Repairing the Healthcare System: Women’s Health Initiative (WHI): Medical Community Is Waking Up

Stanley Feld M.D. FACP, MACE

The Women’s Health Initiative’s conclusions changed how peri-menopausal and post-menopausal women are treated in the U.S.

The conclusions of the study were released to the media before the medical community had a chance to study or debate the findings.

Since the media is the message and damn the facts, it was clear that estrogen caused heart disease, breast cancer, stroke and pulmonary embolism when used in peri-menopausal and post-menopausal women.

The conclusions frightened every peri-menopausal and post menopausal woman in this country. Hormone Replacement Therapy (HRT) usage has decreased by eighty percent since the WHI was published in 2002.

Women were afraid to take HRT because they were afraid to contract these deadly diseases.

Physicians were afraid to prescribe HRT because of the fear of being sued in our litigious society if their patient contracted one of these diseases.

In the years before the WHI, observational data supported the conclusion that estrogen was of great value in treating symptoms associated with the acute menopausal syndrome, namely hot flashes, vaginal dryness, urinary tract irritation, skin changes and emotional instability.

Estrogen also seemed to protect against heart disease, osteoporosis and weight gain and promote a general sense of well being in peri-menopausal and post-menopausal women. There was no good evidence for or against breast cancer.

One common complaint about observational studies is they are not double blind studies. One observes the outcome against a control group that does not have the same outcome.

"One common observational study is about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator.^[1]^[2] This is in contrast with experiments, such as randomized controlled trials, where each subject is randomly assigned to a treated group or a control group."

This NIH sponsored double blind placebo controlled study (WHI) was performed to prove with a level A (double blind placebo controlled) study to test the validity of observational data reports of the positive effects of estrogen.

The WHI reported results that concluded that estrogen had the opposite effects of previous observational studies.

The WHI conclusions were that conjugated estrogen caused breast cancer, heart disease, stroke, and pulmonary embolism. The WHI claimed that conjugated estrogen did protect against osteoporosis.

The media is the message and the conclusion resulted in the media frenzy. The implication was the medical profession was killing women by prescribing estrogen.

Prior to the release of the study’s conclusions many women were afraid to take estrogen on general principles alone. Many felt that estrogen deficiency was part of the aging process.

However, women had a life expectancy of 50 years in the early part of the 20th century. Women today live much longer and observational data suggests estrogen therapy (HRT) results in a healthier life.

There are many statistical problems with the WHI study. These problems have not been discussed in the media.

Practicing physicians were confused by the WHI study’s conclusions. They were also enraged because the results were released to the public before there was peer reviewed by the entire medical community.

Patients taking estrogen were upset at their physicians for giving them estrogen.

There are many defects in the WHI study from a statistical viewpoint.

Age Distribution: 66.6% of the patients were between 60 and 70 years old. 87% of the patients were 60 to 80 years old. The majority of the patients in the study receiving Hormone Replacement Therapy (HRT) for the first time were at least 10 years post-menopausal. This age distribution does not represent the usual population starting HRT.

HRT is usually started just prior to the onset of menopause or at menopause (48 years old).

The drop out rate in the placebo and HRT group was 40%. The significance of the dropout rate was not addressed. This dropout rate nullifies the validity of statistical significance of all the conclusions in the study.

Maximal tolerable dropout rate for statistically significance of data in a study should not be greater than 20%.

Everyone had ignored this important statistical fact.

The unblinding of 3000 women in the study represents a departure from the protocol. It biased the findings of treatment difference.

A hazards ratio (HR) in a statistically significant conclusion should be greater than 2.0 in order for a conclusion to be valid. The Hazard Ration should not be expressed to two decimal places.

A Hazards Ratio of less than two does not discriminate causality from bias and confounding of variables.

A 40% drop out rate nullified the power of the study. The study was not sufficiently powered to yield statistically significant results.

Presenting data as a nominal confidence interval is valid only when one outcome is being studied against one placebo.

Adjusted confidence intervals must be used when multiple outcomes are involved that represent multiple confounding variables.

Confidence interval must not cross 1 to be statistically significant.

The WHI’s statistical conclusions of the WHI study were based on using nominal confidence intervals. The nominal confidence intervals were barely significant.

The WHI nominal confidence intervals came close to touching number one (1).

All of the WHI’s published adjusted confidence intervals were non significant because they all crossed 1.

These are the defects in the WHI study’s statistical analysis that invalidates its statistical significance.

The estimated Hazard Ratios (HRs), (Nominal 95% Confidence Intervals [Nom CIs] and Adjusted 95% Confidence Intervals [Adj CIs ) in the WHI study were as follows:

Cardiac Heart Disease: HR 1.29, Nom CI (1.02-1.63) Adj CI 0.85-1.97.

Conclusion should have been the WHI was statistically insignificant for causing Cardiac Disease.

Breast cancer: HR 1.26, Nom CI(1.00-1.59),

Adj CI 0.83-1.92.

Conclusion should have been the WHI was statistically insignificant for causing Breast Cancer.

Stroke: HR 1.41, Nom CI (1.07-1.85)

Adj CI 0.86-2.31.

Conclusion should have been the WHI was statistically insignificant for causing Stroke.

Pulmonary Embolism: HR 2.13, Nom CI(1.39-3.25),

Adj CI 0.99-4.56.

The WHI conclusion for estrogen causing Pulmonary Embolism might be statistically significant if statistical analysis rules were not disregarded.

The Hazard Ratio (HR) was above 2. The Nominal Confidence limit (Nom Cl) did not go below 1. However it cannot be used for this study.

The Adjusted Confidence limit which must be used for this study crossed 1 making the WHI conclusion not statistically significant.

The adjusted confidence intervals were published in the original paper.

Media blitz publicity of the WHI’s invalid conclusions created a high level of public certainty about the results of the study.

Few physicians were in a position to dispute the statistical weakness of the data. Those who were in a position to dispute the statistical significance either remained silent or were marginalized.

The media blitz’ results changed the approach to women’s health in the U.S. in 2002. Eighty percent of women taking HRT discontinued estrogen replacement therapy.

In my opinion, the results have been a great disservice to women’s health. The media publicity also has had a devastating impact on the physician patient relationship and patients’ confidence in clinical research.

Even though estrogen might cause heart disease, pulmonary embolism, stroke, and breast cancer, the Women’s Health Initiative did not prove it in a statistically significant way.

Once again the media is the message.

Freedom of the press is vital to our freedom of speech, but the media’s tendency to sensationalize issues prior to proper judgment is disruptive to seeking the truth.

The medical community is starting to pick apart the conclusions of the WHI study.

I will describe some of the new and contradicting findings next time.

Dr. Joe Goldzieher, Reproductive Endocrinologist, helped me critique the statistics in 2002.