Fillers POEM

Donepezil is somewhat effective for Alzheimer's, probably better than galantamine

BMJ 2004; 328 doi: (Published 09 January 2004) Cite this as: BMJ 2004;328:0-g

Question Are cholinesterase inhibitors safe and effective for Alzheimer's dementia?

Synopsis A previous meta-analysis of functional and behavioural outcomes found little benefit to cholinesterase inhibitors in patients with Alzheimer's dementia JAMA 2003;289: 210-16). The current meta-analysis used “global response” as the primary outcome, defined as minimal improvement or better as evaluated by clinicians (clinical global impression of change scale) or clinicians and caregivers (clinician's interview-based impression of change plus caregiver input scale). A secondary outcome was “cognitive response,” defined as an improvement of four points or more on the Alzheimer's disease assessment scale cognitive subscale (ADAScog). The authors identified 40 randomised controlled trials, but excluded 24, leaving 16 studies with more than 7800 patients for the final analysis. The JAMA meta-analysis used 29 studies, so the current authors were a bit more selective. All studies had a Jadad score for quality of 3 or higher on a five point scale. Overall, the authors estimated a number needed to treat of 12 for global response and 10 for cognitive response, but they also found a number needed to harm of 12 for any adverse event and 16 for any adverse event severe enough to cause a dropout. All drugs were not equal—donepezil (Aricept) seems somewhat more effective than galantamine (Reminyl) and a bit better tolerated as well. Higher doses did not produce much benefit over lower doses. A flaw in the study is that it combined results from studies even when there was significant heterogeneity (variability between studies). A look at the individual study data for cognitive responders, though, shows that much of this variability may come from combining studies of donepezil and rivastigmine (which clustered together) with those of galantamine. When the drugs were looked at separately, only revastigmine showed significant heterogeneity. If the definition of success was changed to greater than minimal improvement, the number needed to treat was 42 (95% confidence interval 26 to 114), a much less impressive benefit. With global responders, variability came from a study done on exclusively Japanese patients, which detected a large treatment effect.

Bottom line Using a fairly loose criterion for success of “any benefit,” cholinesterase inhibitors helped one patient for every 12 treated, but caused side effects bad enough to force discontinuation of the drug in one of every 16 treated. Donepezil seems to be more effective than galantamine, although head to head trials are lacking. Low doses are similar to high doses in efficacy.

Level of evidence 1a (see Systematic reviews (with homogeneity) of randomised controlled trials.

Lanctot KL, Herrman N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ 2003;169: 557-64

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  • * Patient-Oriented Evidence that Matters. See editorial (BMJ 2002;325: 983)

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