The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three clinical trials (CT) and an observational study (OS). In particular, randomized controlled trials were designed and funded that addressed cardiovascular disease, cancer, and osteoporosis.^{[citation needed]}

In its entirety, the WHI enrolled more than 160,000 postmenopausal women aged 50–79 years (at time of study enrollment) over 15 years, making it one of the largest U.S. prevention studies of its kind, with a budget of $625 million.^[1] A 2014 analysis calculated a net economic return on investment of $37.1 billion for the estrogen-plus-progestin arm of the study's hormone trial alone, providing a strong case for the continued use of this variety of large, publicly funded population study.^[2][3] In the years following the WHI, studies have shown a decrease in breast cancer rates in postmenopausal women, attributed to the decline in use of hormone replacement therapy.^[4]

However, initial interpretation and communication about the studies' findings have come under harsh criticism for failing to clarify that the studies were weighted toward women already 60 or older (average age 63).^[5] This meant that women in their 50s, who tend to be healthier (and have more menopausal symptoms), were underrepresented.^[5] Systemic hormone therapy has decreased dramatically among U.S. women since the WHI results were published because the findings are being misapplied to treatment decisions for women in their 40s and 50s who have distressing vasomotor symptoms. ^[6]

Motivation for the expanded study of women's health

In the 1980s, it had become apparent that past biomedical research had focused disproportionately on white men, often neglecting prevention and treatment studies of diseases that are either unique to or more common in women and minorities. In 1985, the Public Health Service Task Force on Women's Health Issues issued recommendations that biomedical and behavioral research should be expanded to provide for the inclusion diseases and conditions identified among women of all age groups. In 1986, the NIH issued recommendations that women be included in all research studies. To further promote the study of women, in 1990, the NIH created the Office of Research on Women's Health.^{[citation needed]}

In 1990, however, a report was published by the General Accounting Office (GAO), at the request of the Congressional Caucus on Women's Issues, which stated that this NIH policy was not being adequately applied to research grant applications. As a consequence, beginning in 1991, NIH strengthened the policy to require, rather than recommend, the inclusion of women in clinical research (when appropriate) in order to obtain funding.^[7]

It was these changes in societal attitudes and policy toward women's health research, in addition to the demonstration that such a large study was not only feasible, but could be done economically, that gave rise to the WHI.^{[citation needed]}

WHI study antecedents and demonstration of feasibility for a large-scale intervention study

Among postmenopausal women, cardiovascular disease, cancer, and osteoporosis are the leading causes of morbidity and mortality, as well as impaired quality of life. Among women in all age groups, cancer and cardiovascular disease are the leading causes of mortality.^[8][9] As the incidence of these diseases increases according to age, women over the age of 50 bear much of the disease burden.^{[citation needed]}

It had been generally accepted that postmenopausal estrogen deficiency may play a role in these morbidities, and that dietary, behavioral, and drug interventions may forestall their development. However, these findings were identified on the basis of epidemiologic observational studies alone. Such interventions would require testing through clinical trials before they, along with their full range of risks and benefits, could be used as the basis for setting public health policy and creating prevention guidelines.^{[citation needed]}

However, concerns existed about the feasibility of such a complex clinical trial among participants in this demographic of older women, particularly with respect to sufficient recruitment and adherence to the dietary and hormone-treatment regimens.^{[citation needed]}

In 1987, the NIH funded the Postmenopausal Estrogen/Progestin Intervention (PEPI). The trial followed 875 women who underwent treatment with estrogen, estrogen and progestin, or placebo, and — even quite early in the study — demonstrated both successful recruitment and participant retention/adherence in a hormone therapy (HT) setting.^[10][11][12] Many of the operational procedures from PEPI, including the study drug dosing, were retained in the larger WHI-HT clinical trial.^{[citation needed]}

In 1984, the NIH provided funding for a feasibility study pertaining to diet adherence, conducted by the Women's Health Trial (WHT). The WHT, which commenced in 1986 and involved 303 women randomized into dietary intervention and control groups, yielded results demonstrating a high degree of adherence on the basis of both food-intake questionnaires and clinical laboratory findings.^[13][14] The WHT did not proceed with its full-scale trial, as it was not awarded further funding from the NIH on the basis of the potential inability of the study to test the hypothesis in a larger cohort of women. In 1990, however, interest in the impact of diet on cancer and cardiovascular disease in women was renewed, and a joint National Cancer Institute (NCI)-National Heart, Lung, and Blood Institute (NHLBI) workshop concluded that a full-scale dietary trial, with a focus on these two diseases, was warranted.^{[citation needed]}

