Financial Conflicts of Interest

Hormone Treatment of Menopausal Women: What Are the Data Telling Us (and Not Telling Us)? S. Mitchell Harman, M.D., Ph.D. Chief, Endocrine Division Phoenix VA Health Care System Clinical Professor, Medicine University of Arizona College of Medicine Financial Conflicts of Interest The author has no conflicts to declare (but wishes he did). 1

Mortality Rate per 1, History of the Research Evidence that menopause is related to CVD Epidemiologic/observational studies The Heart and Estrogen/Progestin Replacement Study (HERS) and the Women s Health Initiative (WHI) Hormone Trials, initial interpretations The WHI Hormone Trials, revisited: Revisionist views and follow-up studies New RCT data since the WHI Mortality Rates in Women for Different Diseases by Age in Five Year Groups 6 56 16 12 Heart Disease* Lung Cancer Breast Cancer Colon & Rectal Cancer Stroke* Endometrial Cancer 8 4 45-54 55-64 65-74 75-84 85 Age (years) *Mean of years 1995-1998; 1994-1998. Eberhardt MS, et al. Health, United States, 21. Hyattsville, Md: National Ctr for Health Statistics; 21:189,192. Ries LAG, et al. SEER Cancer Statistics Review, 1973-1998. Bethesda, Md: National Cancer Institute; 21. 2

Incidence / 1, Incidence (per 1, women) Incidence of Cardiovascular Events in Women Before and After the Menopause 35 3 25 Average Age of Menopause 2 15 1 5 2-24 25-29 3-34 35-39 4-44 45-49 5-54 55-59 6-64 >65 Age Range F. B. Hu et al. New Engl J Med, 2; 343:53-7 Incidence of Cardiovascular Disease: Relation to Menopause Status Total 28,67 Woman Years 7 6 5 4 Premenopausal Postmenopausal 5 15 5 49 3 2 1 1 3 3 9 <4 4-44 45-49 5-54 Age (years) Kannel W, et al. Ann Intern Med. 1976;85:447-52. 3

Observational Data Before the year 2, research on estrogens, the menopause, and cardiovascular disease (CVD) was mainly limited to retrospective epidemiologic and prospective observational studies comparing rates of CVD in women for whom estrogen was or was not prescribed. Rates of cardiovascular events and all-cause mortality were the usual outcomes reported. Circumstantial Evidence for Cardioprotection by Estrogen? There are multiple plausible mechanisms by which estrogens could help prevent or delay CVD: Lipid effects- lower LDL and Lpa, higher HDL Antioxidant effects- decreased lipid oxidation Vascular effects- ENOS upregulation, vasodilation Inhibition of platelet aggregation Increased prostacyclin (COX-2 activity) Decreases in cell adhesion molecules (CAMs) Impaired CAM tethering of leucocytes Decreases in inflammatory factors (TNF-, IL-6, MCP-1, fibrinogen) Epidemiologic/Observational Studies suggested 4-5% reduction in CHD rates in women taking estrogen 4

Observational Studies of ERT/HRT and CHD Relative Risk Stampfer MJ, et al, 1985 Bush TL, et al, 1987 Petitti DB, et al, 1987 Boysen G, et al, 1988 Criqui MH, et al, 1988 Henderson BE, et al, 1988 van der Giezen AM, et al, 199 Wolf PH, et al, 1991 Falkeborn MI, et al, 1992 Psaty BM, et al, 1994 Folsom AR, et al, 1995 Grodstein F, et al, 1996.5 1. 2. 5. Relative Risk (Hazard Ratio) Adjusted* Relative Risk of Death Among All Postmenopausal Women in the Nurses Health Study Cause of Death NEVER All Causes No. of cases 251 574 112 Relative risk (95% CI) 1..63 (.56-.7) 1.3 (.94-1.12) Coronary Heart Disease No. of cases 289 43 129 Relative risk (95% CI) 1..47 (.32-.69).99 (.75-1.3) Stroke No. of cases 91 28 48 Relative risk (95% CI) 1..68 (.39-1.16) 1.7 (.68-1.69) All Cancer No. of cases 113 353 529 Relative risk (95% CI) 1..71 (.62-.81) 1.4 (.92-1.17) Breast Cancer No. of cases 246 85 94 Relative risk (95% CI) 1..77 (.59-1.).83 (.63-1.9) *CI = Confidence Interval. Values are adjusted for age, age at menopause, type of menopause, BMI, DM, high BP, high cholesterol, smoking, OC use, family H/O MI or breast Ca, parity From: Colditz, et al. N Engl J Med;336:1769-75 (1997) Hormone Use CURRENT PAST 5

