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Dementia: Assessment, management and support for people living with dementia and their carers. London: National Institute for Health and Care Excellence (NICE); 2018 Jun. (NICE Guideline, No. 97.)

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Dementia: Assessment, management and support for people living with dementia and their carers.

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11Cholinesterase inhibitors and memantine for dementia

The three cholinesterase inhibitors, donepezil, rivastigmine, galantamine, and the NMDA receptor antagonist, memantine, are currently the only effective licensed treatments for dementia (O’Brien 2017). They are thought to be largely symptomatic agents and although effects on the underlying disease process have been proposed, there is no convincing evidence that they modify the disease process in Alzheimer’s or any other type of dementia.

There have been several studies demonstrating their efficacy in Alzheimer’s disease, leading to their licensing and NICE HTA approval for use in mild to moderate Alzheimer’s disease (for donepezil, rivastigmine, galantamine) and moderate to severe Alzheimer’s disease (for memantine). There have also been some studies in other disorders, including dementia with Lewy bodies and Parkinson’s disease dementia, where cholinesterase inhibitors have been shown to be effective (Stinton 2015), and frontotemporal and vascular dementia, where they have generally not (O’Brien 2015, O’Brien 2017). Memantine has been trialled in dementia with Lewy bodies and Parkinson’s disease dementia, without clear evidence of efficacy as yet (Stinton 2015).

Historically, initiation of these drugs has been by specialists in dementia, usually based in secondary care. There has often been ongoing specialist review of these drugs, and often recommendations that treatment be withdrawn when a certain stage of illness is reached. However, these drugs have been licenced for over a decade and there is now substantial experience in their use. They are generally safe and side effects are well recognised. Although it is important that the drugs are only started following an appropriate, accurate, specialist diagnosis, the actual initiation and monitoring of these drugs by specialists in secondary care might no longer be needed.

This chapter includes four important and closely related review questions: 1) who should start and review the three cholinesterase inhibitors and memantine in people with Alzheimer’s disease; 2) when and if treatment with these drugs should be withdrawn for those with Alzheimer’s disease; 3) whether there is evidence for the efficacy of co-prescription of cholinesterase inhibitors and memantine (which do have different actions); and 4) whether there is evidence of effectiveness for cholinesterase inhibitors and memantine in Parkinson’s disease and in other dementias.

11.1. Cholinesterase inhibitors and memantine for people living with Alzheimer’s disease

Review question

  • Who should start and review the following pharmacological interventions: (donepezil, galantamine, rivastigmine, memantine) for people with Alzheimer’s disease and how should a review be carried out?

11.1.1. Introduction

The aim of this review question was to determine which clinicians should prescribe and review donepezil, galantamine, rivastigmine or memantine for the cognitive symptoms of dementia in people diagnosed with Alzheimer’s disease. It includes a partial update of the existing NICE technology appraisal guidance TA217 (Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease).

11.1.2. Evidence review

A systematic evidence search was conducted (see appendix D) which identified 6344 articles. The titles and abstracts were screened and 66 full-text papers were identified for inclusion. Sixty three papers were subsequently excluded because they did not fit the inclusion criteria. Two studies described in 3 papers were presented to the committee (Aupperle et al., 2000; Aupperle et al., 2003; Watanabe et al., 2012).

A review flowchart is provided in appendix K, and the excluded studies (with reasons for exclusion) are shown in appendix F.

Table 47. Review summary.

Table 47

Review summary.

For full details of the review protocol please see appendix C.

There was no restriction on study design for inclusion in the evidence review. However, it was anticipated that the most useful study types would be observational designs including prospective/retrospective cohort studies. It was expected that the most appropriate design would be a study that compares non-specialist prescribing of these interventions with specialist prescribing.

The committee was interested in identifying evidence relating to both the prescribing and reviewing of AChEs and memantine. This is because it was expected that the prescribing of these medications for people living with Alzheimer’s disease may be carried out by a different health professional to the person undertaking the review. Evidence associated with these practices was identified independently.

11.1.2.1. Description of included studies

Two observational studies were included in the evidence review. One study presented in 2 papers provided evidence on the prescribing of donepezil for people living with Alzheimer’s disease and 1 paper was identified as evidence for reviewing treatment with donepezil.

The quality of evidence for each outcome was considered using the approach recommended by the Grading Recommendations, Assessment, Development and Evaluation (GRADE) working group. Due to variations in the way the outcome data were reported by each study, the evidence statements were presented by intervention/study rather than by outcome.

For a summary of included studies please see Table 48 (for the full evidence tables and full GRADE profiles please see Appendix E and Appendix G). References for the included studies are given in appendix I.

11.1.3. Health economic evidence

A literature review was undertaken by applying standard health economic filters to the clinical literature searches. In total, 1,049 records were returned; 0 were retained as cost–utility analyses that addressed the review question.

11.1.3.1. Description of included studies

Table 48. Summary of included studies.

Table 48

Summary of included studies.

11.1.4. Evidence statements

11.1.4.1. Prescribing donepezil (speciality versus non-speciality prescribing)

Very low to low-quality evidence from 1 observational study conducted in the USA in the 1990s with 57 participants found at 1 year follow up the number of people receiving a prescription of donepezil was significantly lower for people being seen by a primary care physician compared with those seen by a geriatric psychiatrist.

At 1 year follow up, the study reported a mean Clinical Dementia Rating significantly higher (indicating more severe dementia) for people being seen by a primary care physician compared with those being seen by a geriatric psychiatrist. The use of health and social care support (including number of hospitalisations, use of home health aides and dementia day care programs), and the mean carer distress rating were not significantly different for people being seen by a primary care physician compared with those being seen by a geriatric psychiatrist.

In the same study, at 2 year follow up, (39 participants), the number of people receiving a prescription of donepezil and the use of health and social care support (including number of hospitalisations, use of assisted living and residence in nursing homes) were not significantly different for people being seen by a primary care physician compared with those being seen by a geriatric psychiatrist.

11.1.4.2. Reviewing donepezil (advisory service versus no advisory service)

Very low-quality evidence from 1 before-and-after study conducted in Japan with 111 participants reported the number of people living with Alzheimer’s disease who were continuing to use donepezil after 1 year was significantly greater for people using an advisory consultation service compared with those who had not used this service. The mean duration of donepezil treatment and mean level of understanding for patients and carers was also significantly higher for people using the advisory consultation service compared with those who had not used the service.

11.1.4.3. Health economic evidence

No health economic evidence was identified for this review question.

11.1.5. Evidence to recommendations

Relative value of different outcomesThe Guideline committee agreed it was important that included outcomes considered the impact of medication changes on access to health and social care support and also reflected outcomes for both people living with dementia and their carers. The committee recognised that the outcomes presented in the evidence review were limited and felt this was consistent with the very low quality of the evidence (see ‘Quality of evidence’ below). The committee noted that the processes for issuing and dispensing prescriptions differ across primary and secondary care settings. For example, it was perceived that the issuing of repeat prescriptions in primary care is likely to be more reactive to requests from the person living with dementia, whereas the issuing of prescriptions in specialist services is perceived to be more proactive when treatment is initiated.
The committee noted that the number of prescriptions dispensed may not necessarily equate to adherence with prescribed medication, as it does not indicate whether people take the medicines dispensed.
The committee observed for the outcome concordance and compliance, that the relative risk associated with the number of prescriptions at 2 year follow up did not identify a significant effect; however the primary data indicated a large difference. The committee considered this magnitude of effect as potentially important regardless of statistical significance.
Although, in Aupperle et al. 2003, the authors did not report standard deviation at 2 year follow up the committee noted that, participants who were seen by a geriatric psychiatrist experienced an overall slight improvement in Clinical Dementia Rating (CDR) over 2 years. The committee thought this would be very unusual, as Alzheimer’s disease is a degenerative condition.
The committee agreed that the outcomes reported were in line with their own clinical experience. It was noted that people with dementia in non-specialist settings may be more likely to stop medications.
Quality of evidenceThe committee agreed that the evidence presented was very low quality and noted the methodological limitations of the identified studies.
The committee agreed that the identified research evidence would not necessarily reflect current practice in the UK for the use of AChEs. It was noted that the studies were conducted during the 1990s, when clinicians were much less familiar with AChEs. The included studies were also conducted overseas where healthcare systems and services differ to practice in the UK.
For Aupperle et al. (2000) and Aupperle et al. (2003) the committee noted that the observational design of the studies meant that there was a high risk of selection bias. The committee further noted that the observational design of Aupperle et al. (2003) meant there was a lack of interpretable findings on reasons for attrition, making it difficult to infer whether attrition was a consequence of adverse effects or lack of efficacy.
The committee acknowledged the limitations of the Watanabe et al. (2012) study. They agreed the observational design, small sample size, short follow up and selective reporting reflected that the study was very low quality.
Trade-off between benefits and harmsThe committee discussed the evidence base and agreed that they would be unable to make recommendations based solely on the reported outcomes.
The committee raised concerns about the lack of evidence identified in relation to the initiation of AChEs and memantine but agreed that initiation is implicitly linked to diagnosis. It noted that recommendation 1.1 and 1.2 of TA217 imply that a diagnosis is needed before treatment can be initiated. The committee agreed that the purpose of memory clinics is not solely to prescribe AChEs and memantine but to provide specialist assessment in diagnosing, treating and supporting people living with dementia. The committee noted that the current guideline suggests that diagnosis should be made by a specialist (CG42 1.4.3.1), and that this will be subject to a separate evidence review as part of the ongoing update.
The committee acknowledged the practical issues around the mechanisms for prescribing, dispensing and monitoring medication adherence. Committee members raised concerns that people may have to wait for a diagnosis before they can start treatment but the committee agreed that there should not be an artificial barrier preventing the transfer of care between specialist and non-specialist healthcare settings. The committee was keen to ensure that AChEs and memantine were only initiated following a diagnosis and those treatment recommendations are made by a clinician with appropriate specialist expertise. However, it acknowledged the difficulties that sometimes arise where the diagnosing clinician is required to issue the first prescription for an AChE or memantine. The committee acknowledged that licensing for AChEs and memantine (as set out in each product’s Summary of Product Characteristics; SPC) is clear about initiation and supervision of these drugs and therefore agreed that it was appropriate to reflect this in the recommendations. The committee noted that the SPCs for each of the AChEs and memantine make reference to initiation and supervision of treatment by specialist physicians. However, it noted that the wording of these SPCs pre-dates legislative changes, in the early 2000s, which authorised the use of non-medical prescribers. The committee agreed that any interpretation of the recommendations would need to take account of this different prescribing environment. For this reason, the committee thought it was not necessary to stipulate that treatment should be initiated by physicians (i.e. doctors) alone, and preferred to emphasise that the prescriber starts treatment on advice from a healthcare professional with specialist experience, regardless of professional label. The committee also agreed it was important to note that once a decision has been made to initiate therapy, then prescriptions can be made in primary care.
The committee discussed their concerns over communication of information between specialist and non-specialist settings and agreed that reference to NICE’s Medicines Optimisation guideline (NG5) would be helpful. The committee discussed recommendation 1.2 in the NICE Medicines Optimisation guideline which considers medicines-related communication systems where patients move between care settings, which is of particular relevance. However, following further discussion, it was agreed that reference to all of NG5 would be more appropriate. When considering the monitoring and review of these drugs, the committee noted and agreed that an annual dementia review is mandated. They agreed that these drugs should be part of the annual dementia review as opposed to a standard medicines review. The committee noted again that it would be appropriate to refer to the Medicines Optimisation NICE guidance with regard to medication review, and the arrangements that should be in place between different care settings (in this instance, secondary and primary care).
Trade-off between net health benefits andNo published health economic evidence was identified for this review question. The committee noted that, in the past (including when TA217 was published), the medicines under consideration all had proprietary status, but they are all now available in generic formulations. This change has been accompanied by a significant fall in the acquisition costs of the drugs. The committee felt that, if cost containment had been a motivating factor in restricting prescribing to people with specialist experience of Alzheimer’s disease, this was no longer such a substantial concern. However, the committee emphasised that other reasons for involving specialists remain relevant.
Other considerationsIt was noted that the current recommendations make reference to carers’ views. The committee agreed that this is an important consideration. However following discussion it was agreed that it could be adequately addressed by cross-reference to NICE’s Medicines Optimisation guideline (NG5), which gives detailed guidance on the need to involve carers in the diagnosis, management and treatment of individuals. It was also agreed to be appropriate to add addition cross-references to the NICE guidelines on managing medicines for adults receiving social care in the community, and managing medicines in care homes, in particular because these guidelines includes specific recommendations around covert administration, which will be relevant for some people living with dementia. This guideline will be relevant for people with all dementia subtypes, not only those with Alzheimer’s disease included in this review.
This section also includes the recommendations directly incorporated in to this guideline from NICE technology appraisal 217.

