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 Progestins protect uterus E associated with lower CHD E associated with fewer fractures; higher BMD E associated with higher breast cancer Observational Studies suggest Benefits > Risks 1942: FDA approved Estrogen for treatment of menopausal symptoms CEE in men: blood clots, heart attacks E associated with uterine cancer “Feminine forever” Prescriptions (Millions) 1997: HERS- E+P blood clots 1998: HERS 1 st yr, more heart attacks; 4yr, no benefit 2001: AHA position OCs associated with blood clots, heart attacks 2000: Br CA E+P > E only 1995: PEPI E vs E+P 1996 E+P lower CHD

Increasing Role of Hormones for Preventing Diseases of Aging in Women (e.g. Coronary Heart Disease, Fractures) 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 Sources of Evidence at Outset of WHI (1991)

Risk for Coronary Heart Disease: Estrogen Users vs. Nonusers Barrett-Connor. Annu Rev Public Health. 1998;19: Cohort Studies Grodstein, 1996 Falkeborn, 1992 Wolf, 1991 Henderson, 1991 Sullivan, 1990 Avila, 1990 Criqui, 1988 Petitti, 1987 Bush, 1987 Wilson, 1985 Stampfer, 1985 Angiographic Studies McFarland, 1989 Sullivan, 1988 Gruchow, 1988 Case-Control Studies Mann, 1994 Rosenberg, 1993 Croft, 1989 Beard, 1989 Szklo, 1984 Ross, 1981 Bain, 1981 Adam, 1981 Rosenberg, 1980 Pfeffer, 1978 Talbott, 1977 Rosenberg, 1976 Summary Relative Risk Relative Risk

Risk for Coronary Heart Disease: Estrogen+Progestin Users vs Nonusers Case-Control Studies Relative Risk Psaty, 1994 Mann, 1994 Rosenberg, 1993 Thompson, 1989 Cohort Studies Grodstein, 1996 Falkeborn, 1992 Clinical Trial Nachtigal, 1979 Summary Relative Risk Barrett-Connor. Annu Rev Public Health. 1998;19:55-72.

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

Hormone Trials: Secondary CVD prevention TrialTreatment No.EndpointOutcome HERS CEE + MPA 2763CHDNo benefit; early harm ERA CEE ±MPA 309AngiogramNo benefit WEST 17b-estradiol 664StrokeNo benefit; early harm PHASE transdermal225CHDNo benefit; possible harm estradiol + NETA WAVE CEE ±MPA 423 Angiogram No benefit; possible harm ± Vitamins HERS-II CEE+MPA 2321CHDNo benefit WELL-HART 17b-estradiol 226Angiogram No benefit ±MPA

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

NHBI Survey % 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

Choice of Drug and Dose Conjugated equine estrogens (Premarin) 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 days/cycle –later 2.5 mg daily (Prempro) Most epidemiologic data on CHD risk reduction in PHT users based on use of Premarin mg Data on combination therapy and CHD emerged later; consistent with estrogen-only data but not specific to Prempro

Study Population Postmenopausal Age Minority women Liberal inclusion/exclusion criteria –BMI –CVD risk factors –CVD –Hormone use

WHI HT: Baseline Body Mass Index (kg/m 2 ) Normal OverweightObese IObese IIObese III Mean BMI: 28.5 ± 5.9 % Overweight+Obese: 69.4% BMI (kg/m 2 )

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

Womens’ Health Initiative (WHI): CV Risk Factors at Enrollment l Mean age: 63.3 years (range: 50-79) l Current smoker 10.5% l Diabetic 4.4% l Hypertension35.7% l Hyperlipidemia12.5% l Statin Use 6.9% l ASA Use19.1% l Prior CVD History 6.2% Writing Group for the Women’s Health Initiative. JAMA. 2002;288:

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

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

Future Directions Post-trial surveillance for clinical events –E+P –E alone 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 –Open to other mechanisms of funding