Kang 2009.

Methods	2 x 2 x 2 factorial, randomised, placebo‐controlled trial of 3 antioxidants (vitamin E, vitamin C, and ß‐carotene) with 8.9 years (range 7.8–9.6) of follow‐up.
Participants	Location: Country: USA and Puerto Rico, no of sites etc. not reported. From December 1998 to July 2000 Quote: "From November 1994 to October 1996 an introductory letter, informed consent form, and enrolment questionnaire were mailed to female health professionals who were originally identified through state licensing boards and professional organizations in the continental United States, Alaska and the Commonwealth of Puerto Rico". "Potential candidates were also drawn from a cohort of women with prevalent CVD participating in the long‐running Nurses' Health Study". Recruitment: female health professionals Number randomised: 2824 in cognitive substudy overall, vit E: 1428; overall, vit C: 1406; overall, betaCarot: 1406; placebo vit E, C, betaCarot: 353; placebo vit E: 1396; placebo vit C: 1418; placebo betaCarot: 1418. Participant (baseline) characteristics: Mean age (± SD, range) at randomisation: overall, vit E: 69.1 (4.3; 62.6–87.4) placebo vit E: 69.0 (4.2; 62.6–87.9) overall, vit C: 69.0 (4.2; 62.6–86.9) placebo vit C: 69.1 (4.3; 62.6–87.9) overall, betaCarot: 69.1 (4.3; 62.6–87.9) placebo betaCarot: 69.0 (4.2; 62.6–87.6) Mean age (± SD, range) at initial cognitive assessment: overall, vit E: 72.6 (4.3; 66.1–90.9) placebo vit E: 72.5 (4.2; 66.1–91.3) overall, vit C: 72.5 (4.2; 66.1–90.5) placebo vit C: 72.6 (4.3; 66.1–91.3) overall, betaCarot: 72.6 (4.3; 66.2–91.3) placebo betaCarot: 72.5 (4.2; 66.1–91.2) Gender: women 100% Main diagnosis: female health professionals aged ≥ 40y with cardiovascular disease or ≥ 3 coronary risk factors Inclusion criteria: This was a substudy of cognitive function among 2824 participants aged ≥ 65 years from the Women’s Antioxidant Cardiovascular Study, a randomised placebo‐controlled trial designed to test the effect of a antioxidants on secondary prevention of cardiovascular disease in female health professionals aged ≥ 40 years with cardiovascular disease or ≥ 3 coronary risk factors. Exclusion criteria: not reported for the substudy Exclusion criteria in the main study, quote: "Women were excluded if they had a history of cancer (excluding non‐melanoma skin cancer) within the past ten years, any serious non‐CVD illness, or were currently using warfarin or other anticoagulants. To be eligible for the folic acid/vitamin B6/B12 component, potential participants in the ongoing eight‐arm trial had to be additionally willing to forgo individual supplements of folic acid, vitamin B6, and vitamin B12 at levels beyond the US recommended daily allowance". Only women who were compliant (taking at least two‐thirds of the pill) during the 12‐week pre‐randomisation run‐in period were randomised.
Interventions	Intervention (overall, vitamin E: 1428; overall, vitamin C: 1406; overall, betaCarot: 1406) Vitamin E at a dose of 402 mg (600 IU) every other day, ß‐carotene (50 mg every other day) and vitamin C (500 mg daily) Every 12 months, the women were sent a year’s supply of monthly calendar packs containing active agents or placebo. Comparator group: placebo (placebo vitamin E, vitamin C, ß‐carotene: 353; placebo vit E: 1396; placebo vitamin C: 1418; placebo ß‐carotene: 1418) Use of additional interventions (common to both treatment arms): not reported
Outcomes	Primary Outcomes: global composite score averaging all 5 test results measuring general cognition, verbal memory, and category fluency using z scores. Quote: " We assessed cognitive function by telephone and administered 5 tests measuring general cognition, verbal memory and category fluency." The following tests were used: Telephone Interview of Cognitive Status (TICS) delayed recall of the TICS 10‐word list and the immediate and delayed recalls of the East Boston Memory Test (data not extractable per instrument) category (animal) fluency Secondary Outcomes: 'verbal memory' composite score, calculated by averaging 4 measures of the immediate and delayed recalls of both the East Boston Memory Test and the TICS 10‐word list. Telephone cognitive function testing was administered up to 4 times over 5.4 years. The substudy was initiated a mean of 3.5 years after randomisation. Quote: "The average time from randomization to the initial cognitive assessment was 3.5 years (range 3.1–4.7), and from randomization to the last assessment was 8.9 years (range 7.8–9.6)". Eligible cognitive outcomes: global cognitive function measured with TICS executive function measured with category fluency
Notes	Also known as the WACS study. Funding sources, quote: "Vitamin E and its placebo were provided by Cognis Corporation (LaGrange, IL); all other agents and their placebos were provided by BASF Corporation (Mount Olive, NJ)." "This work is supported by grants AG15933, HL046959 from the National Institutes of Health." Declarations of interest, quote: “none." "Other Financial Disclosures: Dr Gaziano has received investigator initiated study support in the form of vitamin pills and packaging from Wyeth. Dr Buring has received investigator initiated study support in the form of vitamin pills and packaging from Natural Source Vitamin E Association. Dr. Manson has received investigator‐initiated study support in the form of vitamin pills and packaging from Cognis and BASF." Treatment adherence "average compliance (defined as taking at least two‐thirds of assigned study medications) during follow‐up was 83% and did not differ significantly between the two groups". This statement, however, seemed to have referred to the main study and not to this substudy on cognitive function. "At the end of the study, compliance (defined as taking at least two‐thirds of study pills) was comparable across all groups (range 64–68%)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “randomized in a 2 × 2 × 2 factorial design." Comment: method of random sequence generation not reported. Probably adequate
Allocation concealment (selection bias)	Unclear risk	Comment: method of allocation concealment not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: “matching placebo" Comment: same study as Kang 2008 (reported vitamin B arm) in which more detailed description of the methods stated that "Participants and investigators will be blinded to treatment assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: “The telephone cognitive interviews were administered by trained interviewers, who were masked to the participants’ randomized treatment assignment." From the main study: "An endpoints committee of physicians who were blinded to randomized treatment assignment adjudicated all primary and secondary cardiovascular outcome events. Study medications and end point ascertainment were continued in a blinded fashion until the scheduled end of the trial, July 31, 2005." Comment: Physicians were blinded to treatment assignment in the main study. The nurses were the assessors in this cognitive substudy and were apparently not aware of treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	In this review, we used outcome data from the first cognitive assessment (after a mean of 3.5 years) ‐ this included 2824 of 3170 eligible participants (89%) ‐ and the fourth cognitive assessment (after a mean of 8.9 years) ‐ this included 1586 participants (50%). No information was given about the treatment assignments of missing participants. We considered there to be an unclear risk of attrition bias for the first assessment and a high risk for the final assessment.
Selective reporting (reporting bias)	Low risk	Comment: All outcomes reported in the Methods were presented in the Results. In addition, the outcomes specified in the protocol were reported in the article.
Other bias	Low risk	No other risks identified