Donepezil in Vascular Dementia: Combined Analysis of Two Large-Scale Clinical Trials

University of Toronto, Toronto, Ontario, Canada
Dementia and Geriatric Cognitive Disorders (Impact Factor: 3.55). 11/2005; 20(6):338-44. DOI: 10.1159/000088494
Source: PubMed


There are currently no drugs approved to treat vascular dementia (VaD). The objective of this study was to determine if treatment with donepezil, an acetylcholinesterase inhibitor, may provide benefit for VaD patients.
Combined analysis of 2 identical randomized, double-blind, placebo-controlled, 24-week studies involving 1,219 patients enrolled at 109 investigational sites in the USA, Europe, Canada and Australia. Patients were randomized to receive donepezil 5 mg/day (n = 406) or 10 mg/day (after brief titration; n = 421) or placebo (n = 392). Patients were assessed on cognition [Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE)], global function [Clinician's Interview-Based Impression of Change plus (CIBIC-plus), Clinical Dementia Rating-Sum of the Boxes (CDR-SB)] and function [Alzheimer's Disease Functional Assessment and Change Scale (ADFACS); instrumental activities of daily living (ADFACS-IADL)].
Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p < 0.01). Significant global function benefits were seen on the CIBIC-plus in the 5 mg/day group (placebo vs. 5 mg/day, p < 0.001; vs. 10 mg/day, p = 0.006) and on the CDR-SB in the 10 mg/day group (placebo vs. 5 mg/day, p = 0.09; vs. 10 mg/day, p < 0.01). Significant functional benefits were also seen (ADFACS, placebo vs. 5 mg/day, p = 0.08; vs. 10 mg/day, p = 0.02; ADFACS-IADL, p < 0.05 for both donepezil groups). Donepezil was well tolerated, with low withdrawal rates due to adverse events.
This combined analysis of the largest trial on VaD to date showed that donepezil-treated patients had significant benefits in cognition, global function and ability to perform IADL. Based on these findings and reported tolerability, donepezil should be considered as an important therapeutic element in the overall management of patients with VaD.

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    • "The present study, which examined rats that survived for three months after BCCAo, is the first report that ChAT of the basal forebrain was decreased and that hippocamal MAPK signaling was altered. Interestingly, the findings that ChAT of the basal forebrain was decreased are strengthened by the clinical report that patients with VaD show cholinergic deficits in the brain and cerebrospinal fluid (CSF), and that it had significant benefits in cognition following treatment with donepezil, an acetylcholinesterase inhibitor (Roman et al., 2005; Wang et al., 2009). Moreover, the findings that the hippocampal signaling pathway related to MAPKs is altered in an animal model of VaD provide a new therapeutic target for the development of antidementia agents. "
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    • "These effects were reversed after discontinuation of the cholinesterase inhibitor. These behavioral changes were also detected in the absence of significant modifications of the MMSE score and of episodic memory performances in line with the poor effects of donepezil on global cognitive or memory performances in previous vascular dementia trials (Erkinjuntti et al., 2004; Roman et al., 2005; Dichgans et al., 2008). In this study, not only the NPI, that is largely used for the assessment of behavioral alterations, but also the DEX questionnaire was applied to assess the possible changes under donepezil. "
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