Appendix C13Evidence Table of Trials Reporting Outcomes by Subgroups

Author, year; titlePopulationResults (Treatment vs. Placebo)
Colorectal cancer
Ritenbaugh, 2008;50 Conjugated equine estrogens and colorectal cancer incidence and survival: the Women’s Health Initiative randomized clinical trial.
WHI Estrogen only trial
Excluded women with history of breast cancer and medical conditions likely to result in death in the next 3 years.
10,739 Enrolled
5,310 Estrogen
5,429 Placebo
Incidence (annualized rate) of invasive colorectal cancer
Overall: 58 (0.15%) vs. 53 (0.14%); HR, 1.12 (95% CI, 0.77 to 1.63)
History of polyp removal
No: 40 (0.13%) vs. 46 (0.15%); HR, 0.87 (95% CI, 0.57 to 1.33)
Yes: 9 (0.29%) vs. 0 (0.00); HR, not reported
Height (cm); p=0.03
96.0–158.6: 26 (0.21%) vs. 12 (0.10%); HR, 2.12 (95% CI, 1.074 to 4.19)
158.7–163.9: 18 (0.15%) vs. 15 (0.12%); HR, 1.27 (95% CI, 0.64 to 2.52)
164.0–188.3: 14 (0.11%) vs. 26 (0.20%); HR, 0.57 (95% CI, 0.29 to 1.10)
Waist circumference (cm); p=0.03
37.1–84.9: 22 (0.17%) vs. 11 (0.09%); HR, 2.03 (95% CI, 0.98 to 4.19)
85.0–96.9: 18 (0.15%) vs. 17 (0.13%); HR, 1.14 (95% CI, 0.59 to 2.22)
97.0–191.6: 18 (0.14%) vs. 25 (0.20%); HR, 0.68 (95% CI, 0.37 to 1.25)
LaCroix, 2011;49 Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy postintervention.
WHI Estrogen only trial
All women enrolled in WHI trial followed after completion of trial (postintervention phase):
10,739 Enrolled
5,310 Estrogen
5,429 Placebo
Cumulative annualized rates for colorectal cancer
Age at screening (years)
50–59: 14 vs. 18; HR, 0.80 (95% CI, 0.40 to 1.61); p=0.04
60–69: 37 vs. 43 ; HR, 0.90 (95% CI, 0.58 to 1.39); p =0.04
70–79: 38 vs. 21; HR, 1.83 (95% CI, 1.08 to 3.12); p=0.04
Anderson, 2004;42 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy.
WHI Estrogen only trial
Women enrolled in WHI trial (intervention phase):
10,739 Enrolled
5,310 Estrogen
5,429 Plaecbo
Colorectal cancer
Age at screening (years); p=0.048
50–59: 8 vs. 14; HR, 0.59 (95% CI, 0.25 to 1.41)
60–69: 26 vs. 31; HR, 0.88 (95% CI, 0.52 to 1.48)
70–79: 27 vs. 13; HR, 2.09 (95% CI, 1.08 to 4.04)
Breast cancer
Chlebowski, 2010;25 Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.
WHI Estrogen plus progestin trial
All women enrolled in WHI trial followed after completion of trial (postintervention and extension phase).
Estrogen plus progestin
Intervention phase: 8,506
Postintervention phase: 8,056
Extension phase analyzed: 8,506
Placebo
Intervention phase: 8,102
Postintervention phase: 7,682
Extension phase analyzed: 8,102
Prior menopausal hormone therapy use (annualized %)
No prior use: 312 (0.42%) vs. 257 (0.36%); HR, 1.16 (95% CI, 0.98 to 1.37)
Prior use (current/past): 73 (0.44%) vs. 36 (0.23%); HR,1.85 (95% CI, 1.25 to 2.80); p=0.03
Chlebowski, 2003;26 Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial.
