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

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

CLINICAL TRIAL? CLINICAL TRIAL?

F. NAFTOLIN MD, PHDF. NAFTOLIN MD, PHD

DEPARTMENT OF OBSTETRICS AND GYNECOLOGYDEPARTMENT OF OBSTETRICS AND GYNECOLOGYNYU SCHOOL OF MEDICINENYU SCHOOL OF MEDICINE

SUMMARYSUMMARY• WHAT IS THE WHI?WHAT IS THE WHI?• CRITICAL DESIGN FAULTS OF THE WHICRITICAL DESIGN FAULTS OF THE WHI

– ACCEPTING TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL ACCEPTING TO STUDY A DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWERTRIALS IN ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWER

– ACCEPTING BIOLOGICAL IMPLAUSIBILITYACCEPTING BIOLOGICAL IMPLAUSIBILITY– STUDYING OUTCOMES RATHER THAN PROGRESS OF DISEASESTUDYING OUTCOMES RATHER THAN PROGRESS OF DISEASE– APPARENTLY MISSING PLACEBO DATA IN YEAR FIVEAPPARENTLY MISSING PLACEBO DATA IN YEAR FIVE– ASSESSING QUALITY OF LIFE IN WRONG SUBJECTS ASSESSING QUALITY OF LIFE IN WRONG SUBJECTS – SUBSET ANALYSIS OF WOMEN CHOSEN FROM THE LARGER GROUP OF SUBSET ANALYSIS OF WOMEN CHOSEN FROM THE LARGER GROUP OF

RECRUITS BECAUSE OF A SINGLE FACTOR (AGE)RECRUITS BECAUSE OF A SINGLE FACTOR (AGE)– STUDY OF DEMENTIA WITHOUT PRIOR NEUROLOGICAL EXAMINATION STUDY OF DEMENTIA WITHOUT PRIOR NEUROLOGICAL EXAMINATION – INTERPRETATIVE ERRORS – BIOLOGICAL PLAUSIBILITYINTERPRETATIVE ERRORS – BIOLOGICAL PLAUSIBILITY

• DID THE WHI MEET ITS OBJECTIVES – NODID THE WHI MEET ITS OBJECTIVES – NO• WHAT HAS THIS COST?WHAT HAS THIS COST?• REDOING THE WHI – KRONOS EARLY ESTROGEN PREVENTION STUDY REDOING THE WHI – KRONOS EARLY ESTROGEN PREVENTION STUDY

(KEEPS) (KEEPS)

WHAT IS THE WHIWHAT IS THE WHI??

THE WHI IS A STUDY TO DETERMINE THE WHI IS A STUDY TO DETERMINE WHETHER ESTROGEN (E) OR E + WHETHER ESTROGEN (E) OR E + PROGESTIN (P) REPLACEMENT IS PROGESTIN (P) REPLACEMENT IS

CARDIOPROTECTIVE CARDIOPROTECTIVE

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 GroupABSTRACT: 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.

Statistical Issues Arising in the Women’s Health InitiativeRoss L. Prentice, Mary Pettinger, and Garnet L. AndersonBiometrics 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.

WHAT INSPIRED THE WHIWHAT INSPIRED THE WHI??

PRE CLINICAL STUDIES SHOW PRE CLINICAL STUDIES SHOW CARDIOPROTECTION IN LABORATORY AND CARDIOPROTECTION IN LABORATORY AND

ANIMAL STUDIESANIMAL STUDIES

OBSERVATIONAL TRIALS SHOW CLEAR OBSERVATIONAL TRIALS SHOW CLEAR CARDIOPROTECTION IN WOMEN USING CARDIOPROTECTION IN WOMEN USING

MENOPAUSAL HORMONE THERAPYMENOPAUSAL HORMONE THERAPY

OBSERVATIONAL TRIALS ON HRT AND CVDOBSERVATIONAL TRIALS ON HRT AND CVD

From Stampfer and Colditz, PREV MED, 1991From Stampfer and Colditz, PREV MED, 1991

WHAT ARE THE DIFFERENCES WHAT ARE THE DIFFERENCES BETWEEN THE WHI AND THE BETWEEN THE WHI AND THE STUDIES THAT INSPIRED ITSTUDIES THAT INSPIRED IT??

