Risks and benefits of estrogen plus progestin

1
National Institutesof Health National Heart,
Lung, and Blood Institute Womens Health
Initiative (WHI) Clinical Trials (Diet,
Hormones, Calcium/Vit D) and Observational
Study Conducted at 40 Clinical Centers
Coordinating Center
2
A Brief History of Hormone Therapy
Observational Studies suggest Benefits gt Risks
1942 FDA approved Estrogen for treatment of
menopausal symptoms
E associated with fewer fractures higher BMD
OCs associated with blood clots, heart attacks
E associated with lower CHD
E associated with higher breast cancer
E associated with uterine cancer
Feminine forever
2000 Br CA EP gt E only
Progestins protect uterus
CEE in men blood clots, heart attacks
1995 PEPI E vs EP
1996 EP lower CHD
1997 HERS- EP blood clots 1998 HERS 1st yr,
more heart attacks 4yr, no benefit 2001 AHA
position
Prescriptions (Millions)
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Increasing Role of Hormones for Preventing
Diseases of Aging in Women(e.g. Coronary Heart
Disease, Fractures)
Sources of Evidence at Outset of WHI (1991)

• Biological effects (surrogate markers, e.g.
  lipids, bone density)
• Animal models
• Epidemiological studies, e.g. case-control
  (retrospective) and cohort (prospective)
• But no adequate clinical trials with disease
  endpoints

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Risk for Coronary Heart Disease Estrogen Users
vs. Nonusers
Cohort StudiesGrodstein, 1996Falkeborn,
1992Wolf, 1991Henderson, 1991Sullivan,
1990Avila, 1990Criqui, 1988Petitti, 1987Bush,
1987 Wilson, 1985 Stampfer, 1985Angiographic
StudiesMcFarland, 1989Sullivan, 1988Gruchow,
1988Case-Control StudiesMann, 1994Rosenberg,
1993Croft, 1989Beard, 1989Szklo, 1984Ross,
1981Bain, 1981Adam, 1981Rosenberg,
1980Pfeffer, 1978Talbott, 1977Rosenberg,
1976Summary Relative Risk
1
0.1
10
0.01
Relative Risk
Barrett-Connor. Annu Rev Public Health.
19981955-72.
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Risk for Coronary Heart Disease
EstrogenProgestin Users vs Nonusers
Case-Control Studies
Psaty, 1994
Mann, 1994
Rosenberg, 1993
Thompson, 1989
Cohort Studies
Grodstein, 1996
Falkeborn, 1992
Clinical Trial
Nachtigal, 1979
Summary Relative Risk
0.1
10
1
0.01
Relative Risk
Barrett-Connor. Annu Rev Public Health.
19981955-72.
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Known Biases in Observational Studies

• Women who use hormones over an extended time
  differ from those who dont, in many ways besides
  HT use. Compared to non-users, estrogen users
  are generally
• Differences could explain why hormone users
  appear to have a lower CHD risk

• less obese, less likely to smoke, less likely
  to consume diet high in fat and salt, more
  physically active, more highly educated
• more likely to go to doctors regularly
• have cholesterol, BP, etc. monitored
• have mammograms other screening
• more compliant
• be successful users

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Hormone Trials Secondary CVD prevention

• Trial Treatment No. Endpoint Outcome
• HERS CEE MPA 2763 CHD No benefit early
  harm
• ERA CEE MPA 309 Angiogram No
  benefit
• WEST 17b-estradiol 664 Stroke No benefit
  early harm
• PHASE transdermal 225 CHD No benefit possible
  harm
• estradiol
• NETA
• WAVE CEE MPA 423 Angiogram No benefit
  possible harm
• Vitamins
• HERS-II CEEMPA 2321 CHD No benefit
• WELL-HART 17b-estradiol 226 Angiogram No benefit
  
• MPA

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Need for WHI

• NHLBI planning for hormone trial started in
  mid-80s
• HT regarded as promising but unproven
  intervention to prevent CHD
• Increasing use, by millions of healthy older
  women
• Benefits and risks unknown
• Need for rigorous clinical trials
• PEPI trial of intermediate outcomes 1988
• HERS for secondary prevention 1991
• WHI for primary prevention 1991

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NHBI Survey 1995

• 82 of cardiologists, internists, family doctors,
  and general practitioners prescribe hormone
  therapy (HT)
• Of those who prescribe HT
• 93 for menopausal symptoms
• 91 for osteoporosis
• 41 for high blood cholesterol
• 66 for coronary heart disease prevention

Source NHLBI Press Conference, December 4, 1995
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Choice of Drug and Dose

• Conjugated equine estrogens (Premarin) 0.625
  mg/day more commonly prescribed PHT in U.S.
• In women with uterus medroxyprogesterone acetate
  most commonly prescribed added progestin to
  prevent endometrial cancer
• initially 10-12 days/cycle
• later 2.5 mg daily (Prempro)
• Most epidemiologic data on CHD risk reduction in
  PHT users based on use of Premarin 0.625 mg
• Data on combination therapy and CHD emerged
  later consistent with estrogen-only data but not
  specific to Prempro

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Study Population

• Postmenopausal
• Age 50-79
• Minority women
• Liberal inclusion/exclusion criteria
• BMI
• CVD risk factors
• CVD
• Hormone use

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WHI HT Baseline Body Mass Index (kg/m2)
Mean BMI 28.5 5.9 OverweightObese 69.4
BMI (kg/m2 )
Overweight
Obese I
Obese II
Obese III
Normal
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WHI E P Trial Baseline Age Prior Hormone Use
n12,304 (74.1)
n7510 (45.2)
n5522 (33.3)
of Enrolled Population
n3576 (21.5)
n3262 (19.6)
n1035 (6.2)
Age (yrs)
Hormone Use Prior to Study Entry
Writing Group for the Womens Health Initiative.
JAMA. 2002288321-333.
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Womens Health Initiative (WHI) CV Risk Factors
at Enrollment

• Mean age 63.3 years (range 50-79)
• Current smoker 10.5
• Diabetic 4.4
• Hypertension 35.7
• Hyperlipidemia 12.5
• Statin Use 6.9
• ASA Use 19.1
• Prior CVD History 6.2

Writing Group for the Womens Health Initiative.
JAMA. 2002288321-333.
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Future Directions

• EP Publications
• Detailed analysis of breast cancer by prior use
• Overview of major findings
• E alone trial
• Planned termination 2005

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Future Directions

• EP Case-Control Lab Analyses
• CHD, stroke, VT baseline and 1 year lipids,
  coags, inflammation, other biomarkers, allelic
  variations
• Fractures baseline estradiol, SHBG, markers of
  bone turnover, allelic variations in genes
  related to estrogen metabolism
• Breast cancer baseline estradiol, testosterone,
  SHBG, allelic variations in genes related to
  estrogen and progestin metabolism

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Future Directions

• Post-trial surveillance for clinical events
• EP 2002-2007
• E alone 2005-2007
• Further laboratory and data analysis
• Cohort of 160,000 participants in 3 clinical
  trials and observational study (citrate, EDTA,
  serum, DNA, urine)
• WHI and other investigators and entities
• Broad Agency Announcement in 2005, funding
  2006-2010
• Open to other mechanisms of funding