effects of conjugated equine estrogen in postmenopausal women with hysterectomy
DESCRIPTION
Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial JAMA 2004;291:1701-1712. Postmenopausal Hormone Use. Observational studies suggested 30%– 50% reduction in cardiac risk - PowerPoint PPT PresentationTRANSCRIPT
Effects of Conjugated Equine Estrogen in Postmenopausal Women
with Hysterectomy
The Women’s Health Initiative Randomized Controlled Trial
JAMA 2004;291:1701-1712.
Postmenopausal Hormone Use
• Observational studies suggested– 30%– 50% reduction in cardiac risk– 8% – 30% increase in breast cancer– Strong benefit for osteoporosis
• In 1980’s – 90’s– Increasing use of hormone therapy for long-term
cardiovascular disease prevention
WHI Hormone TrialSpecific Aims
• Primary Endpoint: To test whether CEE reduces the incidence of CHD and other CVD
– Definition of CHD: Nonfatal MI plus CHD death
• Primary Safety Endpoint: To assess whether CEE increases the risk of breast cancer
• Secondary Endpoints: To test whether CEE reduces the incidence of hip fractures and all osteoporosis-related fractures separately
Women’s Health InitiativeTimeline
Planning Recruitment Follow-up Close-out
1990 2005
1993 1998
WHI Hormone Trial Design
Hysterectomy
CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d
E Alone N = 10,739
YES
NO
Placebo
Conjugated equine estrogens (CEE) 0.625 mg/d
Placebo
E + PN=16,608
Eligibility
• Age 50-79 years at first screen• Postmenopausal• Likely to reside in clinic area for at least 3
years• Providing written informed consent
Excluded if:• Severely underweight• Severe hypertension
(>200/105)• Severe menopausal
symptoms• Substance abuse,
mental illness, dementia
• History of:– Cancer in last 10 years– Melanoma any time– Stroke or heart attack in
last 6 months– Previous fractures treated
with hormones
• Any condition likely to limit survival < 3 yrs
So these were generally healthy womenand this was a primary prevention trial
Follow-up Methods
• 6 weeks after randomization: phone contact– Assess symptoms– Reinforce adherence
• Every 6 months: phone or clinic contact– Assess adherence– Assess symptoms– Determine if outcomes had occurred
• Annually: clinic visit– Mammograms + clinical breast exams– Assess adherence– Assess symptoms– Determine if outcomes had occurred
Study Medication Use• Intolerable symptoms e.g., breast tenderness
– Reduced number of days of treatment– No unblinding for management
• Major event possibly related to hormones– Study meds stopped
• Temporarily for fracture, immobilization, surgery• Permanently for breast CA, DVT/PE, malignant
melanoma, meningioma, TG > 1000 mg/dl, if participant’s health provider prescribed open label hormones
• Resumption up to participant’s health provider for MI or stroke
– No unblinding for discontinuation of medications
Ascertainment of Outcomes
• Self report of diagnosis/hospitalization• Medical records obtained• Local WHI physician adjudicated (coded) events (blinded
to treatment assignment)• Central adjudication (blinded to treatment assignment)
– CHD– Stroke– VTE– Cancer– Hip fractures
Events during the Hormone Trial
• April 2000 – Participants notified of increase in CV events during first 2 years
• July 2001 – Participants informed risk does not disappear after 2 years
• July 2002 – – E+P trial intervention terminated due to increased breast cancer
risk and overall risks exceeding benefits; Principal results published (JAMA 2002;288:331-333).
– E alone trial is continued.
