Background
Dementia is the term used to describe a group of illnesses, usually developing in late life, in which there is a deterioration in a person’s ability to think, remember, communicate and manage daily activities independently. It can be caused by several different brain diseases, but the most common form is dementia due to Alzheimer’s disease. At the moment, there are no medical treatments which can prevent dementia or stop it from progressing, but there are two classes of drugs – the cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and memantine - which are approved and widely prescribed to treat some of the symptoms. They are used mainly for dementia due to Alzheimer's disease but also sometimes for other types of dementia. Most of the trials studying the effects of these drugs have been quite short (typically six months) even though dementia usually lasts for years. The drugs can have unwanted side effects in some people. There is uncertainty about their long-term effects and about how useful they are for severe dementia, with different countries making different recommendations. Therefore it can be difficult for doctors and patients to decide if and when these drugs should be stopped once they have been started.
What was the aim of this review?
In this review, we aimed to summarise the best evidence about whether stopping cholinesterase inhibitors or memantine was beneficial or harmful to people with dementia who had been taking them for at least two months.
What we did
We searched up to October 2020 for trials which had: recruited people with dementia who were taking a cholinesterase inhibitor or memantine, or both; divided them randomly into a group of patients who continued treatment and a group of patients who stopped treatment; and compared what happened in the two groups.
What we found
We found seven trials (759 participants) to include in the review. All of the participants had dementia due to Alzheimer’s disease, but in some trials, the disease was mild to moderate and in others, it was moderate to severe or very severe. Six trials investigated the effects of stopping a cholinesterase inhibitor and one trial investigated stopping either a cholinesterase inhibitor (specifically, donepezil) or memantine. We decided not to pool its results with the other six trials. Effects were measured over different periods of time in different trials. We looked separately at effects in the first 2 months (short term), between 3 and 11 months (medium term), and after a year or more (long term).
When we looked at the effect on thinking skills and memory, we found that, compared to stopping treatment, continuing treatment with a cholinesterase inhibitor may be beneficial in the short term and medium term and is probably beneficial in the long term. For ability to carry out daily activities, there may be little or no effect in the short term, and the effect in the medium term was very uncertain, but there is probably a benefit to continuing treatment over the longer term. For mood and behavioural problems, continuing treatment may have benefits in the short term and medium term, but not in the long term. We found no clear evidence about the effects of stopping these drugs on patients’ physical health or risk of dying. There was very little evidence about effects on quality of life or on the likelihood of moving to a care home to live. There was not enough evidence for us to see whether results differed with the severity of dementia.
Our certainty in the results varied from moderate to very low, mainly because of small numbers of trials and participants, some problems with the way the trials were conducted, and imprecise statistical results.
Our conclusions
Although there was uncertainty about the results, most of the evidence pointed to benefits of continuing treatment with cholinesterase inhibitors. There was no evidence about types of dementia other than Alzheimer’s disease, and we were unable to draw specific conclusions about continuing or stopping treatment at different stages of the illness. We found no trials that just investigated stopping memantine.
These results may help patients and their doctors to make decisions about whether or not to continue treatment, although other factors, such as side effects in an individual patient and the patient’s preferences, are also important.
This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.
Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment.
To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes.
We searched the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources.
We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs.
Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods.
We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias.
Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty).
Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty).
We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review.