WHI study announced and planning begins

On April 19, 1991, Dr. Bernadine Healy, newly appointed as the first female director of the NIH, announced her plan for the Women's Health Initiative (WHI).^[15] Planning for the WHI CT/OS study began that year. In order to promote cross-institutional collaboration, and to prevent the loss of funding to other women's health-related studies, funding was requested and obtained directly from Congress in the form of a discrete line item, with a projected budget of $625 million over the life of the 15-year study.^[16][17]

The NIH awarded the role of Clinical Coordinating Center (CCC) to the Fred Hutchinson Cancer Research Center (FHCRC), located in Seattle, Washington. The CCC's responsibilities included the coordination of the 40 study clinics that would eventually recruit women nationwide, as well as ensuring their consistent adherence to the study design and guidelines.^{[citation needed]}

Design overview, eligibility, and enrollment

In 1991, working groups were formed to determine the study plan for both the clinical trials (CT) and the observational study (OS). These groups included experts from diverse arenas of medicine, public health, and clinical trial design from both within and outside the NIH.^{[citation needed]}

Study organization and implementation

Given the complexity of the WHI study, both in terms of the number of interventions and outcomes studied, as well as the number and geographic distribution of participants and clinical centers, careful orchestration was required. To this end, the WHI maintained a carefully designed organizational structure, along with governance- and science-specific committees and communications channels for staff and investigators to resolve study-related questions and exchange information. As the study launched concurrently with the early stages of modern Internet connectivity, the study centers had to be supplied with computing and networking equipment to connect to the WHI network; WHI-hosted e-mail facilitated the efficient exchange of information among staff and scientists, as well as the transfer of study-related data.^{[citation needed]}

The launch of the study was undertaken in two stages. At first, 16 "vanguard" study centers entered active operation, to evaluate the study protocol and procedures. Once this initial portion of the study was underway, the remaining 24 study centers entered the study around a year later, each assigned to one of the "vanguard" study centers for purposes of mentorship. Study centers were subdivided into four regions, each under the supervision of a regional center, to further facilitate communication and information exchange among study centers.^{[citation needed]}

Eligibility and enrollment

The WHI study recruited postmenopausal women in the 50-79 age range, and sought to be as inclusive as practical. The wide nature of the age range balanced the need to observe the effects of hormone therapy on younger women, while also attempting to capture physical and cognitive outcomes in older populations. In addition, a 20% minority enrollment rate was set for all components, to accurately represent the proportion of minorities within the study demographic (17% at the time of the 1990 U.S. Census). To achieve this, 10 of the 40 WHI clinical centers were designated as minority recruitment centers, with enhanced minority recruitment goals.^[18]

Eligibility and exclusion criteria also were defined, both study-wide and component-specific. Global inclusion criteria included postmenopausal women, between 50 and 79 years of age, who were willing and able to provide written consent, and who planned to reside in the study recruitment for a least three years after enrollment. Global exclusion criteria included medical conditions that would be predictive of a survival of less than three years, possessing characteristics or conditions that may diminish study adherence (e.g., substance abuse, mental illness, or cognitive impairment), or concurrent enrollment in another randomized controlled clinical trial.^{[citation needed]}

For the CT, a partial factorial study design was utilized for the investigation of three overlapping interventions (dietary modification, hormone therapy, and calcium/vitamin D supplementation), as this would provide considerable cost efficiencies. Willing study-eligible women were asked to join either the hormone therapy (HT trial), the dietary modification (DM) trial, or both. After one year, willing and eligible CT participants were also asked to join the calcium/vitamin D trial (CaD).^{[citation needed]}

Recruitment goals for the HT, DM, and CaD components of the CT were 27,500, 48,000, and 45,000, respectively, each obtained on the basis of calculations of statistical power with regard to the outcomes of interest for each component.^{[citation needed]}

