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Hormone Replacement Therapy for Prevention: More Evidence, More Pessimism

Hormone Replacement Therapy for Prevention: More Evidence, More Pessimism Most physicians and researchers were surprised by the results of the Heart and Estrogen/progestin Replacement Study (HERS).1 This randomized trial assessed the efficacy of hormone replacement for secondary prevention of coronary heart disease (CHD)—that is, the ability of hormone replacement therapy (HRT) to prevent CHD events in women with established coronary disease. After an average of 4.1 years of follow-up, there was no overall difference in CHD end points between women randomized to receive placebo or HRT given as a continuous combined regimen of 0.625 mg/d of estrogen plus 2.5 mg of medroxyprogesterone acetate. However, when these results were reported, based on a trend of decreasing risk of CHD events with increasing duration of HRT use, the HERS authors speculated that the HERS results were a consequence of domination of the antiatherogenic effects of HRT by its early thrombotic effects.1 The implication was that a net benefit for CHD would have been observed with longer durations of HRT use. This speculation was translated into a "don't start, don't stop" message for physicians: don't start HRT for women with coronary disease because of the increased risk of CHD events in the early years after initiation of use, but don't discontinue HRT in women who have used it for several years because they have already weathered the period of risk and have entered the late period of putative benefit. In this issue of THE JOURNAL, Grady et al2 report on CHD outcomes in a follow-up study of women recruited to HERS (HERS II). After an additional 2.7 years of follow-up, the anticipated overall net benefit of HRT use for coronary events did not materialize. The lower rates of coronary disease in long-term users of HRT were not sustained. In HERS II, treatment assignment was unblinded in 1998. Subsequent use of HRT was based on decisions made by women and their physicians. HERS II is not as robust as a design in which randomized assignment to placebo or HRT would have continued for all women recruited to the study. However, a remarkably low percentage of women who had been assigned to placebo (only 8%) began taking HRT after treatment assignment was unblinded, and 45% of women assigned to HRT remained adherent to HRT at the end of the follow-up period. Furthermore, the results of analyses of CHD end points based only on women who continued to use HRT according to their assigned treatment, as well as analyses that adjusted for differences between women who continued and did not continue treatment assignment, yielded results that were the same as the analysis based on original treatment assignment. Although women assigned to placebo were more likely to use statins than women assigned to HRT, differences in statin use did not explain the lack of benefit of HRT for prevention of CHD events in women with coronary disease. The findings of HERS and HERS II with regard to a lack of benefit of HRT in high-risk women are supported by findings of 2 randomized trials that assessed the effect of HRT on progression of atherosclerosis.3-5 The Estrogen Replacement Atherosclerosis trial3 randomized 309 postmenopausal women with angiographically verified coronary disease to receive placebo, estrogen replacement therapy (ERT) as 0.625 mg/d of conjugated equine estrogen, or HRT as daily estrogen plus progestin, as in HERS. After 3.2 years of follow-up, the mean minimal coronary artery diameter on repeat coronary angiograms was not significantly different among women assigned to placebo, ERT, and HRT. The findings were unchanged in an analysis limited to patients who complied with treatment. In the Postmenopausal Hormone Replacement Against Atherosclerosis trial,4,5 321 postmenopausal women with increased carotid intima-media thickness based on B-mode ultrasound were randomly assigned to receive placebo or 1 of 2 HRT regimens (1 mg/d of 17 β-estradiol, with administration from day 17 through day 28 of 0.025 mg of gestodene either every 4 weeks or every 12 weeks). After 48 weeks, there was no difference between the placebo and active treatment groups in progression of atherosclerosis measured as a change in carotid4 or femoral5 intima-media thickness. In HERS II, HRT provided no benefit for prevention of ischemic stroke, confirming a prior report from the randomized portion of HERS.6 The HERS and HERS II findings for ischemic stroke among high-risk women are consistent with the results of the Women's Estrogen for Stroke Trial.7 In this trial, 