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: HHSN C, HHSN C, HHSN C, HHSN C, HHSN C, HHSN C)

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 ( ) 115,403 participants enrolled in WHI Extension Study ,500 participants enrolled in WHI Extension Study

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

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 Median Cumulative Follow-Up of 13 years (Follow-up Continues Through 2015) 2015

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

Methods 27,347 postmenopausal women randomly assigned to one of two regimens Estrogen-plus-progestin if intact uterus (N=16,608): Conjugated equine estrogens 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) 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:

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

WHI Hormone Therapy Trials Baseline Demographic Characteristics Characteristic CEE+MPA TrialCEE-Alone Trial Active (n=8506) Placebo (n=8102) Active (n=5310) Placebo (n=5429) N%N%N%N% Age (baseline) Race/ethnicity White Black Hispanic Am. Indian Asian/ Pac. Islander Unknown Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

Characteristic CEE+MPA TrialCEE-Alone Trial Active (n=8506) Placebo (n=8102) Active (n=5310) Placebo (n=5429) N%N%N%N% Years since menopause < <  Hormone use Never Past Current (before washout) Vasomotor sx None Mild Mod/severe WHI Hormone Therapy Trials Baseline Clinical Characteristics Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

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

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

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

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

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

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

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

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

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

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

Stroke Hormones increased risk by 1/3 compared with placebo in both trials No differences by age or time since menopause Pulmonary embolism Hormones increased risk in both trials; effects greater for estrogen-plus-progestin than estrogen-alone No differences by age or time since menopause Colorectal cancer Estrogen-plus-progestin: decreased risk; cancers diagnosed at more advanced stages; no differences by age Estrogen-alone: neutral effects on risk; results more adverse in older compared with younger women (p for trend=0.02) Summary of Results: Intervention Phase

Endometrial cancer (Estrogen-plus-progestin only) Neutral results Hip fracture Hormones decreased risk by 1/3 in both trials Estrogen-alone: more favorable results in women with greater time since menopause Overall illness and death (global index) Estrogen-plus-progestin: Risk exceeded benefit by 12%; no differences by age Estrogen-alone: Risk-benefit profile neutral; benefits more favorable in younger women (p for trend=0.02) Summary of Results: Intervention Phase

Probable dementia (women  65 years at enrollment) Estrogen-plus-progestin: increased risk 2-fold compared with placebo Estrogen-alone: increased risk by 47% (p<.17) Diabetes Hormones decreased risk by 14-19% in both trials Gallbladder disease and urinary incontinence Hormones increased risk by 50-60% in both trials Other self-reported symptoms Decreased vasomotor symptoms and joint pain in both trials; estrogen-plus-progestin effects greater than estrogen-alone Hormones increased breast tenderness in both trials Summary of Results: Intervention Phase

Health-related quality of life Estrogen-plus-progestin: small benefits for physical functioning, role-physical, bodily pain, general health Estrogen-alone: nominally significant adverse effects for social functioning and role-emotional Depressive symptoms No significant differences in either trial Analyses of women without hormone use before randomization, stratified by age Estrogen-plus-progestin: findings similar to primary analyses Estrogen-alone: Global index significantly better compared to placebo for women ages 50-59; excess events among women ages Summary of Results: Intervention Phase

Analyses stratified by vasomotor symptoms at baseline Women ages with moderate to severe symptoms had high risk of CHD on hormones compared with placebo No elevated CHD risk in younger women Sensitivity analyses censoring for nonadherence (taking < 80% of study pills) Results similar to intention-to-treat, but effects accentuated in both trials Summary of Results: Intervention Phase

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

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

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

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

WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Overall Combined Phases) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Overall Combined Phases) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

WHI Hormone Therapy Trials: Secondary and Self- Reported Endpoints (Overall Combined Phases) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

WHI HT Trials: Primary and Global Index Endpoints (Overall Combined Phases by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

WHI HT Trials: Total MI Results (Overall Combined Phases by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

Coronary heart disease Neutral results in both trials Women years taking estrogen-alone: lower risk of MI during intervention phase became more pronounced cumulatively (p for trend 0.007) Invasive breast cancer Estrogen-plus-progestin: Risk remained statistically significantly elevated Estrogen-alone: Risk reduction became statistically significant during cumulative follow-up Stroke Neutral results in both trials postintervention Cumulatively, hormones increased risk in both trials Summary of Results: Postintervention and Overall Combined Phases

Pulmonary embolism Neutral results in both trials postintervention Cumulatively, increased risk seen in both trials was statistically significant only with estrogen-plus-progestin Colorectal cancer Neutral results in both trials Endometrial cancer (Estrogen-plus-progestin only) Reduced risk compared with placebo postintervention and cumulatively Summary of Results: Postintervention and Overall Combined Phases

Hip fracture Risk reductions attenuated in both trials postintervention Cumulatively, significant benefit persisted for estrogen- plus-progestin compared with placebo; neutral results for estrogen-alone Overall illness and death (global index) Neutral results in both trials Diabetes Reductions in risk dissipated in both trials Estrogen-plus-progestin: increased risk postintervention, neutral results cumulatively Estrogen-alone: neutral results postintervention and cumulatively Summary of Results: Postintervention and Overall Combined Phases

Major Endpoints InterventionPost-InterventionOverall Combined CEE+MPACEECEE+MPACEECEE+MPACEE CHD Breast cancer  ??  0  Stroke  00 ?? ?? PE  000  0 Colorectal cancer  000 ??0 Endometrial cancer 0NA   Hip fracture  00  0 All-cause mortality Global index  000  0 WHI HT Trials: Summary of Results for Primary and Global Endpoints by Study Phase Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

Major Endpoints InterventionPost-InterventionOverall Combined CEE+MPACEECEE+MPACEECEE+MPACEE Total MI ??000 ??0 CABG or PCI DVT  0  0 All CVD  00  0 CVD deaths Lung cancer Ovarian cancer 0NR0 0 All cancers Cancer deaths Diabetes  000 WHI HT Trials: Summary of Selected Secondary and Self-Reported Endpoints by Study Phase Manson, Chlebowski, Stefanick et al. JAMA 2013;310:

Conclusions Hormone therapy Use for chronic disease prevention not supported by findings Increased risks of stroke, venous thrombosis, gallstones, and urinary incontinence, irrespective of age Reasonable option for short-term management of moderate to severe menopausal symptoms in younger women Caution indicated when considering use in older women, including those with vasomotor symptoms, because of high risk of CHD and other outcomes Estrogen-plus-progestin for women with intact uterus Risks outweigh benefits, irrespective of age Estrogen-alone for women with previous hysterectomy More favorable risk-to-benefit ratio in younger women

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker For a list of all the investigators who have contributed to WHI science see: WHI Investigators (A Short List)

Thanks to the WHI participants