Comparative efficacy of cholinesterase inhibitors and memantine on cognition in AD patients with application of network meta‐analysis

Abstract

AbstractBackgroundThis study aimed to assess the comparative efficacy of monotherapy and combined therapy of cholinesterase inhibitors plus memantine on cognition in AD and determine efficacy across doses for these pharmacological drugs.MethodThe screening of 2,113 articles were initiated. Finally, forty randomized controlled trials (RCTs) from PubMed, Web of Science, and Scopus databases inception to the end of Dec. 2022 were finally included in this review. The included RCTs contain donepezil, rivastigmine, galantamine and memantine alone or in any combination of them were compared with placebo in terms of MMSE score. The mean difference (MD) in MMSE score was considered as the effect size of efficacy. The quality of the RCTs were appraised using the Cochrane risk‐of‐bias tool (RoB‐2). An additive network meta‐analysis (NMA) was applied to compare the efficacy of the drugs. Trends of efficacy across doses for each available treatment were checked using a dose‐response modeling. Finally, P‐score as a probability of being the most effective treatment, was used to rank the treatments. All statistical analyses were done using netmeta and dosresmeta R packages. The study protocol was registered in the PROSPERO (CRD42022358469).ResultThese RCTs included 16,785 AD patients with mean age 73 (SD = 3.5) yrs., and weight 64.5 (SD = 5.55) kg. Of these patients, 65.15% were women. The median follow‐up time was 6 (range = 3‐48) months. The main NMA results showed that galantamine 32mg/day (MD = 3.71; 95% CI = 2.21, 5.21; P‐score = 0.89), donepezil 10mg/day combined with memantine 20mg/day (MD = 3.27; 95% CI = 1.79, 4.76; P‐score = 0.83), and then galantamine 24mg/day (MD = 3.02; 95% CI = 2.19, 3.84; P‐score = 0.79) were significantly the most effective treatments compared with placebo, respectively. According to the sub‐group analysis of stages, donepezil 10mg/day combined with memantine 20mg/day (MD = 4.78; 95% CI = 2.86, 6.71) and galantamine 32mg/day (MD = 3.81; 95% CI = 2.20, 5.34) were recommended for moderate to severe and mild to moderate AD patients, respectively. Moreover, we found there was a significant positive linear trend of efficacy across doses of galantamine.ConclusionMonotherapy with a high dose of galantamine or the combination of donepezil plus memantine have the most favorable effects on cognition for 6 months follow up in AD patients.