Uncertain but Determined Let’s talk about WHO, WHI and WHY

Peter van de Weijer MD PHD

The Netherlands

1

March

2005

Hongkong

CliniciansWome

n

© PHMvdW 2005

Health care for Women

Researchers

Not an issue for just one group

Policy makers

Healthcare industry

Health EducatorsEpidemiologists

Healthcare administrators

Nurses

Clinician Women

© PHMvdW 2005

Provide

Medical Practice

relationship

ongoing personal

Experience

Health care for Women

health care

Medical Knowledge , based on the best available evidence

• to understand and evaluate research findings• to apply “true” research evidence to clinical practice

The need to be taken care of

• tto communicate about evidence, risks and benefits

1960 Symptom relief – preservation of “youth”

© PHMvdW 2005

History

1970

1980

Unopposed estrogen - endometrial cancer

Prevention of osteoporosis ; coronary heart disease ; Alzheimer’s disease

Progestins eliminate risk endometrial cancer

1993 Women’s Health Initiative to evaluate putative protective effects of HT on chronic diseases of aging

National Institutes of Health 700 million dollar – public

funding

Women’s Health Initiative (WHI) Study Outline

Examination of long-term strategies for the prevention of morbidity and mortality in postmenopausal women.

The WHI program includes 4 clinical studiesmore than 100.000 women participating

1) Effects of PremPro® (0.625mg CEE/2.5mg MPA) on CHD

2) Effects of Premarin® (0.625 mg CEE) on CHD

3) Effects of a low-fat and high-fiber diet

4) Effects of vitamin D + calcium

To Understand and Evaluate Research Findings

CHD: Coronary Heart Disease

12-year duration

Women’s Health Initiative (WHI) Study Outline

To Understand and Evaluate Research Findings

Two large, randomized, placebo-controlled clinical trials planned duration 8.5 years.

Prempro® (0.625 mg CEE, 2.5 mg MPA) vs. placebo– 16,608 women– 50-79 years of age (mean age 63.2 years)

Premarin® (0.625 mg CEE) vs. placebo– 10,739 women with prior hysterectomy,– 50-79 years of age (mean age 63.6 years)

Outcomes

Primary outcome Coronary heart diseases (CHD)

non-fatal myocardial infarction and CHD death

Secondary outcome Stroke, Venous Thromboembolism, Colorectal Cancer,

Osteoporosis-related fractures, all-cause Mortality

Primary adverse outcome Invasive breast cancer

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

I. Study design and level of evidence

II. Results ; Absolute risks

IV. Population studied similar to your practice population

III. Time of initiation of therapy and duration

V. Decision analysis based on all health outcomes

To Understand and Evaluate Research Findings

Observation

Estimation

Hypothesis

TestRandomised double blind

placebo controlled

Test does not support hypothesis

Test does support hypothesis

revise

Observational studies

RCT

MWS

WHI

© PHMvdW 2005

Clinical research

HERS

NHS

Types of Studies Used in Investigating HT

Observational studies

Studies in defined groups of the population.

They observe factors determining and influencing the

frequency (incidence) and distribution of health-related

events.

Observed factors are instrumental in defining endpoints

for further randomised clinical studies.

Only RR > 3 are probably causational; RR: 1-2 attributable to bias

Nurses’ Health Study (NHS); Million Women Study

Types of Studies Used in Investigating HT

Randomised controlled trials

Studies on individuals

to evaluate the efficacy of HT in comparison with a control group (e.g. vs. placebo).

