The Women’s Health Initiative Memory Study (WHIMS)

The Women’s Health Initiative Memory Study (WHIMS): A Trial of the Effect of Estrogen Therapy in Preventing and Slowing the Progression of Dementia Sally A. Shumaker, PhD, Beth A. Reboussin, PhD, Mark A. Espeland, PhD, Stephen R. Rapp, PhD, Wendy L. McBee, MA, Maggie Dailey, MPH, Deborah Bowen, PhD, Tim Terrell, MA, MS, and Beverly N. Jones, MD, for the WHIMS Investigators Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina (S.A.S., B.A.R., M.A.E., W.L.M., M.D., T.T.); Department of Psychiatry and Behavioral Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina (S.R.R., B.N.J.); and Fred Hutchinson Cancer Research Center, Seattle, Washington (D.B.)

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

Address reprint requests to: Dr. Beth A. Reboussin, Wake Forest University School of Medicine, Department of Public Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. Received December 29, 1997; accepted June 8, 1998. Controlled Clinical Trials 19:604–621 (1998)  Elsevier Science Inc. 1998 655 Avenue of the Americas, New York, NY 10010

0197-2456/98/$19.00 PII S0197-2456(98)00038-5

WHIMS Design and Rationale

profound public health implications for older women’s health and functioning. trolled Clinical Trials 1998;19:604–621  Elsevier Science Inc. 1998

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KEY WORDS: Aging, Alzheimer’s, cognitive impairment, dementia, estrogen

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. 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– 17], hippocampal neurons [18–21], and cerebral blood flow [22], which in turn affect cognitive and neuropsychological function. Additionally, clinical reports suggest an association between menopause and poorer memory function [23–

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25]. Early research based on subjective self-reporting indicates that estrogen replacement therapy (ERT) is more effective than placebo in alleviating menopausal symptoms and is associated with improvements in memory [26]. Implementing a more formal testing procedure, Phillips and Sherwin [27] reported that women on placebo showed a decrease in immediate and delayed recall after surgical menopause, whereas those on ERT showed no change. Other research indicates that women perform worse on neuropsychological tests that favor women’s abilities during their luteal phase [28, 29]. Evidence from retrospective and prospective studies, and some smaller clinical trials, conflicts. Although some retrospective studies report significantly fewer estrogen users among women with AD [30, 31], a study by Graves et al. [32] found no significant difference. A prospective observational study of postmenopausal women who were initially free of cognitive impairment found a greater risk for AD in nonestrogen users than in estrogen users, with the greatest reduction in risk occurring among women who took estrogen for longer than 1 year [33]. In a preliminary unblinded clinical trial, Fillit et al. [34] demonstrated that some older women with AD experienced clear cognitive benefit (as measured by attention, orientation, and mood) from oral estradiol treatment. In a subsequent placebo-controlled study using low-dose transdermal estradiol, these researchers failed to demonstrate cognitive benefits after ERT [35]. Similarly, the Rancho Bernardo study found no effect on ERT on cognitive performance [36]. Several recent small estrogen-treatment trials in AD (all but one unblinded) reported a significant effect in treated women [37, 38]. Many potential reasons may account for these conflicting results. Most importantly, the delineation of cases of dementia is difficult because comorbid illness often hinders accurate diagnosis. Studies based on self-reporting that lack neuropsychological assessment most likely represent a mixture of types of dementia. Older individuals or individuals with dementia may not accurately recall episodes or they may minimize or may be unable to report symptoms. The low prevalence of dementia also makes it difficult to recruit enough subjects for investigations, whereas studies of prevalent cases may be flawed by selection bias resulting from mortality and migration related to dementia. The study of incident cases, although possibly providing a clearer picture, requires a longer period for a sufficient number of cases to accrue. Finally, studies that do not randomize women to hormone therapy may have a bias because women who choose to take such therapy tend to be healthier in general. For these reasons, a controlled, randomized, long-term clinical trial is clearly needed. 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:

