Background: Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer’s disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial.
Objective: To compare the effects of three AChEIs, donepezil (Aricept®), galantamine (Reminyl®) and rivastigmine (Exelon®), in an Italian national, prospective, observational study representative of the ‘real world’ clinical practice of AChEI treatment for AD.
Methods: 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants.
Results: No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2–3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE ε4 allele did not influence the effect of drug therapy.
Conclusion: Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because ‘real world’ practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.
Rivastigmine Galantamine Rivastigmine Group Galantamine Group Cronos Project
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.
This work was supported by: the PRRIITT (Programme for Industrial Research, Innovation and Technology Transfer) programme of the Emilia-Romagna Region (and Fondi Strutturali Obiettivo 2); the Italian Ministry of Health Grant ‘Progetto Finalizzato Studio delle differenze uomo-donna nei meccanismi patogenetici delle malattie cardiovascolari’; the Italian Ministry of Health Grant ex art 56 533F/B 1; the Italian Ministry of University and Research (MiUR) PRIN 2006 Project (♯2006061707); the Italian Ministry of Health Grant “An integrated approach to identify functional, biochemical and genetic markers in centenarians and Alzheimer’s disease patients”; the University of Bologna Grant ‘Ricerca Fondamentale Orientata (RFO ex 60%) 2005’; and Roberto and Cornelia Pallotti Legacy for Cancer Research Grants to Claudio Franceschi. The authors have no conflicts of interest that are directly relevant to the content of this study.
Musial A, Bajda M, Malawska B. Recent developments in cholinesterase inhibitors for Alzheimer’s disease treatment. Curr Med Chem 2007; 14(25): 2654–79PubMedCrossRefGoogle Scholar
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367: 1057–65PubMedCrossRefGoogle Scholar
Feldman HH, Lane R, Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2007; 78: 1056–63PubMedCrossRefGoogle Scholar
Cummings J, Winblad B. A rivastigmine patch for the treatment of Alzheimer’s disease and Parkinson’s disease dementia. Expert Rev Neurother 2007; 7: 1457–63PubMedCrossRefGoogle Scholar
Winblad B, Cummings J, Andreasen N, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease: rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007; 22: 456–67PubMedCrossRefGoogle Scholar
Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000; 54: 2261–8Google Scholar
Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321: 1445–9Google Scholar
Lanctôt KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ 2003; 169(6): 557–64PubMedGoogle Scholar
Ritchie CW, Ames D, Clayton T, et al. Meta-analysis of randomized trials of the efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer disease. Am J Geriatr Psychiatry 2004; 12(4): 358–69PubMedGoogle Scholar
Rockwood K. Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004; 75(5): 677–85PubMedCrossRefGoogle Scholar
Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006; (1): CD005593Google Scholar
Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, et al. Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials. BMJ 2005; 331: 321–7PubMedCrossRefGoogle Scholar
Wilkinson DG, Passmore AP, Bullock R, et al. A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int J Clin Pract 2002; 56: 441–6PubMedGoogle Scholar
Wilcock G, Howe I, Coles H, et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer’s disease. Drugs Aging 2003; 20: 777–89PubMedCrossRefGoogle Scholar
Fuschillo C, Ascoli E, Franzese G, et al. Alzheimer’s disease and acetylcholinesterase inhibitor agents: a two-year longitudinal study. Arch Gerontol Geriatr Suppl 2004; (9): 187–94Google Scholar
Mossello E, Tonon E, Caleri V, et al. Effectiveness and safety of cholinesterase inhibitors in elderly subjects with Alzheimer’s disease: a “real world” study. Arch Gerontol Geriatr Suppl 2004; (9): 297–307Google Scholar
Jones RW, Soininen H, Hager K, et al. A multinational, randomized, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry 2004; 19: 58–67PubMedCrossRefGoogle Scholar
Cedazo-Mínguez A. Apolipoprotein E and Alzheimer’s disease: molecular mechanisms and therapeutic opportunities. J Cell Mol Med 2007; 11: 1227–38PubMedCrossRefGoogle Scholar
