Alzheimer's disease (AD) is the most common form of dementia, affecting more than 4 million Americans. Commonly used treatments, including cholinesterase inhibitors and memantine (the latter of which has mainly been shown to be effective in moderately severe stages of the disorder), are only modestly effective in altering the course of relentless progression. Although in previous trials vitamin E supplementation has not been shown to decrease the rate of conversion from mild cognitive impairment (MCI) to dementia, Dysken and colleagues (2014) aimed to explore its efficacy in mild to moderate AD.
The authors enrolled patients with mild to moderate AD (defined as a Mini-Mental State Examination score between 12 and 26) who were already taking a cholinesterase inhibitor into a double-blind, parallel-group, placebo-controlled trial of vitamin E 2000 IU per day and memantine 20 mg per day. Patients were randomized to vitamin E, memantine, the combination of vitamin E and memantine, or placebo in a 1:1:1:1 fashion. The primary outcome examined was scores on the functionally focused Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) inventory at the end of the study (mean follow-up, 2.27 years).
A total of 613 patients were randomized with a mean age of 79 years; nearly all of the participants were male. More than 40% of the patients did not complete the trial—half due to death. The authors found that patients receiving vitamin E had a significantly slower decline than those assigned to placebo, equal to a delay in clinical progression of 19%, or about 6 months (change in ADCS-ADL, 3.15 units; p = .03). This delay in progression was sustained throughout the trial at each time point examined. There was no significant delay in progression with memantine compared with placebo nor with the combination of vitamin E and memantine compared with placebo. All secondary outcomes examined showed no significant differences between the groups, although caregiver time increased least over the course of the study in the vitamin E group.
Given that high-dose vitamin E has been associated with adverse events in elderly patients in other trials, the safety data from this study were eagerly anticipated. The authors found no significant differences between any of the groups in rates of adverse events or serious adverse events. Annualized mortality rates were 7.3% in the vitamin E group, 11% in the memantine group, 9.0% in the combination group, and 9.4% in the placebo group.
This well-executed, long-term, large AD trial did indeed demonstrate modest efficacy of high-dose vitamin E in mild to moderate AD using the functional primary endpoint chosen. In addition to the beneficial effects of vitamin E, two main take-home points arise. First, vitamin E at this dose appeared to be safe—a result that will lead to its greater use given concerns generated by other studies using similar doses. In addition, yet another large study failed to demonstrate the utility of memantine in patients at this stage of AD, calling into question whether this drug should be used outside of the moderately severe stage of the disorder for which it was initially approved. For clinicians caring for patients with AD, cholinesterase inhibitors remain the mainstay of treatment for mild to moderate forms. Adding memantine appears to have no benefit at this stage, but adding vitamin E may be worthwhile. All of these observations need to be interpreted in the context of the small amount of disease progression delay these drugs confer, even under the best of circumstances, emphasizing the need for the development of therapies that are far more effective for this common and disabling disorder.
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