Abstract
BACKGROUND: Vascular disease is the second commonest cause of dementia after Alzheimer's disease. There are difficulties in classifying patients with this type of cognitive impairment owing to varied clinical presentation and different types of arterial disease. There is some degree of overlap in the neuropathology of Alzheimer's and vascular dementia. Deficient cholinergic neurotransmission, a characteristic of Alzheimer's disease, has been postulated to contribute to the cognitive impairment of vascular disease of the brain. Cholinesterase inhibitors, such as donepezil, may therefore be a rational treatment. OBJECTIVES: To assess the clinical efficacy and tolerability of donepezil on cognitive function, clinical global impression, activities of daily living and social functioning of people with vascular cognitive impairment. SEARCH STRATEGY: Relevant randomized controlled trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group Specialized Register on 21 July 2003 using the terms donepezil, E2020 and Aricept. This Register consists of records from all major healthcare databases and many ongoing trials databases. Unpublished trials were requested from the drug company Eisai Inc and they provided us with the required data. SELECTION CRITERIA: All unconfounded randomized double-blind trials comparing donepezil with placebo were eligible for inclusion. Trials using combinations of donepezil with other pharmacological interventions were excluded. DATA COLLECTION AND ANALYSIS: Both reviewers assessed studies against the criteria for inclusion and extracted data. Data were pooled where appropriate, and weighted mean differences or Peto odds ratios with 95% confidence intervals calculated. Intention-to-treat analysis was undertaken when possible. MAIN RESULTS: Two large-scale, randomized, double-blind, parallel-group controlled trials were identified for inclusion. A total of 1219 people with mild to moderate cognitive decline due to probable or possible vascular dementia (according to the NINCDS/AIREN criteria and the Hachinski Ischemia Scale) were recruited. Donepezil, at doses of 5 or 10 mg a day was compared with placebo for 24 weeks. For each outcome measure, mean change from baseline at weeks 12 and 24, using a last observation carried forward analysis, was calculated. Cognitive function: The donepezil groups showed statistically significantly better performance than the placebo groups on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) at 12 and 24 weeks. The donepezil groups produced statistically significantly better scores than the placebo groups on the Mini-Mental State Examination (MMSE) at 12 and 24 weeks. Global function: The sum of the boxes of the Clinical Dementia Rating (CDR-SB) showed at 24 weeks a statistically significant benefit of 10 mg donepezil daily over both placebo and a 5 mg daily dosage. The Clinician's Interview-Based Impression of Change-plus version (CIBIC-plus) showed improved global function of participants taking 5 mg of donepezil daily compared with the placebo group but this was not seen in the higher dose group. Activities of daily living and social behaviour: On the Instrumental Activity of Daily Living (IADL) scale, there was no statistically significant difference between the groups taking donepezil 5mg per day donepezil and placebo, but the group taking 10 mg of donepezil a day showed benefit compared with placebo There were statistically significant benefit for donepezil at either dosage compared with placebo on the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS). Tolerability and adverse effects: Broad range of adverse events were reported in the studies and data confirmed that donepezil was well tolerated, and most of the side effects were transient and were resolved by stopping the medication. Some of these events, especially nausea, diarrhoea, anorexia and cramp appeared more frequently on the 10 mg dose where there was a statistically significant difference compared with placebo. Drop-out: The drop-out rate was similar between the groups, 84.2% (330) patients completed the studies. The withdrawal rate was low and due mainly to side effects. REVIEWER'S CONCLUSIONS: Evidence from the available studies support the benefit of donepezil in improving cognition function, clinical global impression and activities of daily living in patients with probable or possible mild to moderate vascular cognitive impairment after 6 months treatment. Extending studies for longer periods would be desirable to establish the efficacy of donepezil in patients with advanced stages of cognitive impairment. Moreover, there is an urgent need for establishing specific clinical diagnostic criteria and rating scales for vascular cognitive impairment.