Approaches to assessing risks & benefits: Lessons from postmenopausal hormone therapy studies
description
Transcript of Approaches to assessing risks & benefits: Lessons from postmenopausal hormone therapy studies
Presented byJudith Hsia, M.D.
at the December 2, 2004
meeting of theAdvisory Committee for Reproductive
Health Drugs
Approaches to assessing risks & benefits: Lessons from
postmenopausal hormone therapy studies
• Biomarkers
• Observational studies
• Randomized trials
• Intermediate outcomes
Change in Lipids After Menopause
90
100
110
-24 6-18 -12 -6 0
% o
f le
vel a
t -6
mon
ths
befo
re m
enop
aus
e
Jensen J et al. Maturitas 1990;12:321-31.
Total Cholesterol
90
100
110
-24 6-18 -12 -6 0
HDL-C
Months
90
100
110
-24 6-18 -12 -6 0
% o
f le
vel a
t -6
mon
ths
befo
re m
enop
aus
e
LDL-C
Months
90
100
110
-24 6-18 -12 -6 0
Triglycerides
Estrogen + Progestin and Intermediate Outcomes (% change, E+P minus Placebo)
Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides Glucose Insulin
Systolic BP Diastolic BP Weight Waist Circumference
Waist-to-Hip Ratio
% Change from Baseline (E+P minus Placebo)
*-2.5
*-12.7
7.3*
6.9*
*-5.4
-7.1
0.9*
-0.1
*-0.4
*-0.9
-0.2
Year 1 minus baseline (95% CI)
Legend% change, E+P minus placebo
*p <0.05
NEJM 2003;349:523-34
Observational Studies with Estrogen +Progestin
Relative Risk
Breast cancer
<5y
>5y
1.15
1.53
Hip fracture 0.75 (0.68-0.84)
Stroke 1.45 (1.10-1.92)
Pulmonary embolism 2.1 (1.2-3.8)
Coronary heart disease 0.61 (0.45-0.82)
NEJM 2003;248:7
Stroke?
Coronary Artery DiseaseBreast Cancer
Risk Benefit
Plan to follow to 2005 (average 8.5 years)
Additional Benefits:• Bone (Hip) Fractures• Overall Mortality
Additional Risks:• VTE (PE, DVT)
WHI Hormone Program: Baseline Hypotheses
Initiated screening (N = 373,092)
Women who had no uterus at start of study
N= 10,739
Women who had a uterus at
start of study
N= 16,608
CEE+daily MPA PlaceboCEE Placebo
Women’s Health Initiative Hormone Trials
WHI: Clinical outcomes in the Estrogen Plus Progestin Trial
Outcome E+P
RRNominal95% CI
Coronary Heart Disease 1.24 1.00-1.54
Strokes 1.31 1.02-1.68
Venous thromboembolism 2.11 1.58-2.82
Breast cancer 1.24 1.02-1.50
Colorectal cancer 0.61 0.42-0.87
Hip fractures 0.67 0.47-0.96
Dementia 2.05 1.21-3.48
Various WHI papers
WHI E+P: Absolute risk or benefitE
vent
s pe
r 10
,000
wom
an-y
ears
0
10
20
30
40
50
60
CHD
Stroke
VTE
Breast
ca
Colon ca
Hip F
x
Dementia
Placebo
Active
24% Increase Breast Cancer
Also: DVTs
Fracture Reduction (Hip 23%)
STOPPED Early, Clear Harm
Threshold Level
24% Increase CHD31% Increase
Stroke
RisksBenefits
JAMA. 2002;288:321-333
Stopped 3.3 yrs early
111% Increase Pulmonary Emboli
39% Reduction Colorectal Cancer
WHI E+P Trial Findings, July 2002 (avg 5.2 y)
105% Increase Dementia
Observational Study vs Randomized Trial Results
Observational
Studies
Breast cancer
<5y
>5y
1.15
1.53
Hip fracture 0.75 (0.68-0.84)
Stroke 1.45 (1.10-1.92)
Pulmonary embolism 2.1 (1.2-3.8)
Coronary heart disease 0.61 (0.45-0.82)NEJM 2003;248:7
WHI E+P
1.24 (1.02-1.50)
0.67 (0.47-0.96)
1.31 (1.02-1.68)
2.13 (1.45-3.11)
1.24 (1.00-1.54)Various WHI papers
Possible explanations
• Confounding due to “healthy user” effect
• Compliance bias – women adherent to hormones may also adhere to other healthful behaviors
• Outcomes identification bias
• Incomplete capture of early clinical events
NEJM 2003;348:7
CEE vs CEE+MPA
WHI: Relative risk or benefit
Outcome E+P E Alone
RR Nominal95% CI RR Nominal
95% CI
Coronary Heart Disease
1.24 1.00-1.54 0.91 0.75-1.12
Strokes 1.31 1.02-1.68 1.39 1.10-1.77
Venous thrombo-embolism
2.11 1.58-2.82 1.33 0.99-1.79
Breast cancer 1.24 1.02-1.50 0.77 0.59-1.01
Colorectal cancer 0.61 0.42-0.87 1.08 0.75-1.55
Hip fractures 0.67 0.47-0.96 0.61 0.41-0.91
Dementia 2.05 1.21-3.48 1.49 0.83-2.66
JAMA 2004;291:1701-12
JAMA 2004;291:2947-58 Various WHI papers
WHI: Absolute risk or benefitE
vent
s pe
r 10
,000
wom
an-y
ears
E Alone
E+P
0
10
20
30
40
50
60
Placebo
Active
0
10
20
30
40
50
60
CHD
Stroke
VTE
Breast
ca
Colon ca
Hip F
x
Dementia
Placebo
Active
Also: DVTs
Fracture Reduction (Hip 39%)
STOPPED Early, suggestion of harm
Threshold Level
Neutral for CHDNeutral for breast cancer
39% Increase Stroke
Risks
Benefits
JAMA 2004;291:2947-58
Stopped 1.7 yrs early
34% Increase Pulmonary Emboli
WHI E Alone Trial Findings, 2/04 (avg 6.8 y)
49% Increase Dementia
Impact of added androgen may be difficult to predict
Intermediate Outcomes
Estrogen Trials with Intermediate Outcomes
• Coronary angiography – 3 randomized trials demonstrated no benefit (or harm) with PHT
• Carotid ultrasound – 1 randomized trial demonstrated benefit with estradiol
• Coronary calcification – no trial data
NEJM 2000;343:522JAMA 2002;288:2432NEJM 2003;349:535 Ann Intern Med 2001;135:939
Approaches to evaluating risk
• Biomarkers – mixed picture; may not be predictive• Observational studies – subject to bias &
confounding; suitable cohorts may not be available• Randomized trials with intermediate outcomes –
potentially useful• Randomized trials with clinical outcome – long &
expensive