We investigated the effect of cholinesterase inhibitors (ChEIs) on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention- and patient-related covariates on the risk-benefit of ChEIs for Alzheimer’s disease (AD).


A systematic review and meta-analysis of randomized placebo-controlled clinical trials (RPCCT) comparing ChEIs and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework.


Forty-four RPCCT involving 16,245 patients were included. All-cause discontinuation was higher with ChEIs (OR = 1.67), as was discontinuation due to adverse events (AEs) (OR = 1.75). ChEIs improved cognitive function (SMD= 0.38), global symptomatology (SMD = 0.28) and functional capacity (SMD = 0.16) but not neuropsychiatric symptoms. Rivastigmine was associated with a poorer outcome on all-cause discontinuation (Diff OR = 1.66) and donepezil with a higher efficacy on global change (Diff SMD = 0.41). Higher doses of ChEIs were associated with a higher frequency of AEs (Diff OR = 0.539). The proportion of patients with serious AEs decreased with age (Diff OR = -0.088) and increased with study length (Diff OR = 0.015). Mortality was lower with ChEIs than with placebo (OR = 0.71) but this outcome reduced with time (Diff OR = 0.018).


While ChEIs show a poor risk-benefit relationship as indicated by mild symptom improvement and a higher than placebo all-cause discontinuation, a reduction of mortality was suggested. Intervention- and patient-related factors modify the effect of ChEIs in patients with AD.

Author notes

CORRESPONDENCE: Xavier Castells, PhD. Address: Emili Grahit, 77, 17003 Girona, Spain. Telephone number: 972419629. Electronic address: xavier.castells@udg.edu
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