“Thousands of patients with advanced Alzheimer’s disease could benefit from drugs,” according to BBC News.
The broadcaster said the results of a new medical trial suggest that the drug Aricept reduces the rate at which memory declines during advanced Alzheimer’s disease.
Aricept, also known as donepezil, is already used to help manage earlier stages of Alzheimer’s disease. But new research has looked at the effect of continuing the drug during moderate and severe stages of the disease. In this research, 295 Alzheimer’s patients in England and Scotland were randomly assigned to either continue or stop using the drug for a period of 12 months.
The study found that over 12 months, patients who stayed on donepezil had a slower decline in their mental ability than those who stopped using the drug, as assessed in certain tests. However, improvements in mental ability and the ability to manage daily activities associated with donepezil were small compared with the overall decline that all participants experienced.
The benefits of this modest improvement need to be considered from the patients’ perspective, and this study is likely to ignite debate about whether donepezil should continue to be prescribed to people with dementia once they progress past moderate symptoms. Another factor that contributes to the debate is that much cheaper versions of the drug have reportedly become available recently.
Where did the story come from?
The study was carried out by researchers from England and Scotland and was funded by the UK Medical Research Council and the Alzheimer’s Society. Many of the researchers declared having a conflict of interest, as they received payments (such as grants, lecture fees, consultation fees and expenses) from commercial drug companies. These included Eisai and Pfizer, which developed and marketed the drug donepezil under the trade name Aricept.
The study was published in the peer-reviewed New England Journal of Medicine.
This study received wide media coverage, with many sources fielding debate on whether Alzheimer’s patients should continue using donepezil once they progress past moderate symptoms. The reporting of the study in these articles was generally balanced.
What kind of research was this?
This double-blind, placebo-controlled randomised controlled trial looked at continuing Alzheimer’s medication in patients who had previously received donepezil (Aricept) and who had moderate or severe Alzheimer’s disease. It also looked at using the drug alongside another medicine called memantine, which is used to treat Alzheimer’s disease and other forms of dementia.
Dementia is a long-term progressive mental disorder that adversely affects memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement. The National Institute for Health and Clinical Excellence (NICE) reports that Alzheimer’s is the most common form of dementia and estimates that around 50-64% of people with the condition have mild to moderately severe disease. Approximately 50% of people with Alzheimer’s are estimated to have moderate to severe disease.
The study authors reported that clinical trials have shown the benefits of drug treatments for mild to moderate Alzheimer’s disease. However, it is not known whether treatment benefits continue after it has progressed to moderate to severe disease.
The researchers say that very limited evidence is available to guide the difficult decision of whether to stop or continue Alzheimer’s drug treatments when the disease progresses. However, continued treatment is known to be associated with an increase in adverse outcomes, such as loss of consciousness, the need for pacemakers and hip fractures.
What did the research involve?
The researchers recruited 295 Alzheimer’s patients in England and Scotland who had been taking donepezil (Aricept) for at least three months and who had moderate or severe Alzheimer’s. Patients were recruited during the period from February 2008 to March 2010. All patients were “community living”, in other words were not in hospital or nursing homes, but had carers who lived with them or visited regularly. The researchers wanted to see if continuing using the Alzheimer’s drug donepezil would benefit these patients and whether starting a second drug, called memantine, could also be beneficial.
A moderate to severe diagnosis of Alzheimer’s disease was defined as a score of 5 to 13 on a recognised cognitive examination called the Standardized Mini-Mental State Examination (SMMSE). Scores range from 0 to 30, with higher scores indicating better mental function.
Once recruited, patients were randomised into four groups to receive different combinations of active drugs and inactive placebos. They were not told which combination they would take. The groups received the following treatment plans for 52 weeks:
- continue on donepezil alongside a memantine placebo
- discontinue donepezil, begin taking donepezil placebo alongside a memantine placebo
- discontinue donepezil and start memantine alongside a donepezil placebo
- continue on donepezil and start memantine
Patients, caregivers, clinicians, researchers and statisticians were unaware of the treatments that were assigned. This is a standard procedure used during trials, known as blinding. It is designed to help prevent the study’s results being distorted by people’s knowledge of what drug they are taking.