Participants who either did not qualify for or declined to participate in the CT were, if eligible and willing to consent, enrolled in the observational study (OS), which had an enrollment goal of 100,000.^{[citation needed]}

Study components and primary findings

The WHI study was composed of four study components, to include three overlapping clinical trial (CT) interventions and one observational study (OS). Component enrollment^[19] and the primary findings are summarized in the following two tables, respectively, with additional detail following subsequently:

Hormone therapy

The design of the hormone therapy trial (HT) was approached with the hypothesis that estrogen therapy would result in a decrease in coronary heart disease and osteoporosis-related fractures. As such, the primary outcome of interest was coronary heart disease, as this is a major cause of morbidity and mortality among women, particularly those over age 65, and because, at the time, no clinical trial had been undertaken to prove the cardioprotective effects of HT. Due to the concern over the relationship between HT and elevated breast cancer risk, breast cancer was selected as the primary adverse outcome. Additional outcomes monitored included stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.^{[citation needed]}

Two regimens were selected, in addition to a placebo group. Women assigned to the intervention group who had previously undergone a hysterectomy were treated with unopposed estrogen, specifically conjugated estrogens (Premarin, manufactured by Wyeth), at a dosage of 0.625 mg/day ("E-alone," n = 5310; placebo, n = 5429). Women with an intact uterus were treated by a combined estrogen plus progestin regimen ("E+P," n = 8506; placebo, n = 8102), specifically the aforementioned estrogen regimen with the addition of 2.5 mg/day of medroxyprogesterone acetate (MPA; Prempro, also manufactured by Wyeth). The addition of progestin has been linked to a marked reduction in the risk for the development of endometrial cancer in women receiving estrogen treatment who have not undergone a hysterectomy.^[48]

In addition to the global exclusion criteria, women were ineligible for the HT component if safety was a concern. Such concerns included a breast cancer diagnosis at any time in the past, other cancers (excluding non-melanoma skin cancer) diagnosed within the previous 10 years, or low hematocrit or platelet counts.^{[citation needed]}

HT component findings and ensuing events

The HT component had originally been designed to include a follow-up period of nine years. However, interim monitoring of the combined estrogen/progestin treatment group indicated an increased risk of breast cancer, coronary heart disease, stroke, and pulmonary embolism, which outweighed the evidence indicating a benefit in preventing colorectal cancer and fractures. As a consequence, the HT study pills were stopped in July 2002, with an average follow-up period of 5.2 years.^[49] The unopposed estrogen trial was halted in February 2004, after an average follow-up period of 6.8 years, on the basis that unopposed estrogen did not appear to affect the risk of heart disease, the primary outcome, which was in contrast to the findings of previous observational studies. On the other hand, there were indications for an increased risk of stroke. Unopposed estrogen did reduce the risk for osteoporotic fractures and, unlike the estrogen/progestin treatment, showed a decrease in breast cancer risk.^[50]

As a consequence of the findings, which indicated that the incurred risks of HT outweigh the identified benefits, the study authors recommended that HT not be prescribed for the purpose of chronic disease prevention in postmenopausal women.^{[citation needed]}

The hypothesized and observed risks of specific clinical outcomes are summarized in the following table. Of particular interest are the contrasts between several of the hypothesized risks and the observed attributable risks, which are instructive in demonstrating the distinct differences between the HT trial findings and those of previous observational studies.^{[citation needed]}

Of all the WHI study findings, the HT findings could be argued to have yielded the farthest-reaching societal and economic^[51][52][53] impacts, and received substantial media attention.^{[1][54][55][56][57]} Large reductions in HT prescriptions ensued,^{[58][59][60][61]} resulting in a substantial loss of revenue in sales of this class of drugs, with a presumably commensurate savings to patients and insurers.^[62] More importantly, in subsequent years, studies have shown a decrease in breast cancer rates in postmenopausal women, attributed to the decline in use of HT.^[4] In 2014, an analysis was conducted to determine the economic impact of the estrogen-plus-progestin trial findings, which calculated the net economic return on investment to be $37.1 billion, owing to a combination of averted health-related expenditures and increased number of quality-adjusted life years (QALYs).^[2][3] Zdroj:https://en.wikipedia.org?pojem=Women's_Health_Initiative
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