McKhann G, Drachman D, Folstein M, 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: 939–44PubMedCrossRefGoogle Scholar
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: 189–98PubMedCrossRefGoogle Scholar
Morris JC, Edland S, Clark C, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD): part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer’s disease. Neurology 1993; 43: 2457–65Google Scholar
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984 Nov; 141(11): 1356–64PubMedGoogle Scholar
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psycho-pathology in dementia. Neurology 1994; 44: 2308–14PubMedCrossRefGoogle Scholar
Katz S, Ford AB, Moskowitz RW, et al., Studies of illness in the aged. The Index of ADL: a standardized measure of biological and psychosocial function. J Am Med Assoc 1963; 165: 94–9Google Scholar
Lawton MP, Brody EM. Assessment of older people: self-maintaining and Instrumental Activities of Daily Living. Gerontologist 1969; 9: 179–86PubMedCrossRefGoogle Scholar
Peripheral and Central Nervous System Drugs Advisory Committee Meeting, July 7, 1989. Rockville (MD): Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1989: 227Google Scholar
Anonymous Committee for Proprietary Medicinal Products (CPMP). Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. CPMP/986/96. London: Committee for Proprietary Medicinal Products, 1997Google Scholar
Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990; 31: 545–8PubMedGoogle Scholar
Stern RG, Mohs RC, Davidson M, et al. A longitudinal study of Alzheimer’s disease: measurement, rate, and predictors of cognitive deterioration. Am J Psychiatry 1994; 151: 390–6PubMedGoogle Scholar
Raschetti R, Maggini M, Sorrentino GC, et al. A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer’s disease. Eur J Clin Pharmacol 2005; 61: 361–8PubMedCrossRefGoogle Scholar
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148: 379–97PubMedGoogle Scholar
Cortes F, Portet F, Touchon J, et al. Six and 18-month changes in mild to moderate Alzheimer’s patients treated with acetylcholinesterase inhibitors: what can we learn for clinical outcomes of therapeutic trials? J Nutr Health Aging 2007; 11: 330–7PubMedGoogle Scholar
Sun Y, Lai MS, Lu CJ, et al. How long can patients with mild or moderate Alzheimer’s dementia maintain both the cognition and the therapy of cholinesterase inhibitors: a national population-based study. Eur J Neurol 2008; 15: 278–83PubMedCrossRefGoogle Scholar
Nordberg A, Darreh-Shori T, Peskind E, et al. Different cholinesterase inhibitor effects on CSF cholinesterases in Alzheimer patients. Curr Alzheimer Res 2009 Feb; 6(1): 4–14PubMedCrossRefGoogle Scholar
Relkin NR. Beyond symptomatic therapy: a re-examination of acetylcholinesterase inhibitors in Alzheimer’s disease. Expert Rev Neurother 2007; 7: 735–48PubMedCrossRefGoogle Scholar
Bizzarro A, Marra C, Acciarri A, et al. Apolipoprotein E epsilon4 allele differentiates the clinical response to donepezil in Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 20: 254–61PubMedCrossRefGoogle Scholar
Choi SH, Kim SY, Na HR, et al. Effect of ApoE genotype on response to donepezil in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2008; 25: 445–50PubMedCrossRefGoogle Scholar
Farlow M, Lane R, Kudaravalli S, et al. Differential qualitative responses to rivastigmine in APOE epsilon 4 carriers and noncarriers. Pharmacogenomics J 2004; 4: 332–5PubMedCrossRefGoogle Scholar
Blesa R, Aguilar M, Casanova JP, et al. Relationship between the efficacy of rivastigmine and apolipoprotein E (epsilon4) in patients with mild to moderately severe Alzheimer disease. Alzheimer Dis Assoc Disord 2006; 20: 248–54PubMedCrossRefGoogle Scholar
MacGowan SH, Wilcock GK, Scott M. Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. Int J Geriatr Psychiatry 1998; 13: 625–30PubMedCrossRefGoogle Scholar
Aerssens J, Raeymaekers P, Lilienfeld S, et al. APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer’s disease. Dement Geriatr Cogn Disord 2001; 12: 69–77PubMedCrossRefGoogle Scholar
Suh GH, Jung HY, Lee CU, et al. Effect of the apolipoprotein E epsilon4 allele on the efficacy and tolerability of galantamine in the treatment of Alzheimer’s disease. Dement Geriatr Cogn Disord 2006; 21: 33–9PubMedCrossRefGoogle Scholar
Babic T, Mahovic Lakusic D, Sertić J, et al. ApoE genotyping and response to galantamine in Alzheimer’s disease: a real life retrospective study. Coll Antropol 2004; 28: 199–204PubMedGoogle Scholar