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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

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Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease

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Review published: .

CRD summary

This review assessed the use of acetyl-L-carnitine (Alcar) for cognitive decline and mild Alzheimer's disease. The authors concluded that Alcar improves mild cognitive impairment, prevents deterioration and is well tolerated. The authors' conclusions are based on pooling the effects of treatment measured by various different instruments and may not, therefore, be reliable. The clinical importance of the statistically significant findings was not clear.

Authors' objectives

To assess the effects of gamma-trimethyl-beta-acetylbutyrobetaine (acetyl-L-carnitine, Alcar) in patients with mild cognitive impairment and mild Alzheimer's disease (AD).

Searching

MEDLINE, EMBASE, Derwent Drug File and SciSearch were searched from 1975 to 2001, not limited to English studies; the search terms were stated. The reference lists in identified studies were checked. The internal publication data bank of Sigma-Tau was also searched and the bibliographies of identified studies were reviewed.

Study selection

Study designs of evaluations included in the review

Double-blind, parallel-group, randomised controlled trials (RCTs) were eligible for inclusion if they presented sufficient data to determine an effect size (ES).

Specific interventions included in the review

Studies that compared Alcar with placebo over at least 3 months were eligible for inclusion. The included studies lasted from 3 to 12 months and used Alcar in doses ranging from 1.5 to 3.0 g/day.

Participants included in the review

Studies of patients with a diagnosis compatible with mild cognitive impairment or AD, or a sufficiently detailed description of the patients to merit an equivalent diagnosis, were eligible for inclusion.

Studies that included patients with varying severity of AD were only included if it were possible to extract data for mild cases. However, 3 small studies of patients with mild to moderate AD that did not present separate data for mild AD were included. Over all studies, 59% of participants were female and the mean age was 72 years. The years of schooling varied in those studies reporting it. The studies used twelve different test batteries to describe the patients' condition at baseline.

Outcomes assessed in the review

Studies that reported defined measures of cognitive function, or an overall outcome, were eligible for inclusion. The primary outcomes in the review were efficacy based on clinical tests and psychometric tests combined, and clinicians' rating of efficacy based on the Clinical Global Impression of Change (CGI-CH) or the Clinician's Interview Based Impression of Change. The secondary outcomes were efficacy measured by five categories of psychometric test: memory, attention or performance, learning, drawing, and higher intellectual functions. The included studies used 54 different scales (including 12 clinical test batteries and 40 different psychometric tests) to assess the outcomes. The review also assessed side-effects and adverse events.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction.

Outcome data were extracted as differences in the mean from baseline and the standard deviation for each treatment group, or other available data that could be used to calculate an ES. For each study, the ES and 95% confidence intervals (CIs) were calculated for each category of outcome. ESs for most studies were calculated using data from patients who had an assessment at every follow-up visit (completer dataset); ESs for other studies were based on data from patients assessed at the considered visit. Data from the last available follow-up were used in the calculation of ESs. For studies that used multiple scales to assess one category of outcome, all ESs were pooled to give one outcome for that category for each study, taking account of correlated data. Statistical heterogeneity was tested across scales within studies using an approximate chi-squared test.

Methods of synthesis

How were the studies combined?

The studies were combined using a meta-analysis. Pooled Hedge's d ESs and 95% CIs were calculated for all clinical and psychometric tests combined, clinical tests alone, psychometric tests alone and CGI alone. The studies were weighted using the sample size and the variance. A funnel plot was used to assess publication bias.

How were differences between studies investigated?

Statistical heterogeneity among studies was assessed using an approximate chi-squared test. Where heterogeneity was statistically significant, the meta-analysis was repeated after the exclusion of one RCT with a very high ES. Other studies thought to be responsible for the heterogeneity were pointed out, but possible explanations for heterogeneity were not discussed. The relationships between the overall ES and educational level and between the ES and Alcar dose were tested. The time course of the Alcar treatment effect was explored by calculating the ES using data from studies reporting outcomes at 3 and 6 months.

