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Recent data from the Women's Health Initiative (WHI) support an extensive body of evidence that estrogen therapy (ET) reduces total mortality and coronary heart disease (CHD) in women less than age 60 who initiate ET in close proximity to menopause (1). With the release of these data, the role of hormone therapy (HT), specifically ET for the primary prevention of CHD in postmenopausal women is clearer especially when appreciated in relation to other commonly used therapies (2-4).
All medications have risks and benefits. Hormones for postmenopausal hormonal replacement therapy are no exception. The hormone risks of most concern are breast cancer, stroke and venous thrombosis. However, as with all approved medications that withstand the test of time, the risks associated with HT are small and those of ET even smaller. In fact, the risks associated with ET occur at an absolute frequency of <1 additional event per 1,000 treated women and are considered rare risks by WHO criteria (Table 1) (2).
The benefits of HT are well appreciated (3,4) and as the most current data from WHI indicate (1), the major remaining risk concern for ET is venous thromoboembolic events (VTE) (Table 2). However, the overall risk for VTE events is rare with ET (0.8 additional events/1,000 women/year of conjugated equine estrogen (CEE) therapy) and it is even rarer in women less than 60 years old (0.4 additional events/1,000 women/year of CEE therapy) (2,5). The VTE risks of CEE are similar to other commonly used medications, such as fenofibrate in diabetics (2).
Putting medications and standard therapies into clinical perspective is perhaps the most common approach to understanding overall utility and reasonable acceptance of risks and benefits. Two therapies recommended for the primary prevention of CHD in women are aspirin and lipid-lowering therapy. However, neither aspirin nor lipid-lowering therapy has been demonstrated to significantly reduce total mortality or CHD in women (2). On the other hand, the cumulated data indicate that ET reduces CHD and total mortality in women <60 years old (2-4). The risks associated with ET in postmenopausal women <60 years old are rare and of the same magnitude as aspirin and lipid-lowering therapy when used for primary prevention of CHD (2). In addition, ET, specifically CEE provides benefits beyond other primary prevention therapies, such as prevention of bone fractures (Table 2) (3,4).
Lipid-lowering medications, predominantly statins are one of the mainstays for the primary prevention of CHD. As clinical trials have primarily enrolled men, the cumulated data across 6 randomized trials and 11,435 women are not sufficiently large to demonstrate that lipid-lowering significantly reduces total mortality (Relative risk [RR], 0.95; 95% Confidence interval [CI], 0.62-1.46), CHD mortality (RR, 1.07; 95% CI, 0.47-2.40), CHD events (RR, 0.87; 95% CI, 0.69-1.09) or nonfatal myocardial infarction (RR, 0.61; 95% CI, 0.22-1.68) when used for primary prevention of CHD in women (6).
The cumulated data across 23 randomized controlled trials of 39,049 women followed for 191,340 patient-years indicate a 32% (Odds ratio [OR], 0.68; 95% CI, 0.48-0.96) significant reduction of CHD in women less than 60 years old or less than 10 years since menopause when randomized to HT relative to placebo (7). Under primary prevention conditions in WHI, CEE significantly reduced several composite CHD outcomes by approximately 34-45% in 3,310 postmenopausal women less than 60 years old (8).
In addition, the cumulated data indicate a 39% (OR, 0.61; 95% CI, 0.39-0.95) significant reduction in total mortality in women less than 60 years old who were randomized to HT relative to placebo (9). Recent WHI data show that CEE + medroxyprogesterone acetate (MPA) (HR, 0.71; 95% CI, 0.46-1.11) and CEE alone (HR, 0.69; 95% CI, 0.44-1.07) each reduce total mortality 30% relative to placebo (1). When both the WHI CEE and CEE + MPA data were combined, total mortality was significantly reduced 30% relative to placebo (HR, 0.70; 95% CI, 0.51-0.96) (1).
Unlike lipid-lowering therapy, ET reduces coronary artery calcium (10). The Coronary Artery Calcium Substudy of WHI (WHI-CACS) adds to the growing evidence that women who initiate ET in close proximity to menopause have reduced coronary artery atherosclerotic heart disease (2-4). As a direct measure of calcium, a component of atherosclerosis WHI-CACS provides insight into another mechanism by which ET reduces CHD (10). The effect of ET was greatest in the women who were the most compliant with ET consistent with the large body of evidence that ET reduces atherosclerosis, cardiovascular disease (CVD) and total mortality in women less than 60 years old (1-4,7-9,11).
