effects of conjugated equine estrogen in postmenopausal women with hysterectomy

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.