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1. Women randomly assigned to receive hormone therapy (either with or without a progestational agent) will have a reduced incidence of clinically diagnosed all-cause dementia compared with those assigned to receive placebo. 2. Women randomly assigned to receive hormone therapy (either with or without a progestational agent) will have a reduced incidence of clinically diagnosed AD compared with those assigned to receive placebo. We have designed WHIMS to provide more than 80% statistical power to detect an observed 40% relative reduction in the incidence rate of clinically diagnosed all-cause dementia associated with randomization to receive hormone therapy and more than 70% statistical power to detect the same treatment effect on the incidence rate of Alzheimer’s-related dementia. We based power calculations on a proportional hazards model [39, 40] for contrasting hazard ratios (HRT versus placebo) associated with the incidence of all-cause dementia at the two-sided 0.05 level. An outside advisory committee suggested that a reduction in the (instantaneous) rate of all-cause dementia by 40% for the comparison of randomization with HRT versus placebo was clinically important. This observed relative treatment effect was chosen to reflect influences of participant dropins and dropouts; however, because precise information on the relative magnitudes of these effects was not available, we also examined the required sample size for a 35% treatment effect. No strong evidence suggested a differential effect of ERT with progestin versus estrogen alone, so we assumed them equally effective in power calculations. We also assumed incidence rates in the placebo group to be highly dependent on age and to double every 5 years. In particular, we assumed age-specific incidence rates per thousand person-years in the placebo group to range from 2.2 at age 65 to 36.4 at age 85. Age-specific rates of losses to follow-up were assumed to range from 5 to 14% per year. Based on these assumptions and a projected enrollment of 8300 women, we expect approximately 165 (40% treatment effect) to 170 (35% treatment effect) incident cases of all-cause dementia by the end of the study period. Of the 170 incident cases of all-cause dementia, we expect 60% to be of the Alzheimer’s type, resulting in approximately 100 expected cases of AD over the study period. If our projections are correct, WHIMS will provide 91% (40% treatment effect) to 80% (35% treatment effect) statistical power for testing its primary hypothesis. We have also designed WHIMS to 1. Quantify the efficacy of HRT in reducing the incidence of clinically diagnosed all-cause dementia separately in women who have had a hysterectomy and are assigned to unopposed therapy to those who have not had a hysterectomy and are assigned to combined estrogen and progestin therapy; 2. Describe the effects of HRT on all-cause dementia in subgroups defined by age, ethnicity, and clinical site; 3. Describe the incidence of AD and other subtypes of dementia in the WHIMS cohort; 4. Describe the effects of HRT on the progression of symptoms associated with dementia in women with all-cause and Alzheimer’s-type dementia.

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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. 2. 3. 4.

HRT trial; Dietary modification trial; Calcium/vitamin D supplementation trial; Observational study of health.

Conducted at 40 clinical centers in the United States, the randomized clinical trials performed by the WHI assess the effects of three different interventions— HRT, changes in diet, and supplementation with calcium and vitamin D—on the prevention of disease. Enrollment for the trials began in September 1993 and will end in mid-1998. An average of 9 years of follow-up per subject is planned. The HRT trial will study the effect of HRT on the prevention of coronary heart disease and osteoporotic fractures. Expecting to enroll 27,500 women aged 50 to 79, the WHI randomizes hysterectomized women to either estrogen (conjugated equine estrogens 0.625 mg/day) or placebo and women with a uterus to either estrogen (conjugated equine estrogens 0.625 mg/day) plus progestin (medroxyprogesterone acetate 2.5 mg/day continuous) or placebo. Criteria for inclusion in the WHI are as broad as possible so that results may generalize to the larger population of postmenopausal women. To participate, a woman must be a postmenopausal volunteer of any race or ethnicity, with or without a uterus; must be aged between 50 and 79, inclusively at the first screening; must be likely to reside in the study area for at least 3 years after randomization or enrollment; and must provide written informed consent. Appendix A lists exclusion criteria. 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 questions because the participant’s full understanding of the study’s components is important both for ethical reasons and for adherence to study protocol. Staff ask each eligible woman to decide, by the time of the third WHI screening visit and immediately after HRT randomization, whether she also wants to participate in WHIMS. If she does, she signs her informed consent. To enroll in WHIMS she must be eligible for and enrolled in the HRT trial of the WHI; must be between 65 and 79 years old, inclusively at the time of her enrollment in WHIMS; must be able and willing to undergo cognitive assessment annually for 4–6 years; and must

