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Women’s Health Initiative (WHI) Extension 2010-15 Brainstorming: Important Analyses/Ancillary Studies

UCSF K Scholars Seminars - November 12, 2010. Women’s Health Initiative (WHI) Extension 2010-15 Brainstorming: Important Analyses/Ancillary Studies (Special Focus: CVD & Physical Activity/Body Composition) Marcia L. Stefanick, Ph.D. Professor of Medicine

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Women’s Health Initiative (WHI) Extension 2010-15 Brainstorming: Important Analyses/Ancillary Studies

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  1. UCSF K Scholars Seminars - November 12, 2010 Women’s Health Initiative (WHI) Extension 2010-15 Brainstorming: Important Analyses/Ancillary Studies (Special Focus: CVD & Physical Activity/Body Composition) Marcia L. Stefanick, Ph.D. Professor of Medicine Stanford Prevention Research Center Professor of Obstetrics and Gynecology Stanford University School of Medicine

  2. Funded by National Institutes of Health National Heart, Lung, and Blood Institute Women’s Health Initiative (WHI) Clinical Trials (Diet, Hormones, Calcium/Vit D)and Observational Study Conducted at 40 Clinical Centers + Clinical Coordinating Center (Fred Hutchinson Cancer Research Center) www.whi.org www.whiscience.org

  3. WHI Clinical Trials Postmenopausal Women, aged 50-79; Not moving < 3 yrs Diet Modification (DM) Trial Primary Outcomes: Breast & Colorectal Cancer Secondary Outcome: Coronary Heart Disease (CHD) Hormone Trials Primary Outcome: CHD Secondary Outcomes: Hip Fracture, Breast Cancer Ancillary Study: Memory (Dementia) Design ~ 9 years average follow-up Diet (DM) 48,836 (40:60) 11.8% Overlap Hormone 27, 347 (50:50) Total CT = 68,133

  4. WHI Calcium Vitamin D Trial:Relationship to CT Calcium + Vitamin D (CaD) Primary Outcome: Hip Fracture Secondary Outcomes: Colorectal Cancer; Other Fractures Diet (DM) 25,210 of 48,836 (52%) 1000 mg calcium carbonate + 400 IU vitamin D* 53.3% of CT Hormone 16,089 of 27,347 (59%) CaD 36,282 Placebo at 1st (or 2nd) Annual Visit *Choice: Chewable or Swallowable Pills 1/2 in morning, 1/2 in evening (500 mg Ca + 200 IU Vit D) Total CT = 68,133 Annual Clinic Visits Baseline & 1 Yr blood

  5. WHI: Observational Study (OS) Women screened for the DM or HT trials could enroll in the OS, if ineligible for the CT, or chose not to join either DM or HT trials. Some women enrolled directly in the OS. Annual Questionnaires Purpose of OS: • secular control for the CT • improve risk prediction for primary outcomes • case-control approach to study sub-clinical markers for disease • associations between genetic, biochemical, psychosocial, physiological factors and events • impact of changes in risk factors on incident disease and mortality OS 93, 676 Clinic Visits Baseline & 3 Yr (blood) 1% subsample Total WHI Sample (CT + OS) = 161,809

  6. Women’s Health Initiative (WHI)Hormone Therapy (HT) Trials E+P Trial Generally Healthy Postmenopausal Women aged 50-79 years NO N= 16,608 CEE + MPA(medroxy-progesterone acetate, 2.5 mg/d) = Prempro® Placebo Hysterectomy E-alone Trial CEE (Conjugated equine estrogens, 0.625 mg/d) YES N= 10,739 = Premarin® Placebo *Initially: CEE only (N=331), CEE+MPA, or Placebo (Post-PEPI: CEE only were converted to CEE+MPA) Current HT required 3-month wash-out before baseline testing.

  7. WHI HT Trials: Sample Size, Outcomes, Follow-up Women, aged 50-79 Total HT trials = 27,347 Hormone Trials Primary Outcome: Coronary Heart Disease Secondary Outcomes: WHI Memory Study (WHIMS) - for women aged ≥ 65:Dementia Average Follow-up 5.6 years* E+P 16,608 • Stroke, Blood Clots • Lungs (PE, pulmonary emboli) • Legs(DVT, deep vein thrombosis) • Breast, Colorectal, Uterine Cancers • Hip Fracture; Other Deaths Average 7.1 years* E-Alone 10,739 *design ~ 8.5 years

  8. WHI Hormone Trials: Baseline (1993-1998) Hypotheses Anticipated Risk Expected Benefit Coronary Artery Disease (Heart Attacks) Stroke? Breast Cancer Threshold LevelEarly STOPPING for HARM Threshold LevelEarly STOPPING for BENEFIT • Additional Risks: • Blood Clots, VTE • Lungs=PE; Legs=DVT • Additional Benefits: • Hip (Bone) Fractures • Overall Mortality Plan to follow to 2005 (average 8.5 years) • Colon Cancer • Global Index:overall balance of benefits and risks • Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer

  9. WHI Memory Study (WHIMS) - ancillary study (Postmenopausal Women, aged 65-79) WHIMS E+P and E-only trials = 7,479 • Primary Outcome: • Probable Dementia (PD) Secondary Outcomes: • Combined PD & Mild Cognitive Impairment (MCI) - Supporting Data: Global Cognitive Function • (by annual Modified Mini-mental • State Examination, 3MSE)) E+P (women with a uterus) 4532 Average Follow-up 4.1 years* Average 5.2 years* E-Alone (post-hystX) 2947 *design ~ 7 years

