Cardiovascular Disease in Women: Update on Menopausal Hormone Therapy and Selective Estrogen Receptor Modulators (SERMs

1. Cardiovascular Disease in Women: Update on Menopausal Hormone Therapy and Selective Estrogen Receptor Modulators (SERMs)

2. “Hormone Replacement Therapy” Risk-Benefit Balance: 1960s-1990s Benefits CHD Osteoporosis Vasomotor Symptoms GU Symptoms Skin Preservation Risks 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. Source: Limacher 2002, Grady 1992.

3. Effects of Postmenopausal Estrogen Therapy on CVD Risk Factors 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 Sources: Grady 1992, Mendelsohn 1999, Espeland 1998

4. 15 Estrogen-Progestin Placebo 10 5 1 0 2 3 4 5 Heart and Estrogen/Progestin Replacement Study (HERS): Cumulative Incidence of CHD Events Incidence, % (113) (2763) (2631) (2506) (2392) (1435) Follow-up, yrs (No. at Risk) Source: Adapted from Hulley 1998

5. 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 5 Source: Writing Group for the WHI Investigators 2002

6. 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 6 Source: Writing Group for the WHI Investigators 2002

7. Women’s Health Initiative: Estrogen Alone in Postmenopausal Women Compared to Placebo: Major Clinical Outcomes * * Favors Treatment Favors Placebo * P < .05 Source: Adapted from WHI Steering Committee 2004

8. Hormone Therapy Risk-Benefit Balance: 2004 Benefits Vasomotor Symptoms Osteoporosis Vaginal Atrophy Colon Cancer Skin Preservation Depression Risks DVT/PE Gallbladder Disease Breast Cancer Breast/Bleeding Side Effects CHD Stroke Dementia Pancreatitis ?Ovarian Cancer Source: ACOG Task Force for Hormone Therapy 2004, Mosca 2004.

9. 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 9 Source: Hulley 1998, Rossouw 2002, Anderson 2004, Barrett-Connor 2006

10. Raloxifene Use for the Heart (RUTH) Trial: Primary and Secondary CVD Outcomes Number of events * p < .05 10 Source: Adapted from Barrett Connor 2006

11. 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 Sources: Mosca 2011, Lee 2005, Lonn 2005, Bønaa 2006, Loscalzo 2006. 11

12. What The Experts Are Saying About Hormone Therapy And Cardiovascular Disease NIH – “New analyses from the Women's Health Initiative (WHI) confirm that combination hormone therapy increases the risk of heart disease in healthy postmenopausal women. Researchers report a trend toward an increased risk of heart disease during the first two years of hormone therapy among women who began therapy within 10 years of menopause.” –“WHI Study Data Confirm Short-Term Heart Disease Risks of Combination Hormone Therapy for Postmenopausal Women,” NIH News, Monday, February 15, 2010 Source: Toh 2010 12

13. What The Experts Are Saying About Hormone Therapy And Cardiovascular Disease American Congress of Obstetricians & Gynecologists (ACOG): • “Menopausal HT should not be used for the primary or secondary prevention of CHD at the present.” • “Hormone therapy use should be limited to the treatment of menopausal symptoms at the lowest effective dosage over the shortest duration possible and continued use should be reevaluated on a periodic basis.” 13 Source: ACOG 2008

14. Ongoing Studies About Hormone Therapy: Does the Timing and Type of Estrogen Matter? • KEEPS: Kronos Early Estrogen Prevention Study • 660 women aged 48-52, randomized to placebo, oral conjugated equine estrogen, or transdermal 17 beta-estradiol with placebo or pulsed progesterone for 12 days/month • Endpoint: Progression of atherosclerosis measured by carotid intima media thickness and coronary artery calcification • ELITE: Early versus Late Intervention Trial with Estradiol • 504 women either less than 6 years from menopause or more than 10 years from menopause randomized to oral 17 beta-estradiol or placebo, with progesterone gel or placebo • Endpoint: Progression of atherosclerosis measured by carotid intima media thickness 14 Source: Miller 2009

15. Estrogen Alone Caused Stroke in Women’s Health Initiative • Women randomized to conjugated equine estrogen (CEE) for an average of 6.8 years had statistically significantly more strokes (odds ratio = 1.39) • Statistical analysis did not show that the risk of stroke was affected by age of initiation of therapy • Follow-up studies showed the risk of stroke was no longer elevated once CEE was discontinued 15 Source: Anderson 2004, LaCroix 2011

16. Estrogen Alone Did Not Effect CHD Events in WHI; After Cessation of Estrogen, Younger Women Who Had Taken CEE‡ Had Fewer CHD Events Number of CHD Events * Statistically significant difference Age at Initiation of CEE (Average 5.9 years of use and 10.7 years of follow up) ‡ CEE: conjugated equine estrogen 16 Source: Anderson 2004; LaCroix 2011

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