ASAP 2003Low.

Methods	The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Randomised, partially double‐blind, placebo‐controlled trial with two‐by‐two factorial design.
Participants	Country: Finland. Number of participants randomised: 520, 256 men and 264 postmenopausal women, smoking and non smoking, aged 45 to 69 years with serum cholesterol > 5 mmol/L (193 mg/dL). Inclusion criteria: participants with hypercholesterolaemia defined as serum cholesterol levels > 5 mmol/L (193 mg/dL). Exclusion criteria: regular intake of antioxidants, acetosalicylate, or any other drug with antioxidative properties, severe obesity (body mass index >32 kg/m2), type 1 diabetes, uncontrolled hypertension (sitting diastolic blood pressure >105 mm Hg), any condition limiting mobility, or severe disease shortening life expectancy. Premenopausal women and those taking oral oestrogen therapy were also excluded.
Interventions	The study consisted of 8‐week dietary counselling and placebo lead‐in phase, a 3‐year double‐masked treatment period, and a 3‐year open treatment period. The participants were randomly allocated to receive twice daily with meal: group 1: d‐alpha tocopherol 91 mg (corresponding to 100 mg of d‐alpha‐tocopheryl acetate and 136 IU of vitamin E) (n = 130); group 2: 250 mg slow‐release vitamin C (n = 130); group 3: both d‐alpha‐tocopherol and slow‐release ascorbic acid in a single tablet (CellaVie), (n = 130); group 4: placebo only (n = 130); for a period of 6 years.
Outcomes	The primary outcome measure was: progression of carotid atherosclerosis.
Notes	Compliance with treatment was checked by random serum assessments. Of the 390 participants randomised to supplementation, 335 continued the study after 3 years and 256 (76.4%) took the supplements as instructed for 6 years, whereas 62 participants stopped the supplements during the first 3 study years and additional 18 participants during the last 3 study years. The mean plasma alpha‐tocopherol and ascorbate concentration increased in 6 years in the group randomised to supplementation, and in the non supplemented group decrease. Of the 520 participants randomised, 440 (84.6%) completed the study and underwent the six‐year re‐examination. overall, 55 participants in the three vitamin groups and 25 participants in the placebo group were lost to follow‐up. Ferrosan A/S, Denmark, provided the vitamin supplements.
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.