Objective: Evaluation of the efficacy and tolerability of the selective acetylcholinesterase inhibitor, donepezil, in patients with probable or possible Vascular Dementia (VaD).
Background: Cholinesterase inhibitors have proven benefits in Alzheimer’s disease (AD), and clinical evidence to suggest that patients with VaD may also benefit from treatment with cholinesterase inhibitors is accumulating.
Design: A randomized, double-blind, placebo-controlled, 24-week, parallel-group study (Study 307).
Materials and Methods: A diagnosis of probable or possible VaD according to NINDS-AIREN criteria was required for inclusion (ie, evidence of dementia and a probable or possible relationship between dementia and cerebrovascular disease [CVD]). Patients with a prior diagnosis of AD and subsequent cognitive impairment due to stroke or CVD were excluded. Patients were randomized to receive placebo, donepezil 5 mg/day, or donepezil 10 mg/day (5 mg/day for first 28 days). Efficacy assessments included the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), the Clinician’s Interview-Based Impression of Change-plus version (CIBIC-plus), the Clinical Dementia Rating–Sum of the Boxes (CDR–SB), and the Alzheimer's Disease Functional Assessment Scale (ADFACS). Results are reported for intent-to-treat, observed cases, least-square mean change from baseline score, treatment effect size.
Results: 603 patients were enrolled (placebo, n=199; donepezil 5 mg/day, n=198; donepezil 10 mg/day, n=206); 425 (70%) had probable VaD and 178 (30%) had possible VaD. At week 24, significant differences in cognitive function in favor of both donepezil-treated groups compared with placebo were observed (ADAS-cog: donepezil 5 mg/day, -1.90, P=0.001; donepezil 10 mg/day, -2.33, P=0.0001). At Week 24, significant differences versus placebo were also seen in global function for donepezil 10 mg/day (CDR-SB; donepezil 5 mg/day, -0.19, P=0.267; donepezil 10 mg/day, -0.48, P=0.007), and donepezil 5 mg/day (% of patients rated as showing improvement on the CIBIC-plus: placebo, 32%; donepezil 5 mg/day, 38%, P=0.014; donepezil 10 mg/day, 31%, P=0.273; Overall P=0.046). Significant benefits on activities of daily living (ADL) versus placebo were observed for both donepezil-treated groups at Week 24 (ADFACS: donepezil 5 mg/day, -1.311, P=0.022; donepezil 10 mg/day, -1.305, P=0.025). Donepezil was well tolerated in this population (of whom 89% had comorbid cardiovascular disease), with low withdrawal rates due to adverse events (placebo, 11.1%; donepezil 5 mg/day, 11.1%; donepezil 10 mg/day, 21.8%) and a similar incidence of cardiovascular adverse events across all treatment groups (placebo, 18.1%; donepezil 5 mg/day, 20.7%; donepezil 10 mg/day, 20.4%).
Conclusion: Donepezil-treated patients with probable or possible VaD demonstrated significant benefits in cognition and global function compared with placebo-treated patients. Donepezil treatment may also help to delay functional decline in patients with VaD. Donepezil was well tolerated in this population, which has a high incidence of cardiovascular disease.
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