risks and benefits of hormone therapy: an overview of findings from the womens health initiative a...
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Risks and Benefits of Hormone Therapy: An Overview
of Findings From the Women’s Health Initiative
A CME Slide Library From the
Council on Hormone Education
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Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
Section 1: Introduction
Section 2: Study Design and Methods
Section 3: Baseline Characteristics
Section 4: Overview of Clinical Outcomes
Section 5: Cardiovascular Events
Section 6: Breast Cancer
Section 7: Other Cancers
Section 8: Fractures
Section 9: Dementia and Mild Cognitive Impairment
Section 10: Mortality
Section 11: Summary and Conclusions
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Section 1:
Introduction
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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HT = hormone therapy (estrogen alone [E-alone], estrogen plus a progestin [E+P]).The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.
Women’s Health Initiative (WHI) Clinical Trials of HT
Large, parallel, NIH-sponsored, randomized, placebo-controlled, clinical trials
– Conjugated equine estrogen (CEE) alone
– CEE plus medroxyprogesterone acetate (MPA)
Purpose: Assess long-term risks and benefits of CEE alone and CEE/MPA in chronic disease prevention
Over 27,000 women aged 50 to 79 years (mean age, ~63 years) randomized between 1993 and 1998; originally scheduled to conclude in 2005
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Women’s Health Initiative (WHI) Clinical Trials of HT
CEE/MPA trial stopped in July 2002 after a mean follow-up of 5.2 years1
CEE-alone trial stopped in March 2004 after a mean follow-up of 6.8 years2
Trials originally designed for approximately 8 years of follow-up
1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. 2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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WHI: Data and Safety Monitoring Board Recommendations on 5/31/02
Terminate CEE/MPA Study Excess of breast cancer
– Crossed pre-specified monitoring boundary
Global index: trend towards greater risk than benefits
Continue CEE-only Study Uncertain benefit/risk ratio
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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WHI: National Institutes of Health Decision on 2/2/04
Terminate CEE-alone Study Early Increased risk of stroke
– Did not cross predefined stopping boundary
– Deemed unacceptable in healthy women enrolled in 1° prevention trial
No increased risk of heart disease or breast cancer
Reduced risk of hip fracture
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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Section 2:
Study Design and Methods
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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The WHI CEE/MPA Trial
373,092 Women Initiated Screening
18,845 Provided Consent and Reported No Hysterectomy
16,608 Randomized
8506Assigned to CEE/MPA
• 42% discontinued study drug
• 6% initiated HT through own HCP
• Unblinded: n = 3444
HCP = health care provider.Adapted from Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved.
8102 Assigned to Placebo
• 38% discontinued study drug
• 11% initiated HT through own HCP
• Unblinded: n = 548
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The WHI CEE-Only Trial
373,092 Women Initiated Screening
11,941 Provided Consent andReported Hysterectomy
10,739 Randomized
5310 Assigned to CEE
• 54% discontinued study drug
• 6% Initiated HT through own HCP
• Unblinded: n = 100
Adapted from Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
5429 Assigned to Placebo
• 54% discontinued study drug
• 9% Initiated HT through own HCP
• Unblinded: n = 83
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The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.
WHI HT Trials: Eligibility Criteria
Postmenopausal
– S/P hysterectomy (for CEE-alone)
– Intact uterus (for CEE/MPA) Age 50 to 79 years at initial screening Ability and willingness to provide written and
informed consent Resident in study area for 3 years following
enrollment
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The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.