CHRONOLOGIC AGE OF SUBJECTSCHRONOLOGIC AGE OF SUBJECTS

MENOPAUSAL AGE (YEARS SINCE MENOPAUSAL AGE (YEARS SINCE LAST MENSTRUAL PERIOD)LAST MENSTRUAL PERIOD)

PHYSICAL CONDITION OF PHYSICAL CONDITION OF SUBJECTSSUBJECTS

THE ILL-EFFECT OF STUDY DESIGN THE ILL-EFFECT OF STUDY DESIGN ON SUBJECT AGE IN THE WHION SUBJECT AGE IN THE WHI

WHI ACCEPTED TO STUDY A WHI ACCEPTED TO STUDY A DIFFERENT POPULATION THAN IN DIFFERENT POPULATION THAN IN THE OBSERVATIONAL TRIALS IN THE OBSERVATIONAL TRIALS IN

ORDER TO AVOID DROPOUTS AND ORDER TO AVOID DROPOUTS AND TO HAVE SUFFICIENT POWERTO HAVE SUFFICIENT POWER

WHI AVOIDED SYMPTOMS (VASO-WHI AVOIDED SYMPTOMS (VASO-MOTOR EPISODES) THAT WOULD MOTOR EPISODES) THAT WOULD BETRAY THE PLACEBO/INCREASE BETRAY THE PLACEBO/INCREASE

DROP-OUTSDROP-OUTS

WHI STUDIED DISEASE EVENTS WHI STUDIED DISEASE EVENTS RATHER THAN PROGRESS OF RATHER THAN PROGRESS OF

DISEASEDISEASE

MENOPAUSAL MENOPAUSAL TRANSITIONTRANSITION


HRTHRTHRTHRT NO NO HRTHRTNO NO

HRTHRT

OBSERVATIONAL OBSERVATIONAL STUDIESSTUDIES

SUBJECTS SELF-SELECTSUBJECTS SELF-SELECTBY SYMPTOMSBY SYMPTOMS

AVERAGE 12 YEARS AVERAGE 12 YEARS POST-MENOPAUSAL POST-MENOPAUSAL

WOMENWOMEN

AVERAGE 12 YEARS AVERAGE 12 YEARS POST-MENOPAUSAL POST-MENOPAUSAL

WOMENWOMEN

HTHTHTHT NO HTNO HTNO HTNO HT



HRTHRTHRTHRT NO NO HRTHRTNO NO

HRTHRT

OBSERVATIONAL OBSERVATIONAL STUDIESSTUDIES

SUBJECTS SELF-SELECTSUBJECTS SELF-SELECTBY SYMPTOMSBY SYMPTOMS

(WHI) RCT(WHI) RCT

TRIAL ASSIGNS TREATMENTTRIAL ASSIGNS TREATMENTIRRESPECTIVE OF SYMPTOMS IRRESPECTIVE OF SYMPTOMS

WHI ACCEPTED TO IGNORE WHI ACCEPTED TO IGNORE BIOLOGICAL PLAUSABILITY BIOLOGICAL PLAUSABILITY

(AND PUBLISHED DATA) (AND PUBLISHED DATA) REGARDING AGE AND HEART REGARDING AGE AND HEART

DISEASEDISEASE

0

20

40

60

80

Per

cen

t of

Gro

up

45-49 50-54 55-59 60-64 65-70

Age

Percentiles of Coronary Calcium

25th

75th

90th

Modified from Raggi, et al. Modified from Raggi, et al. Circulation Circulation 2000;10:850-855 2000;10:850-855

ATHEROSCLEROTIC PLAQUE BURDEN MEASURED BY ATHEROSCLEROTIC PLAQUE BURDEN MEASURED BY CORONARY CALCIUM INCORONARY CALCIUM IN ASYMPTOMATIC ASYMPTOMATIC WOMEN WOMEN UNDERGOING ELECTRON BEAM TOMOGRAPHY.UNDERGOING ELECTRON BEAM TOMOGRAPHY.

