1. The Vivian Pinn Women's Health Research Keynote Lecture - March 16, 2012
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 & Gynecology
Stanford University School of Medicine
2. DISCLOSURE
I have nothing to disclose
Marcia L. Stefanick, Ph.D.
Professor of Medicine, Stanford Prevention Research Center
Professor of Obstetrics & Gynecology
Stanford University School of Medicine
3. 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
www.whi.org (Fred Hutchinson Cancer Research Center)
www.whiscience.org EXTENSIONS: 2005-2010, 2010-2015
Funded by National Institutes of Health
National Heart, Lung, and Blood Institute
4.
5. WHI Clinical Trials
Postmenopausal Women, aged 50-79; Not moving < 3 yrs
Diet Modification (DM) Trial Design
Primary Outcomes: ~ 9 years
Breast & Colorectal Cancer Diet (DM) average
follow-up
Secondary Outcome: 48,836
Coronary Heart Disease (CHD) (40:60)
11.8%
Hormone Trials Overlap
Hormone
Primary Outcome: CHD
27, 347
Secondary Outcomes: (50:50)
Hip Fracture, Breast Cancer
Ancillary Study: Memory (Dementia)
Total CT = 68,133
6. 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:
qsecular control for the CT
qimprove risk prediction for primary outcomes OS
qcase-control approach to study 93, 676
sub-clinical markers for disease
qassociations between genetic, biochemical,
psychosocial, physiological factors and events
qimpact of changes in risk factors on incident
disease and mortality
Total WHI Sample (CT + OS) = 161,809
7. WHI Clinical Trials and Observational Study Timeline: 1991 – 2011
Estrogen + Progestin (E+P) WHI
Trial Stopped for Harm > Benefit EXTENSION 2
Diet and Calcium plus 2010-2015
Hormone Vitamin D JAMA 2002 BEGINS
Clinical Trials Clinical Trial
Begin Begins Diet and Estrogen only
Hormone Trials DM Results .
Trial: stopped
JAMA 2006
Recruitment JAMA 2004
completed CaD Results
NEJM 2006
1991 92 93 94 95 96 97 98 99 2000 2001 2002 03 2004 2005 06 07 08 09 2010 2011
DM, CaD Trials: E+P Post-
Closeout visits stopping (2.4 yrs)
Observational completed JAMA 2011
Study
Begins Observational E only
Study
Post-stopping
Observational Year 3 clinic
WHI Begins Study visits complete WHI EXTENSION JAMA 2011
Recruitment 2005-2010 BEGINS
completed
8. WHI Diet Trial: Sample Size, Key Outcomes; Criteria:
Postmenopausal Women, aged 50-79; Not moving < 3 yrs
Design
q Excluded if
~ 9 years
q % Energy from Fat Diet (DM) average
< 32% by Food Frequency follow-up
Questionnaire (FFQ)
48,836
(40:60)
q History of Breast or Intervention:
Colorectal Cancer
N = 19,541
Comparison:
Dietary Change Goals N = 29,294
q 20% energy from fat
q ≥ 5 vegetable & fruit
servings per day
q ≥ 6 grain servings daily
q NO Weight Change Goals
10. WHI Diet Trial: PRIMARY CANCER OUTCOMES
N=48,325; 8.1 yrs follow-up
INVASIVE BREAST CANCER COLORECTAL CANCER
1,727 total diagnoses (3.5% ppts) 480 total diagnoses (1% of ppts)
q HR 0.91 (95% CI: 0.83-1.01) q HR 1.08 (95% CI: 0.90-1.29)
q Self-reported polyps & adenomas
There was a significant interaction of diet
assignment with baseline % calories from HR 0.91 (95% CI: 0.87-0.95)
fat, by quartile (p=0.04): JAMA 2006; 295; 643-654
Women who consumed highest % Relative 1 Yr Hormone Changes (Subsample)
Figure 3. Change* from Baseline to Year 1 in the Intervention Compared to the
Comparison Group for Blood Hormone Concentrations Adjusted for Baseline
fat at baseline (≥ 36.8%) had
Differences
E2
0.85
Estradiol
significant 22% reduction in Estrone
0.98
E1
invasive breast cancer if assigned Estrone-sulfate
0.96
Estrone Sulfate
to DIET vs Control
T
0.99
Testosterone
(HR: 0.78; 95% CI: 0.64,0.95). Sex Hormone Binding Globulin
1.09
SHBG
JAMA 2006; 295; 629-642 0.6 0.7 0.8 0.9 1 1.1
Change Estimate and 95% Confidence Interval
1.2 1.3 1.4 1.5 1.6
*Logarithm of change based on intervention minus control group average difference between year one and baseline log-biomarker values
11. WHI Calcium Vitamin D Trial: Relationship to CT
