Menopausal Hormone Therapy and Health Outcomes During the - PowerPoint PPT Presentation

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials JE Manson, RT Chlebowski, ML Stefanick, AK Aragaki, JE Rossouw, RL Prentice, G Anderson, BV Howard, CA Thomson, AZ LaCroix, J Wactawski-Wende, RD Jackson, M Limacher, KL Margolis, S Wassertheil-Smoller, SA Beresford, JA Cauley, CB Eaton, M Gass, J Hsia, KC Johnson, C Kooperberg, LH Kuller, CE Lewis, S Liu, LW Martin, JK Ockene, MJ O’Sullivan, LH Powell, MS Simon, L Van Horn, MZ Vitolins, RB Wallace

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services Contracts: HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C)

Women’s Health Initiative (WHI)  Goal: Answer major questions about postmenopausal women’s health (cancers, heart disease, osteoporosis- related bone fractures)  Vast scientific undertaking • 161,808 participants from 40 U.S. centers followed up to 12 years in main study (1993-2005) • 115,403 participants enrolled in WHI Extension Study 2005-2010 • 93,500 participants enrolled in WHI Extension Study 2010-2015

WHI Components and Primary Outcomes Hormone Therapy Trials: Coronary Heart Disease and Fractures 27,347 3 Controlled Trials Adverse effect for Breast Cancer? (16,608 E+P; 10,739 E-Alone) Calcium/Vitamin D Trial: 36,282 Fractures and Colorectal Cancer Dietary Modification Trial: Breast and Colorectal Cancers and Coronary 48,835 Heart Disease 1 Observational Study Observational Study 93,676 161,808 women total

WHI Eligibility Criteria  General inclusion criteria • Aged 50 to 79 years • Postmenopausal • Planning to reside in the area for at least 3 years • Able/willing to provide written informed consent  Additional eligibility criteria specific to each study component, related to: • Safety • Competing risk • Adherence/retention

Objectives of Current Analyses  Provide a comprehensive, integrated overview of findings from WHI Hormone Therapy Trials with extended post-intervention follow-up • Synthesize results of risks and benefits from over 117 different published reports on WHI primary, secondary, and quality-of-life outcomes • Show side-by-side comparisons • Findings during intervention phase, post-intervention follow-up, and total cumulative follow-up • Stratified analyses by age group and time since menopause • Conduct additional analyses • Without pre-randomization use of hormone therapy, stratified • Presence or absence of vasomotor symptoms at baseline • Censoring for study pill nonadherence

WHI Hormone Therapy Trials Timeline Planning Recruitment Follow-up Close-out 1st Extension 2nd Extension 1993 1998 2005 2010 1990 2015 Median Cumulative Follow-Up of 13 years (Follow-up Continues Through 2015)

WHI Hormone Therapy Trials Design Conjugated equine estrogens Estrogen- alone (CEE) 0.625 mg/day N=10,739 YES Placebo Hysterectomy CEE 0.625 mg/d + NO medroxyprogesterone acetate (MPA) 2.5 mg/day Estrogen-plus- progestin N=16,608 Placebo

Methods  27,347 postmenopausal women randomly assigned to one of two regimens • Estrogen-plus-progestin if intact uterus (N=16,608): Conjugated equine estrogens 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily (Prempro, Wyeth Ayerst) or placebo • Estrogen-alone if previous hysterectomy (N=10,739): Conjugated equine estrogens (CEE) 0.625 mg daily (Premarin, Wyeth Ayerst) or placebo  Primary outcomes • Efficacy: Coronary heart disease (CHD) • Safety: Invasive breast cancer, respectively

Methods  Estrogen-plus-progestin • Intervention (median): 5.6 years (ended July 7, 2002 because of increased breast cancer risk and an unfavorable risk-to-benefit ratio) • Post-intervention follow-up : 8.2 years • Cumulative follow-up : 13.2 years  Estrogen-alone • Intervention (median): 7.2 years (ended February 29, 2004 because of increased stroke risk, no overall CHD benefit) • Post-intervention follow-up : 6.6 years • Cumulative follow-up : 13.0 years  Post-intervention follow-up through September 30, 2010 based on 81.1% of surviving participants providing written informed consent

