Kang 2006.

Methods	Cognitive substudy of the Women's Health Study, a randomized, placebo‐controlled, 2 x 2 factorial trial of vitamin E and low‐dose aspirin with follow‐up to approximately 10 years
Participants	Location: USA, number of sites not reported Recruitment: female health professionals Number randomised: 3184 in intervention, 3193 in comparator Participant (baseline) characteristics: Age at randomisation: vitamin E group: 66.2 (± 4)(range 60.4‐89.9) placebo: 66.3 (± 4.1)(range 60.4‐87.1) Age at initial cognitive assessment: vitamin E group : 71.8 (± 4)(range 66.1‐95.5) placebo: 71.9 (± 4.1)(range 66.0‐92.8) · Gender: women 100% · Baseline cognitive function: not assessed Inclusion criteria: Women 65 years or older participating in the Women's Health Study. Inclusion criteria for the main study: "Women were eligible if they were 45 years of age or older; had no history of coronary heart disease, cerebrovascular disease, cancer (except non‐melanoma skin cancer), or other major chronic illness; had no history of side effects to any of the study medications; were not taking aspirin or nonsteroidal antiinflammatory medications (NSAIDs) more than once a week (or were willing to forego their use during the trial); were not taking anticoagulants or corticosteroids; and were not taking individual supplements of vitamin A, vitamin E, or beta carotene more than once a week." Exclusion criteria: not reported for the cognitive substudy
Interventions	Intervention (n = 3184): Vitamin E supplementation (600 IU α‐tocopherol acetate; Natural Source Vitamin E Association, La Grange Ill) on alternate days Comparator group (n = 3193): Placebo Participants also randomised to aspirin 100 mg on alternate days in 2 x 2 factorial design Use of additional interventions (common to both treatment arms): not reported
Outcomes	The first cognitive assessment was a mean of 5.6 years (range 4.4 to 6.8 years) after randomisation and the final assessment was a mean of 4 years (range 2.6 to 5.7 years) later. We considered that all assessments fell into our duration category of > 5‐10 years of treatment and, following the protocol, used the latest, i.e. the final, assessment only. Primary Outcomes: global composite score averaging performance on general cognition, verbal memory and category fluency Tests used: Telephone Interview of cognitive status (TICS) East Boston Memory test immediate and delayed recall Delayed recall of the TICS 10‐word list Secondary Outcomes: composite score of verbal memory, averaging performance across 4 measures of verbal memory Cognitive assessments of general cognition, verbal memory, and category fluency were administered by telephone at 2‐year intervals by trained nurses. Time from randomisation to final cognitive assessment: approximately 10 years Eligible cognitive outcomes: global cognitive function measured at approximately 10 years, with higher values indicating benefit executive functioning measured at approximately 10 years, with higher values indicating benefit episodic memory measured with TICS 10‐word test delayed recall at approximately 10 years, with higher values indicating benefit Function outcome extracted: none reported Quality of life outcome extracted: none reported Safety outcome extracted: none reported
Notes	Primary aim of study was to investigate effects of interventions on the primary prevention of cardiovascular disease and cancer. At the time of initiation of the cognitive substudy, participants had been treated for a mean of 5.6 years since randomisation. Funding sources, quote: “This work was supported by grants CA47988 and AG15933 from the National Institute of Health", "The funding agency did not play any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript". Declarations of interest, For the sub‐study: none reported. For the main study, quote: "Dr. Ridker reports having received grant support from Bayer. Dr. Cook reports having served as a consultant to Bayer. Dr. Gaziano reports having served as a consultant to, and receiving grant support from, Bayer and McNeil. Dr. Hennekens reports having served as a consultant to Bayer and McNeil and receiving grant support from Bayer". Treatment adherence Quote: "compliance was comparable between the 2 groups: as of the final cognitive assessment, the percentage that reported taking at least two thirds of the assigned pill was 75.4% for the vitamin E group and 76.9% for the placebo group".
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: method of random sequence generation not reported. Probably adequate
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment not reported. Probably adequate
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The WHS is a double‐blind, .... RCT."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: for the substudy on cognitive function, blinding of outcome assessment was not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: 18% of patients randomised and included in the substudy were not included in the analysis at last assessment.
Selective reporting (reporting bias)	Unclear risk	Comment: All outcomes in the Methods were reported in the results. Protocol not available
Other bias	Low risk	No other risks identified