Cardiovascular Disease in Women Module VI: Update on Menopausal Hormone Therapy and Selective Estrogen Receptor Modulators (SERMs) This slide set was updated April 2008.

Menopausal Hormone Therapy Observational Data and Assumptions Randomized Trial Data Summary of Current Prescribing Guidelines

“Hormone Replacement Therapy” Risk-Benefit Balance: 1960’s-1990’s Risks Benefits CHD Osteoporosis Vasomotor Symptoms GU Symptoms Skin Preservation SLIDE INFORMATION SOURCE: Limacher MC. Hormones and heart disease: what we thought, what we have learned, and what we still need to know. Trans Am Clin Climatol Assoc 2002; 113: 31-41. Hormone replacement therapy for menopausal women was widely advocated on the basis of perceived health benefits. By the 1990s, the most compelling argument for hormone replacement therapy was the belief, based on data from observational and cohort studies, that it prevented CHD(1). (1) Grady et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016-1037 Source: Limacher 2002

Postmenopausal Estrogen Therapy Meta-analysis of observational data: 35% CHD risk reduction in women using hormone therapy Lipid Effects:  LDL Cholesterol  Lipoprotein (a)  HDL Cholesterol Metabolic Effects:  Fasting glucose  Fasting insulin levels Fibrinolytic Effects:  tissue plasminogen activator,  plasminogen-activator inhibitor 1 SLIDE INFORMATION SOURCES: Grady et al., "Hormone therapy to prevent disease and prolong life in postmenopausal women" Ann Intern Med 1992; 117: 1016-1037; Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340:1801-1811; Espeland MA, et al. Effect of postmenopausal therapy on glucose and insulin concentrations. Diabetes Care 1998; 21:1589-1595. A meta-analysis of 32 epidemiological studies published in 1992 found a 35% reduction in CHD risk in women using hormone therapy. Other meta-analyses have found even greater reductions of up to 45% (1). Several mechanisms have been proposed to support a beneficial effect of estrogen on the cardiovascular system, including beneficial effects on lipid profile and coagulation, vasodilatory and antioxidant effects, and early restoration of endothelial integrity after injury (2). (1) Grady et al., "Hormone therapy to prevent disease and prolong life in postmenopausal women" AnnIntern Med 1992; 117: 1016-1037. (2) Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340:1801-1811. Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

HERS: Cumulative Incidence of CHD Events 2 3 4 5 1 10 15 Incidence, % Estrogen-Progestin Placebo SLIDE INFORMATION SOURCE: Hulley S, et al. 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. The Heart and Estrogen/Progestin Replacement study was the first randomized, blinded, placebo controlled trial testing the effects of hormone therapy in women with established coronary heart disease (1). 2763 women were enrolled; 1380 in the active treatment arm, and 1383 in the placebo arm(1). At the end of an average of 4.1 years of follow-up, there was no difference between groups for endpoint of nonfatal MI ,CHD death, or coronary revascularization(1). An increase in CHD events was found in year 1. The authors speculated this might be due to a prothrombotic, proarrythmic, or proischemic effect of estrogen treatment that is balanced over time by beneficial lipid effects(1) (1) Hulley S, et al. 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. (2763) (2631) (2506) (2392) (1435) (113) Follow-up, yrs (No. at Risk) Source: Adapted from Hulley 1998

Women’s Health Initiative Estrogen and Progestin Arm: Absolute Excess Risk Excess CHD events: 7/10,000 woman-years Excess stroke events : 8/10,000 woman-years Excess pulmonary emboli: 8/10,000 woman-years Excess invasive breast cancer: 8/10,000 woman-years SLIDE INFORMATION SOURCE: Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333. The Women’s Health Initiative randomized 16,608 healthy postmenopausal women (average age 63 years) to conjugated equine estrogen .625 mg/d and medroxyprogesterone acetate 2.5 mg/d or placebo(1). After a mean of 5.2 years of follow-up the study was stopped by the data and safety monitoring board because a global assessment of risks had outweighed potential benefits(1). Risks and benefits were expressed in terms of excess events for 10,000 woman-years of hormone use(1). (1) Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333. Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative Estrogen and Progestin Arm: Absolute Benefits Fewer colorectal cancers: 6/10,000 woman-years Fewer hip fractures: 5/10,000 woman-years SLIDE INFORMATION SOURCE: Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333. The Women’s Health Initiative randomized 16,608 healthy postmenopausal women (average age 63 years) to conjugated equine estrogen .625 mg/d and medroxyprogesterone acetate 2.5 mg/d or placebo(1). After a mean of 5.2 years of follow-up the study was stopped by the data and safety monitoring board because a global assessment of risks had outweighed potential benefits(1). Risks and benefits were expressed in terms of excess events for 10,000 woman-years of hormone use(1). (1) Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333. Source: Writing Group for the WHI Investigators 2002