ObservationalObservational WHIWHI

0

5

10

15

20

0 1 2 3 4 5

Early CVD Early CVD EventsEvents in HERS in HERS

Modified from Herrington DM, et al. Circulation. 2002;105:2962-7.

Inci

den

ce

(%

)

With CEE/MPAWith Placebo

Follow-up (years)

AGE-SPECIFIC OCCURRENCE OF VENOUS THROMBOSIS AGE-SPECIFIC OCCURRENCE OF VENOUS THROMBOSIS IN THE E+P ARM OF THE WOMEN’S HEALTH INITIATIVEIN THE E+P ARM OF THE WOMEN’S HEALTH INITIATIVE

Cushman M, Kuller LH, Prentice R, et al.; Cushman M, Kuller LH, Prentice R, et al.; JAMAJAMA. 2004;292(13):1573-1580. 2004;292(13):1573-1580

WHI BASELINE WHI BASELINE CHARACTERISTICSCHARACTERISTICS

Writing Group for the Women’s Health Initiative Investigators. Writing Group for the Women’s Health Initiative Investigators. JAMAJAMA. 2002;288:321-333.. 2002;288:321-333.

*Values are means (SD); *Values are means (SD); ††Overall incidence of prior cardiovascular disease = 7.7%; Overall incidence of prior cardiovascular disease = 7.7%; ‡‡PP = .04 vs HRT = .04 vs HRT..

63.3 (7.1)63.3 (7.1)25.625.628.5 (5.9)28.5 (5.9)50.050.0

4.44.436.436.4

6.86.815.315.3

1.91.91.51.5‡‡

63.2 (7.1)63.2 (7.1)26.126.128.5 (5.8)28.5 (5.8)49.649.6

4.44.435.735.7

6.96.916.016.0

1.61.61.11.1

Age at screening, yrs*Age at screening, yrs*Prior hormone use, %Prior hormone use, %Body mass index, kg/mBody mass index, kg/m22**Never smokers, % Never smokers, % Diabetes, %Diabetes, %Hypertension, %Hypertension, %Statin use at baseline, %Statin use at baseline, %Family Hx breast cancer, %Family Hx breast cancer, %History of MI,History of MI,†† % %History of CABG/PTCA,History of CABG/PTCA,†† % %

PlaceboPlacebon = 8,102n = 8,102

HRTHRTn = 8,506n = 8,506CharacteristicCharacteristic

WHI WHI EVENTSEVENTS: VTE: VTESummary by YearSummary by Year

YearHRTn (%)

Placebon (%)

Hazard Ratio*

11

22

33

44

55

6+6+

49 (0.58)49 (0.58)

26 (0.31)26 (0.31)

21 (0.25)21 (0.25)

27 (0.34)27 (0.34)

16 (0.27)16 (0.27)

12 (0.23)12 (0.23)

13 (0.16)13 (0.16)

11 (0.14)11 (0.14)

12 (0.15)12 (0.15)

14 (0.19)14 (0.19)

6 (0.11)6 (0.11)

11 (0.26)11 (0.26)

3.603.60

2.262.26

1.671.67

1.841.84

2.492.49

0.900.90

Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

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 modelwith time-dependent treatment effects. VTE includes deep vein thrombosis (DVT) and PE.

WHI WHI EVENTSEVENTS: CHD: CHDSUMMARY BY YEARSUMMARY BY YEAR

YearYearHRTHRTn (%)n (%)

PlaceboPlacebon (%)n (%)

Hazard Hazard Ratio*Ratio*

11

22

33

44

55

6+6+

43 (0.51)43 (0.51)

36 (0.43)36 (0.43)

20 (0.24)20 (0.24)

25 (0.32)25 (0.32)

23 (0.39)23 (0.39)

17 (0.33)17 (0.33)

23 (0.29)23 (0.29)

30 (0.38)30 (0.38)

18 (0.23)18 (0.23)

24 (0.32)24 (0.32)

9 (0.16)9 (0.16)

18 (0.42)18 (0.42)

1.781.78

1.151.15

1.061.06

0.990.99

2.382.38

0.780.78


n = number of patients; (%) = annualized % calculated from average exposure over n = number of patients; (%) = annualized % calculated from average exposure over 60 months.60 months.**zz score for trend across all years = score for trend across all years = ––1.19; test for trend based on Cox proportional hazard model1.19; test for trend based on Cox proportional hazard modelwith time-dependent treatment effects.with time-dependent treatment effects.

