Dement Geriatr Cogn Disord 2005;19:51–56

A 12-Month Study of the Efficacy of Rivastigmine in Patients with Advanced Moderate Alzheimer’s Disease

Karaman Y.a · Erdoğan F.a · Köseoğlu E.a · Turan T.b · Ersoy A.Ö.a
Departments of aNeurology and bPsychiatry, Medical Faculty, Erciyes University, Kayseri, Turkey
email Corresponding Author

 goto top of outline Key Words

  • Advanced moderate Alzheimer’s disease
  • Rivastigmine

 goto top of outline Abstract

The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713), in patients with advanced moderate Alzheimer’s disease (AD) was evaluated in a 12-month placebo-controlled study. We aimed to investigate whether there was any evidence for the benefits of rivastigmine in patients with severe disease. These patients were compared with matched controls. In this study, 24 patients with advanced moderate AD received rivastigmine for 12 months. Another 20 patients received placebo. Mean daily doses of rivastigmine in the higher-dose group at 3, 6, 9, and 12 months were 6.1 ± 1.0, 8.3 ± 1.2, 8.9 ± 1.3, and 10.7 ± 1.6 mg/day, respectively. Cognitive abilities were assessed using the 11-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Forty-five percent of placebo-treated patients declined by at least 4 points on the ADAS-cog. Conversely, only 18.3% of patients treated with rivastigmine declined by 4 or more points. Functional disabilities, as assessed using the Disability Assessment for Dementia Scale, remained significantly superior in rivastigmine-treated patients compared with placebo-treated patients. Patients benefited from high-dose rivastigmine treatment on all outcome measures, including the Mini-Mental State Examination, Progressive Deterioration Scale, as well as the Global Deterioration Scale. Patients receiving rivastigmine for 12 months significantly improved compared with placebo-treated patients (p < 0.001). By 52 weeks, patients originally treated with 6–12 mg/day rivastigmine had a significantly better cognitive function than patients originally treated with placebo. Long-term rivastigmine treatment appeared to be well tolerated in patients with advanced moderate AD and significantly benefits the cognitive and functional symptoms of AD.

Copyright © 2005 S. Karger AG, Basel

 goto top of outline References
  1. Blass JP: Pathophysiology of Alzheimer’s syndrome. Neurology 1993;43(suppl 4):S25–S38.
  2. Gauthier S: Clinical Diagnosis and Management of Alzheimer’s Disease. London, Martin Duniz Ltd, 1999, pp 57–67, 249–269.
  3. Davis KL, Haroutunian V: Strategies for the treatment of Alzheimer’s disease. Neurology 1993;43(suppl 4):S52–S55.
  4. Engelborghs S, Deyn PP: The neurochemistry of Alzheimer’s disease. Acta Neurol Belg 1997;97:67–84.
  5. Selkoe DJ: The molecular pathology of Alzheimer’s disease. Neuron 1991;6:487–498.
  6. Sands LP, Katz I, Schneider L: Assessing individual patients for cognitive benefits from acetylcholinesterase inhibitors. Alzheimer Dis Assoc Disord 1999;13:26–34.
  7. Sarter M, Bruno JP: Cognitive functions of cortical acetylcholine. Brain Res Brain Res Rev 1997;23:28–46.
  8. Sirvio J: Strategies that support declining cholinergic neurotransmission in Alzheimer’s disease patients. Gerontology 1999;45(suppl 1):3–14.