Months Highest High Average Low Lowest Estimated Change in Life Expectancy with MHT 4 35 3 25 2 15 1 5-5 -1 Quintiles for Breast Cancer Risk Highest High Moderate Low Lowest Quintiles for Cardiovascular Disease Risk From: Col, et al. JAMA 277:114-1147 (1997) Selection bias Inherent Biases in Observational Studies Healthier women prescribed HT Prevention bias Monitoring and treatment of CVD risk factors more intensive in women prescribed HT Compliance bias Patients with greater adherence (even to placebo) may have better outcomes Survivor bias HT may be stopped due to illness and those women counted as nontreated Prevalence-incidence bias Early adverse effects of HT not observed if user dies before becoming eligible for inclusion in cohort 6

Prospective Trials: HERS and the WHI The need for randomized prospective trials of estrogen effect on CVD risk in menopausal women was widely appreciated, but the magnitude of the effort required to reach acceptable power was daunting Heart and Estrogen/Progestin Replacement Study (HERS)- A trial of secondary prevention Womens Health Initiative (WHI) Hormone Studies- A trial of primary prevention HERS: A Secondary Prevention Trial Goal: Determine CHD event risk in women with documented CHD MI, CABG, cutaneous angioplasty, or 5% narrowing of coronary artery 2763 postmenopausal women (average age 67) randomized to receive either CEE.625, CEE with MPA 2.5 mg daily, or placebo During the average follow-up of 6.8 yrs, the incidence of myocardial infarctions and coronary deaths were about the same in both groups 7

HERS Trial: Clinical Outcomes Outcome RR (95% CI) Total mortality Nonfatal and fatal MI CABG Percutaneous revascularization Stroke / TIA Venous thromboembolism Gallbladder disease All cancers Breast cancer 1.8 (.84-1.38).99 (.8-1.22).87 (.66-1.16).95 (.77-1.17) 1.13 (.85-1.48) 2.89 (1.5-5.58) 1.38 (1.- 1.92) 1.12 (.84-1.5) 1.3 (.77-2.19) JAMA. 1998;28(7):65-613. HERS: Conclusion Estrogen treatment should not be used to reduce the risk of CVD events in older postmenopausal women with established coronary heart disease. 8

% of Enrolled Population Women s Heath Initiative (WHI) Hormone Trials Randomized, double-blinded placebo-controlled trials- intended as test of primary prevention in women ages 5-79, planned for 8.5 years Estrogen + Progestin (uterus intact); stopped at 5.2 years PremPro.625 CEE/2.5 MPA daily); n=856 Placebo; n=812 Estrogen alone (hysterectomized); stopped at 6.8 years Premarin.625 CEE daily; n=531 Placebo; n=5429 Endpoints Cardiovascular events (new heart attack, cardiac death,) Other clinical events (fractures, cancers, VTE, stroke) WHI E+P Trial: Subject Characteristics Mean age 63 BMI 28.5 kg/m 2 Past User 2% Current User 6% Never User 74% 5 4 3 2 1 N=751 N=5522 N=3576 5-59 6-69 7-79 Age Hormone Use Prior to Study Entry 9

Outcomes Clinical Event Incidences in the WHI Estrogen + Progestin Arm vs. Placebo CHD Events Deaths All Fractures DVT/PE Strokes 67 151 86 127 122 164 218 231 2.11 (1.58-2.82) 1.41 (1.7 1.85) 1.24 (1. 1.54)* 293 Breast Cancer 385 1.25 (1.7-1.46) 46 5 1 15 2 JAMA 22 288:321-333 Number per 1, Women per Year * Manson, et al. New Engl J Med, 23;349:53 Chlebowski RT, et al. JAMA 21;34:1684 (12 y follow-up data) 67.98 (.82-1.18) 65 788 Colon Cancer.63 (.43-.92).76 (.69-.85) Placebo E + P Clinical Outcomes in the E-only Arm of the WHI HT Trial Fractures 53 724.7 (O.63-.79) Breast Cancer Thromboembolic Disease Stroke Coronary Heart Disease 124 94 78 11 118 158 199 177.75 (.51-1.9)* 1.33 (O.99-1.79) 1.39 (1.1-1.77).91 (O.75-1.12) Placebo CEE 5 1 15 2 25 Rates per 1, Women/Year JAMA 24:291;171-1712 * LaCroix, JAMA 211:35:135-1314 (1.7year f/u) 1

