Clinical Trials Examining Postmenopausal Hormone Use for Secondary Prevention
The Heart and Estrogen Replacement Study (HERS I) 17 was the first secondary prevention trial to determine if HRT altered the risk of cardiovascular events in women with known CHD (Table 1). An unexpected finding was that there was no significant difference in the risk for cardiac events in women taking HRT compared to women taking placebo. In addition, there was a significant time trend, indicating more cardiac events for women within the first few years of initiating HRT. A clinical recommendation from this study was that HRT should not be used for the secondary prevention of heart disease. Like PEPI, however, there were improvements in the lipid profiles of women taking HRT. Since HERS I reported decreased cardiac events in years 3 to 5 of the study, it was possible that long-term HRT might reduce future cardiac events by sustained lipid improvements. Therefore, HERS II 18 was conducted (Table 1). This was an unblinded follow-up of 2.7 additional years with women from HERS I who agreed to participate. Unfortunately, HERS II did not demonstrate a reduced risk of cardiac events in women taking HRT. The recommendation not to use HRT for secondary prevention was sustained.
Other studies for the secondary prevention of heart disease have also been conducted (Table 1). Two studies have included measurements of intermediate endpoints, such as progression of atherosclerosis and lipid improvements. The Estrogen Replacement and Atherosclerosis (ERA) Study reported no difference in angiographic data at 3 years follow-up suggesting that ERT and HRT did not alter the progression of coronary atherosclerosis, although lipid improvements were consistent with other trials. 19 The Womens' Estrogen/Progestin Lowering Hormone Atherosclerosis Regression Trial (WELLHART) is examining whether ERT and/or HRT alters the extent of atherosclerosis examined via cardiac angiogram and carotid ultrasound in postmenopausal women on lipid lowering therapy; data will be published in 2003 (F. Watcher, personal communication, January 2003).
Other secondary prevention studies (Table 1) have included the Women's Estrogen for Stroke Trial (WEST), 20 the PAPworth HRT Atherosclerosis Study (PHASE), 21 the Estrogen in Prevention of Reinfarction Trial (ESPRIT), 22 and the Women's Angiographic Vitamin and Estrogen Trial (WAVE). 23 All of these studies reported either no cardiovascular benefit or increased risk when taking hormone therapy. Findings from the Estrogen and Graft Atherosclerosis Research (EAGAR) are forthcoming. 24
Clinical Trials Examining Postmenopausal Hormone Use for Primary Prevention
The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) examined the progression of subclinical atherosclerosis, an intermediate end point. 25 The rate of progression of carotid intima-media thickening was slower in women taking ERT as well as in those not on lipid medications (probably because they were healthier). These findings were inconsistent with previous research, and the reason for this may be that EPAT included younger women without known heart disease. The authors suggest that early intervention in the progression of atherosclerosis, especially at the start of menopause, may be the key to the prevention of CVD.
The WHI is the largest randomized, controlled primary prevention trial to be conducted in the United States (planned duration 8.5 years). 5 Over 160,000 postmenopausal women aged 50 to 79 years have been enrolled into the clinical trial(s) (testing post-menopausal hormone use, low-fat dietary patterns, and calcium and vitamin D supplementation) or the observational study. For the hormone trials of the WHI, women with a uterus were randomized to HRT (conjugated equine estrogen (CEE) 0.625 mg/day plus continuous medroxyprogesterone acetate (MPA) of 2.5 mg/day, ie, continuous-combined therapy, Prempro) or placebo. Women without a uterus were randomized to either ERT (CEE 0.625 mg/day) or placebo. The primary outcome of the estrogen plus progestin was CHD, while hip fractures were secondary outcomes. Invasive breast cancer was designated as the primary adverse outcome. Additional outcomes included other CVDs (stroke and thromboembolism), cancers (endometrial and colon), and fractures (vertebral). 5 After a mean of 5.2 years of follow-up, a data safety monitoring board recommended stopping the HRT trial because the “test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect.” 5 (p321) These findings stunned the medical community because the risks for HRT appeared to outweigh the benefits that were necessary for a primary prevention therapy.
The findings from the combined estrogen plus progestin trial of the WHI revealed that the relative risk for CHD, as well as other diseases, was significantly greater in women taking HRT compared to those on placebo (Table 2). The assumption in the calculation of relative risk is that those who are not taking HRT have a risk of “1.” The relative risk of CHD for women taking HRT was 1.29 with a confidence interval of 1.02 to 1.63. This means that the elevated risk from taking HRT ranged from 0.02 to 0.63, which is equivalent to an increased relative risk ranging from 2% to 63%. The best estimate was 0.29 or 29% greater risk among those taking HRT compared to those taking placebo. While this percentage reflecting the increased risk for the HRT group seems high, the actual annual increased risk, or absolute risk, in the population was quite small. Regardless of treatment, women of this age group will suffer cardiac events. During a year of the WHI, on an average there were 37 CHD events, defined as nonfatal MI or CHD death, per 10,000 women in the HRT group compared to 30 events per 10,000 women in the placebo group. This means there were 7 more women per 10,000 in the HRT group who suffered cardiac events. This increased risk was evident in the first year of the study.