WHI HT Trials: Exclusion Criteria
Exclusions Competing risks (conditions associated with survival
of <3 years) Safety reasons (eg, prior breast cancer within 10
years, low hematocrit or platelet counts) Adherence and retention concerns
– Alcoholism, dementia, transportation problems
Discouraged From Participating Women with moderate or severe menopausal
symptoms
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WHI HT Trials: Regimens and Doses
CEE/MPA trial1
– CEE 0.625 mg/d + MPA 2.5 mg/d (n = 8506)
– Placebo (n = 8102) CEE-alone trial2
– CEE 0.625 mg/day (n = 5310)
– Placebo (n = 5429)
1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.2Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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WHI: Outcomes
Primary outcome: coronary heart disease (CHD) events (nonfatal myocardial infarction [MI] and CHD death)
Primary adverse outcome: invasive breast cancer
Global index: an untested summary measure of the effects of HT on major disease outcomes recorded during the trial
– Menopausal symptoms, quality of life (QOL), venous thromboembolism (VTE), and cognitive function not included
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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WHI: Factors Included in the Global Index
CHD event (nonfatal MI, CHD death) Breast cancer Stroke Pulmonary embolism (PE) Endometrial cancer Colorectal cancer Hip fracture Death due to other causes
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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Interpreting the Global Index From WHI Data
QOL was not included in the global index, therefore not considered in the risk-benefit profile for HT
Global index was created for this study and has not been tested for validity
Significance of assigning equal weights to various conditions has not been examined
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WHI: Statistical Analyses Outcome comparisons presented as hazard
ratios (HR) with nominal and adjusted 95% confidence intervals (CI)
Nominal CI (nCI): describes variability in risk estimates that would result from a trial with a single outcome– Most appropriate for primary outcomes
(CHD, breast cancer) and global index Adjusted CI (aCI): variability of risk estimates
corrected for multiple comparisons– Most appropriate for all other outcomes
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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Section 3:
Baseline Characteristics
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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CEE/MPA Trial: Baseline Characteristics
*Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
CharacteristicCEE/MPA (n = 8506)
Placebo (n = 8102)
Mean age at screening, y (SD) 63.2 (7.1) 63.3 (7.1)Age group at screening, n (%)
50–59 years 2839 (33.4) 2683 (33.1)60–69 years 3853 (45.3) 3657 (45.1)70–79 years 1814 (21.3) 1762 (21.7)
Race/ethnicity, n (%)
White 7140 (83.9) 6805 (84.0)Minority* 1366 (16.1) 1297 (16.0)
Hormone use, n (%)
Never 6280 (73.9) 6204 (74.4)Past 1674 (19.7) 1588 (19.6)Current 548 (6.4) 487 (6.0)
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CharacteristicCEE/MPA (n = 8506)
Placebo (n = 8102)
Body mass index, kg/m2* 28.5 (5.8) 28.5 (5.9)
Never smokers, % 49.6 50.0
Current smokers, % 10.5 10.5
Diabetes, % 4.4 4.4
Hypertension, % 35.7 36.4
Statin use at baseline, % 6.9 6.8
History of MI, %† 1.6 1.9
History of CABG/PTCA, %† 1.1 1.5‡
Family history breast cancer, % 16.0 15.3
CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty.*Values are means (SD); ††Overall incidence of prior cardiovascular disease = 7.7%; ‡P = .04 vs CEE/MPA.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
CEE/MPA Trial: Baseline Characteristics
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CEE-Alone Trial: Baseline Characteristics
*Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown.†Required a 3-month washout prior to randomization.Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
CharacteristicCEE
(n = 5310)Placebo (n = 5429)
Mean age at screening, y (SD) 63.6 (7.3) 63.6 (7.3)Age group at screening, n (%)
50–59 years 1637 (30.8) 1673 (30.8)60–69 years 2387 (45.0) 2465 (45.4)70–79 years 1286 (24.2) 1291 (23.8)
Race/ethnicity, n (%)
White 4007 (75.5) 4075 (75.1)Minority* 1303 (24.5) 1354 (24.9)
Hormone use, n (%)
Never 2769 (52.2) 2770 (51.1)Past 1871 (35.2) 1948 (35.9)Current† 669 (12.6) 708 (13.0)
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CharacteristicCEE
(n = 5310)Placebo (n = 5429)
Body mass index, kg/m2* 30.1 (6.1) 30.1 (6.2)
Never smokers, % 51.9 50.4
Current smokers, % 10.3 10.6
Diabetes, % 7.7 7.6
Hypertension, % 48.0 47.4
Statin use at baseline, % 7.4 7.9
History of MI, % 3.1 3.2
History of CABG/PTCA, % 2.3 2.1
Family history breast cancer, % 18.0 17.1
CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty.*Data available for 5281 CEE and 5391 placebo participants; values are means (SD).Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
CEE-Alone Trial: Baseline Characteristics
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Section 4:
Overview of Clinical
Outcomes
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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WHI CEE/MPA: Preliminary Results
*VTE includes deep vein thrombosis and PE.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
CHD
Breast Cancer
Stroke
VTE*
Endometrial Cancer
Colorectal Cancer
Hip Fracture
Total Fracture
Death
Hazard Ratio0.5 1.0 5.02.0
95% nCI
95% aCI
Primary Outcomes
Additional Outcomes
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0
10
20
30
40
50
60
ColorectalCancer
EndometrialCancer
WHI CEE/MPA Results: Number of Cases/Year in 10,000 Women
Nu
mb
er p
er Y
ear
per
10,
000
Wo
men
Adapted from National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: http://www.nhlbi.nih.gov/health/women/upd2002.htm. Accessed 6/22/02.
