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

It is difficult to see why a combination of vitamin C with other vitamins should reduce its protective effects, if they were real, and 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 the figure for vitamin C.

Abstract

In observational studies, antioxidant vitamins have been inversely associated with cardiovascular disease, cancer, and all-cause mortality. 1 Khaw KT Bingham S Welch A et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001; 357: 657-663 Summary Full Text Full Text PDF PubMed Scopus (452) Google Scholar , 2 Rimm EB Stampfer MJ Ascherio A Giovannuci E Colditz GA Willet WC Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993; 328: 1450-1456 Crossref PubMed Scopus (2131) Google Scholar , 3 Stampfer MJ Hennekens CH Manson JE Colditz GA Rosner B Willett WC Vitamin E consumption and the risk of coronary heart disease in women. N Engl J Med. 1993; 328: 1444-1449 Crossref PubMed Scopus (1916) Google Scholar However, well conducted randomised controlled trials have shown that supplementation with antioxidants does not protect against these disorders. 4 The Alpha-Tocopherol Beta Carotene cancer prevention study group The effect of vitamin E and Beta carotene on the incidence of lung cancer and other causes in male smokers. N Engl J Med. 1994; 330: 1029-1035 Crossref PubMed Scopus (4379) Google Scholar The figure, for example, summarises the effects of vitamin C seen in the largest randomised controlled trial to date, 5 Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 23-33 Summary Full Text Full Text PDF PubMed Scopus (1364) Google Scholar and in a large observational study. 1 Khaw KT Bingham S Welch A et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001; 357: 657-663 Summary Full Text Full Text PDF PubMed Scopus (452) Google Scholar 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 observational 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 Rimm EB Stampfer MJ Ascherio A Giovannuci E Colditz GA Willet WC Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993; 328: 1450-1456 Crossref PubMed Scopus (2131) Google Scholar , 3 Stampfer MJ Hennekens CH Manson JE Colditz GA Rosner B Willett WC Vitamin E consumption and the risk of coronary heart disease in women. N Engl J Med. 1993; 328: 1444-1449 Crossref PubMed Scopus (1916) Google Scholar , 4 The Alpha-Tocopherol Beta Carotene cancer prevention study group The effect of vitamin E and Beta carotene on the incidence of lung cancer and other causes in male smokers. N Engl J Med. 1994; 330: 1029-1035 Crossref PubMed Scopus (4379) Google Scholar Beyond randomised versus observational studiesIn this week's Lancet, Debbie Lawlor and colleagues and Jan Vandenbroucke discuss the role of observational studies and randomised controlled trials in patient-oriented research. Lawlor and colleagues urge a more careful approach to observational studies, such as adjusting for all measured potential confounding variables, including exposures in early life (or subsequent adult biomarkers), and mathematical sensitivity analyses of unmeasured confounders. Vandenbroucke, addressing the same issue, suggests a three-pronged restriction of observational studies, in terms of research topics (such as adverse events), study design (for types of exposure), and analysis (when adjusting for confounding factors). Full-Text PDF