Elsevier

Controlled Clinical Trials

Volume 19, Issue 6, December 1998, Pages 604-621
Controlled Clinical Trials

The Women’s Health Initiative Memory Study (WHIMS): A Trial of the Effect of Estrogen Therapy in Preventing and Slowing the Progression of Dementia

https://doi.org/10.1016/S0197-2456(98)00038-5Get rights and content

Abstract

Evidence from animal, human cross-sectional, case-control, and prospective studies indicate that hormone replacement therapy (HRT) is a promising treatment to delay the onset of symptoms of dementia. The Women’s Health Initiative Memory Study (WHIMS) is the first double-masked, randomized, placebo-controlled, long-term clinical trial designed to test the hypothesis that HRT reduces the incidence of all-cause dementia in women aged 65 and older. WHIMS, an ancillary study to the Women’s Health Initiative (WHI) funded by the National Institutes of Health, will recruit a subgroup of women aged 65 and older from among those enrolling in the HRT trial of the WHI. The WHI clinical centers and 10 affiliated satellites plan to enroll approximately 8300 women into WHIMS over a 2-year period. Participants will be followed annually for 6 years, receiving cognitive assessments via the Modified Mini-Mental State (3MS) Examination. Women who screen positively for cognitive impairment on the basis of an educational and age-adjusted 3MS cutpoint proceed to more extensive neuropsychological testing and neurologic evaluation. Each woman suspected to have dementia then undergoes a series of laboratory tests that confirm the clinical diagnosis and classify the type of dementia. WHIMS is designed to provide more than 80% statistical power to detect a 40% reduction in the rate of all-cause dementia, an effect that could have profound public health implications for older women’s health and functioning. Controlled Clinical Trials 1998;19:604–621

Introduction

Dementia, an illness characterized by the progressive decline of multiple cognitive functions, is associated with neuropsychiatric and emotional abnormalities. It often becomes severe enough to cause dysfunction in daily living. There are several types, but Alzheimer’s disease (AD) is the most common, accounting for about 60% of cases [1]. AD is characterized by an insidious onset with slow declines in memory accompanied by declines in language, visuospatial skills, personality, or cognition that interfere significantly with work, usual social activities, or interpersonal relationships [2].

Although dementia affects only 1% of 60 to 64 year olds, its prevalence is believed to double every 5 years beginning at age 60, affecting 30–40% of persons over age 85 [3]. The estimated prevalence of AD ranges from 3 to 10% of community residents aged 65 and older 1, 4. Some data suggest that women may be two to three times likelier than men to develop AD, with 50–70% of women over the age of 80 affected [5]. In a study of AD in an East Boston community, age had a significant impact on AD, with incidence ranging from 6 per thousand person-years at ages 65–69 to 84 per thousand person-years at ages 85 and older [6]. In the Framingham cohort, incidence of dementia and AD also increased with age [7]. The cumulative 5-year incidence rates of dementia ranged from 7 per thousand person-years at ages 65–69 to 118 per thousand person-years at ages 85–89, and incidence of AD increased from 4 per thousand person-years at ages 65–69 to 73 per thousand person-years at ages 85–89 years. Results from other longitudinal studies are similar 8, 9.

Clearly, the projection for the elderly population in the United States to double approximately in size by the year 2025 [10] has serious implications for health care professionals and family caregivers, because it will mean a significant increase in prevalence. Dementia will substantially increase the already sizable economic burden, individual grief, and familial strain experienced by victims and caregivers unless we find adequate treatments to slow its onset and possibly its progression. Currently, no therapies have been shown conclusively to prevent the onset of symptoms associated with all-cause dementia and Alzheimer’s specific dementia.

Section snippets

Rationale

Evidence from animal, human cross-sectional, case-control, and prospective studies support the hypothesis that hormone replacement therapy (HRT) represents a promising treatment for the delay of symptoms of dementia and possibly for slowed progression. Several studies have examined potential biologic mechanisms underlying the effects of hormones on the central nervous system 11, 12, 13, 14, 15, 16, 17, hippocampal neurons 18, 19, 20, 21, and cerebral blood flow [22], which in turn affect

Objectives of whims

Overall, the Women’s Health Initiative Memory Study (WHIMS) aims to determine the incidence of all-cause dementia, diagnosed through the screening of cognitive functioning and neurologic and neuropsychological evaluations in women at least 65 years of age who are participating in the HRT trial of the Women’s Health Initiative (WHI). Specifically, WHIMS is designed to test the following hypotheses:

  • 1.

