Vitamins E And C Trial Shows No CVD-Prevention Benefits In “Healthy” Men

A study finding no link between vitamin E or vitamin C supplementation and cardiovascular disease prevention in men was conducted using subjects largely regarded as healthy - a population that supplement industry stakeholders have called the true measuring stick for evaluating nutrient benefits.

However, questions remain about the Physicians' Health Study II randomized controlled trial, with some in the industry asking how closely the subjects mirror the general population and whether the study design could have yielded nutrient benefits at all.

The 10-year PHS II, conducted by researchers at Boston's Brigham and Women's Hospital and Harvard University, followed 14,641 U.S. male physicians who took 400 IU of vitamin E every other day, 500 mg of vitamin C daily, or a placebo.

It was published online Nov. 9 by the Journal of the American Medical Association to coincide with the American Heart Association's scientific sessions in New Orleans and is included in JAMA's Nov. 12 issue.

The researchers led by Howard D. Sesso, of Brigham and Women's preventive medicine and aging departments, say neither vitamins E or C was found to independently have an effect on the primary prevention of major cardiovascular events in the participants.

"The Gold Standard"

Barbara Howard, a senior scientist with Columbia, Md.-based MedStar Research Institute, called the study's data "very conclusive" due to its clinical endpoints, standardization of events and "excellent adherence and retention."

Howard, also an AHA spokeswoman, added that clinical research such as PHS II remains "the gold standard" and proves conclusively that vitamin supplementation is not necessary for CV health as long as a person follows dietary guidelines and maintains a healthy weight.

In February 2007, AHA clarified in its guidelines that vitamins E and C and other antioxidant supplements should not be used for primary or secondary prevention of CVD (¹ (Also see "AHA Guidelines Rate Aspirin, Antioxidants, Omega-3s For Prevention" - Pink Sheet, 26 Feb, 2007.), p. 16).

Andrew Shao, VP of scientific and regulatory affairs for the Council for Responsible Nutrition, emphasized that consumers should not expect to prevent CVD with vitamin supplementation alone, but rather in conjunction with other healthy lifestyle activities.

Due to randomized controlled trials' "narrow, reductionist nature, a single trial cannot simply trump decades worth of in vitro, animal and human epidemiological data" on the nutrients' benefits, Shao said in an e-mail.

CRN has previously questioned the efficacy of using RCTs to study nutrients and has pressed for more emphasis on observational, case-control and cohort studies in evaluating nutrient-disease relationships (² (Also see "JAMA Vitamin E Citation Report Supports Looking Past Traditional Trial Model" - Pink Sheet, 10 Dec, 2007.), p. 6).

Howard pointed out subjects in observational nutrient studies generally engage in other healthy behaviors that cannot be measured or corrected for.

"Observational data are just too prone to confounding for nutrition because of the complex interrelationships of foods and the fact that people who eat certain things have different lifestyles," she said.

But the clinical study results were likely confounded anyway by vitamins E and C found in food sources, said Daniel Fabricant, VP of scientific and regulatory affairs for the Natural Products Association.

"If your placebo group is already getting an 'effective intake' of those, then how do you distinguish your placebo group from your group that was supplemented?" he said.

"That's just basic experimental design, you have to have a negative control."

Population Evaluation

The study authors say 95 percent of the subjects "were of low initial risk of cardiovascular disease." Recruiting participants from this generally under-studied population adds to the "strength" of the study results, they add.

But the self-assessed healthiness of the participants does not withstand scrutiny, according to Fabricant.

While the physician subjects were "more healthy than we're used to seeing in these types of studies," Fabricant pointed out that about 60 percent had a body mass index above 25 and more than 40 percent were current or former smokers - both indicators of predisposition to CVD.

Shao, on the other hand, takes issue with the physician subjects representing an atypically healthy population "at their plateau of health," adding that an even larger pool of subjects and longer follow-up time would be necessary before benefits of supplementation could emerge and be noted.

NPA criticized a meta-analysis JAMA published in February 2007 for concluding that antioxidant supplements may increase mortality risk in healthy populations, since the studies involved used participants with existing conditions (³ (Also see "Industry, Researchers Pan Study Showing Antioxidants May Up Mortality Risk" - Pink Sheet, 5 Mar, 2007.), p. 17).

Still, beginning the vitamin supplementation after age 50, as the study does, may have little effect on reducing CV risk, according to Mohsen Meydani, professor of nutrition at Tufts University.

Meydani has conducted animal studies showing preventative CV effects from supplementation starting early in life. But once "there's already lesions and fat deposits and inflammation going on, obviously vitamin E at [the level given in the study] is not effective," he said.

A Stroke Of Bad Luck?

According to the PHS II results, vitamin E was associated with a 74 percent increase in risk of hemorrhagic stroke.

Howard said, the study report's link between vitamin E and hemorrhagic strokes "really makes a big statement" and must be explored further, given that the nutrient is known to extend blood clotting time.

However, supplement industry consultant Annette Dickinson said, the link between vitamin E and hemorrhagic stroke seemed potentially coincidental, given "the absence of such an effect in studies with higher doses."

Meydani said, 400 IU of vitamin has not been shown to prevent short-term blood clotting, but sustained supplementation may affect blood coagulation.

Despite the stroke finding, the study authors "found no significant effect between vitamin E and total mortality after up to 10 years of treatment and follow-up."

- Dan Schiff ([email protected])