11.1.6. Recommendations

Recommendations shaded in grey are taken directly from NICE technology appraisal guidance 217 and were not updated as part of this guideline, and therefore no changes to these recommendations can be made.

60.

The three acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine as monotherapies are recommended as options for managing mild to moderate Alzheimer’s disease under all of the conditions specified in 62 and 63.

61.

Memantine monotherapy is recommended as an option for managing Alzheimer’s disease for people with:

  • moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE inhibitors or
  • severe Alzheimer’s disease.

Treatment should be under the conditions specified in recommendation 6.

62.

Treatment should be under the following conditions:

  • For people who are not taking an AChE inhibitor or memantine, prescribers should only start treatment with these on the advice of a clinician who has the necessary knowledge and skills. This could include:
    • secondary care medical specialists such as psychiatrists, geriatricians and neurologists
    • other healthcare professionals (such as GPs, nurse consultants and advanced nurse practitioners), if they have specialist expertise in diagnosing and treating Alzheimer’s disease.
  • Once a decision has been made to start cholinesterase inhibitors or memantine, the first prescription may be made in primary care.
  • Ensure that local arrangements for prescribing, supply and treatment review follow the NICE guideline on medicines optimisation.

63.

If prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if it is considered appropriate when taking into account adverse event profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles.

64.

When using assessment scales to determine the severity of Alzheimer’s disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the results and make any adjustments they consider appropriate. Healthcare professionals should also be mindful of the need to secure equality of access to treatment for patients from different ethnic groups, in particular those from different cultural backgrounds.

65.

When assessing the severity of Alzheimer’s disease and the need for treatment, healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so. These include:

  • if the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient’s dementia because of the patient’s learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or
  • if it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or
  • if there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia.

In such cases healthcare professionals should determine the need for initiation or continuation of treatment by using another appropriate method of assessment.

66.

For guidance on managing medicines (including covert administration), see the NICE guidelines on managing medicines for adults receiving social care in the community and managing medicines in care homes.

11.2. Co-prescription and withdrawal of cholinesterase inhibitors and memantine in Alzheimer’s disease

Review questions

  • How effective is the co-prescription of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease?
  • When should treatment with donepezil, galantamine, rivastigmine, memantine be withdrawn for people with Alzheimer’s disease?

11.2.1. Introduction

The aim of these review questions was to determine the effectiveness and cost-effectiveness of memantine plus a cholinesterase inhibitor for cognitive enhancement in Alzheimer’s disease and to determine the clinically appropriate points to withdraw treatment with donepezil, galantamine, rivastigmine and memantine for people with Alzheimer’s disease.

The review identified studies that fulfilled the conditions specified in Table 49 and Table 50. For full details of the review protocols, see Appendix C.

Table 49. Review summary: co-prescription of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease.

Table 49

Review summary: co-prescription of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease.

Table 50. Review summary: withdrawal of cholinesterase inhibitors and memantine for people living with Alzheimer’s disease.

Table 50

Review summary: withdrawal of cholinesterase inhibitors and memantine for people living with Alzheimer’s disease.

11.2.2. Evidence review

Two separate systematic searches were undertaken to address the 2 questions in this section.

For the co-prescription of cholinesterase inhibitors and memantine a systematic search identified 1,914 references. Fifty three references were ordered for full text review after screening upon title and abstract and 8 papers were included in the final review.

Five papers (Howard, 2012; Tariot 2004; Dysken 2014; Porsteinsson 2008 and Grossberg 2013) recruited people who were currently receiving a cholinesterase inhibitor as treatment for their Alzheimer’s disease and involved randomisation to co-prescription with memantine or placebo memantine. To assist with analysis, additional data was sought from the authors of the DOMINO-AD trial (Howard, 2012; please see Appendix E for this information). Two papers (Araki 2014; Choi 2011) compared co-prescription of a cholinesterase inhibitor to monotherapy with the same cholinesterase inhibitor. One paper (Shao 2015) randomised people with mild to moderate Alzheimer’s disease to different treatment arms for each cholinesterase inhibitor and compared these to placebo. For a detailed list of excluded studies and reasons for exclusion see Appendix F.

For discontinuation of cholinesterase inhibitors and memantine, the search identified 1,242 references. The references were screened on their titles and abstracts and 35 references were ordered for full text review. Thirty two papers were subsequently excluded because they did not fit the inclusion criteria (see Appendix F for a detailed list of excluded studies and reasons for their exclusion). Three papers were included in the evidence review. A further 3 papers included outcomes for people discontinued from cholinesterase inhibitors, but these did not meet the criteria for the review as they did not include a population of people taking a cholinesterase inhibitor at start of the study, but rather people were included in the study, started on treatment and then had the treatment withdrawn as part of the same study.

All 3 included papers involved randomisation to withdrawal of a cholinesterase inhibitor and replacement with placebo. One study reported in 2 papers (Howard et al., 2012; Howard et al., 2015) additionally randomised people within each arm to receive active or placebo memantine, creating a 2x2 factorial trial design. The other study (Herrmann et al., 2016) recruited people on a range of cholinesterase inhibitors (rivastigmine, galantamine, donepezil) and reported outcomes without stratifying by the specific cholinesterase inhibitor which had been continued or withdrawn.

A summary of the characteristics of the included studies is provided in and Table 51 and Table 52. Data from the included studies were extracted into evidence tables. See Appendix E for the full evidence tables, and for the full GRADE profiles see Appendix G. References for the included studies are given in appendix I.

Results for co-prescription versus cholinesterase inhibitor monotherapy are presented in 2 separate ways. The first analysis uses the full dataset, and stratifies the analysis into mild-to-moderate, and moderate-to-severe populations, as each of the included trials recruits 1 of those 2 subpopulations. The second analysis subdivides the population into separate mild, moderate and severe subgroups, using additional information obtained from a Cochrane review of memantine in dementia, and from the authors of the DOMINO-AD trial. It was not possible to obtain data for all outcomes of all trials in this format, and therefore this analysis contains only a subset of the participants included in the full analysis.

11.2.2.1. Description of included studies

Table 51. Included studies for co-prescription of cholinesterase inhibitors and memantine.

Table 51

Included studies for co-prescription of cholinesterase inhibitors and memantine.

Table 52. Included studies for withdrawal of cholinesterase inhibitors or memantine.

Table 52

Included studies for withdrawal of cholinesterase inhibitors or memantine.

11.2.3. Health economic evidence

As for the cost-effectiveness searches, 2 separate systematic searches were undertaken to address the 2 questions in this section. For full details of the search strategies, please see Appendix D.

