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A previous meta-analysis of functional and behavioural outcomes found little benefit to cholinesterase inhibitors in patients with Alzheimer’s dementia (JAMA 2003;289:210-6).
The current study 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 a four-point or greater improvement on the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog). The authors identified 40 studies, but excluded 24, leaving 16 studies with more than 7,800 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 three or higher on a five-point scale.
Overall, they estimate a number-needed-to- treat of 12 for global response and 10 for cognitive response. However, 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) appears 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 they combine results from studies even when there is 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 looking at the drugs separately, only rivastigmine exhibited significant heterogeneity.
If the definition of success was changed to greater than minimal improvement, the number- needed-to-treat was 42 (95% CI, 26–114), a much less impressive benefit. With global responders, variability came from a study done on exclusively Japanese patients, which detected a large treatment effect.
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 appears 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–)
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.