Risk & Prevention 2013.

Methods	RCT, parallel, (n‐3 vs olive oil), 60 months Summary risk of bias: moderate or high
Participants	Patients with multiple cardiovascular risk factors N: 6244 intervention, 6269 control (analysed, intervention: 6239 control: 6266) Level of risk for CVD: high Men: 62.3% intervention, 60.6% control Mean age in years (SD): 63.9 (9.3) intervention, 64.0 (9.6) control Age range: not reported Smokers: 22.1% intervention, 21.4% control. Hypertension: 84.6% intervention, 84.5% control Medications taken by at least 50% of those in the control group: not reported Medications taken by 20%‐49% of those in the control group: ACE inhibitor; ARB; diuretic agent; calcium‐channel blocker; beta‐blocker; oral hypoglycaemic drug; statin; antiplatelet agent Medications taken by some, but less than 20% of the control group: insulin Location: Italy Ethnicity: not reported
Interventions	Type: supplement (n‐3 capsules) Comparison: EPA + DHA vs MUFA Intervention: 1 g/d n‐3 capsules polyunsaturated fatty acid ethyl esters (EPA and DHA content 850‐882 mg with an average ratio of 1.0 to 1.2). Dose: ˜0.87 g/d EPA + DHA Control: 1 g/d olive oil capsules Compliance: measured by self‐report during follow‐up visits but no results reported Duration of intervention: 60 months
Outcomes	Main study outcome: composite of time to death from cardiovascular causes or hospital admission for cardiovascular causes Dropouts: intervention: 5 withdrew consent before baseline, 43 lost to follow‐up, 1115 stopped treatment. 6239 analysed. Control: 3 (withdrew consent before baseline), 39 lost to follow‐up, 1218 stopped treatment. 6266 analysed Available outcomes: mortality, CV mortality, CV events, coronary related events and mortality, MI, AF, heart failure, side effects, stroke, cancer diagnosis, cancer death. Authors provided data on diabetes diagnosis, glucose and HbA1c. Response to contact: yes
Notes	All continuous outcomes change data are reported as least squares mean hence not used. Study funding, quote: "The steering committee had the full and sole responsibility for planning and coordinating the study, analyzing and interpreting the data, and preparing the manuscript and submitting it for publication. Società Prodotti Antibiotici, Pfizer, and Sigma Tau funded the trial but had no role in the study design, planning, conduct, or analysis or in the interpretation or reporting of the results"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Treatment was centrally assigned by means of telephone on the basis of a concealed, computer‐generated randomization list, stratified according to general practitioner."
Allocation concealment (selection bias)	Low risk	As above
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Patients, general practitioners, coordination and statistical staff, and outcome assessors were unaware of the study assignments until the final analyses were completed." However, there was no mention of placebo appearance or other methods of blinding, so unclear.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Patients, general practitioners, coordination and statistical staff, and outcome assessors were unaware of the study assignments until the final analyses were completed." Quote: "All events included in the primary efficacy end point were documented with the use of a narrative summary and supporting documentation and were adjudicated on the basis of prespecified criteria by an ad hoc committee consisting of a cardiologist, an internist, and a neurologist who were unaware of the study assignments"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Analyses were performed in the intention‐to‐treat population, except for a prespecified per protocol analysis of the primary end point in patients with no major protocol violations who did not permanently stop treatment." Figures differ in Visentin 2008: (p. i73)"At the end of March 2006, 12 521 patients have been Randomized"; "After 1‐year of follow‐up, 2.5% of the patients withdrawn from the trial and 5% of the patients discontinued treatment. The reasons for drug discontinuation were 1.7% for side effects (mainly gastrointestinal) and 3.3% others (clinical or patient's refusal)… After 1‐year of follow‐up, 1.0% had CV death and 3.4% hospitalisation for CV events (primary end point)"
Selective reporting (reporting bias)	High risk	Primary endpoint was amended part way through study. Differences in groupings of cardiovascular events in tables 2; S4 and S5. For hospital admissions notes each patient could have more than one cardiovascular cause
Attention	Unclear risk	Does not state attention differs or is the same between groups‐ regularly see GP for follow‐up and blinding not clear
Compliance	Unclear risk	No results
Other bias	Low risk	None noted