Introduction to WHI. From inception to current Extension study: Overview of WHI Protocol and study components and results

Transcription

1 Introduction to WHI From inception to current Extension study: verview of WHI Protocol and study components and results Garnet Anderson WHI Clinical Coordinating Center Fred Hutchinson Cancer Research Center September 9, 2015

2 Women s Health Initiative: riginal objectives Dr. Bernadine Healy, Former Director of NIH To test three chronic disease prevention strategies in full scale randomized trials: Hormone therapy (HT) A low-fat diet (Dietary Modification, DM) Calcium & vitamin D supplements (CaD) To identify risk factors for the major causes of morbidity and mortality in post-menopausal women Design of the Women's Health Initiative clinical trial and observational study. Control ClinTrials Feb;19(1):

3 bservational Study Partial factorial Clinical Trial WHI Components and utcomes HT: 27,347 CaD: 36,282 DM: 48,835 Hormone Therapy Trials Primary: Coronary Heart Disease Secondary: Hip Fracture Safety: Breast Cancer Calcium/Vitamin D Trial: Primary: Hip fractures Secondary: Colorectal Cancer Dietary Modification Trial: Primary: Breast Cancer and Colorectal Cancer Secondary: Coronary Heart Disease 93,676 bservational Study Total: 161,808 women Anderson et al., Ann Epidemiol ct;13(9 Suppl):S

4 Thanks to the WHI participants 4

5 WHI participants Inclusion criteria Postmenopausal, years of age Expected survival > 3 years Likely to live in the area for 3 years Willing to provide written informed consent Exclusion criteria specific to each trial based on Safety Adherence Competing risk 5

6 Participants recruited by 40 Clinical Centers, Fred Hutchinson Cancer Research Center Kaiser Foundation Research Institute Univ. of California, Davis Univ. of Nevada, Reno Kaiser Foundation Research Institute Stanford University Univ. of Minnesota Med. CtrA. Medical College of Wisconsin SUNY Univ. of Wisconsin Buffalo Univ. of Mass Univ. of Iowa Wayne State Univ. Med. Ctr. Albert Einstein Brigham & Women s Hosp. Col. of Med. Mem. Hosp. of Rhode Is. Rush-Presb. Northwestern Univ. of Pittsburgh St. Luke s Univ. SUNY, Stony Brook hio State Univ. Univ. of Med. & Dent. Med. Ctr. of New Jersey Univ. of Cincinnati Medical Center Medlantic Res. Inst./Howard Univ. George Washington Univ. Univ. of California, Los Angeles Univ. of California, Irvine Harbor-UCLA Research & Education Inst. Univ. of Tennessee Wake Forest University Univ. of North Carolina Univ. of California, San Diego Univ. of Arizona at Tucson Univ. of Alabama Emory Univ. Sch. of Medicine Univ. of Texas Health Science Ctr., San Antonio Baylor College of Medicine Univ. of Florida Univ. of Miami Univ. of Hawaii I

7 WHI recruitment Emphasis on assuring representation of minorities consistent with population in this age-group Age-specific goals and actual distribution for each CT component (as % of total): Goal E-alone E+P DM CaD Hays et al, Ann Epidemiol ct;13(9 Suppl):S

8 Follow-up and utcomes collection CT semi-annual contacts with annual clinic visits required Intervention adherence Brief physical exam Mammography, breast exam, ECG (q3 years) Medical history update (Form 33) 6% subsample randomly selected at baseline for additional data collection S annual mail follow-up (F33), limited exposure assessments and clinic visit at 3 years Documentation and adjudication of priority health events CHD and related outcomes Cancer Hip Fracture All deaths Curb et al., Ann Epidemiol ct;13(9 Suppl):S

9 Hormone therapy trial design YES N= 10,739 Conjugated equine estrogen (CEE mg/d) [aka ERT, E-alone, CEE] Placebo Hysterectomy N N= 16,608 CEE + medroxyprogesterone acetate (CEE+MPA 2.5 mg/d) [aka PERT, E+P, CEE+MPA] Placebo WHI Study Group. Control Clin Trials. 1998;19(1):61-109; or Stefanick et al, Ann Epidemiol ct;13(9 Suppl):S