WHI-CACS provides important information about a therapeutic effect of ET not seen with any other intervention for coronary artery disease, that is, the reduction of coronary artery calcium, a component of late stage atherosclerosis lesions. It has been hypothesized for many years that calcium within atherosclerotic plaques is immutable. For example, over 1 to 4 years of randomized intervention, even aggressive lipid-lowering therapy has failed to slow the progression of coronary artery calcium accumulation (12-14). Estrogen has effects on calcium metabolism at the arterial wall level that could account for its unique ability to reduce calcium content of atherosclerotic plaques (15,16).
Seven randomized controlled trials have reported the effect of statin therapy on breast cancer risk; the risk ranges from −10 to 75 additional breast cancers/10,000 women/year of statin therapy (Table 3). A recent meta-analysis reported data from 5 randomized controlled trials of statin therapy compared to placebo indicating a 33% (OR, 1.33; 95% CI, 0.79-2.26) increased risk of breast cancer associated with statin use, or 7 additional breast cancer cases/10,000 women who used statin therapy (17). A previous meta-analysis of 7 randomized controlled trials of statin therapy showed a 4% (RR, 1.04; 95% CI, 0.81-1.33) increased risk of breast cancer associated with statin use, or 2 additional breast cancer cases/10,000 women who used statin therapy (18). Site-specific cancers especially breast cancer incidence, have not been reported in all lipid-lowering randomized controlled trials and thus the breast cancer-related risk remains unknown across all lipid-lowering medications. Although the oncogenicity of lipid-lowering medications including statins is complex and incompletely understood, there is biological plausibility for induction of cancer in general and specifically for breast cancer (19-21).
After an average of 7.1 years of randomized treatment in the WHI trial, breast cancer was decreased with CEE therapy relative to placebo 18% (HR, 0.82; 95% CI, 0.65-1.04) resulting in 8 fewer cases of breast cancer/10,000 women/year of CEE therapy (Table 3) (22). The reduction in breast cancer incidence by CEE relative to placebo was seen across the entire 50 to 79 age range (23). More importantly, breast cancer was significantly reduced 33% in the women who were at least 80% compliant with ET (RR=0.67; 95% CI, 0.47-0.97) (22). In addition, breast cancer incidence was significantly reduced 29% in those women who developed the most common form of breast cancer, ductal carcinoma (HR, 0.71; 95% CI, 0.52-0.99) (22). In the Women's Estrogen for Stroke Trial (WEST), breast cancer incidence did not differ in women treated with 17B-estradiol alone compared to placebo (Table 3) (24).
Prophylactic use of aspirin for primary prevention of CHD is a common medical practice and recommended by major health organizations (25). However, the Women's Health Study (WHS) of 39,876 healthy women randomized to aspirin 100 mg every other day or placebo for 10 years showed a null effect of aspirin on the primary trial end point of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death (RR, 0.91; 95% CI, 0.80-1.03) (26). Total mortality and cardiovascular death from any cause were also unaffected by aspirin. Within the null finding was no significant effect on fatal or nonfatal myocardial infarction (RR, 1.02; 95% CI, 0.84-1.25) and a 17% (RR, 0.83; 95% CI, 0.69-0.99) reduction in stroke with aspirin relative to placebo (26). Although ischemic stroke was reduced 24% (RR, 0.76, 95% CI, 0.63-0.93) with aspirin relative to placebo, hemorrhagic stroke was increased 24% (RR, 1.24; 95% CI, 0.82-1.87) with aspirin (26).
Bleeding diatheses were all significantly increased with aspirin versus placebo in WHS (26). Any gastrointestinal bleeding was increased 22% (RR, 1.22; 95% CI, 1.10-1.34) with aspirin versus placebo and gastrointestinal bleeding requiring blood transfusion was increased 40% (RR, 1.40; 95% CI, 1.07-1.83) with aspirin versus placebo (26). The absolute increased risk for any gastrointestinal bleeding was 8 additional cases/10,000 women/year of aspirin use (26).
