Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease The TEAM-AD VA Cooperative Randomized Trial

• Autores: Maurice W. Dysken, Mari Sano, Sanjay Asthana, Julia E. Vertrees
• Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 311, Nº. 1, 2014, págs. 33-44
• Idioma: inglés
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• Resumen

  • Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.

    Objective To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.

    Design, Setting, and Participants Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.

    Interventions Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).

    Main Outcomes and Measures Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.

    Results Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).

    Conclusions and Relevance Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.

    Trial Registration clinicaltrials.gov Identifier: NCT00235716 Alpha tocopherol, a fat-soluble vitamin and antioxidant, has been studied in patients with moderately severe Alzheimer disease (AD)1 and in participants with mild cognitive impairment (MCI)2 but has not been studied in patients with mild to moderate AD. In patients with moderately severe AD,1 alpha tocopherol (2000 IU/d) was shown to be effective in slowing clinical progression. In participants with MCI,2 however, alpha tocopherol (2000 IU/d) had no benefit compared with placebo in reducing the rate of conversion to AD.

    Memantine, a moderate-affinity NMDA antagonist, was shown to be effective in 2 randomized clinical trials (RCTs),3,4 both of which were in patients with AD and moderately severe dementia. Three RCTs of memantine in AD patients with mild to moderate dementia have been published5- 7and reviewed in a meta-analysis.8 There were no significant differences between memantine and placebo in patients with mild AD, either within any of the trials or when data were combined. For patients with moderate AD, there were small improvements in cognitive but not functional measures. Because the duration of each of these trials was only 6 months, these studies do not assess the long-term efficacy of memantine in AD patients with mild to moderate dementia.

    The Trial of Vitamin E and Memantine in Alzheimer’s Disease (TEAM-AD) examined the effectiveness and safety of alpha tocopherol (vitamin E), memantine (Namenda), and the combination for treatment of functional decline in patients with mild to moderate AD who were taking a background acetylcholinesterase inhibitor (AChEI).