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Vol. 20, No. 2-3, 2005
Issue release date: August 2005
Dement Geriatr Cogn Disord 2005;20:192–197
(DOI:10.1159/000087301)

Efficacy of Rivastigmine in Alzheimer’s Disease Patients with Rapid Disease Progression: Results of a Meta-Analysis

Farlow M.R.a · Small G.W.b · Quarg P.c · Krause A.c
aIndiana University School of Medicine, Indianapolis, Ind., bUCLA Neuropsychiatric Institute, Los Angeles, Calif., USA; cNovartis Pharma AG, Basel, Switzerland
email Corresponding Author

Abstract

Background: Alzheimer’s disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. Methods: Rapidly and slowly progressing patients were identified by rates of cognitive decline [≧4 points and <4 points, respectively, on the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0–26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26–52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. Results: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p = 0.029), who experienced a modest decline in cognitive symptoms at the end of the study. Comment: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.


 goto top of outline Key Words

  • Cholinesterase inhibitor
  • Rivastigmine
  • Alzheimer’s disease
  • Rapid progression

 goto top of outline Abstract

Background: Alzheimer’s disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. Methods: Rapidly and slowly progressing patients were identified by rates of cognitive decline [≥4 points and <4 points, respectively, on the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0–26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26–52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. Results: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p = 0.029), who experienced a modest decline in cognitive symptoms at the end of the study. Comment: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Rosenstein LD: Differential diagnosis of the major progressive dementias and depression in middle and late adulthood: A summary of the literature of the early 1990s. Neuropsychol Rev 1998;8:109–167.
  2. Wiebusch H, Poirier J, Sevigny P, Schappert K: Further evidence for a synergistic association between APOE epsilon 4 and BCHE-K in confirmed Alzheimer’s disease. Hum Genet 1999;104:158–163.
  3. Lehmann DJ, Johnston C, Smith AD: Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer’s disease. Hum Mol Genet 1997;6:1933–1936.
  4. Panegyres PK, Mamotte CD, Vasikaran SD, Wilton S, Fabian V, Kakulas BA: Butyrylcholinesterase K variant and Alzheimer’s disease. J Neurol 1999;246:369–370.
  5. Selkoe DJ: Alzheimer’s disease: Genes, proteins, and therapy. Physiol Rev 2001;81:741–766.
  6. Jacobs D, Sano M, Marder K, Bell K, Bylsma F, Lafleche G, et al: Age at onset of Alzheimer’s disease: Relation to pattern of cognitive dysfunction and rate of decline. Neurology 1994;44:1215–1220.
  7. Chui H, Lyness S, Sobel E, Schneider L: Extrapyramidal signs and psychiatric symptoms predict faster cognitive decline in Alzheimer’s disease. Arch Neurol 1994;51:676–681.
  8. Stern Y, Tang M, Albert M, Brandt J, Jacobs DM, Bell K, et al: Predicting time to nursing home care and death in individuals with Alzheimer disease. JAMA 1997;277:806–812.
  9. Doody RS, Massman P, Dunn JK: A method for estimating progression rates in Alzheimer disease. Arch Neurol 2001;58:449–454.
  10. Hui JS, Wilson RS, Bennett DA, Bienias JL, Gilley DW, Evans DA: Rate of cognitive decline in Alzheimer’s disease. Neurology 2003;61:1356–1361.
  11. Farlow MR, Hake A, Messina J, Hartman R, Veach MS, Anand R: Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression. Arch Neurol 2001;58:417–422.
  12. Corey-Bloom J, Anand R, Veach J: A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J GeriatrPsychopharmacol1998;1:55–65.
  13. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomised controlled trial. BMJ 1999;318:633–640.
  14. Schneider A, Anand R, Farlow M: Systematic review of the efficacy of rivastigmine for patients with Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998;1:S26–S34.
  15. Anand R, Messina J, Hartman R: Dose-response effect of rivastigmine in the treatment of Alzheimer’s disease. Int J Geriatr Psychopharmacol 2000;2:68–72.
  16. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  17. 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.
  18. Mesulam M, Guillozet A, Shaw P, Quinn B: Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 2002;9:88–93.
  19. Perry EK, Perry RH, Blessed G, Tomlinson BE: Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 1978;4:273–277.
  20. Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S: Cholinesterases: Roles in the brain during health and disease. Curr Alzheimer Res 2005, in press.
  21. Wright CI, Geula C, Mesulam MM: Neurological cholinesterases in the normal brain and in Alzheimer’s disease: Relationship to plaques, tangles and patterns on selective vulnerability. Ann Neurol1993;34:373–384.
  22. Perry E, McKeith I, Ballard C: Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies. Neurology 2003;60:1852–1853.
  23. O’Brien KK, Saxby BK, Ballard GG, Grace J, Harrington F, Ford GA, et al: Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 2003;13:231–239.
  24. Holmes C, Ballard C, Lehman D, David Smith A, Beaumont H, Day IN, Nadeem Khan M, Lovestone S, McCulley M, Morris CM, Munoz DG, O’Brien K, Russ C, Del Ser T, Warden D: Rate of progression of cognitive decline in Alzheimer’s disease: effect of butyrylcholinesterase K gene variation. J Neurol Neurosurg Psychiatry 2005;76:640–643.