CHD Strokes BreastCancer
VTE HipFractures
Total Deaths
Risks Neutral Benefits
CEE/MPAPlacebo
PE
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EventOverall
HR
Confidence Intervals
Attributable Risk per 10,000
Women/Year
Benefitper 10,000
Women/Year95%
Nominal95%
Adjusted
CHD 1.24 1.00–1.54 0.97–1.60 6
Breast cancer 1.24 1.01–1.54 0.97–1.59 8
Strokes 1.31 1.02–1.68 0.93–1.84 7
VTE 2.11 1.58–2.82 1.26–3.55 18
PE 2.13 1.39–3.25 0.99–4.56 8
Colorectal cancer 0.56 0.38–0.81 0.33–0.94 7
Hip fractures 0.67 0.47–0.96 0.41–1.10 5
Total fractures 0.76 0.69–0.83 -- 47
WHI CEE/MPA Results: Overall Relative and Attributable Risk
Women 50 to 79 Years of Age at Baseline
Cauley JA, et al. JAMA. 2003;290:1729-38; Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; Chlebowski RT, et al. JAMA. 2003;289:3243-53; Manson JE, et al. N Engl J Med. 2003;349:523-34; Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; Writing Group for the WHI Investigators. JAMA. 2002;288:321-33.
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WHI CEE Alone: Preliminary Results
VTE = venous thromboembolism (includes deep vein thrombosis and PE).Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
CHD
Breast Cancer
Stroke
VTE
Pulmonary Embolism
Colorectal Cancer
Hip Fracture
Total Fracture
Death
Hazard Ratio0.5 1.0 5.02.0
95% nCI
95% aCI
Primary Outcomes
Additional Outcomes
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0
10
20
30
40
50
60
70
80
90
WHI CEE-Alone Results: Number of Cases/Year in 10,000 Women
Nu
mb
er p
er Y
ear
per
10,
000
Wo
men
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Risks Neutral Benefits
CEEPlacebo
ColorectalCancer
CHDStrokes BreastCancer
VTE HipFractures
Total Deaths
PE
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EventOverall
HR
Confidence Intervals
Attributable Risk per 10,000
Women/Year
Benefitper 10,000
Women/Year95%
Nominal95%
Adjusted
CHD 0.91 0.75–1.12 0.72–1.15 5
Breast cancer 0.77 0.59–1.01 0.57–1.06 7
Strokes 1.39 1.10–1.77 0.97–1.99 12
VTE 1.33 0.99–1.79 0.86–2.08 7
PE 1.34 0.87–2.06 0.70–2.55 3
Colorectal cancer 1.08 0.75–1.55 0.63–1.86 1
Hip fractures 0.61 0.41–0.91 0.33–1.11 6
Total fractures 0.70 0.63–0.79 0.59–0.83 56
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
WHI CEE-Alone Results: Overall Relative and Attributable Risk
Women 50 to 79 Years of Age at Baseline
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Section 5:
Cardiovascular Events
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (years)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
WHI Results: Effect of CEE Alone on Risk of CHD
HR = 0.91
95% nCI = 0.75–1.12
95% aCI = 0.72–1.15
Kaplan-Meier Estimate
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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0.0 0.5 1.0 1.5 2.0 2.5 3.0
Hazard Ratio
WHI Results: Effect of CEE Alone on Risk of CHD by Age
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Annualized Percentage of CHD
Subgroup CEE Placebo HR
Age (years)
50–59 0.14 0.24 0.56
60–69 0.54 0.59 0.92
70–79 0.88 0.84 1.04
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CEE/MPA
Placebo
0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7
Years of Follow-up
Cu
mu
lati
ve H
azar
d f
or
CH
DWHI Results: Effect of CEE/MPA
on Risk of CHDKaplan-Meier Estimate
Manson JE, et al. N Engl J Med. 2003;349:523-34.
HR = 1.24
95% nCI = 1.00–1.54
95% aCI = 0.97–1.60
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
1 2 3 4 5 6+
Pe
rce
nt
CH
D E
ve
nts
*
CEE/MPA
Placebo
HazardYear Ratio 95% CI
1 1.81 (1.09-3.01)
2 1.34 (0.82-2.18)
3 1.27 (0.64-2.50)
4 1.25 (0.74-2.12)
5 1.45 (0.81-2.59)
6+ 0.70 (0.42-1.14)
WHI Results: Annualized Percent CHD Events by Year
Year
P = .02 for trend over time (z score = –2.36).
HR = 1.24
95% nCI = 1.00–1.54
95% aCI = 0.97–1.60
*Includes 9 silent MIs.Manson JE, et al. N Engl J Med. 2003;349:523-34.
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WHI: Effect of CEE/MPA on Risk of CHD by Age and Years Since Menopause
The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant.Manson JE, et al. N Engl J Med. 2003;349:523-34.
