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Meta-Analysis
. 2004;2004(1):CD004395.
doi: 10.1002/14651858.CD004395.pub2.

Donepezil for vascular cognitive impairment

R Malouf  1 , J Birks
Affiliations
Meta-Analysis

Donepezil for vascular cognitive impairment

R Malouf et al. Cochrane Database Syst Rev. 2004.

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 Unpublished trials were requested from the drug company Eisai Inc and they provided us with the required data.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.

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Conflict of interest statement

None known

Figures

1.1
1.1. Analysis
Comparison 1 Donepezil vs placebo, Outcome 1 ADAS‐cog Completers.
1.2
1.2. Analysis
Comparison 1 Donepezil vs placebo, Outcome 2 ADAS‐cog ITT‐LOCF.
1.3
1.3. Analysis
Comparison 1 Donepezil vs placebo, Outcome 3 MMSE Completers.
1.4
1.4. Analysis
Comparison 1 Donepezil vs placebo, Outcome 4 MMSE ITT‐LOCF.
1.5
1.5. Analysis
Comparison 1 Donepezil vs placebo, Outcome 5 CDR‐SB completers.
1.6
1.6. Analysis
Comparison 1 Donepezil vs placebo, Outcome 6 CDR‐SB ITT‐LOCF.
1.7
1.7. Analysis
Comparison 1 Donepezil vs placebo, Outcome 7 IADL completers.
1.8
1.8. Analysis
Comparison 1 Donepezil vs placebo, Outcome 8 IADL ITT‐LOCF.
1.9
1.9. Analysis
Comparison 1 Donepezil vs placebo, Outcome 9 ADFACS Completers.
1.10
1.10. Analysis
Comparison 1 Donepezil vs placebo, Outcome 10 ADFACS ITT‐LOCF.
1.11
1.11. Analysis
Comparison 1 Donepezil vs placebo, Outcome 11 CIBIC‐plus (total number of patients who clinicaly improved).
1.12
1.12. Analysis
Comparison 1 Donepezil vs placebo, Outcome 12 CIBIC‐plus (total number of pateints who clinically declined).
1.13
1.13. Analysis
Comparison 1 Donepezil vs placebo, Outcome 13 Total number of patients who suffered from one side effect or more at 24 weeks.
1.14
1.14. Analysis
Comparison 1 Donepezil vs placebo, Outcome 14 Total number of patients who suffered from cardiovascular side effects at 24 weeks.
1.15
1.15. Analysis
Comparison 1 Donepezil vs placebo, Outcome 15 Total number of patients who suffered from hypertension at 24 weeks.
1.16
1.16. Analysis
Comparison 1 Donepezil vs placebo, Outcome 16 Total number of patients who suffered from syncope at 24 weeks.
1.17
1.17. Analysis
Comparison 1 Donepezil vs placebo, Outcome 17 Total number of patients who suffered from bradycardia at 24 weeks.
1.18
1.18. Analysis
Comparison 1 Donepezil vs placebo, Outcome 18 Total number of patients who had hypotension at 24 weeks.
1.19
1.19. Analysis
Comparison 1 Donepezil vs placebo, Outcome 19 Total number of patients who suffered from digestive system side effects at 24 weeks.
1.20
1.20. Analysis
Comparison 1 Donepezil vs placebo, Outcome 20 Total number of patients who suffered from anorexia at 24 weeks.
1.21
1.21. Analysis
Comparison 1 Donepezil vs placebo, Outcome 21 Total number of patients who suffered from constipation at 24 weeks.
1.22
1.22. Analysis
Comparison 1 Donepezil vs placebo, Outcome 22 Total number of patients who suffered from diarrhoea at 24 weeks.
1.23
1.23. Analysis
Comparison 1 Donepezil vs placebo, Outcome 23 Total number of patients who suffered from nausea at 24 weeks.
1.24
1.24. Analysis
Comparison 1 Donepezil vs placebo, Outcome 24 Total number of patients who suffered from dyspepsia at 24 weeks.
1.25
1.25. Analysis
Comparison 1 Donepezil vs placebo, Outcome 25 Total number of patients who suffered from vomiting at 24 weeks.
1.26
1.26. Analysis
Comparison 1 Donepezil vs placebo, Outcome 26 Total number of patients who suffered from neurological side effects at 24 weeks.
1.27
1.27. Analysis
Comparison 1 Donepezil vs placebo, Outcome 27 Total number of patients who suffered from back pain at 24 weeks.
1.28
1.28. Analysis
Comparison 1 Donepezil vs placebo, Outcome 28 Total number of patients who suffered from headache at 24 weeks.
