Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

doi:10.1136/bmj.331.7512.321

BMJ 2005;331:321-327 (6 August), doi:10.1136/bmj.331.7512.321

Paper

Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials

Hanna Kaduszkiewicz, research fellow¹, Thomas Zimmermann, research fellow¹, Hans-Peter Beck-Bornholdt, professor¹, Hendrik van den Bussche, director¹

¹ Department of Primary Medical Care, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany

Corresponding author: H Kaduszkiewicz kaduszki{at}uke.uni-hamburg.de

Objectives Pharmacological treatment of Alzheimer's diseasefocuses on correcting the cholinergic deficiency in the centralnervous system with cholinesterase inhibitors. Three cholinesteraseinhibitors are currently recommended: donepezil, rivastigmine,and galantamine. This review assessed the scientific evidencefor the recommendation of these agents.

Data sources The terms "donepezil", "rivastigmine", and "galantamine",limited by "randomized-controlled-trials" were searched in Medline(1989-November 2004), Embase (1989-November 2004), and the CochraneDatabase of Systematic Reviews without restriction for language.

Study selection All published, double blind, randomised controlledtrials examining efficacy on the basis of clinical outcomes,in which treatment with donepezil, rivastigmine, or galantaminewas compared with placebo in patients with Alzheimer's disease,were included. Each study was assessed independently, followinga predefined checklist of criteria of methodological quality.

Results 22 trials met the inclusion criteria. Follow-up rangedfrom six weeks to three years. 12 of 14 studies measuring thecognitive outcome by means of the 70 point Alzheimer's diseaseassessment scale—cognitive subscale showed differencesranging from 1.5 points to 3.9 points in favour of the respectivecholinesterase inhibitors. Benefits were also reported fromall 12 trials that used the clinician's interview based impressionof change scale with input from caregivers. Methodological assessmentof all studies found considerable flaws—for example, multipletesting without correction for multiplicity or exclusion ofpatients after randomisation.

Conclusion Because of flawed methods and small clinical benefits,the scientific basis for recommendations of cholinesterase inhibitorsfor the treatment of Alzheimer's disease is questionable.

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Rapid Responses:

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Evidence for cholinesterase inhibitors in AD: David G Wilkinson
bmj.com, 13 Aug 2005 [Full text]
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