664 postmenopausal women who had recently had an ischemic stroke or transient ischemic attack were randomized to receive placebo or ERT as 1 mg/d of 17 β-estradiol. After 2.8 years of follow-up, the relative risk of nonfatal stroke in women assigned to ERT was 1.0 (95% confidence interval, 0.7-1.4). Also in this issue of THE JOURNAL, Hulley et al8 report on noncardiovascular end points in HERS II. An overall increase in the risk of venous thromboembolism and biliary tract surgery in HRT users, reported in other HERS publications,9,10 persisted. Of considerable importance, the risk of fracture was not decreased in HRT users in HERS II. Randomized trials have established the effectiveness of ERT and HRT in preventing postmenopausal bone loss.11 Epidemiologic studies are consistent in showing a decreased risk of hip fracture outcomes in users of estrogen.12 The lack of information about use of bisphosphonates and raloxifene after unblinding makes the HERS II findings on fracture somewhat difficult to interpret. These drugs have been shown in randomized trials to prevent fracture.13,14 For instance, if more women initially assigned to placebo initiated use of bisphosphonates or raloxifene after unblinding, any benefit of HRT use for fracture prevention would be obscured. However, the difference in use of these drugs between women initially assigned to placebo and those assigned to HRT would have to be very large to change the observed fracture risk in HRT users into a large overall decrease in fracture risk. Since the HERS results were published, many physicians have clutched at every hint that HRT might have benefit in preventing disease, death, and long-term disability in postmenopausal women. More evidence brings more pessimism about the preventive benefits of HRT and ERT. What then remains? It is possible that ERT or HRT might prevent CHD in women free of coronary disease. The Estrogen Prevention of Atherosclerosis Trial15 provides limited evidence. This trial assessed the effect of ERT on carotid intima-media thickness in 222 postmenopausal women without preexisting cardiovascular disease and low-density lipoprotein cholesterol levels of at least 130 mg/dL (≥3.37 mmol/L) who were randomized to receive placebo or 1 mg/d of 17 β-estradiol. After 2 years of follow-up, the rate of atherosclerosis progression measured as change in intima-media thickness was less in the ERT-treated group than in the placebo group, but the benefit of ERT was limited to women who did not also take a lipid-lowering medication. The Women's Health Initiative (WHI) is a randomized trial that has recruited 27 348 participants to its hormone replacement component.16 Women without a uterus have been randomized to receive placebo or ERT as 0.625 mg/d of conjugated equine estrogen; women with a uterus have been randomized to receive placebo or HRT as continuous combined estrogen plus progestin, as in HERS. While full results have not been published, following meetings of the WHI study's data and safety monitoring board in April 2000 and February 2001,17 it was announced that the risks of venous thromboembolism, stroke, and myocardial infarction were increased in women assigned to hormone replacement. A net benefit of ERT, HRT, or both in preventing vascular disease in the WHI would require these early increases in the risk of vascular events—stroke and CHD—to be offset by decreases in vascular risk in women with longer durations of use. This scenario was more plausible before publication of the HERS II results than now. Prospective observational studies continue to suggest that ERT might protect against cognitive decline18 and the development of dementia.19 Data on ERT and HRT to prevent cognitive decline and dementia are not consistent,20-22 however, and randomized trials of estrogen in the treatment of Alzheimer disease show no evidence of benefit.23,24 Observational studies of HRT and CHD were consistent, yet randomized trials have failed to confirm benefit. The WHI25 will address these issues, and observational research should continue since some studies show benefit of HRT only in the oldest old.18 Pessimism about HRT and ERT does not mean pessimism about disease prevention in postmenopausal women. Randomized trials that included women provide strong support for the use β-blockers26 and aspirin to prevent CHD events and ischemic stroke in women with coronary disease or a history of ischemic stroke or transient ischemic attack.27 The Heart Outcomes Prevention Evaluation (HOPE) trial showed that angiotensin-converting enzyme inhibitors prevent CHD events in women at high risk of cardiovascular disease.28 Randomized trials show that blood