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Vol. 20, No. 6, 2005
Issue release date: November 2005
Section title: Original Research Article
Dement Geriatr Cogn Disord 2005;20:338–344
(DOI:10.1159/000088494)

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

Román G.C.a · Wilkinson D.G.e · Doody R.S.b · Black S.E.f · Salloway S.P.c · Schindler R.J.d
aDepartment of Medicine (Neurology), University of Texas Health Science Center and Audie Murphy Veterans Hospital, San Antonio, Tex., bDepartment of Neurology, Baylor College of Medicine, Houston, Tex., cClinical Neuroscience, Brown Medical School, Providence, R.I., and dPfizer Inc., New York, N.Y., USA; eMemory Assessment and Research Center, Moorgreen Hospital, Southampton, UK; fDepartment of Medicine (Neurology), Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto, Canada
email Corresponding Author

Abstract

Background and Objective: 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. Methods: 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)].Results: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. Conclusions: 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.

© 2005 S. Karger AG, Basel


  

Key Words

  • Vascular dementia
  • Cholinesterase inhibitors
  • Donepezil
  • Cognitive benefit
  • Global function benefit

References

  1. Román GC: Vascular dementia revisited: diagnosis, pathogenesis, treatment, and prevention. Med Clin North Am 2002;86:477–499.
  2. Looi JC, Sachdev PS: Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 1999;53:670–678.
  3. Boyle PA, Cohen RA, Paul R, Moser D, Gordon N: Cognitive and motor impairments predict functional declines in patients with vascular dementia. Int J Geriatr Psychiatry 2002;17:164–169.
  4. Desmond DW, Moroney JT, Sano M, Stern Y: Mortality in patients with dementia after ischemic stroke. Neurology 2002;59:537–543.
  5. Johannsen P: Long-term cholinesterase inhibitor treatment of Alzheimer’s disease. CNS Drugs 2004;18:757–768.
  6. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, Lou Lou MM, Einarson TR: Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ 2003;169:557–564.
  7. Swartz RH, Sahlas DJ, Black SE: Strategic involvement of cholinergic pathways and executive dysfunction: does location of white matter signal hyperintensity matter? J Stroke Cerebrovasc Dis 2003;12:29–36.

    External Resources

  8. Mesulam M, Siddique T, Cohen B: Cholinergic denervation in a pure multi-infarct state: observations on CADASIL. Neurology 2003;60:1183–1185.
  9. Wilkinson D, Doody R, Helme R, Taubman K, Mintzer J, Kertesz A, Pratt RD, Donepezil 308 Study Group: Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 2003;61:479–486.
  10. Black S, Román GC, Geldmacher DS, Salloway S, Hecker J, Burns A, Perdomo C, Kumar D, Pratt R, Donepezil 307 Vascular Dementia Study Group: Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003;34:2323–2330.
  11. Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al: Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250–260.
  12. World Medical Association Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277:925–926.
  13. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  14. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  15. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman M, Thomas RG, Ferris SH: Validity and reliability of the Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11 (suppl 2):S22–S32.

    External Resources

  16. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL: A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572.
  17. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD, the ‘312’ Study Group: A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology2001;57:481–488.
  18. Cohen J: Statistical Power Calculations for the Behavioural Sciences, ed 2. Hillsdale, Lawrence Erlbaum Associates, 1988.
  19. Bender R: Number needed to treat (NNT); in Armitage P, Colton T (eds): Encyclopedia of Biostatistics, ed 2. Chichester, Wiley, 2004.
  20. Pratt RD: Patient populations in clinical trials of the efficacy and tolerability of donepezil in patients with vascular dementia. J Neurol Sci 2002;203–204:57–65.
  21. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV: Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet2002;359:1283–1290.
  22. Kittner B, De Deyn PP, Erkinjuntti T: Investigating the natural course and treatment of vascular dementia and Alzheimer’s disease: parallel study populations in two randomized, placebo-controlled trials. Ann NY Acad Sci 2000;903:535–541.
  23. Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, Hachinski VC: Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol1997;54:697–703.
  24. Wilcock G, Mobius HJ, Stoffler A: A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002;17:297–305.
  25. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F: Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;33:1834–1839.
  26. Rockwood K: Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75:677–685.

  

Author Contacts

Gustavo C. Román, MD
University of Texas Health Science Center, School of Medicine at San Antonio
Department of Medicine, Division of Neurology, Mail Code 7883, 7703 Floyd Curl Drive
San Antonio, TX 78229-3900 (USA)
Tel. +1 210 617 5161, Fax +1 210 567 4659, E-Mail romang@uthsca.edu

  

Article Information

Accepted: June 21, 2005
Published online: September 23, 2005
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 3, Number of References : 26

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 20, No. 6, Year 2005 (Cover Date: Released November 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background and Objective: 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. Methods: 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)].Results: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. Conclusions: 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.