BECAUSE IT DEVIATED FROM THE BECAUSE IT DEVIATED FROM THE STUDIES THAT INSPIRED THE WHISTUDIES THAT INSPIRED THE WHI

THE WHI RCT IS ~10-FOLD THE WHI RCT IS ~10-FOLD UNDERPOWERED TO TEST THE UNDERPOWERED TO TEST THE

CARDIOPROTECTIVE EFFECTS OF CARDIOPROTECTIVE EFFECTS OF HRT IN WOMEN IN THE HRT IN WOMEN IN THE

MENOPAUSAL TRANSITION (AGE MENOPAUSAL TRANSITION (AGE ~49-55)~49-55)

SOURCE OF THE INFORMATION ON THE 50-SOURCE OF THE INFORMATION ON THE 50-54 Y.O. MODERATE-SEVERELY 54 Y.O. MODERATE-SEVERELY

SYMPTOMATIC SUBJECTS IN THE E+P AND SYMPTOMATIC SUBJECTS IN THE E+P AND PLACEBO GROUPS OF THE WHIPLACEBO GROUPS OF THE WHI

E+PE+P PlaceboPlacebo

Age 50-59 (% of total group)Age 50-59 (% of total group) 2839 (33.4)2839 (33.4) 2868 (33.1)2868 (33.1)

50-79 MENOPAUSAL AGES50-79 MENOPAUSAL AGES

<5<5 1315 (17.1)1315 (17.1) 1224 (16.3)1224 (16.3)

5- <105- <10 1467 (19.1)1467 (19.1) 1488 (19.8)1488 (19.8)

10- <1510- <15 1611 (21.0)1611 (21.0) 1566 (20.9)1566 (20.9)

=/>15=/>15 3286 (42.8)3286 (42.8) 3231 (43.0)3231 (43.0)

Δ 12.0Δ 12.0 (Information from: Hays et al., NEJM, 348:1839-54, 2003)(Information from: Hays et al., NEJM, 348:1839-54, 2003)

CHARACTERISTICS OF THE SUBJECTS MAKING CHARACTERISTICS OF THE SUBJECTS MAKING UP THE 50-59 Y.O. WHI ESTROGEN+PROGESTIN UP THE 50-59 Y.O. WHI ESTROGEN+PROGESTIN

AND PLACEBO GROUPSAND PLACEBO GROUPS

574

5522

0

1000

2000

3000

4000

5000

6000

50-54 50-59

TOTAL (E+P PLUS PLACEBO) MODERATE-TOTAL (E+P PLUS PLACEBO) MODERATE-SEVERELY SYMPTOMATIC 50-54 YR SEVERELY SYMPTOMATIC 50-54 YR

SUBJECTS VS. TOTAL 50-59 YR SUBJECTSSUBJECTS VS. TOTAL 50-59 YR SUBJECTS

(287/GROUP)

(2761/GROUP)

((IInnffoorrmmaattiioonn ffrroomm:: HHaayyss eett aall..,, NNEEJJMM,, 334488::11883399--5544,, 22000033))

(Information from: Hays et al., NEJM, 348:1839-54, 2003)(Information from: Hays et al., NEJM, 348:1839-54, 2003)

•THE WHI 50-54 YO MODERATE-SEVERELY THE WHI 50-54 YO MODERATE-SEVERELY SYMPTOMATIC GROUP HAD ~287 SUBJECTS PER SYMPTOMATIC GROUP HAD ~287 SUBJECTS PER GROUP.GROUP.

