The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

Abstract

BackgroundComparative evidence for efficacy and safety of second‐generation cholinesterase inhibitors (ChEIs) is still sparse.ObjectivesThe purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild‐to‐moderate Alzheimer's disease (AD).MethodsWe conducted a systematic review for published articles and included randomised, double‐blind, placebo‐controlled trials and head‐to‐head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS‐Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview‐Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta‐analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions.ResultsAmong the 21 trials included, network meta‐analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS‐Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety.ConclusionsOur analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild‐to‐moderate AD.

Effect of Apolipoprotein E ɛ4 Carrier Status on Cognitive Response to Acetylcholinesterase Inhibitors in Patients with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

“…Our result was in line with previous studies [54,55], suggesting that AChEIs had greater efficacy than placebo for cognition change assessment. However, with the association between APOE genotype and AD as a major risk factor, APOE ɛ4 is expected to be a potential predictor of response to treatment.…”

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

“…ChEIs are widely used to treat the symptoms of AD 52,53 , with four agents (tacrine, donepezil, rivastigmine, and galantamine) approved by the U.S. FDA and the European Medicines Agency (EMA). Each of these ChEIs varies from one another in how they inhibit ChE, and in their pharmacokinetics, safety, and long-term efficacy 54 . Furthermore, selective butyrylcholinesterase inhibition increased brain acetylcholine, augmented learning, and reduced Aβ peptide in rodents.…”

Long-term effect of galantamine on cognitive function in patients with Alzheimer’s disease versus a simulated disease trajectory: an observational study in the clinical setting

“…Indeed, a previous pooled analysis of studies on donepezil conducted between 1990 and 1999 revealed that patients allocated to placebo therapy showed slower cognitive decline in more recent trials compared with older trials, despite having more comorbidities 23. Furthermore, our previous network meta-analysis of ChEI therapy revealed an increasing placebo effect on cognitive function over time across various drugs of this class 24. These results suggest that there may have been possible overestimation of the speed of cognitive decline based on Mendiondo’s model in the present study.…”