Differences Between Prior MHT Studies and the WHI E and E+ P Trials Characteristic Prior Studies E+P Trial E Trial Study Design Observational Cohort Case Control Prospective Randomized Blinded Age at Onset of Therapy 4-55 years (mean 51.1) 55-79 years (mean 62.7) 55-79 years (mean 63.6) Treatment Modality Mainly CE Some + MPA PremPro CE.625 mg +MPA 2.5 mg Premarin CE.625 mg Duration Rx 1-15 years 5 years 7 years The WHI Hormone Trials, Revisited: Follow-up Studies and Revisionist Analyses WHI investigators analyzed outcomes by subgroups of age and time since menopause WHI investigators conducted a follow-up study measuring CAC in women in the E-alone trial WHI critics examined distribution of CVD events by time of occurrence in the study New interpretations of WHI data Effects of HRT on CVD are dependent upon time HRT is initiated relative to menopause and/or age (the timing hypothesis ) Longer duration of treatment may be required for CVD benefit to become apparent 11

Risk Ratio For CVD Estrogen plus Progestin and the Risk of CHD in Various Subgroups of WHI Women* Subgroup E + P Placebo P value for Interaction Hazard Ratio for CHD *From Manson, et al. New Engl J Med, 23;349:53 (Fig. 3) Assume mean postmenopausal durations of 5, 15, and 25 years for the <1, 1-2, and 2 year groups, respectively (actual means not provided). Draw best fit regression line Extrapolate the best fit regression line to a value of postmenopausal years. 2.6 2.4 2.2 2. 1.8 1.6 1.4 1.2 1..8.6.4.2. <1? HR=.62 1-19 r =.994 p=.71 2 5 1 15 2 25 3 Years Postmenopause at Randomization Event Hazard Ratios by Age Subgroups in WHI Estrogen-only Arm Coronary 5-59 6-69 Heart Disease 7-79 5-59 Stroke 6-69 7-79 5-59 Thromboembolism 6-69 7-79 5-59 Breast Cancer 6-69 7-79 JAMA 24:291;171-1712..5 1. 1.5 2. 2.5 3. Hazard Ratio (95% Confidence Limits) In 5-59 Group HR=.56 HR=1.8 HR=1.22 HR=.72 12

Multivariate Odds Ratios for a Coronary-Artery Calcium Score of More Than 1, According to Randomized-Group Assignment and Coronary-Risk-Factor Status Manson JE, et al. N Engl J Med 27;356:2591-262 CHD Events Associated with HRT in Younger and Older Women: Meta-analysis of 23 Randomized Controlled Trials (191,34 patient-years) All Ages >1 years since menopause, >6 years old.99 (.88-1.11) 1.3 (.91-1.16) <1 years since menopause, <6 years old.68 (.48-.96).25.5 1. 1.5 2. Relative Risk (95% CI) Salpeter SR, et al. J Gen Intern Med 26;21:363-366. 13

Annual Rate per 1 Subject Years Primary Prevention of Atherosclerotic Disease Adventitia Media Internal Elastic Lamina Fatty Streak/Plaque MMP-9 VASCULAR BIOLOGIST'S DEFINITION OF PRIMARY PREVENTION Gradual, Progressive Years Fibrous Cap Estrogen Effects CARDIOLOGIST'S DEFINITION OF PRIMARY PREVENTION Plaque Fibrous Cap Plaque Necrotic Core Sudden, Rapid, Hours? Thrombus Estrogen Effects After Clarkson T, unpublished Event Rates of Coronary Heart Disease Outcomes and Absolute Numbers of Events (numerals in bars) in the E+P and Placebo Groups by Year in the WHI Hormone Trial..6.5.4.3.2.1 43 23 36 3 2 18 25 1 2 3 4 5 6 Year Data from JAMA 288:321-333, 22 E+P Placebo 24 23 9 17 18 14