•THE AGE-CORRECTED NUMBER OF EXPECTED THE AGE-CORRECTED NUMBER OF EXPECTED EVENTS (NURSES HEALTH STUDY) IS EVENTS (NURSES HEALTH STUDY) IS 0.73 EVENTS 0.73 EVENTS PER 275 WOMEN PER 5 YEARSPER 275 WOMEN PER 5 YEARS

•IF THE ONE GROUP HAD 2 X 0.73 EVENTS DURING IF THE ONE GROUP HAD 2 X 0.73 EVENTS DURING THE 5 YEAR OBSERVATION PERIOD AND THE OTHER THE 5 YEAR OBSERVATION PERIOD AND THE OTHER GROUP HAD 0 EVENTS, IT WOULD GROUP HAD 0 EVENTS, IT WOULD REQUIRE > 4000 REQUIRE > 4000 WOMEN IN EACH ARMWOMEN IN EACH ARM TO SHOW A STATISTICALLY TO SHOW A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN GROUPS.SIGNIFICANT DIFFERENCE BETWEEN GROUPS.

•WITH A 42% DROPOUT RATE (WHI), THE NUMBER OF WITH A 42% DROPOUT RATE (WHI), THE NUMBER OF SUBJECTS NEEDED PER GROUP BECOMES ~9000.SUBJECTS NEEDED PER GROUP BECOMES ~9000.

Naftolin F, Taylor H, Karas R, Fertil Steril. 81(6):1498-501. 2004

POWER ANALYSIS FOR 50-54 Y.O. WHI SUBJECTSPOWER ANALYSIS FOR 50-54 Y.O. WHI SUBJECTS

MISSING PLACEBO DATA IN MISSING PLACEBO DATA IN YEAR FIVE RAISED THE YEAR FIVE RAISED THE

HAZARD RATIO AND HAZARD RATIO AND TRIGGERED ACTION BY THE TRIGGERED ACTION BY THE DRUG SAFETY MONITORING DRUG SAFETY MONITORING

BOARDBOARD

WHI EVENTS: VTEWHI EVENTS: VTESummary by YearSummary by Year

YearHRTn (%)

Placebon (%)

Hazard Ratio*

11

22

33

44

55

6+6+

49 (0.58)49 (0.58)

26 (0.31)26 (0.31)

21 (0.25)21 (0.25)

27 (0.34)27 (0.34)

16 (0.27)16 (0.27)

12 (0.23)12 (0.23)

13 (0.16)13 (0.16)

11 (0.14)11 (0.14)

12 (0.15)12 (0.15)

14 (0.19)14 (0.19)

6 (0.11)6 (0.11)

11 (0.26)11 (0.26)

3.603.60

2.262.26

1.671.67

1.841.84

2.492.49

0.900.90

Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

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 modelwith time-dependent treatment effects. VTE includes deep vein thrombosis (DVT) and PE.

WHI EVENTS: CHDWHI EVENTS: CHDSUMMARY BY YEARSUMMARY BY YEAR

YearYearHRTHRTn (%)n (%)

PlaceboPlacebon (%)n (%)

Hazard Hazard Ratio*Ratio*

11

22

33

44

55

6+6+

43 (0.51)43 (0.51)

36 (0.43)36 (0.43)

20 (0.24)20 (0.24)

25 (0.32)25 (0.32)

23 (0.39)23 (0.39)

17 (0.33)17 (0.33)

23 (0.29)23 (0.29)

30 (0.38)30 (0.38)

18 (0.23)18 (0.23)

24 (0.32)24 (0.32)

9 (0.16)9 (0.16)

18 (0.42)18 (0.42)

1.781.78

1.151.15

1.061.06

0.990.99

2.382.38

0.780.78


n = number of patients; (%) = annualized % calculated from average exposure over n = number of patients; (%) = annualized % calculated from average exposure over 60 months.60 months.**zz score for trend across all years = score for trend across all years = ––1.19; test for trend based on Cox proportional hazard model1.19; test for trend based on Cox proportional hazard modelwith time-dependent treatment effects.with time-dependent treatment effects.

