Menopausal hormone therapy currently has no evidence-based role for

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1 IN PERSPECTIVE HT and CVD Prevention: From Myth to Reality Nanette K. Wenger, M.D. What the studies show, in a nutshell The impact on coronary prevention Alternative solutions Professor of Medicine (Cardiology), Emory University School of Medicine; Chief of Cardiology, Grady Memorial Hospital; Consultant, Emory Heart & Vascular Center Menopausal hormone therapy has no evidence-based role for the primary or secondary prevention of coronary heart disease. Coronary prevention should involve lifestyle and pharmacologic interventions documented as beneficial in randomized clinical trials and promulgated in national guidelines. Menopausal hormone therapy currently has no evidence-based role for the primary or secondary prevention of coronary heart disease. Such therapy appears to exacerbate rather than reduce cardiovascular risk in menopausal women. The approach to coronary risk reduction in women should involve application of proved therapies. These include lifestyle modifications of a heart-healthy diet, weight management, regular physical activity, and smoking avoidance or cessation, with pharmacologic management of hypertension and hyperlipidemia if lifestyle measures do not by themselves achieve the nationally recommended goal levels. This challenge is important for the 50 million U.S. women who are currently menopausal and the 45% of all U.S. women who will be menopausal by For many years reliance was placed on multiple observational studies of menopausal hormone therapy and meta-analyses of these studies, which suggested a 35% to 50% reduction in coronary events in women taking both unopposed estrogen and estrogen/progestin combinations, particularly for current hormone users (1). An important bias in these observational data, though, is that women who use hormone therapy differ from nonusers in many aspects, but prominently so in general health status, in health consciousness, in coronary risk attributes, and in socioeconomic and educational status. These variables were addressed in a recent meta-analysis of the observational studies cited above that adjusted for socioeconomic status, education, and major coronary risk factors (2). This adjusted metaanalysis failed to demonstrate cardiac protection with hormone therapy and to American Society for Reproductive Medicine Published by Elsevier Inc.

2 support the use of such therapy for the primary prevention of coronary and cardiovascular disease. The HERS Studies The landmark Heart and Estrogen/progestin Replacement Study (HERS) (3) enrolled women with documented coronary heart disease, who were randomly given either a daily dose of an estrogen/progestin combination (conjugated equine estrogen plus medroxyprogesterone acetate) or a placebo. There was no significant difference between the hormone and placebo groups in the primary trial outcome of coronary events, which included nonfatal myocardial infarction and coronary death. However, a significant time trend raised concern for an excess number of coronary events in the hormone group compared with placebo during the first year of treatment and a trend to fewer events in years 3 5. To ascertain whether this trend toward a reduced risk of coronary events with hormone use in the later years of HERS would persist with additional follow-up and result in an overall decrease in the risk of coronary events, the majority of surviving HERS participants (93%) had extended follow-up for an additional 2.7 years in an observational study (HERS II). In this open-label study, women were encouraged to remain on their original drug assignment and about half did so. According to the HERS II results, this hormone regimen failed to reduce the risk of coronary events (overall risk hazard 0.99), even after adjustment for potential confounding factors, including statin use. Nor were the results altered with analysis of women adherent to their randomized treatment assignment (4). Given that coronary heart disease is the major cause of death for U.S. women, if cardiovascular benefits of hormone therapy had already been demonstrated, limited harms might be acceptable. If there is a lack of cardiovascular benefit, however, potential harms including a twofold increase in the risk of venous thromboembolism, predominantly in the initial years, and a nearly 50% increase in the rate of gallbladder disease requiring surgery assume substantial importance. The HERS II data indicate that in older women with established coronary heart disease, this estrogen/progestin regimen did not provide cardiovascular benefit and caused significant harm. Therefore, this hormone regimen should not be used to decrease the risk of cardiovascular events in women with coronary heart disease. Data from the Women s Health Initiative Primary prevention data derive from the Women s Health Initiative (WHI), which enrolled predominantly healthy menopausal women aged 50 through 79. Approximately 27,000 women of the 160,000 in the observational cohort participated in a randomized placebo-controlled hormone trial. They were randomly assigned to conjugated equine estrogen plus medroxyprogesterone acetate daily versus placebo if they had an intact uterus, or conjugated equine estrogen alone daily versus placebo if they had had a hysterectomy. As in HERS, this regimen was selected as the hormone preparation most commonly used by U.S. women. The Data Safety and Monitoring Board of WHI, in both 2000 and 2001, recommended reporting to all participants a small and unanticipated increase in myocardial infarction and stroke, involving fewer than 1% of the women, and occurring in both the estrogen and estrogen/progestin groups compared with placebo. This was in addition to the anticipated increase in venous thromboembolism. 11

