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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.

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Women’s Health Initiative (WHI)

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  1. 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

  2. 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)

  3. 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

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

  5. 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

  6. 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

  7. WHI Hormone Therapy Trials Timeline 1993 1998 2005 2010 1990 2015 Median Cumulative Follow-Up of 13 years (Follow-up Continues Through 2015)

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

  9. 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

  10. 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

  11. 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

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

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

  14. WHI Hormone Therapy Trials Baseline Demographic Characteristics Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

  15. WHI Hormone Therapy Trials Baseline Clinical Characteristics Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

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

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

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

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

  20. 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

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

  22. 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

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

  24. 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

  25. 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

  26. Summary of Results: Intervention Phase • 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)

  27. 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)

  28. 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

  29. 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

  30. 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

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

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

  33. WHI Hormone Therapy Trials: SecondaryEndpoints (Postintervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

  34. WHI Hormone Therapy Trials: Self-ReportedEndpoints (Postintervention Phase) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

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

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

  37. WHI Hormone Therapy Trials: Secondary and Self-Reported Endpoints (Overall Combined Phases) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

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

  39. WHI HT Trials: Total MI Results(Overall Combined Phases by Age Group) Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

  40. Summary of Results: Postinterventionand Overall Combined Phases • 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

  41. Summary of Results: Postinterventionand 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

  42. Summary of Results: Postinterventionand 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

  43. WHI HT Trials: Summary of Results for Primary and Global Endpoints by Study Phase Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

  44. WHI HT Trials: Summary of Selected Secondary and Self-Reported Endpoints by Study Phase Manson, Chlebowski, Stefanick et al. JAMA 2013;310:1358-68

  45. 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

  46. 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)

  47. Thanks to the WHI participants

  48. Thanks to the WHI participants

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