Letters

Role of antioxidant vitamins in prevention of cardiovascular diseases

Meta-analysis seems to exclude benefit of vitamin C supplementation

Authors' reply

Meta-analysis seems to exclude benefit of vitamin C supplementation

EDITORThe first article in the series on evidence based cardiology summarises evidence on the effect of antioxidant vitamins on the risk of cardiovascular disease.¹ The summary of the trial evidence for vitamin C supplementation is, however, incomplete, and the authors' interpretation of the available data on antioxidants is too optimistic.

The authors describe Wilson et al's trial of vitamin C, in which 538 patients admitted to an acute geriatric unit were randomised to receive 200 mg of vitamin C or placebo daily for six months.² We are aware of two further trials of vitamin C supplementation in Western populations that have reported on mortality from all causes. Burr et al randomised 297 elderly people with low vitamin C concentrations to receive vitamin C (150 mg a day for 12 weeks and 50 mg a day thereafter) or placebo for two years.³ Hunt et al randomised 199 elderly patients to receive 200 mg of vitamin C or placebo daily for six months.⁴

We performed a meta-analysis of all three trials using a fixed effects model (figure). Even though the three trials were small and relatively short, the combined results seem to exclude any substantial early benefit of vitamin C supplementation. The overall relative risk shows an increase in mortality of 8%, with the 95% confidence interval ranging from a 7% reduction to a 26% increase in mortality (P=0.29). An earlier meta-analysis of the  carotene trials also showed a moderate adverse effect, which was significant (P=0.005).⁵

View larger version (18K): [in this window] [in a new window]   Results of meta-analysis of three trials of vitamin C supplementation in elderly subjects, showing mortality from all causes. *Amount that each study contributes to pooled estimate of effect of vitamin C supplements.

Lonn and Yusuf argue that the strong biological rationale and observational epidemiological data relating antioxidants to lower cardiovascular risk justify ongoing trials. We believe that the disappointing results for vitamin C and  carotene should lead us to re-evaluate critically the status of the antioxidant hypothesis and to consider confounding as an alternative explanation for the lower cardiovascular risk observed in epidemiological studies.⁵

The ongoing trials of antioxidant vitamins should continue because we need to know whether vitamin supplementswidely used in preparations sold over the counterproduce any benefit or are in fact harmful. When potentially protective dietary constituents are identified in the future it may be more sensible to undertake trials of foods that are rich sources of these constituents rather than supplementation trials.

Andy Ness, senior lecturer in epidemiology. 
Andy.Ness{at}bris.ac.uk

Matthias Egger, senior lecturer in epidemiology and public health medicine. 
George Davey Smith, professor of clinical epidemiology. 
Department of Social Medicine, Bristol BS6 7DP

Authors' reply

EDITORWe do not believe that there is any major disagreement between our views and those expressed in Ness et al's letter. The two additional negative trials of vitamin C that they mention were quite small clinical trials, and overall we believe that the clinical trials data for vitamin C remain inconclusive. As we stated in our review article, we found the observational data for vitamin C to be not particularly supportive of a role for the vitamin in reducing cardiovascular risk. The use of vitamin C supplements (in isolation) in cardiovascular prevention is therefore not promising.

The epidemiological data for ß carotene and especially for vitamin E are more promising. We agree with Ness et al that the clinical trials of ß carotene, although performed only in men and in primary prevention settings, have effectively shown the lack of efficacy of supplementation with ß carotene. As the authors are aware, interesting epidemiological data exist for other carotenoids and for diets rich in fruit and vegetables with high contents of carotenoids as potential protective factors in cardiovascular prevention. Further clinical trials data are needed for vitamin E.

We do not believe that our view is too optimistic. As we clearly stated in our paper, we agree that results of clinical trials do not at present support the use of antioxidant vitamin supplements in cardiovascular prevention. We do, however, believeas do many other investigators around the worldthat clinical trials are warranted to clarify this issue, particularly regarding vitamin E.

Several large clinical trials are ongoing or have been completed recently. The GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardio) prevention study, conducted in 12 000 patients after myocardial infarction, reported a modest, non-significant 4.7% reduction in risk for the end point cluster of total mortality, non-fatal myocardial infarction, and cerebrovascular accident. These data further put into question the results of other trials and experimental basic research studies and epidemiological investigations.

We believe that the medical community should await the results of the other ongoing trials of vitamin E, including the study coordinated by our centre. This is the heart outcomes prevention evaluation trial, in 9541 patients, which will provide more conclusive results regarding a potential role for vitamin E in cardiovascular prevention.

Eva Lonn, associate professor of medicine. 
lonnem{at}fhs.mcmaster.ca

Salim Yusuf, professor of medicine. 
Division of Cardiology, Hamilton Health Sciences Corporation, General Site, Hamilton, ON L8L 2X2, Canada