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

摘要

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. cholinesterase inhibitor , Alzheimer’s disease , discontinuation , efficacy , Bayesian meta-analysis Significance Statement In this article, we report the results of a systematic review and meta-analysis investigating the discontinuation, efficacy, and safety of cholinesterase inhibitors for Alzheimer’s disease. We included 43 randomized clinical trials involving 16106 patients. We used a Bayesian framework. While cholinesterase inhibitors showed a poor risk-benefit relationship, as indicated by small symptom improvement, and a higher all-cause discontinuation than placebo, a reduction in mortality was also found, which could indicate some disease progression-modifying effect these drugs. This finding could renew interest in clinical research on cholinesterase inhibitors. Nevertheless, the clinical relevance of reduction in mortality accompanied by only a small improvement in symptoms is uncertain. Finally, intervention- and patient-related factors, but not study design, were found to modify the effect of cholinesterase inhibitors in patients with Alzheimer’s disease. To the best of our knowledge, this is the largest meta-analysis in the field, the first to focus on clinically relevant outcomes, to find a reduction in mortality, and to identify patient-, intervention-, and study design-related covariates that modify the efficacy, safety, and discontinuation of cholinesterase inhibitors in patients with Alzheimer’s disease.