Transcript WHAT IS THE WHI? - Bulletin of the NYU Hospital for Joint

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
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)
WHAT IS THE WHI?
THE WHI IS A STUDY TO DETERMINE
WHETHER ESTROGEN (E) OR E +
PROGESTIN (P) REPLACEMENT IS
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 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.
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.
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
OBSERVATIONAL TRIALS ON HRT AND CVD
From Stampfer and Colditz, PREV MED, 1991
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
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
WHI AVOIDED SYMPTOMS (VASOMOTOR EPISODES) THAT WOULD
BETRAY THE PLACEBO/INCREASE
DROP-OUTS
WHI STUDIED DISEASE EVENTS
RATHER THAN PROGRESS OF
DISEASE
OBSERVATIONAL
STUDIES
SUBJECTS SELF-SELECT
BY SYMPTOMS
MENOPAUSAL
TRANSITION
HRT
NO
HRT
OBSERVATIONAL
STUDIES
(WHI) RCT
SUBJECTS SELF-SELECT
BY SYMPTOMS
TRIAL ASSIGNS TREATMENT
IRRESPECTIVE OF SYMPTOMS
MENOPAUSAL
TRANSITION
HRT
NO
HRT
AVERAGE 12 YEARS
POST-MENOPAUSAL
WOMEN
HT
NO HT
WHI ACCEPTED TO IGNORE
BIOLOGICAL PLAUSABILITY
(AND PUBLISHED DATA)
REGARDING AGE AND HEART
DISEASE
ATHEROSCLEROTIC PLAQUE BURDEN MEASURED BY
CORONARY CALCIUM IN ASYMPTOMATIC WOMEN
UNDERGOING ELECTRON BEAM TOMOGRAPHY.
Percent of Group
80
60
Percentiles of
Coronary Calcium
90th
40
75th
25th
20
0
45-49
50-54
Observational
55-59
Age
60-64
65-70
WHI
Modified from Raggi, et al. Circulation 2000;10:850-855
Early CVD Events in HERS
Incidence (%)
20
With CEE/MPA
With Placebo
15
10
5
0
0
1
2
3
4
5
Follow-up (years)
Modified from Herrington DM, et al. Circulation. 2002;105:2962-7.
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
WHI BASELINE
CHARACTERISTICS
Characteristic
HRT
n = 8,506
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
Placebo
n = 8,102
63.3 (7.1)
25.6
28.5 (5.9)
50.0
4.4
36.4
6.8
15.3
1.9
1.5‡
*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.
WHI EVENTS: VTE
Summary by Year
Year
1
2
3
4
5
6+
HRT
n (%)
Placebo
n (%)
Hazard
Ratio*
49 (0.58)
26 (0.31)
21 (0.25)
27 (0.34)
16 (0.27)
12 (0.23)
13 (0.16)
11 (0.14)
12 (0.15)
14 (0.19)
6 (0.11)
11 (0.26)
3.60
2.26
1.67
1.84
2.49
0.90
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.
WHI EVENTS: CHD
SUMMARY BY YEAR
Year
HRT
n (%)
Placebo
n (%)
Hazard
Ratio*
1
43 (0.51)
23 (0.29)
1.78
2
36 (0.43)
30 (0.38)
1.15
3
20 (0.24)
18 (0.23)
1.06
4
25 (0.32)
24 (0.32)
0.99
5
23 (0.39)
9 (0.16)
2.38
6+
17 (0.33)
18 (0.42)
0.78
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.
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)
SOURCE OF THE INFORMATION ON THE 5054 Y.O. MODERATE-SEVERELY
SYMPTOMATIC SUBJECTS IN THE E+P AND
PLACEBO GROUPS OF THE WHI
CHARACTERISTICS OF THE SUBJECTS MAKING
UP THE 50-59 Y.O. WHI ESTROGEN+PROGESTIN
AND PLACEBO GROUPS
E+P
Age 50-59 (% of total group)
Placebo
2839 (33.4)
2868 (33.1)
<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)
50-79 MENOPAUSAL AGES
Δ 12.0
(Information from: Hays et al., NEJM, 348:1839-54, 2003)
TOTAL (E+P PLUS PLACEBO) MODERATESEVERELY SYMPTOMATIC 50-54 YR
SUBJECTS VS. TOTAL 50-59 YR SUBJECTS
5522 (2761/GROUP)
6000
5000
4000
3000
2000
1000
574 (287/GROUP)
0
50-54
50-59
(Information from: Hays et al., NEJM, 348:1839-54, 2003)
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
MISSING PLACEBO DATA IN
YEAR FIVE RAISED THE
HAZARD RATIO AND
TRIGGERED ACTION BY THE
DRUG SAFETY MONITORING
BOARD
WHI EVENTS: VTE
Summary by Year
Year
1
2
3
4
5
6+
HRT
n (%)
Placebo
n (%)
Hazard
Ratio*
49 (0.58)
26 (0.31)
21 (0.25)
27 (0.34)
16 (0.27)
12 (0.23)
13 (0.16)
11 (0.14)
12 (0.15)
14 (0.19)
6 (0.11)
11 (0.26)
3.60
2.26
1.67
1.84
2.49
0.90
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.
WHI EVENTS: CHD
SUMMARY BY YEAR
Year
HRT
n (%)
Placebo
n (%)
Hazard
Ratio*
1
43 (0.51)
23 (0.29)
1.78
2
36 (0.43)
30 (0.38)
1.15
3
20 (0.24)
18 (0.23)
1.06
4
25 (0.32)
24 (0.32)
0.99
5
23 (0.39)
9 (0.16)
2.38
6+
17 (0.33)
18 (0.42)
0.78
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.
WHI EVENTS: INVASIVE BREAST
CANCER
SUMMARY BY YEAR
Year
HRT
n
Placebo
n
Hazard
Ratio*
1
11 (0.0013)
17 (0.0021)
0.62
2
3
4
5
26 (0.0031)
28 (0.0034)
40 (0.0050)
34 (0.0057)
30 (0.0038)
23 (0.0029)
22 (0.0029)
12 (0.0022)
0.83
1.16
1.73
2.64
6+
27 (0.0053)
20 (0.0047)
1.12
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.
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
MODERATE-SEVERELY SYMPTOMATIC 50-54
YR SUBJECTS VS. TOTAL 50-59 YR
SUBJECTS (E+P PLUS PLACEBO)
5522 (2761/GROUP)
6000
5000
4000
3000
2000
1000
574 (287/GROUP)
0
50-54
50-59
(Information from: Hays et al., NEJM, 348:1839-54, 2003)
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
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).
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)
HAS THE WHI RESOLVED THE
ISSUE OF CARDIOPROTECTION OR
NEUROPROTECTION BY E OR E + P
IN WOMEN STARTING TREATMENT
DURING THE MENOPAUSAL
TRANSITION?
NO
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.
SO, WHERE ARE WE NOW?
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
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
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
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)
SUPPORT
FN HAS RECEIVED SUPPORT
FROM NIH, PHARMA AND
OTHER COMMERCIAL
INTERESTS IN THE PAST FIVE
YEARS
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)