10 Statistical power for the hormone therapy component Power % at Selected Sample Sizes Women with Hysterectomized Average Disease Probability Uterus (55%) Women (45%) Intervention Years of ( 100) PERT vs. Placebo ERT vs. Placebo Effect % Follow-up Control Intervention 25,000 27,500 30,000 25,000 27,500 30,000 Coronary Heart Disease Hip Fractures Combined Fractures >99 >99 > >99 Breast Cancer * = Absolute value of one minus intervention versus control incidence rates at planned study termination, multiplied by 100. = Power for design assumption based on a weighted logrank statistic highlighted. WHI Study Group, Control Clin Trials 1998;19(1):

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12 1997 Fall 1998 Spring 1998 Fall 1999 Spring 1999 Fall 2000 Spring 2000 Fall 2001 Spring 2001 Fall 2002 Spring 2002 Fall 2003 Spring 2003 Fall 2004 Spring 2004 Fall Final Analysis 1997 Fall 1998 Spring 1998 Fall 1999 Spring 1999 Fall 2000 Spring 2000 Fall 2001 Spring 2001 Fall 2002 Spring 2002 Fall 2003 Spring 2003 Fall 2004 Spring 2004 Fall Final Analysis E+P monitoring boundaries and results CHD Stroke Stopping Boundaries and bserved Z-values Stopping Boundaries and bserved Z-values 6 Upper Boundary for Benefit Lower Boundary for Harm Unweighted Z Weighted Z 6 Lower Boundary for Harm (CHD Value) Unweighted Z Weighted Z Z 0 Z Planned Analyses -6 Planned Analyses Clin Trials. 2007;4(3): Control Clin Trials Dec;17(6):

13 1997 Fall 1998 Spring 1998 Fall 1999 Spring 1999 Fall 2000 Spring 2000 Fall 2001 Spring 2001 Fall 2002 Spring 2002 Fall 2003 Spring 2003 Fall 2004 Spring 2004 Fall Final Analysis 1997 Fall 1998 Spring 1998 Fall 1999 Spring 1999 Fall 2000 Spring 2000 Fall 2001 Spring 2001 Fall 2002 Spring 2002 Fall 2003 Spring 2003 Fall 2004 Spring 2004 Fall Final Analysis 1997 F 1998 Spr 1998 F 1999 Spr 1999 F 2000 Spr 2000 F 2001 Spr 2001 F 2002 Spr 2002 F 2003 Spr 2003 F 2004 Spr 2004 F Final Analy 1997 F 1998 Spr 1998 F 1999 Spr 1999 F 2000 Spr 2000 F 2001 Spr 2001 F 2002 Spr 2002 F 2003 Spr 2003 F 2004 Spr 2004 F Final Analy E+P monitoring boundaries and results, continued Invasive Breast Cancer Stopping Boundaries and bserved Z-values Global Index Stopping Boundaries and bserved Z-values 6 Lower Boundary for Harm Unweighted Z Weighted Z 6 Upper Boundary for Benefit Lower Boundary for Harm Unweighted Z Weighted Z Z 0 Z Planned Analyses -6 Planned Analyses Clin Trials. 2007;4(3): Control Clin Trials Dec;17(6):

14 Clinical utcomes in the WHI Postmenopausal Hormone Therapy Trials Intervention phase results Estrogen+Progestin Estrogen-alone HR 95% CI HR 95% CI Coronary heart disease Stroke Venous thromboembolism Invasive breast cancer Colorectal cancer Endometrial cancer Hip fracture Death due to other causes Global index WHI Study Group, JAMA 2002; WHI Steering Committee, JAMA

15 Clinical utcomes in the WHI Postmenopausal Hormone Therapy Trials Intervention phase results Estrogen+Progestin Estrogen-alone HR 95% CI HR 95% CI Coronary heart disease Stroke Venous thromboembolism Invasive breast cancer Colorectal cancer Endometrial cancer Hip fracture Death due to other causes Global index WHI Study Group, JAMA 2002; WHI Steering Committee, JAMA

16 Clinical utcomes in the WHI Postmenopausal Hormone Therapy Trials Intervention phase results Estrogen+progestin Estrogen-alone HR 95% CI HR 95% CI Coronary heart disease Stroke Venous thromboembolism Invasive breast cancer Colorectal cancer Endometrial cancer Hip fracture Death due to other causes Global index WHI Study Group, JAMA 2002; WHI Steering Committee, JAMA