1.29
1.29. Analysis
Comparison 1 Donepezil vs placebo, Outcome 29 Total number of patients who suffered from agitation at 24 weeks.
1.30
1.30. Analysis
Comparison 1 Donepezil vs placebo, Outcome 30 Total number of patients who suffered from stroke at 24 weeks.
1.31
1.31. Analysis
Comparison 1 Donepezil vs placebo, Outcome 31 Total number of patients who suffered from confusion at 24 weeks.
1.32
1.32. Analysis
Comparison 1 Donepezil vs placebo, Outcome 32 Total number of patients who suffered from depression at 24 weeks.
1.33
1.33. Analysis
Comparison 1 Donepezil vs placebo, Outcome 33 Total number of patients who suffered from dizziness at 24 weeks.
1.34
1.34. Analysis
Comparison 1 Donepezil vs placebo, Outcome 34 Total number of patients who suffered from insomnia at 24 weeks.
1.35
1.35. Analysis
Comparison 1 Donepezil vs placebo, Outcome 35 Total number of patients who suffered from at least one serious adverse event( SAE) at 24 weeks.
1.36
1.36. Analysis
Comparison 1 Donepezil vs placebo, Outcome 36 Total number of patients who suffered from skin carcinoma at 24 weeks.
1.37
1.37. Analysis
Comparison 1 Donepezil vs placebo, Outcome 37 Total number of patients who suffered from pathologic fracture at 24 weeks.
1.38
1.38. Analysis
Comparison 1 Donepezil vs placebo, Outcome 38 Total number of patients who suffered from pneumonia at 24 weeks.
1.39
1.39. Analysis
Comparison 1 Donepezil vs placebo, Outcome 39 Total number of patients who suffered from TIA at 24 weeks.
1.40
1.40. Analysis
Comparison 1 Donepezil vs placebo, Outcome 40 Total number of patients who suffered from angina at 24 weeks.
1.41
1.41. Analysis
Comparison 1 Donepezil vs placebo, Outcome 41 Total number of patients who suffered from a convulsion at 24 weeks.
1.42
1.42. Analysis
Comparison 1 Donepezil vs placebo, Outcome 42 Total number of patients who suffered from colitis at 24 weeks.
1.43
1.43. Analysis
Comparison 1 Donepezil vs placebo, Outcome 43 Total number of patients who suffered from asthenia at 24 weeks.
1.44
1.44. Analysis
Comparison 1 Donepezil vs placebo, Outcome 44 Total numbers of patients who suffered from cramps and leg cramps at 24 weeks.
1.45
1.45. Analysis
Comparison 1 Donepezil vs placebo, Outcome 45 Total number of patients who suffered from skin abrasion at 24 weeks.
1.46
1.46. Analysis
Comparison 1 Donepezil vs placebo, Outcome 46 Total number of patients who suffered from peripheral oedema at 24 weeks.
1.47
1.47. Analysis
Comparison 1 Donepezil vs placebo, Outcome 47 Total number of patients who suffered from abnormal dreams at 24 weeks.
1.48
1.48. Analysis
Comparison 1 Donepezil vs placebo, Outcome 48 Total number of patients who suffered from rhinitis at 24 weeks.
1.49
1.49. Analysis
Comparison 1 Donepezil vs placebo, Outcome 49 Total number of patients who suffered from infection at 24 weeks.
1.50
1.50. Analysis
Comparison 1 Donepezil vs placebo, Outcome 50 Total number of patients who suffered from pain at 24 weeks.
1.51
1.51. Analysis
Comparison 1 Donepezil vs placebo, Outcome 51 Total number of patients who suffered from skin rash at 24 weeks.
1.52
1.52. Analysis
Comparison 1 Donepezil vs placebo, Outcome 52 Total number of patients who suffered from urinary incontinence at 24 weeks.
1.53
1.53. Analysis
Comparison 1 Donepezil vs placebo, Outcome 53 Total number of patients who suffered from urinary tract infection at 24 weeks.
1.54
1.54. Analysis
Comparison 1 Donepezil vs placebo, Outcome 54 Total number of patients who withdrew before the end point of the intervention.
1.55
1.55. Analysis
Comparison 1 Donepezil vs placebo, Outcome 55 Total number of patients who suffered from syncope at 24 weeks.
1.56
1.56. Analysis
Comparison 1 Donepezil vs placebo, Outcome 56 Total number of patients who died by endpoint.
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Comment in