• February 2004 – NIH terminates E-alone intervention due to increased stroke risk and absence of CHD benefit
• March 1, 2004 – E- alone participants stop study pills
Baseline Characteristics of women in the WHI Estrogen alone
trial
Age at entry
CEE
N = 5310
Placebo
N = 5429
50-59 1637 (30.8) 1673 (30.8)
60-69 2387 (45.0) 2465 (45.4)
70-79 1286 (24.2) 1291 (23.8)
Age of E-alone participants at entry
05
10152025
303540
4550
50-59 60-69 70-79
CEE Placebo
Percent
Race/Ethnicity
75.5 75.1
14.7 15.4
6.1 6.10.8 0.6 1.6 1.4 1.4 1.4
0
10
20
30
40
50
60
70
80
White Black Hispanic Am Indian Asian/PI Unknown
CEE PlaceboPercent
Age at hysterectomy
CEE
N = 5310
Placebo
N = 5429
< 40 2100 (39.8) 2149 (39.8)
40-49 2281 (43.2) 2275 (42.2)
50-54 501 (9.5) 566 (10.5)
> 55 401 (7.6) 404 (7.5)
Bilateral Oophorectomy
CEE
N = 5310
Placebo
N = 5429
Bilateral Oophorectomy 1938 (39.5) 2111 (42.0)
History of Hormone Use
CEE
N = 5310
Placebo
N = 5429
Never 2769 (52.2) 2770 (51.1)
Past 1871 (35.2) 1948 (35.9)
Current (3 month wash-out before randomization)
669 (12.6) 708 (13.0)
Duration of prior hormone use
CEE
N = 5310
Placebo
N = 5429
< 5 yrs 1352 (53.2) 1412 (53.1)
5-10 yrs 469 (18.5) 515 (19.4)
> 10 yrs 720 (28.3) 732 (27.5)
Body Mass Index
CEE
N = 5310
Placebo
N = 5429
< 25 1110 (21.0) 1096 (20.3)
25-29 1795 (34.0) 1912 (35.5)
> 30 2376 (45.0) 2383 (44.2)
Mean BMI 30.1 30.1
Smoking Status
CEE
N = 5310
Placebo
N = 5429
Never 2739 (51.9) 2705 (50.4)
Past 1986 (37.8) 2089 (38.9)
Current 542 (10.3) 571 (10.6)
Medical History
CEE
N = 5310
Placebo
N = 5429
Prior MI* 165 (3.1) 172 (3.2)
CABG/PTCA* 120 (2.3) 114 (2.1)
Angina 308 (5.8) 306 (5.7)
Stroke 76 (1.4) 92 (1.7)
DVT/PE 87 (1.6) 84 (1.5)
* 441 (4.1%) women with “hard” CHD events prior to enrollment (> 6mos)
CHD Risk Status at Entry
CEE
N = 5310
Placebo
N = 5429
Diabetes treatment 410 (7.7) 411 (7.6)
Hypertension (Rx or > 140/90)
2386 (48.0) 2387 (47.4)
Elevated Cholesterol (on Rx)
694 (14.5) 766 (15.9)
Statin Use 394 (7.4) 427 (7.9)
Aspirin Use 1030 (19.4) 1069 (19.7)
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
N Mean SD N Mean SD
Age (yrs) at screening 5310 63.6 7.3 5429 63.6 7.3
BMI (kg/m2) 5281 30.1 6.1 5391 30.1 6.2
Systolic BP (mm Hg) 5310 130.4 17.5 5429 130.2 17.6
Diastolic BP (mm Hg) 5310 76.5 9.2 5429 76.5 9.4
CEE Placebo
Ethnicity
White 4007 75.5 407575.1
Black 782 14.7 83515.4
Hispanic 322 6.1 3336.1
American Indian 41 0.8 340.6
Asian/Pacific Islander 86 1.6 781.4
Unknown 72 1.4 741.4
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Treated diabetes 410 7.7 4117.6
Treated for hypertension 2386 48.0 238747.4
or BP > 140/90
High cholesterol 694 14.5 76615.9
requiring pills
Statin use at baseline 394 7.4 4277.9
Aspirin (>80mg) use 1030 19.4 106919.7
at baseline