Oral Estrogen First Pass Hepatic Effects of Estrogens Taken by Mouth Altered Estrogens Liver Decreased anti-clotting factors Increased clotting factors Increased C-reactive protein Increased HDL Cholesterol Systemic Circulation Skin Intestine Ovary Estradiol Patch Differential Effects of Oral vs. Transdermal Estrogen Therapy on Thromboembolic Complications Study Publication Oral Estrogen Transdermal Estrogen Scarabin, et al. Lancet, 23, 362(9382): p. 428-32. Canonico, et al. Circulation, 27,115: 84-845 Odds Ratios and (Confidence Intervals) 3.5 (1.8-6.8) 4.2 (1.5-11.6).9 (.5-1.6).9 (.4-2.1) 15

Cumulative Hazard Might Duration of Trial Be an Important Factor? Observational Studies followed subjects for 1-15 Years CHD event rates appear to accelerate 5-1 years after the age of menopause New areas of plaque probably do not cause clinical events for 5 or more years If HRT only prevents new plaque formation, then more than 5 years may be required before protection against events becomes apparent Kaplan-Meier Estimates of Cumulative Hazards for CHD Events by Follow-up Year in the WHI E-Only Arm vs. Placebo.6.4 Coronary Heart Disease HR.91 (95% CI.75-1.12).3.2.1 Events 1 2 3 4 5 6 7 8 CEE 26 27 22 21 3 31 13 6 1 Placebo 23 23 25 27 24 26 28 17 6 No. at Risk CEE 531 521 5147 567 4978 4874 334 2248 999 Placebo 5429 5336 5254 5171 572 495 415 2331 116 JAMA 24:291;171-1712 16

Events per 1, Women per Year Coronary Heart Disease Event Rates per Thousand Women Active by Follow-up Year in the WHI E-Only Arm vs. Placebo 9. 8. 7. 6. CEE Placebo CHD Hazard Ratio Years 6-8+.41 5. 4. 3. 2. 1. 1 2 3 4 5 6 7 8+ Years Data from JAMA 24:291;171-1712 New Data Since the WHI Danish Osteoporosis Prevention Study (DOPS) Kronos Early Estrogen Prevention Study (KEEPS) Early versus Late Intervention Trial with Estradiol (ELITE) 17

Proportion of Subjects Danish Osteoporosis Prevention Study (DOPS) CVD Outcome p =.15 p =.2 Schierbeck LL, et al. BMJ 212;3456:e649. Year No. at risk HRT 52 52 498 496 483 487 484 477 155 Control 54 52 497 492 484 475 466 455 9 Various CVD and Mortality Outcomes Danish Osteoporosis Prevention Study 16 Years Randomized Treatment Outcomes Outcomes Control Treated HR p value Primary Endpoint 53 33.61.2 Death 4 27.66.1 CVD death 23 6 Other death 17 21 Heart Failure 8 3.37.15 Myocardial Infarction 11 5.45.14 Schierbeck LL, et al. BMJ 212;345:e649 18

Relative Risk Adverse Outcomes in the Danish Osteoporosis Prevention Study 16 Years Randomized Treatment Events Control Treated HR p value Stroke 21 19.89.71 Deep vein thrombosis 5 4.8.74 Pulmonary embolus 3 1.33.34 All Cancers Breast cancer 26 24.9.72 Other cancer 43 52 1.21.35 *3 women with both breast and other cancer Schierbeck LL, et al. BMJ 212;345:e649 Carotid Artery Wall Imaging Carotid Artery Intima-media Thickness (CIMT Skin surface Far wall carotid artery Scanner Transducer Jugular vein Common Carotid artery 5 4.5 p trend <.1 p trend <.1 4 3.5 3 p trend <.1 p trend <.1 2.5 2 1.5 1.5 MI, Coronary Death All CVD Events <.11 mm/yr.11 -.18 mm/yr.18 -.34 mm/yr >.34 mm/yr Hodis HN, et al. Ann Intern Med 1998;128:262-269. Hodis HN, et al. Ann Intern Med 21;135:939 953. Hodis HN, et al. Circulation 22;16:1453 1459. 19