Subgroup
CEE/MPA Placebo
Number of Cases of CHD (annualized percentage)
Age (years)
50–59
60–69
70–79
37 (0.22)
75 (0.35)
76 (0.78)
27 (0.17)
68 (0.34)
52 (0.55)
Years Since Menopause
<10
10–19
20
31 (0.19)
63 (0.38)
74 (0.75)
34 (0.22)
51 (0.32)
44 (0.46)
0.5 1.0 1.5 2.0 2.5
Hazard Ratio for CHD
1.27
1.05
1.44
0.89
1.22
1.71
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Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (years)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Kaplan-Meier Estimate
HR = 1.39
95% nCI = 1.10–1.77
95% aCI = 0.97–1.99
WHI Results: Effect of CEE Alone on Risk of Stroke
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Annualized Percentage of Stroke
Subgroup CEE Placebo HR
Age (years)
50–59 0.16 0.16 1.08
60–69 0.49 0.30 1.65
70–79 0.71 0.57 1.25
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Hazard Ratio
WHI Results: Effect of CEE Alone on Risk of Stroke by Age
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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0.000
0.005
0.010
0.015
0.020
0.025
0.030
0 1 2 3 4 5 6
Time (years)
Cu
mu
lati
ve H
azar
dWHI Results: Effect of CEE/MPA
on Risk of Stroke
Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84.
CEE/MPA
Placebo
Kaplan-Meier Estimate
HR = 1.31
95% nCI = 1.02–1.68
95% aCI = 0.93–1.84
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0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (year)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
WHI Results: Effect of CEE Alone on Risk of Pulmonary Embolism
Kaplan-Meier Estimate
HR = 1.34
95% nCI = 0.87–2.06
95% aCI = 0.70–2.55
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0
0.01
0.02
0.03
0 1 2 3 4 5 6 7
Time (year)
Cu
mu
lati
ve H
azar
d
HR = 2.13
95% nCI = 1.39–3.25
95% aCI = 0.99–4.56
WHI Results: Effect of CEE/MPA on Risk of PE
Placebo
CEE/MPA
Kaplan-Meier Estimate
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved.
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0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
1 2 3 4 5 6+
Per
cen
t V
TE
Eve
nts
CEE/MPA
PlaceboHazardYear Ratio
1 3.60
2 2.26
3 1.67
4 1.84
5 2.49
6+ 0.90
WHI CEE/MPA Results: Annualized Percent VTE Events by Year
P < .05, significant fordecreasing risk over time.
Year
HR = 2.11
95% nCI = 1.58–2.82
95% aCI = 1.26–3.55
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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Section 6:
Breast Cancer
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time, y
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Kaplan-Meier Estimate
HR = 0.77
95% nCI = 0.59–1.01
95% aCI = 0.57–1.06
WHI Results: Effect of CEE Alone on Risk of Invasive Breast Cancer
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0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7
WHI Results: Effect of CEE/MPA on Risk of Invasive Breast Cancer
Cu
mu
lati
ve P
rop
ort
ion
Time (years)
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
Placebo
CEE/MPAUnweighted HR = 1.24
95% CI, 1.01–1.54
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WHI CEE/MPA Trial: Risk of Breast Cancer in Women With and Without Prior HT Use
Hazard Ratio (95% CI)
0.1 0.5 1.0 4.02.0
Prior HT Use
None
<5 Years
5 Years
Overall
% of Population
74.0
14.8
11.2
100
6.0
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
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WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers
SEER = Surveillance, Epidemiology, and End Results.Chlebowski RT, et al. JAMA. 2003;289:3243-53.
E+P(n = 199)
Placebo(n = 150) P-Value
Tumor size, mean ± SD (cm) 1.7 ± 1.1 1.5 ± 0.9 .04
Positive lymph nodes, % 25.9 15.8 .03
SEER stage, %
Localized 74.6 82.7
Regional 24.4 14.0 .048
Metastatic 1.0 2.0
Morphology, grade, %
Well differentiated 25.0 20.3
Moderately differentiated 43.3 47.7 .61
Poorly differentiated/anaplastic 31.7 32.0
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ER = estrogen receptor; PR = progesterone receptor.Chlebowski RT, et al. JAMA. 2003;289:3243-53.
WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers (continued)
E+P(n = 199)
Placebo(n = 150) P-Value
ER status, %
Positive 86.8 88.2.72
Negative 13.2 11.8
PR status, %
Positive 75.0 69.9.33
Negative 25.0 30.0
Deaths attributed to breast cancer, no. (%) 4 (2.0) 4 (2.7)
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WHI CEE/MPA Trial: Mammography Results
*Abnormal mammograms included those that were associated with recommendations for short-term follow-up, showed a suspicious abnormality, or were highly suggestive of malignancy.†P < .001 vs E+P.
