Increased risk of hemorrhagic stroke with vitamin E cancels lesser benefits on ischemic stroke

 A meta-analysis of current relevant research provides more evidence of opposing effects of vitamin E on stroke subtypes. The researchers found a 22% increased risk of hemorrhagic stroke and a 10% decreased risk of ischemic stroke with vitamin-E supplementation, although the absolute effects are small.

The findings were published online November 4, 2010 in BMJ.

"Vitamin-E supplementation does not appear to be as safe as it was believed," first author Markus Schürks (Brigham and Women's Hospital, Boston, MA) noted in an email.

"Vitamin E appears to increase the risk for brain hemorrhage," he added. "Although there is also a reduced risk for ischemic stroke, hemorrhagic strokes are usually more severe than ischemic strokes, and the potential gain with regard to ischemic stroke is low."

Schürks especially noted, "The gain from other established stroke-prevention measures, such as blood-pressure control, healthy diet, weight control, and not smoking, is much higher and extends to both ischemic and hemorrhagic stroke. Hence, widespread and uncontrolled use of vitamin E should be cautioned against."

Composite end points may obscure effects

A number of large controlled clinical trials, as well as two recent meta-analyses, have investigated the effects of vitamin E on incident major cardiovascular events. The results of these investigations have been "largely disappointing," the investigators note in their report, with no overall effect of vitamin E on main composite end points, including MI, total stroke, and mortality.

But use of a composite outcome may be problematic, Schürks said, because there is evidence that the underlying pathophysiologies for MI and stroke and ischemic and hemorrhagic stroke are different, and so these composite end points may obscure effects on different kinds of vascular outcomes.

Therefore, Schürks and associates from the US, France, and Germany conducted a systematic review and meta-analysis of nine randomized controlled trials that looked only at vitamin E and its reported effect on incident stroke and stroke subtypes. The trials included a total of 118 765 subjects (59 357 randomized to vitamin E and 59 408 to placebo).

Only trials that investigated the effect of pure vitamin-E supplements on stroke were included; trials that included multivitamins or fixed vitamin combinations were excluded.

Differential effects by subtype

According to the researchers, none of the seven trials that provided data on total stroke suggested that vitamin E significantly alters the risk of total stroke. There were 1438 strokes among 58 225 subjects randomized to vitamin E and 1475 among 58 342 subjects randomized to placebo, yielding a pooled relative risk of 0.98 (95% CI 0.91-1.05; p=0.53).

A different picture emerged when the effect of vitamin E was analyzed by type of stroke. In the five trials that provided data on hemorrhagic stroke, a total of 223 hemorrhagic strokes occurred among the 50 334 assigned to vitamin E and 183 hemorrhagic strokes occurred among the 50 414 assigned to placebo. The pooled relative risk for hemorrhagic stroke with vitamin E was 1.22 (95% CI 1.00-1.48; p=0.045).

In the five trials that provided data on ischemic stroke, a total of 884 ischemic strokes occurred among 45 670 subjects assigned to vitamin E and 983 ischemic strokes occurred among 45 733 assigned placebo, yielding a pooled relative risk of 0.90 (95% CI 0.82-0.99; p=0.02).

"There was little evidence for heterogeneity among studies," the investigators note. "Meta-regression did not identify blinding strategy, vitamin-E dose, or morbidity status of participants as sources of heterogeneity."

They point out that, in terms of absolute risks and benefits, their findings translate into one additional hemorrhagic stroke for every 1250 individuals taking vitamin E and one ischemic stroke prevented per 476 individuals taking vitamin E.

Reasons for the diametric effects unclear

Why vitamin E may increase in the risk for hemorrhagic stroke and perhaps reduce the risk for ischemic stroke is not entirely clear.

In an email, Dr Francesco Violi (Sapienza University of Rome, Italy), who was not involved in the study, noted that vitamin E has several properties that may potentially account for these divergent effects.

"Vitamin E has antiatherosclerotic and antiplatelet effects that may reduce the rate of ischemic stroke. On the other hand, vitamin E exerts an anticoagulant effect via inhibition of vitamin K-dependent clotting-factors activation," Violi explained.

"Many biological mechanisms of vitamin E," Schürks added, "are just being discovered, and these might help to understand the effects seen in the future."