WHAT CAN WE LEARN FROM DESIGN FAULTS IN THE WOMEN'S HEALTH INITIATIVE RANDOMIZED CLINICAL TRIAL?

1. WHAT CAN WE LEARN FROM DESIGN FAULTS IN THE WOMEN'S HEALTH INITIATIVE RANDOMIZED CLINICAL TRIAL? F. NAFTOLIN MD, PHD DEPARTMENT OF OBSTETRICS AND GYNECOLOGY NYU SCHOOL OF MEDICINE

2. SUMMARY • WHAT IS THE WHI? • CRITICAL DESIGN FAULTS OF THE WHI • ACCEPTING TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWER • ACCEPTING BIOLOGICAL IMPLAUSIBILITY • STUDYING OUTCOMES RATHER THAN PROGRESS OF DISEASE • APPARENTLY MISSING PLACEBO DATA IN YEAR FIVE • ASSESSING QUALITY OF LIFE IN WRONG SUBJECTS • SUBSET ANALYSIS OF WOMEN CHOSEN FROM THE LARGER GROUP OF RECRUITS BECAUSE OF A SINGLE FACTOR (AGE) • STUDY OF DEMENTIA WITHOUT PRIOR NEUROLOGICAL EXAMINATION • INTERPRETATIVE ERRORS – BIOLOGICAL PLAUSIBILITY • DID THE WHI MEET ITS OBJECTIVES – NO • WHAT HAS THIS COST? • REDOING THE WHI – KRONOS EARLY ESTROGEN PREVENTION STUDY (KEEPS)

3. WHAT IS THE WHI? THE WHI IS A STUDY TO DETERMINE WHETHER ESTROGEN (E) OR E + PROGESTIN (P) REPLACEMENT IS CARDIOPROTECTIVE

4. Design of the Women’s Health Initiative Clinical Trial and Observational Study Controlled Clin Trials 1998;19:61–109 by The Women’s Health Initiative Study Group ABSTRACT: The Women’s Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components—dietary modification (DM) or hormone replacement therapy (HRT)—of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS.

5. Statistical Issues Arising in the Women’s Health Initiative Ross L. Prentice,Mary Pettinger,and Garnet L. Anderson Biometrics 61, 899–941 December 2005 Summary. A brief overview of the design of the Women’s Health Initiative (WHI) clinical trial and observational study is provided along with a summary of results from the postmenopausal hormone therapy clinical trial components. Since its inception in 1992, the WHI has encountered a number of statistical issues where further methodology developments are needed. These include measurement error modeling and analysis procedures for dietary and physical activity assessment; clinical trial monitoring methods when treatments may affect multiple clinical outcomes, either beneficially or adversely; study design and analysis procedures for high-dimensional genomic and proteomic data; and failure time data analysis procedures when treatment group hazard ratios are time dependent. This final topic seems important in resolving the discrepancy between WHI clinical trial and observational study results on postmenopausal hormone therapy and cardiovascular disease.

6. WHAT INSPIRED THE WHI? PRE CLINICAL STUDIES SHOW CARDIOPROTECTION IN LABORATORY AND ANIMAL STUDIES OBSERVATIONAL TRIALS SHOW CLEAR CARDIOPROTECTION IN WOMEN USING MENOPAUSAL HORMONE THERAPY

7. OBSERVATIONAL TRIALS ON HRT AND CVD From Stampfer and Colditz, PREV MED, 1991

8. WHAT ARE THE DIFFERENCES BETWEEN THE WHI AND THE STUDIES THAT INSPIRED IT? CHRONOLOGIC AGE OF SUBJECTS MENOPAUSAL AGE (YEARS SINCE LAST MENSTRUAL PERIOD) PHYSICAL CONDITION OF SUBJECTS

9. THE ILL-EFFECT OF STUDY DESIGN ON SUBJECT AGE IN THE WHI WHI ACCEPTED TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWER

10. WHI AVOIDED SYMPTOMS (VASO-MOTOR EPISODES) THAT WOULD BETRAY THE PLACEBO/INCREASE DROP-OUTSWHI STUDIED DISEASE EVENTS RATHER THAN PROGRESS OF DISEASE