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
% Abnormal*
E+P Placebo
Year 1Year 1 9.49.4 5.45.4††
OverallOverall 31.531.5 21.221.2††
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Section 7:
Other Cancers
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (year)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Kaplan-Meier Estimate
HR = 1.08
95% nCI = 0.75–1.55
95% aCI = 0.63–1.86
WHI Results: Effect of CEE Alone on Risk of Colorectal Cancer
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0.000
0.005
0.010
0.015
0 1 2 3 4 5 6 7
Time (year)
Cu
mu
lati
ve H
azar
dWHI Results: Effect of CEE/MPA
on Risk of Colorectal Cancer
Placebo
E+P
Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004.
HR = 0.56
95% nCI = 0.38–0.81
95% aCI = 0.33–0.94
Kaplan-Meier Estimate
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WHI Results: Hazard Ratio for Invasive Ovarian Cancer With CEE/MPA
Incidence rate of invasive ovarian cancer for the total study population was 34 cases per 100,000 person-years.Anderson GL, et al. JAMA. 2003;290:1739-48.
Hazard Ratio
0.1 0.5 1.0 5.02.0
95% nCI
95% aCI
E+P
Placebo
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WHI Results: Hazard Ratio for Endometrial Cancer With CEE/MPA
Incidence rate of endometrial cancer for the total study population was 62 cases per 100,000 person-years.Anderson GL, et al. JAMA. 2003;290:1739-48.
Hazard Ratio
E+P
0.1 0.5 1.0 5.02.0
95% nCI
95% aCI
Placebo
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Section 8:
Fractures
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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HR = 0.61
95% nCI = 0.41–0.91
95% aCI = 0.33–1.11
0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (year)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
WHI Results: Effect of CEE Alone on Risk of Hip Fracture
Kaplan-Meier Estimate
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WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores
Normal(>–1.0)
Low Bone Mass(–1.0 to –2.4)
E+P Placebo
P = .29
Cauley JA. Available at: http://www.fda.gov/ohrms/dockets/ac/cder03.html#EndocrinologicMetabolicDrugs. Accessed 1/7/04.
In 6% of Participants (n = 1024)
32%
58%
10%
35%
53%
12%
Osteoporosis(–2.5 )
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-1
0
1
2
3
4
5
6
7
0 1 2 3
-1
0
1
2
3
4
5
6
7
0 1 2 3
PlaceboHT
-1
0
1
2
3
4
5
6
7
0 1 2 3
WHI Results: Mean Change in BMD During 3 Years of E+P
Follow-up (years)
Cauley JA, et al. JAMA. 2003;290:1729-38.
Mea
n C
han
ge
in B
MD
F
rom
Bas
elin
e (%
)
Total Hip Spine
In 6% of Participants (n = 1024)
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WHI Results: Fracture Outcomes
Hip
Vertebral
Lower Arm/Wrist
Total
Hazard Ratio
95% nCI
95% aCI
0.5 1.0 2.0
Adjusted confidence interval reported only for hip fracture.Cauley JA, et al. JAMA. 2003;290:1729-38.
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0
50
100
150
200
Total Fractures
WHI Results: Effect of CEE/MPA in Preventing Fractures
0
20
40
60
80
Hip ClinicalVertebral
Wrist/LowerArm
Nu
mb
er o
f F
ract
ure
s/Y
ear
in 1
0,00
0 W
om
en
PlaceboCEE/MPA
Number of Fractures/Year in 10,000 Women
Type of FractureCauley JA, et al. JAMA. 2003;290:1729-38.
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0.00
0.01
0.02
0.03
0 1 2 3 4 5 6 7
HR = 0.6795% nCl = 0.47–0.9695% aCI = 0.41–1.10
WHI Results: Effect of CEE/MPAon Risk of Hip Fracture
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
d
Placebo
E+P
Cauley JA, et al. JAMA. 2003;290:1729-38.
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0.0
0.1
0.2
0.3
0.4
0.5
0 1 2 3 4 5 6 7
WHI Results: Effect of CEE/MPA on Risk of Lower Arm/Wrist Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
d HR = 0.7195% nCl = 0.59–0.85
Placebo
E+P
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0.0
0.1
0.2
0.3
0 1 2 3 4 5 6 7
WHI Results: Effect of CEE/MPA on Risk of Vertebral Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
Kaplan-Meier Estimate
Time (year)
Cu
mu
lati
ve H
azar
d HR = 0.6595% nCl = 0.46–0.92
Placebo
E+P
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0.00
0.05
0.10
0.15
0 1 2 3 4 5 6 7
Cu
mu
lati
ve H
azar
d
Time (year)
WHI Results: Effect of CEE/MPAon Risk of Total Fracture
Adjusted confidence interval not reported.Cauley JA, et al. JAMA. 2003;290:1729-38.
