title: Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.
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.
  
  
  RESULTS
  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]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Medical Research Council and UK Alzheimer's Society.
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Howard
authors.affiliation: Oxford Health NHS Foundation Trust, Warneford Hospital, Headington, Oxford, UK.
authors.forename: Rupert
authors.initials: R
authors.lastname: McShane
authors.affiliation: Health Sciences, University of Leicester, Leicester, UK.
authors.forename: James
authors.initials: J
authors.lastname: Lindesay
authors.affiliation: Centre for Brain Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Ritchie
authors.affiliation: Five Boroughs Partnership NHS Foundation Trust, Winwick, Warrington, UK.
authors.forename: Ashley
authors.initials: A
authors.lastname: Baldwin
authors.affiliation: Centre for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Barber
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Alistair
authors.initials: A
authors.lastname: Burns
authors.affiliation: Institute of Mental Health, University of Nottingham, Nottingham, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Dening
authors.affiliation: Kingsway Care Centre, Dundee, UK.
authors.forename: David
authors.initials: D
authors.lastname: Findlay
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.affiliation: Department of Pyschiatry, University of Nottingham, Nottingham, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Jones
authors.affiliation: Research Institute for the Care of Older People, Bath, UK.
authors.forename: Roy
authors.initials: R
authors.lastname: Jones
authors.affiliation: Newcastle; University Institute for Ageing, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: McKeith
authors.affiliation: Ayrshire and Arran NHS, University Hospital Crosshouse, Crosshouse, Kilmarnock, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Macharouthu
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: Oxford University Hospitals NHS Trust, Headington, Oxford, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Sheehan
authors.affiliation: National Perinatal Epidemiology Unit Clinical Trials Unit, University of Oxford, Oxford, UK.
authors.forename: Edmund
authors.initials: E
authors.lastname: Juszczak
authors.affiliation: Division of Psychiatry, University College London, London, UK.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Katona
authors.affiliation: Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.affiliation: London School of Economics, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Wolfson Centre for Age Related Disorders, King's College London, London, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: Department of Psychology, King's College London, London, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brown
authors.affiliation: Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, UK.
authors.forename: Sube
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Old Age Psychiatry, King's College London, London, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Adams
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Johnson
authors.affiliation: Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bentham
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Patrick P J
authors.initials: PP
authors.lastname: Phillips
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000451:nursing; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006707:Homes for the Aged; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009735:Nursing Homes; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D012720:Severity of Illness Index
chemical_list: D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine