. (2012) Donepezil and Memantine for moderate-to-severe Alzheimer's disease. New England Journal of Medicine, Vol.366 (No.10). pp. 893-903. ISSN 0028-4793

Preview

PDF WRAP_Sheehan_nejmoa1106668.pdf - Published Version - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader Download (729Kb)

Abstract

Background Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer’s disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer’s disease (a score of 5 to 13 on the Standardized Mini–Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. Results Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. Conclusions In patients with moderate or severe Alzheimer’s disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Health Sciences
Library of Congress Subject Headings (LCSH):	Alzheimer's disease -- Treatment, Cholinesterase inhibitors
Journal or Publication Title:	New England Journal of Medicine
Publisher:	NEJM.org
ISSN:	0028-4793
Date:	March 2012
Volume:	Vol.366
Number:	No.10
Page Range:	pp. 893-903
Identification Number:	10.1056/NEJMoa1106668
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Medical Research Council (Great Britain) (MRC), Alzheimer’s Society (AS)
References:	1. Kaduszkiewicz H, Zimmerman T, Beck-Bornholdt HP, van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials. BMJ 2005;331: 321-7. 2. Burback D, Molnar FJ, St John P, Man- Son-Hing M. Key methodological features of randomized controlled trials of Alzheimer’s disease therapy: minimal clinically important difference, sample size and trial duration. Dement Geriatr Cogn Disord 1999;10:534-40. 3. National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. NICE technology appraisal guidance 217, 2011 (http://guidance.nice.org.uk/TA217). 4. Areosa SA, Sherriff F, McShane R. Memantine for dementia. Cochrane Database Syst Rev 2005;3:CD003154. 5. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317-24. 6. Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT. Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res 2008;5:83-9. 7. Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001;57: 613-20. [Erratum, Neurology 2001;57:2153.] 8. Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebocontrolled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc 2001;49:1590-9. 9. Feldman H, Gauthier S, Hecker J, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer’s disease: a subgroup analysis from a randomised, placebo-controlled trial. Int J Geriatr Psychiatry 2005;20:559-69. 10. Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallelgroup, placebo-controlled study. Lancet 2006;367:1057-65. [Errata, Lancet 2006; 367:1980, 368:1650.] 11. Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 2007;69:459-69. 12. Homma A, Imai Y, Tago H, et al. Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord 2008;25:399-407. 13. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med 2009;169:867-73. 14. Jones R, Sheehan B, Phillips P, et al. DOMINO-AD protocol: Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease — a multicentre randomised controlled trial. Trials 2009;10:57. 15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRADA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939-44. 16. Molloy DW, Standish TI. A guide to the standardized Mini-Mental State Examination. Int Psychogeriatr 1997;9:Suppl 1:87-94. 17. McEntegart DJ. The pursuit of balance using stratified and dynamic randomization techniques: an overview. Drug Inf J 2003;37:293-308. 18. Bucks RS, Ashworth DL, Wilcock GK, Siegfried K. Assessment of activities of daily living in dementia: development of the Bristol Activities of Daily Living Scale. Age Ageing 1996;25:113-20. 19. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308-14. 20. Smith SC, Lamping DL, Banerjee S, et al. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology. Health Technol Assess 2005;9:1-93. 21. Goldberg DP, Gater R, Sartorius N, et al. The validity of two versions of the GHQ in the WHO study of mental illness in general health care. Psychol Med 1997; 27:191-7. 22. Armitage P, Berry G, Matthews JNS. Statistical methods in medical research. 4th ed. Malden, MA: Blackwell Science, 2002. 23. Akaike H. A new look at the statistical model identification. IEEE Trans 1974;19: 716-23. 24. Stata statistical software, release 11. College Station, TX: StataCorp, 2009. 25. Cook RJ, Farewell VT. Multiplicity considerations in the design and analysis of clinical trials. J R Stat Soc [A] 1996; 159:93-110. 26. Howard R, Phillips P, Johnson T, et al. Determining the minimum clinically important differences for outcomes in the DOMINO trial. Int J Geriatr Psychiatry 2010;26:812-7. 27. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41:582-92. 28. Peripheral and Central Nervous System Drugs Advisory Committee Meeting materials. Rockville, MD: Food and Drug Administration, July 7, 1989:227. 29. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15. 30. Cummings JL, Schneider E, Tariot PN, Graham SM. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006;67:57-63. 31. Singh S, Dudley C. Discontinuation syndrome following donepezil cessation. Int J Geriatr Psychiatry 2003;18:282-4.
URI:	http://wrap.warwick.ac.uk/id/eprint/43439

Request changes to a record

Actions (login required)

View Item