The researchers looked for changes in patients’ mental ability using SMMSE scores taken before, during and after they received the study treatment. The researchers also assessed patients’ functional ability to manage daily activities. They used a test designed specifically for use in patients with dementia, called the caregiver-rated Bristol Activities of Daily Living Scale (BADLS), which assesses 20 daily living abilities. The researchers reported that the minimum clinically important difference in scores would be a 1.4 point difference on the SMMSE and a 3.5 point difference on the BADLS.
Patients were excluded from the study if they had severe or unstable medical conditions, were receiving memantine before the study or were considered unlikely to adhere to the study regimens.
The statistical analysis of the study’s results was appropriate and on an “intention to treat” basis. This type of analysis looks at the outcomes of all participants originally entered into the study, and not just those who completed the study. It gives a more realistic picture of the effect of the drugs in real world situations, as it includes people who stop taking the drug during the study for various reasons. These reasons could include unpleasant side effects or worsening of the patients’ condition, although often participants simply drop out of the trial and the reasons for leaving cannot be recorded.
What were the basic results?
Many comparisons were reported in the study. The key results are highlighted below:
- In all groups, mental ability declined as assessed by the SMMSE, on average from a score of approximately 9 at the start of the study to a score of 3–6 after 52 weeks. Scores on the BADLS test of daily living increased from around 26–29 at the start of the study to 34–42 after 52 weeks. These results indicate an overall decline in mental ability and function over the 12-month study period.
- Patients who continued donepezil scored on average 1.9 points higher (95% confidence interval [CI] 1.3 to 2.5) on the SMMSE compared with those who discontinued donepezil. This suggests continuing the drug was beneficial.
- Patients who continued donepezil scored on average 3.0 points lower (95% CI 1.8 to 4.3) on the BADLS compared with those who discontinued donepezil. This indicated less impairment when continuing the drug treatment.
- The severity of dementia at enrolment significantly influenced the effect donepezil had on SMMSE scores. Larger benefits were observed in patients with moderate disease compared with those who had severe disease.
- Patients assigned to receive memantine alongside donepezil placebo had an SMMSE score on average 1.2 points higher (95% CI 0.6 to 1.8) and a BADLS score that was 1.5 points lower (95% CI 0.3 to 2.8) compared with those assigned memantine placebo alongside donepezil placebo.
- The effectiveness of donepezil and memantine did not differ significantly in the presence or absence of each other.
- There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
- There was no evidence that serious adverse events or death differed according to the treatment groups assigned.
How did the researchers interpret the results?
The authors concluded that, in patients with moderate or severe Alzheimer’s disease, continued treatment with donepezil was associated with cognitive benefits, which exceeded the minimum clinically important differences they had set out before the trial. They said that donepezil led to significant functional benefits over the course of 12 months.
The drug donepezil is already clinically used to treat earlier stages of Alzheimer’s disease, but this new research examined the value of using it as Alzheimer’s disease progresses. To examine the issue, researchers used a robust study design, called a double-blind, placebo-controlled trial. They enrolled community-living patients with moderate or severe Alzheimer’s disease who were already receiving treatment with donepezil. Overall, its results showed that there were modest cognitive and functional benefits of continuing donepezil over the course of 12 months.
The study provides important new information on the use of medicines to manage Alzheimer’s symptoms, but the following limitations should be considered when interpreting the results:
- The improvements in cognition (SMMSE score) and function (BADLS) associated with donepezil and memantine were small compared with the size of the decline overall in cognitive and functional ability experienced by all patients. A “clinically important difference” was defined before the study started, and only the difference in SMMSE score reached this threshold. The impact that this small slowing of decline could have for patients should be given due consideration when debating whether this is an effective treatment.
- The study excluded patients who “were considered to be unlikely to adhere to the study regimens”. This would have the effect of biasing the study, to make it more likely that a beneficial effect was found by giving the drugs. Outside a clinical study, people who are unlikely to adhere to drug treatment may still be given the drug, and the beneficial effect in these patients is likely to be lower than that described in the study.
- All patients were “community living”, in other words not in hospitals or nursing homes. As a large number of people with moderate to severe Alzheimer’s are likely to live in these settings, it will be important to demonstrate a beneficial effect in this setting too.
This study is likely to re-ignite debate about whether donepezil (Aricept) should continue to be prescribed to people with dementia once they progress past moderate symptoms. An additional factor sparking renewed interest in the debate is that much cheaper versions of the drug have reportedly become available recently.
- Howard R, McShane R, Lindesay J et al. Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease. New England Journal of Medicine 2012; 366:893-903