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