1. The Rise and Fall of Hormone Replacement Therapy
Evidence Based Medicine Story
Hale Arık Taşyıkan, MD, MPH
Department of Public Health
Yeditepe University

2. Do we really know what makes us healthy?
What if it is just bad science?

3. Hormone Replacement Therapy
By the mid-1990s, hormone replacement therapy (HRT) had become one of the most widely prescribed medications for women, especially in North America.

4. Observational Studies
Observational studies Showed cardiovascular benefit for HRT.
Nurses’ Health Study (1991)
48,470 postmenopausal women
years old
No history of cancer or CVD at baseline
10 years follow-up
After adjustment for age and other risk factors: RR of major coronary disease in women currently taking estrogen was 0.56 (CI: 0.40 – 0.80)

5. Nurses’ Health Study

6. Nurses’ Health Study
CONCLUSION: The investigators concluded that «current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease»

7. Observational Studies
Systematic review of observational studies, 1992:
Pooled RR: 0.65 (35% reduction in CHD)
«There is evidence that estrogen therapy decreases risk for CHD,…hormone therapy should probably be recommended for women who have had a hysterectomy and for those with CHD or at high risk for CHD»

8. Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women
Aim: To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease
Study Design: Randomized, blinded, placebo-controlled secondary prevention trial
Setting: Outpatient and community settings at 20 US clinical centers
Population: A total of 2763 women with coronary disease, younger than 80
years, and postmenopausal with an intact uterus. Mean age was 66.7 years.

9. Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women
Intervention: Either mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383).
Follow-up: Averaged 4.1 years;
Lost to follow-up: 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75%at the end of 3 years
Outcome: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death

12. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women’s Health Initiative Randomized Controlled Trial (2002)
Aim: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.
Study Design: Estrogen plus progestin component of the Women’s Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years).
Population: postmenopausal women aged years with an intact uterus at baseline were recruited by 40 US clinical centers in

13. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women’s Health Initiative Randomized Controlled Trial
Intervention: Participants received conjugated equine estrogens, mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n=8506) or placebo (n=8102)
Follow-up: After a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits.

14. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women’s Health Initiative Randomized Controlled Trial
Outcome: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

16. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women Principal Results From the Women’s Health Initiative Randomized Controlled Trial
Conclusion: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

17. Biases??? Healthy user bias
People who faithfully engage in activities that are good for them — taking a drug as prescribed, for instance, or eating what they believe is a healthy diet — are fundamentally different from those who don't.
One thing epidemiologists have established with certainty, for example, is that women who take HRT differ from those who don't in many ways, virtually all of which associate with lower heart-disease risk: they're thinner; they have fewer risk factors for heart disease to begin with; they tend to be more educated and wealthier; to exercise more; and to be generally more health conscious.

18. Biases??? Healthy continuer – Compliance or adherer effect (bias)
Individuals who comply or adhere with their doctors' orders when given a prescription are different and healthier than people who don't.
Those who took HRT everyday, in all likelihood, did other things that may have reduced their risk of heart disease (avoid smoking, daily exercise, better diet, etc.).

19. Biases??? Lack of adequate adjustment for bias due to SES
Observational studies did adjust for confounding, but probably residual confounding remained.
In a BMJ editorial entitled "The scandal of poor epidemiological research", the authors pointed out that; a protective effect of HRT was evident in studies that did not control for socioeconomic status, but not in studies that did.
Higher socioeconomic position is strongly associated with both more frequent use of hormone replacement therapy and lower risk of coronary heart disease.

20. Biases??? Lack of adequate adjustment for bias due to SES
Meta-analysis of cohort studies and case-control studies of hormone replacement therapy and coronary heart disease. There is little evidence for a protective effect when analyses are adjusted for, in contrast to studies not adjusted for, socioeconomic status.

21. Summary
By the mid-1990s, hormone replacement therapy (HRT) had become one of the most widely prescribed medications for women, especially in North America.
Several observational studies had shown that women who took long-term estrogen replacement therapy had lower risk of cardiovascular disease.
In the late 1990s, a clinical trial called HERS [Heart and Estrogen-progestin Replacement Study], found that estrogen therapy increased, rather than decreased, the likelihood that women who already had heart disease would suffer a heart attack.

22. Summary
In 2002, a second trial, the Women's Health Initiative [WHI], concluded that HRT constituted a potential health risk for all postmenopausal women.
Randomized trials had suddenly over-turned the long-held belief (from observational studies) that HRT was beneficial for prevention of heart disease.
Subsequently, the use of HRT declined worldwide.

23. Conclusion
Observational epidemiologic studies should always be interpreted cautiously, because confounding is almost always likely, and not all studies are able to prevent or adjust for confounding adequately.
The HRT story also reminds us that repeated observational studies can consistently show the same effect, but all can be consistently biased!
Lastly, new therapies and interventions must be subjected to rigorous randomized controlled trials, before they become widely used

24. Conclusion
Epidemiology is that it's not enough to just measure one thing very accurately. To get the right answer, you may have to measure a great many things very accurately.

25. Source: The B files – Case studies of bias in real life epidemiologic studies
Department of Epidemiology, Biostatistics and occupational health,
McGill University, Montreal, Canada