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CCCDTD5 recommendations on the deprescribing of cognitive enhancers in dementia

Abstract Introduction Cognitive enhancers (ie, cholinesterase inhibitors and memantine) can provide symptomatic benefit for some individuals with dementia; however, there are circumstances in which the risks of continuing treatment may potentially outweigh benefits. The decision to deprescribe cognitive enhancers must consider each patient's preferences, treatment indications, current clinical status and symptoms, prognosis, and dementia type. Methods The 5th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD5) established a subcommittee of experts to review current evidence on the deprescribing of cognitive enhancers. The questions answered by this group included: When should cognitive enhancers be deprescribed in persons with dementia and mild cognitive impairment? How should cognitive enhancers be deprescribed? And, what clinical factors should be considered when deprescribing cognitive enhancers? Results Patient and care‐partner preferences should be incorporated into all decisions to deprescribe cognitive enhancers. Cognitive enhancers should be discontinued in individuals without ongoing evidence of benefit or when the indication for cognitive enhancer use was inappropriate (eg, mild cognitive impairment). Deprescribing should occur gradually and cognitive enhancers should be reinitiated if patients’ cognition or function deteriorates. Cognitive enhancers should be continued in individuals whose neuropsychiatric symptoms improve in response to treatment. Clinicians should not deprescribe cognitive enhancers in individuals with significant neuropsychiatric symptoms until symptoms have stabilized. Conclusion CCCDTD5 deprescribing recommendations provide evidence‐informed recommendations related to cognitive enhancer deprescribing that will facilitate shared decision making among patients, care partners, and clinicians.

There has been increasing interest and evidence for use of cognitive enhancers in the management of severe dementia. [3][4][5] Similarly, considerations for the cessation of cognitive enhancers in individuals with advanced dementia 6 or end of life care, and in other situations, has become a topic of increasing interest. Efforts such as Choosing Wisely 7 and deprescribing initiatives 8 have identified the need to carefully examine the use of medications in frail older adults for whom the benefits of therapy may be uncertain or for which risks may outweigh benefits. 9 In 2012, the 4th CCCDTD first identified recommendations for deprescribing of ChEIs. 1 These guidelines identified that discontinuation of ChEIs should be considered when there is unclear evidence of ongoing benefit, adverse events develop, or when an individual has end-stage dementia. Discontinuation of cognitive enhancers should be gradual and patients should be monitored for worsening of cognitive or neuropsychiatric symptoms that may necessitate restarting therapy ( Table 1).
The purpose of the 5th CCCDTD guideline working group on the deprescribing of cognitive enhancers was to consider the previous recommendations from CCCDTD4 1 in light of new evidence related to deprescribing of cognitive enhancers. Our group also considered new topics related to discontinuation of cogni-tive enhancers that were not addressed in the previous CCCDTD recommendations.

Selection of topics for guideline recommendations
A deprescribing subcommittee was created including experts in family practice and nursing home care, geriatric psychiatrists, geriatricians, and neurologists. We also sought to have representation from junior and senior clinicians and researchers as well as geographic representation from across Canada. A total of 13 individuals were included in this guideline recommendation group (Appendix A in supporting information).

Guideline recommendation review process
An initial list of recommendations was drafted by the project leads (DS, NH) following review of existing guidelines and areas that required updated recommendations. This initial list of recommendations was then distributed to the full subcommittee for review and revision. One additional guideline recommendation was suggested after preliminary review of guideline recommendations by the deprescribing subcommittee (Recommendation 1). The subcommittee also provided strength of recommendation and quality of evidence assessments for each recommendation.
After consensus was reached by the subcommittee, the recommendations were voted on by the CCCDTD5 conference attendees.

RESULTS
Our literature review identified one systematic review on the discontinuation of cognitive enhancers, 12

