A recent Journal of the American Medical Association (JAMA) metanalysis (Volume 285(1), 3 January 2001, pp 67-72) shows that “treatment with [the antioxidant supplements] beta carotene, vitamin A, and vitamin E may increase mortality“. As a nutritionist, Holford disagrees with this argument; unfortunately (given that many will trust Holford’s recommendations on which supplements to take) Holford’s objections to the article are largely invalid.
Holford gave his response to the JAMA article in a press release, and e-mailed it to his 100% health e-mail list. I’ve quoted (in italics) from Holford’s e-mail below; the press release is reproduced here.
The first way to investigate whether an analysis of studies is biased is to read the summary, and see if it correlates with the actual result. The conclusion of this study says ‘treatment with beta carotene, vitamin A, and vitamin E may increase mortality’ creating the impression these antioxidants are no good. What it fails to say, all of which are clearly shown in the results, is that ‘vitamin C given singly, or in combination with other antioxidants, and selenium given singly or in combination with other antioxidant supplements may reduce mortality’.
– The abstract of the JAMA article says that “The potential roles of vitamin C and selenium on mortality need further study.” It therefore does say that there’s a need for further study on the role of vitamin C and selenium supplementation, and that they may have reduce (or increase) mortality. This seems quite clear to me, and does correlate well with the conclusions of the meta-analysis.
The meta-analysis doesn’t explicitly say that different combinations of antioxidants may have different effects (or, for example, that antioxidant may have different effects if you exercise regularly, smoke 30 a day, etc.) It didn’t seek to analyse every possible combination of factors, and it wouldn’t have been feasible to do this.
The next way to investigate whether an analysis is a stitch up is to see if all trials are included, how trials are excluded, and what the trials actually say. Two classic primary prevention studies, where vitamin E is given to healthy people, are those of Stampfer et al, published in the New England Journal of Medicine, the first of which gave 87,200 nurses were given 67mg of vitamin E daily for more than two years. A 40 per cent drop in fatal and non-fatal heart attacks was reported compared to those not taking vitamin E supplements (1). In another study, 39,000 male health professionals were given 67mg of vitamin E for the same length of time and achieved a 39 per cent reduction in heart attacks (2). Guess what? They are not included.
– The JAMA paper explicitly sets out to analyse randomised trials. The Stampfer et al article was nothing of the sort – it analyses the correlation between heart disease and vitamin E consumption. There’s no randomisation, and people who eat lots of vitamin E or take a supplement may differ from those who don’t in significant ways (for example, if you’re concerned enough about your health to take a supplement, you may be more likely to eat a decent diet). Stampfer et al are quite clear about what their study does and does not show in the abstract “Although these prospective data do not prove a cause-and-effect relation, they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of these trials.” The paper is freely available here, for those who want to assess it themselves.
The second article Holford mentions – Rimm et al – is in the same issue of NEJM here. Again, it’s not a randomised study: they look at correlations between vitamin consumption and heart disease in health professionals. The authors conclude by stating that “These data do not prove a causal relation, but they provide evidence of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men. Public policy recommendations with regard to the use of vitamin E supplements should await the results of additional studies.”
The next test is to see if the most negative studies were actually negative. These studies can skew results on an overall analysis. One the studies most cited to show increase risk of gastrointestinal cancer is that of Correa et al. So I read the actual paper and contacted the author, Dr Pelayo Correa from the pathology department at the Louisiana State University Health Sciences Centre in New Orleans, and asked about the increased risk he had supposedly found. He was amazed, he said, because his research, far from being negative, had shown clear benefit from taking vitamins…Without this study the main conclusion, that antioxidants may increase gastrointestinal cancer, becomes completely invalid.
– Firstly, Holford’s largely right about the Correa et al study, although the published study was much more cautious in its conclusions: it argues that “In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.”* However, I’m not sure how Holford concludes that the JAMA meta-analysis assumes that Correa et al’s paper is negative: the results would have been included in the meta-analysis as would the results of all the other trials with low bias risk. Others may have misread Corea et al’s article as showing that taking vitamin E could have been damaging, but I can’t see any evidence that the JAMA meta-analysis has done the same thing.
Secondly, the JAMA meta-analysis does not conclude (as a main conclusion, or otherwise) “that antioxidants may increase gastrointestinal cancer”. The meta-analysis states explicitly that “We found that antioxidant supplements, with the potential exception of selenium, were without significant effects on gastrointestinal cancers”.
Holford concludes by arguing that:
I will keep doing what I’ve always been doing, because this study confirms it – and that is to supplement a combination of antioxidants, including selenium and high dose vitamin C, because, as this study says, it seems to make you live longer and reduce your risk of premature death.
– The JAMA meta-analysis does not say this. It concludes that “Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study”. Moreover, “In low-bias risk trials, after exclusion of selenium trials, beta carotene…vitamin A…and vitamin E …singly or combined, significantly increased mortality.” In the trials included in the meta-analysis, “Vitamin C and selenium had no significant effect on mortality.” This does not verify Holford’s claim that such supplementation ‘seems to make you live longer and reduce your risk of premature death’.
* see Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 2000;92:1881–1888.