WHI Estrogen plus progestin trial
Women enrolled in WHI trial:
16,608 Enrolled
8,506 Estrogen plus progestin
8,102 Placebo
Invasive breast cancer
Without prior menopausal hormone therapy use
Treatment (6,277) vs. placebo (6,020)
Year 1 after entry: 7 (0.11%) vs. 14 (0.23%); HR, 0.48 (95% CI, 0.19 to 1.20)
Year 2 after entry: 15 (0.24%) vs. 22 (0.37%); HR, 0.65 (95% CI, 0.34 to 1.25)
Year 3 after entry: 19 (0.31%) vs. 19 (0.33%); HR, 0.96 (95% CI, 0.51 to 1.82)
Year 4 after entry: 35 (0.58%) vs. 23 (0.40%); HR, 1.45 (95% CI, 0.85 to 2.45)
Year 5 after entry: 28 (0.54%) vs.17 (0.34%); HR, 1.61 (95% CI, 0.88 to 2.94)
Year 6 or more after entry: 37 (0.69%) vs. 26 (0.56%); HR, 1.24 (95% CI, 0.75 to 2.05)
z score=2.31
With prior menopausal hormone therapy use
Treatment (2,225) vs. placebo (2,079)
Year 1 after entry: 5 (0.23%) vs. 5 (0.24%); HR, 0.90 (95% CI, 0.26 to 3.15)
Year 2 after entry: 11 (0.50%) vs. 10 (0.49%); HR, 1.10 (95% CI, 0.47 to 2.61)
Year 3 after entry: 10 (0.46%) vs. 3 (0.15%); HR, 3.09 (95% CI, 0.84 to 11.27)
Year 4 after entry: 9 (0.42%) vs. 4 (0.20%); HR, 2.16 (95% CI, 0.66 to 7.05)
Year 5 after entry: 15 (0.82%) vs. 4 (0.23%); HR, 3.56 (95% CI, 1.18 to 10.73)
Year 6 or more after entry: 8 (0.39%) vs. 3 (0.17%); HR, 1.99 (95% CI, 0.52 to 7.60)
z score=1.62
Overall
Year 1 after entry: 12 (0.14%) vs. 19 (0.24%); HR, 0.60 (95% CI, 0.29 to 1.23)
Year 2 after entry: 26 (0.31%) vs. 32 (0.40%); HR, 0.77 (95% CI, 0.46 to 1.30)
Year 3 after entry: 29 (0.35%) vs. 22 (0.28%); HR, 1.26 (95% CI, 0.73 to 2.20)
Year 4 after entry: 44 (0.54%) vs. 27 (0.35%); HR, 1.54 (95% CI, 0.95 to 2.49)
Year 5 after entry: 43 (0.61%) vs. 21 (0.32%); HR, 1.99 (95% CI, 1.18 to 3.35)
Year 6 or more after entry: 45 (0.61%) vs. 29 (0.45%); HR, 1.35 (95% CI, 0.85 to 2.16)
z score=2.56
All p values >0.05 for:
Age at screening, Gail risk assessment, prior oral contraceptive use, prior menopausal hormone use, prior estrogen only use, prior estrogen plus progestin use, recency of hormone use, BMI, smoking, NSAID use
(Note: prior menopausal hormone therapy use ≥5 years: HR, 2.27 (95% CI, 1.00 to 5.15); border significance
LaCroix, 2011;49 Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy postintervention.
WHI Estrogen only trial
All women enrolled in WHI trial followed up after completetion of trial (postintervention phase):
10,739 Enrolled
5,310 Estrogen
5,429 Placebo
Cumulative annualized rates for invasive breast cancer
Age at screening (years)
50–59: 43 vs 54; HR, 0.80 (95% CI, 0.53 to 1.19); p=0.96
60–69: 68 vs. 95; HR, 0.73 (95% CI, 0.54 to 1.00); p=0.96
70–79: 40 vs. 50; HR, 0.81 (95% CI, 0.53 to 1.23); p=0.96
Rossouw, 2002;12 Risks and benefits of estrogen plus progestin in healthy postmenopausal women.
WHI Estrogen plus progestin trial
Women enrolled in WHI trial (intervention phase):
16,608 Enrolled
8,506 Estrogen plus progestin
8,102 Placebo
Invasive breast cancer (annualized %)
By followup year
Year 1: 11 (0.13) vs. 17 (0.21); HR, 0.62
Year 2: 26 (0.31) vs. 30 (0.38); HR, 0.83
Year 3: 28 (0.34) vs. 23 (0.29); HR, 1.16
Year 4: 40 (0.50) vs. 22 (0.29); HR, 1.73
Year 5: 34 (0.57) vs. 12 (0.22); HR, 2.64
Year 6 and later: 27 (0.53) vs. 20 (0.47); HR, 1.12
Anderson, 2004;42 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy.
WHI Estrogen only trial
Women enrolled in WHI trial (intervention phase):
10,739 Enrolled
5,310 Estrogen
5,429 Plaecbo
Invasive breast cancer
Age at screening (years); p=0.51
50–59: 25 vs. 35; HR, 0.72 (95% CI, 0.43 to 1.21)
60–69: 42 vs. 60; HR, 0.72 (95% CI, 0.49 to 1.07)
70–79: 27 vs. 29; HR, 0.94 (95% CI, 0.56 to 1.60)
Gramling, 2009;31 Hormone replacement therapy, family history, and breast cancer risk among postmenopausal women.