Similarly, there was a 41% increased relative risk for stroke. In terms of absolute risk, there were 8 more women per 10,000 in the HRT group who had stroke events compared to the non-HRT users. Risk of venous thromboembolism was associated with the greatest increased relative risk (111%) in HRT users. About 18 more women per 10,000 in the HRT group had venous thromboembolism (deep vein thrombosis or pulmonary embolism) than in the placebo group. Although there was a 26% increase in relative risk for invasive breast cancer in the HRT group, it was not statistically significant. However, 8 more women per 10,000 in the HRT group developed invasive breast cancer. There was a 37% decrease in the relative risk of colorectal cancer for women taking HRT. In terms of absolute risk, 6 fewer women per 10,000 who took HRT developed colon cancer. Finally, HRT was associated with a 34% decreased relative risk in hip fractures. Five fewer women per 10,000 developed hip fractures in the HRT group. In terms of overall death, there was no significant difference between groups. The conclusions from the WHI were that (1) overall health risks exceeded the benefits when taking continuous-combined CEE plus MPA (Prempro) for an average of 5.2 years, (2) the risk-benefit profile is not acceptable for the primary prevention of chronic diseases, and (3) Prempro should not be initiated or continued for the primary prevention of CHD.
Potential Reasons for Lack of Cardioprotective Effect of Replacement Therapy
Why have clinical trials of hormone therapy failed to show protection from CVD as was suggested by observational studies? Both methodologic and biologic factors have been reported as possible explanations for the difference in the findings. 11 The methodologic factors contributing to study differences include a healthy user effect, compliance bias, and incomplete capture of early clinical events in the observational studies. In these studies, women who took estrogen were more likely to be healthy and have better access to the healthcare system (healthy user effect). These women were probably compliant users because they were seeking treatment for relief of menopausal symptoms or osteoporosis and may have been more willing to take estrogen (compliance bias). In contrast, in the WHI, it was reported that for women taking estrogen plus progestin, 42% had stopped the drug some time during the study. Finally, observational studies may not have captured earlier cardiac events because of study design. For example, in the Nurses' Health Study, 7,8 data were collected at 2-year intervals. Since it has been reported that the cardiovascular events associated with HRT were greatest with the initiation of therapy (both HERS and WHI), observational studies may not have captured these early events.
The biologic factors contributing to study differences may have to do with the women's age at the initiation of hormone therapy, genetic factors, and the drug regimen used. Findings from primate studies suggest that one reason for the differences may be the “timing” of the initiation of hormone therapy. 26 In observational studies such as the Nurses' Health Study, women were younger (age ranged from 30 to 55 at enrollment), and most began hormone replacement within 2 years after menopause. 11 In most of the clinical trials (Table 1), hormone therapy was started long after menopause (63 and older). Indeed by age 65, most women have already developed advanced atherosclerotic lesions; ie, “vulnerable” plaque having a necrotic core and covered with a fibrous cap. 27 Estrogen has been shown to have effects that mitigate the development of atherosclerosis, such as inhibiting vascular smooth muscle proliferation and migration, stimulating the proliferation of vascular endothelial cells, facilitating vasodilation, inhibiting platelet activation, and decreasing expression of adhesion molecules that facilitate sticking of leukocytes to the vessel wall (which is important in the inflammatory response), and decreased calcium deposition. 13,14,28,29 In arteries with advanced atherosclerosis these protective actions of estrogen are reduced or absent. 26 In addition, most recently, HRT has been shown to increase matrix metalloproteinase-9 (MMP-9), which can degrade the fibrous cap of vulnerable plaque and cause rupture, 26,30 thereby precipitating a possible cardiac event. Therefore, HRT initiated in older postmenopausal women may increase the occurrence of negative cardiac events because of established atherosclerosis. 26
It may also be that hormone therapy is protective for some women but harmful to others depending on their genetic profile. Most of the negative cardiovascular effects of hormone therapy demonstrated in clinical trials are related to increased thrombosis. Two coagulation factor mutations, factor V Leiden (FVL) and prothrombin G20210A have been shown to interact synergistically with HRT to increase the risk of venous thromboembolism. 31 FVL causes expression of an abnormal blood protein, which results in an increased tendency toward coagulation. 31,32 Prothrombin G20210A mutation results in increased prothrombin levels. 31,33 Both of these mutations would tend to tip regulation of thrombosis toward a prothombotic state. Therefore, a genetic/drug interaction may explain why there is an early increased risk of negative events in hormone therapy clinical trials.
