HPS 2002Low.

Methods	Heart Protection Study (HPS). Randomised, double‐blind, placebo‐controlled trial with two‐by‐two factorial design.
Participants	Country: United Kingdom. Number of participants randomised: 20,536; 15,454 males and 5082 females at an age 40 to 80 years. Inclusion criteria: adults with coronary disease, other occlusive arterial disease, or diabetes, and non‐fasting blood total cholesterol concentrations of at least 3.5 mmol/L. Exclusion criteria: other life‐threatening conditions, such as chronic liver disease, severe renal disease, severe heart failure, severe chronic airways disease, or diagnosed cancer (other than non‐melanoma skin cancer). In addition, anyone already taking high‐dose vitamin E supplements, or in whom such supplements were considered indicated, was not to be randomised.
Interventions	Participants were randomly assigned to receive: group 1: 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta‐carotene daily (n = 10,269); group 2: matching placebo capsules (n = 10,267), daily during the scheduled five‐year treatment period.
Outcomes	The primary outcome measures were: major coronary events (for overall analyses) and fatal or non‐fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.
Notes	Compliance with treatment was assessed at each follow‐up by reviewing the calendar packed tablets remaining and, for those who had stopped, the reasons for doing so were sought. An average of 83% of participants in each treatment group remained compliant during the scheduled five‐year treatment period. To assess the effects of the treatment allocation on blood concentrations of the vitamins being studied, assays were performed in non‐fasting samples collected from about 5% of participants at the initial screening visit and at an average of about three years of follow‐up (the approximate mid‐point of the study). There were 99.7% of the participants were with complete follow‐up for average of 5 years in vitamins allocated group and 99.6% in placebo group. Overall, 25 participants allocated to vitamins group and 35 participants to placebo group were lost to follow‐up. Vitamins were provided by Roche. Data were extracted from the primary publication, but additional information was received through personal communication with the authors.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)	Low risk	Allocation was controlled by a central and independent randomisation unit, so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)	Low risk	Pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
Other bias	Low risk	The trial appears to be free of other components that could put it at risk of bias.