HIGHLIGHTS
• The decision to deprescribe cognitive enhancers should take into account patient and family member preferences. Discontinuing ChEls in patients with moderate to severe AD may lead to worsening of cognitive function and greater functional impairment as compared with continued therapy (Grade 2B). This risk must be balanced with the risk for known side effects and drug costs if therapy continues. It is suggested that ChEls be discontinued when: 1. The patient and/or their proxy decision maker decide to stop after being appraised of the risks and benefits of continuation and discontinuation; 2. The patient is sufficiently nonadherent with the medication that continued prescription of it would be useless, and it is not possible to establish a system for the administration of the medication to rectify the problem; 3. The patient's rate of cognitive, functional, and /or behavioral decline is greater or treatment compared with that prior to being treated; 4. The patient experiences intolerable side effects that are definitely or probably related to the ChEl; 5. The comorbidities of the patient make continued use of the agent either unacceptably risky or futile (eg, terminally ill); or 6. The patient's dementia progress to a stage (eg, Global Deterioration Scale stage 7. where there would be no clinically meaningful benefit from continued therapy. When a decision has been made to discontinue therapy because of a perceived lack of effectiveness, the suggestion is that the dose be tapered before stopping the agent and that the patient be monitored over the 1 to 3 months for evidence of an observable decline. If this decline occurs, it is suggested that consideration be given to reinstating therapy. neurodegenerative conditions), ChEI should be discontinued. 1B (93%). 4. For individuals taking memantine for AD, PDD, DLB, or VD for >12 months, discontinuation should be considered if: (a) there has been a clinically meaningful worsening of dementia as reflected in changes in cognition, functioning, or global assessment over the past 6 months in the absence of other medical conditions (eg, presence of delirium, significant concomitant medical illness) or environmental factors (eg, recent transition in residence) that may have contributed significantly to the observed decline; (b) no clinically meaningful benefit was observed at any time during treatment (improvement, stabilization, decreased rate of decline); (c) the individual has severe or end-stage dementia (dependence in most basic activities of daily living, inability to respond to environment or limited life expectancy); (d) development of intolerable side effects (eg, confusion, dizziness, falls); (e) medication adherence is poor and precludes safe ongoing use of the medication or inability to assess the effectiveness of the medication. 1C (96%) 5. For individuals prescribed memantine for indications other than AD, PDD, DLB, or VD (eg, frontotemporal dementia, other neurodegenerative conditions), memantine should be discontinued. 1C (91%) 6. Deprescribing of ChEIs or memantine should occur gradually and treatment reinitiated if the individual shows clinically meaningful worsening of cognition, functioning, neuropsychiatric symptoms, or global assessment that appears to be related to cessation of therapy. 1B (98%) 7. Dose reduction during deprescribing should follow general guidelines for deprescribing of medications with a reduction of dose by 50% every 4 weeks until the initial starting dose is obtained. After 4 weeks of treatment on the recommended starting dose, the cognitive enhancer could be discontinued. 2C (96%) 8. ChEIs should not be discontinued in individuals who currently have clinically meaningful psychotic symptoms, agitation, or aggression until these symptoms have stabilized unless these symptoms appear to have been worsened by the initiation of a ChEI or an increase in ChEI dose. 2B (78%, 100%) 9. Individuals who have had a clinically meaningful reduction in neuropsychiatric symptoms (eg, psychosis) with cognitive enhancers should continue to be treated with the cognitive enhancer even if there is evidence of cognitive and functional decline. Similar to the decision related to initiation of cognitive enhancers, 2 the process of deprescribing cognitive enhancers should take into account the wishes of persons living with dementia and their families and significant others. 6 Often the decision to discontinue cognitive enhancers will occur for individuals who have advanced dementia or who may be nearing end of life. In these circumstances the person living with dementia will most often lack capacity to make these decisions on their own and informed consent for discontinuing cognitive enhancers will be provided by a family member or other substitute decision maker. These discussions should include information about the potential risks and benefits of discontinuing treatment, a plan for monitoring response to discontinuation, and discussion about plans for reintroducing therapy if it is determined that deterioration in clinical status has occurred following discontinuation. It should be acknowledged that even when persons living with dementia have entered hospice services the decision to discontinue cognitive enhancers can be challenging for families. 16 In many health regions, insurance coverage for cognitive enhancers is dependent on specific cognitive test scores or quantitative assessment of ongoing benefits of treatment. 17 These policies should be used to guide discussions of deprescribing of cognitive enhancers but not used solely in the decision to deprescribe as there may be clinical benefit in continuing cognitive enhancers in advanced dementia where cognitive test scores are below the cut-offs for ongoing insurance coverage. 6 In these circumstances discussions with the person living with dementia or family should also include information about the financial costs of continuing treatment with the cognitive enhancer. Intolerable side effects are uncommon during long-term treatment with ChEIs; however, the presence of symptoms known to be associated with their use may prompt deprescribing. These side effects tend to occur early in treatment when they do occur, but side effects can develop at any time during treatment. ChEIs are less likely to produce benefits, and more likely to contribute to side effects, when they are administered inconsistently and in the absence of medication adherence these medications should be discontinued. although the benefits of memantine for treating these types of dementia also tend to be modest. It should also be noted that much of the evidence for the use of memantine in dementia has been in the context of combination with a ChEI. As such, the benefit of continued treatment with memantine alone following discontinuation of the ChEI needs to also be considered.