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
History of MI 165 3.1 1723.2
History of angina 308 5.8 3065.7
History of CABG/PTCA 120 2.3 1142.1
History of stroke 76 1.4 921.7
History of DVT or PE 87 1.6 841.5
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Hormone useNever 2769 52.2 2770 51.1Past 1871 35.2 1948 35.9Current 669 12.6 708 13.0
Duration of priorhormone use (years)
<5 1352 53.2 1412 53.15 - 10 469 18.5 515 19.410+ 720 28.3 732 27.5
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Parity
Never pregnant / 489 9.3 4618.5 no term pregnancy
>1 term pregnancy 4779 90.7 493291.5
Age at first birth
<20 1193 28.1 1234 28.020 - 29 2846 67.0 2914
66.130+ 210 4.9 260 5.9
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Female relative had 893 18.0 87017.1
breast cancer
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Fracture at age 55+ 676 14.0 64313.2
Falls in last 12 months
0 3300 67.0 323064.8
1 975 19.8 1024 20.52 422 8.6 478 9.63 or more 231 4.7 255
5.1
CEE Placebo
N % N %
Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment
Cumulative Drop-out and Drop-in Rates by Randomization Assignment and Follow-up Time
0
10
20
30
40
50
60
1 2 3 4 5 6 7 8
Year
Perc
en
t
Dropout CEE
Drop-in CEE
Dropout Placebo
Drop-in Placebo
Intermediate Outcomes
Lipid Levels (8.6% subsample)
-13.7
-1
15.1
1.1
25
3
-2.3 -1.4
-15
-10
-5
0
5
10
15
20
25
LDL chol HDL chol TG Total chol
CEE PlaceboPercent change, 1 yr
Baseline AV 1 AV 2 AV 3 AV 4 AV 5 AV 6 AV 7 AV 8 AV 9
122
123
124
125
126
127
128
129
130
131
Mea
n (S
E)
Syst
olic
BP
(mm
Hg)
Mean (SE) Systolic Blood Pressure for HRT Participants Without Uterus
CEEPlacebo
Baseline AV 1 AV 2 AV 3 AV 4 AV 5 AV 6 AV 7 AV 8 AV 9
68
69
70
71
72
73
74
75
76
77
Mea
n (S
E)
Dia
stol
ic B
P (m
m H
g)
Mean (SE) Diastolic Blood Pressure for HRT Participants Without Uterus
CEEPlacebo
Clinical Outcomes
CEE and Coronary Heart Disease Events (Annualized %) by randomization assignment
CHD † 177 (0.49%) 199 (0.54%) 0.91 (0.75,1.12) (0.72,1.15)
CHD Death 54 (0.15%) 59 (0.16%) 0.94 (0.65,1.36) (0.54,1.63)
Non-fatal MI 132 (0.37%) 153 (0.41%) 0.89 (0.70,1.12) (0.63,1.26)
* Adjusted for multiple comparisons across time (OBF procedures). A Bonferroni adjustment for 6 outcomes was applied to all outcomes other than CHD, Breast Cancer and the global Index.
† CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths. There were 14 silent MIs.
95% CICEE Placebo Hazard Ratio Nominal Adjusted *
Kaplan-Meier Estimates of Cumulative Hazards for CHD
CHDHR, 0.9195% nCI, 0.75-1.12
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
CHD events by years since randomization
Year CEE Placebo HR
1 26 23 1.16
2 27 23 1.20
3 22 25 0.89
4 21 27 0.79
5 30 24 1.28
6 31 26 1.23
7+ 20 51 0.40
P-value for trend with time, 0.02.