 goto top of outline Author Contacts

Dr. Martin R. Farlow
Department of Neurology, Clinical Building, Room 299
541 Clinical Drive, Indiana University School of Medicine
Indianapolis, IN 46202-5111 (USA)
Tel. +1 317 274 2893, Fax +1 317 278 3930, E-Mail mfarlow@iupui.edu


 goto top of outline Article Information

Disclosures: Dr. Martin Farlow receives grants from Novartis, Pfizer, Forest Laboratories, Eunoe Inc., Janssen, Eli Lilly and Co., Elan and Pharmanet LLC. Dr. Farlow has acted as a paid consultant for Novartis, Janssen, Eli Lilly and Co., Best Practice, Memory, and Accera Inc., and is on speaker bureaus for Novartis, Forest Research, and Eisai/Pfizer. Dr. Gary Small reports having been a consultant for, having served on advisory boards for, and having received honoraria for lectures from Pfizer, Eisai, Novartis, Lilly, Organon, Forest, Janssen, Abbott, Memory Fitness Institute, Amersham, and CTI. Dr. Peter Quarg and Andreas Krause are employees of Novartis Pharma AG, Basel, Switzerland.

Accepted: March 7, 2005
Published online: August 3, 2005
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 2, Number of References : 24


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 20, No. 2-3, Year 2005 (Cover Date: Released August 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: Alzheimer’s disease (AD) patients experiencing more rapid symptom progression are likely to have a poorer prognosis than those experiencing slow symptom progression. In a recent retrospective analysis, treatment effects of rivastigmine were more pronounced in AD patients with rapid cognitive decline than in those with slow cognitive decline. This warranted further investigation. Methods: Rapidly and slowly progressing patients were identified by rates of cognitive decline [≧4 points and <4 points, respectively, on the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)] during 26 weeks of placebo treatment in four randomized controlled trials (weeks 0–26). This meta-analysis evaluated rates of cognitive decline in both subgroups during subsequent open-label rivastigmine 26-week extension studies (weeks 26–52). A longitudinal mixed effects model compared cognitive decline in rapidly and slowly progressing patients, including correction for possible regression to the mean. Results: 180 (75%) rapidly and 337 (78%) slowly progressing patients provided ADAS-cog data after 26 weeks of open-label rivastigmine treatment. Improvements in cognitive symptoms were observed during the first 12 weeks, which were more pronounced in patients with rapid progression than in those with slow progression. Rapidly progressing patients experienced significantly greater cognitive benefits than slowly progressing patients (p = 0.029), who experienced a modest decline in cognitive symptoms at the end of the study. Comment: Patients experiencing rapid symptom progression may receive greater benefit from rivastigmine than those with slow progression. In this study, cholinesterase inhibition appeared to be of particular utility in the management of AD patients whose symptoms were rapidly worsening.



 goto top of outline Author Contacts

Dr. Martin R. Farlow
Department of Neurology, Clinical Building, Room 299
541 Clinical Drive, Indiana University School of Medicine
Indianapolis, IN 46202-5111 (USA)
Tel. +1 317 274 2893, Fax +1 317 278 3930, E-Mail mfarlow@iupui.edu


 goto top of outline Article Information

Disclosures: Dr. Martin Farlow receives grants from Novartis, Pfizer, Forest Laboratories, Eunoe Inc., Janssen, Eli Lilly and Co., Elan and Pharmanet LLC. Dr. Farlow has acted as a paid consultant for Novartis, Janssen, Eli Lilly and Co., Best Practice, Memory, and Accera Inc., and is on speaker bureaus for Novartis, Forest Research, and Eisai/Pfizer. Dr. Gary Small reports having been a consultant for, having served on advisory boards for, and having received honoraria for lectures from Pfizer, Eisai, Novartis, Lilly, Organon, Forest, Janssen, Abbott, Memory Fitness Institute, Amersham, and CTI. Dr. Peter Quarg and Andreas Krause are employees of Novartis Pharma AG, Basel, Switzerland.

