NIHR Signal Stopping Donepezil may be linked to nursing home placement for people with Alzheimer’s disease, but a “cause and effect” not conclusive

Published on 11 December 2015

This follow up study examined whether the drugs donepezil or memantine affected the chance that people with Alzheimer’s disease could continue to live in the community, rather than move permanently to a nursing home. One or both of the drugs was taken for a year and then participants could have any treatment thereafter. The study found that stopping donepezil doubled the risk of going into a nursing home up to a year afterwards, compared with continuing to take donepezil. However, there was no difference over the subsequent three years. Memantine did not affect the risk. By four years from the start of the trial, the likelihood of having moved into a nursing home was the same for people on all the drug treatment regimens. This was an exploratory study with some limitations, but it shows that donepezil may have the potential to slow down worsening of symptoms and save care costs.

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Why was this study needed?

Dementia affects 850,000 people in the UK, at a cost of over £26 billion per year, mainly to unpaid carers, health services and social services. Alzheimer’s disease is the most common cause of dementia affecting 553,000 people. Symptoms include worsening memory loss, difficulty thinking and carrying out everyday activities and deteriorating behaviour. Whether a person can continue to live in the community depends on many factors such as availability and age of family carers. Moving to a more dependent setting, such as a nursing home, is often triggered by worsening symptoms, particularly behaviour. Donezepil is commonly prescribed for mild to moderate dementia, although as with other dementia drugs, it makes a small difference to the symptoms. It is available as a relatively cheap, generic drug which is often stopped in the later stages of dementia or if symptoms do not improve. A previous randomised controlled trial did not find that donepezil could delay admission to a nursing home for people with mild to moderate Alzheimer’s disease. This was the first randomised controlled trial and follow up study to see whether drug treatment of moderate to severe Alzheimer’s disease could delay permanently moving into a nursing home.

What did this study do?

This was a follow up study from the DOMINO-AD trial of 295 people living in the community with moderate to severe Alzheimer’s disease who were already taking donepezil. In the original study people were recruited into the trial from 15 memory clinics in England and Scotland.

The participants were randomly allocated to one of the following four treatment regimens for one year:

  • stop taking donepezil and start taking placebo memantine,
  • stop taking donepezil and start taking active memantine,
  • continue taking donepezil and start taking placebo memantine,
  • continue taking donepezil and start taking active memantine.

After one year, treatment was left to the choice of participants and their doctors.

The original DOMINO-AD trial was set up to investigate changes in brain functioning after receiving one of these treatments for a year. This follow-up analysis of the DOMINO-AD trial looked at the secondary outcome of permanently moving into a nursing home over the next four years. Analysis of the risk during the first year of the trial was not planned at the trial’s outset, which limits the reliability of these results.

What did it find?

  • By four years after the trial’s start, 55% of the participants had moved into a nursing home, with similar rates for each of the four groups. This exploratory study was too small to analyse risk of nursing home placement by different levels of symptom severity.
  • Whether participants took active memantine or placebo did not affect the risk of nursing home placement at any time up to four years.
  • Participants who discontinued donepezil in the first year had double the risk of moving into a nursing home by the end of that year than those who continued to take donepezil (hazard ratio 2.09, 95% confidence interval 1.29 to 3.39). However, discontinuation did not affect the risk over the four year study period.
  • The participants in each group had similar characteristics and stage of disease at the beginning of the trial, but we don’t know what medication they took in the last three years of the study. The authors considered that the overall trial design was representative of usual care.

What does current guidance say on this issue?

NICE 2011 guidance recommends donepezil (or one of the related acetyl cholinesterase inhibitors, galantamine or rivastigmine) as a medical option to treat cognitive symptoms of mild to moderate Alzheimer’s disease, provided symptoms improve during treatment. However, the guidance states that donepezil brings only modest benefits, and that treatment could be stopped if not leading to improved symptoms and ability to carry out activities of daily life. This means that donepezil is not recommended for people in the more severe stages of the disease. In contrast, this study did use donepezil to treat people with moderate to severe Alzheimer’s disease and found benefit in terms of reduced risk of moving into a nursing home, though the results should be viewed with caution.

What are the implications?

People with Alzheimer’s disease live an average of seven years after diagnosis. Receiving residential care is much more costly than living in the community, but moving to residential care is highly likely for people who already have moderate or severe disease. Delaying this move could save significant health and social care costs and potentially improve quality of life for people with Alzheimer’s disease.

NICE guidelines currently suggest that people with severe Alzheimer’s disease do not benefit from taking donepezil. The study had some limitations and its findings are modest and exploratory at present. However, as the first randomised controlled trial of treatment for people with later stages of Alzheimer’s disease, it may suggest that prescribers could be more cautious when considering stopping the drug in patients who are on established treatment.

Citation

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.

Funded by MRC and the UK Alzheimer’s Society, and managed by NIHR on behalf of the MRC-NIHR partnership.

