Reexamination of a Meta-Analysis of the Effect of Antioxidant Supplementation on Mortality and Health in Randomized Trials

Abstract

A recent meta-analysis of selected randomized clinical trials (RCTs), in which population groups of differing ages and health status were supplemented with various doses of β-carotene, vitamin A, and/or vitamin E, found that these interventions increased all-cause mortality. However, this meta-analysis did not consider the rationale of the constituent RCTs for antioxidant supplementation, none of which included mortality as a primary outcome. As the rationale for these trials was to test the hypothesis of a potential benefit of antioxidant supplementation, an alternative approach to a systematic evaluation of these RCTs would be to evaluate this outcome relative to the putative risk of greater total mortality. Thus, we examined these data based on the primary outcome of the 66 RCTs included in the meta-analysis via a decision analysis to identify whether the results provided a positive (i.e., benefit), null or negative (i.e., harm) outcome. Our evaluation indicated that of these RCTs, 24 had a positive outcome, 39 had a null outcome, and 3 had a negative outcome. We further categorized these interventions as primary (risk reduction in healthy populations) or secondary (slowing pathogenesis or preventing recurrent events and/or cause-specific mortality) prevention or therapeutic (treatment to improve quality of life, limit complications, and/or provide rehabilitation) studies, and determined positive outcomes in 8 of 20 primary prevention studies, 10 of 34 secondary prevention studies, and 6 out of 16 therapeutic studies. Seven of the eight RCTs with a positive outcome in primary prevention included participants in a population where malnutrition is frequently described. These results suggest that analyses of potential risks from antioxidant supplementation should be placed in the context of a benefit/risk ratio.

Adverse effects of antioxidative vitamins

“…Regarding oncology, a meta-analysis by Myung et al [107] affirmed the preventive effects of supplementation with vitamins E, C and β-carotene against cervical neoplasms, including invasive cancer. At the end of this review of meta-analyses, it is worth referring to a recently published work, which questions credibility of the aforementioned alarmist results that have been earlier reported by Bjelakovic et al It is a reanalysis of two meta-analyses by these researchers [98,99] made by Biesalski et al [108] using the same dataset. This reanalysis has led to statement contradictory to the above results that 36% of source studies revealed beneficial effects of supplementation with antioxidants, 60% null…”

“…Hypervitaminosis A can take the form of acute or chronic poisoning. The first of these two forms appears after the IJOMEH 2012;25(2) 108 be administered under strict medical control (it is advisable to eliminate animal liver from the diet) [3,37,38]. High-dose vitamin A therapy in breast-feeding women, which could cause symptoms of hypervitaminosis in infants, is contraindicated [20,21].…”

Oxidative and Nitrosative Stress on Phagocytes’ Function: from Effective Defense to Immunity Evasion Mechanisms

“…Pathogens display many different antioxidant systems to deactivate phagocyte free radicals. Considering that the majority of randomized clinical trials with antioxidant therapy in healthy subjects or infectious diseases patients had no effects on morbidity and mortality or had negative outcomes (Ackerman et al 2009;Biesalski et al 2010;Charunwatthana et al 2009;Lykkesfeldt and Poulsen 2009), and that in chronic hepatitis C antioxidant therapy had just mild positive effects for patients (Gabbay et al 2007), the concept of antioxidant therapy is questionable and should regard the role of phagocyte oxidative/nitrosative burst in infectious and parasitic diseases.…”

Skeletal muscle reactive oxygen species: A target of good cop/bad cop for exercise and disease

“…However, it should be noted that many of these large studies were limited by study design and subject selection factors. 37 Moreover, most studies lacked insight into the mode of action of specific antioxidants and their biological targets, 37,38 thus making the interpretation of the findings difficult.…”