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
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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
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
lled
Tria
ls1
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
• 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: 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 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
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 70-79
Summary of Results: Intervention Phase
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
Summary of Results: Intervention Phase
WHI Hormone Therapy Trials: Primary Endpoints, Mortality, and Global Index (Postintervention Phase)
Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68
WHI Hormone Therapy Trials: Primary and Global Index Endpoints (Postintervention Phase)
Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68
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
Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68
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