The Case of the Women's Health Initiative Randomized Trial: A Statistician Reads a Paper

Dan Freeman, Ph.D.Professor, Preventive Medicine and Community Health

Director, Office of Biostatistics

2-6355 dfreeman@utmb.edu

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The Rationale for the Trial

“The preponderance of evidence from the epidemiologic studies strongly supports the view that postmenopausal estrogen therapy can substantially reduce the risk for coronary heart disease....This effect is unlikely to be explained by confounding factors or selection.”

(Stampfer Colditz 1991: p 61)

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And, an unexpected ending

“Results from the WHI [Women’s Health Initiative] indicate that the combined postmenopausal hormones ... should not be initiated or continued for the primary prevention of CHD ....”

(Writing Group for the Women’s Health Initiative Investigators 2002: p 332)

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July 10, 2002

Hormone Replacement Study A Shock to the Medical System By GINA KOLATA with MELODY PETERSEN

The announcement yesterday that a hormone replacement regimen taken by six million American women did more harm than good was met with puzzlement and disbelief by women and their doctors across the country.

September 3, 2002

Sorting Through the Confusion Over EstrogenBy JANE E. BRODY

   Susan McGee of Bethesda, Md., and Jane Quinn of Brooklyn were not planning to take hormones at menopause. But after many months of sleep disrupted nightly by drenching sweats and changes of bedclothes, they gave in.

JAMA, November 6, 2002 – Vol 288, No. 17

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What went wrong?

• Was it study design?– Observational vs Experimental

• Was it statistical inference?– Multiple Comparisons

• Conclusions

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Study Designs in Medical Research

• Observational Studies– Traditional medicine

• Experimental Studies– Scientific basis of modern medicine

• Meta-analyses– Evidenced based medicine

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Controlled Trials

Study EligibleSubjects

Direction of Inquiry and Time

Onset of Study

Controls

Experimental

NoOutcome

Outcome

What will happen?

NoOutcome

Outcome

Intervention

Randomization

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Controlled Trials: Examples• Physician’s Health

Study – Aspirin and

cardiovascular disease

• Women’s Health Initiative – HRT

• Virtually, all new drug applications require RCT’s

Lind’s study of scurvy

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Comparison of ProportionsScience 297, 19 July 2002: 326

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Multiple Hypothesis

Tests

Something has to be ‘significant’

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Confidence Intervals

Uncertainty. The range of likely risk from hormone therapy is wider when the data are adjusted for multiple sampling.

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Conclusions

1. The statistical issues hinge on multiple comparisons

2. The earlier observational studies were correctly executed but have inherent weaknesses.

3. It is possible that the factors that led to the long-term use are also protective against CHD: Exercise – Diet – Not Smoking

4. Further clinical trials are critical

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Further Conclusions

Dr. Susan Hendrix, a gynecologist at Wayne State University in Detroit who was an investigator in the federal study. "It's pretty astounding to go from a year ago thinking this is one of the most benign drugs to a 180-degree turn in the opposite direction."