11. OBSERVATIONAL STUDIES SUBJECTS SELF-SELECT BY SYMPTOMS MENOPAUSAL TRANSITION HRT NO HRT

12. OBSERVATIONAL STUDIES SUBJECTS SELF-SELECT BY SYMPTOMS (WHI) RCT TRIAL ASSIGNS TREATMENT IRRESPECTIVE OF SYMPTOMS MENOPAUSAL TRANSITION AVERAGE 12 YEARS POST-MENOPAUSAL WOMEN HRT NO HRT HT NO HT

13. WHI ACCEPTED TO IGNORE BIOLOGICAL PLAUSABILITY (AND PUBLISHED DATA) REGARDING AGE AND HEART DISEASE

14. ATHEROSCLEROTIC PLAQUE BURDEN MEASURED BY CORONARY CALCIUM IN ASYMPTOMATIC WOMEN UNDERGOING ELECTRON BEAM TOMOGRAPHY. 80 Percentiles of Coronary Calcium 60 90th Percent of Group 40 75th 25th 20 0 45-49 50-54 55-59 60-64 65-70 Age Observational WHI Modified from Raggi, et al. Circulation 2000;10:850-855

15. With CEE/MPA With Placebo Early CVD Events in HERS Incidence (%) Follow-up (years) Modified from Herrington DM, et al. Circulation. 2002;105:2962-7.

16. AGE-SPECIFIC OCCURRENCE OF VENOUS THROMBOSIS IN THE E+P ARM OF THE WOMEN’S HEALTH INITIATIVE Cushman M, Kuller LH, Prentice R, et al.; JAMA. 2004;292(13):1573-1580

17. Characteristic HRT n = 8,506 Placebo n = 8,102 Age at screening, yrs* Prior hormone use, % Body mass index, kg/m2* Never smokers, % Diabetes, % Hypertension, % Statin use at baseline, % Family Hx breast cancer, % History of MI,† % History of CABG/PTCA,† % 63.2 (7.1) 26.1 28.5 (5.8) 49.6 4.4 35.7 6.9 16.0 1.6 1.1 63.3 (7.1) 25.6 28.5 (5.9) 50.0 4.4 36.4 6.8 15.3 1.9 1.5‡ WHI BASELINE CHARACTERISTICS *Values are means (SD); †Overall incidence of prior cardiovascular disease = 7.7%; ‡P = .04 vs HRT. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

18. WHI EVENTS: VTESummary by Year n = number of patients; (%) = annualized % calculated from average exposure over 60 months. *z score for trend across all years = –2.45; test for trend based on Cox proportional hazard model with time-dependent treatment effects. VTE includes deep vein thrombosis (DVT) and PE. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

19. WHI EVENTS: CHDSUMMARY BY YEAR n = number of patients; (%) = annualized % calculated from average exposure over 60 months. *z score for trend across all years = –1.19; test for trend based on Cox proportional hazard model with time-dependent treatment effects. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

20. BECAUSE IT DEVIATED FROM THE STUDIES THAT INSPIRED THE WHI THE WHI RCT IS ~10-FOLD UNDERPOWERED TO TEST THE CARDIOPROTECTIVE EFFECTS OF HRT IN WOMEN IN THE MENOPAUSAL TRANSITION (AGE ~49-55)

21. SOURCE OF THE INFORMATION ON THE 50-54 Y.O. MODERATE-SEVERELY SYMPTOMATIC SUBJECTS IN THE E+P AND PLACEBO GROUPS OF THE WHI

22. CHARACTERISTICS OF THE SUBJECTS MAKING UP THE 50-59 Y.O. WHI ESTROGEN+PROGESTIN AND PLACEBO GROUPS E+P Placebo Age 50-59 (% of total group) 2839 (33.4) 2868 (33.1) 50-79 MENOPAUSAL AGES <5 1315 (17.1) 1224 (16.3) 5- <10 1467 (19.1) 1488 (19.8) 10- <15 1611 (21.0) 1566 (20.9) =/>15 3286 (42.8) 3231 (43.0) Δ 12.0 (Information from: Hays et al., NEJM, 348:1839-54, 2003)

23. TOTAL (E+P PLUS PLACEBO) MODERATE-SEVERELY SYMPTOMATIC 50-54 YR SUBJECTS VS. TOTAL 50-59 YR SUBJECTS (2761/GROUP) (287/GROUP) (Information from: Hays et al., NEJM, 348:1839-54, 2003) (Information from: Hays et al., NEJM, 348:1839-54, 2003)

