Rossom 2012.
| Methods | Women's Health Initiative Memory Study Post hoc analysis of a 2‐arm randomised double‐blind placebo‐controlled trial |
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| Participants |
Location: US multicentre Recruitment: Forty Women’s Health Initiative (WHI) clinical centres across the United States. Participants were enrolled between 1994 and 1999. Number randomised: 2034 in intervention, 2109 in comparison Participant (baseline) characteristics:
Inclusion criteria: women aged 65 and older without probable dementia or cognitive impairment at baseline who participated in the WHI Calcium and Vitamin D Trial Other inclusion criteria specified in the main study: Eligible women were 50 to 79 years of age at the initial screening and had no evidence of a medical condition associated with a predicted survival of less than three years and no safety, adherence, or retention risks. Exclusion criteria: diseases associated with significant risk of mortality (invasive cancer in the previous 10 years; any history of breast cancer or a suspicion of breast cancer at the time of screening; acute myocardial infarction, stroke, or transient ischaemic attack in the previous 6 months; known chronic active hepatitis or severe cirrhosis), safety (blood cell count indicative of disease, severe hypertension, current use of oral corticosteroids), and adherence or retention (unwillingness or inability to complete baseline study requirements) |
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| Interventions |
Intervention (n=2034): 1000 mg of calcium carbonate and 400 IU of vitamin D3 Two tablets per day in divided doses and with meals Comparator group (n=2109): placebo Two tablets per day in divided doses and with meals Supplements or placebo were provided by GlaxoSmithKline. Active tablets, chewable or swallowable (after July 1997), contained 500 mg of elemental calcium (as calcium carbonate) and 200 IU of vitamin D. Use of additional interventions (common to both treatment arms): Use of personal supplemental calcium up to 1000 mg/day and vitamin D up to 600 IU/day in addition to the study tablets was allowed. Calcium supplement use, n (%):
Vitamin D supplement use, n (%):
See also Notes below |
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| Outcomes |
Outcomes of interest to the review: Quote: "The Women's Health Initiative Calcium and Vitamin D trial (CaD) was designed to determine whether calcium plus vitamin D3 supplementation prevents hip fracture and colorectal cancer". WHIMS (the Women's Health Initiative Memory Study) was an ancillary study. Primary outcomes of WHIMS: classifications of probable dementia, mild cognitive impairment and cognitively normal Quote: "A diagnosis of dementia was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria." Quote: "A diagnosis of MCI was based on accepted criteria at the time of WHIMS initiation, operationally defined as performance in the 10th or lower percentile on at least one Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test based on CERAD norms, a report from the designated informant of functional impairment on the part of the participant that was not severe enough to interfere with basic activities of daily living, no evidence of a psychiatric or medical condition that could account for the cognitive decline, and absence of adjudicated dementia." Secondary outcomes: global cognitive function as assessed annually using the Modified Mini Mental State Examination (3MS) and domain‐specific cognitive functions as assessed annually in a subset of 1420 CaD participants using the WHISCA cognitive battery The WHISCA cognitive battery included the Digit Span Forward and Backward Test, the Primary Mental Abilities Vocabulary test, the Card Rotations Test, letter and semantic fluency tests, the California Verbal Learning Test, the Benton Visual Retention Test, and the Finger Tapping Test. Depressive symptoms were measured using the Burnham screening algorithm. Probable dementia or MCI were assessed during a mean follow‐up of 7.8 years. Domain‐specific measures of cognitive function were obtained in the 1420 women enrolled in the CaD trial and WHISCA seen for an average of 4.9 (treatment) and 5.0 (placebo) annual visits through 2007. Eligible cognitive outcomes:
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| Notes | "All WHIMS participants ... were also participants in the WHI Hormone Therapy trials. Some were also participants in a third trial of dietary modification to compare a low‐fat eating pattern to a usual ad‐libitum diet." Funding sources, quote: "The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through Contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221." "Sponsor’s Role: The sponsors did not play any role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript". Declarations of interest, quote: "Dr. Rossom’s work on this manuscript was supported in part by the Veterans Health Administration through Clinical and Health Services Research and Development Grants 04SCRCOE‐001 and HFP‐98–001. Dr. JoAnn Manson and colleagues at Brigham and Women’s Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the VITamin D and OmegA‐3 TriaL, a large‐scale randomized trial of vitamin D and omega‐3s in the prevention of cancer and cardiovascular disease". Treatment adherence "Adherence was assessed annually in a structured interview and by weighing remaining pills." Adherence (defined as ≥ 80%):
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: “Eligible women were randomly assigned in a double‐blind fashion to receive supplements or placebo (provided by GlaxoSmithKline) in equal proportions with use of a permuted‐block algorithm stratified according to clinical center and age". Comment: method of random sequence generation not reported, probably adequate |
| Allocation concealment (selection bias) | Unclear risk | Quote: “Eligible women were randomly assigned in a double‐blind fashion to receive supplements or placebo (provided by GlaxoSmithKline) in equal proportions with use of a permuted‐block algorithm stratified according to clinical center and age". Comment: method of allocation concealment not reported |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: “1,000 mg of calcium carbonate and 400 IU of vitamin D or identical placebos." , “Eligible women were randomly assigned in a double‐blind fashion". Comment: Participants and personnel were apparently blinded. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: “A central adjudication panel of experts at the WHIMS Clinical Coordinating Center (Wake Forest School of Medicine, Winston‐Salem, NC) made classifications." Comment: not reported but assessors were probably blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: “All primary outcomes were analyzed on a time to‐event basis according to the intention‐to‐treat principle." Comment: All patients included in the post hoc analysis were considered for the main outcome whereas only a subset was analysed for cognitive tests. |
| Selective reporting (reporting bias) | Low risk | Comment: All outcomes described in the methods or protocol (ClinicalTrials.gov number, NCT00000611) were reported in the results. |
| Other bias | Low risk | No other risks identified |