Vitamin E - The Making of Killer E -Truth Behind Controversy

Like an asteroid slamming into the Earth, like a spaceship landing on the White House lawn, last November the news hit that vitamin E increases mortality.  Yes, according to researchers at Johns Hopkins, vitamin E is a killer.  The vitamin supplement that millions of Americans believe to be a good thing is actually a snake in the grass, waiting to do them in.  The findings are so dire, according to the report, that the public should not take any high-dose supplement because, according to the Hopkins researchers, not only are they dangerous, but there is no evidence that they do anything at all.

These researchers were so concerned about the publics health that they advised public health authorities to launch campaigns warning people about supplements.  Never mind that the evidence on which these claims are based is a numbers game.  Never mind that the evidence is a handful of selected studies mostly involving seriously ill, aged people.  Never mind that studies showing that vitamin E might actually prolong life were omitted.  And, who published this analysis directing every public health official in America to act immediately for the public good?  The Annals of Internal Medicinethe journal of Americas internists.  And, why did the Annals of Internal Medicine publish this alarming report that made headlines all over the world?

Although the authors of the report referred to it as a study in their media appearances, it is actually an analysis of existing studies, or a "meta-analysis.  No patients were recruited; not a capsule was swallowed.  This meta-analysis is strictly armchair number crunching done by computer, with the input courtesy of others.  The motivation behind this meta-analysis was strictly personal interest, according to the lead researcher, Edgar R. Miller III.

The Chosen Few
Nineteen studies were chosen for the Hopkins meta-analysis.1  Only studies that lasted at least one year, and in which 10 or more deaths occurred, were considered.  Most of the studies used data from people who had one or more chronic diseasessuch as serious heart disease, diabetes, Parkinsons, Alzheimers, and kidney failureor who were at risk of developing heart disease.  For example, one such study, the so-called WAVE study, enrolled only women with at least one artery blocked 15-75%.  Huge studies such as the EPESE study, in which vitamin Es effects on mortality were tracked for nine years in more than 11,000 people, did not make the cutperhaps because those taking vitamin E lived longer than those who did not supplement.

Of the 19 studies analyzed, only nine pertain to vitamin E alone.  The rest involved combinations of vitamin E and other nutrients.  According to the authors, this is valid because they controlled for whatever impact these other factors might have had on mortality.  When asked how they could control for how other vitamins and minerals affect vitamin Es influence on mortalitygiven that the impacts are mostly unknownthey responded:

In this analysis, data from factorial trials were restricted to participants not exposed to the second factorial intervention.  In addition, we included other study-specific explanatory variables as second level covariates in the categorical and dose-response hierarchical models.  Due to the limited number of trials, we separately evaluated the impact of adding the following variables:  gender distribution, mean age, use of other vitamins/minerals combined with vitamin E, and average time of follow-up.  Finally, we evaluated the influence of each trial on the results by removing each individual study from the analysis.

The authors of the vitamin E meta-analysis reveal conflicted opinions about vitamin Es effects.  As the authors analyzed data, vitamin Es effects mutated from vitamin E supplementation did not affect all-cause mortality (their own words) to for dosages less than 150 IU/d, all-cause mortality slightly but non-significantly decreased, to Policymaking bodies, which currently do not recommend antioxidant vitamin supplement use to the general population, should also caution the public against the use of high-dosage vitamin E supplementation.  This is quite a hop, skip, and jump for one publication, so we decided to take a closer look.

What the Studies Actually Say
As noted earlier, only nine of the 19 studies included in the meta-analysis provide data on vitamin E alonethe rest are studies of combinations of antioxidants and minerals.  Of the nine studies that provide data on vitamin E alone, seven show no effect on overall mortality, one shows a beneficial effect, and one, the CHAOS study, shows both a negative effect and positive effect.  It is not clear why the CHAOS study was included in the meta-analysis, considering that it has been criticized for faulty methodology.  In this study, the vitamin E group had significantly higher serum cholesterol levels and a significantly greater percentage of participants had high blood pressure, diabetes, and severe coronary artery disease.  The CHAOS study showed a increase in mortality that was not statistically significant.  From these studies, which overwhelmingly conclude that vitamin E did not affect mortality, vitamin Es reputation as killer E was created.  So wheres the killer?

Armchair Scientific Research
The killer E meta-analysis includes only one type of study.  Whether called a prevention, intervention, or clinical trial, these studies supply their subjects with up to a years worth of vitamins and instruct them to show up in three or four months for evaluation.  One way to determine whether the participants are taking the supplements is to have them bring their supply to a visit and count the leftover capsules.

Obviously, this kind of compliance check has its drawbacks.  One study states that compliance was measured by refilling drug supplies every 3 months; nothing else was done to determine whether the subjects were actually taking their pills.  In at least one trial, if the participants did not show up for evaluation, they could still receive their vitamins by mail.  To illustrate how poorly controlled many of these trials were, it was later discovered in the CHAOS trial that 78% of those who died while supposedly taking alpha tocopherol were not in fact taking it.  The studys numbers went from giving the impression that vitamin E kills people to suggesting that vitamin E cuts the risk of heart attack in halfall with the stroke of a pen.  According to the researchers, the findings may have underestimated the true benefit of alpha tocopherol.  By the studys end, only about 40% of the subjects were still taking their vitamins.  Rudolph A. Riemersma, a co-author of the killer E meta-analysis, had previously written that the CHAOS trial was probably too small to examine mortality.  He apparently changed his mind, as the CHAOS study was included in the killer E meta-analysis.