Eighteen studies with 295,311 participants were included in the review: 12 prospective observational studies and 6 RCTs Of these studies, 7 (227,493 participants) assessed vitamin E, 12 (246,488 participants) assessed beta-carotene, and 10 (186,985 participants) assessed vitamin C.
Large, prospective cohort studies of vitamin E suggested that, overall, there is a lower risk of cardiovascular disease for vitamin E users. However, there were several inconsistencies in the data. One study clearly identified that the use of vitamin E supplements (i.e. higher doses than generally provided by diet and multivitamins) for prolonged periods of time (100 IU for at least 2 years) was protective. In contrast, another study did not find a protective effect in women taking vitamin E supplements, although it identified vitamin E from food sources to be potentially protective. Similarly, the RCTs included in the review showed vitamin E to be a potentially promising intervention in preventing cardiovascular disease, although its benefit was not clearly and conclusively demonstrated. The authors identified a number of large ongoing randomised trials looking at the effect of vitamin E supplements in both primary and secondary prevention, which may help to clarify the situation.
The evidence from large, prospective epidemiological studies of beta-carotene was somewhat inconsistent, but did suggest the possibility of lower adverse cardiovascular outcomes; in particular, for men who are current or former smokers, and who consume large amounts of dietary beta-carotene provided by nutritional sources or vitamin supplements. Some of the studies also suggested an association between high beta-carotene intake and a lower risk of cancer, particularly lung cancer. This association was strongest in current and former smokers. Evidence from RCTs failed to demonstrate any benefit for beta-carotene supplementation at adequate doses (leading to 4- to 5-fold rises in blood levels), even for prolonged periods of time (over a decade in one study). Certain studies also highlighted concern that an increased risk of cancer was evident; in particular, one large trial amongst smokers (Beta-Carotene and Retinol Efficacy Trial) was terminated earlier than planned due to an increase in lung cancer amongst individuals randomised to receive beta-carotene and vitamin A. There were no adequate trials to assess the role of beta-carotene in secondary prevention.
The evidence from epidemiological studies was inconclusive and did not clearly identify vitamin C intake as a significant protective factor against cardiovascular disease. In addition, few RCTs (not listed in the results tables) rigorously assessed the effects of vitamin C supplements. One small trial of 578 patients, which assessed the use of 200 mg vitamin C supplements in geriatric patients, found that mortality was not reduced after 6 months. A second larger trial, which examined the effect of a combination of vitamin C and molybdenum, failed to find a reduction in overall mortality or mortality from cardiovascular disease.