Supplementation with vitamin E alone is associated with reduced myocardial infarction: A meta-analysis

doi:10.1016/j.numecd.2015.01.008

Nutrition, Metabolism and Cardiovascular Diseases

Volume 25, Issue 4, April 2015, Pages 354-363

https://doi.org/10.1016/j.numecd.2015.01.008 Get rights and content

Highlights

•
We examined the effect of vitamin E alone or in combination with other antioxidants on myocardial infarction.
•
Vitamin E appears ineffective when associated with other antioxidants.
•
When supplemented alone vitamin E reduces myocardial infarction in interventional trials.

Abstract

Background and aims

Previous meta-analyses of interventional trials with vitamin E provided negative results but it remains unclear if this vitamin has some influence on cardiovascular events when supplemented alone. The aim of this study was to compare the effect of vitamin E alone or in combination with other antioxidants on myocardial infarction.

Methods and results

Pubmed, ISI Web of Science, SCOPUS and Cochrane database were searched without language restrictions. We investigated randomized clinical trials studying the effect of vitamin E supplementation on myocardial infarction. Sixteen randomized controlled trials of vitamin E treatment were analyzed in this meta-analysis. The dose range for vitamin E was 33–800 IU. Follow-up ranged from 0.5 to 9.4 years. Compared to controls, vitamin E given alone significantly decreased myocardial infarction (3.0% vs 3.4%) (random effects R.R.: 0.82; 95% C.I., 0.70–0.96; p = 0.01). This effect was driven by reduction of fatal myocardial infarction (random effects R.R.: 0.84; 95% C.I., 0.73–0.96; p = 0.01).

Conclusions

When supplemented alone, vitamin E reduces myocardial infarction in interventional trials while it appears ineffective when associated with other antioxidants.

Introduction

The oxidative stress theory of atherosclerosis is based on the assumption that the initial phase of atherosclerosis is dependent upon oxidative modification of LDL. Thus, LDL accumulates within the arterial wall with ensuing LDL uptake by monocyte-macrophages via the scavenger receptors [1]. Even if recent experimental studies further reinforced the role of reactive oxidant species (ROS) on atherosclerosis [2], [3], a cause–effect association between ROS and plaque destabilization is still elusive. Furthermore, the role of ROS in favoring atherosclerotic damage has been recently questioned because interventional trials with antioxidants in humans provided inconclusive results [2]. Among the antioxidants used in the interventional trials, vitamin E, which inhibits lipid peroxidation, has been the most investigated molecule. The strong interest for this antioxidant was based on observational studies suggesting that in subjects following a diet rich in vitamin E the incidence of cardiovascular events was significantly reduced [3]. Meta-analyses of interventional trials with vitamin E reached conclusions apparently in contrast with observational studies as they consistently failed to show any beneficial effect of vitamin E but even revealed some potentially harmful effects including increase of all-cause mortality [4], [5] or hemorrhagic stroke [6]. These meta-analyses, however, included trials in which vitamin E was used alone or in combination with other antioxidants such as ascorbic acid or carotenoids [4], [5], [6], [7]. As potentially negative interaction between vitamin E and other antioxidants cannot be excluded [8], we investigated if analysis of trials in which only vitamin E was supplemented would have provided different findings. Therefore, we performed two distinct meta-analyses separating the effect of vitamin E in trials where it was supplemented alone with trials where it was supplemented in combination with other antioxidants to evaluate the effect of vitamin E on myocardial infarction.

Section snippets

Eligibility criteria

Types of studies: Randomized clinical trials (RCTs) studying the effect of vitamin E supplementation on myocardial infarction. No language, publication date, or publication status restrictions were imposed.

Information sources

The studies were identified by searching electronic databases. This search was applied to Pubmed, ISI Web of Science, SCOPUS and Cochrane library. The last search was run on December 4th 2014. Reference lists of all studies included in the present systematic review were screened for potential

Study identification

A total of 16 studies [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34] met the inclusion criteria and were included in this meta-analysis (Table 1).

The study identification and selection progression is summarized in Fig. 1.

All studies were written in English. The 16 studies ranged in size from 100 to 39,876 patients (Table 1). Allocation concealment of the RCT is reported in Table 1.

The meta-analysis was performed after identification of

Study population

Clinical characteristics of the study populations are illustrated in Table 1. All the trials included subjects with an average age >50 years. Men and women were almost equally distributed in all trials with the exception of four trials where three recruited only women (WAVE [29], WHS [30] and WACS [21]) and two only men (ATBC [23] and PHS [28]). To avoid the possible influence of hormone replacement therapy and probucol on cardiovascular events, patients randomized to these therapy in the WAVE

Meta-analysis of interventional trials

As a result of widespread heterogeneities among trials we decided to present the analysis with random effects pooling.

Discussion

This study provides evidence that vitamin E supplementation in a range of 400–800 IU/daily is able to decrease myocardial infarction.