24. POWER ANALYSIS FOR 50-54 Y.O. WHI SUBJECTS • THE WHI 50-54 YO MODERATE-SEVERELY SYMPTOMATIC GROUP HAD ~287 SUBJECTS PER GROUP. • THE AGE-CORRECTED NUMBER OF EXPECTED EVENTS (NURSES HEALTH STUDY) IS 0.73 EVENTS PER 275 WOMEN PER 5 YEARS • IF THE ONE GROUP HAD 2 X 0.73 EVENTS DURING THE 5 YEAR OBSERVATION PERIOD AND THE OTHER GROUP HAD 0 EVENTS, IT WOULD REQUIRE > 4000 WOMEN IN EACH ARM TO SHOW A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN GROUPS. • WITH A 42% DROPOUT RATE (WHI), THE NUMBER OF SUBJECTS NEEDED PER GROUP BECOMES ~9000. Naftolin F, Taylor H, Karas R, Fertil Steril. 81(6):1498-501. 2004

25. MISSING PLACEBO DATA IN YEAR FIVE RAISED THE HAZARD RATIO AND TRIGGERED ACTION BY THE DRUG SAFETY MONITORING BOARD

26. WHI EVENTS: VTESummary by Year n = number of patients; (%) = annualized % calculated from average exposure over 60 months. *z score for trend across all years = –2.45; test for trend based on Cox proportional hazard model with time-dependent treatment effects. VTE includes deep vein thrombosis (DVT) and PE. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

27. WHI EVENTS: CHDSUMMARY BY YEAR n = number of patients; (%) = annualized % calculated from average exposure over 60 months. *z score for trend across all years = –1.19; test for trend based on Cox proportional hazard model with time-dependent treatment effects. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

28. WHI EVENTS: INVASIVE BREAST CANCERSUMMARY BY YEAR n = number of patients; (%) = annualized % calculated from average exposure over 60 months. *z score for trend across all years = 2.56; test for trend based on Cox proportional hazard model with time-dependent treatment effects. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

29. ASSESSING QUALITY OF LIFE EFFECTS IN GROUPS WITH ONLY 11% SYMPTOMATIC SUBJECTS RESULTED IN A STUDY THAT WAS VASTLY UNDERPOWERED TO ASSESS CHANGES IN NUMBER OF SYMPTOMS PER DAY

30. MODERATE-SEVERELY SYMPTOMATIC 50-54 YR SUBJECTS VS. TOTAL 50-59 YR SUBJECTS (E+P PLUS PLACEBO) (2761/GROUP) (287/GROUP) (Information from: Hays et al., NEJM, 348:1839-54, 2003)

31. STUDYING A SELECTED SUBSET GROUP FROM THE LARGER RECRUITMENT NO INITIAL NEUROLOGICAL EXAMINATION NO DIRECT DIAGNOSIS OF THE TYPE(S) OF DEMENTIA LATER SHOWN TO HAVE A HIGH RISK OF VENOUS THROMBOEMBOLISM THAT MAY LEAD TO STROKE

32. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women The Women’s Health Initiative Memory Study: A Randomized Clinical Trial Sally A. Shumaker, PhD, Claudine Legault, PhD, Stephen R. Rapp, PhD, et al. JAMA. 2003;289:2651-2662 Design, Setting, and Participants The Women’s Health Initiative Memory Study (WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women’s Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS. Intervention Participants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n=2229), or a matching placebo (n=2303). Results The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval [CI], 1.21-3.48; 45 vs. 22 per 10000 person-years; P=.01). This increased risk would result in an additional 23 cases of dementia per 10000 women per year. Alzheimer disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10000 person-years; P=.72).

33. WHI ESTROGEN-ONLY ARM • CONCORDANT WITH E+P ARM EXCEPT NON-SIGNIFICANT FALL IN NEW BREAST CANCER DIAGNOSES AND CARDIOPROTECTIVE EFFECTS (EVENTS) • INCREASED STROKES (EVENTS) • INCREASED THROMBOEMBOLIC EVENTS • PROTECTIVE EFFECTS ON FRACTURES AND COLON CANCER (EVENTS)

34. HAS THE WHI RESOLVED THE ISSUE OF CARDIOPROTECTION OR NEUROPROTECTION BY E OR E + P IN WOMEN STARTING TREATMENT DURING THE MENOPAUSAL TRANSITION? NO

35. CAN/SHOULD A RCT BE USED TO TEST THE CARDIOPROTECTIVE OR NEUROPROTECTIVE EFFECTS OF HRT? YES (QUALIFIED) BUT, THE STUDY MUST START HRT DURING THE MENOPAUSAL TRANSITION AND BE ADEQUATELY POWERED TO ANSWER THE QUESTIONS IT ASKS. IN THE CASE OF THE MENOPAUSAL TRANSITION THERE ARE NOT ENOUGH EVENTS TO USE EVENTS AS AN ENDPOINT.