WHI Estrogen plus progestin trial
Women enrolled in WHI trial (longitudinal followup):
16,608 Enrolled
8,506 Estrogen plus progestin
8,102 Placebo
Incidence of invasive breast cancer in those with first-degree family member with breast cancer (n=1,009 vs. 895)
Overall: 35 (3.5%) vs. 25 (2.7%)
Incidence of invasive breast cancer in those without first-degree family member with breast cancer (n=7,497 vs. 7,202)
Overall: 164 (2.2%) vs. 125 (1.7%)
Urinary incontinence
Hendrix, 2005;35 Effects of estrogen with and without progestin on urinary incontinence.
WHI Estrogen plus progestin trial
Analysis focused on women with urinary incontinence data at baseline and 1 year:
16,608 Enrolled in WHI
7,247 Estrogen plus progestin (2,675 continent at baseline)
7,056 Placebo (2,507 continent at baseline)
Stress urinary incontinence
Age at screening (years)
50–54: RR, 0.90 (95% CI, 0.58 to 1.40)
55–59: RR, 1.63 (95% CI, 1.18 to 2.27); p<0.001
60–69: RR, 2.11 (95% CI, 1.70 to 2.62); p<0.001
70–79: RR, 2.59 (95% CI, 1.77 to 3.81); p<0.001
Duration since menopause (years)
<5: RR, 1.21 (95% CI, 0.83 to 1.77)
5 to <10: RR, 1.70 (95% CI, 1.19 to 2.44); p=0.005
10 to <15: RR, 2.00 (95% CI, 1.45 to 2.77); p=0.005
≥15: RR, 2.33 (95% CI, 1.79 to 3.03); p=0.005
Menopaual hormone therapy use
Never: RR, 1.87 (95% CI, 1.57 to 2.24); p=0.008
Past: RR, 2.41 (95% CI, 1.71 to 3.41); p=0.008
Current: RR, 0.85 (95% CI, 0.48 to 1.50)
Beta blocker use
Absent: RR, 1.81 (95% CI, 1.55 to 2.11); p=0.03
Present: RR, 6.69 (95% CI, 2.03 to 22.05); p=0.03
Urge urinary incontinence
Age at screening (years)
50–54: RR, 1.18 (95% CI, 0.75 to 1.88)
55–59: RR, 0.90 (95% CI, 0.63 to 1.30)
60–69: RR, 1.26 (95% CI, 1.01 to 1.58)
70–79: RR, 1.20 (95% CI, 0.89 to 1.61)
Duration since menopause (years)
<5: RR, 1.25 (95% CI, 0.80 to 1.93)
5 to <10: RR, 1.17 (95% CI, 0.80 to 1.70)
10 to <15: RR, 1.17 (95% CI, 0.81 to 1.67)
≥15: RR, 1.17 (95% CI, 0.93 to 1.46)
Menopausal hormone therapy use
Never: RR, 1.14 (95% CI, 0.96 to 1.36)
Past: RR, 1.16 (95% CI, 0.83 to 1.62)
Current: RR, 1.38 (95% CI, 0.65 to 2.96)
Diabetes
Absent: RR, 1.21 (95% CI, 1.21 to 1.03); p=0.03
Present: RR, 0.59 (95% CI, 0.32 to 1.09)
Mixed urinary incontinence
Age at screening (years)
50–54: RR, 2.11 (95% CI, 0.55 to 8.06)
55–59: RR, 1.05 (95% CI, 0.58 to 1.91)
60–69: RR, 1.46 (95% CI, 0.94 to 2.26)
70–79: RR, 2.24 (95% CI, 1.17 to 4.30); p=0.26
Duration since menopause (years)
<5: RR,1.32 (95% CI, 0.59 to 2.96)
5 to <10: RR, 1.53 (95% CI, 0.71 to 3.29)
10 to <15: RR, 1.31 (95% CI, 0.67 to 2.56)
≥15: RR, 1.58 (95% CI, 0.99 to 2.50); p=0.73
Menopausal hormone therapy use
Never: RR, 1.43 (95% CI, 1.01 to 2.02); p=0.49
Past: RR, 1.39 (0.69 to 2.79)
Current: RR, 3.64 (0.79 to 16.79)
Hendrix, 2005;35 Effects of estrogen with and without progestin on urinary incontinence.
