Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence?

Both these papers were published in The Lancet, both are thought to be methodologically sound, and both are widely cited, yet their conclusions are contradictory. In this example, in the randomised trial vitamin C was part of a multivitamin supplement, whereas in the observa- tional study plasma concentrations of vitamin C were assessed. However, it is difficult to see why a combination of vitamin C with other vitamins should reduce its protective effects, if they were real. Furthermore, in the case of other antioxidant vitamins, notably vitamin E, results of single-factor trials and observational studies show a similar discordance to those seen in our figure for vitamin C. 2-4 Why did observational studies and randomised controlled trials come up with different answers? Several reasons have been proposed for the disparity between the results of observational epidemiological studies and trials. First, antioxidants might be useful only for primary prevention of cardiovascular disease, and not protective once atherosclerosis is established. 6 However, trials 4,7 found that antioxidants did not reduce cardio- vascular disease risk in participants who had no evidence of this disorder at randomisation. Second, in many of the trials the choice of antioxidant regimen has been criticised. 6