Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases - The Cochrane Library
Abstract
"The increased risk of mortality was associated with
beta-carotene and possibly vitamin E and vitamin A, but was not
associated with the use of vitamin C or selenium. The current evidence
does not support the use of antioxidant supplements in the general
population or in patients with various diseases."
Background
Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.
Objectives
To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.
Search methods
We searched
The Cochrane Library,
MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and
Conference Proceedings Citation Index-Science to February 2011. We
scanned bibliographies of relevant publications and asked pharmaceutical
companies for additional trials.
Selection criteria
We
included all primary and secondary prevention randomised clinical
trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C,
vitamin E, and selenium) versus placebo or no intervention.
Main results
Seventy-eight
randomised trials with 296,707 participants were included. Fifty-six
trials including 244,056 participants had low risk of bias. Twenty-six
trials included 215,900 healthy participants. Fifty-two trials included
80,807 participants with various diseases in a stable phase. The mean
age was 63 years (range 18 to 103 years). The mean proportion of women
was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the
factorial design, and 2 the cross-over design. All antioxidants were
administered orally, either alone or in combination with vitamins,
minerals, or other interventions. The duration of supplementation varied
from 28 days to 12 years (mean duration 3 years; median duration 2
years). Overall, the antioxidant supplements had no significant effect
on mortality in a random-effects model meta-analysis (21,484
dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials,
relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but
significantly increased mortality in a fixed-effect model (RR 1.03, 95%
CI 1.01 to 1.05). Heterogeneity was low with an I
2-
of 12%. In meta-regression analysis, the risk of bias and type of
antioxidant supplement were the only significant predictors of
intertrial heterogeneity. Meta-regression analysis did not find a
significant difference in the estimated intervention effect in the
primary prevention and the secondary prevention trials. In the 56 trials
with a low risk of bias, the antioxidant supplements significantly
increased mortality (18,833 dead/146,320 (12.9%) versus 10,320
dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was
confirmed by trial sequential analysis. Excluding factorial trials with
potential confounding showed that 38 trials with low risk of bias
demonstrated a significant increase in mortality (2822 dead/26,903
(10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15).
In trials with low risk of bias, beta-carotene (13,202 dead/96,003
(13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01
to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561
dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05)
significantly increased mortality, whereas vitamin A (3444 dead/24,596
(14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97
to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283
(9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670
dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97,
95% CI 0.91 to 1.03) did not significantly affect mortality. In
univariate meta-regression analysis, the dose of vitamin A was
significantly associated with increased mortality (RR 1.0006, 95% CI
1.0002 to 1.001, P = 0.002).
Authors' conclusions
We
found no evidence to support antioxidant supplements for primary or
secondary prevention. Beta-carotene and vitamin E seem to increase
mortality, and so may higher doses of vitamin A. Antioxidant supplements
need to be considered as medicinal products and should undergo
sufficient evaluation before marketing.
Plain language summary
Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases
Previous
research on animal and physiological models suggests that antioxidant
supplements have beneficial effects that may prolong life. Some
observational studies also suggest that antioxidant supplements may
prolong life, whereas other observational studies demonstrate neutral or
harmful effects.
Our Cochrane review from 2008 demonstrated that
antioxidant supplements seem to increase mortality.
This review is now
updated.
The present systematic review included 78 randomised
clinical trials. In total, 296,707 participants were randomised to
antioxidant supplements
(beta-carotene, vitamin A, vitamin C, vitamin E,
and selenium) versus placebo or no intervention. Twenty-six trials
included 215,900 healthy participants. Fifty-two trials included 80,807
participants with various diseases in a stable phase (including
gastrointestinal, cardiovascular, neurological, ocular, dermatological,
rheumatoid, renal, endocrinological, or unspecified diseases). A total
of 21,484 of 183,749 participants (11.7%) randomised to antioxidant
supplements and 11,479 of 112,958 participants (10.2%) randomised to
placebo or no intervention died. The trials appeared to have enough
statistical similarity that they could be combined.
When all of the
trials were combined, antioxidants may or may not have increased
mortality depending on which statistical combination method was
employed; the analysis that is typically used when similarity is present
demonstrated that antioxidant use did slightly increase mortality (that
is, the patients consuming the antioxidants were 1.03 times as likely
to die as were the controls). When analyses were done to identify
factors that were associated with this finding, the two factors
identified were better methodology to
prevent bias from being a factor
in the trial (trials with ‘low risk of bias’) and the use of vitamin A.
In fact, when the trials with low risks of bias were considered
separately, the increased mortality was even more pronounced (1.04 times
as likely to die as were the controls). The potential damage from
vitamin A disappeared when only the low risks of bias trials were
considered.
The increased risk of mortality was associated with
beta-carotene and possibly vitamin E and vitamin A, but was not
associated with the use of vitamin C or selenium. The current evidence
does not support the use of antioxidant supplements in the general
population or in patients with various diseases.
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