Women’s Health Initiative: Estrogen Alone in Postmenopausal Women Compared to Placebo: Major Clinical Outcomes * SLIDE INFORMATION SOURCE: Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701-1712. In the estrogen-only arm of the WHI, no increase in CHD or breast cancer was demonstrated after an average of 6.8 years of follow-up. However, stroke risk did significantly increase, and consequently, total CVD risk was slightly increased (1). (1) Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701-1712. * * P < .05 Favors Treatment Favors Placebo Source: Adapted from WHI Steering Committee 2004

HT Risk-Benefit Balance: 2004 Risks DVT/PE Gallbladder Disease Breast Cancer Breast/Bleeding Side Effects CHD Stroke Dementia Pancreatitis ?Ovarian Cancer Benefits Vasomotor Symptoms Osteoporosis Vaginal Atrophy Colon Cancer Skin Preservation Depression SLIDE INFORMATION SOURCE: ACOG Task Force for Hormone Therapy. Summary of Balancing Risks and Benefits. Obstet Gynecol 2004; 104 (4 Suppl): 1S-129S. Randomized trials have shown no benefit of postmenopausal hormone therapy for CHD (1) Although not all possible preparations, doses, and routes of administration of hormone therapy have been studied, results of randomized trials have not shown any difference between preparations, and have shown similar results both for healthy women, and for those with CHD(1). Hormone therapy should not be started or continued for the prevention or treatment of CHD(1,.2). Initiation of hormone therapy for menopausal symptoms should be done with careful consideration of associated risk, including those related to CVD(1). (1) ACOG Task Force for Hormone Therapy. Summary of Balancing Risks and Benefits. Obstet Gynecol 2004; 104 (4 Suppl): 1S-129S. (2) Mosca L, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004; 109:672-693. Source: ACOG Task Force for Hormone Therapy 2004

Raloxifene Use for the Heart (RUTH) Trial: Primary and Secondary CVD Outcomes SLIDE INFORMATION SOURCE: Barrett-Connor E, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355: 125-37. The RUTH trial randomized 10,101 postmenopausal women with a mean age of 67. 5 years to the selective estrogen receptor modulator (SERM) raloxifene 60 mg daily, or placebo. Median follow-up was 5.6 years. Raloxifene had no significant effect on primary coronary events, CHD fatality, or strokes. Raloxifene use was associated with an increase in fatal stroke and venous thromboembolism that reached statistical significance. Raloxifene reduced the risk of invasive breast cancers and vertebral fractures. (1) (1) Barrett-Connor E, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355: 125-37. * * p < .05 Source: Adapted from Barrett Connor 2006

Interventions that are not useful/effective and may be harmful for the prevention of heart disease Hormone therapy and selective estrogen-receptor modulators (SERMs) should not be used for the primary or secondary prevention of CVD SLIDE INFORMATION SOURCE:Mosca L, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007: 115: 1481-501. Both the American College of Obstetricians and Gynecologists (ACOG) and the United States Food and Drug Administration (FDA) have concluded that hormone therapy should not be initiated or continued to prevent CVD in post-menopausal women(1,2). The RUTH trial (Raloxifene Use for the Heart) found that raloxifene did not significantly affect the risk of CHD or stroke, but did find an association between the use of raloxifene and fatal stroke, compared to placebo (hazard ratio 1.49, confidence interval 1.00-2.24) (3). (1) American College of Obstetricians and Gynecologists Task Force for Hormone Therapy. Executive summary. Obstet Gynecol 2004; 104(4 Suppl): 1S-4S. FDA approves new labels for estrogen and estrogen plus progestin therapies for postmenopausal women following review of Women’s Health Initiative data. Rockville, Md: Food and Drug Administration, January 8, 2003. Barrett-Connor E,, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women N Engl J Med 2006; 355: 125-37. Source: Mosca 2007

Menopausal Hormone Therapy, SERMs and CVD: Summary of Major Randomized Trials Use of estrogen plus progestin associated with a small but significant risk of CHD and stroke Use of estrogen without progestin associated with a small but significant risk of stroke Use of all hormone preparations should be limited to short term menopausal symptom relief Use of a selective estrogen receptor modulator (raloxifene) does not affect risk of CHD or stroke, but is associated with an increased risk of fatal stroke SLIDE INFORMATION SOURCES: Hulley S, et al. 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.; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333.; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701-1712.,;ACOG Task Force for Hormone Therapy. Summary of Balancing Risks and Benefits. Obstet Gynecol 2004; 104 (4 Suppl): 1S-129S; Barrett-Connor E, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women N Engl J Med 2006; 355: 125-37. Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006