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Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

ABSTRACT:

Background

Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.

Methods and findings

The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).

Conclusions

The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.

SUBMITTER: Raschetti R

PROVIDER: S-EPMC2082649 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Publications

Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

Raschetti Roberto R Albanese Emiliano E Vanacore Nicola N Maggini Marina M

PLoS medicine 20071101 11

<h4>Background</h4>Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (done ...[more]

PMID: 18044984

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Project description:IntroductionAnalyses of off-label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI-treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI-) subjects while accounting for baseline differences.MethodsWe selected 121 ADNI MCI AChEI+ subjects and 151 AChEI- subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI- also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI-) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI- FDG PET and MRI data.ResultsAt baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI- subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI- subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid-positive and have lower GMD and FDG standardized uptake value ratio than AChEI- at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status.DiscussionOur data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.

Project description:BackgroundThe effectiveness of treatments for mild cognitive impairment is uncertain. The aim of this review was to evaluate the effectiveness and harms of treatment for mild cognitive impairment in adults 65 years of age and older.MethodsWe searched MEDLINE, Embase and Cochrane Central (December 2012-December 2014); citations from 2 systematic reviews were considered for inclusion. We included randomized controlled trials involving community-dwelling adults aged 65 years and older with a diagnosis of mild cognitive impairment. Studies reporting on cognition, function, behaviour, global status, mortality and adverse events for treatment with pharmacologic and nonpharmacologic interventions were included.ResultsSeventeen studies were included. Cholinesterase inhibitor studies evaluating cognition (Alzheimer's Disease Assessment Scale, cognition subscale) showed no difference between intervention and control groups (mean difference [MD] -0.33, 95% CI -0.73 to 0.06]; one behavioural study showed no significant effect on cognition (Alzheimer's Disease Assessment Scale, cognition subscale) for the intervention group when compared to controls (MD -0.60, (95% CI -1.44 to 0.24), and one study on vitamin E showed no difference between intervention and control groups (MD 0.85, 95% CI -0.32 to 2.02). With the Mini-Mental State Examination, cholinesterase inhibitors showed no difference between intervention and control groups (MD 0.17, 95% CI -0.13 to 0.47); behavioural studies showed a significant difference favouring intervention (MD 1.01, 95% CI 0.25 to 1.77), and studies of dietary supplements and/or vitamins showed no difference between intervention and control groups (MD 0.20, 95% CI -0.04 to 0.43). Pharmacologic studies showed no difference in serious adverse events (risk ratio 0.98, 95% CI 0.86 to 1.10). No serious adverse events were reported for nonpharmacologic interventions.InterpretationTreatment of mild cognitive impairment with cholinesterase inhibitors showed no benefit when compared with a control group. A small cognitive benefit was observed using behavioural therapies when compared with the control group. However, the clinical significance of this small benefit remains uncertain. The current evidence does not support the use of cholinesterase inhibitors for treating mild cognitive impairment, and future high-quality research using a standardized approach is needed to affirm the finding of a small benefit on cognition that was observed for behavioural interventions.RegistrationPROSPERO no. CRD42014015431.

Dataset Information

Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

Background

Methods and findings

Conclusions

Publications

Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

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