Research Article: Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer’s disease: a network meta-analysis of 41 randomized controlled trials

Date Published: December 27, 2018

Publisher: BioMed Central

Author(s): Kai-Xin Dou, Meng-Shan Tan, Chen-Chen Tan, Xi-Peng Cao, Xiao-He Hou, Qi-Hao Guo, Lan Tan, Vincent Mok, Jin-Tai Yu.


Cholinesterase inhibitors and memantine have been approved for management of Alzheimer’s disease (AD), but there has been no consensus about the choice of various types and doses of drugs at different stages. Hence, we compared and ranked the efficacy and tolerability of these available drugs.

We searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase for randomized controlled trials (RCTs) published from database inception to July 21, 2017. The primary outcomes were the mean overall changes in cognitive function and responders who had any adverse events. We conducted a random-effects network meta-analysis.

Forty-one RCTs were included in this study. Compared with placebo, galantamine 32 mg daily (standardized mean difference – 0.51, 95% credible interval – 0.67 to − 0.35), galantamine 24 mg daily (− 0.50, − 0.61 to − 0.40), and donepezil 10 mg daily (− 0.40, − 0.51 to − 0.29) were probably the most effective agents on cognition for mild to moderate AD, and memantine 20 mg combined with donepezil 10 mg (0.76, 0.39 to 1.11) was recommended for moderate to severe patients. Memantine showed the best profile of acceptability. Rivastigmine transdermal 15-cm2 patch was the best optional treatment both in function and global changes. None of the medicines was likely to improve neuropsychiatric symptoms through this analysis.

Pharmacological interventions have beneficial effects on cognition, function, and global changes, but not on neuropsychiatric symptoms, through current network meta-analysis. The choice of drugs may mainly depend on the disease severity and clinical symptoms.

The online version of this article (10.1186/s13195-018-0457-9) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia affecting 46.8 million people with an enormous public health impact [1, 2]. Primary manifestations of AD include progressive deterioration of cognition, impairment in functional ability, and alterations of neuropsychiatric symptoms. Currently, there are no therapeutic interventions that can delay the disease progression, but available medications have provided symptomatic benefits [3]. Two main classes of drugs are recommended by the US Food and Drug Administration (FDA) for pharmacological management of AD: cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, which are licensed for mild to moderate AD [4, 5]; and glutamate antagonist memantine for moderate to severe stage [6]. Donepezil is the only ChEI to be indicated for use all across the full spectrum of AD [7]. Owing to fewer treatment options for more serious patients, donepezil 23 mg was approved for moderate to severe AD in recent years [8, 9] and the combination therapy of donepezil plus memantine is proposed for treating patients in this stage [10].

This network meta-analysis comprehensively compares and ranks efficacy and tolerability among current available cognitive enhancers approved by the FDA for AD. The cholinesterase inhibitors result in better outcomes on cognition than memantine for mild to moderate patients, among which galantamine and donepezil are probably the interventions most strongly associated with cognitive improvements. For moderate to severe AD, the combination therapy of donepezil 10 mg with memantine 20 mg is the most effective regimen, followed by donepezil 23 mg alone. However, none of the cognitive enhancers was likely to improve behavior. The higher-dose rivastigmine transdermal patch (15 cm2) was probably the best option considering the benefits of both function and clinical global impression. Memantine shows the best profile of acceptability, while rivastigmine oral form is associated with a high incidence of adverse events. Both clinical efficacy and adverse events related to cognitive enhancers are shown to be dose dependent. Our findings may help physicians choose targeted pharmaceuticals for patients with different stages and clinical symptoms.

Our analysis provides some evidence that galantamine and donepezil may show the highest level of efficacy in cognition for mild to moderate AD, and the combination therapy (memantine 20 mg with donepezil 10 mg) and donepezil 23 mg daily are recommended for moderate to severe patients. The higher-dose rivastigmine transdermal patch (15 cm2) is the best option considering the benefits of both function and clinical global impression. None of the medicines is likely to improve behavior through current network meta-analysis. Memantine shows the best profile of acceptability, while rivastigmine oral form is associated with a high incidence of adverse events. Although the clinical effects are uncertain in the multifactor environment, these findings are helpful for guiding treatment decisions. Hopefully, further research should try to differentiate more clearly the effects of monotherapy versus combined therapies.




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