Methods  All randomized participants according to randomization assignment until last contact  Time-to-event methods based on intention-to-treat  Global index of overall illness and death, calculated as first clinical event for: CHD, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer (estrogen-plus-progestin only) , hip fracture, and death from other causes  Hazard ratios estimated using Cox proportional hazards models for each clinical endpoint, stratified by age, prior disease, randomization status in Dietary Modification trial

WHI Estrogen-Plus-Progestin Trial through Extended Follow-Up Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Estrogen-Alone Trial through Extended Follow-Up Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials Baseline Demographic Characteristics CEE+MPA Trial CEE-Alone Trial Active Placebo Active Placebo Characteristic (n=8506) (n=8102) (n=5310) (n=5429) N % N % N % N % Age (baseline) 50-59 2837 33.4 2683 33.1 1639 30.9 1674 30.8 60-69 3854 45.3 3655 45.1 2386 44.9 2465 45.4 70-79 1815 21.3 1764 21.8 1285 24.2 1290 23.8 Race/ethnicity White 7141 84.0 6805 84.0 4009 75.5 4075 75.1 Black 548 6.4 574 7.1 781 14.7 835 15.4 Hispanic 471 5.5 415 5.1 319 6.0 332 6.1 Am. Indian 25 0.3 30 0.4 41 0.8 34 0.6 Asian/ Pac. 194 2.3 169 2.1 86 1.6 78 1.4 Islander Unknown 127 1.5 109 1.3 74 1.4 75 1.4 Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials Baseline Clinical Characteristics CEE+MPA Trial CEE-Alone Trial Active Placebo Active Placebo Characteristic (n=8506) (n=8102) (n=5310) (n=5429) N % N % N % N % Years since menopause < 10 2780 36.2 2711 36.1 827 18.4 817 17.6 10 - < 20 3049 39.7 2992 39.9 1438 32.0 1500 32.4 ≥ 20 1850 24.1 1805 24.0 2230 49.6 2319 50.0 Hormone use Never 6277 73.8 6022 74.4 2769 52.2 2769 51.0 Past 1671 19.7 1587 19.6 1871 35.2 1947 35.9 Current 554 6.5 490 6.1 669 12.6 709 13.1 (before washout) Vasomotor sx None 5162 61.3 4928 61.5 2962 56.4 3004 56.0 Mild 2190 26.0 2115 26.4 1377 26.2 1441 26.9 Mod/severe 1072 12.7 974 12.1 913 17.4 917 17.1 Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Intervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Intervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI HT Trials: Primary and Global Index Endpoints (Intervention Phase by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Primary Endpoints (Intervention Phase by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: CHD Results According to Vasomotor Symptoms (Intervention Phase by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Secondary Endpoints (Intervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Total MI Results (Intervention Phase by Time Since Menopause, Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Self-Reported Endpoints (Intervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

WHI Hormone Therapy Trials: Results for Other Health- Related Quality of Life Variables (Intervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

Summary of Results: Intervention Phase  Coronary heart disease: No overall indication of prevention effects • Estrogen-plus-progestin : • Risk increased during 1 st year by 80% compared with placebo, but only by 18% over entire intervention phase • Similar risks by age, • Non-significant difference by time since menopause (p for trend=0.08); increased risk in women more than 20 years past menopause • Estrogen-alone : • Neutral results • Suggestion of lower risk of CHD in younger women ( p for trend=0.08), • Lower risk of MI in younger women ( p for trend=0.02)  Invasive breast cancer • Estrogen-plus-progestin : risk increased progressively to 24% overall; cancers diagnosed at more advanced stages • Estrogen-alone : reduced risk of breast cancer ( p <.07) • No differences by age or time since menopause