    External Resources

  9. Hogan DB, Patterson C: Treatment of Alzheimer’s disease and other dementias – Review and comparison of the cholinesterase inhibitors. Can J Neurol Sci 2002;29:306–314.
  10. Taylor P: Development of acetylcholinesterase inhibitors in the therapy of Alzheimer’s disease. Neurology 1998;51(suppl 1):S30–S35.
  11. Knopman D, Morris JC: An update on primary therapies for Alzheimer’s disease. Arch Neurol 1997;54:1406–1409.
  12. Maltby N, Broe GA, Creasey H, Jorm AF, Christensen H, Brooks WS: Efficacy of tacrine and lecithin in mild to moderate Alzheimer’s disease: Double blind trial. BMJ 1994;308:879–883.
  13. Cummings JL, Vinters HV, Cole GM, et al: Alzheimer’s disease. Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 1998;51(suppl 1):S2–S17.
  14. Doody RS, Stevens JC, Beck C, et al: Practice parameter: Management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154–1166.
  15. Weinstock M: Selectivity of cholinesterase inhibition. Clinical implications for the treatment of Alzheimer’s disease. CNS Drugs 1999;12:307–323.
  16. Anand R, Messina J, Hartman R: Dose response effect of rivastigmine in the treatment of Alzheimer’s disease. Int J Geriatr Psychopharmacol 2002;2:68–72.
  17. Cutler ND, Polinsky RJ, Sramek JJ, et al: Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer’s disease. Acta Neurol Scand 1998;97:244–250.
  18. Farlow M, Anand R, Messina JA, Hartman R, Veach J: A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol 2001;46:110.
  19. Spencer CM, Noble S; Rivastigmine. Drug Aging 1998;13:391–411.
  20. Ballard CG: Advances in the treatment of Alzheimer’s disease: Benefits of dual cholinesterase inhibition. Eur Neurol 2002;47:64–70.
  21. Roe CM, Anderson MJ, Spivack B: Use of anticholinergic medication by older adults with dementia. J Am Geriatr Soc 2002;50:836–842.
  22. Giacobini E, Spiegel R, Enz A: Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer’s disease by rivastigmine: Correlation with cognitive benefit. J Neural Transm 2002;109:1053–1065.
  23. Corey-Bloom J, Anand R, Veach J: ENA 713 B352 Study Group. 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 Geriatr Psychopharmacol 1998;1:55–65.
  24. Darreh-Shori T, Almkvist O, Guan ZZ, et al: Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology 2002;59:563–572.
  25. Rosler M, Anand R, Cicin-Sain A: Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomised controlled trial. BMJ 1999;318:633–638.
  26. Williams BR, Nazarians A, Gill MA: A review of rivastigmine: A reversible cholinesterase inhibitor. Clin Ther 2003;25:1634–1653.
  27. McKeith I, DelSer T, Emre M, et al: Efficacy of rivastigmine in dementia with Lewy bodies: A randomised, double-blind, placebo-controlled international study. Lancet 2000;356:2031–2036.
  28. Moretti R, Torre P, Antonello RM, et al: Rivastigmine in subcortical vascular dementia: A comparison trial on efficacy and tolerability for 12 months follow-up. Eur J Neurol 2001;361–363.
  29. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994.
  30. Mc Khann G, DrachmanD, Folstein M, Katzman R, Price D, et al: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944.
  31. Folstein MF, Hug PR, Folstein SE: Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–192.
  32. Rosen WG, Mohs RC, Davis KL: A new rating scala for assessing demented patients. Am J Psychiatry 1984;141:1356–1364.
  33. Schneider LS, Olin JT, Doody RS: Validity and reliability of the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11:22–32.
  34. Gelinas I, Gauthier L, Mclntryne M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: The disability assessment for dementia. Am J Occup Ther 1999;53:471–481.
  35. Galasko D, Bennett D, Sano M, et al: An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11:33–39.
  36. Dejong R, Osterland OW, Roy GW: Measurement of quality of life changes in patients with Alzheimer’s disease. Clin Ther 1989;11:545–554.
  37. Reisberg B, Ferris SH, de Leon MJ, et al: Global deterioration scale (GDS). Psychopharmacol Bull 1988;24:661–663.
  38. Feldman H, Sauter A, Donald A, Gelinas I Gauthier S, et al: The Disability Assessment for Dementia Scale: A 12-month study of functional ability in mild to moderate severity Alzheimer’s disease. Alzheimer Dis Assoc Disord 2001;15:89–95.
  39. Grossberg GT, Stahelin HB, Messina JC, Anand R: Lack of adverse pharmacodynamic drug interactions with rivastigmine and 22 classes of medication. Int J Geriatr Psychiatry 2000;15:242–247.
  40. Doraiswamy M, Hartman R, Graham S: Early intervention with a cholinesterase inhibitor produces long-term beneficial effects in moderately severe AD patients. Neurobiol Aging 2000;21:275.

    External Resources

  41. Farlow MR, Hake A, Messina J, Hartman R, Veach J, 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.
  42. Potki SG, Anand R, Hartman R, Veach J, Grossberg G: Impact of Alzheimer’s disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:713–720.
  43. Desai A, Grossberg G: Review of rivastigmine and its clinical applications in Alzheimer’s disease and related disorders. Eur Neurol 2000;44:236–241.
  44. Forette F, Anand R, Gharabowi G: A phase II study in patients with Alzheimer’s disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine. Eur J Neurol 1999;6:423–429.

 goto top of outline Author Contacts

Füsun Erdoğan
Erciyes University, Medical Faculty
Neurology Department
TR–38039 Kayseri (Turkey)
Tel. +90 352 4374901, Fax +90 352 4375285, E-Mail

 goto top of outline Article Information

Accepted: May 3, 2004
Published online: September 21, 2004
Number of Print Pages : 6
Number of Figures : 0, Number of Tables : 3, Number of References : 44

 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 19, No. 1, Year 2005 (Cover Date: Released December 2004)

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

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