Risk of CHD events by prior disease
CEE Placebo HR 95% CI
Prior MI or revascularization (N=441)
33 31 1.04 0.63-1.71
No prior disease 143 162 0.91 0.73-1.14
CEE and Stroke Events (Annualized %) By randomization assignment
Stroke 158 (0.44%) 118 (0.32%) 1.39 (1.10,1.77) (0.97,1.99)
Fatal stoke 15 (0.04%) 14 (0.04%) 1.13 (0.54,2.34) (0.38,3.36)
Non-fatal stroke 114 (0.32%) 85 (0.23%) 1.39 (1.05,1.84) (0.91,2.12)
95% CICEE Placebo Hazard Ratio Nominal Adjusted
Kaplan-Meier Estimates of Cumulative Hazards for Stroke
StrokeHR, 1.3995% nCI, 1.10-1.77
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
Risk of stroke by prior disease
CEE Placebo HR 95% CI
Prior stroke (N=168) 6 6 1.67 0.52-5.36
No prior stroke 152 112 1.39 1.09-1.78
CEE and Venous Thromboembolic Events (Annualized %) By randomization assignment
VTE† 101 (0.28%) 78 (0.21%) 1.33 (0.99,1.79) (0.86,2.08)
DVT† 77 (0.21%) 54 (0.15%) 1.47 (1.04,2.08) (0.87,2.47)
PE† 48 (0.13%) 37 (0.10%) 1.34 (0.87,2.06) (0.70,2.55)
† VTE, venous thromboembolic disease; DVT, deep vein thrombosis; PE, pulmonary embolism
95% CICEE Placebo Hazard Ratio Nominal Adjusted
Kaplan-Meier Estimates of Cumulative Hazards for PE
PEHR, 1.3495% nCI 0.87-2.06
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
CEE and Cardiovascular Disease Events (Annualized %) By randomization assignment
Total CVD 811 (2.25%) 746 (2.01%) 1.12 (1.01,1.24) (0.97,1.30)
95% CICEE Placebo Hazard Ratio Nominal Adjusted
CEE and Cancer Incidence (Annualized %) By randomization assignment
Invasive breast 94 (0.26%) 124 (0.33%) 0.77 (0.59,1.01)(0.57,1.06)cancer
Colorectal cancer 61 (0.17%) 58 (0.16%) 1.08 (0.75,1.55)(0.63,1.86)
Total cancer 372 (1.03%) 408 (1.10%) 0.93 (0.81,1.07)(0.75,1.15)
95% CICEE Placebo Hazard Ratio Nominal Adjusted
Kaplan-Meier Estimates of Cumulative Hazards for Breast Cancer
Invasive Breast CancerHR, 0.7795% nCI, 0.59-1.01
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
Kaplan-Meier Estimates of Cumulative Hazards for Colorectal Cancer
Colorectal CancerHR, 1.0895% nCI, 0.75-1.55
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
CEE and Fracture Events (Annualized %) By randomization assignment
Hip fracture 38 (0.11%) 64 (0.17%) 0.61 (0.41,0.91)(0.33,1.11)
Vertebral fracture 39 (0.11%) 64 (0.17%) 0.62 (0.42,0.93)(0.34,1.13)
Total fracture 503 (1.39%) 724 (1.95%) 0.70 (0.63,0.79)(0.59,0.83)
95% CICEE Placebo Hazard Ratio Nominal Adjusted
Kaplan-Meier Estimates of Cumulative Hazards for Hip Fracture
Hip FractureHR, 0.6195% nCI, 0.41-0.91
Cum
ula
tive H
azard
0.0
0.0
10
.02
0.0
30
.04
0.0
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
CEE Summary Measures (Annualized %) By randomization assignment
Death from other 193 (0.53%) 185 (0.50%) 1.08 (0.88,1.32) (0.79,1.46)causes
Total death 291 (0.81%) 289 (0.78%) 1.04 (0.88,1.22) (0.81,1.32)
† Global index is the first event for each participant from among the following types: CHD; stroke; PE; breast cancer; colorectal cancer; hip fracture; and death from other causes.