36. SO, WHERE ARE WE NOW?

37. The WHI spent one billion dollars to prove that starting an asymptomatic 63.3-year-old postmenopausal woman on HRT will not decrease her risk of having a heart attack What about the rest of us? Modified from the New Yorker by Erroll Norwitz, 2003

38. HRT: WHERE ARE WE NOW? IN THE NURSES HEALTH STUDY THE CARDIOPROTECTIVE EFFECT DISAPPEARS AT THREE YEARS AFTER STOPPING HRT HERSH A, STEFANICK M, STAFFORD R JAMA 2004 291: 47-53

39. KRONOS EARLY ESTROGEN PROTECTION STUDY (KEEPS) – A FIVE-YEAR 9 CENTER RCT OF WOMEN IN THE MENOPAUSAL TRANSITION (STARTED 2004) WOMEN: HEALTHY 40-55 YEAR-OLDS WITHIN 12-36 MONTHS OF LAST PERIOD THREE TREATMENT ARMS: DAILY CEE PLUS CYCLIC TRANS-VAGINAL PROGESTERONE 10 DAYS PER MONTH; DAILY ESTRADIOL BY SKIN PATCH PLUS CYCLIC VAGINAL PROGESTERONE 10 DAYS PER MONTH; PLACEBO MAIN EVALUATIONS: ANNUAL INTIMA-MEDIA THICKNESS BY CAROTID ARTERY ULTRASOUND YEAR 0, 3, 5 CORONARY ARTERY CALCIUM BY TOMOGRAPHY PLUS: SAFETY STUDIES, ANCILLARY STUDIES

40. SUMMARY • WHAT IS THE WHI? • CRITICAL DESIGN FAULTS OF THE WHI • ACCEPTING TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWER • ACCEPTING BIOLOGICAL IMPLAUSIBILITY • STUDYING OUTCOMES RATHER THAN PROGRESS OF DISEASE • APPARENTLY MISSING PLACEBO DATA IN YEAR FIVE • ASSESSING QUALITY OF LIFE IN WRONG SUBJECTS • SUBSET ANALYSIS OF WOMEN CHOSEN FROM THE LARGER GROUP OF RECRUITS BECAUSE OF A SINGLE FACTOR (AGE) • STUDY OF DEMENTIA WITHOUT PRIOR NEUROLOGICAL EXAMINATION • INTERPRETATIVE ERRORS – BIOLOGICAL PLAUSIBILITY • DID THE WHI MEET ITS OBJECTIVES – NO • WHAT HAS THIS COST? • REDOING THE WHI – KRONOS EARLY ESTROGEN PREVENTION STUDY (KEEPS)

41. SUPPORTFN HAS RECEIVED SUPPORT FROM NIH, PHARMA AND OTHER COMMERCIAL INTERESTS IN THE PAST FIVE YEARS

42. SUMMARY • WHAT IS THE WHI? • CRITICAL DESIGN FAULTS OF THE WHI • ACCEPTING TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWER • ACCEPTING BIOLOGICAL IMPLAUSIBILITY • STUDYING OUTCOMES RATHER THAN PROGRESS OF DISEASE • APPARENTLY MISSING PLACEBO DATA IN YEAR FIVE • ASSESSING QUALITY OF LIFE IN WRONG SUBJECTS • SUBSET ANALYSIS OF WOMEN CHOSEN FROM THE LARGER GROUP OF RECRUITS BECAUSE OF A SINGLE FACTOR (AGE) • STUDY OF DEMENTIA WITHOUT PRIOR NEUROLOGICAL EXAMINATION • INTERPRETATIVE ERRORS – BIOLOGICAL PLAUSIBILITY • DID THE WHI MEET ITS OBJECTIVES – NO • WHAT HAS THIS COST? • REDOING THE WHI – KRONOS EARLY ESTROGEN PREVENTION STUDY (KEEPS)