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Meta-Analysis
. 2012 Sep 12;2012(9):CD009132.
doi: 10.1002/14651858.CD009132.pub2.

Cholinesterase inhibitors for mild cognitive impairment

Tom C Russ  1 , Joanne R Morling
Affiliations
Meta-Analysis

Cholinesterase inhibitors for mild cognitive impairment

Tom C Russ et al. Cochrane Database Syst Rev. .

Abstract

Background: Mild cognitive impairment is hypothesised to represent a pre-clinical stage of dementia but forms a heterogeneous group with variable prognosis.

Objectives: To assess the safety and efficacy of cholinesterase inhibitors in people with mild cognitive impairment.

Search methods: Trials were identified from the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, which is frequently updated from the major healthcare databases (MEDLINE, EMBASE, CINAHL, PsycINFO and Lilacs) as well as trial registers and grey literature.

Selection criteria: Double-blind, placebo-controlled randomised trials of any cholinesterase inhibitor in people with mild cognitive impairment.

Data collection and analysis: Data were extracted from the published reports of the included studies, combined by meta-analysis where appropriate, and treatment efficacy and risk of adverse events were estimated.

Main results: Nine studies (from eight published reports) of 5149 individuals with mild cognitive impairment (however defined) were included in the review. Limited pooling of results was possible owing to different lengths of trials. Meta-analysis of the three studies reporting conversion to dementia gives no strong evidence of a beneficial effect of cholinesterase inhibitors on the progression to dementia at one, two or three years. The risk ratio (RR) for conversion at two years was significantly different from unity (0.67; 95% confidence interval (CI) 0.55 to 0.83), but this is based on only two studies reported in the same article. There was essentially no effect of cholinesterase inhibitors on cognitive test scores.Based on the results from 4207 individuals, there were significantly more adverse events in the cholinesterase inhibitor groups (RR 1.09; 95% CI 1.02 to 1.16), but no more serious adverse events or deaths. Gastrointestinal side effects were much more common (diarrhoea: RR 2.10; 95% CI 1.30 to 3.39; nausea: RR 2.97; 95% CI 2.57 to 3.42; vomiting: RR 4.42; 95% CI 3.23 to 6.05). Cardiac problems were no more likely in either group (RR 0.71; 95% CI 0.25 to 2.02). Other side effects reported significantly more often in the cholinesterase inhibitor group were muscle spasms/leg cramps (RR 7.52; 95% CI 4.34 to 13.02), headache (RR 1.34; 95% CI 1.05 to 1.71), syncope or dizziness (RR 1.62; 95% CI 1.36 to 1.93), insomnia (RR 1.66; 95% CI 1.36 to 2.02) and abnormal dreams (RR 4.25; 95% CI 2.57 to 7.04).

Authors' conclusions: There is very little evidence that cholinesterase inhibitors affect progression to dementia or cognitive test scores in mild cognitive impairment. This weak evidence is overwhelmed by the increased risk of adverse events, particularly gastrointestinal. Cholinesterase inhibitors should not be recommended for mild cognitive impairment.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Conversion to dementia at one year.
Figure 3
Figure 3
Conversion to dementia at two years.
Figure 4
Figure 4
Conversion to dementia at three years.
Figure 5
Figure 5
Any adverse events.
Figure 6
Figure 6
Serious adverse events.
Analysis 1.1
Analysis 1.1
Comparison 1 Conversion to dementia, Outcome 1 Conversion at 1 year.
Analysis 1.2
Analysis 1.2
Comparison 1 Conversion to dementia, Outcome 2 Conversion at 2 years.
Analysis 1.3
Analysis 1.3
Comparison 1 Conversion to dementia, Outcome 3 Conversion at 3 years.
Analysis 2.1
Analysis 2.1
Comparison 2 Adverse events, Outcome 1 Any adverse events.
Analysis 2.2
Analysis 2.2
Comparison 2 Adverse events, Outcome 2 Serious adverse events.
Analysis 2.3
Analysis 2.3
Comparison 2 Adverse events, Outcome 3 Death.
Analysis 2.4
Analysis 2.4
Comparison 2 Adverse events, Outcome 4 Diarrhoea.
Analysis 2.5
Analysis 2.5
Comparison 2 Adverse events, Outcome 5 Nausea.
Analysis 2.6
Analysis 2.6
Comparison 2 Adverse events, Outcome 6 Vomiting.
Analysis 2.7
Analysis 2.7
Comparison 2 Adverse events, Outcome 7 Muscle spasms or leg cramps.
Analysis 2.8
Analysis 2.8
Comparison 2 Adverse events, Outcome 8 Insomnia.
Analysis 2.9
Analysis 2.9
Comparison 2 Adverse events, Outcome 9 Cardiac problems, including coronary artery disease, cardiac disorder and bradycardia.
Analysis 2.10
Analysis 2.10
Comparison 2 Adverse events, Outcome 10 Headache.
Analysis 2.11
Analysis 2.11
Comparison 2 Adverse events, Outcome 11 Syncope or dizziness.
Analysis 2.12
Analysis 2.12
Comparison 2 Adverse events, Outcome 12 Depression.
Analysis 2.13
Analysis 2.13
Comparison 2 Adverse events, Outcome 13 Abnormal dreams.
Analysis 3.1
Analysis 3.1
Comparison 3 Cognitive test scores, Outcome 1 ADAS‐Cog (original) at 6 months.
Analysis 3.2
Analysis 3.2
Comparison 3 Cognitive test scores, Outcome 2 ADAS‐Cog (modified) at 1 year.
Analysis 3.3
Analysis 3.3
Comparison 3 Cognitive test scores, Outcome 3 ADAS‐Cog (modified) at 2 years.
Analysis 3.4
Analysis 3.4
Comparison 3 Cognitive test scores, Outcome 4 CDR sum of boxes at 1 year.
Analysis 3.5
Analysis 3.5
Comparison 3 Cognitive test scores, Outcome 5 Symbol Digit Modalities Test at 6 months.
Analysis 3.6
Analysis 3.6
Comparison 3 Cognitive test scores, Outcome 6 MMSE at 1 year.
Analysis 3.7
Analysis 3.7
Comparison 3 Cognitive test scores, Outcome 7 ADCS‐ADL at 6 months.
Analysis 3.8
Analysis 3.8
Comparison 3 Cognitive test scores, Outcome 8 ADCS‐ADL at 1 year.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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References to studies excluded from this review

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References to ongoing studies

    1. 24‐week, randomized, double‐blind, placebo‐controlled, parallel group study of the Exelon® [rivastigmine] transdermal patch in 120 APOE e4 positive amnestic MCI patients, 2011. http://clinicaltrials.gov/ct2/show/NCT01602198 (accessed 3 August 2012).

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