17 Hypotheses in the DM trial 1 Does a low fat dietary pattern reduce breast cancer incidence? 1 Does a low fat diet reduce colorectal cancer incidence? 2 Does a low fat diet reduce CHD incidence? Note: 2:3 randomization used to reduce costs 19,541 Intervention: Low-fat eating pattern Aim for 20% calories from fat 48,835 randomized Increase fruits/vegetables/grains 29,294 Comparison: Usual diet 84% power to observe a 14% reduction in breast cancer rates after 8.5 years (mean) followup [Anderson et al., Ann Epidemiol 2003] 17

18 Intervention group achieved ~70% of the change in dietary intake specified in the design Servings of fruits/vegetables Servings of grain % energy from saturated fat % energy from fat

19 DM trial found a modest but non-significant benefit for breast cancer but not for colorectal cancer (or CHD) 1,727 total diagnoses 3.5% of all DM participants Invasive breast cancer incidence Prentice RL et al. JAMA 2006 Colorectal cancer incidence Beresford SAA et al, JAMA

20 Women with higher baseline fat intake made bigger changes in fat intake and experienced somewhat greater risk reduction: A case-case analysis using 4DFRs Intervention Comparison Interaction Baseline Variable (Number of (Number of Hazard Ratio cases = 655) cases = 1072) (95% CI) P-value % energy from fat (kcal) 0.04 < (0.79, 1.20) < (0.89, 1.30) 32.3-< (0.70, 1.03) > (0.64, 0.95) Vegetables and fruits (sv/day) < (0.73, 1.09) 2.3-< (0.72, 1.07) 3.3-< (0.67, 1.00) > (0.90, 1.29) 0.07 Prentice RL et al. JAMA 2006

21 Trial results motivate search for nutrition biomarkers to better calibrate selfreported intake and improve inference Prentice et al, AJE

22 Calcium and Vitamin D (CaD) trial hypotheses and design 1 Does supplemental calcium and vitamin D reduce hip fracture rates? 2 Does calcium and vitamin D reduce colorectal cancer incidence? Note: Randomization to CaD trial offered to HT and DM trial participants at/after year 1 visit 36,282 randomized (1:1) Calcium carbonate 1000 mg/d + vitamin D 400 IU/d Placebo 88% power to observe a 21% reduction in hip fracture rates after 7.5 years (mean) follow-up [Anderson et al., Ann Epidemiol 2003] 22

23 Mean Change in BMD from Year 1, % CaD helps to preserve bone mineral density Greater preservation in total hip BMD Average differences between CaD and placebo groups: 0.59% at AV3 0.86% at AV6 1.01% at AV Total Hip P<0.001 CaD Placebo P<0.001 P=0.01 Year 1 Year 3 Year 6 Year 9 Clinical Trial Annual Visit NEJM 2006;354: Jackson et al., NEJM 354;7:

24 Cumulative Hazard Calcium and vitamin D supplements may slightly reduce risk of hip fracture; no benefit seen for colorectal cancer Hip fracture incidence CaD Placebo HR = 0.88 (95% CI, ) P-value = 0.23 Hip Fracture Time (years) CaD: Events N at risk Jackson et al., NEJM 354;7: Placebo: Events Hip fractures HR 0.88; 95% CI CaD vs 16 placebo Lower arm or wrist fractures HR 1.01; 95% CI CaD vs. 44 placebo Total fractures HR 0.94; 95% CI CaD vs 170 placebo Colorectal cancer incidence Wactawski-Wende, et al., NEJM 2006;354:

25 Study timeline & significant events Recruitment by 40 Clinical Centers 1994 Redesign of HT trial 2000 HT participants notified of adverse CVD effects 2001 HT participants informed that adverse CVD effects were continuing 2002 E+P trial intervention stopped by DSMB, all WHI participants notified, follow-up continued 2004 E-alone trial stopped by NHLBI, follow-up continued DM and CaD trials completed; Participants consented to longer-term, centralized followup; 39 Field Centers + CCC continue outcomes procedures (Extension I) 2010 Participants re-consented to extended, followup (Extension II); utcomes documentation streamlined; 4 Regional Centers, 6 satellite sites and CCC Long-Life substudy implemented 2015 Centralized follow-up continues in Extension III 2015 WHISH and CSMS trials begin 25

26 Protocol changes in the Extension Studies CT follow-up reduced to annual, centralized, mailed follow-up (F33 and selected exposure updates) Modest streamlining of outcomes data utcomes documentation/adjudication limited to HT/AA/Hispanic participants (Medical Records Cohort, MRC) Self-Report Cohort (all others) receive annual follow-up Long Life Study of ~8,000 older MRC participants have a home visit with brief physical exam, functional status assessment and blood collection No significant changes 26