11.2.3.1. Co-prescription of cholinesterase inhibitors and memantine

The search identified 820 references. After screening on title and abstract, 12 papers were ordered for full-text review; following detailed perusal, 5 cost–utility analyses (CUAs) were included in the final review.

Three CUAs were closely related: Lachaine et al. (2011) developed a Markov model comparing co-prescription of cholinesterase inhibitors (AChEs) and memantine with AChE monotherapy from a Canadian perspective, whilst Pfeil et al. (2012) and Touchon et al. (2014) replicated the analysis from Swiss and French perspectives, respectively. The models adopted a 3-state structure: the modelled cohorts began in community-based care, with a proportion progressing to full-time residential care and the possibility of transition to death from either state. The probability of requiring full-time residential care was estimated from an observational (retrospective cohort) study, based on a US population, which found that people who had received combination therapy were significantly less likely to enter care than people who had received AChE monotherapy (Lopez et al., 2014). Economic evidence profiles for all three CUAs are available in Appendix M.

All 3 analyses were judged to be partially applicable with very serious limitations. Each concluded that combination therapy dominates AChE monotherapy (that is, it is both less expensive and more effective). All 3 CUAs report setting-specific costs from a ‘healthcare’ perspective and a ‘societal’ perspective. Neither of these is consistent with the NICE reference case, as the ‘healthcare’ perspective omits relevant social care costs, and the ‘societal’ perspective includes these costs but also encompasses estimates of informal carer costs. However, results are not qualitatively different between the 2 perspectives, so it can be inferred that a perspective that sits between the 2 would reach the same conclusions.

Weycker et al. (2007) developed a patient-level cohort ‘micro-simulation’ model, simulating the costs and effects of combination therapy with memantine and donepezil compared with donepezil monotherapy in moderate-to-severe Alzheimer’s disease from a US perspective. Treatment effects for combination therapy were based on severe impairment battery (SIB) results from an RCT comparing memantine and donepezil with donepezil monotherapy that is included in our clinical review (Tariot et al. 2004; see above). However, the effects of donepezil were not drawn from the same RCT; rather, they were based on the donepezil arm of a different, placebo-controlled RCT (Feldman et al., 2001). The authors justify this decision by arguing that the benefits of donepezil observed in the Tariot et al. RCT ‘are probably an artefact of trial participation and not donepezil therapy per se’. SIB results in these 2 trial arms are used to estimate costs, utility and probability of entry to full-time care, via a mapping to MMSE which is, in turn, used to approximate CDR (and, in the case of HRQoL, mapped once again to HUI3).

The CUA was assessed as partially applicable with very serious limitations. It concluded that, over their lifetime, an average patient in the cohort would spend around 2 years in a community setting, followed by a little under 4 years in full-time care, and such a person would accrue a negative QALY aggregate over this period (that is, their remaining quality-adjusted life expectancy should be considered a substantially worse prospect than immediate death). Incremental results suggest that combination therapy dominates donepezil monotherapy (that is, it is both less expensive and more effective).

The final CUA, reported by Knapp et al. (2016), was a UK trial-based analysis conducted alongside the DOMINO-AD RCT, which is described above (Howard et al., 2012). The analysis used directly reported carer-rated EQ-5D results to estimate QALYs over the 1-year duration of the trial. Resource-use data were collected using a comprehensive inventory of health and social care support. Although the trial randomised people to 4 mutually exclusive strategies (donepezil, memantine, donepezil and memantine combination, or placebo), the paper reports incremental results for 3 comparisons that the investigators had pre-specified as of interest: donepezil or combination versus memantine or placebo, combination versus donepezil and memantine versus placebo. The second comparison is of interest for the co-prescription review (see below for analyses of interest to the discontinuation question).

As for the effectiveness review, the investigators shared results stratified by baseline severity, which enabled the committee to consider separate (moderate and severe Alzheimer’s disease [AD]) populations. It also made it possible to assess evidence for comparisons not reported in the paper – for example, combination therapy compared with memantine monotherapy (which is a particularly relevant comparison in people with severe AD, given that memantine is licensed in this population, but donepezil is not). Having access to the stratified data had the substantial advantage that the committee could consider analyses of direct relevance to the decision problems with which it was faced. However, it came with the disadvantage that, as data had been subdivided into smaller subsets, it was not feasible to adjust the analyses for the baseline characteristics of the participants, as had been done in the published analysis.

The CUA was assessed as directly applicable with minor limitations. It had the following results:

  • In moderate disease, combination therapy was associated with increased costs (£1,310 [95%CI: −£3,021 to £5,641]) and reduced quality of life (−0.07 [95%CI: −0.22 to 0.08]) compared with donepezil monotherapy. However, these estimates were subject to substantial uncertainty, as can be seen in the broad confidence intervals with which the disaggregated values are associated.
  • In the severe AD stratum,
    • combination therapy reduced costs (−£1,658 [95%CI: −£6,399 to £3,082]) and increased QALYs (0.11 [95%CI: −0.06 to 0.28]) compared with memantine monotherapy
    • combination therapy reduced costs (−£240 [95%CI: −£4,759 to 4,279]) and increased QALYs (0.11 [95%CI: −0.06 to 0.28]) compared with donepezil alone
    Once again, these estimates were subject to substantial uncertainty, as seen in the broad confidence intervals.
  • Probabilistic analysis is only available in the published analysis, which combines moderate and severe AD. This suggested that there is an exactly 50:50 chance that combination therapy or donepezil monotherapy is optimal, if QALYs are valued at £20,000 each.

11.2.3.2. Discontinuation of cholinesterase inhibitors and memantine

The search identified 346 references. After screening on title and abstract, 8 papers were ordered for full-text review; following detailed perusal, 1 was included in the final review.

The one included CUA was Knapp et al.’s, within-trial analysis for the DOMINO-AD RCT (2016), as described above. For the discontinuation question, the comparisons of interest are donepezil vs placebo and memantine vs placebo in both the moderate and severe subgroups.

The CUA was assessed as directly applicable with minor limitations. It had the following results:

  • In moderate disease,
    • donepezil monotherapy reduced costs (£974 [95%CI: −£2,383 to £4,332]) and increased QALYs (0.26 [95%CI: 0.08 to 0.45]) compared with placebo
    • memantine monotherapy reduced costs (−£1,472 [95%CI: −£4,273 to £1,329]) and increased QALYs (0.18 [95%CI: −0.02 to 0.37]) compared with placebo
  • In severe disease,
    • donepezil monotherapy reduced costs (−£5,711 [95%CI: −£19,015 to £7,592]) and increased QALYs (0.05 [95%CI: −0.11 to 0.21]) compared with placebo
    • memantine monotherapy reduced costs (−£4,293 [95%CI: −£17,677 to £9,091]) and increased QALYs (0.07 [95%CI: −0.10 to 0.23]) compared with placebo

These results were typically associated with substantial uncertainty. The one finding that appeared reliable, at a 95% confidence level, is that discontinuing donepezil, in people with moderate AD, results in a loss of QALYs.

11.2.4. Evidence statements

11.2.4.1. Cholinesterase inhibitor plus memantine versus cholinesterase inhibitor plus placebo

11.2.4.1.1. Full population

Low- to high-quality evidence from up to 5 RCTs containing 1,875 people living with Alzheimer’s disease found global functioning (CIBIC plus), behavioural and psychological symptoms (NPI), care dependency (Behaviour rating scale for geriatric patients- care dependency subscale), verbal fluency (VFT) and activities of daily living (ADCS-ADL/BADLS) were significantly improved in people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo, but could not differentiate cognition (ADAS-cog; MMSE), global assessment (SIB), health-related quality of life (DEMQOL), global health (Global health questionnaire), carer activity (Caregiver activity survey), adverse events, serious adverse events, discontinuations due to adverse events, entry to long term care or mortality.

11.2.4.1.2. Mild to moderate

Low- to moderate-quality evidence from up to 3 RCTs containing 740 people living with mild to moderate Alzheimer’s disease could not differentiate cognition (ADAS-cog; MMSE), activities of daily living (ADCS-ADL/BADLS), global functioning (CIBIC plus), behavioural and psychological symptoms (NPI), health-related quality of life (DEMQOL), adverse events, serious adverse events, discontinuations due to adverse events or mortality between people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo.

11.2.4.1.3. Moderate to severe

Very low- to high-quality evidence from up to 4 RCTs containing 1,166 people living with moderate to severe Alzheimer’s disease found activities of daily living (ADCS-ADL/BADLS), global functioning (CIBIC plus), behavioural and psychological symptoms (NPI), care dependency (Behaviour rating scale for geriatric patients- care dependency subscale) and verbal fluency (VFT) were significantly improved in people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo, but could not differentiate cognition (MMSE), global assessment (SIB), health related quality of life (DEMQOL), global health (Global health questionnaire), adverse events, serious adverse events, discontinuations due to adverse events or carer outcomes (Caregiver activity survey).

Economic evidence

One directly applicable cost–utility analysis with minor limitations found that combination therapy is associated with small, uncertain increases in both costs and QALYs, with a base-case ICER of £19,967. The probability that either approach is optimal is 50%, if QALYs are valued at £20,000 each.

11.2.4.1.4. Mild only

Low- to moderate-quality evidence from up to 2 RCTs containing 315 people living with mild Alzheimer’s disease could not differentiate global assessment, cognitive function or activities of daily living between people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo.

11.2.4.1.5. Moderate only

Low- to moderate-quality evidence from up to 4 RCTs containing 663 people living with moderate Alzheimer’s disease found cognitive function was significantly improved in people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo, but could not differentiate global assessment, activities of daily living, behavioural and psychological symptoms (NPI), health-related quality of life (DEMQOL) or global health (Global health questionnaire).