  10. Summary: WHI E+P* vs. E-Alone** Trial published: *July 2002 **April 2004 • Concordant results • Heart Disease – no benefit (for E+P, early harm) • Strokes, Blood Clots – harmful • Fractures – beneficial • Dementia (if ≥ 65 yrs of age) – harmful • Disparate Results • Breast Cancer • Increased in E+P Trial (women with a uterus) • Not increased in E-Alone Trial (women with prior hysterectomy) • Increased in women with highest baseline risk (Gail Model) • Global Index • Increased in E+P (CEE + MPA) Trial • Neutral in E-Alone (CEE) Trial

  11. WHI E+P Trial: HR (95% CI) - 5.6 Years Follow-up • Cardiovascular • CHD: 1.24 (1.00-1.54); Yr 1: 1.81 (1.09-3.01) NEJM 2003; 349: 523-34 • Stroke: 1.31 (1.02-1.68); Ischemic:1.41(1.09-1.90) JAMA 2003; 289: 2673-84 • Venous Thrombosis: HR 2.06 (1.57-2.70) JAMA 2004; 292: 1573-80 • Fractures • Hip Fracture: 0.76 (0.69-0.83) [risk analysis] JAMA 2003; 290: 1729-38 • Cancer • Breast Cancer: 1.24 (1.01-1.54) JAMA 2003; 289: 3243-53 • Colorectal Cancer: 0.56 (0.38-0.81) NEJM 2004; 350:991-1004 • Gynecologic Cancers: JAMA 2003; 290: 1739-48 • Ovarian Cancer: 1.58 (0.77-3.24) • Endometrial Cancer: 0.81 (0.48-1.36) • Others: too few cases

  12. WHI E+P: Post-Intervention Follow-up After E+P trial was stopped early, WHI followed study participants through the planned termination of the trial (March 31, 2005) Except for stopping the intervention and unmasking, the same trial protocol was followed, e.g. semi-annual monitoring to identify and classify study outcomes Post-intervention information (July 8, 2002 - March 31, 2005) was available on 95% of the women: mean of 2.4 years of follow-up WHI is continuing to follow the participants. WHI E-Alone trial follow-up data will be published next year. Heiss et al,JAMA 2008; 299: 1036-1045

  13. CHD WHI E+P: Post-Intervention Follow-up Heiss et al,JAMA 2008; 299: 1036-1045

  14. WHI E+P: Post-Intervention Follow-up • Cardiovascular risks disappeared • CHD, (Stroke ?), Blood Clots – no longer increased • Fracture benefits disappeared • Hip Fracture - no longer decreased • Cancer • Breast Cancer - 27% (ns) more diagnosed post-Intervention • Colorectal Cancer - no longer decreased • TOTAL CANCER - increased 1.24 (1.04-1.48) • Due to increase in variety of cancers, including Lung Cancer (E+P: 33 events vs placebo:15) • All-cause Mortality -15% (ns) higher • Most due to Cancer (E+P: 101 vs placebo: 69) • only 27 (E+P) and 16 (placebo) due to pre-specified CA Heiss et al,JAMA 2008; 299: 1036-1045

  15. WHI CEE+MPA vs Placebo: Breast Cancer Risk During Intervention Postintervention HR=1.26 (1.02, 1.53) HR=1.27 (0.91, 1.72) Black line = sensitivity analysis: censored 6 mo. after changing pills HR=1.62 (1.10, 2.39) HR=1.26 (0.73, 2.20) Chlebowski et al, N Engl J Med 2009;360(6): 573-87

  16. Observational Study: Estrogen plus Progestin Users vs. Non-users At Entry: Breast Cancer and Serial E+P Use Chlebowski et al, N Engl J Med 2009;360(6): 573-87

  17. WHI Extension Study (ES) - 2005- 2010 Total CT Eligible: 63,331 ES: 52,156(82.4%) OS 93,676 Eligible: 86,744 ES: 63,207 (72.9%) Diet 48,836 Eligible: 45,560 ES: 37,844 (83.1%) Hormone 27,347 Eligible:25,193 ES:20,425(81.1%) Total WHI Sample (CT + OS) = 161,809 Eligible: 150,075 Extension Study = 115,363(76.8%)

  18. WHI Estrogen Plus Progestin Trial First/Second/ThirdEfficacy Analyses (cutoff dates7July2002/31March2005 /14August2009) First: End of intervention period (Per DSMB) Second: Original trial completion date Third: Current pre-planned analysis (note: re-consent required after original completion date) • Mean follow-up time: 5.6/7.9 /11.0years • Invasive breast cancers (n): 349/ 488 / 678 • Breast cancer mortality information reported for first time Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92 Chlebowski, Hendrix, Langer, et al JAMA 2003;289:3243 Chlebowski, Kuller, Prentice, New Eng J Med 2009;360:573

  19. WHI E+P: Invasive Breast Cancer Incidence Quintiles for duration of intervention indicated by shaded regions Hazard ratio (HR) 95% CI and P values from Cox proportional hazards regression models Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

  20. WHI E+P: Deaths After Breast Cancer Diagnosis Mortality due to breast cancer All-cause mortality after breast cancer Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

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