Primary Outcome: Hip Fracture
Secondary Outcomes:
Diet (DM) Colorectal Cancer; Other Fractures
25,210 1000 mg calcium
carbonate +
of 48,836 (52%)
53.3% of CT CaD 400 IU vitamin D*
at 1st (or 2nd) 36,282
Placebo
Hormone Annual Visit
16,089
of 27,347 (59%) * 1/2 (i.e. 500 mg Ca + 200 IU Vit D) AM, 1/2 PM
Choice: Chewable or Swallowable Pills
Hip Fracture: 12% decrease (not significant)
21% significant decrease for ages 60-80
Colorectal Cancer: no benefit
Kidney Stones: increased 17% (significant)
12. Women’s Health Initiative (WHI)
Hormone Therapy (HT) Trials
Generally Healthy
E+P Trial
Postmenopausal NO CEE + MPA (medroxy-
Women N= 16,608 progesterone acetate, 2.5 mg/d)
aged 50-79 years
= Prempro®
Placebo
Hysterectomy
E-alone Trial
CEE (Conjugated equine
YES estrogens, 0.625 mg/d)
N= 10,739
Placebo = Premarin®
*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.
13. WHI HT Trials: Sample Size, Outcomes, Follow-up
Women, aged 50-79 Total HT trials = 27,347
Hormone Trials
Primary Outcome: Average
E+P
Coronary Heart Disease Follow-up
16,608
Secondary Outcomes: 5.6 years*
Stroke, Blood Clots
q Lungs (PE, pulmonary emboli)
E-Alone
Average
q Legs (DVT, deep vein thrombosis)
10,739 7.1 years*
Breast, Colorectal, Uterine Cancers
Hip Fracture; Other Deaths
WHI Memory Study (WHIMS)
*design ~ 8.5 years
- for women aged ≥ 65: Dementia
14. WHI Hormone Trials: Baseline Hypotheses
Anticipated Risk Expected Benefit
Coronary Artery Disease
(Heart Attacks)
Stroke?
Breast Cancer
Threshold Level Threshold Level
Early STOPPING Early STOPPING
for HARM for BENEFIT
Additional Risks: Additional Benefits:
• Blood Clots, VTE Plan to follow to 2005 • Hip (Bone) Fractures
Lungs=PE; Legs=DVT (average 8.5 years) • Overall Mortality
• 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
16. WHI Hormone Trials: Ethnic Distribution by Age
50-59 60-69 70-79
25 E+P 21.5% E+P 12.5% E+P 8.6%
E-Alone 32.7%
20 E-Alone 22.0% E-Alone 13.9%
20
14
15
10 10 10
10 9
Percent
6 5
4
5 4
2 2
0
Black Hispanic Black Hispanic Black Hispanic
Uterus - E+P (84.0 % White ) Hysterectomy- E only (75.3% White)
Stefanick, Cochrane, Hsia, Barad, Liu, Johnson Ann Epidemiol 2003; 13: S78-S86
17. WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs)
Risks
Benefits
26% Increase
Breast Cancer
Threshold Level
STOPPED Early,
Clear Harm Stopped 3.3 yrs early
Also: DVTs * had 0.4 more yrs of data Other Fractures
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
18. WHI E+P Trial: Preliminary* Findings, July 2002 (*aver. 5.2 yrs)
Risks
29% Increase CHD
(Coronary Heart Disease) Benefits
41% Increase 33% Decrease Hip Fracture
Stroke Fewer Colorectal Cancers
113% Increase
Pulmonary Emboli
26% Increase
Breast Cancer
Threshold Level
STOPPED Early,
Clear Harm Stopped 3.3 yrs early
Also: DVTs * had 0.4 more yrs of data Other Fractures
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
19. WHI E+P Trial: Absolute (annualized) Risk (5.2 Yrs*)
*Preliminary Findings
per 10,000 Women per Year
E+P Placebo
Risks*
Number of Cases
60 Additional Events Reduced Neutral
50 7 8 8 8
Events
40
30 6 5
20
10
0 CHD* Stroke* Breast PE* Colorectal Hip Endometrial Deaths
Cancer Cancer* Fracture* Cancer
*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
20. WHI Memory Study (WHIMS) - ancillary study
(Postmenopausal Women, aged ≥ 65 yrs)
WHIMS E+P and E-only trials = 7,479
Primary Outcome: E+P Average
q Probable Dementia (PD) (women with Follow-up
a uterus)
4.1 years*
Secondary Outcomes:
4532
q Combined PD & Mild Cognitive
E-Alone Average
Impairment (MCI) (post-hystX)
5.2 years*
- Supporting Data: 2947
Global Cognitive Function
(by annual Modified Mini-mental
*design ~ 7 years
State Examination, 3MSE))
21. WHIMS E+P: Probable Dementia Hazard Ratio
4532 women, aged 65-80; followed for 4.1 years
E+P
Placebo
Cumulative Hazard
HR, 2.05
95% CI, 1.21__3.48
Years Since Randomization
No. at Risk
E+P 2229 2112 2026 1915 1325 401
Placebo
2303 2200 2125 1984 1392 477
22.
