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Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.
Lancet Neurol 2015; 14(12):1171-81LN

Abstract

BACKGROUND

Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease.

METHODS

In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035.

FINDINGS

Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]).

INTERPRETATION

Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.

FUNDING

Medical Research Council and UK Alzheimer's Society.

Authors+Show Affiliations

Division of Psychiatry, University College London, London, UK; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: robert.howard@ucl.ac.uk.Oxford Health NHS Foundation Trust, Warneford Hospital, Headington, Oxford, UK.Health Sciences, University of Leicester, Leicester, UK.Centre for Brain Sciences, University of Edinburgh, Edinburgh, UK.Five Boroughs Partnership NHS Foundation Trust, Winwick, Warrington, UK.Centre for Ageing and Vitality, Newcastle upon Tyne, UK.Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.Institute of Mental Health, University of Nottingham, Nottingham, UK.Kingsway Care Centre, Dundee, UK.Faculty of Medicine, University of Southampton, Southampton, UK.Department of Pyschiatry, University of Nottingham, Nottingham, UK.Research Institute for the Care of Older People, Bath, UK.Newcastle; University Institute for Ageing, Newcastle University, Newcastle Upon Tyne, UK.Ayrshire and Arran NHS, University Hospital Crosshouse, Crosshouse, Kilmarnock, UK.Department of Psychiatry, University of Cambridge, Cambridge, UK.Oxford University Hospitals NHS Trust, Headington, Oxford, UK.National Perinatal Epidemiology Unit Clinical Trials Unit, University of Oxford, Oxford, UK.Division of Psychiatry, University College London, London, UK.Cardiff University School of Medicine, Cardiff, UK.London School of Economics, London, UK.Wolfson Centre for Age Related Disorders, King's College London, London, UK.Department of Psychology, King's College London, London, UK.Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, UK.Department of Old Age Psychiatry, King's College London, London, UK.Medical Research Council Clinical Trials Unit, University College London, London, UK.Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.Medical Research Council Clinical Trials Unit, University College London, London, UK.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26515660

Citation

Howard, Robert, et al. "Nursing Home Placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) Trial: Secondary and Post-hoc Analyses." The Lancet. Neurology, vol. 14, no. 12, 2015, pp. 1171-81.
Howard R, McShane R, Lindesay J, et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol. 2015;14(12):1171-81.
Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., ... Phillips, P. P. (2015). Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses. The Lancet. Neurology, 14(12), pp. 1171-81. doi:10.1016/S1474-4422(15)00258-6.
Howard R, et al. Nursing Home Placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) Trial: Secondary and Post-hoc Analyses. Lancet Neurol. 2015;14(12):1171-81. PubMed PMID: 26515660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses. AU - Howard,Robert, AU - McShane,Rupert, AU - Lindesay,James, AU - Ritchie,Craig, AU - Baldwin,Ashley, AU - Barber,Robert, AU - Burns,Alistair, AU - Dening,Tom, AU - Findlay,David, AU - Holmes,Clive, AU - Jones,Robert, AU - Jones,Roy, AU - McKeith,Ian, AU - Macharouthu,Ajay, AU - O'Brien,John, AU - Sheehan,Bart, AU - Juszczak,Edmund, AU - Katona,Cornelius, AU - Hills,Robert, AU - Knapp,Martin, AU - Ballard,Clive, AU - Brown,Richard G, AU - Banerjee,Sube, AU - Adams,Jessica, AU - Johnson,Tony, AU - Bentham,Peter, AU - Phillips,Patrick P J, Y1 - 2015/10/27/ PY - 2015/07/20/received PY - 2015/09/21/revised PY - 2015/09/25/accepted PY - 2015/10/31/entrez PY - 2015/10/31/pubmed PY - 2016/3/5/medline SP - 1171 EP - 81 JF - The Lancet. Neurology JO - Lancet Neurol VL - 14 IS - 12 N2 - BACKGROUND: Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. METHODS: In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS: Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]). INTERPRETATION: Withdrawal of donepezil in patients with moderate-to-severe Alzheimer's disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING: Medical Research Council and UK Alzheimer's Society. SN - 1474-4465 UR - https://www.unboundmedicine.com/medline/citation/26515660/Nursing_home_placement_in_the_Donepezil_and_Memantine_in_Moderate_to_Severe_Alzheimer's_Disease__DOMINO_AD__trial:_secondary_and_post_hoc_analyses_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1474-4422(15)00258-6 DB - PRIME DP - Unbound Medicine ER -