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

Authors: M Schurks, R Glynn, P Rist, C Tzourio, T Kurth

Reference: BMJ 2010; 341:c5702 (open access)
http://bit.ly/hNKDo7

Reviewer: Robert Goldberg, PhD, Contributing editor, ProCor; Professor of Medicine and Epidemiology, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Reviewer comments: Stroke remains a leading cause of morbidity, mortality, and disability in men and women in industrialized countries throughout the world. Stroke shares many common risk factors with coronary heart disease (CHD), though the predictive utility of several of these risk factors varies, including the type of stroke be it ischemic, hemorrhagic, or otherwise.

While antioxidants have been shown to have some benefit with regards to the primary prevention of CVD, their role in the prevention of all strokes, as well as the major stroke subtypes, is less clearly delineated. This question remains of considerable public health and clinical importance since a large proportion of the American public takes vitamins and other dietary supplements on a regular basis, including vitamin E. The beneficial effects of antioxidants in general, and vitamin E in particular, have been widely touted in the American media. While vitamin E and other antioxidants appear to play an important role in atherogenesis, what remains unclear is whether individuals who consume a regular heart healthy diet, which includes many beneficial micronutrients, need to have their diet supplemented with other dietary or vitamin products as is currently being promulgated in grocery stores and other establishments (e.g., expensive, but "beneficial", vitamin water).

The results of the present meta analysis, which involved the analysis of data from nine randomized trials which examined the effects of vitamin E supplementation on the development of all strokes and the two major stroke subtypes, found that vitamin E had no effects on the risk for all strokes but appeared to be associated with an increased risk of hemorrhagic strokes and a slightly reduced risk of ischemic strokes. The lack of beneficial effects of vitamin E supplementation was observed in both primary and secondary prevention trials.

These data suggest considerable caution in the use of this fat soluble vitamin, though it may have beneficial effects on the risk of ischemic stroke in as yet unidentified healthy or diseased populations. While the pathophysiological mechanisms underlying the possible differential effects of vitamin E on hemorrhagic and ischemic stroke, if real, remain to be elucidated, it remains unclear whether the intake of vitamin E supplements will yield any additional benefits beyond that of a heart healthy diet or other positive lifestyle attributes. Indeed, abstention from smoking, maintaining optimal body weight, low levels of alcohol consumption, regular exercise, and maintenance of normal blood pressure are highly proven modalities for reducing the risk of stroke. At this point in time, this reviewer sees no good reasons for the widespread use of vitamin E supplements for the prevention of strokes.

Purpose of study: To examine the association between vitamin E intake and the risk of developing stroke and its two major subtypes.

Location of study: Boston, MA, US

Study design: Meta analysis

Results: The investigators reviewed studies published in Medline, the Cochrane collaboration, and other sources for randomized controlled trials that investigated the effects of vitamin E consumption on stroke occurrence, including the 2 major stroke subtypes.

After a thorough review of the published literature, a total of 22 possible articles that addressed this topic were identified; of these, nine trials satisfied the investigators pre-defined inclusion criteria.

These nine trials, three of which were carried out in the US, two in Italy, and the remainder elsewhere, enrolled a wide ranging number and pool of both apparently healthy individuals (four primary prevention trials) and those with either prior clinical events or who were considered to be at high risk for CVD (five secondary prevention trials). The median duration of follow-up in these trials ranged from nearly two years to upwards of 10 years. The dosages of vitamin E employed in these trials varied considerably ranging from as little as 50 mg daily to upwards of 800 International units daily. A total of 118,765 persons were included in these trials with 59,357 individuals randomly assigned to vitamin E and 59,408 to placebo; in these trials, approximately 87,000 participants were enrolled in primary prevention trials while the remainder (approximately 31,000 men and women) were enrolled in secondary prevention trials. A total of seven trials provided data for all strokes while five trials provided information on the occurrence of hemorrhagic and ischemic stroke. A total of 1438 strokes occurred in participants randomized to vitamin E therapy while 1475 strokes occurred in persons randomized to placebo therapy.

Based on the pooled trial findings, vitamin E did not appear to have any beneficial effects on the risk of stroke, but appeared to have differential effects on stroke subtype. For all strokes, the pooled relative risk was 0.98 (95% CI 0.91, 1.05). On the other hand, the risk for hemorrhagic stroke was increased by approximately 22% in those who took, as compared to those who did not use, vitamin E supplements (95% CI 0%, 48%); the risk of developing an ischemic stroke was reduced by approximately 10% (95% CI 1% to 18%) in those who were on vitamin E supplements.

In terms of absolute risk, one additional stroke would occur in every 1250 individuals taking vitamin E whereas one ischemic stroke would be prevented in every 476 individuals taking vitamin E.