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be willing to participate in all aspects of WHIMS, possibly including blood tests and a computerized tomography (CT). WHIMS plans to enroll approximately 8300 women over a 2-year period. This pool represents 90% of the women aged 65 and older from 39 WHI clinical centers and 10 satellites throughout the United States whom we expect to have randomized into the HRT trial of the WHI after May 31, 1996. Our experience to date suggests that, indeed, 90% is a reasonable accrual rate from the ageeligible WHI enrollees. We plan a follow-up period of 4–6 years per subject that will consist of annual clinic visits. To recruit subjects for WHIMS, we developed strategies to target women aged 65 to 79 within the existing framework for the WHI. We increased public awareness about the HRT trial of the WHI and about WHIMS, conducted mass mailings with a WHIMS-specific brochure, advertised in print and broadcast media, and helped local clinics develop means of overcoming recruitment barriers specific to older women. 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. Phase 1 We administer the Modified Mini-Mental Exam (3MS) to WHIMS participants as a primary screening assessment of cognitive functioning [42] at baseline during either the second or the third WHI screening visit and then at annual follow-up visits. WHIMS participants scoring 72 or less on the 3MS with 0 to 8 years of education or scoring 76 or less with 9 or more years of education proceed to phases 2 and 3 of WHIMS. Scores below these cutpoints indicate possible cognitive impairment. We base the cutpoints on recent work by Graham et al. and Tombaugh et al. [43, 44], who assessed the sensitivity and specificity of the 3MS for detecting cases of dementia in a community sample of adults aged 65–89. For participants with 0 to 8 years of education and a cutpoint of 72 and for participants with 9 or more years of education and a cutpoint of 76, we attained approximately 80% sensitivity and 85% specificity. From this sensitivity and specificity and the incidence rates used to power the study, we expect approximately 15% of the women at each phase 1 to continue to phases 2 and 3. Because of the high rates of sensitivity and specificity associated with the 3MS and our need to limit both the clinic’s workload and time burden on participant’s imposed by the more intensive phases 2 and 3, we excuse from phases 2 and 3 those who did not score at or below the cutpoint. These women return for their WHIMS annual visits. Phases 2 and 3 Women identified as phases 2 and 3 participants of WHIMS are scheduled for completion of phases 2 and 3 within 3 months of phase 1. The technician clarifies to each participant at phase 1 that she will return for two additional visits: phases 2 and 3. The window of time between phases 2 and 3 is 1 month

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Figure 1 Diagram of the WHIMS study design.

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or less. Each woman referred to phases 2 and 3 of WHIMS is scheduled for a neuropsychological assessment and a brief neuropsychological interview conducted by a centrally trained and certified technician. The certified technician also conducts a telephone interview about the participant’s functioning with a close friend or relative whom the participant has named. In phase 3, a boardcertified neurologist or geropsychiatrist with expertise in dementia evaluates the participant neurologically. Phases 2 and 3 of the study allow presumptive diagnosis of cognitive functioning. Phase 2 The certified technician collects the following audio-taped data from each woman: 1. Portions of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological test battery [45]. The CERAD tests verbal fluency, naming, constructional praxis (copying designs), constructional praxis recall (copying designs from memory), word-list memory, wordlist recall, and word-list recognition. 2. Trail Making Test, Parts A and B [46]. This test of visual, conceptual, and visuomotor functions is sensitive to brain injury [47]. Part A requires the examinee to draw lines connecting consecutively numbered circles. In Part B, she connects numbered and lettered circles alternatively. The time in seconds that she takes to complete each part is her score. 3. Structured Psychiatric Interview. Adapted from the Primary Care Evaluation of Mental Disorders (PRIME-MD), this brief psychiatric screening interview designed for use by nonmental health providers assesses such disorders as depression, anxiety, panic, and alcohol abuse [48]. 4. Geriatric Depression Scale-Short Form. This is a 15-item version of the 30-item form that measures nonsomatic depressive symptoms [49]. 5. Acquired Cognitive and Behavior Changes (ACBC). Thirty-six structured questions assess participant’s acquired cognitive and behavioral changes by leading them to describe impairments of memory, language, personality, behavior, orientation, activities of daily living, social functioning, and judgment problem-solving. 6. Friend/Family Member Interview. The same questions on functional impairment from the ACBC described above are reworded for third parties. Staff obtain information by telephone or in person during the same week as phase 2 testing. Phase 3 In phase 3, a physician reviews data from phases 1 and 2 and the WHI Medical History Questionnaire. She or he then meets with the participant for a face-to-face semistructured neurologic evaluation that includes 1. A review of past medical history, a clinical evaluation, and an optional Mini-Mental State Exam [50]; 2. An evaluation for the presence of clinically significant depression, anxiety, panic, or alcohol abuse or dependence;

