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Published on 2 March 2007

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Are some vitamin supplements linked with higher mortality risk?

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In a systematic review and meta-analysis that has already gained wide media coverage and predictable criticism, researchers conclude that supplementation with some antioxidant vitamins may actually increase risk of death. The authors note that oxidative stress is common in many diseases, and that antioxidant supplements are widely taken in the belief that they decrease this and its harmful effects. It is not certain, however, whether these supplements are actually beneficial or harmful. Many trials involving them have been carried out, and the aim of this review was to determine from the published trial data whether antioxidant supplements affect all-cause mortality in adults included in the trials.

The authors carried out a comprehensive literature search for randomised controlled trials that compared one or more antioxidant supplements (beta-carotene, vitamins A, C, and E, and selenium) with placebo or no treatment. Trials that involved healthy people were classed as primary prevention, and those involving people with a specific disease as secondary prevention; all routes, doses and durations were included. Analyses included antioxidants singly or in combination and pre-specified subgroups included analyses without selenium trials and those with a high risk of bias. Primary outcome was all-cause mortality at maximum follow-up.

The literature search identified 16,111 references of which 1,201 (815 trials) were reviewed – the most common reason for exclusion was duplication. After exclusions, there were 385 publications describing 68 randomised trials and including 232,606 participants (range 24 to 39,876): 21 trials (n=164,439) were primary prevention and 47 (n=68,167) secondary prevention. Most (47 trials, 69.1%), had a low risk of bias, the remainder had one or more inadequacies that could increase bias. The pooled analysis showed no significant effect on mortality (RR 1.02, 95% CI 0.98-1.06). When only low-bias trials were analysed, antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). When selenium trials were further excluded from this group, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

The authors conclude that treatment with beta-carotene and vitamins A and E, alone in combination, may increase mortality. They discuss the strengths and weakness of the study, and note that their findings contradict observational studies. While there are number of possible explanations for the findings, the authors stress that they should not be extrapolated to fruits and vegetables in the diet.

National Electronic Library for Medicines 01/03/2007, citing JAMA 2007;297:831-41



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