, Anderson PW. Design and methods of the Raloxifene Use for The Heart (RUTH) study. Am J Cardiol 2001;88:392-5
Our mission: To reduce the burden of cardiovascular disease
© 2018 European Society of Cardiology. All rights reserved