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3. Ratings of the Hachinski Scale, a checklist of 13 clinical signs and symptoms used to distinguish progressive dementia from vascular dementia [51]. The clinician then makes a determination regarding the presence of dementia (probable), minor cognitive impairment, or no dementia. Phase 4 Each woman judged to have probable dementia in phase 3 undergoes a series of local laboratory tests that rule out non–dementia-related causes for clinical findings and classify the type of dementia. Of women diagnosed with dementia, we expect approximately 60% to have Alzheimer’s-related dementia and the remaining 40% to have other forms. The laboratory tests include 1. Complete blood count with differential serum chemistry panel that includes the following: sodium, potassium, CO2, chloride, blood urea nitrogen, creatinine, glucose, calcium, magnesium, albumin, total protein, alkaline phosphatase, serum glutamicoxaloacetic transaminase, lactate dehydrogenase, total bilirubin, and total cholesterol; 2. Vitamin B-12 level; 3. Folate level; 4. Syphilis screen; 5. Thyroid-stimulating hormone level; 6. Noncontrast CT. The clinician reviews these test data to confirm or reject the diagnosis of probable dementia, classifies the type of dementia accordingly, and notifies the clinical center WHI Principal Investigator (PI) of the diagnosis. She or he also informs the participant that some test results suggest cognitive impairment and that the findings will be sent to the participant’s primary care physician, so that she may confer with her physician about follow-up. Each woman determined to have a probable dementia continues in WHI and WHIMS. As part of WHIMS, she returns to the clinical center to repeat phases 1 and 2 annually so that the progression may be evaluated. 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, sexual function, quality of life, selfefficacy, physical symptoms, and sleep disturbance), physical activity (with a questionnaire on functional ability), and personal habits (with questionnaires on diet, smoking, alcohol, and on exercise). We update the participant’s medical history on the first, third, and sixth years in the WHI HRT trial. We readminister the psychological questionnaires at the first annual visit for every participant

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and at the third and sixth years on a small subsample. We update information on physical activity on the first and third years. At each visit, we collect information regarding adherence to study medication. Additionally, we obtain information on participation status when follow-up or intervention status changes, and we record the reasons that the participant stopped her activities. 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 received instructions about the study protocol and the procedure for administering the tests and interviews by watching didactic presentations on each component and video-taped demonstrations of the proper techniques and then by engaging in role-play rehearsal with feedback from trainers. Upon completing the session, each was precertified to administer the entire protocol. Once back in her or his respective site, the technician practiced several administrations before audio-taping one for evaluation by the WFUSM-CC clinical staff. If the administration was adequate, then the technician received full certification; if not, she or he received feedback and submitted a tape again, repeating the process until full certification resulted. Experienced clinicians reviewed these tapes centrally, and full certification depended on demonstration of appropriate testing skills. During the course of the study, centrally trained and certified technicians train new technicians. Upon completion of training, new technicians are certified by clinicians in the manner described above. To prevent significant decay in testing skills, the WFUSM-CC recertifies all technicians biannually. Audio-taped protocol administrations are once again sent to the WFUSM-CC for rating. Technicians failing recertification must retape practice sessions until they qualify. Field technicians are encouraged to communicate questions or problems to responsive study staff at the WFUSM-CC. Further to ensure reliable and valid data, a committee reviews each audiotaped administration of phases 2 and 3 to verify scoring and administrative techniques. Staff review in this manner all of the identified cases, as well as 50% of cases identified as positive by the 3MS (phase 1) but found negative by the clinicians (phases 2 and 3). 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 adjudication panel meets

