Methods	Design: randomised, double-blind, placebo-controlled trial. Multicentre international study (13 countries; 145 centres). Follow-up period: five years.
Participants	N: 5522 patients randomised (vitamin: 2758 versus group: 2764 patients). Sex (% males): vitamin: 71.1% versus placebo: 72.4%. Age (mean±SD): vitamin: 68.8 ± 7.1 versus placebo: 68.9± 6.8 Homocysteine level at baseline: 12.2 μmol/L (1.6 mg/L) Inclusion criteria: Men and women aged >55 years, Hstory of vascular disease (coronary, cerebrovascular, or peripheral vascular) or diabetes and additional risk factors for atherosclerosis, Irrespective of their homocysteine levels, from countries with mandatory folate fortification of food (Canada and the United States) and countries without mandatory folate fortification (Brazil, western Europe, and Slovakia) Exclusion criteria: Patients taking vitamin supplements containing more than 0.2 mg of folic acid per day
Interventions	Intervention: Multivitamin therapy with 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 per day Control: Matching placebo daily Treatment duration: 5 years.
Outcomes	Primary outcome (composite): Death from cardiovascular causes, myocardial infarction, stroke Secondary outcomes: Total Ischaemic events (composite of death from cardiovascular causes, myocardial infarction, stroke, hospitalisation for unstable angina, and revascularization), Death from any cause, Hospitalization for unstable angina or congestive heart failure, Revascularization, Incidence and death for cancer. Other outcomes: transient ischaemic attacks, venous thromboembolic events, fractures
Notes	Study phase: III, registered (ClinicalTrials.gov number NCT00106886) Sample calculation a priori: Sample size calculation to detect between a 17 and a 20% (80% and 90% power, respectively) reduction in the risk rate of primary endpoint over 5 years of follow up (assuming an annual event rate of 4% in the placebo group). These numbers resulted in an estimation of 5000 patients. Analyses conducted in ITT basis Sponsors: Public funding (Canadian Institutes of Health Research). The study medication was provide by Jamieson Laboratories. They were not involved in the design, execution, analysis, or reporting of the trial results
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	No information reported about this domain.
Allocation concealment?	Yes	Centralised telephone randomisation (accessible 24h a day).
Blinding? All outcomes	Yes	Vitamins manufactured to be indistinguishable in colour, weight or ability to be dissolved in water
Incomplete outcome data addressed? All outcomes	Yes	21 patients in the treatment group and 16 in the placebo not completed the study. Vital status know for the 99.3% of the sample.