Economic evidence

One directly applicable cost–utility analysis with minor limitations found that donepezil monotherapy may be associated with lower costs and more QALYs than combination therapy with donepezil and memantine. However, this result is subject to substantial uncertainty, such that the data are consistent with either approach providing better value than the other.

11.2.4.1.6. Severe only

Moderate- to high-quality evidence from up to 3 RCTs containing 218 people living with severe Alzheimer’s disease found cognitive function, activities of daily living and behavioural and psychological symptoms (NPI) were significantly improved in people treated with combination therapy of cholinesterase inhibitors plus memantine compared with treatment with a cholinesterase inhibitor plus a placebo, but could not differentiate global assessment, health-related quality of life (DEMQOL) or global health (Global health questionnaire).

Economic evidence

One directly applicable cost–utility analysis with minor limitations found that combination therapy with donepezil and memantine may be associated with lower costs and more QALYs than either agent as monotherapy. However, this result is subject to substantial uncertainty, such that the data are consistent with any approach providing best value.

11.2.4.1.7. Cholinesterase inhibitor plus memantine versus cholinesterase inhibitor monotherapy

Very low- to moderate-quality evidence from up to 2 RCTs containing 183 people living with Alzheimer’s disease found global assessment (Clinical Global Impression-Improvement), cognition (Clock drawing Test), behavioural and psychological symptoms (NPI) and carer burden (Zarit Burden Interview) were significantly improved in people treated with combination therapy of cholinesterase inhibitors plus memantine compared with cholinesterase inhibitor monotherapy, but could not differentiate cognition (MMSE; ADAS-cog), behavioural and psychological symptoms (carer administered), dementia severity (Clinical Dementia rating–sum of boxes; Frontal Assessment Battery), agitation (Cohen Mansfield Agitation Inventory), any adverse events or any serious adverse events.

When data was stratified by baseline dementia severity, cognition (MMSE) was significantly improved for people living with moderate–severe Alzheimer’s disease, but could not be differentiated for people living with mild-to-moderate Alzheimer’s disease.

Economic evidence

Four partially applicable cost–utility analyses with very serious limitations found that, in people with moderate–severe AD, combination therapy with a cholinesterase inhibitor and memantine dominates cholinesterase inhibitor monotherapy (that is, combination therapy is associated with lower costs and more QALYs). All 4 analyses were funded by the manufacturer of memantine, and each derived its estimates of effect from non-randomised comparisons.

11.2.4.1.8. Cholinesterase inhibitor plus memantine versus memantine plus placebo

Very low to low-quality evidence from 1 RCT with 88 people living with mild to moderate Alzheimer’s disease could not differentiate cognition (MMSE); activities of daily living (ADCSADL) or number of adverse events for people treated with combination therapy of cholinesterase inhibitors plus memantine compared with people treated with memantine plus a placebo.

Economic evidence

One directly applicable cost–utility analysis with minor limitations found that, in people with severe AD, combination therapy with donepezil and memantine may be associated with lower costs and more QALYs than memantine monotherapy. However, this result is subject to substantial uncertainty, such that the data are consistent with either approach providing better value than the other.

11.2.4.2. Cholinesterase inhibitor withdrawal

Low- to moderate-quality evidence from up to 2 RCTs containing 148 people living with moderate to severe Alzheimer’s disease could not differentiate cognition, activities of daily living, behavioural and psychological symptoms, quality of life or rates of entry to long term care between people continuing with or discontinuing from cholinesterase inhibitors. Significant benefits from continuation were found for cognition in people with moderate Alzheimer’s disease.

Economic evidence

One directly applicable cost–utility analysis with minor limitations found that

  • in people with moderate AD, switching from donepezil to placebo reduces QALYs and may also increase costs, meaning it is likely to be dominated by continued therapy
  • in people with severe AD, switching from donepezil to placebo may reduce QALYs and may also increase costs, meaning it may be dominated by continued therapy

11.2.4.3. Cholinesterase inhibitor switch to memantine

Low- to moderate-quality evidence from 1 RCT containing 105 people living with moderate to severe Alzheimer’s disease could not differentiate cognition, activities of daily living, behavioural and psychological symptoms, quality of life or rates of entry to long term care between people continuing with cholinesterase inhibitors or switching to memantine. Significant benefits from switching were found for behavioural and psychological symptoms in people with severe Alzheimer’s disease.

Economic evidence

One directly applicable cost–utility analysis with minor limitations could not differentiate costs and QALYs between switching from donepezil to memantine or continuing donepezil, in people with severe AD.

11.2.4.4. Memantine withdrawal

No evidence was identified looking at the outcomes of memantine withdrawal in people living with dementia.

11.2.5. Evidence to recommendations

Relative value of different outcomesThe committee noted that the primary outcome measures in most of the trials was cognitive function (using one of the MMSE, ADAS-cog and SIB). They recognised that in designing trials, these instruments are used as a measure of identifying disease severity. However, in practice, clinicians are more likely to consider global functioning, quality of life, and the impacts on people’s daily activities. In deciding whether to continue treatment, the committee agreed it was important to consider the overall benefit of treatment, rather than simply focusing upon cognitive benefit.
The committee also agreed that it was important to consider evidence on behavioural symptoms, and in particular agitation. There is evidence from the literature on memantine monotherapy that it may have positive effects on agitation, and some evidence that cholinesterase inhibitors may worsen agitation in some individuals. These potential effects are also important to consider.
Trade-off between benefits and harmsDiscontinuation of cholinesterase inhibitors
The committee noted there was clear evidence of harm from discontinuing cholinesterase inhibitors in people with moderate Alzheimer’s disease, with a substantial worsening in cognitive function. The committee noted that the trials effectively used an MMSE score as the trigger for discontinuation, and that decisions in clinical practice were likely to be more complex than this, and cover a range of outcomes for the person living with Alzheimer’s disease. They therefore agreed the evidence demonstrated that it was not possible to use a set cut-off for disease severity to decide when treatment should be discontinued (as no effective cut-off to use was found). This was supported by the primary analysis of the DOMINO-AD study, which found significant worsening on cholinesterase inhibitor withdrawal. The committee therefore agreed it was appropriate to recommend that disease severity should not be used as a reason for treatment discontinuation.
The committee agreed that in practice there may be other reasons why treatments are discontinued (e.g. the person is unable or unwilling or distressed by the process of taking the medicine, they are suffering side effects, or they are entering a terminal phase of the illness and harms are felt to outweigh the benefits of treatment). However, it was agreed these discussions were part of normal clinical decision-making, it was not necessary to make any specific recommendations about them.
Co-prescription of cholinesterase inhibitors and memantine
The committee agreed that is was important to separate the population into those with mild Alzheimer’s disease and those with moderate/severe disease when considering this question, as the evidence on memantine monotherapy suggests that memantine is not effective in mild Alzheimer’s disease.
The committee agreed this same pattern was present in the evidence on co-prescription, with no evidence of effect in the mild subgroup, but improvements in cognitive function and global functioning in both the moderate and severe populations (and additionally, improvements in activities of daily living in the severe population). The magnitudes of the effects were approximately half of those seen for cholinesterase inhibitor monotherapy versus placebo in treatment naive individuals, but were still at a level that would be likely to be clinically meaningful, particularly given that there was no evidence of an increase in adverse events from co-prescription.
The committee therefore agreed it was appropriate to make positive recommendations for co-prescription in both moderate and severe Alzheimer’s disease. A stronger recommendation was made for severe Alzheimer’s disease compared with moderate disease for two reasons: firstly, the magnitudes of effects seen were larger in people with more severe Alzheimer’s disease; and secondly, the trials in moderate to severe Alzheimer’s disease only tended to recruit people at the more severe end of the moderate category, and therefore the evidence of benefit is less clear in people at the milder end of the moderate category.
Switching from cholinesterase inhibitors to memantine
The committee considered the risks and benefits of transferring from monotherapy with cholinesterase inhibitors to monotherapy with memantine. They concluded that, in practice, there may be a risk of doing harm by switching (by moving people off a drug they are known to tolerate), when you have no particular indication to stop. There may be a danger that if a transfer to memantine is not tolerated, people may be left without any prescription, when continuing therapy with cholinesterase inhibitors may have had some benefit. Therefore, the committee agreed the balance of evidence was in favour of co-prescription as opposed to treatment switching in people with severe Alzheimer’s disease.
Trade-off between net health benefits and resource useThe committee noted that, of the economic evaluations identified, only the DOMINO-AD study was directly applicable and subject to only minor limitations: it was the only evidence from the UK, based on an RCT, and that reflected the current prices of the drugs, which have fallen substantially since generic formulations became available. Therefore, the committee agreed it provided more robust evidence than the other studies. The committee noted that the other studies were all judged to be partially applicable with very serious limitations.
It agreed that, as the cost of all of these medicines was now extremely low, any intervention that was clinically effective (in improving quality of life) was almost certain to be cost effective. This was supported by evidence from DOMINO-AD, where, with the exception of 1 analysis, interventions associated with more QALYs were also associated with lower costs. The committee considered this a predictable finding because, if the intervention is effective in maintaining people’s cognition and/or functional independence, the low costs of the drugs themselves will be outweighed by money saved in support required. The committee also noted that the other, lower-quality CUAs were consistent with this pattern, showing that combination therapy dominated monotherapy with a cholinesterase inhibitor alone, resulting in decreased costs and increased QALYs. The committee did not consider these studies to provide convincing evidence, in themselves, that combination therapy provides better value than monotherapy; however, it agreed with the emerging principle that any strategy, in this area, that improves quality of life is also likely to reduce overall costs.
Discontinuation of cholinesterase inhibitors
The committee considered analyses from the DOMINO-AD study comparing donepezil monotherapy versus placebo and memantine monotherapy versus placebo in both moderate and severe AD subgroups. The committee agreed the findings of the analyses agree with the findings of the clinical review that monotherapy in both moderate and severe subgroups with either donepezil or memantine was effective compared with placebo, and resulted in decreased costs and increased QALYs. The committee were confident in the finding that discontinuing donepezil in people with moderate/severe AD resulted in a loss of QALYs, and therefore concluded that donepezil should be not discontinued from people with Alzheimer’s disease solely on the basis of disease progression. There was somewhat more uncertainty in the costs associated with these analyses; however, the committee did not think this was a serious issue, as the clinical data were robust, and the cost data clearly pointed in a direction that reflected the previously stated argument that any effective treatment is likely to be cost effective.
Combination therapy
The analyses found that, in moderate AD, combination therapy was associated with increased costs and reduced quality of life, albeit with substantial uncertainty.
In the case of severe AD, however, combination therapy appeared to be associated with reduced costs and increased QALYs compared with monotherapy with either memantine or donepezil alone. The committee agreed the level of uncertainty in the evidence meant it was hard to draw definitive conclusions from the economics alone, but again felt that the clear clinical benefits justified making recommendations for co-prescription. The stronger evidence for cost effectiveness in the severe population meant an ‘offer’ recommendation was made for that group, whilst only a ‘consider’ recommendation was made for moderate Alzheimer’s disease.
Quality of evidenceThe committee agreed that for the co-prescription review question, the evidence that was most relevant for UK practice came from the trials that compared cholinesterase inhibitors plus memantine against cholinesterase inhibitors plus placebo, in people already taking a cholinesterase inhibitor at baseline. The evidence from these trials was general of moderate to high quality, and therefore the committee was comfortable using this evidence to make strong recommendations. The committee agreed that the additional trials of cholinesterase inhibitors plus memantine versus cholinesterase inhibitor monotherapy (without a placebo) were at much higher risk of bias and therefore represented a much lower standard of evidence. They also noted that these trials were excluded from the recent Cochrane review on this topic, and therefore felt it appropriate that these trials not be included as part of the primary analysis looking at the effect of co-prescription.
The committee noted that there was also evidence on the effectiveness of adding cholinesterase inhibitors to people already taking memantine at baseline, but agreed this comparison was of much less relevance to the UK. Specifically, the technology appraisals formemantine (TA217) state that it is an option in moderate Alzheimer’s disease only if cholinesterase inhibitors are contraindicated, and therefore people should only be started on memantine monotherapy ahead of cholinesterase inhibitor monotherapy if they are contraindicated for cholinesterase inhibitors.
The committee agreed the DOMINO-AD trial (Howard 2012) was a well-conducted and robust trial that provided evidence directly applicable to the UK on the question of withdrawal of cholinesterase inhibitors in people with moderate to severe Alzheimer’s disease. They also noted that this trial was specifically designed to answer questions raised by the 2006 NICE dementia guideline, and therefore was likely to remain the best evidence available to address this question.
No evidence was found that looked at the effect of withdrawing memantine in people with severe Alzheimer’s disease, and therefore the committee agreed it was not appropriate to make any recommendations on this topic.
Other considerationsThe committee considered the practical arrangements for co-prescription. They agreed it was important to apply the recommendations made for these review questions within the context of the published NICE technology appraisal guidance (TA217) related to the use of cholinesterase inhibitors and/or memantine for the treatment of Alzheimer’s disease. They also considered the wording of these recommendations alongside the otherTA217 recommendations updated as part of this guideline, on the appropriate people to initiate treatment with cholinesterase inhibitors and/or memantine.
The committee agreed that those recommendations (which specify that treatment should only be started on the advice of someone with expertise in diagnosing and treating dementia) were to ensure that prescription is made following a correct diagnosis of dementia. However, this is no longer an important issue when considering the addition of a second medication in people who have an established dementia diagnosis and are living with more advanced stages of disease. For this reason, the committee was happy for co-prescription of these medications to be initiated in primary care, in people who already have an established diagnosis of Alzheimer’s disease and are already taking cholinesterase inhibitors.
The committee agreed that, whilst the majority of the included evidence was on donepezil, it was reasonable to assume a class effect for cholinesterase inhibitors, and therefore recommendations were made generally for cholinesterase inhibitors.