pressure control prevents stroke and CHD in women with hypertension.29 Aspirin use has a favorable risk-benefit ratio for primary prevention of CHD in high-risk women.30 Randomized trials support screening and treatment of dyslipidemia to prevent first CHD events in women with average serum cholesterol levels,31,32 and some lipid-lowering drugs may also prevent stroke.33 Randomized trials show that bisphosphonates and raloxifene prevent fracture in women with low bone mineral density or a history of fracture.13,14 An appropriately pessimistic view of HRT as an omnibus agent to prevent disease in postmenopausal women should focus more attention on these preventive interventions, which have a strong evidence base. References 1. Hulley S, Grady D, Bush T. et al. for the HERS Research Group. 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;280:605-613.Google Scholar 2. 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;288:49-57.Google Scholar 3. 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.Google Scholar 4. 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.Google Scholar 5. Angerer P, Stork S, Kothny W, von Schacky C. Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries. Maturitas.2002;41:51-60.Google Scholar 6. Simon JA, Hsia J, Cauley JA. et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation.2001;103:638-642.Google Scholar 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.Google Scholar 8. Hulley S, Furberg C, Barrett-Connor E. et al. for the 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.Google Scholar 9. Simon JA, Hunninghake DB, Agarwal SK. et al. Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med.2001;135:493-501.Google Scholar 10. Grady D, Wenger NK, Herrington D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med.2000;132:689-696.Google Scholar 11. O'Connell D, Robertson J, Henry D, Gillespie W. A systematic review of the skeletal effects of estrogen therapy in postmenopausal women, II: an assessment of treatment effects. Climacteric.1998;1:112-123.Google Scholar 12. Grady D, Rubin SM, Petitti DB. et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med.1992;117:1016-1037.Google Scholar 13. Black DM, Thompson DE, Bauer DC. et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. J Clin Endocrinol Metab.2000;85:4118-4124.Google Scholar 14. Ettinger B, Black DM, Mitlak BH. et al. for the MORE Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA.1999;282:637-645.Google Scholar 15. Hodis HN, Mack WJ, Lobo RA. et al. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med.2001;135:939-953.Google Scholar 16. The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials.1998;19:61-109.Google Scholar 17. Women's Health Initiative Web site. Available at: http://www.nhlbi.nih.gov/whi/index.html. Accessibility verified June 5, 2002. 18. Carlson MC, Zandi PP, Plassman BL. et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology.2001;57:2210-2216.Google Scholar 19. Tang MX, Jacobs D, Stern Y. et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet.1996;348:429-432.Google Scholar 20. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience.2000;101:485-512.Google Scholar 21. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA.2001;285:1489-1499.Google Scholar 22. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA.1998;279:688-695.Google Scholar 23. Henderson VW, Paganini-Hill A, Miller BL. et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology.2000;54:295-301.Google Scholar 24. Mulnard RA, Cotman CW, Kawas C. et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA.2000;283:1007-1015.Google Scholar 25. Shumaker SA, Reboussin BA, Espeland MA. et al. The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin Trials.1998;19:604-621.Google Scholar 26. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA.1993;270:1589-1595.Google Scholar 27. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ.1994;308:81-106.Google Scholar 28. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med.2000;342:145-153.Google Scholar 29. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet.2000;356:1955-1964.Google Scholar 30. Lauer MS. Clinical practice: aspirin for primary prevention of coronary events. N Engl J Med.2002;346:1468-1474.Google Scholar 31. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA.1999;282:2340-2346.Google Scholar 32. Downs JR, Clearfield M, Weis S. et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA.1998;279:1615-1622.Google Scholar 33. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA.1997;278:313-321.Google Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Hormone Replacement Therapy for Prevention: More Evidence, More Pessimism

