New Orleans, LA - Randomized results from the Physicians' Health Study II (PHS2) show no effect of either vitamin E or vitamin C supplements in reducing a composite of nonfatal MI, nonfatal stroke, or cardiovascular death after eight years of treatment.

There was an increase in hemorrhagic stroke with vitamin E supplements that was marginally significant, but no increase in congestive heart failure was seen in this population of male physicians.

"In conclusion, PHS demonstrated that individual vitamin E and vitamin C supplements did not reduce the risk of major cardiovascular events," Dr J Michael Gaziano (Brigham and Women's Hospital and the Harvard School of Public Health, Boston, MA), senior author of the trial, told a press conference here.

"Available trial data do not support the use of vitamin E and vitamin C supplements as part of a comprehensive CVD prevention strategy."

The results were presented here at the American Heart Association Scientific 2008 Sessions and published simultaneously online in the Journal of the American Medical Association ahead of the November 12, 2008 issue.

First author on the publication is Dr Howard D Sesso (Brigham and Women's Hospital and the Harvard School of Public Health). Sesso will present cancer end-point results from the PHS2 next week at the American Association for Cancer Research prevention meeting, in Washington, DC.

Billion-dollar sales

Despite uncertainty about long-term health benefits, vitamin supplements are widely used, with sales in the billions of dollars each year, the authors write. "More than half of Americans consume vitamin supplements on a weekly basis, and vitamin E and vitamin C are among the most widely used," Gaziano said.

Basic research has provided a plausible mechanism by which these antioxidant vitamins might reduce cardiovascular risk, and observational data have suggested that people who take these vitamin supplements have an associated lower risk of cardiovascular disease, he noted. However, trials of vitamin E have had mixed results, he added, and at least when this trial was begun, there were no large-scale randomized trials of vitamin C in this setting.

PHS2 was a randomized, double-blind, placebo-controlled 2x2x2x2 factorial trial of vitamin E (400 IU of synthetic alpha-tocopherol) or placebo every other day, vitamin C (500 mg synthetic ascorbic acid) or placebo every other day, or a multivitamin (Centrum Silver, Wyeth Pharmaceuticals) or placebo daily for the prevention of cancer and cardiovascular disease. This latter arm is still ongoing on the recommendation of the data and safety monitoring board. A fourth arm, studying beta-carotene vs placebo, was reported in 2003 and showed no benefit from beta-carotene supplements.

The study began in 1997, enrolling 14 641 US male physicians who were aged 50 years and older at the study outset. Men with a history of MI, stroke, or cancer were eligible to enroll, and 754 men (5.4%) of the cohort had prevalent CVD at randomization.

The primary end point was a composite of major cardiovascular events, including nonfatal MI, nonfatal stroke, and cardiovascular disease death.

During a mean follow-up of eight years and a total of 120 000 person-years of follow-up, 1245 confirmed cardiovascular events occurred. Almost identical numbers of events occurred in both supplementation and placebo groups. For the vitamin E vs placebo comparison, there were 10.9 events per 1000 person-years in both groups, and curves were "virtually superimposable," Gaziano said.

Among those treated with vitamin C, there were 10.8 events per 1000 person-years, and 10.9 events for those on placebo, again almost identical outcomes, and no associations in the secondary end points that would not be anticipated by chance, he added.

Neither vitamin E nor vitamin C had any effect on total mortality, but treatment with vitamin E was associated with an increased risk for hemorrhagic stroke, although the association was only marginally significant, Gaziano noted. "This is something that has been seen in one other trial, but no other vitamin E trials," he added.

Because of concerns about an increase in congestive heart failure seen in the HOPE trial with vitamin E, they examined the occurrence of new CHF as a prespecified secondary end point and found no effect in this population.

Gaziano said that these findings underline how important it is to take results from observational studies into randomized controlled trials. "I think it's important for any of these nutriceuticals or dietary supplements that we first explore them with the preliminary science and observational studies, but before we are able to say definitively that there's a beneficial effect in preventing chronic diseases, we have to go to the next step and do the large randomized trials," he said.

To do these kinds of large-scale, long-term trials, though, it is important that they are done cheaply, he added. "This was a trial done entirely by mail and cost about $120, $130 per person per year," he noted.

The multivitamin arm of this trial will provide additional information out to 12 years of follow-up, and he noted that the data and safety monitoring board "strongly recommended" continuing that part of the trial.

Other supplements are now in the early stages of investigation, including vitamin D and omega-3 fatty acids, he pointed out, with large, long-term trials now being planned.

Save some money; don't buy supplements

At the meeting here, Dr Barbara V Howard (MedStar Research Institute, in Hyattsville, MD), current chair of the American Heart Association Council on Nutrition, was the invited discussant for this trial. She congratulated the researchers for conducting a long-term end-point trial of vitamin supplements, trials that are both few and essential to being able to properly counsel patients.

During a press conference here, Howard said she sees two take-home messages from these findings. "One of them is there is a big difference when it comes to nutritional studies between observational or short-term trials and a long-term end-point trial."

The problem with observational studies is that "people don't eat a nutrient, they eat foods," she said, and identifying which aspect of the diet is providing a preventive effect is very difficult. "It's also very hard to separate the fact that people who eat healthier are healthier in so many more ways that you can't measure and probably have better access to care." Surrogate end-point trials with end points like vascular reactivity should also be viewed with caution, she noted.

"Given these results and the caveat about observational data, I think it is prudent to follow the guidelines that have been thoughtfully put out and are in agreement with the American Heart Association, the American Diabetes Association, and the American Cancer Society, that people need to balance their calories and activity to maintain weight, eat plenty of vegetables and fruits and whole grains, reduce their saturated and trans fat, and reduce their sodium and sugar intake," Howard concluded.

"This is the way that we think at this point we have the best evidence that cardiovascular disease can be reduced, and in these hard economic times, maybe we can save some money and not buy these supplements," she concluded.

The study was funded by grants from the National Institutes of Health and an investigator-initiated grant from BASF Corporation. Study agents and packaging were provided by BASF Corporation, Wyeth Pharmaceuticals, and DSM Nutritional Products (formerly Roche Vitamins). Sesso reports that he has received investigator-initiated research funding from the National Institutes of Health, American Heart Association, American Cancer Society, California Strawberry Commission, Roche Vitamins (now DSM Nutritional Products), and Cambridge Theranostics. Disclosure information for other coauthors appears in the paper.