23. Annual Number of US Prescriptions for HT 1995 - Aug 2003
Oral E Oral E/P Trnd/Vag
60
50
40
WHI
30 HERS E+P WHI
E-only
20 ??
10
0
Annual Prescriptions by Formulation (millions)
1995 1996 1997 1998 1999 2000 2001 2002 2003
Source: IMS Health NPA Plus
Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53
24. WHI E only Trial: Preliminary Findings, March 2004 (aver. 6.8 yrs)
Risks Benefits
37% Increase Stroke
(55% Increase Ischemic Stroke) 33% Decrease Hip Fracture
STOPPED - Threshold Level
Increased Stroke Stopped 1.5 yrs early
No CHD Benefit * had 0.3 more yrs of data Other Fractures
N.S. 37% Increase No Effect on CHD
Pulmonary Emboli No Increase Breast Cancer
47% increase DVTs No Effect on Colorectal Cancer
*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333
25. WHI E-Alone (CEE) Trial: Absolute (annualized) Risk (6.8 Yrs*)
*Preliminary Findings
Effects of CEE and Placebo on Disease Rates
90
Risk Benefit
80 12 6
70
P=.007 3 PE: ns P=.06 P=0.01
60
6 DVT
50 CEE
P=.03
40 Placebo
30
20
in 10,000 women
10
0
Number of cases per year
clots
Blood Heart
Strokes attacks cancer Deaths Breast Hip
cancer
Colorectal fractures
The Women’s Health Initiative Steering Committee: JAMA 2004; 291: 1701-1712
26. Summary: WHI E+P* vs. E-Alone** Trial
published: *July 2002 **April 2004
Concordant results
s Heart Disease – no benefit (for E+P, early harm)
s Strokes, Blood Clots – harmful
s Fractures – beneficial
s Dementia (if ≥ 65 yrs of age) – harmful *Brain MRI
Disparate Results
s Breast Cancer
s
Increased in E+P Trial (women with a uterus)
s
Not increased in E-Alone Trial (women with prior hysterectomy)
s Colorectal Cancer
s
Decreased in E+P Trial (women with a uterus)
s
No difference in E-Alone Trial
s Global Index (Overall Risk/Benefit)
s
Increased in E+P (CEE + MPA) Trial
s
Neutral in E-Alone (CEE) Trial
27. WHI E-alone: CORONARY HEART DISEASE (CHD)
Total and by Age (Rates per 10,000/year)
p = 0.07 for interaction
N=10,739; 7.1 yrs follow-up
HR: 0.63 HR: 0.94 1.11
HR= 0.95 (95%CI: 0.79-1.16)
(0.36-1.08) (0.71-1.24) (0.82-1.52)
100 96
100 86
80 53 56 80
57 61
60 60
40 40 27
17
20 20
0 0
CHD 50-59 60-69 70-79
CEE only Placebo
CEE only Placebo
Hsia et al Arch Intern Med 2006; 166:357-365.
28. WHI Hormone Trials: Percent Obese
(BMI ≥30 kg/m2)
E+P Trial (Women with a Uterus) E-Alone Trial (Hysterectomy)
Mean BMI = 28.5 kg/m2 Mean BMI = 30.1 kg/m2
34.1% Obese 70 44.6% Obese
PERCENT OF AGE GROUP
(30.6% Normal Wt.) 60 (20.7% Normal Wt.)