Women’s Health Initiative (WHI)

Heart and Estrogen/Progestogen Replacement Study (HERS)

Description of the levels of evidence

Level I properly randomized, controlled trial

Level II-1 well-designed controlled trial, no randomization

Level II-2 well-designed cohort or case-control analytic studypreferably from more than one centre or group

Level II-3 Multiple time series with or without the intervention (cross-sectional, uncontrolled investigational )

Level III Opinions of respected authorities that are based on clinical experience, reports from expert

committees

Report of the US Preventive Services Task Force. Guide to Cinician Preventive Services2nd edition Baltimore Williams & Wilkins 1996

Research findings

© PHMvdW 2005

FDA

Level III

Women’s Health Initiative

HERS

Level II-2

Level II-3

Level II-1

Level I

Nurses Health Study

Million Women Study

Expert opinion / reviews / NAMS position papers / meta-analysis

HERS II

Research findings level of evidence

© PHMvdW 2005

Women’s Health Initiative (WHI) Results

To Understand and Evaluate Research Findings Level I

© PHMvdW 2005

Placebo CEE MPA RR 95% CI

Breastcancer 33 41 1.26 1.00-1.59 4 Chlebowski JAMA 2003;289:3243-53

CHD 33 39 1.24 1.00-1.54 3 Manson N Engl J Med 2003;349:523-9

Stroke 24 31 1.44 1.09-1.90 4 Rossouw JAMA 2002;288:321-333

Deep Ven Thr 13 26 2.11 1.58-2.82 9 Rossouw JAMA 2002

Coloncancer 16 10 0.63 0.43-0.92 -3 Rossouw JAMA 2002

Endom. Cancer 6.9 5.6 0.81 0.48-1.36 -0,7 Anderson JAMA 2003;290:1739-48

Ovarian Cancer 2.7 4.2 1.58 0.77-3.24 0,8 Anderson JAMA 2003

Hipfracture 16 11 0.67 0.47-0.96 -2,5 Cauley JAMA 2003;290:1729-38

Tot fractures 199 152 0.76 0.69-0.83 -23,5 Cauley JAMA 2003

Tot Mortality 53 52 0.98 0.82-1.18 -0,5 Rossouw JAMA 2002

Absolute riskN / 10000 /yr

Relative risk ReferenceCEE /MPA

extra 5 yrs risk

per 1000 women

Women’s Health Initiative (WHI) Results

To Understand and Evaluate Research Findings Level I

© PHMvdW 2005

Placebo CEE MPA

Breastcancer 33 41 4

CHD 33 39 3

Stroke 24 31 4

Deep Ven Thr 13 26 9

Coloncancer 16 10 -3

Endom. Cancer 6.9 5.6 -0,7Ovarian

Cancer 2.7 4.2 0,8

Hipfracture 16 11 -2,5

Tot fractures 199 152 -23,5

Tot Mortality 53 52 -0,5

Absolute riskN / 10000 /yr

CEE /MPAextra 5 yrs risk

per 1000 women

HT should not be started or continued for

Primary prevention of CHD

Secundary prevention of CHD

HT for the treatment of osteoporosis

will require balancing risks and benefits including

Risks and benefits of alternatives to HT

Women’s Health Initiative (WHI) Results

To Understand and Evaluate Research Findings Level I

© PHMvdW 2005

Placebo CEE MPA RR 95% CI

Breastcancer 33 26 0.77 0.59-1.01 -3.5 WHI Steering JAMA 2004;291:1701-12

CHD 54 49 0.91 0.75-1.12 -2,5 WHI Steering JAMA 2004

Stroke 32 44 1.39 1.10-1.77 6 WHI Steering JAMA 2004

Deep Ven Thr 21 28 1.33 0.99-1.79 3,5 WHI Steering JAMA 2004

Coloncancer 16 17 1.08 0.75-1.55 0.5 WHI Steering JAMA 2004

Endom. Cancer

Ovarian Cancer

