pm 1.30 stefanick
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The Women’s Health Initiative (WHI)
What Have We Learned?
Marcia L. Stefanick, Ph.D. Professor of Medicine
Stanford Prevention Research Center
Professor of Obstetrics & GynecologyStanford University School of Medicine
The Vivian Pinn Women's Health Research Keynote Lecture - March 16, 2012
DISCLOSURE
I have nothing to disclose
Marcia L. Stefanick, Ph.D. Professor of Medicine, Stanford Prevention Research Center
Professor of Obstetrics & GynecologyStanford University School of Medicine
Women’s Health Initiative (WHI) Clinical Trials
(Diet, Hormones, Calcium/Vit D) and Observational Study
Postmenopausal Women
aged 50-79 yrs (1993-1998)Residing in area (likely to survive) ≥ 3 yrs
Conducted at 40 Clinical Centers+ Clinical Coordinating Center
(Fred Hutchinson Cancer Research Center)
EXTENSIONS: 2005-2010, 2010-2015
Funded by National Institutes of HealthNational Heart, Lung, and Blood Institute
www.whi.orgwww.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
OS93, 676
Total WHI Sample (CT + OS) = 161,809
WHI: Observational Study (OS) 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
WHI Clinical Trials and Observational Study Timeline: 1991 – 2011
WHI Begins
Observational Study
Begins
Diet and Hormone Trials
Recruitment completed
Estrogen + Progestin (E+P) Trial Stopped for Harm > Benefit
JAMA 2002
DM, CaD Trials:Closeout visits
completed
DM Results .JAMA 2006
CaD ResultsNEJM 2006
Diet and Hormone
Clinical Trials Begin
Observational Study
Recruitment completed
WHI EXTENSION 2005-2010 BEGINS
Observational Study
Year 3 clinic visits complete
Calcium plus Vitamin D
Clinical Trial Begins Estrogen only
Trial: stoppedJAMA 2004
1991 92 93 94 95 96 97 98 99 2000 2001 2002 03 2004 2005 06 07 08 09 2010
E+P Post-stopping (2.4 yrs)
JAMA 2011
E only Post-stopping
JAMA 2011
2011
WHI EXTENSION 2
2010-2015 BEGINS
WHI Diet Trial: Sample Size, Key Outcomes; Criteria:Postmenopausal Women, aged 50-79; Not moving < 3 yrs
Excluded if % Energy from Fat < 32% by Food Frequency Questionnaire (FFQ) History of Breast or
Colorectal Cancer
Dietary Change Goals 20% energy from fat
≥ 5 vegetable & fruit servings per day
≥ 6 grain servings daily NO Weight Change Goals
Intervention: N = 19,541Comparison: N = 29,294
Design ~ 9 years average
follow-up
Diet (DM)48,836(40:60)
WHI Diet Trial: INVASIVE BREAST CANCERN=48,325; 8.1 yrs follow-up HR 0.91 (95% CI: 0.83-
1.01)
JAMA 2006; 295; 629-642
1,727 total diagnoses (3.5% of all DM participants)
9% (not significant)
Invasive Breast Cancer
Cumulative Hazard
0 1 2 3 4 5 6 7 8 9
Time (years)0.00
0.01
0.02
0.03
0.04
ComparisonIntervention
HR, 0.91(95% CI, 0.83-1.01)
Events
Intervention 47 79 92 80 72 94 89 46 33
Comparison 74 140 123 137 136 137 145 97 58
Number at Risk
Intervention 19541 19328 19084 18798 18520 18263 17900 15507 10245 5075
Comparison 29294 28908 28536 28195 27806 27372 26977 23337 15373 7580
Rates per 10,000/yearCumulative Hazard Ratio
INVASIVE BREAST CANCER
1,727 total diagnoses (3.5% ppts) HR 0.91 (95% CI: 0.83-1.01)
There was a significant interaction of diet assignment with baseline % calories from fat, by quartile (p=0.04):
Women who consumed highest % fat at baseline (≥ 36.8%) had significant 22% reduction in invasive breast cancer if assigned to DIET vs Control
(HR: 0.78; 95% CI: 0.64,0.95).