27 Study milestones may be important in analyses Example: Breast cancer hazard ratios during and after intervention in the E+P trial Chlebowski RT, Kuller L, Prentice R, et al, NEJM, 2009 Chlebowski RT, Kuller L, Prentice R, et al. N Engl J Med 360;6:

28 Cohort attrition by study phase 161,808 participants from 40 U.S. centers followed for up to 12 years ( ) 115,403 participants enrolled in WHI Extension Study I ( ) 93,500 participants enrolled in WHI Extension Study II ( ) ~78,000 currently alive and in active follow-up Passive follow-up data Linkage to Medicare established for ~142,000 women (96% of those with valid social security numbers) NDI searches to determine vital status and cause of death 28

29 Age distribution of active participants on September 30, 2015 (N=81,330) < MRC SRC

30 WHI cohort composition changes over time Baseline American Indian Asian/Pacific Islander Black Hispanic White Unknown 30

31 WHI organizations & functions Funding and oversight by NHLBI (Shari Ludlam, Program fficer) Clinical Coordinating Center (PI: Garnet Anderson) Centralized mail follow-up Coordinate outcomes adjudication Support study committees, SIGs Maintain databases and biospecimen Fisher Bioservices Provide analytic support Four Regional Centers (PIs: Rebecca Jackson, Sally Shumaker, Marcia Stefanick, Jean Wactawski-Wende) and 5 satellite sites Follow-up of mail non-responders Document outcomes Provide analytic support Engage investigators/support SIGs 31

32 WHI Committees & Governance Steering Committee (Rebecca Jackson, chair) utcomes Advisory Committee (Karen Margolis, chair) Ancillary Study Committee (Robert Brunner, chair) Publications and Presentations Committee (Barbara Howard and Cynthia Thomson, co-chairs) Scientific Resources Working Group (Rebecca Jackson, chair) Scientific Interest Groups Aging, Bone/Fracture/Body Composition, Cancer, CVD, Genetics/Proteomics/Biomarkers, Health Services, Minorities & Health Disparities, Nutrition/Energy Balance, besity/diabetes, Physical & Built Environment, Psychosocial & Behavior Health 32

33 Study Policies: Publications and Presentations Manuscript proposals, including analytic plan must be approved by P&P and writing committee membership offered to WHI investigators Final manuscript must be approved by P&P prior to journal submission Meeting abstracts need prior approval by P&P All papers must acknowledge WHI funding, investigators Additional information at 33

34 Study Policies: Ancillary Studies Definition: Any study that generates new data not covered by the WHI protocol New questionnaires Analyses of biospecimens Linkage to external data Approvals All proposed ancillary studies must be reviewed and recommended by the ASC and approved by the Steering Committee and NHLBI Ancillary studies with participant burden must be reviewed by the DSMB Additional information at: 34

35 WHIMS suite of studies in HT participants 35

36 LILAC LIFE AND LNGEVITY AFTER CANCER THE WHI CANCER SURVIVR CHRT Garnet Anderson, Bette Caan, Electra Paskett, mpis Filling the gaps in WHI data and biospecimen collection for cancer survivorship and molecular epidemiology studies 36

37 A Pragmatic Trial : Physical Activity to Improve CV Health in Women PIs: Marcia Stefanick, Charles Kooperberg, Andrea LaCroix, Ph.D Eligible based on existing data no yes Follow, per WHI protocol Randomize Control (n ~25,000) Intervention (n ~ 25,000) Follow, per WHI protocol pt ut: no Consent yes Follow, per WHI protocol WHISH PA (Go4Life ) Intervention deliver mail-based [+ website, etc.] ± IVR** (phone) + live advisor, PRN ** Interactive Voice Response System (Consent)

38 Ccoa Supplement and Multivitamin utcomes Study PIs: JoAnn E. Manson, Howard Sesso WHI women aged 65 y + VITAL non-randomized men aged 60 y Cocoa flavanols N=9,000 Placebo N=9,000 Multivitamin N=4,500 Placebo N=4,500 Multivitamin N=4,500 Placebo N=4,500 Primary utcomes: Major cardiovascular events (MI, stroke, CVD death, and coronary revascularization) and total cancer (excluding non-melanoma skin cancer) 38

39 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: HHSN C, HHSN C, HHSN C, HHSN C, HHSN C, HHSN C) 39