WHI Estrogen only trial
Analysis focused on women with urinary incontinence data at baseline and 1 year:
10,739 Enrolled in WHI
4,476 Estrogen (1,526 continent at baseline)
4,517 Placebo (1,547 continent at baseline)
Stress urinary incontinence
Age at screening (years)
50–54: RR, 1.13 (95% CI, 0.69 to 1.86)
55–59: RR, 2.32 (95% CI, 1.42 to 3.77); p=0.002
60–69: RR, 2.10 (95% CI, 1.60 to 2.74); p=0.002
70–79: RR, 3.91 (95% CI, 2.31 to 6.60); p=0.002
Duration since menopause (years)
<5: RR, 0.95 (95% CI, 0.47 to 1.90)
5 to <10: RR, 2.18 (95% CI, 1.04 to 4.57); p=0.02
10 to <15: RR, 2.01 (95% CI, 1.17 to 3.44); p=0.02
≥15: RR, 2.56 (95% CI, 1.93 to 3.39); p=0.02
Menopausal hormone therapy use
Never: RR, 2.25 (95% CI, 1.72 to 2.95); p=0.55
Past: RR, 2.24 (95% CI, 1.62 to 3.10); p=0.55
Current: RR, 1.60 (95% CI, 0.93 to 2.75)
Urge urinary incontinence
Age at screening (years)
50–54: RR, 0.85 (95% CI, 0.44 to 1.66)
55–59: RR, 0.94 (95% CI, 0.56 to 1.57)
60–69: RR, 1.49 (95% CI, 1.14 to 1.95); p=0.05
70–79: RR, 1.45 (95% CI, 1.07 to 1.98); p=0.05
Duration since menopause (years)
<5: RR, 1.37 (95% CI, 0.60 to 3.12)
5 to <10: RR, 1.26 (95% CI, 0.62 to 2.58)
10 to <15: RR, 0.74 (95% CI, 0.43 to 1.26)
≥15: RR, 1.46 (95% CI, 1.16 to 1.84); p=0.35
Menopausal hormone therapy use
Never: RR, 1.33 (95% CI, 1.03 to 1.70); p=0.58
Past: RR, 1.23 (95% CI, 0.92 to 1.64)
Current: RR, 1.81 (95% CI, 0.94 to 3.49)
Mixed urinary incontinence
Age at screening (years)
50–54: RR, 1.07 (95% CI, 0.38 to 2.99)
55–59: RR, 0.69 (95% CI, 0.23 to 2.06)
60–69: RR, 2.05 (95% CI, 1.25 to 3.35); p=0.04
70–79: RR, 2.63 (95% CI, 1.32 to 5.25); p=0.04
Duration since menopause (years)
<5: RR, 2.62 (95% CI, 0.94 to 7.30)
5 to <10: RR, 0.36 (95% CI, 0.7 to 1.74)
10 to <15: RR, 0.89 (95% CI, 0.36 to 2.20)
≥15: RR, 2.11 (95% CI, 1.35 to 3.30); p=0.46
Menopausal hormone therapy use
Never: RR, 1.36 (95% CI, 0.85 to 2.18)
Past: RR, 2.65 (95% CI, 1.47 to 4.79); p=0.15
Current: RR, 1.75 (95% CI, 0.57 to 5.35)
Smoking status
Never: RR, 2.57 (95% CI, 1.55 to 4.27); p=0.05
Past: RR, 1.51 (95% CI, 0.89 to 2.58)
Current: RR, 0.38 (0.08 to 1.86)
Diabetes
Margolis, 2004;38 Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative hormone trial.
Estrogen plus progestin trial
Excluded women with self-reported diabetes at baseline:
15,641 Eligible from WHI
8,014 Estrogen plus progestin
7,627 Placebo
Incidence of new diabetes diagnosis
BMI <25: 32 vs. 34; HR, 1.00
BMI 25–29: 57 vs. 75; HR, 1.77 (95% CI, 1.32 to 2.38); p=0.0002
BMI ≥30: 123 vs. 143; HR, 4.06 (95% CI, 3.09 to 5.35); p<0.0001
Waist circumference >88 cm: 138 vs. 189; HR, 3.57 (95% CI, 2.90 to 4.39); p<0.0001
Change in waist circumference from baseline to year 1 of >2.0 cm: 59 vs. 78; HR, 1.31 (95% CI, 1.04 to 1.65); p=0.020
Bonds, 2006;43 The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial.
Estrogen only trial
Excluded women with self-reported diabetes at baseline:
9,712 Eligible from WHI
4,806 Estrogen
4,906 Placebo
Incidence of new diabetes diagnosis
Current smoker: 31 (0.6%) vs. 59 (1.2%); HR, 0.54 (95% CI, 0.35 to 0.84); p=0.02

Abbreviations: BMI=body mass index; CI=confidence interval; HERS=Heart and Estrogen/Progestin Replacement Study; HERS II=Heart and Estrogen/Progestin Replacement Study Phase II; HR=hazard ratio; ITT=intention-to-treat; NSAID=nonsteroidal anti-inflammatory drug; RR=relative risk; WHI=Women’s Health Initiative; WISDOM=Women’s International Study of Long-Duration Oestrogen After Menopause.

From: Appendix C, Evidence and Quality Tables

Cover of Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions
Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Systematic Review to Update the 2002 and 2005 U.S. Preventive Services Task Force Recommendations.
Evidence Syntheses, No. 93.
Nelson HD, Walker M, Zakher B, et al.

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