11.2.6. Recommendations

67.

Do not stop AChE inhibitors in people with Alzheimer’s disease because of disease severity alone.

68.

For people with an established diagnosis of Alzheimer’s disease who are already taking an AChE inhibitor:

  • consider memantine in addition to an AChE inhibitor if they have moderate disease
  • offer memantine in addition to an AChE inhibitor if they have severe disease.

69.

For people with an established diagnosis of Alzheimer’s disease who are already taking an AChE inhibitor, primary care prescribers may start treatment with memantine (see recommendation 68) without taking advice from a specialist clinician.

11.3. Pharmacological management of dementia with Lewy bodies

Review question

  • What is the comparative effectiveness of donepezil, galantamine, memantine and rivastigmine for cognitive enhancement in dementia associated with Parkinson’s disease?

11.3.1. Introduction

Dementia (the progressive loss of global cognitive function) is common in Parkinson’s disease; 48% to 80% of people develop dementia at some point in their condition. Traditionally, dementia developing more than 1 year after the onset of the motor symptoms of Parkinson’s disease is referred to as Parkinson’s disease dementia (PDD). Dementia developing within 1 year of the onset of motor symptoms is referred to as dementia with Lewy bodies (DLB).

The relationship between DLB and PDD is unclear, but they have many common clinical features and there is some opinion that they may be the same condition. Therefore, the committee agreed that the population included in this review question should cover people with DLB and PDD. Studies that included people with mild cognitive impairment were excluded.

The aim of this review question was to assess the comparative efficacy of pharmacological interventions for cognitive enhancement in dementia associated with Parkinson’s disease, compared with placebo or other active comparator(s). This updates the evidence reviews on:

  • Cholinesterase inhibitors for cognitive enhancement in Parkinson’s disease from the 2006 guideline on Parkinson’s disease (CG35).
  • Cholinesterase inhibitors or memantine for the treatment of cognitive symptoms of Dementia with Lewy bodies from the 2006 guideline on Dementia (CG42).
  • Cholinesterase inhibitors or memantine for the treatment of non-cognitive symptoms of dementia with Lewy bodies from the 2006 guideline on Dementia (CG42).

This updated review incorporates some studies that were included in the previous guidelines together with newly published evidence.

The review focused on identifying studies that fulfilled the conditions specified in Table 53.

Table 53. Review summary: effectiveness of pharmacological for cognitive enhancement in dementia associated with Parkinson’s disease.

Table 53

Review summary: effectiveness of pharmacological for cognitive enhancement in dementia associated with Parkinson’s disease.

For full details of the review protocol, please see Appendix C. Randomised controlled trials (RCTs) were considered to be the most appropriate study design to derive treatment effect metrics, and were therefore considered to be the highest quality within a GRADE framework. All other study designs were excluded from this review, including case–control studies, cohort studies, and case reports.

11.3.2. Evidence review

A systematic search of the literature was conducted (see appendix D) which identified 1,152 references. This search was restricted to studies published from 2005 onwards to avoid duplicates of studies considered in the previous Parkinson’s disease guideline (CG35). After removing duplicates the references were screened on their titles and abstracts and full papers of 130 references were obtained and reviewed against the inclusion and exclusion criteria in the review protocol (see appendix C).

Overall, 121 studies were excluded as they did not meet the eligibility criteria, such as not utilising a randomised-control design. The 9 remaining published papers met the eligibility criteria and were included in the review. A list of excluded studies and reasons for their exclusion is provided in appendix F.

Five RCTs included in previous guidelines on Parkinson’s disease (CG35) and Dementia (CG42) were reviewed. Of these, 2 RCTs were already included from the search (McKeith et al., 2000, Ravina et al., 2005) and 2 RCTs (Aarsland et al., 2002; Emre et al., 2004) met the present inclusion and exclusion criteria and were included. The remaining RCT (Leroi et al., 2004) was excluded as people in the study had mild cognitive impairment associated with Parkinson’s disease.

Systematic reviews identified in the literature search were also analysed to identify any published papers meeting the eligibility criteria that had not been identified in the search. No further studies were identified. 5 published papers were identified through a rerun of the literature search in June 2016, none of which were included. Therefore, a total of 11 RCTs were included in the evidence review.

Data were extracted into detailed evidence tables (see appendix E), and further summarised in GRADE profiles (appendix G).

11.3.2.1. Description of included studies

See Table 54 for a summary of included studies. References for the included studies are given in appendix I.

11.3.2.1.1. Pharmacological interventions in DLB

3 double-blind placebo-controlled RCTs assessed the effectiveness of a cholinesterase inhibitor in people with DLB:

  • donepezil (Ikeda et al., 2015, Mori et al., 2012)
  • rivastigmine (McKeith et al., 2000).

1 double-blind placebo-controlled RCT (Emre et al., 2010) assessed the effectiveness of memantine in people with DLB.

No studies assessed the effectiveness of a combination of cholinesterase inhibitor plus memantine in people with DLB.

11.3.2.1.2. Pharmacological interventions in PDD

4 double-blind placebo-controlled RCTs (reported in 5 publications) assessed the effectiveness of a cholinesterase inhibitor in people with PDD:

  • donepezil (Aarsland et al., 2002, Dubois et al., 2012, Ravina et al., 2005)
  • rivastigmine (Emre et al., 2004, Dujardin et al., 2006 [secondary publication]).

