Women’s Health Initiative (WHI) Extension 2010-15
OPPORTUNITIES FOR COLLABORATION
Marcia L. Stefanick, Ph.D. Professor of Medicine
Stanford Prevention Research CenterProfessor of Obstetrics and Gynecology
Stanford University School of Medicine
UCSF K Scholars Seminars – March 4, 2011
Women’s Health Initiative (WHI) Clinical Trials
(Diet, Hormones, Calcium/Vit D)
Observational StudyConducted at 40 Clinical Centers+ Clinical Coordinating Center
(Fred Hutchinson Cancer Research Center)
EXTENSION STUDY (2005-2010)
EXTENSION STUDY (2010-2015)
Funded by National Institutes of HealthNational Heart, Lung, and Blood Institute
www.whi.org www.whiscience.org
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)
11.8% Overlap
Design ~ 9 years average
follow-up
Hormone27, 347(50:50)
Diet (DM)48,836(40:60)
Total CT = 68,133
WHI Calcium Vitamin D Trial: Relationship to CT
Calcium + Vitamin D (CaD) Primary Outcome: Hip Fracture Secondary Outcomes: Colorectal Cancer; Other Fractures
CaD36,282 at 1st (or 2nd)
Annual Visit
Total CT = Total CT = 68,133Annual Clinic Visits
Baseline & 1 Yr blood
1000 mg calcium carbonate +
400 IU vitamin D*
Diet (DM) 25,210
of 48,836 (52%)
Hormone16,089
of 27,347 (59%)
Placebo
53.3% of CT
* Choice: Chewable or Swallowable Pills 1/2 in morning, 1/2 in evening
(500 mg Ca + 200 IU Vit D)
WHI: Observational Study (OS)
OS93, 676
Total WHI Sample (CT + OS) = 161,809
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 CTimprove risk prediction for primary outcomescase-control approach to study
sub-clinical markers for diseaseassociations between genetic, biochemical,
psychosocial, physiological factors and eventsimpact of changes in risk factors on incident disease and mortality
Clinic VisitsBaseline & 3 Yr (blood)
1% subsample
Women’s Health Initiative (WHI) Hormone Therapy (HT) Trials
Hysterectomy
CEE (Conjugated equine estrogens, 0.625 mg/d)
CEE + MPA (medroxy-progesterone acetate, 2.5 mg/d)
NO N= 16,608
YESN= 10,739
Placebo
Placebo = Premarin®
= Prempro®
E-alone Trial
E+P TrialGenerally HealthyPostmenopausal
Women aged 50-79 years
*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.
E-Alone10,739
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*
Average
7.1 years*
E+P16,608
*design ~ 8.5 years
Stroke, Blood Clots Lungs (PE, pulmonary emboli) Legs (DVT, deep vein thrombosis)
Breast, Colorectal, Uterine CancersHip Fracture; Other Deaths
Stroke?
Threshold LevelEarly STOPPING
for HARM
Threshold Level Early STOPPING
for BENEFIT
Coronary Artery Disease(Heart Attacks)
Breast Cancer
Anticipated Risk Expected Benefit
Plan to follow to 2005 (average 8.5 years)
Additional Benefits:• Hip (Bone) Fractures• Overall Mortality
Additional Risks:• Blood Clots, VTE
Lungs=PE; Legs=DVT
WHI Hormone Trials: Baseline (1993-1998) Hypotheses
• 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
E-Alone (post-hystX)
2947
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))
Average Follow-up 4.1 years*
Average
5.2 years*
E+P (women with a uterus)
4532
*design ~ 7 years
Summary: WHI E+P* vs. E-Alone** Trialpublished: *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
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
WHI E+P: Post-Intervention Follow-up
Heiss et al, JAMA 2008; 299: 1036-1045
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.