We were unable to find any systematic reviews, and only a limited number of observational studies, investigating the discontinuation of memantine. One observational study of nursing home residents who were deprescribed memantine found that discontinuation of memantine was associated with a worsening of cognition and neuropsychiatric symptoms compared to ongoing treatment. 32 Our working group recommended that deprescribing of memantine be considered in clinical situations similar to those situations in which ChEIs are being considered for discontinuation although it should be noted that memantine tends to be associated with fewer side effects than ChEIs. 18  Our working group was unable to find any consistent evidence to suggest that memantine is effective in the treatment of dementias other that those indicated in Recommendation 4. Therefore, it is recommended that memantine be deprescribed in individuals who are currently receiving treatment with memantine for conditions other than AD, VD, DLB, or PDD. This includes deprescribing in those with frontotemporal dementia 34 in the absence of obvious benefit and in consultation with the patient and/or care partner. Inventory: -0.32, 95% CI: -0.51 to -0.12, P = 0.001) and higher rates of trial dropouts (risk ratio = 1.33, P = 0.002). Most of the studies included in this review were conducted in community-based settings (eg, not in nursing homes) and most studies included individuals with mild to moderate severity of AD. Although deprescribing may be appropriate to consider, this meta-analysis would argue for careful monitoring and follow-up should a deprescribing decision be made. An RCT of ChEI discontinuation in nursing home residents with advanced dementia was published after this meta-analysis. This small trial found that there was no significant difference in the proportion of participants who experienced clinical worsening for the deprescribing group when compared to the continuation group. 35 While many individuals with advanced dementia can have cognitive enhancers discontinued without worsening of clinical status, some individuals can have a worsening of cognition, function, or neuropsychiatric symptoms during deprescribing. 12 Most RCTs of deprescribing of ChEIs have used an abrupt approach to discontinuation without dose tapering. 12 It can be difficult to predict in advance which individuals are more likely to experience clinical deterioration following deprescribing of cognitive enhancers but some features such as the presence of neuropsychiatric symptoms have been associated with an increased risk of clinical deterioration following deprescribing. 35 Therefore, it is recommended that cognitive enhancers be gradually reduced over time and if clinical deterioration occurs during discontinuation that appears to be related to dose reduction or cessation of therapy then the cognitive enhancer should be reinstituted. 15 The cognitive enhancer may be considered for deprescribing at another time in the future when a process of gradual dose reduction and observation can be attempted. In situations in which cognitive enhancers are deprescribed due to intolerable side effects or poor adherence the cognitive enhancer should be discontinued unless measures have been put in place to correct these factors. However, some individuals may have limited cognitive or functional response to treatment but have clinically significant improvement in neuropsychiatric symptoms. 18,30,39 For some types of dementia like DLB and PDD, 23,24 cognitive enhancers can be associated with reductions in neuropsychiatric symptoms such as psychosis, and the risks associated with alternative medications such as antipsychotics can be particularly problematic. For these reasons, if an individual has had a significant improvement in neuropsychiatric symptoms during treatment with a cognitive enhancer, consideration should be given to continuing treatment, even if the benefits on cognition or functioning have been marginal. In these circumstances, insurance providers may not provide ongoing insurance coverage for treatment with the cognitive enhancer and discussions with the person with dementia and their family members may need to occur to determine ability to pay for ongoing treatment in this context.

Recommendation 10: ChEIs and memantine should be deprescribed for individuals with mild cognitive impairment. (1B)
There is no evidence that cognitive enhancers are associated with improvements in cognition or function in mild cognitive impairment (MCI or mild neurocognitive disorder in Diagnostic and Statistical Manual of Mental Disorders 5th Edition [DSM5] terminology). [41][42][43] Cognitive enhancers are associated with adverse effects in individuals with MCI. 43 Individuals that have been prescribed cognitive enhancers should have their cognitive enhancer deprescribed due to the lack of evidence for benefit and the potential for side effects. Whether individuals with MCI who also have biomarker evidence to suggest early development of AD or other types of dementia benefit from treatment with cognitive enhancers requires further study.

CONCLUSION
Deprescribing of cognitive enhancers in individuals with dementia is an important and challenging clinical issue. Our guideline recommendations will facilitate shared decision making among patients, care partners, and clinicians related to cognitive enhancer deprescribing, specifically, the risks and benefits of deprescribing in individual cases. While the underlying evidence used to generate our recommendations is relatively strong and consistent in some areas related to deprescribing of cognitive enhancers, additional research is required to better understand the risks and benefits of cognitive enhancer deprescribing and potential treatment alternatives.