Accepted: March 7, 2005
Published online: August 3, 2005
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 2, Number of References : 24


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 20, No. 2-3, Year 2005 (Cover Date: Released August 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

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. Rosenstein LD: Differential diagnosis of the major progressive dementias and depression in middle and late adulthood: A summary of the literature of the early 1990s. Neuropsychol Rev 1998;8:109–167.
  2. Wiebusch H, Poirier J, Sevigny P, Schappert K: Further evidence for a synergistic association between APOE epsilon 4 and BCHE-K in confirmed Alzheimer’s disease. Hum Genet 1999;104:158–163.
  3. Lehmann DJ, Johnston C, Smith AD: Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer’s disease. Hum Mol Genet 1997;6:1933–1936.
  4. Panegyres PK, Mamotte CD, Vasikaran SD, Wilton S, Fabian V, Kakulas BA: Butyrylcholinesterase K variant and Alzheimer’s disease. J Neurol 1999;246:369–370.
  5. Selkoe DJ: Alzheimer’s disease: Genes, proteins, and therapy. Physiol Rev 2001;81:741–766.
  6. Jacobs D, Sano M, Marder K, Bell K, Bylsma F, Lafleche G, et al: Age at onset of Alzheimer’s disease: Relation to pattern of cognitive dysfunction and rate of decline. Neurology 1994;44:1215–1220.
  7. Chui H, Lyness S, Sobel E, Schneider L: Extrapyramidal signs and psychiatric symptoms predict faster cognitive decline in Alzheimer’s disease. Arch Neurol 1994;51:676–681.
  8. Stern Y, Tang M, Albert M, Brandt J, Jacobs DM, Bell K, et al: Predicting time to nursing home care and death in individuals with Alzheimer disease. JAMA 1997;277:806–812.
  9. Doody RS, Massman P, Dunn JK: A method for estimating progression rates in Alzheimer disease. Arch Neurol 2001;58:449–454.
  10. Hui JS, Wilson RS, Bennett DA, Bienias JL, Gilley DW, Evans DA: Rate of cognitive decline in Alzheimer’s disease. Neurology 2003;61:1356–1361.
  11. Farlow MR, Hake A, Messina J, Hartman R, Veach MS, Anand R: Response of patients with Alzheimer disease to rivastigmine treatment is predicted by the rate of disease progression. Arch Neurol 2001;58:417–422.
  12. Corey-Bloom J, Anand R, Veach J: A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J GeriatrPsychopharmacol1998;1:55–65.
  13. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomised controlled trial. BMJ 1999;318:633–640.
  14. Schneider A, Anand R, Farlow M: Systematic review of the efficacy of rivastigmine for patients with Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998;1:S26–S34.
  15. Anand R, Messina J, Hartman R: Dose-response effect of rivastigmine in the treatment of Alzheimer’s disease. Int J Geriatr Psychopharmacol 2000;2:68–72.
  16. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–1364.
  17. 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.
  18. Mesulam M, Guillozet A, Shaw P, Quinn B: Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol Dis 2002;9:88–93.
  19. Perry EK, Perry RH, Blessed G, Tomlinson BE: Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 1978;4:273–277.
  20. Ballard CG, Greig NH, Guillozet-Bongaarts AL, Enz A, Darvesh S: Cholinesterases: Roles in the brain during health and disease. Curr Alzheimer Res 2005, in press.
  21. Wright CI, Geula C, Mesulam MM: Neurological cholinesterases in the normal brain and in Alzheimer’s disease: Relationship to plaques, tangles and patterns on selective vulnerability. Ann Neurol1993;34:373–384.
  22. Perry E, McKeith I, Ballard C: Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies. Neurology 2003;60:1852–1853.
  23. O’Brien KK, Saxby BK, Ballard GG, Grace J, Harrington F, Ford GA, et al: Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 2003;13:231–239.
  24. Holmes C, Ballard C, Lehman D, David Smith A, Beaumont H, Day IN, Nadeem Khan M, Lovestone S, McCulley M, Morris CM, Munoz DG, O’Brien K, Russ C, Del Ser T, Warden D: Rate of progression of cognitive decline in Alzheimer’s disease: effect of butyrylcholinesterase K gene variation. J Neurol Neurosurg Psychiatry 2005;76:640–643.