WHI E+P: Post-Intervention Follow-up CHD
Heiss et al, JAMA 2008; 299: 1036-1045
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
WHI CEE+MPA vs Placebo: Breast Cancer Risk
Black line = sensitivity analysis: censored 6 mo. after changing pills HR=1.62 (1.10, 2.39) HR=1.26 (0.73, 2.20)
HR=1.26 (1.02, 1.53) HR=1.27 (0.91, 1.72)
During Intervention Postintervention
Chlebowski et al, N Engl J Med 2009;360(6): 573-87
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
WHI Extension Study (ES) - 2005- 2010
Hormone27,347
Eligible:25,193
ES:20,425 (81.1%)
Diet48,836
Eligible: 45,560
ES: 37,844 (83.1%)
OS93,676
Eligible: 86,744
ES: 63,207 (72.9%)
Total CT Eligible: 63,331ES: 52,156 (82.4%)
Total WHI Sample (CT + OS) = 161,809Eligible: 150,075
Extension Study = 115,363 (76.8%)
WHI Estrogen Plus Progestin Trial
First/Second/Third Efficacy Analyses (cutoff dates 7July2002 / 31March2005 / 14August2009)
First: End of intervention period (Per DSMB)Second: Original trial completion dateThird: Current pre-planned analysis(note: re-consent required after original completion date)
• Mean follow-up time: 5.6 / 7.9 / 11.0 years• 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
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
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
Summary of NHLBI Project Office Report to WHI OSMB, November 2010
• Original mission: To address etiology and prevention of morbidity and mortality in postmenopausal women
– First study period 1993-2005: 161,808 women age 50-79 • 3 Clinical Trials (Menopausal Hormones, Low-Fat Diet,
Calcium/Vitamin D Supplements)
• Observational Study – Follow-up 2005-2010: 115,406 (77% of eligible) age 57-91
– Follow-up period 2010-2015
• Goal enrollment 100,000 (80% of eligible) age 62-96 • Includes 24,000 in “Medical Records Cohort” which will
get complete Outcomes Assessment (HT Trial, African American and Hispanic – most of whom have GWAS data)
WHI 2010-2015: Progress Report to OSMB
• 4 Regional Centers funded October 1, 2010– Marcia Stefanick, Stanford – Western Region– Becky Jackson, OSU– Midwestern Region
– Jean Wactawski-Wende, NYU-Buffalo – Northeastern Region
– Sally Shumaker, WFU – Southeastern
• CCC renewal, April, 2011• NIA taking over lead in funding WHIMS, WHIMS-Y• NCI funding adjudication of cancer outcomes in
“Self-reported Cohort” (no central adjudication of CVD outcomes in this cohort)
New Mission, per NHLBI: 2010-2015
• Study factors leading to increased risk of CVD in older women of diverse race and ethnicity• CHD, Stroke, Heart Failure, Atrial Fibrillation, Peripheral Artery
Disease (no ABI data, Venous Thromboembolism
• Conversely what factors determine absence of CVD as part of successful aging
• Facilitate ancillary studies, consortium studies, and clinical trials requiring large numbers of clinical outcomes
• Mentor new investigators• Restructure study field centers and committees to train new
investigators and increase collaborations
•Make data and biologic resources widely available-current status
Cohort workshop at NWU Chicago, July 2010
NAMS workshop in Chicago, October 2010
Collaboration welcomed—see www.whiscience.org Study data up to 2005 available from NHLBI Data Repository; 2009 update scheduled for May 1, 2011 WHI SHARe GWAS data available from
NCBI/dbGAP since January 13, 2010
New Mission, per NHLBI: 2010-2015
WHI 2010-2015
• Study factors leading to increased risk of CVD in older women of diverse race and ethnicity Add Atrial Fibrillation (self-report, CMS/HMO) Add improved Heart Failure documentation & adjudication (self-
report, records abstraction, adjudication, CMS/HMO) Add valvular heart disease (self-report, HMO/CMS)
Face to face visit in 8,000 women aged >80 years Physical exam (includes Short Physical Function Battery) Blood Collection (including DNA) Objective assessment of physical activity (if AS funded*)
*includes Validation Study at Stanford and one other site
Continue longitudinal assessment of cognition and dementia (WHIMS)
WHI 2010-2015
• CVD Biomarkers on SHARE & EA GWAS cohorts, N~24,000 • (insulin, glucose, CRP, creatinine, Total, HDL, LDL Cholesterol, TG)
• Additional WHI genomics data to be added to dbGAP, e.g. PAGE, GARNET, planned EA GWAS, WHISP
• Funding for BAA3 secured (2012 and 2014)– Objective is to encourage the wider scientific community to maximize the return
on the WHI cohort by applying newer high-throughput technologies to the biological specimens
– Example: serial archived bloods plus bloods to be collected in 2011-2012 provide an opportunity study such questions as the determinants of change over time in biomarkers, DNA methylation, RNA expression, proteome, metabolome, telomere length, and the association of these changes on subsequent health outcomes
•Make data and biologic resources widely available
WHI 2010-2015• Facilitate ancillary studies, consortium studies, and clinical trials requiring large numbers of clinical outcomes. In early development:
• Dietary supplements (vitamin D, ALA, resveratrol)
• Physical activity• Program to enhance use of EMR for clinical outcomes
• GWAS and CVD biomarkers in ~12,000 EA women in addition to the ~12,000 AA and Hispanic women in SHARe
• Mentor new investigators• Deliverable for Regional Centers• BAA3
WHI 2010-2015 Cohort, as of 2/28/11
Current Age Total Medical Records Cohort
60-64 607 207
65-69 13530 3473
70-74 22604 5865
75-79 22453 5865
80-84 19354 5007
85-89 10089 2655
90-94 2539 728
95-99 45 13
TOTAL 91,221 21625
WHI 2010-2015 Cohort, as of 2/28/11
Race/Ethnicity Total Medical Records Cohort
White (non Hispanic) 79,832 14,297
Black (African American) 5821 5821
Hispanic 2375 2375
Asian/Pacific Islander 1831 232
American Indian/Alaskan Native
305 68
Other 871 162
Not specified 186 29
TOTAL 91,221 21,625