I know there ia alot of peop[le on this site taking vitamin e for its antioxidant effects and taking it in doses greater than 400iu daily
Nov. 12, 2004 Results of a meta-analysis of 19 randomized, placebo-controlled trials suggest that high dosages of vitamin E increase risk of all-cause mortality, and this dose-dependent increase begins at doses of 150 IU/day, said lead author Edgar R. Miller, III, MD, PhD, an associate professor at Johns Hopkins University in Baltimore, Maryland.
The study was presented at the American Heart Association 2004 Scientific Sessions, New Orleans, Louisiana, and simultaneously published in the Nov. 10, 2004, Early Release Article issue of the Annals of Internal Medicine.
Miller said that when he pooled data from almost 136,000 patients who participated in 19 clinical trials of vitamin E, "it was clear that as the vitamin E dose increased, so does all cause mortality. At 400 IUs, which is the most common marketed dose, the risk of dying is about 10% higher than risk among people not taking the vitamin."
At mega-doses, such as the 2,000 IU/day used in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial and in the Alzheimer's Disease Cooperative Study (ADCS) the increased risk was more than 20%, Dr. Miller said.
"Based on our findings, high dose vitamin E supplementation is unjustified," Dr. Miller said. Although vitamins and other supplements are not regulated by the Food and Drug Administration, an Institute of Medicine report issued in 2000 recommended 1,000 IU/day as the "upper tolerable limit" for vitamin E. "We recommend that the upper tolerable limit be lowered to 400 IUs/day," Dr. Miller said. Dr. Miller noted that adults receive about 10 IU of vitamin E from diet.
"This is the most important story from this meeting," Raymond Gibbons, MD, a professor of medicine at the Mayo Clinic in Rochester, Minnesota, told Medscape. Dr.Gibbons, who served as chair of the scientific program committee at the meeting, said he has been urging his patients to stop taking vitamin E for years. Dr. Gibbons said that
cardiovascular disease prevention guidelines from "vitamin E is not recommended'. It doesn't get clearer than that don't take it."
Gibbons said he hopes this latest report will finally debunk the vitamin E myth.
That is unlikely judging from the lightening fast response from the Council for Responsible Nutrition (CRN), the trade group that lobbies for the supplement industry. Annette Dickinson, PhD, president of CRN told Medscape, "18 of the 19 studies in the analysis showed no statistically significant increase in total mortality. I believe he [Dr. Miller] pooled the data to arrive at a conclusion that is based on a statistical artifact."
Asked to comment on that criticism, Dr. Gibbons said, "that is just flat out wrong. In the British Heart Protection Study, the patients taking vitamin E ended up on the wrong side of the survival line. It was not a statistical glitch; it was a clear indication of increased mortality." The Medical Research Council/British Heart Foundation Heart Protection Study, which is the study cited by Dr. Gibbons, randomized 10,269 patients to 660 IU/day of vitamin E and 10,267 to placebo control. The vitamin E group was associated with about a 10% increase in mortality. The study also evaluated the effect of statin therapy.
Moreover, Dickinson said that all the people in the 19 studies were "already sick. They had
heart disease or cancer or Alzheimer's disease. The definitive study to test vitamin E in a healthy population has not been done."
Again, Dr. Gibbons took exception with this statement. "There's no question that the British Heart Protection study was done in patients with known or presumed heart disease. However, the potential benefit [of a drug] is usually greater in those with the greatest risk. Aspirin is the prime example. Daily aspirin in people with heart disease reduces the risk of heart attack. No ifs, ands or buts risk is reduced. But if you look at primary prevention with aspirin giving aspirin to people with no heart disease the results are mixed and low risk individuals shouldn't be taking daily aspirin."
In a prepared statement sent out to health care reporters nationwide, CRN quotes Dr. Miller's study this way: "The researchers themselves noted limitations in their meta-analysis, stating the generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult.'"
However, a review of the published article finds that CRN has done some creative editing. Miller and his coauthors actually write: "In addition, high-dosage vitamin E trials were often performed in patients with various chronic diseases, and we could not evaluate the generalizability of our findings to healthy adults." Later in the same paragraph, the authors write, "Hence, although identifying precisely the threshold at which risk increases is difficult, our meta-analysis probably provides the best estimate of the dose-response effect of vitamin E supplementation on mortality."
The news about vitamin E will be surprising to many people because the vitamin was so widely touted for its ability to reduce the risk of heart disease, said Miller. In fact, at one point physicians many of whom were taking the vitamin themselves used to recommend that patients take vitamin E.
