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expert reaction to study investigating the effect of cholinesterase inhibitors on delaying the symptoms of Alzheimer’s disease and nursing home placement

Publishing in The Lancet Neurology journal, researchers have published their work looking for current therapies that may have an impact on Alzheimer’s. They report a secondary analysis of the DOMINO trial (announced in 2012)which  suggests an off-patent drug may be able to delay the need for Alzheimer’s patients to enter nursing homes. These comments accompanied a briefing.

 

Dr Elizabeth Coulthard, Consultant Senior Lecturer in Dementia Neurology, University of Bristol, said:

“Donepezil is one of the drugs already licensed for treatment of dementia. It is usually not possible to tell in an individual patient whether or not the drug is helping. So, studies such as this are extremely useful for guiding clinical practice.

“We already know that donepezil improves day-to-day life for people with late stage Alzheimer’s disease. Although these new results are exploratory, it is heartening to think that donepezil might also delay entry to a nursing home. This is potentially good news for people with Alzheimer’s and their families. When multiplied across the large numbers with dementia, even small reductions in care needs for an individual could result in significant cost savings overall.

“Although positive, donepezil only limited symptoms by a relatively small amount and new drugs in the pipeline that might actually slow the progression of disease are desperately needed.”

 

Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience, University of Reading, said:

“Cholinesterase inhibitors work by increasing the levels of chemicals within the brain that allow nerve cells to communicate. We know levels are reduced in Alzheimer’s and these drugs help to prolong effects brought about these chemicals .

“This study was a follow project to the initial  DOMINO-AD so the results presented have their caveats, for example it was not set-up to report on institutionalisation. However it provides a much needed three year insight into AD progression under current treatment plans, improving our understanding of today’s options and their long-term effects for AD patients.

“However, while confirming that donepezil can prolong valuable time at home for those suffering from Alzheimer’s, it reinforces that we are still behind the game – current Alzheimer’s medications offering only symptomatic relief.

“We desperately need to conduct clinical trials in patients pre-symptoms to determine the brain changes that lead to Alzheimer’s. Only then will we have a chance to target the disease process itself and provide medicines that can delay the progress of Alzheimer’s.

“The study also highlights that there is a growing need for better partnerships between patient, carers and the healthcare team to provide appropriate treatment plans. Alzheimer’s is a disease which can affect loved ones who are looking after patients as much the patients themselves.”

 

Dr Tara Spires-Jones, Reader and Chancellor’s Fellow, Centre for Cognitive and Neural Systems, University of Edinburgh, said:

“The best drug treatment regimen for people with advanced stage Alzheimer’s disease is still up for debate.  The study by Robert Howard and colleagues suggests that continuing donepezil treatment into the late stages of disease may slightly delay the need to move into permanent nursing home care. This is good news, but the results should be interpreted with caution. This drug offers only very small improvements in cognition and a correspondingly small reduction in risk of nursing home placement, which did not persist after 12 months. In addition, this trial was not designed to answer the question of whether continued drug treatment delays nursing home placement, so there were not enough people included to definitively answer the question.  The bottom line is we need more research to find new treatments that will have substantial beneficial effects. ”

 

Prof. John Hardy, Professor of Neuroscience, UCL, said:

“Neurons which use acetyl choline as a signaling molecule are among those lost in Alzheimer’s disease.  The drug donepezil partially replaces this lost signaling molecule.  Previously, this has only been shown to have small, statistically significant beneficial effects early in the disease process and significant effect could not be shown late in the disease.  These findings informed prescribing practice and often the drug was discontinued in late stage disease.  This paper shows that, in a practical sense, the drug seems to have some benefit later in the disease too and this may lead to a change in prescribing policies with the drug being given throughout the disease.”

 

Prof. Richard Gray, Professor of Medical Statistics, Clinical Trial Service Unit (CTSU), University of Oxford, said:

“As noted by the authors, these results should be deemed exploratory and they need to be interpreted cautiously. Over all time periods there was no difference in the numbers going into residential care, 54% of those continuing donepezil compared to 56% of those who discontinued donepezil. The emphasis on the results in the first year, when 18% went into care with donepezil compared to 31% who stopped, is inappropriate because this was not a pre-planned analysis and is therefore potentially misleading. The apparent halving of the risk of entering residential care in the first year seems implausibly large given that the study has previously reported only a small effect of continuing donepezil has on patients’ ability to undertake activities of daily living. Benefits that seem too good to be true usually aren’t true.”

 

Dr Simon Ridley, Director of Research at Alzheimer’s Research UK said:

“This study is not testing new treatments for Alzheimer’s but looking at the effectiveness of current symptomatic treatments in people in the later stages of the disease. The new analysis builds on an earlier clinical trial that reported modest benefits on cognition and day-to-day activities when treatment with the drug donepezil was continued into the later stages of Alzheimer’s. While the findings suggest that treatment with donepezil in people with advanced Alzheimer’s could help them to stay at home for longer, the authors highlight that the results are exploratory and we know that the factors influencing a move to care are complex.

