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National Institutes of Health National Heart, Lung, and Blood Institute Women’s Health Initiative (WHI) Clinical Trials

National Institutes of Health National Heart, Lung, and Blood Institute Women’s Health Initiative (WHI) Clinical Trials (Diet, Hormones, Calcium/Vit D) and Observational Study Conducted at 40 Clinical Centers + Coordinating Center. A Brief History of Hormone Therapy.

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National Institutes of Health National Heart, Lung, and Blood Institute Women’s Health Initiative (WHI) Clinical Trials

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  1. National Institutesof Health National Heart, Lung, and Blood Institute Women’s 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 > Risks 1942: FDA approved Estrogen for treatment of menopausal symptoms E associated withfewer fractures; higher BMD OCs associated with blood clots, heart attacks E associated with lower CHD E associated with higher breast cancer Eassociated withuterine cancer “Feminine forever” 2000: Br CA E+P > E only Progestins protect uterus CEE in men: blood clots, heart attacks 1995: PEPIE vs E+P 1996 E+P lower CHD 1997: HERS- E+P blood clots 1998: HERS 1st yr, more heart attacks; 4yr, no benefit 2001: AHA position Prescriptions (Millions)

  3. 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

  4. 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. 1998;19:55-72.

  5. Risk for Coronary Heart Disease: Estrogen+Progestin 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 1 10 0.01 Relative Risk Barrett-Connor. Annu Rev Public Health. 1998;19:55-72.

  6. Known Biases in Observational Studies • Women who use hormones over an extended time differ from those who don’t, 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

  7. 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 423AngiogramNo benefit; possible harm ± Vitamins HERS-IICEE+MPA 2321 CHD No benefit WELL-HART 17b-estradiol 226 Angiogram No benefit ±MPA

  8. 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

  9. 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

  10. 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

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

  12. WHI HT: Baseline Body Mass Index (kg/m2) Mean BMI: 28.5± 5.9 % Overweight+Obese: 69.4% BMI (kg/m2 ) Overweight Obese I Obese II Obese III Normal

  13. WHI E +P Trial:Baseline Age & Prior Hormone Use n=12,304 (74.1%) n=7510 (45.2%) n=5522 (33.3%) % of Enrolled Population n=3576 (21.5%) n=3262 (19.6%) n=1035 (6.2%) Age (yrs) Hormone Use Prior to Study Entry Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.

  14. 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 Women’s Health Initiative. JAMA. 2002;288:321-333.

  15. Future Directions • E+P Publications • Detailed analysis of breast cancer by prior use • Overview of major findings • E alone trial • Planned termination 2005

  16. Future Directions • E+P 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

  17. Future Directions • Post-trial surveillance for clinical events • E+P 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

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