A major limitation of our current knowledge regarding the effect of hormone therapy on the incidence of negative cardiac events is that the largest trial, the WHI, used only one drug regimen (ie, continuous-combined CEE and MPA, Prempro) (Table 1). It is now understood that there is a complex relationship between estrogen and progesterone. Estrogen up-regulates the progesterone receptor whereas progesterone down-regulates the estrogen receptor. 34 Physiologically this makes sense relative to the menstrual cycle (early phase of the cycle is estrogen dominant and the later phase is progesterone dominant). Given the relationship between the two hormones and their receptors, it is difficult to know the effect of giving both hormones together daily. It is possible that this regimen may negate the putative benefits of estrogen.
Another major limitation is that the WHI and most other trials used one protocol (ie, continuous-combined daily doses of CEE and MPA, Prempro), which cannot be generalized to other protocols whereby an estrogenic drug would be given alone for a period of time, followed by the addition of progesterone for a period of time such as was used in the PEPI trial. In addition, the use of other estrogenic and progestogenic agents (eg, norethindrone acetate/ethinyl estradiol tablets, FemHRT) are being explored such as in the Women's Ischemia Syndrome Evaluation (WISE) FemHRT Ancillary Study (Dr N. B. Merz, personal communication, July 2003). Because the ERT trial of the WHI is still in progress, the cardioprotective effects of CEE given alone in women without a uterus are unknown.
Adherence to the protocol was also an issue in the WHI. It was reported that many women stopped drug therapy at some time (42% estrogen plus progestin and 38% placebo) or initiated drug therapy through their own personal clinician (6.2% estrogen plus progestin and 10.7% of placebo). It has been suggested that because of moderate adherence rates in the trial, the results reported may actually under-represent both adverse and the beneficial effects of HRT.
Finally, another limitation of the WHI and the other clinical trials was the lack of minority representation. The estrogen plus progestin trial of the WHI had the following racial/ethnic distribution: 84% White, 7% Black, 5% Hispanic, 2% Asian/Pacific Islander, 0.5% American Indian, and 1.5% unknown. This distribution was consistent or somewhat better than most of the secondary prevention trials (eg, percent of individuals in ethnic minority groups: HERS 11%, ERA 18%, WEST 16%, ESPRIT 3%). The EPAT study, which reported positive effects from unopposed ERT on subclinical atherosclerosis (Table 1), had the largest ethnic minority sample (42%). These findings suggest the need to examine the benefits and risks of different hormone preparations on larger samples of racial and ethnic groups.
Clinical Practice Recommendations
It is important to remember that the primary indication approved by the FDA for hormone therapy has been the treatment of menopausal symptoms (eg, hot flashes and vaginal dryness). Although epidemiologic evidence was originally thought to be strong for post-menopausal use of estrogen in the prevention of heart disease, clinical trial evidence does not support these findings. Research indicates that at least the hormone agents and regimens reported in these clinical trials (Table 1) should not be used for primary or secondary prevention. Instead, established methods to lower cardiac risk in women should be used, such as controlling blood pressure and cholesterol through lifestyle and drug therapy. 35 Although there may be a need to use HRT for the treatment of menopausal symptoms, current recommendations include taking the lowest dose for the shortest period of time. 36
Future of Postmenopausal Hormone Use in Disease Prevention
Whether HRT can be cardioprotective in younger women, at lower doses, and with different preparations, is open for investigation. Because of the potential breast cancer risk involved with long-term use and the significant cost of another large, clinical trial to examine this benefit, it is doubtful that this research will be conducted.
For this reason and others, researchers are examining designer estrogens, called selective estrogen receptor modulators (SERMs), for their effects in disease prevention. 37 For example, a study of Raloxifene for the Use in the Heart (RUTH) is currently being conducted. This clinical trial is examining 10,000 postmenopausal patients at risk for CHD to see if this drug can prevent coronary events. 38 It should be noted, however, that raloxifene does not help menopausal symptoms, and in some cases may actually exacerbate symptoms. 37
Since there are estrogen receptors in many tissues of the body, the ability to differentially stimulate or inhibit the estrogen receptor in target tissues will be important in the development of new SERMS. Further research on the effect of progesterone on receptor activity as well as the relationship between estrogen and progesterone is needed. The ideal SERM would work in the brain to prevent hot flashes and enhance memory, in the bloodstream to prevent blood clots, in the breast and reproductive track to prevent cancer, in the liver to improve the lipid profile, and in the bones to prevent osteoporosis. For now, however, the use of HRT for cardioprotection should not be advocated. Traditional strategies such as diet and exercise must continue to be recommended for the primary and secondary prevention of CVD.