51.0
50 50 45.8
36.6
40 35.2 40 34.1
27.7
30 30
20 20
10 10
0 0
50-59 60-69 70-79 50-59 60-69 70-79
BMI: 28.9 28.6 27.5 BMI: 31.2 30.2 28.6
Stefanick, et al Ann Epidemiol 2003; 13: S78-S86
29. Prior HT Use by Age at Baseline
CEE +MPA CEE only
80
70
60
50
40 50-59 y
60-69 y
30
Percentage 70-79 y
20
10
0
Intact Bilat Ooph No Bilat
Uterus Ooph
(36.5%) (56%)
Hysterectomy
Rossouw JAMA 2007;297:1465-1477
30. 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
31. WHI E+P: Post-Intervention Follow-up
Cardiovascular risks disappeared
s CHD, Stroke*, Blood Clots – no longer increased
Fracture benefits disappeared
s Hip Fracture - no longer decreased
Cancer
s Breast Cancer - 27% (ns) more diagnosed post-Int.
s Colorectal Cancer - no longer decreased
s TOTAL CANCER - increased 1.24 (1.04-1.48)
s Due to increase in variety of cancers, incl. Lung Cancer
All-cause Mortality -15% (ns) higher
s Most due to Cancer (E+P: 101 vs placebo: 69)
s only 27 (E+P) and 16 (placebo) due to pre-specified CA
Heiss et al, JAMA 2008; 299: 1036-1045
32. N Engl J Med
2007; 356:16
Number of Prescriptions of Menopausal Hormone Therapy in U.S. by Year
33. Breast Cancer Incidence: Initiating (CT) or Using (OS),
then Stopping, Menopausal Estrogen + Progestin in WHI
During Intervention (Trial) After Stopping Study Pills
WHI Clinical Trial (CT) HR = 1.26 (1.02, 1.53) HR = 1.27 (0.91,
1.72)
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
WHI
Observational Study (OS)
Estrogen+Progestin Users
vs. Non-users - at Entry
Serial E+P Use
N Engl J Med 2009;360(6): 573-87
Chlebowski et al (Stefanick)
34. 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
35. 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
36. 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
37. WHI E-only: Post-Intervention Follow-up
Cardiovascular: Stroke & VTE no longer elevated
s CHD: aged 50-59baseline: HR 0.59 (0.38-0.90); age, pinteraction=0.05
s 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)
s
Colorectal Cancer: women aged 70-79, 2-fold higher in CEE
All-cause Mortality AGE, p for interaction = 0.04
s Women aged 50-59 @ baseline: HR 0.73 (0.53-1.00)
s No increase for women 60-69; slight increase for women 70-79
Global Index AGE, p for interaction = 0.009
s aged 50-59: HR 0.85 (0.70-1.03) – possible benefit
JAMA 2011;305):1305-1314
38. U.S. MHT Trends by Routes of Administration
9,000
Oral ET 62%
WHI E+P
8,000 June 2002
Oral EPT 76%
7,000 WHI E alone
April 2004
Vaginal 32%
6,000
Transdermal
5,000
Intramuscular 58%
4,000
3,000
2,000
1,000
0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
Tsai, Stefanick, Stafford. Menopause 2011; 18(4): 385-392
39. WHI Extension Study (ES) - 2005- 2010
Diet
CT 48,836 OS
Eligible: 45,560 93,676
Eligible: 86,744
ES: 37,844
ES: 63,207
(83.1%) (72.9%)
Hormone
27,347
Eligible:25,193
Total WHI (CT + OS) = 161,809
ES:20,425 Eligible:150,075
(81.1%) Extension Study = 115,363 (77% of Eligible)
Ages 57-91
SHARe – Genome–wide Association Study (NHLBI): African-American & Hispanic Ppts
Added rest of Hormone Trial Cohort, Core Biomarkers, e.g. lipids, glucose, creatinine
CMS (Medicare) linkage, Medication Inventory
40. WHI Extension 2010-2015
Total CT Eligible: 107,706 2010-15 Cohort
consented: 93,544 (87%) Mean Age = 78 yrs
Baseline* Number % of
Age Group Eligible
50-54 14,470 91.2
55-59 21,527 90.7
Diet OS
60-69 43,352 87.1
(86.2%) (88.2%)
70-79 14,195 77.4
*Baseline 60-79: 1993-1998
nH White, 88% nH Black, 79%
Hispanic, 77% Asian/PI, 83%
Hormone Native American/Alaskan, 84%
(82.9%)
Regional Centers: Ongoing Outcomes Collection
In-Person Visit: 8000 women aged ≥72 yrs
Ancillary Studies, e.g. WHIMS-Y, OPACH, NPAAS
- currently working on a WHI Physical Activity Trial Proposal
