Questions about validity of HOPE TOO vitamin E study

A study published in the March 16 issue of Journal of the American Medical Association (JAMA) suggesting that a "daily-dose" of vitamin E (400 international units) among high-risk (chronically ill) cardiovascular patient populations is associated with a greater risk of heart failure is being challenged by leading health researchers around the country who claim the study lacks the adequate research and controlled sampling audience to justify this conclusion.

Numerous other studies with much larger patient populations have shown significant cardiovascular benefits from vitamin E supplementation and its role as an effective and safe part of a healthy lifestyle among average consumers.

"There was not a definitive conclusion to this study, except to state that more studies were needed, so the claim is a bit of a leap at best," said David Seckman, executive director and CEO of the National Nutritional Foods Association (NNFA). "I understand why the public may find this study concerning, but let's not overreact to one study. Numerous scientific studies have attested to vitamin E's great health benefits and safety, not only for cardiovascular health, but also for immune function, DNA repair and to help protect the body against the effects of free radicals. Vitamin E continues to be a safe and effective part of a healthy diet, and the suggested findings are incomplete and misleading."

"As the HOPE TOO investigators themselves note, the single observation of an adverse event in their study was unexpected and cannot be confirmed by any other trials," said Dr. Jeffrey Blumberg, professor in the Friedman School of Nutrition Science and Policy and director of the Antioxidants Research Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. "It was unusual to find these researchers applying stringent statistical rules to data suggesting a potential anticancer effect of vitamin E, but failing to do so for the only indication of harm."

Other leading medical professionals who have long recommended vitamin E for its health benefits agree that the study has its flaws, and are not ready to abandon their confidence in the supplement.

"It is important to point out that those participating in the study suffered from a range of degenerative diseases, with varying levels of severity," said Dr. C. Wayne Callaway, an expert in internal medicine, endocrinology, metabolism, and clinical nutrition, and former head of the lipid and nutrition programs at the Mayo Clinic. "To focus on a relatively small increase in vitamin E in some patients who also had heart failure ignores other risk factors. For example, many people with type-2 diabetes and/or obesity also have increased 'small, dense particles' associated with their low-density lipoproteins or 'LDL cholesterol,'" Dr. Callaway continued. "Small, dense particles can increase the risk for heart failure. Vitamin E content is reduced by the small dense particles and oxidative damage is worsened. Meanwhile, I would not recommend to any of my patients that they discontinue their vitamin E supplements on the basis of this study."

The patients of the study were at least 55 years old with vascular disease or diabetes mellitus, and at least one other significant cardiovascular risk factor. Of 7,030 patients enrolled, 916 were deceased at the beginning of the extension, 1,382 refused participation, 3,994 continued to take the study intervention, and 738 agreed to follow-up. Study participants received a daily dose of natural source vitamin E (400 IU) or matching placebo over a median of 7.0 years.

Furthermore, subjects in the study were typically taking five different medications in addition to vitamin E -- including beta-blockers, anti-platelet agents, statins, diuretics, calcium channel blockers and ACE inhibitors -- yet the increase in heart failure (from 12.1 percent in the placebo group to 13.5 percent in the vitamin E group) was attributed exclusively to vitamin E, with no adjustment for pharmacotherapy. Total vitamin E blood levels may appear to be normal but the person is still at risk because of the small, dense lipoprotein particles -- another factor that appears not to have been addressed by the study in question.

"From a clinical perspective, the study does not factor in the emerging obesity epidemic afflicting vast numbers of patients while the study was being conducted," said Dr. Callaway. "Given possible aggravating health factors, in response to insulin resistance and/or obesity, it's entirely possible the dosage was insufficient, or even ineffective."

The randomized, double-blind, placebo-controlled trial (Heart Outcomes Prevention Evaluation [HOPE]) was initially conducted between December 21, 1993, and April 15, 1999. This trial was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) to between April 16, 1999, and May 26, 2003. One of the concluding findings in the first, larger sampling stated in the final publication that "there were no significant adverse effects of vitamin E."