1 open-label RCT (Emre et al., 2014) assessed the effectiveness of rivastigmine capsules compared with rivastigmine patches in people with PDD.

2 double-blind placebo-controlled RCTs, reported in 3 publications (Emre et al., 2010; Leroi et al., 2009, Leroi et al., 2014 [secondary publication]) assessed the effectiveness of memantine in people with PDD.

No studies assessed the effectiveness of a combination of cholinesterase inhibitor plus memantine in people with PDD.

11.3.2.1.3. Mixed population (PDD or DLB)

1 double-blind placebo-controlled RCT assessed the effectiveness of memantine in a mixed population of people with PDD or DLB (Aarsland et al., 2009).

11.3.2.1.4. Prioritisation of outcomes

A large number of outcomes were reported in the studies, particularly those measuring cognitive function. Some outcomes were reported frequently (for example, MMSE) while others were reported only in a single small RCT. Therefore, the committee prioritised some key critical outcomes for the analyses.

Key critical outcomes prioritised by the committee were:

  • Adverse events
  • Cognitive function, measured by:
    • Mini Mental State Examination (MMSE)
    • Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)
    • Mattis Dementia Rating Scale (MDRS)
    • Delis-Kaplan Executive Functions System verbal fluency test (D-KEFS)
    • 10-point clock drawing test
    • Cognitive Drug Research computerised assessment system (CDR)
    • Brief test of attention (BTA)
  • Global assessment
  • Activities of daily living
  • Carer-reported outcomes
  • Other non-cognitive outcomes, including
    • Neuropsychiatric Inventory (NPI)
    • Unified Parkinson’s Disease Rating Scale – motor subscale (UPDRS III)

Analyses

The following analyses were conducted:

  • pharmacological interventions in people with DLB:
    • cholinesterase inhibitors versus placebo
    • memantine versus placebo
  • pharmacological interventions in people with PDD:
    • cholinesterase inhibitors versus placebo
    • memantine versus placebo
    • rivastigmine patches versus capsules
  • combined analyses – pharmacological interventions in a mixed population (PDD or DLB)
    • cholinesterase inhibitors versus placebo
    • memantine versus placebo
    • network meta-analyses of pharmacological interventions versus placebo

The combined analyses were only carried out for outcomes when data were available for both PDD and DLB populations.

For studies which had more than one active treatment arm, for example different doses, the active treatment arms were combined together to give an overall effect.

The evidence across outcomes was appraised using the GRADE framework and forest plots are presented where appropriate (see appendix G and appendix H).

Table 54. Summary of included studies.

Table 54

Summary of included studies.

11.3.3. Health economic evidence

Literature searches were undertaken to find any existing cost–utility analyses (CUAs) assessing pharmacological interventions for cognitive enhancement in dementia associated with Parkinson’s disease. In total, 344 articles were returned, of which 2 were selected as potentially relevant and retrieved for full text review. Both were included. Studies were assessed using the quality appraisal criteria as outlined in the NICE guidelines manual (NICE, 2012).

Willan et al. (2006) compared rivastigmine with placebo in people with mild PDD (MMSE 20–24), based on evidence from the EXPRESS RCT (Emre et al. 2004). The analysis concentrated solely on short-term cognitive effect, as measured by MMSE at 24 weeks, which was translated to health-related quality of life (EQ-5D) using a mapping function based on a Scandinavian population with Alzheimer’s disease (Jönsson, 2003). For further details, please see the economic evidence profile in Appendix M. The authors’ base case adopted a broad societal perspective, including an attempt to value carer time; however, disaggregated results are reported, enabling the recalculation of results with a perspective that is consistent with the NICE reference case (that is, NHS and PSS costs only). This suggests that rivastigmine is associated with an ICER of around £58,600 per QALY gained. However, this analysis comes from a time when rivastigmine was only available as a proprietary product; since then, it has become available generically and costs have decreased substantially. Therefore, to approximate the results of this CUA from a present-day perspective, the developer recalculated results by:

  • removing costs borne by patients and carers;
  • re-estimating rivastigmine drug cost, assuming the overall change is proportional to the change in price of a 28 x 3 mg pack (£2004=£34.02 [BNF 47]; £2016=£2.57 [NHS Drug Tariff Feb 2016]; reduction of 92.4%);
  • inflating all other costs from £2004/05 to £2015/16 using PSSRU hospital & community health services inflators.

This analysis estimated an ICER of approximately £16,000 per QALY gained.

Gustavsson et al. (2009) simulated a population with DLB (from which people with PDD were explicitly excluded) receiving unspecified AChE inhibitors. For further details, please see the economic evidence profile in Appendix M. The authors drew treatment effects from a UK observational audit for the first 4 months, and extrapolated these to 5 years using a Scandinavian longitudinal study in Alzheimer’s disease (Wallin et al., 2007). Additional non-cognitive symptoms (extra-pyramidal symptoms and psychosis) were assumed for DLB. The authors used 3 separate models, and compared results. The first was a reconstruction of the Southampton Alzheimer’s disease model (Loveman et al., 2006); the second was a micro-simulation model; and the third was a Markov model with 4 discrete MMSE states. When applied to people with all severities of dementia, ICERs of between £2,700 and £46,800 per QALY were estimated; when the population was limited to people with moderate dementia (MMSE 10–20), AChE inhibitors were dominant in all 3 models (that is, they were predicted to save money and improve health). Again, it was possible to estimate present-day results for these analyses, by:

  • re-estimating AChE inhibitor drug costs, assuming the original model used the cost of donepezil 10 mg daily and assumed 2 monitoring visits per year, and that the overall change in drug costs is proportional to the change in price of a 28 x 10 mg pack of donepezil (£2005=£89.06 [BNF 49]; £2016=£1.45 [NHS Drug Tariff Feb 2016]; reduction of 98.4%);
  • inflating all other costs from £2005/06 to £2015/16 using PSSRU hospital & community health services inflators

This recalculation estimated that treatment with AChE inhibitors is less costly and more effective than placebo in all analyses, regardless of population modelled or model preferred.

11.3.4. Evidence statements

11.3.4.1. Evidence statements – Dementia with Lewy bodies

11.3.4.1.1. Adverse events
Cholinesterase inhibitors

Moderate-quality evidence from 3 RCTs could not differentiate the risk of any adverse events, serious adverse events or adverse events requiring treatment withdrawal between cholinesterase inhibitors and placebo.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the risk of any adverse events, serious adverse events or adverse events requiring treatment withdrawal between memantine and placebo.

11.3.4.1.2. Cognitive function
Cholinesterase inhibitors

High-quality evidence from 3 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve cognitive function as assessed by the MMSE.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on cognitive function between memantine and placebo, as assessed by the 10-point clock drawing.

11.3.4.1.3. Global assessment
Cholinesterase inhibitors

High-quality evidence from 1 RCT suggests that, compared with placebo, donepezil significantly improves global response as assessed by CIBIC+.

High-quality evidence from 1 RCT suggests that, compared with placebo, donepezil significantly improves global response as assessed by at least minimal improvement in CIBIC+.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on global response between memantine and placebo, as assessed by ADCS-CGIC.

11.3.4.1.4. Activities of daily living
Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on activities of daily living between memantine and placebo, as assessed by ADCS-ADL.

11.3.4.1.5. Carer-reported outcomes
Cholinesterase inhibitors

High-quality evidence from 2 RCTs suggests that, compared with placebo, donepezil significantly improves carer burden as assessed by the Zarit caregiver burden interview.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on carer burden between memantine and placebo, as assessed by the Zarit caregiver burden interview.

11.3.4.1.6. Other non-cognitive outcomes
Cholinesterase inhibitors

Low-quality evidence from 3 RCTs could not differentiate the effect on neuropsychiatric symptoms between cholinesterase inhibitors and placebo, as assessed by the NPI-10 item score.

High-quality evidence from 2 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve neuropsychiatric symptoms (hallucinations, delusions, dysphoria and apathy) as assessed by the NPI-4 item score.

Low-quality evidence from 2 RCTs could not differentiate the effect on neuropsychiatric symptoms (hallucinations, cognitive fluctuation) between donepezil and placebo, as assessed by the NPI-2 item score.

Low-quality evidence from 2 RCTs could not differentiate the effect on motor symptoms between cholinesterase inhibitors and placebo, as assessed by UPDRS III.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on neuropsychiatric symptoms between memantine and placebo, as assessed by the NPI-12 item score.

Moderate-quality evidence from 1 RCT could not differentiate the effect on motor symptoms between memantine and placebo, as assessed by UPDRS III.

11.3.4.1.7. Economic evidence statements

One partially applicable cost–utility analysis with very serious limitations concluded that, in all people with DLB, AChEs improve QALYs at increased cost, with ICERs ranging from £2,700 to £46,800, depending on modelling assumptions. In a subgroup of people with moderate DLB, AChEs were found to be cost-saving. An approximation to 2016 costs suggests that, now generic AChEs are available at lower cost, treatment would be dominant in all models and all populations. The study undertook no exploration of uncertainty.

11.3.4.2. Evidence statements – Parkinson’s disease dementia

11.3.4.2.1. Adverse events
Cholinesterase inhibitors

Moderate-quality evidence from 4 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly increase the risk of any adverse events.

Moderate-quality evidence from 2 RCTs could not differentiate the risk of serious adverse events between cholinesterase inhibitors and placebo.

Moderate-quality evidence from 3 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly increase the risk of study withdrawal due to adverse events.

Moderate-quality evidence from 2 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly reduce the risk of hallucinations.

Low-quality evidence from 1 RCT could not differentiate the risk of any adverse events, serious adverse events, study withdrawal due to adverse events or hallucinations between rivastigmine patches and rivastigmine capsules.