Kaplan-Meier Estimate
HR = 0.7695% nCl = 0.69–0.83
Placebo
E+P
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1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.
WHI: Summary Fracture Risk Score
WHI Investigators1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index2
Predictive validity of FRACTURE Index has been shown2
Validity of WHI fracture risk score not established
– WHI reported fracture risk score showed moderate predictive strength for hip fracture1
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1Cauley JA, et al. JAMA. 2003;290:1729-38.2Black DM, et al. Osteoporosis Int. 2001;12:519-28.
WHI: Summary Fracture Risk Score
Differences between FRACTURE Index and WHI risk score1,2:
– WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m2
– FRACTURE Index includes age, prior fracture after age 50 years, maternal hip fracture after age 50 years, weight 125 lbs, current smoking, use of arms to stand from a chair, and total hip BMD (if available)2
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HR for Global Index: Stratified by Fracture Risk Scores
Highest
Middle
Lowest
Hazard Ratio (95% nCI)
Fracture Risk*
0.5 1.0 2.0
*Stratified by tertiles of summary fracture risk scores; the WHI Global Index measure and WHI Fracture Risk Score have not been validated.Cauley JA, et al. JAMA. 2003;290:1729-38.
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Summary: WHI Results and Considerations
CEE/MPA significantly decreased the risk of hip fractures, vertebral fractures, and all other fractures in a population not specifically selected for being at increased risk of fracture1
This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy
1Cauley JA, et al. JAMA. 2003;290:1729-38.
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Section 9:
Dementia and Mild Cognitive
Impairment
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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Women’s Health Initiative Memory Study (WHIMS)
1Shumaker SA, et al. JAMA. 2003;289:2651-62.2Rapp SR, et al. JAMA. 2003;289:2663-72.
Ancillary study to the WHI, a randomized, multicenter study of CEE alone and CEE plus MPA
Primary outcome measure: probable dementia
Two studies from WHIMS have been published
– Effect of CEE/MPA on probable dementia and mild cognitive impairment1
– Effect of CEE/MPA on global cognitive function2
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WHIMS: Dementia and Mild Cognitive Impairment
1Shumaker SA, et al. JAMA. 2003;289:2651-62.
4532 postmenopausal women with a uterus and free of probable dementia, aged 65 years, were recruited from WHI centers and enrolled in the E+P arm of the WHIMS1
Study drug administration was stopped early
– Mean time between randomization and last 3MSE in WHIMS was 4.05 years
The ending of the CEE-only component of WHI and WHIMS ~1 year before its planned completion was announced by the NIH on March 2, 2004
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OutcomeE+P
(n = 2229)Placebo
(n = 2303) HR (95% CI)
Probable dementia, n 40 21 2.05 (1.21–3.48)
Follow-up, mean (SD), years 4.01 (1.21) 4.06 (1.18)
Rate per 10,000 person-years 45 22
Mild cognitive impairment, n 56 55 1.07 (0.74–1.55)
Follow-up, mean (SD), years 3.99 (1.23) 4.04 (1.20)
Rate per 10,000 person-years 63 59
Cases of Probable Dementia and Mild Cognitive Impairment
Shumaker SA, et al. JAMA. 2003;289:2651-62.
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0
0.01
0.02
0.03
0.04
0 1 2 3 4 5
Years Since Randomization
Cu
mu
lati
ve H
azar
dCumulative HR for a Diagnosis of
Mild Cognitive Impairment
Shumaker SA, et al. JAMA. 2003;289:2651-62.
HR, 1.0795% CI, 0.74–1.55
CEE/MPA
Placebo
Number of Events
CEE/MPA 5 18 18 11 4
Placebo 7 8 18 12 6
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Cumulative HR for a Diagnosis of Probable Dementia
Shumaker SA, et al. JAMA. 2003;289:2651-62.
0
0.01
0.02
0.03
0 1 2 3 4 5
Years Since Randomization
Cu
mu
lati
ve H
azar
d
HR, 2.0595% CI, 1.21–3.48
CEE/MPA
Placebo
Number of Events
CEE/MPA 5 7 8 11 4
Placebo 3 2 3 3 9
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Classification of Probable Dementia Cases by Treatment Assignment
Shumaker SA, et al. JAMA. 2003;289:2651-62.