Bibliography

Alzheimer’s Society. Dementia 2014 infographic. London: Alzheimer’s Society; 2014.

Alzheimer’s Society. Drug treatments for Alzheimer’s Disease [internet]. London: Alzheimer’s Society; 2014.

Client Service Receipt Inventory: referenced in:

Beecham J, Knapp M. Costing psychiatric interventions. In: Measuring mental health needs (2nd edition). Edited by Thornicroft G. London: Gaskell;2001. 200-224.

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.

NICE. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. TA217. London: National Institute for Health and Care Excellence; 2011.

NICE. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. Commissioning guide. London: National Institute for Health and Care Excellence; 2013.

NICE. Dementia: supporting people with dementia and their carers in health and social care. CG42. London: National Institute for Health and Care Excellence; 2006.

Why was this study needed?

Dementia affects 850,000 people in the UK, at a cost of over £26 billion per year, mainly to unpaid carers, health services and social services. Alzheimer’s disease is the most common cause of dementia affecting 553,000 people. Symptoms include worsening memory loss, difficulty thinking and carrying out everyday activities and deteriorating behaviour. Whether a person can continue to live in the community depends on many factors such as availability and age of family carers. Moving to a more dependent setting, such as a nursing home, is often triggered by worsening symptoms, particularly behaviour. Donezepil is commonly prescribed for mild to moderate dementia, although as with other dementia drugs, it makes a small difference to the symptoms. It is available as a relatively cheap, generic drug which is often stopped in the later stages of dementia or if symptoms do not improve. A previous randomised controlled trial did not find that donepezil could delay admission to a nursing home for people with mild to moderate Alzheimer’s disease. This was the first randomised controlled trial and follow up study to see whether drug treatment of moderate to severe Alzheimer’s disease could delay permanently moving into a nursing home.

What did this study do?

This was a follow up study from the DOMINO-AD trial of 295 people living in the community with moderate to severe Alzheimer’s disease who were already taking donepezil. In the original study people were recruited into the trial from 15 memory clinics in England and Scotland.

The participants were randomly allocated to one of the following four treatment regimens for one year:

  • stop taking donepezil and start taking placebo memantine,
  • stop taking donepezil and start taking active memantine,
  • continue taking donepezil and start taking placebo memantine,
  • continue taking donepezil and start taking active memantine.

After one year, treatment was left to the choice of participants and their doctors.

The original DOMINO-AD trial was set up to investigate changes in brain functioning after receiving one of these treatments for a year. This follow-up analysis of the DOMINO-AD trial looked at the secondary outcome of permanently moving into a nursing home over the next four years. Analysis of the risk during the first year of the trial was not planned at the trial’s outset, which limits the reliability of these results.

What did it find?

  • By four years after the trial’s start, 55% of the participants had moved into a nursing home, with similar rates for each of the four groups. This exploratory study was too small to analyse risk of nursing home placement by different levels of symptom severity.
  • Whether participants took active memantine or placebo did not affect the risk of nursing home placement at any time up to four years.
  • Participants who discontinued donepezil in the first year had double the risk of moving into a nursing home by the end of that year than those who continued to take donepezil (hazard ratio 2.09, 95% confidence interval 1.29 to 3.39). However, discontinuation did not affect the risk over the four year study period.
  • The participants in each group had similar characteristics and stage of disease at the beginning of the trial, but we don’t know what medication they took in the last three years of the study. The authors considered that the overall trial design was representative of usual care.

What does current guidance say on this issue?

NICE 2011 guidance recommends donepezil (or one of the related acetyl cholinesterase inhibitors, galantamine or rivastigmine) as a medical option to treat cognitive symptoms of mild to moderate Alzheimer’s disease, provided symptoms improve during treatment. However, the guidance states that donepezil brings only modest benefits, and that treatment could be stopped if not leading to improved symptoms and ability to carry out activities of daily life. This means that donepezil is not recommended for people in the more severe stages of the disease. In contrast, this study did use donepezil to treat people with moderate to severe Alzheimer’s disease and found benefit in terms of reduced risk of moving into a nursing home, though the results should be viewed with caution.

What are the implications?

People with Alzheimer’s disease live an average of seven years after diagnosis. Receiving residential care is much more costly than living in the community, but moving to residential care is highly likely for people who already have moderate or severe disease. Delaying this move could save significant health and social care costs and potentially improve quality of life for people with Alzheimer’s disease.

NICE guidelines currently suggest that people with severe Alzheimer’s disease do not benefit from taking donepezil. The study had some limitations and its findings are modest and exploratory at present. However, as the first randomised controlled trial of treatment for people with later stages of Alzheimer’s disease, it may suggest that prescribers could be more cautious when considering stopping the drug in patients who are on established treatment.

Citation

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.

