The R i se and Fall of Hormone Replacement Therapy - PowerPoint Presentation

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The Rise and Fall of Hormone Replacement Therapy

Evidence Based Medicine Story

Hale Arık Taşyıkan, MD, MPH

Department

of

Public

Health

Yeditepe

University

Slide2

Do we really know

what makes us healthy?

What

if it is just bad

science

?Slide3

Hormone Replacement TherapyBy the mid-1990s, hormone replacement therapy (HRT) had become one of the most widely prescribed medications for women, especially in North America. Slide4

Observational Studies Observational studies Showed cardiovascular benefit for HRT.

Nurses

’ Health Study (1991)

48,470

postmenopausal

women

30 -63 years oldNo history of cancer or CVD at baseline10 years follow-upAfter 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)Slide5

Nurses’ Health StudySlide6

Nurses’ Health StudyCONCLUSION:

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» Slide7

Observational StudiesSystematic 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» Slide8

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention

of

Coronary Heart Disease in Postmenopausal WomenAim: 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 centersPopulation: A total of 2763 women with coronary disease, younger than 80years, and postmenopausal with an intact uterus. Mean age was 66.7 years.Slide9

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention

of

Coronary Heart Disease in Postmenopausal WomenIntervention: Either 0.625 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 yearsOutcome: The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD deathSlide10
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Risks and Benefits of Estrogen Plus Progestinin Healthy Postmenopausal WomenPrincipal 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: 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.Slide13

Risks and Benefits of Estrogen Plus Progestinin Healthy Postmenopausal WomenPrincipal Results From the Women’s Health Initiative

Randomized

Controlled TrialIntervention: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n=8506) or placebo (n=8102)Follow-up

:

A

fter

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.Slide14

Risks and Benefits of Estrogen Plus Progestinin Healthy Postmenopausal WomenPrincipal Results From the Women’s Health Initiative

Randomized

Controlled TrialOutcome: 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.Slide15
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Risks and Benefits of Estrogen Plus Progestinin Healthy Postmenopausal WomenPrincipal Results From the Women’s Health Initiative

Randomized

Controlled TrialConclusion: 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.Slide17

Biases???Healthy user biasPeople 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.Slide18

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.).Slide19

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. Slide20

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.Slide21

SummaryBy 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. Slide22

SummaryIn 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. Slide23

ConclusionObservational 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 usedSlide24

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. Slide25

Source: The B files – Case studies of bias in real life epidemiologic studies Department of Epidemiology, Biostatistics and occupational

health, McGill University, Montreal, Canada