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