Number (%) of Cases
Dementia Type CEE/MPA (n = 40) Placebo (n = 21)
Vascular dementia 5 (12.5) 1 (4.8)
Alzheimer’s disease 20 (50.0) 12 (57.1)
Other dementia types
Mixed type 5 (12.5) 3 (14.3)
Normal pressure hydrocephalus 2 (5.0) 0
Parkinson 0 1 (4.8)
Frontal lobe type 2 (5.0) 0
Alcohol related 1 (2.5) 0
Other dementia 3 (7.5) 2 (9.5)
Etiology unknown 2 (5.0) 2 (9.5)
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Patient Adherence in WHIMS
2534 participants (55.9%) were nonadherent at some point during the trial
Nonadherent patients stopped study medication, took less than 80% of pills, or started HT outside of the trial
When nonadherent participants were censored 6 months after first becoming nonadherent, the number of probable dementia cases that occurred before censoring was reduced from 41 to 21 in the E+P group and from 20 to 6 in the placebo group (HR, 3.22; 95% CI, 1.25–8.29; P = .02)
Shumaker SA, et al. JAMA. 2003;289:2651-62.
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Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
WHI: Effect of E+P on Stroke IncidenceE
ven
ts (
per
10,
000
per
son
-yea
rs)
0
10
20
30
40
1 2 3 4 5 6
CEE/MPAPlacebo
Year of Follow-up
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Related Study
WHISCA – Women’s Health Initiative Study on Cognitive Aging
Ancillary study to WHIMS
Designed to determine if estrogen or E+P reduces the rate of cognitive decline in women 65 years of age
Planned 6-year follow-up
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What WHIMS and WHISCA Cannot Address
Whether there is a critical period of initiation of HT for prevention of
– Cognitive aging
– AD Whether dose, types of HT, or duration of
treatment may have different effects
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Observational vs Randomized Studies
Observational Prospective Studies
Typical patterns of HT use (age, treatment)
Mostly E alone Risk for AD
Women’s Health Initiative Memory Study (WHIMS)
Only women 65 years of age
CEE + MPA Risk of all-cause
dementia
HT and AD
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Section 10:
Quality of Life
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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WHI Quality of Life (QOL) Study
Health and functional status—RAND-36
Depression — CES-D
Sleep quality — WHI Insomnia Rating Scale
Satisfaction with sexual functioning — 1 item with 4-point response scale
Cognitive functioning — mMMSE
Menopausal symptoms — 5-item checklist
CES-D = Center for Epidemiological Studies-Depression; mMMSE = modified Mini-Mental State Examination.Hays J, et al. N Engl J Med. 2003;348:1839-54.
QOL-Related Assessments
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One-Year Change in RAND-36 Scores
-3 -2 -1 0 1 2 3
Mental Health
Social Functioning
Energy and Fatigue
Bodily Pain
Physical Functioning
General Health
Physical Role Limitations
Emotional Role Limitations
CEE/MPA
Placebo
Change From Baseline at Year 1
*
For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect.*P < .01 compared with placebo at Year 1.Hays J, et al. N Engl J Med. 2003;348:1839-54.
0
*
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For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect.*P < .01 compared with placebo at Year 1.Hays J, et al. N Engl J Med. 2003;348:1839-54.
One-Year Change in Other QOL-Related Measures
-1 0 1 2
CEE/MPA
Placebo
Change From Baseline at Year 1
*
0
0
Depression
Sleep Disturbance
Satisfaction With Sex
mMMSE
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WHI QOL: Summary of Findings
The WHI1 found
– No significant clinical QOL benefit on any of the outcomes, including general health, vitality, mental health, or sexual satisfaction
– A statistically—but not clinically—significant benefit in sleep disturbance, physical functioning, and body pain at 1 year
Findings were similar to HERS2
– No improvement in QOL was seen with E+P use in older, asymptomatic, postmenopausal women
1Hays J, et al. N Engl J Med. 2003;348:1839-54.2Hlatky MA, et al. JAMA. 2002;287:591-7.
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WHI QOL: Study Considerations
Only 12% of participants reported moderate or severe vasomotor symptoms
Unclear how “moderate” and “severe” vasomotor symptoms were defined
Vaginal symptoms were not evaluated Outcome scores were high at baseline, limiting
potential for therapy to increase them further 63% of the participants were ≥10 years
postmenopausal No validated menopausal QOL tools used
Hays J, et al. N Engl J Med. 2003;348:1839-54.
