Alzheimer's disease; EFNS/ENS Guidelines; Grading of Recommendations Assessment, Development and Evaluation; cholinesterase inhibitors; dementia; memantine; meta-analysis; treatment; Cholinesterase Inhibitors; Excitatory Amino Acid Antagonists; Memantine; Alzheimer Disease/drug therapy; Cholinesterase Inhibitors/therapeutic use; Excitatory Amino Acid Antagonists/therapeutic use; Humans; Memantine/therapeutic use; Drug Therapy, Combination; Practice Guidelines as Topic; Neurology; Neurology (clinical); EFNS; ENS Guidelines; Grading of Recommendations Assessment; Development and Evaluation
Abstract :
[en] [en] BACKGROUND AND PURPOSE: Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL).
METHODS: A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.
RESULTS: Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95% CI -0.37; -0.17) and behaviour (SMD -0.19; 95% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak.
CONCLUSIONS: We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.
Disciplines :
Neurology
Author, co-author :
Schmidt, R; Department of Neurology, Medical University of Graz, Graz, Austria
Hofer, E; Department of Neurology, Medical University of Graz, Graz, Austria ; Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
Bouwman, F H; Alzheimer Centre, VU University Medical Centre, Amsterdam, Netherlands
Buerger, K; Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Munich, Germany
Cordonnier, C; Department of Neurology, Univ Lille Nord de France, UDSL, CHU Lille, Lille, France
Fladby, T; Department of Neurology, Akershus University Hospital, Ahus, Norway
Galimberti, D; Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, IRCCS Ospedale Maggiore Policlinico, Fondazione Cà Granda, Milan, Italy
Georges, J; Alzheimer Europe, Luxembourg City, Luxembourg
HENEKA, Michael ; Clinic and Polyclinic for Neurology, Clinical Neuroscience Unit, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany
Hort, J; Second Faculty of Medicine, Department of Neurology, Charles University in Prague and Motol University Hospital, Prague 5, Czech Republic ; International Clinical Research Centre, St Anne's University Hospital, Brno, Czech Republic
Laczó, J; Second Faculty of Medicine, Department of Neurology, Charles University in Prague and Motol University Hospital, Prague 5, Czech Republic ; International Clinical Research Centre, St Anne's University Hospital, Brno, Czech Republic
Molinuevo, J L; Alzheimer's Disease and other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, IDIBAPS, Barcelona, Spain
O'Brien, J T; Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
Religa, D; Karolinska Institutet Alzheimer Disease Research Centre, Karolinska University Hospital, Stockholm, Sweden ; Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Scheltens, P; Alzheimer Centre, VU University Medical Centre, Amsterdam, Netherlands
Schott, J M; Dementia Research Centre, Institute of Neurology, UCL Queen Square, London, United Kingdom
Sorbi, S; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Parsons CG, Danysz W, Dekundy A, Pulte I. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. Neurotox Res 2013; 24: 358-369.
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006: CD005593.
McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev 2006: CD003154.
EMEA Committee for Medicinal Products for Human. Plenary Meeting Monthly Report. http://www.emea.europe.eu/pdfs/human/press/pr/36234805en.pdf (accessed 18/03/2014).
Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291: 317-324.
van Dyck CH, Schmitt FA, Olin JT, Memantine MEMMDSG. A responder analysis of memantine treatment in patients with Alzheimer disease maintained on donepezil. Am J Geriatr Psychiatry 2006; 14: 428-437.
Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 2008; 22: 209-221.
Porsteinsson AP, Grossberg GT, Mintzer J, Olin JT, Memantine MEMMDSG. 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: 83-89.
Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry 2009; 80: 600-607.
Choi SH, Park KW, Na DL, et al. Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study. Curr Med Res Opin 2011; 27: 1375-1383.
Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012; 366: 893-903.
Wilkinson D, Fox NC, Barkhof F, Phul R, Lemming O, Scheltens P. Memantine and brain atrophy in Alzheimer's disease: a 1-year randomized controlled trial. J Alzheimers Dis 2012; 29: 459-469.
Cummings JL, Schneider E, Tariot PN, Graham SM, Memantine MEMMDSG. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology 2006; 67: 57-63.
Feldman HH, Schmitt FA, Olin JT, Memantine MEMMDSG Activities of daily living in moderate-to-severe Alzheimer disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord 2006; 20: 263-268.
(NICE) NIfCE. Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease. NICE Technology Appraisal Guidance 217 (Review of NICE Technology Appraisal Guidance 111). http://publications.nice.org.uk/donepezil-galantamine-rivastigmine-and-memantine-for-the-treatment-of-alzheimers-disease-ta217/guidance (accessed 18/03/2014).
Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther 2013; 5: S5.
Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer's disease: a systematic review. BMJ Open 2012; 2: e000917.
Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924-926.
Leone MA, Brainin M, Boon P, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations 2012. Eur J Neurol 2013; 20: 410-419.
Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol 2011; 64: 395-400.
The Cochrane Dementia and Cognitive Improvement Group. ALOIS: a comprehensive register of dementia studies. http://www.medicine.ox.ac.uk/alois/ (accessed 02/06/2014).
Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors. CNS Drugs 2013; 27: 469-478.
Schneider LS, Insel PS, Weiner MW. Alzheimer's disease neuroimaging I. Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. Arch Neurol 2011; 68: 58-66.
The Cochrane Collaboration. Review Manager (RevMan). 5.2., 2012.
Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383-394.
Brozek J, Oxman A, Schünemann H. GRADEpro. 3.2 for Windows, 2008.
Winblad B, Jones RW, Wirth Y, Stoffler A, Mobius HJ. Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord 2007; 24: 20-27.
Cummings JL. Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry 2000; 157: 4-15.
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: 2308-2314.
Murman DL, Chen Q, Powell MC, Kuo SB, Bradley CJ, Colenda CC. The incremental direct costs associated with behavioral symptoms in AD. Neurology 2002; 59: 1721-1729.