JAMA , Volume 288 (1) – Jul 3, 2002

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References (42)

Publisher
American Medical Association
Copyright
Copyright © 2002 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.288.1.99
Publisher site
See Article on Publisher Site

Abstract

Most physicians and researchers were surprised by the results of the Heart and Estrogen/progestin Replacement Study (HERS).1 This randomized trial assessed the efficacy of hormone replacement for secondary prevention of coronary heart disease (CHD)—that is, the ability of hormone replacement therapy (HRT) to prevent CHD events in women with established coronary disease. After an average of 4.1 years of follow-up, there was no overall difference in CHD end points between women randomized to receive placebo or HRT given as a continuous combined regimen of 0.625 mg/d of estrogen plus 2.5 mg of medroxyprogesterone acetate. However, when these results were reported, based on a trend of decreasing risk of CHD events with increasing duration of HRT use, the HERS authors speculated that the HERS results were a consequence of domination of the antiatherogenic effects of HRT by its early thrombotic effects.1 The implication was that a net benefit for CHD would have been observed with longer durations of HRT use. This speculation was translated into a "don't start, don't stop" message for physicians: don't start HRT for women with coronary disease because of the increased risk of CHD events in the early years after initiation of use, but don't discontinue HRT in women who have used it for several years because they have already weathered the period of risk and have entered the late period of putative benefit. In this issue of THE JOURNAL, Grady et al2 report on CHD outcomes in a follow-up study of women recruited to HERS (HERS II). After an additional 2.7 years of follow-up, the anticipated overall net benefit of HRT use for coronary events did not materialize. The lower rates of coronary disease in long-term users of HRT were not sustained. In HERS II, treatment assignment was unblinded in 1998. Subsequent use of HRT was based on decisions made by women and their physicians. HERS II is not as robust as a design in which randomized assignment to placebo or HRT would have continued for all women recruited to the study. However, a remarkably low percentage of women who had been assigned to placebo (only 8%) began taking HRT after treatment assignment was unblinded, and 45% of women assigned to HRT remained adherent to HRT at the end of the follow-up period. Furthermore, the results of analyses of CHD end points based only on women who continued to use HRT according to their assigned treatment, as well as analyses that adjusted for differences between women who continued and did not continue treatment assignment, yielded results that were the same as the analysis based on original treatment assignment. Although women assigned to placebo were more likely to use statins than women assigned to HRT, differences in statin use did not explain the lack of benefit of HRT for prevention of CHD events in women with coronary disease. The findings of HERS and HERS II with regard to a lack of benefit of HRT in high-risk women are supported by findings of 2 randomized trials that assessed the effect of HRT on progression of atherosclerosis.3-5 The Estrogen Replacement Atherosclerosis trial3 randomized 309 postmenopausal women with angiographically verified coronary disease to receive placebo, estrogen replacement therapy (ERT) as 0.625 mg/d of conjugated equine estrogen, or HRT as daily estrogen plus progestin, as in HERS. After 3.2 years of follow-up, the mean minimal coronary artery diameter on repeat coronary angiograms was not significantly different among women assigned to placebo, ERT, and HRT. The findings were unchanged in an analysis limited to patients who complied with treatment. In the Postmenopausal Hormone Replacement Against Atherosclerosis trial,4,5 321 postmenopausal women with increased carotid intima-media thickness based on B-mode ultrasound were randomly assigned to receive placebo or 1 of 2 HRT regimens (1 mg/d of 17 β-estradiol, with administration from day 17 through day 28 of 0.025 mg of gestodene either every 4 weeks or every 12 weeks). After 48 weeks, there was no difference between the placebo and active treatment groups in progression of atherosclerosis measured as a change in carotid4 or femoral5 intima-media thickness. In HERS II, HRT provided no benefit for prevention of ischemic stroke, confirming a prior report from the randomized portion of HERS.6 The HERS and HERS II findings for ischemic stroke among high-risk women are consistent with the results of the Women's Estrogen