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Section 10:
Mortality
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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0.00
0.05
0.10
0.15
0.20
0 1 2 3 4 5 6 7 8
Time (year)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
WHI Results: Effect of CEE-Alone on Total MortalityKaplan-Meier Estimate
HR = 1.04
95% nCI = 0.88–1.22
95% aCI = 0.81–1.32
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WHI Results: Causes of Death* in the CEE/MPA Trial
*Causes of death for placebo versus CEE/MPA were not statistically different.n = number of patients; % = annualized % calculated from average exposure over 60 months.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
OutcomeCEE/MPA (n = 8506)
n (%)Placebo (n = 8102)
n (%)
Total deaths 231 (0.52) 218 (0.53)
Adjudicated deaths 215 (0.49) 201 (0.49)
Cardiovascular 65 (0.15) 55 (0.13)
Breast cancer 3 (0.01) 2 (<0.01)
Other cancer 104 (0.24) 86 (0.21)
Other known cause 34 (0.08) 41 (0.10)
Unknown cause 9 (0.02) 17 (0.04)
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0.00.10.20.30.40.50.60.70.80.91.01.1
1 2 3 4 5 6+
Per
cen
t A
ll-C
ause
Dea
ths
CEE/MPA
Placebo
Year
WHI CEE/MPA Trial: Annualized Percent of All-Cause Deaths by Year
P = NS for trend over time.
HR = 0.98
95% nCI = 0.82–1.18
95% aCI = 0.70–1.37
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
HazardYear Ratio
1 1.24
2 0.96
3 1.06
4 1.09
5 0.87
6+ 0.83
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Section 11:
Summary and Conclusions
Risks and Benefits of Hormone Therapy: An Overview of Findings From the
Women’s Health Initiative
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Summary of CEE/MPA Study
The overall risks of CEE 0.625 mg/d plus MPA 2.5 mg/d exceeded the benefits after an average of 5.2 years of follow-up in asymptomatic women ages 50 to 79 years at initial screening
Results from WHI indicate that CEE 0.625 mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD
Risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture and colon cancer
Conclusions of the WHI Writing Group
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
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Summary of CEE-Alone Study
In women with prior hysterectomy, the use of CEE-alone
– increases the risk of stroke
– decreases the risk of hip fracture
– does not affect the incidence of CHD A possible reduction in breast cancer with
use of CEE alone requires further study CEE alone not recommended for chronic
disease prevention
Conclusions of the WHI Writing Group
Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
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Interpretation of the Results from the WHI HT Trials
Average age at screening was 63 years; studies stopped when two-thirds or more of patients were 68 years
Results cannot be extrapolated to the typical population using HT
– Majority of women initiate HT to alleviate menopausal symptoms
– Women with moderate-to-severe menopausal symptoms were discouraged from participating
– 75% of HT users initiate therapy within 5 years of menopause; mean age of menopause, 51 years
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12; Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; Newton KM, et al. J Womens Health. 1997;6:459-65; The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109; McKinlay SM, et al. Maturitas. 1992;14:103-15; Brett KM, Chong Y. Hormone Replacement Therapy: Knowledge and Use in the United States. Hyattsville, Md: National Center for Health Statistics; 2001:1-29.
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Interpretation of the Results from the WHI HT Trials
Results may not relate to lower doses of these drugs or other estrogens or progestins, or other formulations or routes of administration
In the absence of clinical trial data, one cannot assume greater safety of other estrogens and/or progestins
Other Considerations
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Treatment Discontinuation & Crossover
Interpretation of the CEE/MPA Results
Rates of discontinuation were high
– CEE/MPA = 42%
– Placebo = 38%
A number of women initiated HT with their own clinicians
– CEE/MPA = 6.2%
– Placebo = 10.7%
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Unblinding
Interpretation of the CEE/MPA Results
Clinic gynecologists were unblinded to treatment assignment at higher rate in CEE/MPA group
– 41% unblinded in CEE/MPA
– 7% unblinded in placebo Effects of unblinding in CEE/MPA group
unclear; could influence patient monitoring for breast cancer and other conditions in the global index
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National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, 2002. Available at: http://www.nhlbi.nih.gov/whi/hrtupd/ep_facts.htm. Accessed 7/15/02.
WHI: NIH Recommendations HT should not be continued or started to prevent
heart disease For osteoporosis prevention, women should consult
their doctor and weigh the benefits of HT against their personal risks; alternate treatments are available
While short-term use was not studied, women taking HT for relief of menopausal symptoms may reap more benefits than risks
Risk/benefit profiles must be individualized for each patient
Women should talk with their doctor about their personal risks and benefits
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American College of Obstetricians and Gynecologists. Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, 2002. Available at: http://www.acog.org/from_home/publications/press_releases/nr07-09-02.cfm. Accessed 7/15/02.
WHI: American College of Obstetrics and Gynecology (ACOG) Advisory
Women who have been taking HT for a number of years should not panic, but discuss their individual situation with their physician
With respect to women’s short-term use of HT for relief of menopausal symptoms, it may be reasonable for women to continue use for this purpose, since the benefits are likely to outweigh the risks
Regarding a women’s short-term use of HT for relief of menopausal symptoms, ACOG continues to recommend that this be a personal, individualized decision, made after consultations between a woman and her physician—taking into account a woman’s individual benefits and risks from such use