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to establish consensus. The panel makes the final determination in cases of conflicting diagnoses. Cases of dementia, which constitute the clinical end points of the WHIMS trial, are based on the adjudicated determination, not the clinician’s diagnosis. 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. Forms from phases 1–4 are photocopied and sent to the WFUSM-CC for data entry, longterm storage, and adjudication. Each clinical site retains originals in the participants’ file. Phase 2 audiotapes also go to the WFUSM-CC. 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 secondary analyses to explore observed associations more fully. All significance levels for the primary and secondary comparisons will be two-sided. The type I error rate for testing the primary study hypothesis will be 0.05. The main comparisons of hormone therapy with respect to the distribution of time until first diagnosis of dementia will be based on survival analysis. We shall obtain Kaplan-Meier estimates of the distribution of times until dementia diagnoses for persons randomized to receive and not receive hormone therapy [52]. We shall estimate the proportion of participants who remain free of dementia at prespecified time points and the associated confidence intervals [53]. To compare the placebo and intervention groups, we shall use a proportional hazards model [39] if the underlying assumptions appear warranted. We shall use log/log plots of survival to examine the assumption of proportional hazards. Standard survival methods depend on “noninformative” censoring, that is, the assumption that the participant’s time until failure is independent of the censoring mechanism. This assumption may be unwarranted in some situations. We shall monitor closely any apparent differences in censored versus uncensored participants and shall apply the techniques described in Link [54] and Wu and Bailey [55], if necessary, to form conservative approaches to analysis if informative censoring seems apparent. Depending on initial differences in treatment groups on selected factors such as age, ethnicity, and use of prior hormones, we shall use those factors as covariates in the analysis.

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Secondary analyses will involve descriptions of the survival experience for subgroups defined by hysterectomy status, clinical center, ethnic group, age, and prior use of hormones using Kaplan-Meier curves and proportional hazards models. We shall also explore the role of other potentially important baseline covariates and other demographic variables. We shall consider time-dependent covariates, such as adherence and measures of quality of life, as prognostic factors in the proportional hazards model or log-linear models for survival data [56]. With repeated measures techniques [57–59], we shall describe the progression of symptoms related to dementia using cases identified in the WHIMS cohort. Participant characteristics associated with missing data will be examined and, if warranted, techniques such as pattern-mixture approaches [60] or propensity scores adjustments [61], which are more robust for nonrandom missing data mechanisms, will be adopted in the secondary analyses of repeated measures. Post-hoc evaluation will include a description of adherence measures and reported success of participants in meeting intervention goals with each group. These descriptive data will help us evaluate the overall success of the trial. 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 prevention trial for all-cause dementia and AD. 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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APPENDIX A: EXCLUSION CRITERIA FOR WOMEN’S HEALTH INITIATIVE (WHI) HORMONE REPLACEMENT THERAPY (HRT) TRIAL A woman is ineligible to participate in the WHI HRT trial if she • • • • • • • • • • • • • • • • • • •

Has a history of bleeding disorder serious enough to require transfusion; Is currently on anticoagulants; Has had a previous osteoporosis-related fracture treated with HRT; Has femoral neck bone mineral density of more than 3.0 standard deviations below the age-specific mean (in bone densitometry clinics only); Has had invasive cancer of any type in the past 10 years; Has had breast cancer at any time (in situ or invasive); Has shown baseline mammogram or clinical breast examination findings suggestive of breast cancer; Has had endometrial cancer of any stage at any time; Has had endometrial hyperplasia at baseline (no recycling); Has had malignant melanoma of any stage at any time; Is currently on tamoxifen; Has abnormalities in baseline Pap smear, pelvic exam, or pelvic ultrasound (if performed); Has had stroke or transient ischemic attack in the past 6 months; Has had acute myocardial infarction in the past 6 months; Has dementia (according to clinical judgment); Has hematocrit ,32%; Has platelets ,75,000 cells/mL; Has triglycerides .500 mg/dL; Has known chronic active hepatitis or severe cirrhosis;

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Has a history of mental illness, including severe depression; Has a history of any pulmonary embolism or deep vein thrombosis or pulmonary embolism in the past 6 months; Has systolic blood pressure .200 mmHg or diastolic blood pressure .105 mmHg; Currently uses oral corticosteroids; Has body mass index ,18 kg/m2 or unintentional loss of 15 or more pounds in the previous 6 months; Has any medical condition associated with predicted survival of less than 3 years in the judgment of a clinic physician (e.g., class IV congestive heart failure, obstructive lung disease requiring long-term ventilation or supplemental oxygen in the past, severe chronic liver disease with jaundice or ascites, kidney failure requiring dialysis, sickle cell anemia); Is alcoholic (by clinical judgment); Shows drug dependency (by clinical judgment); Has severe menopausal symptoms that would make placebo therapy intolerable; Adhered inadequately to placebo run-in (less than 80% of daily pills taken); Is unable or unwilling to discontinue use of HRT for at least 3 months before baseline measures; Is unable or unwilling to discontinue use of oral or injectable testosterone for at least 3 months before baseline measures; Participating actively in any other interventional trial where participants are individually randomized to an intervention or control group; or Is unwilling to participate in baseline or follow-up examination components such as mammograms, clinical breast exams, phlebotomy, electrocardiograms, endometrial aspirations (women with a uterus), questionnaires, and forms or is unable to complete baseline study requirements.