Funded by MRC and the UK Alzheimer’s Society, and managed by NIHR on behalf of the MRC-NIHR partnership.

Bibliography

Alzheimer’s Society. Dementia 2014 infographic. London: Alzheimer’s Society; 2014.

Alzheimer’s Society. Drug treatments for Alzheimer’s Disease [internet]. London: Alzheimer’s Society; 2014.

Client Service Receipt Inventory: referenced in:

Beecham J, Knapp M. Costing psychiatric interventions. In: Measuring mental health needs (2nd edition). Edited by Thornicroft G. London: Gaskell;2001. 200-224.

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.

NICE. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. TA217. London: National Institute for Health and Care Excellence; 2011.

NICE. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. Commissioning guide. London: National Institute for Health and Care Excellence; 2013.

NICE. Dementia: supporting people with dementia and their carers in health and social care. CG42. London: National Institute for Health and Care Excellence; 2006.

Nursing home placement in the donepezil and memantine in moderate to severe Alzheimer's disease (DOMINO) trial: secondary and post-hoc analyses of a randomised trial

Published on 30 September 2015

Howard, Robert

Lancet Neurology , 2015

Background: Observational studies have suggested delay in nursing home placement (NHP) with dementia drug treatment, but an earlier randomised trial in patients with mild to moderate Alzheimer’s disease (AD) showed no effect. We investigated the effects of continuing or discontinuing donepezil and starting memantine on subsequent NHP in moderate to severe AD. Methods: In the DOMINO trial (ISRCTN49545034) 295 community living patients with moderate to severe AD recruited from 15 centres in England and Scotland from February 2008 to March 2010 were randomised with double-blind placebo-control to continue donepezil (73), discontinue donepezil (73), discontinue donepezil and start memantine (76), or continue donepezil and start memantine (73) for 52 weeks. After 52 weeks choice of treatment was left to participants and their physicians. Place of residence was recorded at outcomes assessment points during the first 52 weeks of the trial and subsequently every 26 weeks for a further 3 years. Nursing home placement was an irreversible move from independent accommodation to a residential caring facility and was a secondary trial endpoint. Analyses restricted to the risk of placement in the first year of follow-up were post-hoc. Findings: 162 patients (55%) underwent NHP within 4 years of randomisation. Numbers of NHPs were similar for all arms (36 in patients who continued donepezil, 42 who discontinued donepezil, 41 who discontinued donepezil and started memantine, and 43 who continued donepezil and started memantine). There was significant (p=0.010) heterogeneity of treatment effect over time with significantly more NHPs in the donepezil discontinuation group during the first year (HR 2.09 (95% CI, 1.29 to 3.39)) and no difference later (HR 0.89 (95% CI, 0.58 to 1.35)). Subsequent analyses focussed on the first year of the trial and on donepezil only were post-hoc. 1-year NHP risk was 17% higher (95% CI 6% to 28%) in patients allocated to discontinue donepezil compared to continuing donepezil. There was no effect of starting memantine compared to no memantine during the first year (HR 0.92 (95% CI 0.58 to 1.45)) or later (HR 1.23 (95% CI 0.81 to 1.87)); difference in 1-year NHP risk 1% (95% CI -12% to 10%). Interpretation: Withdrawing donepezil in patients with moderate to severe AD increased the risk of NHP during 12 months of trial treatment, but made no difference to NHP over 4 years of follow-up. Decisions to stop or continue drug treatment at this stage should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.

A nursing home was defined by the study authors as a residential caring facility. To clarify what this included, the study used the Client Service Receipt Inventory (CSRI), which lists:

  • a care home providing nursing care,
  • a care home providing personal care,
  • a dual-registered home (providing both personal and nursing care),
  • an acute psychiatric ward,
  • a general medical ward,
  • a rehabilitation ward.

Community living was defined in the CSRI as residence in “an owner-occupied house or flat, a privately rented house or flat, a house or flat rented from a housing association or local authority, sheltered or warden-controlled housing, or extra care housing”.

Expert commentary

This secondary analysis of the DOMINO-AD trial has shown an increased risk of a nursing home placement in the first year of withdrawal of Donepezil. Although the effects are generally small, this does draw attention to the challenge for clinicians in withdrawing a treatment due to perceived lack of benefit. The same situation arises in Parkinson’s Disease, where withdrawal is often associated with dramatic declines in function, although the clinical effects of cholinesterase inhibitors are much less than those of Levodopa. Donepezil in Alzheimer’s disease confers less obvious benefit but within a small group effect there may be individuals who respond very well. This further analysis of the DOMINO-AD data is a valuable contribution to our understanding of the use of cholinesterase inhibitors and urges caution in discontinuing the drug in patients who are on established tolerated dosages.

Professor Martin Rossor, Professor of Clinical Neurology, University College London; NIHR National Director for Dementia Research; Director, NIHR Queen Square Dementia Biomedical Research Unit