WHI EVENTS: INVASIVE BREAST WHI EVENTS: INVASIVE BREAST CANCERCANCER

SUMMARY BY YEARSUMMARY BY YEAR

YearYearHRTHRT

nnPlaceboPlacebo

nnHazardHazardRatio*Ratio*

11

22

33

44

55

6+6+

11 (0.0013)11 (0.0013)

26 (0.0031)26 (0.0031)

28 (0.0034)28 (0.0034)

40 (0.0050)40 (0.0050)

34 (0.0057)34 (0.0057)

27 (0.0053)27 (0.0053)

17 (0.0021)17 (0.0021)

30 (0.0038)30 (0.0038)

23 (0.0029)23 (0.0029)

22 (0.0029)22 (0.0029)

12 (0.0022)12 (0.0022)

20 (0.0047)20 (0.0047)

0.620.62

0.830.83

1.161.16

1.731.73

2.642.64

1.121.12


n = number of patients; (%) = annualized % calculated from average exposure over n = number of patients; (%) = annualized % calculated from average exposure over 60 months.60 months.**zz score for trend across all years = 2.56; test for trend based on Cox proportional hazard model score for trend across all years = 2.56; test for trend based on Cox proportional hazard modelwith time-dependent treatment effects.with time-dependent treatment effects.

ASSESSING QUALITY OF LIFE ASSESSING QUALITY OF LIFE EFFECTS IN GROUPS WITH ONLY EFFECTS IN GROUPS WITH ONLY 11% SYMPTOMATIC SUBJECTS 11% SYMPTOMATIC SUBJECTS

RESULTED IN A STUDY THAT WAS RESULTED IN A STUDY THAT WAS VASTLY UNDERPOWERED TO VASTLY UNDERPOWERED TO

ASSESS CHANGES IN NUMBER OF ASSESS CHANGES IN NUMBER OF SYMPTOMS PER DAYSYMPTOMS PER DAY

574

5522

0

1000

2000

3000

4000

5000

6000

50-54 50-59

MODERATE-SEVERELY SYMPTOMATIC 50-54 MODERATE-SEVERELY SYMPTOMATIC 50-54 YR SUBJECTS VS. TOTAL 50-59 YR YR SUBJECTS VS. TOTAL 50-59 YR SUBJECTS (E+P PLUS PLACEBO) SUBJECTS (E+P PLUS PLACEBO)

(287/GROUP)

(2761/GROUP)

(Information from: Hays et al., NEJM, 348:1839-54, 2003)(Information from: Hays et al., NEJM, 348:1839-54, 2003)

STUDYING A SELECTED SUBSET STUDYING A SELECTED SUBSET GROUP FROM THE LARGER GROUP FROM THE LARGER

RECRUITMENTRECRUITMENT

NO INITIAL NEUROLOGICAL EXAMINATIONNO INITIAL NEUROLOGICAL EXAMINATIONNO DIRECT DIAGNOSIS OF THE TYPE(S) OF NO DIRECT DIAGNOSIS OF THE TYPE(S) OF

DEMENTIADEMENTIALATER SHOWN TO HAVE A HIGH RISK OF LATER SHOWN TO HAVE A HIGH RISK OF VENOUS THROMBOEMBOLISM THAT MAY VENOUS THROMBOEMBOLISM THAT MAY