3 Because of the low incidence of these adverse events and the potential for late benefit, continuation of the study was recommended by the Data Safety and Monitoring Board (5). The estrogen/progestin therapy arm of the WHI hormone trial was halted prematurely in July 2002, however, after an average follow-up of 5.2 years. The discontinuation involved the increased risk of invasive breast cancer that exceeded the preset trial stopping boundaries, in combination with a lack of global risk benefit, based on a pre-established global risk score (6). (The parallel estrogen-only vs placebo arm of WHI is continuing.) In addition to the 26% increased risk for invasive breast cancer with estrogen/progestin therapy, harms included a 29% increase in the risk of coronary events (predominantly nonfatal infarction), 41% increased stroke risk, and doubled risk for venous thromboembolism. This contrasted to benefits that included a 37% decrease in colorectal cancer, a 33% decrease in hip fracture, and a 24% decrease in total fracture, without effect on total mortality. The increased risk for myocardial infarction began within the initial year of therapy and that for stroke within the initial 2 years. Although invasive breast cancer was the trigger for stopping the trial, coronary events, stroke, pulmonary embolism, and invasive breast cancer provided equal contributions to harm. Translated to the care of an individual woman, if 10,000 women were treated with this hormone regimen for 1 year there would be an excess of 7 coronary events, 8 strokes, 8 cases of invasive breast cancer, and 8 more pulmonary emboli, in contrast to 6 fewer colorectal cancers and 5 fewer hip fractures. Although the majority of WHI women had no adverse events, one adverse event can be anticipated among each 100 such women treated for 5 years. Furthermore, the population risk, when extrapolated to the 10 million menopausal women who are hormone users, becomes substantial i.e., the risks exceed the benefits for chronic health conditions. The WHI investigators thus concluded that the global risk-benefit profile does not warrant recommendation of this therapy for women as a widespread preventive intervention. Prescription of hormone therapy for moderate-tosevere menopausal symptoms is advised at the lowest effective dose for the shortest duration possible. Within the background of higher morbidity associated with estrogen plus progestin, healthrelated quality of life was reported based on assessments in all WHI women at baseline and at 1 year and in a subgroup at 3 years. Hormone therapy resulted in no clinically meaningful effects on measures of general health, vitality, mental health, depressive symptoms, or sexual satisfaction (7). Improvement in vasomotor symptoms and a small benefit in sleep disturbance occurred among 50- to 54-year-old women with moderate-to-severe baseline vasomotor symptoms, but there was no improvement in other health-related quality of life outcomes. Note, however, that severely symptomatic menopausal women were unlikely to participate either in WHI or in HERS, given their 50% likelihood of allocation to a placebo group. Again, in contrast to some prior observational data, are two recent reports from the Women s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, reflecting the population in the continuous combined estrogen/progestin therapy vs placebo group. Although the absolute risk of dementia was low, hormone-treated women had a doubled likelihood of developing dementia. There was no effect of hormone therapy on mild cognitive impairment (8). In another WHIMS study, global cognitive function as measured by the Modified Mini-Mental State Examination showed that hormone-treated women had significantly smaller average increases in total cognition scores, although differences were not clinically significant. How- 12