APPENDIX B: STUDY ORGANIZATION Although an ancillary study, WHIMS is a complex investigation requiring substantial expertise both within and external to the WHI. WHIMS is directed by faculty and staff at the Wake Forest University School of Medicine (WFUSM), Winston-Salem, North Carolina. Experts from WFUSM, outside expert consultants, and representatives from the WHI Clinical Centers and WHI Central Coordinating Center helped develop the final protocol and select instruments (see list of participants below). The WFUSM-CC trains and certifies WHIMS technicians at each WHI clinical center, monitors the performance of centers in conducting WHIMS, and prepares regular reports to the WHI Steering Committee and the Data and Safety Monitoring Board (see list of participating clinical centers and key staff members). WFUSM-CC personnel also conduct all WHIMS-specific visits for quality assurance biannually at all WHIMS clinical centers. In addition, the WFUSM-CC analyzes the WHIMS data. The primary contract for the ancillary study is through the WFUSM-CC that, in turn, subcontracts to each of the clinical sites and the WHI Central Coordinating Center. The WHIMS Steering Committee (consisting of the WHIMS principal investigator [PI], the WHIMS Co-PIs, the WHIMS PI of the WHI Central Coordinating

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Center, the chairperson of each subcommittee, and ad hoc representatives from Wyeth Ayerst, the WHI Project Office, and the WHI Central Coordinating Center) and an Executive Committee (consisting of the WHIMS PI, the WHIMS Co-PIs, and the WHIMS project managers) administer the study and provide annual progress reports to the WHI Council. Sally A. Shumaker chairs the Steering and Executive Committees. There are four standing subcommittees whose members are nominated by the PIs from the clinical centers participating in WHIMS. The subcommittees and their chairpersons are as follows: Consultants Subcommittee (Leon Thal), Policy and Procedures Subcommittee (Gary Small), Publications and Ancillary Studies Committee (Mary Haan), and Psychosocial Advisory Committee (Lynda Powell). Clinical Centers Atlanta, Georgia, Emory University School of Medicine: Dallas Hall, Margaret Huber; Birmingham, Alabama, University of Alabama, Birmingham: Albert Oberman, Mona Fouad, Phyllis Millhouse, Eve S. Rose; Boston, Massachusetts, Brigham and Women’s Hospital: JoAnn Manson, Kate Kalan, Barbara Richmond; Bronx, New York, Albert Einstein College of Medicine: Sylvia Smoller, Michele Caban; Buffalo, New York, State University of New York, Buffalo: Maurizio Trevisan, Diane Franczak, Marilyn Norman; Chapel Hill, North Carolina, University of North Carolina, Chapel Hill: Barbara Hulka, Rebecca Damin, Grandella Gipson, Carol Murphy; Chicago, Illinois, Northwestern University Medical School: Julie Dunn, Nancy Blanchard, Dale LaPedus, Candice Lipe, Mark Mapstone; Chicago, Illinois, Rush-Presbyterian–St. Luke’s Medical Center: Lynda Powell, Jennifer Ryan, Marilou Valena; Cincinnati, Ohio, University of Cincinnati Medical Center: James Liu, Kathy Burton, Sue Goldman; Columbus, Ohio, The Ohio State University Medical Center: Rebecca Jackson, Christina Havens, Carol Werden; Detroit, Michigan, Wayne State University: Susan Hendrix, Sandy Council, Gayle Kusch; Gainesville, Florida, University of Florida: Marian Limacher, Sheila Anderson, Yvonne Brinson, Ann Coutou; Satellite– Jacksonville: Joette Anderson, Diane Yuhas; Honolulu, Hawaii, University of Hawaii: J. David Curb, Kamal Masaki, Stephanie Terashita, Elena Yeban; Houston, Texas, Baylor College of Medicine: Jennifer Cousins, Patricia Allen, Mary Ann DePoe; Iowa City, Iowa, University of Iowa: Robert Wallace, Deb Feddersen, Satellites–Davenport: Kathy Brake, Deb Romeo; Des Moines: Kim O’Brien, Kay Shabold; Los Angeles, California, University of California Los Angeles Medical Center: Howard Judd, Kathleen Kawakami, Anne Wagner; Madison, Wisconsin, University of Wisconsin: Catherine Allen, Sharyn Streicher; Memphis, Tennessee, University of Tennessee, Memphis: William Applegate, Lisa Anderson, Karen Johnson, Nancy Miles, Donna Valenski; Satellite–Pauline: Loverta Lindsey; Miami, Florida, University of Miami: Marianna Baum, Anna Giannella; Milwaukee, Wisconsin, Medical College of Wisconsin: Jane Morley Kotchen, Mary Benes-Malone, Julie Rieder; Minneapolis, Minnesota, University of Minnesota: Richard Grimm, Cathy Heuer, Mary Perron; Newark, New Jersey, University of Medicine and Dentistry of New Jersey: Norman Lasser, Norman Hymowitz, Barbara Miller, Barbara Schatz; Satellite–New Brunswick: Celeste Cardona, Nora Cosgrove; Oakland, California, Kaiser Foundation Research Institute: Robert Hiatt, Geri Bailey, Teresa Picchi, Joanna Truman; Orange,