The other randomized controlled trials of aspirin that included women were of smaller size and shorter duration than WHS but showed similar magnitudes of risk with no overall reduction in cardiovascular events; Hypertension Optimal Treatment (HOT) (n=8883 women, 3.8 years) (27) and Primary Prevention Project (PPP) (n=2583 women, 3.6 years) (26,28).
It has been argued that the long-term risks associated with ET are unknown and that the adverse effects of ET increase as a woman ages. However, this argument can be made for all therapies used in the primary prevention of CHD since no CHD prevention has been studied over decades under randomized controlled trial conditions. In fact, ET is one of the longest studied primary prevention therapies, average 7.1 years of randomized controlled trial experience---longer than any statin trial. Additionally, HT and ET have the greatest information derived from observational studies in which women used HT for 10 to 40 years. WHI, other trials and observational studies (including the WHI observational study) demonstrate significant trends in the reduction of total mortality and CHD with time, indicating benefit on these outcomes with duration of therapy (Table 4) (2-4). Most importantly, there is no evidence to indicate that if a woman at 50 years old initiates ET that her risks from ET will increase as she ages. The assumption that events with ET will increase with time (in fact, WHI has shown the opposite (8,23)) contradicts the paradigm of prevention since with all preventive therapies, the earlier initiated the greater the benefit. All that WHI can tell us is that women who initiate ET at age 60 or less will have greater benefit than risk and women over 60 will have greater risk when initiating ET.
The cumulated data indicate that in postmenopausal women <60 years old, ET significantly reduces total mortality and CHD. In addition, the risks of concern for ET such as stroke and breast cancer were not elevated in postmenopausal women <60 years old. VTE associated with ET is rare and no greater than other commonly used medications. The risks and benefits of ET compare favorably to aspirin and lipid-lowering therapy for the primary prevention of CHD.
With the risks and benefits of ET in clinical perspective, the cumulated data indicate that ET is an effective therapy for the primary prevention of CHD if initiated in postmenopausal women <60 years old. The large and consistent body of observational and randomized controlled trial data indicate that in recently menopausal women, ET reduces total mortality and CHD. Surveying randomized controlled trial evidence indicates that ET has the strongest evidence for reducing both total mortality and CHD in postmenopausal women when initiated before age 60 (2-4).
The evidence for a preventive role of ET in certain postmenopausal women is stronger than ever (2-4). WHI has not only confirmed the known benefits of ET from observational studies but has also shown the relative safety of ET under randomized controlled conditions in women under age 60. WHI confirms 40 years of consistent observational data that women who initiate ET in close proximity to menopause have a significant reduction in total mortality and CHD. In addition, WHI has shown that ET (CEE) reduces breast cancer risk similar to that of SERM agents (29) and the remaining risk, VTE associated with ET is rare (<1/1,000). In general, the risks in women less than 60 years old who initiate ET in close proximity to menopause are no greater than other medications used for the primary prevention of CHD in women (2).
The Early versus Late Intervention Trial with Estradiol (ELITE) funded by the National Institute on Aging is designed to specifically address the ‘timing of initiation hypothesis’ (2-4) providing further insight into the effect of ET in young versus older postmenopausal women (30). Although the Kronos Early Estrogen Prevention Study (KEEPS), a privately funded trial does not have a comparative older group of women, it will provide insight into the effects of several HT regimens in young postmenopausal women.
Until shown otherwise, women and health care providers can feel comfortable that the cumulated data including those from WHI indicate that ET, in particular CEE, is safe and effective in reducing total mortality and CHD in women who initiate ET in close proximity to menopause.
Howard N. Hodis, Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology Professor of Medicine and Preventive Medicine Professor of Molecular Pharmacology and Toxicology Director, Atherosclerosis Research Unit Keck School of Medicine University of Southern California 2250 Alcazar Street, CSC 132 Los Angeles, CA 90033 (323) 442-1478 (323) 442-2685 Fax ; Email: ude.csu@orehta.
Wendy J. Mack, Atherosclerosis Research Unit Keck School of Medicine University of Southern California 1540 Alcazar Street, CHP 234 Los Angeles, CA 90033 (323) 442-1820 323) 442-2993 Fax ; Email: ude.csu@kcamw.