Memantine

Moderate-quality evidence from 2 RCTs could not differentiate the risk of any adverse events, serious adverse events or study withdrawal due to adverse events between memantine and placebo.

11.3.4.2.2. Cognitive function
Cholinesterase inhibitors

High-quality evidence from 4 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve cognitive function as assessed by the MMSE.

High-quality evidence from 3 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve cognitive function as assessed by ADAS-cog.

Low- to moderate-quality evidence from 1 RCT could not differentiate the effect on cognitive function between rivastigmine patches and rivastigmine capsules at 24 weeks, as assessed by the MDRS total score, but there was a significant benefit for rivastigmine capsules at 76 weeks.

Memantine

Low-quality evidence from 1 RCT could not differentiate the effect on cognitive function between memantine and placebo, as assessed by the MMSE and by the 10-point clock drawing test.

11.3.4.2.3. Global assessment
Cholinesterase inhibitors

Moderate-quality evidence from 4 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve global function as assessed by different measures.

High-quality evidence from 3 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve global response as assessed by different measures of at least minimal improvement.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on global function between memantine and placebo, as assessed by ADCS-CGIC.

Low-quality evidence from 1 RCT could not differentiate the effect on global response between memantine and placebo, as assessed by at least minimal improvement in CIBIC+.

11.3.4.2.4. Activities of daily living
Cholinesterase inhibitors

High-quality evidence from 2 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve activities of daily living as assessed by different ADL measures.

Low- to moderate-quality evidence from 1 RCT could not differentiate the effect on activities of daily living between rivastigmine patches and rivastigmine capsules at 24 weeks, as assessed by ADCS-ADL, but there was a significant benefit for rivastigmine capsules at 76 weeks.

Memantine

Moderate-quality evidence from 1 RCT could not differentiate the effect on activities of daily living between memantine and placebo, as assessed by ADCS-ADL.

11.3.4.2.5. Carer-reported outcomes
Memantine

Moderate-quality evidence from 2 RCTs could not differentiate the effect on carer burden between memantine and placebo, as assessed by the Zarit caregiver burden interview.

11.3.4.2.6. Other non-cognitive outcomes
Cholinesterase inhibitors

High-quality evidence from 2 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve neuropsychiatric symptoms as assessed by the NPI-10 item score.

Low- to moderate-quality evidence from 1 RCT could not differentiate the effect on neuropsychiatric symptoms between rivastigmine patches and rivastigmine capsules at 24 weeks, as assessed by the NPI-10 item score, but there was a significant benefit for rivastigmine patches at 76 weeks.

Low-quality evidence from 2 RCTs could not differentiate the effect on motor symptoms between donepezil and placebo, as assessed by UPDRS III.

Low-quality evidence from 1 RCT could not differentiate the effect on motor symptoms between rivastigmine patches and rivastigmine capsules, as assessed by UPDRS III.

Memantine

Moderate-quality evidence from 2 RCTs could not differentiate the effect on neuropsychiatric symptoms (NPI-10 item or NPI-12 item scores) or motor symptoms (UPDRS III) between memantine and placebo.

11.3.4.2.7. Economic evidence statements

One partially applicable cost–utility analysis with very serious limitations explored proprietarily-priced rivastigmine for the treatment of PDD. It concluded that rivastigmine is likely to improve quality-adjusted life expectation and may reduce overall costs. However, when an NHS and PSS perspective is adopted, rivastigmine is no longer cost-saving, with an ICER of £58,600/QALY. An approximation to 2016 costs suggests that, now generic rivastigmine is available at lower cost, it would be associated with an ICER of around £16,000/QALY.

11.3.4.3. Evidence statements – mixed population (PDD or DLB)

11.3.4.3.1. Adverse events
Cholinesterase inhibitors

High-quality evidence from 7 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly increase the risk of any adverse events.

Moderate-quality evidence from 5 RCTs could not differentiate the risk of serious adverse events between cholinesterase inhibitors and placebo.

High-quality evidence from 6 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly increase the risk of adverse events requiring treatment withdrawal.

Memantine

Low- to moderate-quality evidence from 2 RCTs could not differentiate the risk of any adverse events, serious adverse events or study withdrawal due to adverse events.

11.3.4.3.2. Cognitive function
Cholinesterase inhibitors

High-quality evidence from 8 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve cognitive function as assessed by the MMSE.

Memantine

Low-quality evidence from 2 RCTs could not differentiate the effect on cognitive function between memantine and placebo, as assessed by the MMSE.

11.3.4.3.3. Global assessment
Cholinesterase inhibitors

Moderate-quality evidence from 5 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve global function as assessed by different measures.

High-quality evidence from 4 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve global response as assessed by different measures of at least minimal improvement.

Memantine

Moderate-quality evidence from 2 RCTs suggests that, compared with placebo, memantine significantly improves global function as assessed by different measures.

11.3.4.3.4. Activities of daily living
Memantine

Moderate-quality evidence from 2 RCTs could not differentiate the effect on activities of daily living between memantine and placebo, as assessed by different ADL measures.

11.3.4.3.5. Carer-reported outcomes
Memantine

Moderate-quality evidence from 2 RCTs could not differentiate the effect on carer burden between memantine and placebo, as assessed by the Zarit caregiver burden interview.

11.3.4.3.6. Other non-cognitive outcomes
Cholinesterase inhibitors

High-quality evidence from 5 RCTs suggests that, compared with placebo, cholinesterase inhibitors significantly improve neuropsychiatric symptoms as assessed by the NPI-10 item score.

Low-quality evidence from 4 RCTs could not differentiate the effect on motor symptoms between donepezil and placebo, as assessed by UPDRS III.

Memantine

Moderate-quality evidence from 3 RCTs could not differentiate the effect on neuropsychiatric symptoms between memantine and placebo, as assessed by the NPI-10 item or NPI-12 item scores.

Moderate-quality evidence from 3 RCTs could not differentiate the effect on motor symptoms between memantine and placebo, as assessed by UPDRS III.

11.3.4.3.7. Network meta-analyses

Moderate- to high-quality evidence from a network meta-analysis of 9 RCTs showed that cholinesterase inhibitors are associated with a significant increase in any adverse events, compared with placebo, but the data could not differentiate between memantine compared with placebo or cholinesterase inhibitors.

Moderate-quality evidence from a network meta-analysis of 7 RCTs could not differentiate the rates of serious adverse events between any treatment alternative compared with placebo, or between cholinesterase inhibitors and memantine.

Low- to high-quality evidence from a network meta-analysis of 8 RCTs showed that cholinesterase inhibitors are associated with a significant increase in treatment withdrawal due to adverse events, compared with placebo, but the data could not differentiate between memantine compared with placebo or cholinesterase inhibitors.

Low- to high-quality evidence from a network meta-analysis of 10 RCTs showed that cholinesterase inhibitors are associated with a significant improvement in cognitive function assessed by the MMSE, compared with placebo, but the data could not differentiate between memantine compared with placebo or cholinesterase inhibitors.

Moderate- to high-quality evidence from a network meta-analysis of 7 RCTs showed that cholinesterase inhibitors are associated with a significant improvement in global function, compared with placebo, but the data could not differentiate between memantine compared with placebo or cholinesterase inhibitors.

Moderate- to high-quality evidence from a network meta-analysis of 8 RCTs showed that cholinesterase inhibitors are associated with a significant improvement in neuropsychiatric symptoms, compared with placebo, but the data could not differentiate between memantine compared with placebo or cholinesterase inhibitors.

Low- to moderate-quality evidence from a network meta-analysis of 7 RCTs could not differentiate the effect on motor symptoms between any treatment alternative compared with placebo, or between cholinesterase inhibitors and memantine.