LEAD TO STROKELEAD TO STROKE

Estrogen Plus Progestin and the Incidence of Dementia and Mild Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women The Women’s Cognitive Impairment in Postmenopausal Women The Women’s Health Initiative Memory Study: Health Initiative Memory Study: A Randomized Clinical TrialA Randomized Clinical TrialSally A. Shumaker, PhD, Claudine Legault, PhD, Stephen R. Rapp, PhD, et al.Sally A. Shumaker, PhD, Claudine Legault, PhD, Stephen R. Rapp, PhD, et al.JAMA. 2003;289:2651-2662JAMA. 2003;289:2651-2662Design, Setting, and Participants The Women’s Health Initiative Memory StudyDesign, Setting, and Participants The Women’s Health Initiative Memory Study(WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrolling(WHIMS), a randomized, double-blind, placebo-controlled clinical trial, began enrollingparticipants from the Women’s Health Initiative (WHI) estrogen plus progestin trialparticipants from the Women’s Health Initiative (WHI) estrogen plus progestin trialin May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women postmenopausal women free of probable dementia, aged 65 years or olderfree of probable dementia, aged 65 years or older, and , and recruitedrecruitedfrom 39 of 40 WHI clinical centers were enrolled in the WHIMS.from 39 of 40 WHI clinical centers were enrolled in the WHIMS.Intervention Participants received either 1 daily tablet of 0.625 mg of conjugatedIntervention Participants received either 1 daily tablet of 0.625 mg of conjugatedequine estrogen plus 2.5 mg of medroxyprogesterone acetate (n=2229), or a matchingequine estrogen plus 2.5 mg of medroxyprogesterone acetate (n=2229), or a matchingplacebo (n=2303).placebo (n=2303).Results The mean (SD) time between the date of randomization into WHI and theResults The mean (SD) time between the date of randomization into WHI and thelast Modified Mini-Mental State Examination (3MSE) for all WHIMS participants waslast Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was4.05 (1.19) years. Overall, 61 women were diagnosed with 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementiaprobable dementia, 40, 40(66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo(66%) in the estrogen plus progestin group compared with 21 (34%) in the placebogroup. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence intervalgroup. The hazard ratio (HR) for probable dementia was 2.05 (95% confidence interval[CI], 1.21-3.48; [CI], 1.21-3.48; 45 vs. 22 per 10000 person-years45 vs. 22 per 10000 person-years; ; PP=.01). This increased risk=.01). This increased riskwould result in an additional 23 cases of dementia per 10000 women per year. would result in an additional 23 cases of dementia per 10000 women per year. AlzheimerAlzheimerdisease was the most common classification of dementia in both study groups.disease was the most common classification of dementia in both study groups.Treatment effects on mild cognitive impairment did not differ between groups (HR,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; 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10000 person-years; PP=.72).=.72).

WHI ESTROGEN-ONLY ARM WHI ESTROGEN-ONLY ARM

CONCORDANT WITH E+P ARM EXCEPT CONCORDANT WITH E+P ARM EXCEPT NON-SIGNIFICANT FALL IN NEW BREAST NON-SIGNIFICANT FALL IN NEW BREAST

CANCER DIAGNOSES AND CANCER DIAGNOSES AND CARDIOPROTECTIVE EFFECTS (EVENTS)CARDIOPROTECTIVE EFFECTS (EVENTS)

•INCREASED STROKES (EVENTS)INCREASED STROKES (EVENTS)•INCREASED THROMBOEMBOLIC EVENTSINCREASED THROMBOEMBOLIC EVENTS•PROTECTIVE EFFECTS ON FRACTURES AND PROTECTIVE EFFECTS ON FRACTURES AND COLON CANCER (EVENTS)COLON CANCER (EVENTS)

HAS THE WHI RESOLVED THE HAS THE WHI RESOLVED THE ISSUE OF CARDIOPROTECTION OR ISSUE OF CARDIOPROTECTION OR NEUROPROTECTION BY E OR E + P NEUROPROTECTION BY E OR E + P IN WOMEN STARTING TREATMENT IN WOMEN STARTING TREATMENT

DURING THE MENOPAUSAL DURING THE MENOPAUSAL TRANSITIONTRANSITION??

NONO

CAN/SHOULD A RCT BE USED TO CAN/SHOULD A RCT BE USED TO TEST THE CARDIOPROTECTIVE OR TEST THE CARDIOPROTECTIVE OR NEUROPROTECTIVE EFFECTS OF NEUROPROTECTIVE EFFECTS OF

HRTHRT??