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California, University of California, Irvine: Nancy Greep, Joana Chrysler, Judith Hollingshead; Palo Alto, California, Stanford University: Marcia Stefanick, Sue Swope, Betsy Titus; Pawtucket, Rhode Island, The Memorial Hospital: Annlouise Assaf, Elizabeth Coccia, Patricia McKee, Gretchen Sloane; Satellite–Charlton Memorial Hospital, Fall River: Tina Cameron, Mary Gustave; Pittsburgh, Pennsylvania, University of Pittsburgh: Lewis Kuller, Mary Anne Biagetti, Peg Meyer; Portland, Oregon, Kaiser Foundation Research Institute: Barbara Valanis, Joan Porterie, Brenda Rush; Reno, Nevada, University of Nevada, Reno: Sandra Daugherty, Robert Brunner, Betty Clark; Sacramento/Davis, California, University of California, Davis: Mary Haan, Maris Ramos; San Antonio, Texas, University of Texas Health Science Center, San Antonio: Donald Royall, Sara Olivari, Marsha Polk; San Diego/La Jolla, California, University of California, San Diego: Robert Langer, Maria Ligia Alvarado, Michele Edwards, Lilia Robledo; Satellite–Chula Vista: Connie Zaragoza; Stony Brook, New York, Research Foundation of SUNY: Dorothy Lane, Iris Granek, Bette Taylor; Torrance, California, Harbor-UCLA Research and Education Institute: Rowan Chlebowski, Marjorie Boze, Marie Jackson, HoJung Lim; Tucson, Arizona, University of Arizona, Tucson: Tamsen Bassford, Barbara Altimari, Amelia Lobos; Satellite–Phoenix: Marta Klein; Washington, DC, George Washington University: Judy Hsia, Donna Embersit, Nancy Freeborne; Washington, DC, Medlantic Research Institute: Barbara Howard, Eleanor Bicknell, Kay Mickel; WinstonSalem, North Carolina, Wake Forest University School of Medicine: Lynne Wagenknecht, Linda Coleson, Carol Jeffery; Satellite–Greensboro: Patricia Austin, Pamela Gibson; Worcester, Massachusetts, University of Massachusetts Medical Center: Judith Ockene, Cindy Cadoret, Sue Druker, Phil Merriam. WHIMS Central Coordinating Center Wake Forest University School of Medicine, Winston-Salem, NC: Sally A. Shumaker, Mark A. Espeland, Stephen R. Rapp, John Absher, Beverly N. Jones, Beth A. Reboussin, Maggie Dailey, Wendy L. McBee, Michael Backfield, Beth Dugan, Shellie Ellis, Patricia Hogan, Sue Jones, Pam Nance, Cheryl Summerville, Tim Terrell, Carol Wasilauskas, Claudine Legault. WHI Central Coordinating Center Fred Hutchinson Cancer Research Center, Seattle, WA: Deborah Bowen, Gretchen VanLom, Carolyn Burns. WHI Project Office National Institutes of Health, Bethesda, MD: Jacques Rossouw. Wyeth-Ayerst Laboratories Clinical Development Division, Medical Affairs Department: David Colasante, Raymond Klein.