Global index † 692 (1.92%) 705 (1.90%) 1.01 (0.91,1.12) (0.89,1.14)
95% CICEE Placebo Hazard Ratio Nominal Adjusted
Kaplan-Meier Estimates of Cumulative Hazards for Death
DeathHR, 1.0495% nCI, 0.88-1.22
Cum
ula
tive H
azard
0.0
0.0
50
.10
0.1
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
Kaplan-Meier Estimates of Cumulative Hazards for Global Index
Global IndexHR, 1.0195% nCI, 0.91-1.12
Cum
ula
tive H
azard
0.0
0.0
50
.10
0.1
5
0 1 2 3 4 5 6 7 8
Time (years)
CEEPlacebo
Causes of Death (Annualized Percentages) byRandomization Assignment
CEE Placebo
Number randomized 5310 5429Mean follow-up time (months)
Total deaths 291 (0.81%) 289 (0.78%)
Adjudicated deaths 278 (0.77%) 272 (0.73%)
Cardiovascular 93 (0.26%) 95 (0.26%)
Breast cancer 4 (0.01%) 8 (0.02%)
Other cancer 110 (0.30%) 118 (0.32%)
Other known cause 51 (0.14%) 38 (0.10%)
Unknown cause 20 (0.06%) 13 (0.04%)
CEE Effects on Cardiovascular Outcomes by Age
P valuefor interaction
Coronary heart disease
50-59 16 (0.14) 29 (0.24)
60-69 87 (0.54) 98 (0.59)
70-79 74 (0.88) 72 (0.84)
Stroke
50-59 19 (0.16) 19 (0.16)
60-69 79 (0.49) 50 (0.30)
70-79 60 (0.71) 49 (0.57)
Venous thromboembolism
50-59 18 (0.15) 15 (0.13)
60-69 49 (0.31) 39 (0.23)
70-79 34 (0.40) 24 (0.28)
0.392
No. of cases (annualized %)
0.144
0.590
CEE Placebo
1.44
1.31
1.22
1.25
1.65
1.08
1.04
0.92
0.56
0.0 0.5 1.0 1.5 2.0
Hazard Ratio
CEE Effects on Cancer Outcomes by Age
P valuefor
interaction
Invasive breast cancer
50-59 25 (0.21) 35 (0.29)
60-69 42 (0.26) 60 (0.36)
70-79 27 (0.32) 29 (0.34)
Colorectal cancer
50-59 8 (0.07) 14 (0.12)
60-69 26 (0.16) 31 (0.19)
70-79 27 (0.32) 13 (0.15)
No. of cases (annualized %)
0.512
0.048
CEE Placebo
2.09
0.88
0.59
0.94
0.72
0.72
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Hazard Ratio
CEE Effects on Hip Fracture by Age
P valuefor interaction
Hip fracture
50-59 5 (0.04) 1 (0.01)
60-69 6 (0.04) 19 (0.11)
70-79 27 (0.32) 44 (0.52)
No. of cases (annualized %)
0.395
CEE Placebo
0.62
0.33
5.04
0.0 1.0 2.0 3.0 4.0 5.0
Hazard Ratio
»
Summary Measures of CEE Effects by Age
P valuefor interaction
Total death
50-59 34 (0.29) 47 (0.39)
60-69 127 (0.79) 131 (0.79)
70-79 130 (1.54) 111 (1.30)
Global index
50-59 104 (0.89) 132 (1.11)
60-69 312 (1.95) 327 (1.97)
70-79 276 (3.28) 246 (2.88)
No. of cases (annualized %)
0.195
0.079
CEE Placebo
0.73
1.01
1.2
0.80
0.98
1.16
0.1 0.6 1.1 1.6
Hazard Ratio
Sensitivity Analyses
HR (compliers) HR (int. to treat)
Stroke 1.74 1.39
PE 1.99 1.34
Total Mortality 1.26 1.04
CHD 0.89 0.91
Breast CA 0.65 0.77
Colorectal CA 0.92 1.08
Hip fracture 0.48 0.61Higher risk; Lower risk
Women’s Health Initiative Trial of E–Alone
Summary
Absolute risk differences per 10,000 person/years with CEE
• 12 more strokes (p = .007)• 6 fewer hip fractures (p = .01)
– 56 fewer osteoporotic fractures at any site (p < .001)
• 7 more VTE events (ns)• 7 fewer breast cancers (ns)• 5 fewer CHD events (ns)• No difference in colorectal cancer• No difference in total mortality• No difference in pre-defined global index
WHI E-Alone: summary
• 1st large-scale, long-term, randomized, double-blind, placebo-controlled trial to test unopposed estrogen on rates of chronic diseases finds that CEE– Increases risk of stroke – Reduces hip and other fractures– Does not significantly affect CHD rates – Does not increase risk of breast cancer risk
Implications
• CEE provides no clear benefit for chronic disease prevention
• Overall findings support current FDA recommendations to use postmenopausal hormone therapy for severe symptoms, at the lowest effective dose, for the shortest time.
• Women should be counseled about stroke risk, but no increased risk of heart disease or breast cancer for 6.8 years of use.