Discontinuation, Efficacy, and Safety of Cholinesterase Inhibitors for Alzheimer’s Disease: a Meta-Analysis and Meta-Regression of 43 Randomized Clinical Trials Enrolling 16 106 Patients

Abstract

Background:We investigated the effect of cholinesterase inhibitors on all-cause discontinuation, efficacy and safety, and the effects of study design-, intervention-, and patient-related covariates on the risk-benefit of cholinesterase inhibitors for Alzheimer’s disease.Methods:A systematic review and meta-analysis of randomized placebo-controlled clinical trials comparing cholinesterase inhibitors and placebo was performed. The effect of covariates on study outcomes was analysed by means of meta-regression using a Bayesian framework.Results:Forty-three randomized placebo-controlled clinical trials involving 16106 patients were included. All-cause discontinuation was higher with cholinesterase inhibitors (OR = 1.66), as was discontinuation due to adverse events (OR=1.75). Cholinesterase inhibitors improved cognitive function (standardized mean difference = 0.38), global symptomatology (standardized mean difference=0.28) and functional capacity (standardized mean difference=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 standardized mean difference = 0.41). The proportion of patients with serious adverse events decreased with age (Diff OR = -0.09). Mortality was lower with cholinesterase inhibitors than with placebo (OR = 0.65).Conclusion:While cholinesterase inhibitors 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 cholinesterase inhibitors in patients with Alzheimer’s disease.

Effect of anticholinergic burden on treatment modification, delirium and mortality in newly diagnosed dementia patients starting a cholinesterase inhibitor: A population‐based study

“…Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine are widely recommended and used for the treatment of dementia, especially for mild‐to‐moderate Alzheimer's disease (AD). The use of cholinesterase inhibitors continues despite some evidence suggesting that they have a poor risk‐benefit relationship, that is, that they produce mild to no symptom improvement, especially in nursing homes, and have a high rate of all‐cause discontinuation . Drugs with anticholinergic properties that have the opposite mechanism of action can reduce the therapeutic effect of cholinesterase inhibitors when used in combination.…”

Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors

“…At present, treatment of AD is mainly provided with acetylcholinesterase (AChE) inhibitors, compounds which increase the level of acetylcholine in the brain. However, since there are frequent adverse side-effects including hepatic injury, diarrhea, or cardiovascular damage [3–5], the discovery of new, selective AChE inhibitors is of interest. In this context, many natural products or their derivatives have been found to have AChE inhibitory activity [6–9].…”

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

“…While the AChase inhibitors-tacrine, donepezil, galantamine, and rivastigminewere developed and approved for the treatment of AD, issues with their side effects and modest efficacy (Blanco-Silvente et al, 2017) have limited their use. Considerable efforts were also expended in the 1990s in developing selective muscarinic M 1 (xanomeline; Bodick et al, 1997) and nicotinic α4β2 (epiboxidine; Arneric, Holladay, & Williams, 2007) cholinergic agonists for the treatment of AD.…”