JAMA 2006; 295; 629-642
COLORECTAL CANCER 480 total diagnoses (1% of ppts) HR 1.08 (95% CI: 0.90-1.29)
Self-reported polyps & adenomas HR 0.91 (95% CI: 0.87-0.95)
JAMA 2006; 295; 643-654
Figure 3. Change* from Baseline to Year 1 in the Intervention Compared to the Comparison Group for Blood Hormone Concentrations Adjusted for Baseline
Differences
0.85
0.98
0.96
0.99
1.09
0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6
Estradiol
Estrone
Estrone-sulfate
Testosterone
Sex Hormone Binding Globulin
Change Estimate and 95% Confidence Interval
Relative 1 Yr Hormone Changes (Subsample)
E2
E1
SHBG
T
Estrone Sulfate
WHI Diet Trial: PRIMARY CANCER OUTCOMESN=48,325; 8.1 yrs follow-up
WHI Calcium Vitamin D Trial: Relationship to CT
Primary Outcome: Hip Fracture Secondary Outcomes: Colorectal Cancer; Other Fractures
CaD36,282 at 1st (or 2nd)
Annual Visit
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
* 1/2 (i.e. 500 mg Ca + 200 IU Vit D) AM, 1/2 PMChoice: Chewable or Swallowable Pills
Hip Fracture: 12% decrease (not significant) 21% significant decrease for ages 60-80
Colorectal Cancer: no benefitKidney Stones: increased 17% (significant)
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 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
05
101520253035
50-54 55-59 60-64 65-69 70-74 75-79
Percent
Intact Uterus:E+P Hysterectomy: CEE only
WHI HT: Baseline Age DistributionMean (SD): E+P Trial = 63.3(7.1) E-Alone Trial = 63.6 (7.3)
60-69E+P 45%
E-alone 45%
70-79 E+P 22%
E-alone 24%
50-59E+P 33%
E-alone 31%
Stefanick, Cochrane, Hsia, Barad, Liu, Johnson Ann Epidemiol 2003; 13: S78-S86
Goal: 50-54: 10%55-59: 20% 60-69: 45% 70-79: 25%
WHI Hormone Trials: Ethnic Distribution by Age
50-59 60-69 70-79
E+P 21.5% E+P 12.5% E+P 8.6% E-Alone 32.7% E-Alone 22.0% E-Alone 13.9%
10 9
64
2
20
54
2
10
14
10
0
5
10
15
20
25
Black Hispanic Black Hispanic Black Hispanic
Percent
Uterus - E+P (84.0 % White ) Hysterectomy- E only (75.3% White)
Stefanick, Cochrane, Hsia, Barad, Liu, Johnson Ann Epidemiol 2003; 13: S78-S86
26% Increase Breast Cancer
Also: DVTs
STOPPED Early, Clear Harm
Threshold Level
Risks
Benefits
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
Stopped 3.3 yrs early* had 0.4 more yrs of data
WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs)
Other Fractures
26% Increase Breast Cancer
Also: DVTs
33% Decrease Hip Fracture
STOPPED Early, Clear Harm
Threshold Level
29% Increase CHD (Coronary Heart Disease)
41% Increase Stroke
Risks
Benefits
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
Stopped 3.3 yrs early* had 0.4 more yrs of data
113% Increase Pulmonary Emboli
Fewer Colorectal Cancers
Other Fractures
WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs)
PlaceboE + P
Deaths
Neutral
Nu
mb
er o
f C
ases
per
10,
000
Wo
men
per
Yea
r
60
50
40
30
20
10
0 CHD* Stroke* BreastCancer
PE* ColorectalCancer*
HipFracture*
EndometrialCancer
Risks*
7 8 8 8Additional Events
6 5
Reduced
Events
*Statistically significant based on 95% nominal CI on Hazard Ratios
Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
WHI E+P Trial: Absolute (annualized) Risk (5.2 Yrs*)*Preliminary Findings
E-Alone (post-hystX)
2947
WHI Memory Study (WHIMS) - ancillary study
(Postmenopausal Women, aged ≥ 65 yrs)
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
Years Since Randomization
Cum
ulat
ive
Haz
ard
HR, 2.0595% CI, 1.21__3.48
WHIMS E+P: Probable Dementia Hazard Ratio
4532 women, aged 65-80; followed for 4.1 years
E+PPlacebo
No. at Risk
E+P
Placebo
2229 2112 2026 1915 1325 401 2303 2200 2125 1984 1392 477
Source: IMS Health NPA Plus
0
10
20
30
40
50
60
1995 1996 1997 1998 1999 2000 2001 2002 2003Annual Prescriptions by Formulation (millions)
Oral E Oral E/P Trnd/Vag
Annual Number of US Prescriptions for HT 1995 - Aug 2003
HERSWHIE+P WHI
E-only??
Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53
STOPPED - Increased StrokeNo CHD Benefit
Threshold Level
37% Increase Stroke(55% Increase Ischemic Stroke)
Risks Benefits
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
Stopped 1.5 yrs early* had 0.3 more yrs of data
N.S. 37% Increase Pulmonary Emboli
47% increase DVTs
WHI E only Trial: Preliminary Findings, March 2004 (aver. 6.8 yrs)
Other Fractures
33% Decrease Hip Fracture
No Effect on CHD No Increase Breast Cancer
No Effect on Colorectal Cancer
Effects of CEE and Placebo on Disease Rates
0
1020
3040
5060
7080
90
StrokesBloodclots
HeartattacksColorectal
cancerDeaths BreastcancerHip
fractures
Number of cases per year
in 10,000 women
CEEPlacebo
WHI E-Alone (CEE) Trial: Absolute (annualized) Risk (6.8 Yrs*)*Preliminary Findings
The Women’s Health Initiative Steering Committee: JAMA 2004; 291: 1701-1712
Risk Benefit
P=.007 P=0.01P=.063 PE: ns6 DVTP=.03
12 6
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 *Brain MRI
Disparate Results Breast Cancer
Increased in E+P Trial (women with a uterus) Not increased in E-Alone Trial (women with prior hysterectomy)
Colorectal Cancer Decreased in E+P Trial (women with a uterus) No difference in E-Alone Trial
Global Index (Overall Risk/Benefit) Increased in E+P (CEE + MPA) Trial Neutral in E-Alone (CEE) Trial
WHI E-alone: CORONARY HEART DISEASE (CHD)Total and by Age (Rates per 10,000/year)
53 56
0
20
40
60
80
100
CHD
CEE only Placebo
N=10,739; 7.1 yrs follow-upHR= 0.95 (95%CI: 0.79-1.16)
1727
57 61
9686
0
20
40
60
80
100
50-59 60-69 70-79
CEE only Placebo
p = 0.07 for interaction
Hsia et al Arch Intern Med 2006; 166:357-365.
HR: 0.63(0.36-1.08)
HR: 0.94(0.71-1.24)
1.11(0.82-1.52)
Stefanick, et al Ann Epidemiol 2003; 13: S78-S86
36.6 35.227.7
0
10
20
30
40
50
50-59 60-69 70-79
BMI: 28.9 28.6 27.5
Mean BMI = 28.5 kg/m2
34.1% Obese (30.6% Normal Wt.)
WHI Hormone Trials: Percent Obese (BMI ≥30 kg/m2)
E+P Trial (Women with a Uterus)
PE
RC
EN
T O
F A
GE
GR
OU
P
51.045.8
34.1
010203040506070
50-59 60-69 70-79
Mean BMI = 30.1 kg/m2
44.6% Obese (20.7% Normal Wt.)
BMI: 31.2 30.2 28.6
E-Alone Trial (Hysterectomy)
Prior HT Use by Age at Baseline
0
10
20
30
40
50
60
70
80
Percentage
IntactUterus
Bilat Ooph No BilatOoph
50-59 y60-69 y70-79 y
Hysterectomy(36.5%) (56%)
CEE +MPA CEE only
Rossouw JAMA 2007;297:1465-1477
WHI E+P: Post-Intervention Follow-up
After E+P trial was stopped early (mean 5.6 yrs of intervention), 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 to March 31, 2005) available on 15,730 (95% of eligible) participants:
mean of 2.4 years of post-trial follow-up
WHI has continued follow-up since 2005
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-Int. Colorectal Cancer - no longer decreased TOTAL CANCER - increased 1.24 (1.04-1.48)
Due to increase in variety of cancers, incl. Lung Cancer
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
Number of Prescriptions of Menopausal Hormone Therapy in U.S. by Year
N Engl J Med 2007; 356:16
Breast Cancer Incidence: Initiating (CT) or Using (OS), then Stopping, Menopausal Estrogen + Progestin in WHI
N Engl J Med 2009;360(6): 573-87Chlebowski et al (Stefanick)
WHI Observational Study (OS) Estrogen+Progestin Usersvs. Non-users - at Entry
Serial E+P Use
WHI Clinical Trial (CT)
Estrogen + Progestin vs.Placebo
Black Line = Sensitivity Analysis*
Intervention Phase HR =1.62 (1.02, 2.39)
Postintervention HR =1.26 (0.73, 2.20)