    Women randomly assigned to receive hormone therapy (either with or without a progestational agent)

Design of whi

The National Institutes of Health established the WHI to study the health of postmenopausal women. The WHI focuses on cardiovascular disease, cancer, and osteoporosis. Details of the design of WHI appear elsewhere [41]. Briefly, women in the WHI have the opportunity to participate in at least one of the following components:

  • 1.

    HRT trial;

  • 2.

    Dietary modification trial;

  • 3.

    Calcium/vitamin D supplementation trial;

  • 4.

    Observational study of health.

Conducted at 40 clinical centers in the United States, the

Design of whims

WHIMS is an ancillary study to the WHI. Thirty-nine of the WHI clinical centers and 10 satellites participate in WHIMS, which is a double-masked, placebo-controlled, clinical trial designed to recruit a subgroup of women aged 65 or older from among those randomized into the HRT trial of the WHI. At the HRT screening visits, study staff provide written materials describing WHIMS to women aged 65 and older. Each woman has the opportunity to discuss WHIMS with personnel and to ask related

Annual whims measurement procedures

The WHIMS measurement protocol at baseline and annually has four ordered phases with each requiring specific measurements. Figure 1 presents a diagram of the phases.

Additional measurements

In addition to collecting data in phases 1 through 4 of WHIMS, we collect data on participants as part of their enrollment in the WHI HRT trial. At baseline, we assess the following for each subject: demographic information, socioeconomic status, physical measurements, hysterectomy status, prior use of hormones, current use of medication, menstrual history, medical history, familial history, psychological information (with questionnaires covering social support, general health and well-being,

Training of technicians

At each clinical center and satellite, we identified at least two persons to serve as trained technicians. Technicians administer the cognitive screening, the neuropsychological testing, the neuropsychological interview, and the interview with family members and coordinate the clinician’s evaluation.

Each technician trained at the Wake Forest University School of Medicine Coordinating Center (WFUSM-CC) during one of three intensive 2-day training sessions. During these sessions, technicians

Adjudication

All phase 3 participants diagnosed as having probable dementia, a 50% random sample of participants diagnosed with minor cognitive impairment, and a 20% random sample of participants without dementia are adjudicated at the WFUSM-CC by a panel consisting of clinicians with recognized expertise in dementia. Blinded to the clinicians’ assessments, the members of the panel conduct their reviews independently without discussion among themselves. In each case of disagreement with the clinician, an

Data management and tracking

WHIMS technicians complete a customized 3MS form for each WHIMS participant; these forms scan into the main WHI database. Data are transferred from the forms electronically and entered into an ORACLE database at each site. They are backed up nightly over a dedicated T1 phone line to the WHI Central Coordinating Center and the central study database. The WFUSM-CC receives a quarterly transfer of WHIMS phase 1 data, WHIMS enrollment, and demographic data from the WHI Central Coordinating Center.

Data analysis

Testing of primary hypotheses will adhere to the intention-to-treat approach, regardless of treatment status at the time of the analysis. We may perform secondary analyses to account for crossovers and dropouts from the initial treatment group. We plan no stratification to test the primary hypothesis. We shall perform supporting secondary analyses in which we shall stratify participants by clinical center, hysterectomy status, age, and ethnic group. We may perform additional stratification as

Summary

In summary, WHIMS provides a unique and relatively cost-effective opportunity to test the critical hypotheses regarding the relationship between hormone therapy and dementia in postmenopausal women. The integration of this ancillary study into the already complex WHI required the cooperation and expertise of WHI investigators and staff and the expertise of external investigators to the Women’s Health Initiative (see Appendix B). To date, the resulting protocol represents the only long-term

Acknowledgements

The Women’s Health Initiative Memory Study (WHIMS), an ancillary study to the Women’s Health Initiative (WHI) funded by the National Institutes of Health, is supported through funding by Wyeth-Ayerst Laboratories.

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