for Stroke Trial.7 In this trial, 664 postmenopausal women who had recently had an ischemic stroke or transient ischemic attack were randomized to receive placebo or ERT as 1 mg/d of 17 β-estradiol. After 2.8 years of follow-up, the relative risk of nonfatal stroke in women assigned to ERT was 1.0 (95% confidence interval, 0.7-1.4). Also in this issue of THE JOURNAL, Hulley et al8 report on noncardiovascular end points in HERS II. An overall increase in the risk of venous thromboembolism and biliary tract surgery in HRT users, reported in other HERS publications,9,10 persisted. Of considerable importance, the risk of fracture was not decreased in HRT users in HERS II. Randomized trials have established the effectiveness of ERT and HRT in preventing postmenopausal bone loss.11 Epidemiologic studies are consistent in showing a decreased risk of hip fracture outcomes in users of estrogen.12 The lack of information about use of bisphosphonates and raloxifene after unblinding makes the HERS II findings on fracture somewhat difficult to interpret. These drugs have been shown in randomized trials to prevent fracture.13,14 For instance, if more women initially assigned to placebo initiated use of bisphosphonates or raloxifene after unblinding, any benefit of HRT use for fracture prevention would be obscured. However, the difference in use of these drugs between women initially assigned to placebo and those assigned to HRT would have to be very large to change the observed fracture risk in HRT users into a large overall decrease in fracture risk. Since the HERS results were published, many physicians have clutched at every hint that HRT might have benefit in preventing disease, death, and long-term disability in postmenopausal women. More evidence brings more pessimism about the preventive benefits of HRT and ERT. What then remains? It is possible that ERT or HRT might prevent CHD in women free of coronary disease. The Estrogen Prevention of Atherosclerosis Trial15 provides limited evidence. This trial assessed the effect of ERT on carotid intima-media thickness in 222 postmenopausal women without preexisting cardiovascular disease and low-density lipoprotein cholesterol levels of at least 130 mg/dL (≥3.37 mmol/L) who were randomized to receive placebo or 1 mg/d of 17 β-estradiol. After 2 years of follow-up, the rate of atherosclerosis progression measured as change in intima-media thickness was less in the ERT-treated group than in the placebo group, but the benefit of ERT was limited to women who did not also take a lipid-lowering medication. The Women's Health Initiative (WHI) is a randomized trial that has recruited 27 348 participants to its hormone replacement component.16 Women without a uterus have been randomized to receive placebo or ERT as 0.625 mg/d of conjugated equine estrogen; women with a uterus have been randomized to receive placebo or HRT as continuous combined estrogen plus progestin, as in HERS. While full results have not been published, following meetings of the WHI study's data and safety monitoring board in April 2000 and February 2001,17 it was announced that the risks of venous thromboembolism, stroke, and myocardial infarction were increased in women assigned to hormone replacement. A net benefit of ERT, HRT, or both in preventing vascular disease in the WHI would require these early increases in the risk of vascular events—stroke and CHD—to be offset by decreases in vascular risk in women with longer durations of use. This scenario was more plausible before publication of the HERS II results than now. Prospective observational studies continue to suggest that ERT might protect against cognitive decline18 and the development of dementia.19 Data on ERT and HRT to prevent cognitive decline and dementia are not consistent,20-22 however, and randomized trials of estrogen in the treatment of Alzheimer disease show no evidence of benefit.23,24 Observational studies of HRT and CHD were consistent, yet randomized trials have failed to confirm benefit. The WHI25 will address these issues, and observational research should continue since some studies show benefit of HRT only in the oldest old.18 Pessimism about HRT and ERT does not mean pessimism about disease prevention in postmenopausal women. Randomized trials that included women provide strong support for the use β-blockers26 and aspirin to prevent CHD events and ischemic stroke in women with coronary disease or a history of ischemic stroke or transient ischemic attack.27 The Heart Outcomes Prevention Evaluation (HOPE) trial showed that angiotensin-converting enzyme inhibitors prevent CHD events in women at high risk of cardiovascular disease.28 Randomized trials show that blood pressure control prevents