1. North American Menopause Society. Clinical challenges of perimenopause: consensus opinion of the North American Menopause Society. Menopause
2. North American Menopause Society. Menopause Guidebook: Helping Women Make Informed Decisions Through Perimenopause and Beyond
. Cleveland, Ohio: North American Menopause Society; 2003.
3. American Heart Association. Heart Disease and Stroke Statistics—2003 Update
. Dallas, Tex: American Heart Association; 2002.
4. Mosca L, Collins P, Herrington D, et al, for American Heart Association. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation
5. 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.
6. Bush T, Barrett-Connor E, Cowan L, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Clinics Research Program follow-up study. Circulation
7. Stampfer M, Colditz G, Willett W, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses' Health Study. N Engl J Med.
8. Grodstein F, Manson J, Colditz G, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med.
9. Henderson B, Paganini-Hill A, Ross R. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol
10. Penckofer S, Schwertz D. Hormone replacement therapy: primary and secondary prevention. J Cardiovasc Nurs
11. Grodstein F, Clarkson T, Manson J. Understanding the divergent data on postmenopausal hormone therapy. New Engl J Med.
12. Michels K, Manson JE. Postmenopausal hormone therapy: a reversal of fortune. Circulation
13. Schwertz D, Penckofer S. Sex differences and the effects of sex hormones on hemostasis and vascular reactivity. Heart Lung
14. Christian RC, Harrington S, Edwards WD, et al. Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women. J Clin Endocrinol Metab.
15. The Writing Group, for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA.
16. The Writing Group, for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in post-menopausal women: the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA.
17. 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.
18. Grady D, Herrington D, Bittner V, et al, for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA.
19. Herrington D, Reboussin D, Brosnihan B, et al. Effects of estrogen replacement on the progression of coronaryartery atherosclerosis. N Engl J Med.
20. Viscoli C, Brass L, Kernan W, et al. A clinical trial of estrogen replacement therapy after ischemic stroke. N Engl J Med.
21. Clark S, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacement in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study. BJOG
22. Espirit Team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet
23. Waters D, Alderman E, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA.
25. Hodis H, Mack W, Lobo R, et al. Estrogen in the prevention of atherosclerosis. Ann Intern Med.
26. Karas R, Clarkson T. Considerations in interpreting the cardiovascular effects of hormone replacement therapy observed in the WHI: timing is everything. Menopausal Med.
27. Clarkson T. The new conundrum: do estrogens have any cardiovascular benefit. Int J Fertil
28. Thompson J, Khalil RA. Gender differences in the regulation of vascular tone. Clin Exp Pharmacol Physiol
29. Jayachandran M, Miller VM. Molecular and cellular mechanisms of estrogen's action. In: Douglas PS, ed. Cardiovascular Health and Disease in Women.
2nd ed. Philadelphia: Saunders; 2002:207–230.
30. Zanger D, Yang BK, Ardans J, et al. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol
31. Rossouw J. Early risk of cardiovascular events after commencing hormone replacement therapy. Curr Opin Lipidol
32. Glueck CJ, Wang P, Fontaine RN, et al. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the factor V Leiden mutation (resistance to activated protein C). Am J Cardiol
33. Glueck CJ, Wang, P Fontaine RN, et al. Interaction of estrogen replacement therapy with thrombophilic 20210 G/A prothrombin gene mutation for atherothrombotic vascular disease: a cross sectional study of 275 hyperlipidemic women. Metabolism
34. Bulun SE, Adashi EY. The physiology and pathophysiology of the female reproductive axis. In: Larsen PR, Kronenberg H, Melmed S, Polansky KS, eds. Williams Textbook of Endocrinology
. 10th ed. Philadelphia: Saunders; 2003:611.
35. Pearson T, Blair S, Daniels S, et al. AHA Guidelines for primary prevention of cardiovascular disease and stroke: 2002 update. Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation
. 2002; 106:388–391.
36. North American Menopause Society. Amended report from the NAMS advisory panel on postmenopausal hormone therapy. Menopause Manage
37. Riggs L, Hartmann L. Review article: selective estrogen-receptor modulators-mechanisms of action and application to clinical practice. New Engl J Med.
38. Mosca L, Barrett-Connor E, Wenger N, et al. Design and methods of the raloxifene use for the heart (RUTH) study. Am J Cardiol
Keywords:© 2003 Lippincott Williams & Wilkins, Inc.
clinical trials; coronary heart disease; estrogen; hormone replacement therapy; Women's Health Initiative