01.02.2014

by John Gever
Deputy Managing Editor, MedPage Today

Older veterans with mild to moderate Alzheimer’s disease who took vitamin E supplements in a randomized trial showed less progression of functional impairment, researchers said.

With mean follow-up of 2.27 years (SD 1.22), the 140 patients assigned to daily supplements of 2,000 IU of vitamin E (alpha tocopherol) had mean declines in Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores of 13.81 points (SD 1.11), compared with a drop of 16.96 points (SD 1.11) in a placebo group, reported Maurice Dysken, MD, of the Minneapolis VA Health System, and colleagues.

The difference of 3.15 points was statistically significant (95% CI 0.92-5.39), the researchers reported in the Jan. 1 issue of the Journal of the American Medical Association. It remained significant after adjusting for baseline factors, with a P value of 0.03.

But this finding came with some others that raised questions about vitamin E’s effects in these patients. Another group that received a combination of vitamin E and memantine (Namenda) failed to see a statistically significant benefit (mean difference from the placebo group 1.76 points, 95% CI -0.48-4.00) — similar to results seen in a third active-treatment group receiving memantine alone.

Also, none of the three active treatment groups showed a benefit relative to placebo in scores assessing cognitive function specifically.

Instead, vitamin E’s clinical effect appeared to be focused on functional outcomes, such as the need for caregiver assistance.

Implications

In an accompanying editorial, three scientists from Rush University in Chicago suggested that the study’s real implication is that research into treatments for Alzheimer’s disease should take a back seat to prevention.

“As with almost all previous Alzheimer’s disease trials, the therapeutic effect seen was modest and more relevant to Alzheimer’s disease symptoms and consequences than to reversal of the disease process,” wrote Denis A. Evans, MD, and colleagues. “Considering the difficulties inherent in trying to treat rather than prevent very high-prevalence diseases and the limitations thus far of the therapeutic efforts for people with Alzheimer’s disease, shifting to more emphasis on prevention seems warranted.”

On the other hand, study co-author Mary Sano, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, told MedPage Today that the study results were robust enough to warrant a recommendation that patients with mild to moderate Alzheimer’s disease start taking vitamin E supplements.

She pointed out that the results, in addition to demonstrating a functional benefit for vitamin E, also indicated that it was safe, at least in terms of mortality — in contrast to a 2005 meta-analysis that suggested higher death rates for people taking vitamin E supplements.

In addition, a 1997 trial in patients with more advanced Alzheimer’s disease, and a more recent observational study, both had found that vitamin E was beneficial.

Study Design

The current study, called the Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD), enrolled a total of 613 patients in the VA system who were randomized to the three active treatments or placebo. Enrollment began in August 2007 and continued through March 2012.

Adequate follow-up data were lacking in 52 patients, about evenly divided among the four groups, leaving 561 for analysis. Their mean age was 79 and, because they were drawn from the older VA population, they were nearly all male.

Patients with scores on the Mini-Mental State Examination (MMSE) of 12 to 26 and currently taking an acetylcholinesterase inhibitor such as donepezil (Aricept) were eligible for the study. Participants continued to take such medications during the study.

Mean baseline MMSE scores were about 21 in all four groups. Scores on the ADCS-ADL scale averaged about 57 at study entry.

Other outcome measures included the Alzheimer’s Disease Assessment Scale’s cognition score (ADAS-Cog), the Caregiver Activity Survey, and the Dependence Scale.

Results and Limitations

At the end of follow-up and with data adjusted for baseline characteristics, neither MMSE nor ADAS-Cog scores differed significantly among groups, nor did Caregiver Activity Scale scores. The only clear benefit of any of the active treatments was the finding of improvement relative to placebo with vitamin E alone on ADCS-ADL scores.

However, among patients followed for longer than 30 months, all three active treatments appeared to slow functional decline relative to placebo in Dependence Scale scores — specifically, the time to an event leading to loss of one dependence level in the instrument’s scoring system. By month 48, virtually all patients in the placebo group had lost at least one dependence level, whereas about 70-80% of patients in each of the other groups had experienced such an event.

Sano told MedPage Today that it would be inappropriate to conclude that vitamin E was superior to the other active treatments in preserving functional ability, because the analysis only compared each of the active treatments with placebo, not with each other.

Moreover, there is no obvious reason that memantine would interfere with vitamin E action, Sano and colleagues wrote in the JAMA paper.

Their review of adverse events showed no safety problems for either vitamin E or memantine alone, although the combination was associated with more cases of pneumonia, and patients in all three active-treatment groups had higher rates of infections and infestations of all types (13%-20% versus 7% for placebo).

Limitations to the study included lower enrollment than initially planned, leading the researchers to extend the follow-up as a means to compensate. Also, the almost exclusively male sample meant that the results may not apply to female Alzheimer’s disease patients.

In the editorial, Evans and colleagues expressed concern about the lack of even additive effect with the memantine-vitamin E combination, saying it “deserves further investigation.”

They also argued that the current study’s safety findings must be weighed against those summarized in the 2005 meta-analysis that found an increased mortality risk with high-dose vitamin E supplements.

And, Evans and colleagues were intrigued by vitamin E’s lack of effect on cognitive function, even as it appeared to slow decline in the less specific ADCS-ADL measure of functional ability. They noted that vitamin E is mainly an antioxidant and thus has actions that go beyond Alzheimer’s disease pathology.

• Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 01.03.2014