The driving force behind rise in popularity of vitamin E was reports from observational studies that people who took vitamin E had fewer heart attacks and strokes. The evidence for vitamin E benefit, said Dr.Miller, was very much like the "evidence" that postmenopausal women taking hormone replacement therapy had less heart disease and just like estrogen, when put to rigorous scientific testing the benefit disappeared.
"But there was a general sense that while vitamin E didn't prevent heart disease, it didn't do any harm either," said Miller. In fact, three earlier meta-analyses reported that "vitamin E had no effect good or bad on survival," Dr. Miller said. Yet, a handful of studies of high-dose vitamin E reported increases in mortality, although the increases were not statistically significant.
"Individual studies usually test only one or two doses and we suspected that there might be a dose response between mortality risk and vitamin E, which is why we did this meta-analysis that includes doses as low at 16.5 IU all the way up to 2000 IU a day," Miller said.
Dr. Miller said there are several theories about why vitamin E increases risk. One theory is that it increases bleeding risk, which would increase the risk of hemorrhagic stroke, while another theory suggests that at high doses vitamin E stops working like an antioxidant that mops up free radicals that attack cells that line blood vessels and instead becomes a prooxidant and actually promotes the production of free radicals.
Still another scenario suggests that high-doses of vitamin E tend to destroy other fat-soluble antioxidants, which disrupts the body's natural antioxidant protection system.
Yet, even without a clear explanation of how vitamin E could increase mortality, Miller and colleagues conclude that vitamin E supplements should be avoided.
Ann Intern Med. Posted online Nov. 10, 2004.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
List possible physiologic and clinical adverse events associated with vitamin E supplementation.
Specify dosages at which vitamin E supplementation presents the greatest risk of mortality.
Clinical Context
Vitamin E supplementation is used by patients for a variety of health goals, from reducing the risk of cardiovascular disease to slowing the progression of Alzheimer's disease. However, the authors of the current study note that vitamin E supplementation may cause negative physiologic and clinical effects. Although the antioxidant effects of vitamin E have been well-documented, high-dose supplements of vitamin E may possess prooxidant effects. This may be in part due to vitamin E displacing other fat-soluble antioxidants at such doses. Vitamin E can also act as an anticoagulant and has been linked to an increased risk of hemorrhagic stroke. Finally, high-dose supplementation with vitamin E may lead to a withdrawal syndrome on discontinuation of supplementation.
The authors also note that vitamin E supplementation has not conclusively been shown to impact all-cause mortality. They performed the following meta-analysis to determine if vitamin E supplementation might provide a survival benefit compared with no supplementation.
Study Highlights
The authors reviewed articles from MEDLINE and The Cochrane Library if they met the following criteria:
The study was a randomized, controlled trial.
Vitamin E was used in one of the treatment groups, either alone or in combination with other supplements.
The duration of vitamin E supplementation was at least one year.
The trial included at least 10 deaths.
36 studies were initially identified, of which 19 qualified for review. The total number of participants in these trials was 135,967, and the number of cumulative deaths was 12,504. The mean age ranged between 47 to 84 years old. 17 trials included men and women, while 2 trials were conducted that isolated men and women separately for analysis. Most trials involved patients at high risk of chronic disease, such as coronary heart disease.
Average follow-up time for the studies examined was from 1.4 to 8.2 years. The median dose of vitamin E was 400 IU/day but ranged between 16.5 to 2,000 IU/day.
The overall mortality rate was 1,022 per 10,000 subjects. The pooled risk ratio for all-cause mortality associated with vitamin E supplementation was 1.01, a nonsignificant difference.
Eight trials examined vitamin E supplementation at doses less than 400 IU/day. The risk ratio of mortality associated with vitamin E supplementation for these trials was 0.98.
Eleven trials examined vitamin E supplementation at doses of 400 IU/day or more. The risk ratio of mortality associated with vitamin E supplementation for these trials was 1.04, a significant increase in the risk of death compared with no supplementation.
In a dose-response analysis, mortality increased fairly steadily as the dose of vitamin E supplementation rose to more than 150 IU/day. A nonsignificant decrease in mortality was associated with doses of less than 150 IU/day.
The effects of vitamin E on mortality did not change following adjustment for sex distribution, mean age, or average follow-up across trials. However, in controlling for the concomitant use of other supplements in addition to vitamin E, the risk of mortality associated with vitamin E increased slightly.
Data were reanalyzed after removing results from each of the 19 individual trials, and no one study dominated the findings.
Pearls for Practice
Vitamin E supplementation, especially at high doses, may be associated with multiple deleterious effects, including prooxidant effects, anticoagulant effects, and withdrawal.
Vitamin E at doses of 400 IU/day or more may increase all-cause mortality.
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