“This study addresses the important issue of improving treatment for those in the moderate to severe stages of Alzheimer’s disease. With only a handful of symptomatic treatments available to treat Alzheimer’s, it is vital that we better understand the most effective ways to use these drugs to help improve quality of life. Increased investment in dementia research is critical, both to improve the use of current symptomatic treatments and to find treatments that can halt the spread of damage through the brain.”

 

Dr Ian Maidment, Senior Lecturer in Clinical Pharmacy at Aston University, and spokesperson for the Royal Pharmaceutical Society said:

“This is an interesting study which adds to the jigsaw of information we have about the treatment of dementia. It demonstrates that if you withdraw donepezil in people with moderate to severe Alzheimer’s disease (the most common form of dementia) you increase the likelihood of their admission to a care home in the first 12 months after withdrawal. However, longer-term, withdrawal had no further effect. Starting memantine (another medication for the symptoms of dementia) also had no effect on nursing home placement. This study should be considered preliminary and ideally requires confirmation.

“Most people with dementia and their carers want to live at home for as long as possible.  Stopping donepezil could worsen the ability of the person with dementia to cope with the usual activities of daily living which may mean that living at home becomes impossible. Therefore, you should certainly think twice about withdrawing donepezil if you have a friend or relative who is on the donepezil and ‘just about’ managing at home with appropriate support from carers.”

 

Dr Frank Gray, Physician Lead, Rare Disease Unit, GSK Medicines Research Centre, said:

“This is a fairly robust study. The caveats to emphasise are that the primary study is small, less than 100 patients per group, and that this was not a pre-specified analysis but rather a post-hoc addition. The authors have however conducted some sensitivity analysis which support their conclusions and make it more robust.

It is important to note that the benefit from the medication was limited to a year following stopping treatment and then the difference disappears. However given the small number of subject per group, this means that the number at risk at later time points is small – probably too small to show a difference. In addition, patients’ illness will be progressing at the same time. A larger study would be required to see if benefit (reduced risk/chance of being admitted to care) was maintained for longer than a year.

“This treatment is not a cure, rather the benefit for patients that continued treatment with pro-cognitive medications (cholinesterase inhibitors) instead of stopping treatment when their Alzheimer’s disease worsened is that they have less chance of being moved to a nursing home for a year. In other words they have a better chance of staying at home with family.

“Currently when a patient’s AD gets worse their medication is stopped to save on costs as it is felt they no longer get benefit. This study shows that that may not be the best option and that they should rather continue treatment to reduce the chance of moving to care, which is expensive. Plus, patients would have better quality of life at home. Also these treatment are now generic so additional cost to healthcare system would be limited if medication was continued.

It is important to note that this study showed a benefit for the first year only, and after that the chance of going into care was similar (but per previous point it may just be that the numbers were too small at this time).

“The implication from these finding is that patients whose AD worsens should continue with their cognitive enhancing (cholinesterase inhibitors) treatment, although the data set was too small to determine if this benefit would be limited to certain groups of patients.”

 

Dr Vincenzo Libri, Head of the Leonard Wolfson Experimental Neurology Centre, Institute of Neurology & The National Hospital for Neurology and Neurosurgery, UCL, said:

“This is the first good evidence based study suggesting that discontinuation of donepezil in moderate-severe Alzheimer’s disease patients increases the risk of nursing home placement within 12 months from discontinuation (but not beyond). However, there are reports highlighting the potential clinical benefit of continuing donepezil beyond the historical 6-12 month time points (particularly in LBD).

“Overall, while these results add value to the future management of moderate/severe AD patients, they don’t change the primary use of the drug as symptomatic rather than a disease modifier (managing?). None of the patients who continued with donezepil (with or without memantine as add-on) after completion of the 52 week double-blind trial treatment had a reduced risk to nursing home placement beyond the first year follow up. Additionally, time to nursing home placement was a secondary objective, so the study was not designed or powered for this outcome.”

 

Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial: secondary and post-hoc analyses’ by Howard et al. will be published in The Lancet Neurology at 00:01 UK time on Tuesday 27th Octobers, which is also when the embargo will lift. 

 

Declared interests

Dr Elizabeth Coulthard: I have no conflicts

Dr Mark Dallas: Has some research funded by Alzheimer’s Research UK

Dr Tara Spires-Jones: I have no conflicts of interest

Prof. John Hardy: Consults on Alzheimer therapy for Eisai pharmaceuticals

Prof. Richard Gray: I was the chief investigator of the AD2000 trial showing no worthwhile benefit from donepezil (including no reduction in nursing home placement) as initial treatment of mild to moderate Alzheimer’s disease (Lancet 2004; 363: 2105–15). I was subsequently the leading statistician in a small group that developed the DOMINO protocol, I was on the study’s trial management group and was a co-author of the main publication (Howard et al, N Engl J Med 2012;366:893-903. I was invited to be a co-author of the present paper but, because of concerns about the statistical methods used and the interpretation of these analyses, declined co-authorship. I have no other conflict of interest; CTSU staff policy excludes honoraria or consultancy fees.

Dr Simon Ridley: No conflicts of interest to declare

Dr Ian Maidment: No conflicts of interest

Dr Frank Grey: My only conflict is that I work for GSK. GSK do not market cholinesterase inhibitors or other drugs for the treatment of AD

Dr Vincenzo Libri: I have no conflicts of interest

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