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

• Published in: The international journal of neuropsychopharmacology Vol. 20; no. 7; pp. 519 - 528
• Main Authors: Blanco-Silvente, Lídia, Castells, Xavier, Saez, Marc, Barceló, Maria Antònia, Garre-Olmo, Josep, Vilalta-Franch, Joan, Capellà, Dolors
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-07-2017
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - mortality; Cholinesterase Inhibitors - therapeutic use; Drug Administration Schedule; Editor's Choice; Humans; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Regression Analysis; Regular; Treatment Outcome; Alzheimer’s disease; discontinuation; efficacy; cholinesterase inhibitor; Bayesian meta-analysis
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyx012

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.