Five RCTs (reported in 12 publications) were included in the review of effectiveness (n=47,289 participants). Sample size ranged from 71 to 29,584 participants. Study quality was generally fair for trials of cancer, cardiovascular disease, cataracts and age-related macular degeneration, and poor for trials of hypertension. The principal problems were poor reporting of allocation concealment, independent outcome evaluation and concomitant medication use. Four RCTs and three case reports were included in the assessment of safety.
Cancer: One very large RCT in a poorly nourished Chinese population found a reduced incidence of gastric cancer and a reduced overall cancer mortality rate (RR 0.87, 95% CI 0.75 to 1.00) in the groups given a multivitamin supplement containing beta-carotene, alpha-tocopherol and selenium, with or without other nutrients, compared with groups receiving supplements without these nutrients. No significant differences were found for any other cancer outcome. There was also a reduced incidence of noncardia stomach cancer in groups receiving supplements containing retinol and zinc. A large French RCT found no benefit for use of antioxidant supplements in women but a reduction in risk of cancer in men (RR 0.69, 95% CI 0.53 to 0.91).
Cardiovascular disease: The large Chinese RCT found a lowered risk of death from stroke in people receiving beta-carotene, alpha-tocopherol, selenium, retinol and zinc (RR 0.71, 95% CI 0.50 to 1.00). A second RCT found no differences between groups in incidence of ischaemic cardiovascular disease.
Hypertension: The large Chinese RCT found an increased rate of isolated diastolic hypertension in people receiving beta-carotene, alpha-tocopherol and selenium, but a lowered rate in people given riboflavin, niacin, vitamin C and molybdenum. No other significant findings were reported and a second large RCT found no differences in incidence of hypertension.
Total mortality rate: Inconsistent results were reported. A Chinese RCT found a decrease in overall mortality in people receiving beta-carotene, alpha-tocopherol and selenium (RR 0.91, 95% CI 0.84 to 0.99). A second trial found a decrease in mortality in men (RR 0.63, 95% CI 0.42 to 0.93), but not women given antioxidants; while a third study found a non-significant increase in mortality in such groups.
Cataracts and age-related macular degeneration: There was some evidence for the efficacy of antioxidants plus zinc in two trials (RR 0.73, 95% CI 0.54 to 0.99 for moderate visual acuity loss and for advanced macular degeneration (RR 0.72, 95% CI 0.52 to 0.98).
The strength of evidence for the efficacy of supplements in the general adult USA population was considered very low for all these indications.
Safety: No consistent pattern of increased adverse events was evident from four RCTs.