Hipfracture 17 11 0.61 0.41-0.91 -3 WHI Steering JAMA 2004

Tot fractures 195 139 0.70 0.63-0.79 -28 WHI Steering JAMA 2004

Tot Mortality 78 81 1.04 0.88-1.22 1,5 WHI Steering JAMA 2004

Absolute riskN / 10000 /yr

Relative risk ReferenceCEE extra 5 yrs risk

per 1000 women

Women’s Health Initiative (WHI) Results

To Understand and Evaluate Research Findings Level I

© PHMvdW 2005

Placebo CEE MPA RR 95% CI

Breastcancer 33 26 0.77 0.59-1.01 -3.5 WHI Steering JAMA 2004;291:1701-12

CHD 54 49 0.91 0.75-1.12 -2,5 WHI Steering JAMA 2004

Stroke 32 44 1.39 1.10-1.77 6 WHI Steering JAMA 2004

Deep Ven Thr 21 28 1.33 0.99-1.79 3,5 WHI Steering JAMA 2004

Coloncancer 16 17 1.08 0.75-1.55 0.5 WHI Steering JAMA 2004

Endom. Cancer

Ovarian Cancer

Hipfracture 17 11 0.61 0.41-0.91 -3 WHI Steering JAMA 2004

Tot fractures 195 139 0.70 0.63-0.79 -28 WHI Steering JAMA 2004

Tot Mortality 78 81 1.04 0.88-1.22 1,5 WHI Steering JAMA 2004

Absolute riskN / 10000 /yr

Relative risk ReferenceCEE extra 5 yrs risk

per 1000 women

HT should not be started or continued for

Primary prevention of CHD

Secundary prevention of CHD

HT for the treatment of osteoporosis

will require balancing risks and benefits including

Risks and benefits of alternatives to HT

Low dose therapy less risk

for stroke and DVT

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

I. Study design and level of evidence

II. Results ; Absolute risks

To Understand and Evaluate Research Findings

Absolute risks are relevant for general practice

Risk factor Accounts for …percent

of breastcancer

ModifiableRisk factor ?

Age (increasing) 70% -80% No

Familial (multiple genetic/environmental factors)

15%-20% Possible

Herediatary Predisposition (single gene mutation)

5% - 10% No

BREAST CANCER

ACOG Bulletin Breastcancer Obstet Gynecol 2004: 104; 11-16

© PHMvdW 2005

Most of the recognized risk factors for breastcancer

are not modifiable

Risk factor Accounts for …percent

of breastcancer

ModifiableRisk factor ?

Age (increasing) 70% -80% No

Familial (multiple genetic/environmental factors)

15%-20% Possible

Herediatary Predisposition (single gene mutation)

5% - 10% No

BREAST CANCER

ACOG Bulletin Breastcancer Obstet Gynecol 2004: 104; 11-16© PHMvdW 2005

Risk factor Relative risk Modifiable ?

Age at menarche 14 yrs vs 11 yrs 1 : 1.3 No

Parity multiparous : nulliparous

1 : 1.3 possible

Age at first birth 20 yrs vs 30 yrs 1 : 1.5 possible

Age at menopause 42 yrs vs 52 yrs 1 : 2.0 possible

Body weight normal weight : obesity

1 : 1.5 yes

Serum lipids normal vs raised 1 : 1.6 yes

Antibiotic use never vs 1-50 days/life

1 : 1.5 yes

Alcohol consumption none vs ≥20 g daily 1 : 1.3 yes

Hormone Therapy none vs CEE/MPA/5yrs

1 : 1.3 yes

Physical Activity active vs non-active 1 : 1.2 yes

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

E+P 8506 8378 8277 8150 7000 4234 2064 801

P 8102 8037 7891 7772 6819 3922 1740 523

Writing Group for the WHI Investigators.

