Approaches to assessing risks & benefits: Lessons from postmenopausal hormone therapy studies

1. Presented byJudith Hsia, M.D.at the December 2, 2004 meeting of theAdvisory Committee for Reproductive Health Drugs

2. Approaches to assessing risks & benefits: Lessons from postmenopausal hormone therapy studies • Biomarkers • Observational studies • Randomized trials • Intermediate outcomes

3. 110 110 100 100 90 90 110 110 100 100 90 90 Change in Lipids After Menopause Total Cholesterol HDL-C % of level at -6 months before menopause -24 -18 -12 -6 0 6 -18 -24 -12 -6 0 6 LDL-C Triglycerides % of level at -6 months before menopause -24 -18 -12 -6 0 6 -24 -18 -12 -6 0 6 Months Months Jensen J et al. Maturitas 1990;12:321-31.

4. Legend % change, E+P minus placebo Year 1 minus baseline (95% CI) *p <0.05 *-5.4 Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides Glucose Insulin Systolic BP Diastolic BP Weight Waist Circumference Waist-to-Hip Ratio *-12.7 7.3* 6.9* *-2.5 -7.1 0.9* -0.1 *-0.4 *-0.9 -0.2 % Change from Baseline (E+P minus Placebo) Estrogen + Progestin and Intermediate Outcomes (% change, E+P minus Placebo) NEJM 2003;349:523-34

5. Observational Studies with Estrogen +Progestin NEJM 2003;248:7

6. WHI Hormone Program: Baseline Hypotheses Risk Benefit Stroke? Coronary Artery Disease Breast Cancer • Additional Risks: • VTE (PE, DVT) • Additional Benefits: • Bone (Hip) Fractures • Overall Mortality Plan to follow to 2005 (average 8.5 years)

7. Women’s Health Initiative Hormone Trials Initiated screening (N = 373,092) Women who had no uterus at start of study Women who had a uterus at start of study N= 10,739 N= 16,608 CEE Placebo CEE+daily MPA Placebo

8. WHI: Clinical outcomes in the Estrogen Plus Progestin Trial Various WHI papers

9. WHI E+P: Absolute risk or benefit Events per 10,000 woman-years

10. WHI E+P Trial Findings, July 2002 (avg 5.2 y) Risks Benefits 105% Increase Dementia Fracture Reduction (Hip 23%) 24% IncreaseCHD 39% Reduction Colorectal Cancer 31% Increase Stroke 111% Increase Pulmonary Emboli 24% Increase Breast Cancer Threshold Level STOPPED Early, Clear Harm Stopped 3.3 yrs early Also: DVTs JAMA. 2002;288:321-333

11. Observational Study vs Randomized TrialResults NEJM 2003;248:7 Various WHI papers

12. Possible explanations • Confounding due to “healthy user” effect • Compliance bias – women adherent to hormones may also adhere to other healthful behaviors • Outcomes identification bias • Incomplete capture of early clinical events NEJM 2003;348:7

13. CEE vs CEE+MPA

14. WHI: Relative risk or benefit JAMA 2004;291:1701-12 JAMA 2004;291:2947-58 Various WHI papers

15. WHI: Absolute risk or benefit E Alone Events per 10,000 woman-years E+P

16. WHI E Alone Trial Findings, 2/04 (avg 6.8 y) Neutral forCHD Neutral for breast cancer Risks 49% Increase Dementia Benefits 39% Increase Stroke Fracture Reduction (Hip 39%) 34% Increase Pulmonary Emboli Threshold Level STOPPED Early, suggestion of harm Stopped 1.7 yrs early Also: DVTs JAMA 2004;291:2947-58

17. Impact of added androgen may be difficult to predict

18. Intermediate Outcomes

19. Estrogen Trials with Intermediate Outcomes • Coronary angiography – 3 randomized trials demonstrated no benefit (or harm) with PHT • Carotid ultrasound – 1 randomized trial demonstrated benefit with estradiol • Coronary calcification – no trial data NEJM 2000;343:522 JAMA 2002;288:2432 NEJM 2003;349:535 Ann Intern Med 2001;135:939

20. Approaches to evaluating risk • Biomarkers – mixed picture; may not be predictive • Observational studies – subject to bias & confounding; suitable cohorts may not be available • Randomized trials with intermediate outcomes – potentially useful • Randomized trials with clinical outcome – long & expensive