stroke and CHD in women with hypertension.29 Aspirin use has a favorable risk-benefit ratio for primary prevention of CHD in high-risk women.30 Randomized trials support screening and treatment of dyslipidemia to prevent first CHD events in women with average serum cholesterol levels,31,32 and some lipid-lowering drugs may also prevent stroke.33 Randomized trials show that bisphosphonates and raloxifene prevent fracture in women with low bone mineral density or a history of fracture.13,14 An appropriately pessimistic view of HRT as an omnibus agent to prevent disease in postmenopausal women should focus more attention on these preventive interventions, which have a strong evidence base. References 1. Hulley S, Grady D, Bush T. et al. for the HERS Research Group. 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;280:605-613.Google Scholar 2. 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;288:49-57.Google Scholar 3. 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.Google Scholar 4. 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.Google Scholar 5. Angerer P, Stork S, Kothny W, von Schacky C. Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries. Maturitas.2002;41:51-60.Google Scholar 6. Simon JA, Hsia J, Cauley JA. et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation.2001;103:638-642.Google Scholar 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.Google Scholar 8. Hulley S, Furberg C, Barrett-Connor E. et al. for the 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.Google Scholar 9. Simon JA, Hunninghake DB, Agarwal SK. et al. Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med.2001;135:493-501.Google Scholar 10. Grady D, Wenger NK, Herrington D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med.2000;132:689-696.Google Scholar 11. O'Connell D, Robertson J, Henry D, Gillespie W. A systematic review of the skeletal effects of estrogen therapy in postmenopausal women, II: an assessment of treatment effects. Climacteric.1998;1:112-123.Google Scholar 12. Grady D, Rubin SM, Petitti DB. et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med.1992;117:1016-1037.Google Scholar 13. Black DM, Thompson DE, Bauer DC. et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. J Clin Endocrinol Metab.2000;85:4118-4124.Google Scholar 14. Ettinger B, Black DM, Mitlak BH. et al. for the MORE Investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA.1999;282:637-645.Google Scholar 15. Hodis HN, Mack WJ, Lobo RA. et al. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med.2001;135:939-953.Google Scholar 16. The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials.1998;19:61-109.Google Scholar 17. Women's Health Initiative Web site. Available at: http://www.nhlbi.nih.gov/whi/index.html. Accessibility verified June 5, 2002. 18. Carlson MC, Zandi PP, Plassman BL. et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology.2001;57:2210-2216.Google Scholar 19. Tang MX, Jacobs D, Stern Y. et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet.1996;348:429-432.Google Scholar 20. Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience.2000;101:485-512.Google Scholar 21. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA.2001;285:1489-1499.Google Scholar 22. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA.1998;279:688-695.Google Scholar 23. Henderson VW, Paganini-Hill A, Miller BL. et al. Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial. Neurology.2000;54:295-301.Google Scholar 24. Mulnard RA, Cotman CW, Kawas C. et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA.2000;283:1007-1015.Google Scholar 25. Shumaker SA, Reboussin BA, Espeland MA. et al. The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin Trials.1998;19:604-621.Google Scholar 26. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA.1993;270:1589-1595.Google Scholar 27. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ.1994;308:81-106.Google Scholar 28. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med.2000;342:145-153.Google Scholar 29. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet.2000;356:1955-1964.Google Scholar 30. Lauer MS. Clinical practice: aspirin for primary prevention of coronary events. N Engl J Med.2002;346:1468-1474.Google Scholar 31. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA.1999;282:2340-2346.Google Scholar 32. Downs JR, Clearfield M, Weis S. et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA.1998;279:1615-1622.Google Scholar 33. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA.1997;278:313-321.Google Scholar

Journal

JAMAAmerican Medical Association

Published: Jul 3, 2002

Keywords: hormone replacement therapy,negative attitude

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