Clinical Trial Commentary

1. Clinical Trial Commentary HERS, ERA and WHI: Recent trials in hormone replacement therapy Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

2. Women’s Health Initiative (WHI) Estrogen Replacement and Atherosclerosis (ERA) Heart and Estrogen/Progestin Replacement Study (HERS) Postmenopausal Estrogen/Progestin Interventions trial (PEPI) • Recent trials in hormone replacement therapy (HRT)

3. 309 postmenopausal women with established coronary disease (defined as 1 or more stenosis of < 30%) randomized to: 0.625 mg/d conjugated equine estrogen (CEE), or CEE plus medroxyprogesterone acetate 2.5 mg/d, versus placebo. Primary outcome was within subject mean minimum lumen diameter (MLD) measured by quantitative coronary angiography. At the end of 3.2 years, angiographic follow up was available for 248 women. • Estrogen Replacement and Atherosclerosis (ERA) David Herrington MD, et al. Wake Forest University, Winston-Salem, NC

4. Estrogen Replacement and Atherosclerosis (ERA) • After 3.2 years, it was found that neither estrogen nor estrogen plus progesterone had any effect on the progression of coronary artery disease as measured by quantitative angiography. • Women in the treatment arms showed significant reductions in LDL cholesterol (9-16%) and significant increases in HDL cholesterol (12-14%) over placebo. • There was a trend toward a greater incidence of deep venous thrombosis and pulmonary embolism in the treated groups (p=0.16). • Although not pre-defined as outcomes, no significant differences were noted in clinical endpoints.

5. Postmenopausal Estrogen, Progestin Interventions (PEPI) • 875 women were randomized to CEE (unopposed or combined with continuous or cyclic medroxyprogesterone), CEE plus micronized progesterone, or placebo. • All estrogen regimens decreased LDL cholesterol, raised HDL cholesterol, and raised triglycerides. • From these surrogate endpoints, researchers concluded the best regimen for women without a uterus was likely to be unopposed CEE, and for those with a uterus, CEE plus micronized progesterone. • More definitive conclusions awaited results of randomized trials with clinical endpoints. Writing group for the PEPI Trial. [published correction appears in JAMA 1995;274:1676]. JAMA 1995;273:199-208

6. Heart and Estrogen/Progestin Replacement Study (HERS) • A total of 2763 women under the age of 80 with documented CHD and an intact uterus were randomized to receive either 0.625 mg/d of CEE plus 2.5 mg medroxyprogesterone acetate or placebo. • After an average of 4.1 years of follow-up, no significant differences were seen in primary or secondary cardiovascular endpoints. • More CHD events occurred in the treated group compared to placebo at 1 year, with fewer events in the treated group over 4 to 5 years. • There were greater numbers of venous thromboembolic events in the treated group (34 versus 12, for a relative hazard of 2.89). Hulley S, et al. JAMA 1998; 280:605-613

7. Women’s Health Initiative (WHI) • The larger study follows over 161 000 women aged 50-79, under varying observational and preventive strategies for heart disease, breast and colorectal cancer and osteoporosis, and includes 3 different arms: • 1) 68 000 women in 3 randomized controlled clinical trials; evaluating HRT vs placebo for the prevention of heart disease, a low-fat diet for the prevention of breast and colorectal cancer, and calcium and vitamin-D supplementation in the prevention of osteoporotic fractures • 2) an observational study of 83 000 women to identify predictors of disease • 3) a study of community approaches to developing healthful behaviors

8. Women’s Health Initiative (WHI) • The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI), along with the National Cancer Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the Office of Disease Prevention, and the Office of Research on Women's Health. • Full results are not expected until 2005.

9. Women’s Health Initiative (WHI) • A Hormone Replacement Therapy (HRT) arm includes 16 609 women with a uterus randomized to CEE and medroxyprogesterone acetate versus placebo, and 10 739 women without a uterus randomized to CEE or placebo. • - primary endpoints include nonfatal myocardial infarction and coronary heart disease death • - secondary endpoints include requirement for revascularization and occurrence of unstable angina

10. Women’s Health Initiative (WHI) • The NHLBI has recently updated the informed consent for entry into the trial following a recent meeting of the Data and Safety Monitoring Board. • Sufficient data were judged to be available from the first 2 years of follow-up to indicate that women receiving HRT had “somewhat” more cardiovascular events than those receiving placebo. These events included MI, stroke, deep venous thrombosis, and pulmonary embolism. • For women already on HRT these results suggest that there is no evidence of early benefit, although long-term benefit cannot yet be ruled out. However, there has not been real evidence to date of cardiovascular benefits from the use of HRT.

11. HRT to protect the heart? “It has become abundantly clear over the past two years that the relationship between estrogen and heart disease is far more complex than we ever imagined… Women who currently have heart disease should not be taking estrogen with the expectation that they will be deriving cardiovascular benefit from it.” Dr David Herrington Wake Forest University School of Medicine Winston-Salem, NC Heartbeat / Apr 7, 2000 / HRT to protect the heart?

12. Evidence-based medicine • The need for evidence-based medicine in the form of randomized, clinical trials is well established. • Guidelines for data and safety monitoring committees have not been well standardized. • A greater investment is required in people sharing their experiences on clinical trials, in order to develop an intellectual enterprise around how clinical trials are done. • There is a lack of infrastructure in government supported clinical trials.

13. Natural estrogens “…the concern is whether any large scale trials will ever be done now that the largest trial in history has failed to show benefit. I agree about not prematurely dismissing this preventive therapy, but not sure we're going to have a different, compelling new data set in our lifetime.” Dr Eric Topol …on the use of natural estrogens in lieu of conjugated equine estrogen as hormone replacement therapy

14. Future research in estrogens • Smaller studies are needed to understand better the role of biomarkers in women treated with hormone replacement therapy. • Selective estrogen receptor modulators (SERM’s) are currently being studied in large scale clinical trials. • With regard to osteoporosis, there has never been a trial showing reduction of fractures in women on HRT.

15. Alternative medicine • Soy and phyto-based estrogens are sold on claims that they reduce a woman’s risk of heart disease • Sudden death and cardiovascular complications are possible in patients taking ephedra or ma huang, particularly after myocardial infarction. • Multiple medication interactions have been documented with St John’s Wort.

16. Alternative medicine • The confusional state surrounding the traditional medical indications for HRT may drive patients to seek alternative remedies. • The use of alternative medicines may reflect the way medical information is disseminated to the public, as well as a mistrust of general clinical research. • Regulation of alternative medicines by the FDA is desperately needed.

17. Alternative medicine: a recipe for disaster “…every increase in regulation of the FDA has occurred because of a discrete national disaster… so it's just a matter of time until there's a discrete disaster that will wake people up and say we've got to understand these things better and regulate them.” Dr Rob Califf …on the public’s increasing use of alternative medicines