JAMA. 2002;288:321-33

Previous HRT cc-HT Placebo

Never 73,9 % 74,4 %

Past 19,7 % 19,6 %

RR 1.26

95% CI 1.01-1.54

53 yr

124

166

Chlebowski et al

JAMA 2003;289:3243-53

cumulative number of BrCA

0

50

100

150

200

250

1 2 3 4 5 >5

year of treatment

E+Pplacebo

No extra increase in breastcancer

the first 4-5 yrs of first time

CEE / MPA use

© PHMvdW 2005

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

Lesson

No extra increase in breastcancer

the first 4-5 yrs of first CEE / MPA use

started after the age of 50 years

Level I

Evidence

Time of initiation of treatmentDuration of therapy

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

I. Study design and level of evidence

II. Results ; Absolute risks

To Understand and Evaluate Research Findings

Absolute risks are relevant for general practice

Time of initiation of therapy and duration

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

I. Study design and level of evidence

II. Results , Absolute risks

III. Time of initiation of therapy and duration

“Study findings indicate that combined HT is associated with an increased

risk of breast cancer. Women considering HT should be counseled that

the absolute risk of breastcancer for any individual remains relatively low“

ACOG Breastcancer Obstet Gynecol 2004;104: 11-16

To Understand and Evaluate Research Findings

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

Applicability to general practice

I. Study design and level of evidence

II. Results; Absolute risks

IV. Population studied similar to your practice population

III. Time of initiation of therapy and duration

To Understand and Evaluate Research Findings

Women’s Health Initiative (WHI)Study Population

Mean age at recruitment: 63 years

Past or current smokers: 50%

Women treated for hypertension: 36-48%

Women on lipid lowering medications: 13-15%

BMI > 25: 70-79%

Women treated for diabetes: 4-8%

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

I. Study design and level of evidence

II. Results; Absolute risks

IV. Population studied similar to your practice population

III. Time of initiation of therapy and duration

V. Decision analysis based on all health outcomes

To Understand and Evaluate Research Findings

Fisher WA et al. Maturitas 2000 ; 37 : 1-14

© PHMvdW 2005

Decision analysis based on all health outcomes

Global index

Coronary heart disease

Stroke

Pulmonary embolism

Breastcancer

Colorectal cancer

Hip-fracture

Death

Prevention

CEE + MPA

CEE

10 serious adverse events

for every 10000 women

using HT for 1 year 1

2 serious adverse events

for every 10000 women

using HT for 1 year 2

NS

NS

1. Grady D. N Engl J Med 2003; 348:1835-7 (level III)

2. Anderson GL et al. JAMA 2004;291:1701-12 (level I)

3. Col et al. Arch Intern Med 2004;164: 1634-40 (decision analysis)

Symptomatic 3

Asymptomatic / HT 2 yrs

Quality adjusted life expectancy

Mild symptoms / HT 2 yrs

Severe symptoms / HT 2 yrs

- 1-3 months

+ 3 - 4 months

+ 7 -8 months

Clinician Women

© PHMvdW 2005

Health care for Women

Provide

Medical Practice

The need to be taken care of

relationship

ongoing personal

health care

45 yrs 50 55 yrs

Fertility

Menstrual cycle problems

Flushes / night sweats

Urogenital atrophy

OsteoporosisDiabetes CVD

Contraception

PMS

Pre

Arthritis

CarcinomaBreast Colon

Ovarian Cervical

Perimenopause Post

EyesightHearing

?

?

Climacteric Medicine

UterineBleeding

© PHMvdW 2004

Cognitivefunction

» Strength

Menopause

45 yrs 50 55 yrs

Menstrual cycle problems

Flushes / night sweats

Pre Perimenopause Post

Climacteric Medicine

© PHMvdW 2004

Menopause

HT

No randomised trials for risks

Progestagens

No risk demonstrated

OC

No randomised trials

No change in practice necessary

45 yrs 50 55 yrs

Flushes / night sweats

Pre Perimenopause Post

Climacteric Medicine

© PHMvdW 2004

Menopause

First 5 yrs HT use

No increase for Br Ca

QALY > Symptomatic

No change in practice necessary No change in practice necessary

45 yrs 50 55 yrs

Pre Perimenopause Post

Climacteric Medicine

© PHMvdW 2004

Menopause

HT should not be started or continued for

Primary prevention of CHD

Secundary prevention of CHD

HT for the treatment of

osteoporosis

will require balancing risks and benefits including

Risks and benefits of alternatives to HT

Menopause

45 yrs 50 yrs 55 yrs

Menstrual cycle problemsBleeding problems

Flushes Night sweats

Urogenital atrophy

DUPHASTON ® 10 / 20

FEMOSTON ® 1 / 10

FEMOSTON ® 1 / 5

Low dose

for

estrogens

Proper dose

for

progestagens

Clinician Women

© PHMvdW 2004

Health care for Women

Medical Practice

relationship

ongoing personal

The Art of Medicine the unique combination of

ExperienceMedical Knowledge Intuition

Judgment Communication

Curiosity Compassion

EpidemiologistsHealth care industry PolicymakersAdministrators Researchers