Expert Commentary

What is the clinical and economic return on taxpayers’ $260M investment in the WHI?

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145,000 more quality-adjusted life years and at least $23.1 billion. According to sensitivity analysis, the 95% confidence interval for the net economic return of the Women’s Health Initiative (WHI) estrogen plus progestin trial was $23.1 to $51.2 billion. Beyond life years, base-case analysis also indicated 126,000 fewer breast cancers and 76,000 fewer cardiovascular disease cases occurred because of the WHI, though 263,000 more fractures occurred.

Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women’s Health initiative estrogen plus progestin clinical trial: A modeling study. Ann Intern Med. 2014;160(9):549–602.



The WHI estrogen plus progestin (EPT) clinical trial, a $260 million venture, is among the most expensive projects ever undertaken by the National Institutes of Health. Following 2002 publication of its initial findings, use of EPT and estrogen alone (ET) hormone therapy (HT) among US women plummeted. Investigators, including WHI leadership, estimated the clinical and economic impact of this trial from a payer perspective.

Details of the study
For the years 2003 to 2012, the authors used a disease-simulation model to evaluate the effect of the WHI EPT trial on women aged 50 to 79 with an intact uterus (women who were combined-HT [cHT], or EPT, eligible). They compared outcomes between a “WHI scenario,” in which the prevalence of cHT use was based on actual WHI findings, with a “no-WHI” scenario, in which pre-WHI trends in cHT use (from 1998 to 2002) were linearly extrapolated.

The simulation model predicted that 9.5 million women used cHT in the no-WHI scenario, 4.3 million more than actually used cHT in the WHI scenario. The authors estimated that, compared with the no-WHI scenario, 126,000, 76,000, and 80,000 fewer respective cases of breast cancer, cardiovascular disease (CVD), and venous thromboembolism occurred and that 263,000 and 15,000 more respective cases of fractures and colorectal cancer occurred among women as a result of the WHI.

Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; February 2014)

Regarding economic outcomes, the authors estimated that the WHI resulted in $35.2 billion in direct medical expenditure savings—principally from fewer prescriptions for EPT and associated office visits ($26.2 billion), but also from decreased breast cancer incidence ($4.5 billion) and decreased CVD incidence ($2.2 billion), among other savings, which offset increases in expenditures for greater fracture incidence ($4.8 billion) and colorectal cancer ($1.0 billion).

Related article: In the latest report from the WHI, the data contradict the conclusions. Holly Thacker, MD (Commentary; March 2014)

In addition, the investigators reported a tremendous gain in quality of life years (145,000) in the WHI versus the no-WHI scenario, attributing the difference to the greater health-related quality-of-life effect associated with decreased breast cancer and CVD incidence in the WHI scenario.

What this evidence means for practice
At first glance, the clinical and economic benefits of the WHI EPT trial appear enormous. However, the authors surprisingly failed to take into consideration relevant issues well known to women’s health clinicians: lower use of systemic HT (both in women with an intact uterus and those posthysterectomy) has resulted in many more women suffering from bothersome vasomotor and sleep-related menopausal symptoms, with resultant impairment of quality of life.
In addition, the authors did not account for the major reduction in use of ET after the 2002 WHI findings in women who have had a hysterectomy; given that ET reduces the incidence of breast cancer and cardiovascular disease, declines in ET use have resulted in increased morbidity and mortality from these conditions.1
Finally, as the profound declines in use of systemic HT have not been accompanied by a substantive increase in the use of vaginal estrogen, we have an epidemic of symptomatic vulvovaginal atrophy, with attendant sexual dysfunction and impaired quality of life.
Andrew M. Kaunitz, MD

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