Vitamins E and C -- antioxidant supplements taken by many American adults -- don't protect against cardiovascular disease when taken individually, according to a long-term study of more than 14,000 male physicians presented at the American Heart Association's Scientific Sessions 2008. Results of the Physician's Health Study II (PHS II) were presented as a late-breaking clinical trial. The study was simultaneously published in the Journal of the American Medical Association.

"We found no compelling evidence that either individual vitamin E or vitamin C reduces the risk of cardiovascular disease," said J. Michael Gaziano, M.D., M.P.H., principal investigator of the study and a cardiologist at Brigham and Women's Hospital and VA Boston Healthcare System in Boston, Mass.

Gaziano said results of the study add to the growing consensus about vitamin E's lack of cardiovascular protection based on several earlier trials that failed to find any effect.

The randomized, double-blind, placebo-controlled trial included 14,641 U.S. physicians 50 and older. Cardiovascular disease in the study included nonfatal heart attack, nonfatal stroke and fatal cardiovascular disease

"This is one of the first large-scale, long-term clinical trials of individual vitamin C supplementation in the prevention of cardiovascular disease," said Howard D. Sesso, Sc.D., M.P.H., co-author and project director of PHS II and assistant professor of medicine at Brigham and Women's Hospital.

Unlike several earlier studies in which vitamins E and C were often given as part of an antioxidant cocktail, this study investigated the two vitamins individually, he said.

The findings are an example of the importance of randomized clinical trials to test promising hypotheses generated by laboratory or observational research, Sesso said. Antioxidant vitamins appeared promising in previous laboratory research and in observational human studies, in which people who reported eating a diet rich in vitamins E and C seemed to have fewer cardiovascular problems.

Fruits and vegetables may provide some protective effect beyond the vitamins they contain, or it could be that people who report eating a lot of fruits and vegetables have other characteristics that lead to better health, Sesso said.

Therefore, researchers needed a large, well-designed, placebo-controlled clinical trial -- one that included a dedicated group of participants.

Each year, the investigators mailed participants calendar packs containing each vitamin or its placebo, depending upon the group to which each physician had been randomly assigned. The doses used in the study (400 international units of vitamin E every other day and 500 milligrams of vitamin C daily) correspond to typical amounts available commercially, Gaziano said.

During an average eight years of follow-up, participants provided annual updates on compliance, various risk factors and health outcomes, allowing the investigators access to their medical records when necessary to confirm cardiovascular events or cause of death.

"Broadly speaking, there has been great interest in antioxidants in the prevention of cardiovascular disease," said Sesso. "Despite promising findings from laboratory research and observational studies, our results from PHS II point to the need for large-scale, long-term clinical trials testing the antioxidant hypothesis."

The final arm of PHS II, testing daily multivitamin supplementation, is ongoing.

Individual author disclosures are available on the abstract.

The study was funded by grants from the National Institutes of Health in Bethesda, Md., and an investigator-initiated grant from BASF Corporation in Florham Park, N.J. BASF Corporation, Wyeth Pharmaceuticals in Madison, N.J., and DSM Nutritional Products, Inc., formerly Roche Vitamins, in Parsippany, N.J., provided study agents and packaging.

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