Results of the review

Twenty-one RCTs (n=1,479) were included. Data from 1,204 patients were used in the analyses.

All clinical and psychometric tests combined (21 RCTs).

The meta-analysis showed that Alcar significantly increased the ES compared with placebo (ES 0.201, 95% CI: 0.107, 0.295). Significant statistical heterogeneity was found (P=0.03). After excluding one RCT with a very high ES, heterogeneity was no longer statistically significant and the pooled ES remained significant (ES 0.191, 95% CI: 0.10, 0.29). CGI alone (11 RCTs).

The meta-analysis showed that Alcar significantly increased the ES compared with placebo (ES 0.32, 95% CI: 0.18, 0.47). Significant statistical heterogeneity was found (P<0.001).

Clinical tests alone.

Significant statistical heterogeneity was found for the meta-analysis of clinical test outcomes (P<0.001). Heterogeneity remained statistically significant after excluding one RCT with a very high ES.

Psychometric tests.

No significant statistical heterogeneity was detected for all psychometric test outcomes combined. A statistically significant effect of Alcar was found in the meta-analyses for memory, attention or performance, and higher intellectual function outcomes. The ES was 0.29 (95% CI: 0.132, 0.449) for memory (10 RCTs), 0.221 (95% CI: 0.090, 0.352) for attention or performance (13 RCTs), and 0.373 (95% CI: 0.173, 0.573) for intellectual function (7 RCTs). The effect of Alcar was not statistically significant for drawing (6 RCTs) or learning (5 RCTs).

Time course (16 RCTs): the ES for clinical and psychometric outcomes increased from 3 to 6 months, but clinician-rating outcomes (CGI) did not increase. Alcar dose: no significant relationship was found between the Alcar dose and ES.

Side-effects: the type and severity of side-effects and adverse events were similar between the treatment groups. Some studies reported more frequent gastrointestinal events, insomnia, agitation and appetite increase with Alcar. The number of early drop-outs was small and similar between treatment groups.

The funnel plot showed no evidence of publication bias.

Authors' conclusions

Compared with placebo, Alcar improved mild cognitive impairment or prevented deterioration, and was well tolerated.

CRD commentary

The review question was clear in terms of the study design, intervention, participants and outcomes. However, the inclusion criteria for the outcomes were very broad and appeared to be driven by what was reported in the trial reports, and the inclusion criteria for the participants were not strictly adhered to. Several relevant sources were searched and attempts were made to minimise language bias. The methods used to select the studies and extract the data were not described, so it is not known whether any efforts were made to reduce errors and bias. Only double-blind RCTs were eligible, but validity was not otherwise addressed. In particular, the validity of the methods used to measure the outcomes was not discussed.

The data were combined using a meta-analysis and statistical heterogeneity was assessed. In the analyses, methods were used to address the use of multiple measures to assess one outcome. Where significant heterogeneity was found, the authors did not discuss potential reasons for this. The authors stated that most of the included studies were sponsored by Sigma-Tau and that this company provided advice on the statistical analysis for the review. The authors' conclusions were based on pooling the effects of treatment measured by a variety of different instruments; the clinical importance of the statistically significant findings was unclear.

Implications of the review for practice and research

The authors did not state any implications for practice or further research.

Bibliographic details

Montgomery S A, Thal L J, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. International Clinical Psychopharmacology 2003; 18(2): 61-71. [PubMed: 12598816]

Indexing Status

Subject indexing assigned by NLM

MeSH

Acetylcarnitine /therapeutic use; Aged; Alzheimer Disease /drug therapy /psychology; Cognition /drug effects; Humans; Nootropic Agents /therapeutic use; Prospective Studies; Randomized Controlled Trials as Topic

AccessionNumber

12003009511

Database entry date

31/05/2005

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

Copyright © 2014 University of York.
Bookshelf ID: NBK69816

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