© 2005 S. Karger AG, Basel


  

Author Contacts

Gustavo C. Román, MD
University of Texas Health Science Center, School of Medicine at San Antonio
Department of Medicine, Division of Neurology, Mail Code 7883, 7703 Floyd Curl Drive
San Antonio, TX 78229-3900 (USA)
Tel. +1 210 617 5161, Fax +1 210 567 4659, E-Mail romang@uthsca.edu

  

Article Information

Accepted: June 21, 2005
Published online: September 23, 2005
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 3, Number of References : 26

  

Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 20, No. 6, Year 2005 (Cover Date: Released November 2005)

Journal Editor: Chan-Palay, V. (New York, N.Y.)
ISSN: 1420–8008 (print), 1421–9824 (Online)

For additional information: http://www.karger.com/dem


Article / Publication Details

First-Page Preview
Abstract of Original Research Article

Received: 6/23/2005
Published online: 11/17/2005
Issue release date: November 2005

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 3

ISSN: 1420-8008 (Print)
eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Román GC: Vascular dementia revisited: diagnosis, pathogenesis, treatment, and prevention. Med Clin North Am 2002;86:477–499.
  2. Looi JC, Sachdev PS: Differentiation of vascular dementia from AD on neuropsychological tests. Neurology 1999;53:670–678.
  3. Boyle PA, Cohen RA, Paul R, Moser D, Gordon N: Cognitive and motor impairments predict functional declines in patients with vascular dementia. Int J Geriatr Psychiatry 2002;17:164–169.
  4. Desmond DW, Moroney JT, Sano M, Stern Y: Mortality in patients with dementia after ischemic stroke. Neurology 2002;59:537–543.
  5. Johannsen P: Long-term cholinesterase inhibitor treatment of Alzheimer’s disease. CNS Drugs 2004;18:757–768.
  6. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, Lou Lou MM, Einarson TR: Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ 2003;169:557–564.
  7. Swartz RH, Sahlas DJ, Black SE: Strategic involvement of cholinergic pathways and executive dysfunction: does location of white matter signal hyperintensity matter? J Stroke Cerebrovasc Dis 2003;12:29–36.

    External Resources

  8. Mesulam M, Siddique T, Cohen B: Cholinergic denervation in a pure multi-infarct state: observations on CADASIL. Neurology 2003;60:1183–1185.
  9. Wilkinson D, Doody R, Helme R, Taubman K, Mintzer J, Kertesz A, Pratt RD, Donepezil 308 Study Group: Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 2003;61:479–486.
  10. Black S, Román GC, Geldmacher DS, Salloway S, Hecker J, Burns A, Perdomo C, Kumar D, Pratt R, Donepezil 307 Vascular Dementia Study Group: Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo-controlled clinical trial. Stroke 2003;34:2323–2330.
  11. Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al: Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250–260.
  12. World Medical Association Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997;277:925–926.
  13. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  14. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  15. Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman M, Thomas RG, Ferris SH: Validity and reliability of the Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11 (suppl 2):S22–S32.

    External Resources

  16. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL: A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572.
  17. Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD, the ‘312’ Study Group: A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology2001;57:481–488.
  18. Cohen J: Statistical Power Calculations for the Behavioural Sciences, ed 2. Hillsdale, Lawrence Erlbaum Associates, 1988.
  19. Bender R: Number needed to treat (NNT); in Armitage P, Colton T (eds): Encyclopedia of Biostatistics, ed 2. Chichester, Wiley, 2004.
  20. Pratt RD: Patient populations in clinical trials of the efficacy and tolerability of donepezil in patients with vascular dementia. J Neurol Sci 2002;203–204:57–65.
  21. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV: Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet2002;359:1283–1290.
  22. Kittner B, De Deyn PP, Erkinjuntti T: Investigating the natural course and treatment of vascular dementia and Alzheimer’s disease: parallel study populations in two randomized, placebo-controlled trials. Ann NY Acad Sci 2000;903:535–541.
  23. Bowler JV, Eliasziw M, Steenhuis R, Munoz DG, Fry R, Merskey H, Hachinski VC: Comparative evolution of Alzheimer disease, vascular dementia, and mixed dementia. Arch Neurol1997;54:697–703.
  24. Wilcock G, Mobius HJ, Stoffler A: A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002;17:297–305.
  25. Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F: Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;33:1834–1839.
  26. Rockwood K: Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75:677–685.