*censored 6 months after changing pills
During Intervention (Trial) After Stopping Study Pills HR = 1.26 (1.02, 1.53) HR = 1.27 (0.91, 1.72)
WHI E-only: Post-Intervention Follow-up
After E-only trial was stopped early (mean 7.1 yrs intervention), WHI continued to follow study participants through the planned termination of the trial (March 31, 2005)
By this time 54% of participants had stopped study medication. Median time on treatment: 5.9 or 5.8 years in active vs. placebo Median adherent time on treatment was 3.5 years
Postintervention follow-up: 47.2 (20.7) mo. ( thru August 14, 2099)
Consent obtained for annual mail and telephone follow-up for outcomes ascertainment in 78% of surviving eligible women 81% had at least 1 mammogram; 4.7% of active & 2.7% of placebo reported use of E alone after stopping
Intention-to-treat analysis, time-to-event methods
LaCroix, et al. JAMA 2011;305(13):1305-1314
Estrogen Alone Results All Participants by Intervention Period
Intervention Post-intervention Overall FU
CHD/Total MI 0 0 0
Stroke 0 0
DVT/PE 0
Breast cancer
Colorectal cancer 0 0 0
Hip fracture 0
All-cause mortality 0 0 0
Global index 0 0 0
LaCroix, et al. JAMA 2011;305(13):1305-1314
Estrogen Alone: Age Specific Results
50-59 years 60-69 years 70-79 years
CHD/Total MI 0
Stroke 0
DVT/PE 0 0
Breast cancer
Colorectal cancer 0 0
Hip fracture 0 0 0
All-cause mortality 0
Global index 0
LaCroix, et al. JAMA 2011;305(13):1305-1314
WHI E-only: Post-Intervention Follow-upCardiovascular: Stroke & VTE no longer elevated
CHD: aged 50-59baseline: HR 0.59 (0.38-0.90); age, pinteraction=0.05 MI: aged 50-59: HR 0.54 (0.34-0.86); 60-69,HR 1.05; 70-79,HR 1.23
age pinteraction=0.007 All CVD events: HR 1.06 (0.98-1.15)
Fracture: benefits disappeared
Cancer: Breast Cancer significantly lower in CEE (HR 0.77), all ages (Not high risk, e.g. family history, benign breast disease; Lancet Oncology, E March 2012)
Colorectal Cancer: women aged 70-79, 2-fold higher in CEE
All-cause Mortality AGE, p for interaction = 0.04 Women aged 50-59 @ baseline: HR 0.73 (0.53-1.00) No increase for women 60-69; slight increase for women 70-79
Global Index AGE, p for interaction = 0.009 aged 50-59: HR 0.85 (0.70-1.03) – possible benefit aged 70-79: HR 0.85 (1.01-1.32) – HARM
JAMA 2011;305):1305-1314
U.S. MHT Trends by Routes of Administration
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Oral ET
Oral EPT
Vaginal
Transdermal
Intramuscular
WHI E aloneApril 2004
WHI E+PJune 2002
62%
76%
32%
58%
Tsai, Stefanick, Stafford. Menopause 2011; 18(4): 385-392
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 WHI (CT + OS) = 161,809Eligible:150,075
Extension Study = 115,363 (77% of Eligible)Ages 57-91
CT
SHARe – Genome–wide Association Study (NHLBI): African-American & Hispanic PptsAdded rest of Hormone Trial Cohort, Core Biomarkers, e.g. lipids, glucose, creatinineCMS (Medicare) linkage, Medication Inventory
Hormone(82.9%)
Diet(86.2%)
OS (88.2%)
Total CT Eligible: 107,706consented: 93,544 (87%)
2010-15 Cohort Mean Age = 78 yrs
Regional Centers: Ongoing Outcomes Collection
In-Person Visit: 8000 women aged ≥72 yrs Ancillary Studies, e.g. WHIMS-Y, OPACH, NPAAS
WHI Physical Activity Trial Proposal
Baseline*Age Group
Number % of Eligible
50-54 14,470 91.2
55-59 21,527 90.7
60-69 43,352 87.1
70-79 14,195 77.4
*Baseline 60-79: 1993-1998nH White, 88% nH Black, 79% Hispanic, 77% Asian/PI, 83% Native American/Alaskan, 84%
WHI Extension 2010-2015
- currently working on a