4 ever, more hormone-treated women had statistically significant and clinically important declines in the Modified Mini-Mental State Examination scores (9). Other Recent Studies Comparable cardiovascular data derive from more recent studies. In the Women s Angiographic Vitamin and Estrogen (WAVE) trial, menopausal women with angiographic evidence of coronary heart disease were randomized to hormone therapy vs placebo and antioxidant vitamin supplements vs placebo. Neither the hormones nor the antioxidant vitamin supplements provided cardiovascular benefit, with potential for harm suggested for each treatment (10). In the British ESPRIT (EStrogen in the Prevention of ReInfarction Trial) (11), which randomly assigned menopausal women aged 50 through 69 who were survivors of an initial heart attack to estradiol vs placebo therapy, there was no reduction in the overall risk of further cardiac events with hormone therapy. There was no difference in the frequency of reinfarction or cardiac death at 24 months. However, this study raised concern because of the low adherence to therapy in the intervention group and the substantial crossover to hormone use in the control population. A scientific review conducted for the U.S. Preventive Services Task Force (12) found that hormone therapy helps to prevent osteoporotic fracture and colorectal cancer, had uncertain benefit for the prevention of dementia, but increased the risk of coronary disease, stroke, thromboembolic events, breast cancer (with 5 or more years of hormone use), and cholecystitis. The conclusion was that the harms of estrogen/progestin therapy were likely to exceed chronic disease prevention benefits for most women. Nonetheless, a recent poll identified that almost one-third of older U.S. women continue to believe that hormone therapy is protective against heart disease, breast cancer, and stroke (13). Uncertainties persist about the effects of estrogen alone; recommendations await completion of the estrogen arm of WHI. The recommendation of the U.S. Preventive Services Task Force was that hormone therapy should not be used routinely for the prevention of chronic conditions in menopausal women; the task force emphasized that these findings should provide an impetus to increase attention to proved coronary risk reduction interventions designed to enhance the cardiovascular health of menopausal woman (14). Importantly, no data are currently available on the risk benefit relationships of complementary medicine preparations used for menopausal symptoms. Information is also lacking on their potential for interaction with prescription drug therapy. New FDA Labeling Requirements In January 2003, the U.S. Food and Drug Administration (FDA) outlined new labeling requirements for all estrogen and estrogen/progestin products, likely reflecting the lack of evidence that other hormone formulations differ significantly in their risk benefit profiles (15). The labels are to state that these products are not approved for heart disease prevention and must highlight the increased risks of heart disease, heart attack, stroke, and breast cancer. Prescription of hormone therapy for moderate-to-severe menopausal symptoms is advised at the lowest effective dose for the shortest duration possible. Consideration of approved non-estrogen therapies is recommended for osteoporosis prevention. Importantly, the FDA advises women to discuss with their healthcare providers other approaches to reducing heart disease risk factors e.g., diet, smoking cessation, and blood pressure control. To these I would add exercise and lipid management, interventions documented to improve coronary heart disease outcomes. Nanette K. Wenger, M.D. Emory University School of Medicine 69 Jesse Hill Jr. Drive, SE Atlanta, GA nwenger@emory.edu 13

5 References 1. Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19: Humphrey LL, Chan BKS, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137: Hulley S, Grady D, Bush T, et al. for the Heart and Estrogen-progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280: Grady D, Herrington D, Bittner V, et al. for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288: Click on HRT Update-English. 6. 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: Hays J, Ockene JK, Brunner RL, et al. for the Women s Health Initiative Investigators. Effect of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348: Shumaker SA, Legault C, Rapp SR, et al for the WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289: Rapp SR, Espeland MA, Shumaker SA, et al. for the WHIMS Investigators. Effect of estrogen plus progestin on global cognitive function in postmenopausal women. The Women s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289: Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. A randomized controlled trial. JAMA 2002;288: The ESPRIT Team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomized placebo controlled trial. Lancet 2002; 360: Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy. Scientific review. JAMA 2002;288: Partnership for Prevention. Women, hormone replacement therapy and disease prevention. Topline data. Accessed at results.htm on January 1, U.S. Preventive Services Task Force. Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 2002;137: NEW00863.html. 14