References

References to studies included in this review

Study 307/309 {published data only}
    1. Anon. Efficacy and Tolerability of donepezil in vascular dementia: positive results of a 24‐week, multicentre, international, randomized, placebo‐controlled clinical trial. pre‐publication report 2002. - PubMed
    1. Bayer A, Pratt RD, Kumar D. A comparison of the cognitive benefits of donepezil in patients with cortical and subcortical vascular dementia. 8th Congress of the European Federation of the Neurological Sciences. Paris, France. September 4‐7, 2004. 2004.
    1. Black S, RomanG, Geldmacher D, Salloway S, Hecker J, Burns A, Perdomo C, Kumar D, Pratt R, the Donepezil 307 vascular Dementia Study Group. Efficacy and tolerability of donepezil in vascular dementia positive results of a 24‐week multicenter internationl randomized placebo controlled trial. Stroke 2003;43:2323‐32. - PubMed
    1. Doody R, Pratt R, Posner H. Vascular dementia patients who receive donepezil treatment for 12 to 18 months maintain cognitive benefits. NeuroBiology of Aging 2004;25(S2):469.
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Study 308/309 {published data only}
    1. Bayer A, Pratt RD, Kumar D. A comparison of the cognitive benefits of donepezil in patients with cortical and subcortical vascular dementia. 8th Congress of the European Federation of the Neurological Sciences. Paris, France. September 4‐7, 2004. 2004.
    1. Doody R, Pratt R, Posner H. Vascular dementia patients who receive donepezil treatment for 12 to 18 months maintain cognitive benefits. NeuroBiology of Aging 2004;25(S2):469.
    1. Farlow Martin. Efficacy of donepezil in vascular dementia. Neurology 2003;61(4):429. - PubMed
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    1. Pratt RD, Perdomo CA, The Donepezil 307 and 308 VaD Study Groups. Population Characteristics and pattern of cognitive decline in patients with vascular dementia enrolled in two 24‐week, randomized,double‐blind, placebo‐controlled trials. Springfield Conference 2002, The International Symposium on Advances in Alzheimer Therapy, Geneva. 2002, Apr 3‐6:234.

References to studies excluded from this review

Meyer 2002 {published data only}
    1. Meyer JS, Chowdhury MH, Xu G, Li YS, Quach M. Donepezil treatment of vascular dementia. Annals of the New York Academy of Sciences 2002;977:482‐6. - PubMed
Rossor 2003 {published data only}
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Shua‐Haim 2000 {published data only}
    1. Shua‐Haim JR, Shua‐Haim Vered, Comsti E, Ross JS. Donepezil (Aricept R) treatment of multi infarct dementia the caregivers and clinical impression. American Journal of Alzheimer's Disease 2000;15(4):201‐11.

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