In contrast with observational studies showing an inverse association between dietary intake of vitamin E and cardiovascular events [3], supplemental trials with this vitamin provided un-conclusive results. Reviews or meta-analyses of interventional trials consistently showed negative and even harmful effects [6], [42], [43]; in a few cases positive results were

Conflicts of interest

All the Authors approved the submitted version of this manuscript and declare that no conflict of interest exists.

Acknowledgment section

Contributors' statement: LL and FV contributed to the conception and design of the study. All the authors participated in writing the manuscript, and approved the final draft. LL and LP undertook the literature search and retrieval of publications. LL, LP, ADC and LI performed statistical analysis. All authors have read and approved the submission.

References (54)

W.A. Pryor
Vitamin E and heart disease: basic science to clinical intervention trials
Free Radic Biol Med
(2000)
A.R. Jadad et al.
Assessing the quality of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials
(1996)
N.G. Stephens et al.
Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge heart antioxidant study (CHAOS)
Lancet
(1996)
M. Boaz et al.
Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial
Lancet
(2000)
Y.Z. Fang et al.
Free radicals, antioxidants, and nutrition
Nutrition
(2002)
V.P. Palace et al.
Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease
Free Radic Biol Med
(1999)
A.V. Rao et al.
Carotenoids and human health
Pharmacol Res
(2007)
M. Penumetcha et al.
Pretreatment with n-6 PUFA protects against subsequent high fat diet induced atherosclerosis–potential role of oxidative stress-induced antioxidant defense
Atherosclerosis
(2012)
P. Brenneisen et al.
Selenium, oxidative stress, and health aspects
Mol Aspects Med
(2005)
D.P. Vivekananthan et al.
Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials
Lancet
(2003)

R. Ricciarelli et al.

Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition

Free Radic Biol Med

(1999)

A. Azzi

Molecular mechanism of alpha-tocopherol action

Free Radic Biol Med

(2007)

D. Steinberg

Lewis A. Conner memorial lecture. Oxidative modification of LDL and atherogenesis

Circulation

(1997)

B.G. Brown et al.

Is there any hope for vitamin E?

J Am Med Assoc

(2005)

F. Violi et al.

Should antioxidant status be considered in interventional trials with antioxidants?

Heart

(2004)

G. Bjelakovic et al.

Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases

Cochrane Database Syst Rev

(2012)

G. Bjelakovic et al.

Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis

J Am Med Assoc

(2007)

M. Schurks et al.

Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials

Br Med J

(2010)

S.K. Myung et al.

Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials

Br Med J

(2013)

F.A. McAlister et al.

Analysis and reporting of factorial trials: a systematic review

J Am Med Assoc

(2003)

D. Moher et al.

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

PLoS Med

(2009)

F. Angelico et al.

Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis

Cochrane Database Syst Rev

(2007)

J.P. Higgins et al.

Measuring inconsistency in meta-analyses

Br Med J

(2003)

J. Ludbrook

Multiple comparison procedures updated

Clin Exp Pharmacol Physiol

(1998)

C.B. Begg et al.

Operating characteristics of a rank correlation test for publication bias

Biometrics

(1994)

M. Egger et al.

Bias in meta-analysis detected by a simple, graphical test

Br Med J

(1997)

Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-prevenzione trial. gruppo Italiano per lo studio della sopravvivenza nell'Infarto miocardico

Lancet

(1999)

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^☆: This review was conducted and reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) Statement.

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Meta-analysisSupplementation with vitamin E alone is associated with reduced myocardial infarction: A meta-analysis☆

Highlights

Abstract

Background and aims

Methods and results

Conclusions

Introduction

Section snippets

Eligibility criteria

Information sources

Study identification

Study population

Meta-analysis of interventional trials

Discussion

Conflicts of interest

Acknowledgment section

Free Radic Biol Med

Control Clin Trials

Lancet

Lancet

Nutrition

Free Radic Biol Med

Pharmacol Res

Atherosclerosis

Mol Aspects Med

Lancet

Free Radic Biol Med

Free Radic Biol Med

Lewis A. Conner memorial lecture. Oxidative modification of LDL and atherogenesis

Circulation

Is there any hope for vitamin E?

J Am Med Assoc

Should antioxidant status be considered in interventional trials with antioxidants?

Heart

Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases

Cochrane Database Syst Rev

Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis

J Am Med Assoc

Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials

Br Med J

Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials

Br Med J

Analysis and reporting of factorial trials: a systematic review

J Am Med Assoc

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

PLoS Med

Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis

Cochrane Database Syst Rev

Measuring inconsistency in meta-analyses

Br Med J

Multiple comparison procedures updated

Clin Exp Pharmacol Physiol

Operating characteristics of a rank correlation test for publication bias

Biometrics

Bias in meta-analysis detected by a simple, graphical test

Br Med J

Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-prevenzione trial. gruppo Italiano per lo studio della sopravvivenza nell'Infarto miocardico

Lancet

Meta-analysis
Supplementation with vitamin E alone is associated with reduced myocardial infarction: A meta-analysis☆