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Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

Abstract

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.

Links

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  • Authors+Show Affiliations

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    Minneapolis VA Health Care System, Minneapolis, Minnesota.

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    James J. Peters VA Medical Research Center, New York, New York.

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    William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.

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    Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico.

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    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio6Case Western Reserve University School of Medicine, Cleveland, Ohio.

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    Washington DC VA Medical Center, Washington, DC.

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    Minneapolis VA Health Care System, Minneapolis, Minnesota.

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    University of Pennsylvania School of Medicine, Philadelphia.

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    Minneapolis VA Health Care System, Minneapolis, Minnesota.

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    Miami VA Healthcare System, Miami, Florida.

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    Miami VA Healthcare System, Miami, Florida.

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    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio6Case Western Reserve University School of Medicine, Cleveland, Ohio.

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    VA Maryland Healthcare System, Baltimore11University of Maryland Medical School, Department of Psychiatry, Baltimore.

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    VA North Texas Health Care System, Dallas.

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    VA North Texas Health Care System, Dallas.

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    Ralph H. Johnson VA Medical Center, Charleston, South Carolina14Department of Health Studies, Medical University of South Carolina, Charleston15Roper St Francis Healthcare, Charleston, South Carolina.

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    VA Ann Arbor Healthcare System, Ann Arbor, Michigan.

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    VA Caribbean Healthcare System, San Juan, Puerto Rico.

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    VA Caribbean Healthcare System, San Juan, Puerto Rico.

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    Bay Pines VA Healthcare System, Bay Pines, Florida.

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    Bay Pines VA Healthcare System, Bay Pines, Florida.

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    VA Boston Healthcare System, Boston, Massachusetts.

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    VA Boston Healthcare System, Boston, Massachusetts.

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    VA Puget Sound Health Care System, Seattle, Washington21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.

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    VA Puget Sound Health Care System, Seattle, Washington21Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle.

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    Iowa City VA Medical Center, Iowa City, Iowa23University of Iowa, Iowa City.

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    Iowa City VA Medical Center, Iowa City, Iowa23University of Iowa, Iowa City.

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    W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina.

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    W. G. (Bill) Hefner VA Medical Center, Salisbury, North Carolina.

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    Minneapolis VA Health Care System, Minneapolis, Minnesota.

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    Minneapolis VA Health Care System, Minneapolis, Minnesota.

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    Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven26Yale University School of Public Health, New Haven, Connecticut.

    Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven26Yale University School of Public Health, New Haven, Connecticut.

    Source

    JAMA 311:1 2014 Jan 01 pg 33-44

    MeSH

    Activities of Daily Living
    Aged
    Aged, 80 and over
    Alzheimer Disease
    Antioxidants
    Caregivers
    Cholinesterase Inhibitors
    Disease Progression
    Dopamine Agents
    Double-Blind Method
    Drug Therapy, Combination
    Female
    Humans
    Male
    Memantine
    Middle Aged
    Severity of Illness Index
    Treatment Outcome
    Vitamin E

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    24381967

    Citation

    TY - JOUR T1 - Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. AU - Dysken,Maurice W, AU - Sano,Mary, AU - Asthana,Sanjay, AU - Vertrees,Julia E, AU - Pallaki,Muralidhar, AU - Llorente,Maria, AU - Love,Susan, AU - Schellenberg,Gerard D, AU - McCarten,J Riley, AU - Malphurs,Julie, AU - Prieto,Susana, AU - Chen,Peijun, AU - Loreck,David J, AU - Trapp,George, AU - Bakshi,Rajbir S, AU - Mintzer,Jacobo E, AU - Heidebrink,Judith L, AU - Vidal-Cardona,Ana, AU - Arroyo,Lillian M, AU - Cruz,Angel R, AU - Zachariah,Sally, AU - Kowall,Neil W, AU - Chopra,Mohit P, AU - Craft,Suzanne, AU - Thielke,Stephen, AU - Turvey,Carolyn L, AU - Woodman,Catherine, AU - Monnell,Kimberly A, AU - Gordon,Kimberly, AU - Tomaska,Julie, AU - Segal,Yoav, AU - Peduzzi,Peter N, AU - Guarino,Peter D, PY - 2014/1/2/entrez PY - 2014/1/2/pubmed PY - 2014/1/15/medline SP - 33 EP - 44 JF - JAMA JO - JAMA VL - 311 IS - 1 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/24381967/full_citation L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2013.282834 ER -