YES (QUALIFIED)YES (QUALIFIED)

BUT, THE STUDY BUT, THE STUDY MUSTMUST START HRT DURING START HRT DURING THE MENOPAUSAL TRANSITION AND BE THE MENOPAUSAL TRANSITION AND BE

ADEQUATELY POWERED TO ANSWER THE ADEQUATELY POWERED TO ANSWER THE QUESTIONS IT ASKS. IN THE CASE OF THE QUESTIONS IT ASKS. IN THE CASE OF THE

MENOPAUSAL TRANSITION THERE ARE NOT MENOPAUSAL TRANSITION THERE ARE NOT ENOUGH EVENTS TO USE EVENTS AS AN ENOUGH EVENTS TO USE EVENTS AS AN

ENDPOINT.ENDPOINT.

SO, WHERE ARE WE NOW?SO, WHERE ARE WE NOW?

The WHI spent one billion dollars toThe WHI spent one billion dollars toprove that starting an asymptomaticprove that starting an asymptomatic63.3-year-old postmenopausal woman on HRT will 63.3-year-old postmenopausal woman on HRT will not decrease her risk of having a heart attack not decrease her risk of having a heart attack

What aboutthe rest of us?

Modified from the New Yorker by Erroll Norwitz, 2003Modified from the New Yorker by Erroll Norwitz, 2003

HERSH A, STEFANICK M, STAFFORD R JAMA 2004 291: 47-53HERSH A, STEFANICK M, STAFFORD R JAMA 2004 291: 47-53

HRT: WHERE ARE WE NOW?HRT: WHERE ARE WE NOW?

IN THE NURSES HEALTH IN THE NURSES HEALTH STUDY THE STUDY THE CARDIOPROTECTIVE CARDIOPROTECTIVE EFFECT DISAPPEARS AT EFFECT DISAPPEARS AT THREE YEARS AFTER THREE YEARS AFTER STOPPING HRT STOPPING HRT

KRONOS EARLY ESTROGEN PROTECTION STUDY (KEEPS) KRONOS EARLY ESTROGEN PROTECTION STUDY (KEEPS) – A FIVE-YEAR 9 CENTER RCT OF WOMEN IN THE – A FIVE-YEAR 9 CENTER RCT OF WOMEN IN THE

MENOPAUSAL TRANSITION (STARTED 2004)MENOPAUSAL TRANSITION (STARTED 2004)

WOMENWOMEN: HEALTHY 40-55 YEAR-OLDS WITHIN 12-36 : HEALTHY 40-55 YEAR-OLDS WITHIN 12-36 MONTHS OF LAST PERIODMONTHS OF LAST PERIOD

THREE TREATMENT ARMSTHREE TREATMENT ARMS: DAILY CEE PLUS CYCLIC : DAILY CEE PLUS CYCLIC TRANS-VAGINAL PROGESTERONE 10 DAYS PER MONTH; TRANS-VAGINAL PROGESTERONE 10 DAYS PER MONTH; DAILY ESTRADIOL BY SKIN PATCH PLUS CYCLIC VAGINAL DAILY ESTRADIOL BY SKIN PATCH PLUS CYCLIC VAGINAL PROGESTERONE 10 DAYS PER MONTH; PLACEBOPROGESTERONE 10 DAYS PER MONTH; PLACEBO

MAIN EVALUATIONSMAIN EVALUATIONS: ANNUAL INTIMA-MEDIA THICKNESS : ANNUAL INTIMA-MEDIA THICKNESS BY CAROTID ARTERY ULTRASOUNDBY CAROTID ARTERY ULTRASOUND

YEAR 0, 3, 5 CORONARY ARTERY CALCIUM BY YEAR 0, 3, 5 CORONARY ARTERY CALCIUM BY TOMOGRAPHYTOMOGRAPHY

PLUSPLUS: SAFETY STUDIES, ANCILLARY STUDIES: SAFETY STUDIES, ANCILLARY STUDIES






(KEEPS) (KEEPS)

SUPPORT

FN HAS RECEIVED SUPPORT FN HAS RECEIVED SUPPORT FROM NIH, PHARMA AND FROM NIH, PHARMA AND

OTHER COMMERCIAL OTHER COMMERCIAL INTERESTS IN THE PAST FIVE INTERESTS IN THE PAST FIVE

YEARSYEARS






(KEEPS) (KEEPS)

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

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