Women’s Health Initiative (WHI)

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

Hormone Therapy Trials: Coronary Heart Disease and FracturesAdverse 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 Co

ntro

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Tria

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Obs

erva

tiona

l Stu

dy

27,347

161,808 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

Planning Recruitment Follow-upClose-out 1st Extension 2nd Extension

1990 20051993 1998 2010

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

2015

WHI Hormone Therapy Trials Design

Hysterectomy

CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/day

Estrogen- alone N=10,739

YES

NO

Placebo

Conjugated equine estrogens (CEE) 0.625 mg/day

Placebo

Estrogen-plus-progestinN=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 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

CharacteristicCEE+MPA Trial CEE-Alone Trial

Active (n=8506)

Placebo (n=8102)

Active (n=5310)

Placebo (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 23.8Race/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. Islander 194 2.3 169 2.1 86 1.6 78 1.4

Unknown 127 1.5 109 1.3 74 1.4 75 1.4

Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

CharacteristicCEE+MPA Trial CEE-Alone Trial

Active (n=8506)

Placebo (n=8102)

Active (n=5310)

Placebo (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 50.0Hormone 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 (before washout) 554 6.5 490 6.1 669 12.6 709 13.1

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

WHI Hormone Therapy Trials Baseline Clinical Characteristics


WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Intervention Phase)


WHI HT Trials: Primary and Global Index Endpoints (Intervention Phase by Age Group)


WHI Hormone Therapy Trials: Primary Endpoints (Intervention Phase by Age Group)


WHI Hormone Therapy Trials: CHD Results According to Vasomotor Symptoms (Intervention Phase by Age Group)


WHI Hormone Therapy Trials: Secondary Endpoints (Intervention Phase)


WHI Hormone Therapy Trials: Total MI Results (Intervention Phase by Time Since Menopause, Age Group)


WHI Hormone Therapy Trials: Self-Reported Endpoints (Intervention Phase)


WHI Hormone Therapy Trials: Results for Other Health-Related Quality of Life Variables (Intervention Phase)


Summary of Results: Intervention Phase Coronary heart disease: No overall indication of

prevention effects• Estrogen-plus-progestin:

• Risk increased during 1st 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)


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


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 70-79


Analyses stratified by vasomotor symptoms at baseline• Women ages 70-79 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


WHI Hormone Therapy Trials: Primary Endpoints, Mortality, and Global Index (Postintervention Phase)


WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Postintervention Phase)


WHI Hormone Therapy Trials: SecondaryEndpoints (Postintervention Phase)


WHI Hormone Therapy Trials: Self-ReportedEndpoints (Postintervention Phase)


WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Overall Combined Phases)


WHI Hormone Therapy Trials: Secondary and Self-Reported Endpoints (Overall Combined Phases)


WHI HT Trials: Primary and Global Index Endpoints (Overall Combined Phases by Age Group)


WHI HT Trials: Total MI Results(Overall Combined Phases by Age Group)


Coronary heart disease• Neutral results in both trials• Women 50-59 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


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


MajorEndpoints

Intervention Post-Intervention Overall CombinedCEE+MPA CEE CEE+MPA CEE CEE+MPA CEE

CHD 0 0 0 0 0 0Breast cancer ? 0 Stroke 0 0 ? ?PE 0 0 0 0Colorectal cancer 0 0 0 ? 0Endometrial cancer 0 NA NA NA

Hip fracture 0 0 0All-cause mortality 0 0 0 0 0 0Global index 0 0 0 0

WHI HT Trials: Summary of Results for Primary and Global Endpoints by Study Phase


MajorEndpoints

Intervention Post-Intervention Overall CombinedCEE+MPA CEE CEE+MPA CEE CEE+MPA CEE

Total MI ? 0 0 0 ? 0CABG or PCI 0 0 0 0 0 0DVT 0 0All CVD 0 0 0CVD deaths 0 0 0 0 0 0Lung cancer 0 0 0 0 0 0Ovarian cancer 0 NR 0 NR 0 NRAll cancers 0 0 0 0 0 0Cancer deaths 0 0 0 0 0 0Diabetes 0 0 0

WHI HT Trials: Summary of Selected Secondary and Self-Reported Endpoints by Study Phase


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: https://cleo.whi.org/researchers/SitePages/Write%20a%20Paper.aspx

WHI Investigators (A Short List)

https://www.whi.org/researchers/SitePages/Write%20a%20Paper.aspx

https://www.whi.org/researchers/SitePages/Write%20a%20Paper.aspx

Thanks to the WHI participants

Women’s Health Initiative (WHI)

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