KEEPS Subjects Study Flow 4532 screened by telephone 2811 Screened Out 994 No Showed or Declined 727 Randomized 23 o-cee 222 t-e2 275 Placebo - 15 (65%) completed on protocol - 37 (16%) completed off medications - 43 (19%) discontinued - 132 (59%) completed on protocol - 47 (21%) completed off medications - 43 (19%) discontinued - 184 (67%) completed on protocol -34 (12%) completed study off medications - 57 (21%) discontinued KEEPS Serum Estradiol and Estrone Levels by Treatment and Time 2

Percent Increasing CIMT (mm) Percent Increasing CAC Percent Increasing KEEPS: Effects of Treatment on Imaging Endpoints.4.35.3 A o-cee vs. Pbo: p=.51 T-E2 vs. Pbo: p=.27 o-cee 25 2 B 17.7% o-cee vs. Pbo: p=.44 T-E2 vs. Pbo: p=.7 19.2% 2.7%.25.2.15 t-e2 Placebo 15 1.1 5.5. 12 24 36 48 Month O-CEE T-E2 Placebo Group KEEPS Subgroup Analysis of CAC Increase in Women with and without Baseline CAC 8 7 6 5 4 3 2 1 A 12.3% (2/162) Baseline CAC = N = 53 12.7% (19/15) 13.6% (26/191) O-CEE T-E2 Placebo 8 7 6 5 4 3 2 1 B 63.2% (12/19) Baseline CAC > N = 67 63.6% (14/22) 73.1% (19/26) O-CEE T-E2 Placebo Group Group 21

Carotid Artery Intima-media Thickness (mm) Early versus Late Intervention Trial with Estradiol (ELITE); Enrollment, Randomization, and Follow-up. 2166 screened by telephone 895 screened in clinic <6 years since menopause N = 271 643 randomized >1 years since menopause N = 372 137 allocated to Estradiol 134 allocated to Placebo 186 allocated to Estradiol 186 allocated to Placebo 125 CIMT follow-up 123 CIMT follow-up 172 CIMT follow-up 176 CIMT follow-up Hodis HN et al. N Engl J Med 216;374:1221-1231. ELITE: CIMT Progression According to Study Group and Postmenopause Stratum. Placebo >1 yrs P=.29 Estradiol >1 yrs Placebo <6 yrs P=.8 Estradiol <6 yrs P-value for interaction =.7 Hodis HN et al. N Engl J Med 216;374:1221-1231. Years 22

FDA Black Box Warning for HT Summary I Most large observational studies suggested net benefit of HT administration in menopausal women Reduction in CVD events Reduction in vasomotor symptoms Reduction in fractures The largest randomized controlled trials to date (HERS and WHI) did not show cardiovascular benefits HERS Secondary prevention trial in elderly women Limitations of the WHI included: Inclusion of older women, likely with subclinical CVD Short duration compared to observational studies Use of single dose and type of estrogen (oral.625 mg CEE) Administration of medroxyprogesterone acetate with possible effect to increase breast cancer rate 23

Summary II Secondary analyses of WHI data and WHI follow-up studies suggest: No excess breast cancer risk in E-alone group Lower rates of appearance of CAC in E-alone group Lower rates of CVD events after 5 years of treatment in E- alone group More recent randomized prospective trials show: Lower rates of combined CVD endpoint in estrogen treated women vs. non-treated women after 16 years of observation (DOPS) No difference in CVD progression rates with estrogen treatment vs. placebo in recently menopausal women (KEEPS) Less progression of CIMT with estrogen vs. placebo when initiated within 6 years after menopause but not when initiated 1 or more years after menopause.(elite) Conclusions Results of the WHI parsed and reanalyzed do not justify the current black box warning* and suggest no harm, or even protection, in younger, more recently menopausal women Newer data, consistent with long term observational studies, show no harm (KEEPS) or protection against subclinical CVD progression (ELITE) and CVD events (DOPS) when estrogen treatment is initiated early in the menopause Further research on menopausal HT should be pursued to clarify effects of: Doses and agents (especially progestogens) Route of administration Timing/Age *Opinion of the author and not the Phoenix VAHCS or the U.S. Veterans Administration 24