11.3.5. Evidence to recommendations

Relative value of different outcomesCognitive outcomes were critical to decision-making for this review question. Many different cognitive outcomes were reported in the studies; therefore the committee prioritised those outcomes where more data were available to inform their decision-making. MMSE and ADAS-cog were the most frequently reported cognitive outcomes. However, they recognised the limitations of, for example, MMSE, as a measure of the effectiveness of medication. Frequently, clinicians may be looking for stability, rather than an actual improvement in cognitive function. The committee also recognised that treatments for dementia may have important benefits in non-cognitive outcomes, such as global function, activities of daily living, carer burden and behavioural symptoms.
Trade-off between benefits and harmsThe committee agreed that the evidence overall suggests that the effectiveness of pharmacological interventions is similar in people with PDD and DLB. This supports their original assertion about the similarity between these 2 conditions. The effectiveness of these interventions also appears to be broadly consistent with the effects observed in Alzheimer’s disease (AD). Most RCTs ranged from 12 to 24 weeks, which the committee recognised was a short duration for a long-term degenerative disease. The committee was also aware that no pharmacological interventions are licensed for managing DLB.
Cholinesterase inhibitors
In the previous guideline, the committee was aware that only 1 RCT was identified (McKeith et al., 2000) which showed no significant improvement in cognitive function with rivastigmine, compared with placebo. The new evidence identified for this guideline update shows a significant improvement in cognitive function and other important outcomes with cholinesterase inhibitors, compared with placebo. The committee recognised that caution was needed interpreting the outcomes of RCTs in isolation and patient and clinician factors also needed to be considered.
Overall, evidence was identified for donepezil and rivastigmine; no significant differences were observed between the 2 treatments for any of the outcome measures. The committee discussed whether these results were generalisable for all cholinesterase inhibitors. They were concerned that no efficacy or safety data were available for galantamine in people with DLB, but were aware of data to support its use in AD.
The committee did not expect significant differences to be observed on pharmacological grounds with galantamine compared with either donepezil or rivastigmine. However, they did have concerns about making a recommendation that included galantamine in the absence of evidence, and therefore a first line recommendation was made for donepezil and rivastigmine, with galantamine only given as an option if these agents are not tolerated.
The committee discussed their experience of differences between the cholinesterase inhibitors in their clinical practice. The committee’s experience suggests that donepezil is generally better tolerated than rivastigmine. Rivastigmine is generally better in treating neuropsychiatric symptoms. This is also supported by trends observed in the evidence review, although possible differences observed did not reach conventional levels of statistical significance. In the committee’s view, galantamine is not widely used in practice, compared with donepezil and rivastigmine. Furthermore, clinicians may take acquisition cost into account when making decisions with people about the choice of treatment. Galantamine is significantly more costly that donepezil or rivastigmine.
The committee discussed the importance of appropriate dose titration when taking cholinesterase inhibitors. Donepezil has a simpler dose titration regime, which may be an important consideration for individual patients. The committee had concerns that many people did not have the initial dose of cholinesterase inhibitor titrated up to the maximum tolerated dose. As cholinesterase inhibitors are being used ‘off label’ in people with DLB, there is no recommended dose. However, the committee agreed that they would expect it to be consistent with the doses licensed for Alzheimer’s disease. To reflect the evidence base, the committee agreed that the dose of cholinesterase inhibitor should be titrated up to the maximum tolerated dose.
The committee recognised that the evidence identified was in people with mild to moderate DLB. In their clinical experience, the committee was aware of cholinesterase inhibitors being started in people with mild or moderate DLB and subsequently stopped in some patients because they had reached the severe stage of the disease. They agreed that treatment should not be stopped on this basis alone. The committee were concerned about the detrimental effects observed in many people in clinical practice when cholinesterase inhibitors were stopped. Although, they were also mindful that some people stay on cholinesterase inhibitors indefinitely without appropriate review.
Some people present with DLB in the advanced stages of the disease. The committee recognised this required careful discussion and consideration on a case-by-case basis, weighing up the possible risks and benefits of treatment. The committee emphasised the importance of medicines being considered appropriately at the right time and right stage of disease.
The RCT (Emre et al., 2014) which compared rivastigmine patches with rivastigmine capsules found that the long-term (76-week) effect on cognitive function was significantly better with capsules. However, the committee felt that patient factors such as medicines adherence need to be considered on an individual patient basis. There were no other clinically meaningful differences between patches and capsules, including the risk of adverse effects.
Therefore, the committee concluded that patches may be an option to consider for some people, but could not make a recommendation specifically on their use.
The committee was confident that there is clear evidence of benefit with donepezil and rivastigmine in improving cognition, global function, activities of daily living, carer burden and neuropsychiatric symptoms at a cost that is dominant over placebo. The committee concluded that an ‘offer’ recommendation should be made to reflect the evidence-base. The recommendation to offer treatment applies to people with mild to moderate DLB as there was no evidence of starting treatment in people with severe DLB. The committee also agreed that the recommendation should inform clinicians that donepezil and rivastigmine are not licensed for DLB.
While the committee could not be certain about the effect of galantamine in people with mild to moderate DLB, they agreed that galantamine may be considered for people with mild to moderate DLB if donepezil or rivastigmine are not tolerated. The committee also agreed that the recommendation should inform clinicians that galantamine is not licensed for DLB.
Furthermore, although no RCT evidence was identified, the committee discussed and agreed by consensus that a consider recommendation should be made for donepezil and rivastigmine in people with severe DLB. They noted that although no evidence was found, there was no biological or pharmacological reason to expect that the effect would be less in people with severe dementia, and it was therefore appropriate to extrapolate the evidence to that population.
Memantine
The committee recognised that there were far less data for memantine versus placebo, compared with cholinesterase inhibitor versus placebo. The committee was concerned that memantine was only significantly better than placebo on the global assessment scales. However, the committee recognised the limitations of the available data. The committee did agree, however, that it was appropriate to make a ‘consider’ level recommendation for memantine, but only if cholinesterase inhibitors are not tolerated or are contraindicated.
Combination treatment
Although no studies were identified where participants were randomised to combination treatment with a cholinesterase inhibitor and memantine, the committee recognised that this option was being used in practice. From their clinical experience, some people do respond to combination treatment. As there was no evidence, the committee felt this was an important priority for research and therefore made a research recommendation.
Trade-off between net health benefits and resource useThe committee agreed that the economic evidence presented had very serious limitations, and lacked direct applicability to the question, particularly because they took place at a time before the generic versions of the drugs were available. However, they also noted that, once appropriate adjustments had been made to the price of the drugs, the fact that cholinesterase inhibitors came out as consistently either cost-effective or cost-saving compared with placebo added additional evidence to support the recommendations made.
Quality of evidenceBased on the clear and consistent findings for donepezil and rivastigmine, the committee were confident in making an ‘offer’ recommendation for people with mild to moderate DLB. The evidence-base for memantine was of lower quality and despite a trend towards improvement the committee could not be confident of the effectiveness of memantine.
Other considerationsThe committee noted that the recommendations made here were broadly consistent with those in the NICE Parkinson’s disease guideline on managing Parkinson’s disease dementia. This was agreed to be important as the evidence did not suggest there was any reason to expect the treatments to have different levels of effectiveness in the two groups, and agreed it was appropriate to add a cross-reference to those recommendations in the guideline.

11.3.6. Recommendations

70.

Offer donepezil or rivastigmine to people with mild to moderate dementia with Lewy bodies. a

71.

Only consider galantamineb for people with mild to moderate dementia with Lewy bodies if donepezil and rivastigmine are not tolerated.

72.

Consider donepezil or rivastigmine for people with severe dementia with Lewy bodies. a

73.

Consider memantinec for people with dementia with Lewy bodies if AChE inhibitorsd are not tolerated or are contraindicated.

74.

For guidance on pharmacological management of Parkinson’s disease dementia, see Parkinson’s disease dementia in the NICE guideline on Parkinson’s disease.

11.3.7. Research recommendations

8.

What is the effectiveness of combination treatment with a cholinesterase inhibitor and memantine for people with dementia with Lewy bodies if treatment with a cholinesterase inhibitor alone is not effective or no longer effective?

For more details on the research recommendation made, and the rationale behind it, see appendix L.

11.4. Cholinesterase inhibitors and memantine for types of dementia other than typical Alzheimer’s disease

Review question

  • How effective are cholinesterase inhibitors and memantine for types of dementia other than typical Alzheimer’s disease?

11.4.1. Introduction

The aim of this review question was to determine the comparative effectiveness of donepezil, galantamine, rivastigmine and memantine for cognitive enhancement in dementia types other than typical Alzheimer’s disease. The use of cholinesterase inhibitors and memantine for Parkinson’s disease dementia is covered in the Parkinson’s disease guideline and dementia with Lewy bodies has previously been considered in section 11.3. Therefore these 2 types of dementia were excluded from the evidence review for this question.

The review identified studies that fulfilled the conditions specified in Table 55. For full details of the review protocols, see Appendix C.

Table 55. Review summary: cholinesterase inhibitors and memantine for non-Alzheimer’s dementia.

Table 55

Review summary: cholinesterase inhibitors and memantine for non-Alzheimer’s dementia.

11.4.2. Evidence review

A systematic search identified 1,772 references. The references were screened on their titles and abstracts and 99 references were ordered for full text review. Eighty-three papers were subsequently excluded because they did not fit the inclusion criteria (see Appendix F for a detailed list of excluded studies and reasons for their exclusion). Sixteen randomised controlled trials were included in the evidence review.

11.4.2.1. Description of included studies

All included papers considered treatment versus placebo. Nine studies were included for vascular dementia (3 studies compared donepezil versus placebo, 2 studies compared galantamine versus placebo, 2 studies compared rivastigmine versus placebo and 2 studies compared memantine versus placebo).

Three studies were included for frontotemporal dementia (1 paper compared galantamine versus placebo and 2 papers compared memantine versus placebo). The data was stratified into participants with behavioural variant frontotemporal dementia and those with semantic variant frontotemporal dementia.

Three studies were included for cognitive impairment in people with multiple sclerosis (1 study compared donepezil versus placebo, 1 paper considered rivastigmine versus placebo and 1 paper considered memantine versus placebo).

One study was included for Huntington’s disease and compared rivastigmine versus placebo.

A summary of the characteristics of the included studies is provided in Table 56. Data from the included studies were extracted into evidence tables. Please see Appendix E for the full evidence tables, and for the full GRADE profiles please see Appendix G. References for the included studies are given in appendix I.

11.4.3. Health economic evidence

A total of 381 citations was returned from the search for this question. Following review of titles and abstracts, the full texts of 10 studies were retrieved for detailed consideration, but none met the inclusion criteria. One study, Wong et al. (2009) was considered to be potentially relevant, presenting dominant results from a cost-effectiveness analysis, permissible in some circumstances by Developing NICE guidelines (2014). However, its short time horizon (24-28 weeks) and limited costing perspective (only intervention costs and physician costs), in addition to the absence of QALYs, led to the conclusion that the study would not be appropriate to support decision-making. Therefore, no cost–utility analyses were identified for this question.

11.4.3.1. Description of included studies

Table 56. Included studies.

Table 56

Included studies.

11.4.4. Evidence statements

11.4.4.1. Vascular dementia

11.4.4.1.1. Cholinesterase inhibitors versus placebo

Moderate- to high-quality evidence found global cognition (measured by the MMSE, ADASCog, ADAS-Cog-11, VaDAS-cognitive subscale) was significantly better in people receiving cholinesterase inhibitors compared with placebo, but low-quality evidence found it could not be differentiated when measured by the EXIT-25.

High-quality evidence found neuropsychiatric symptoms (measured by the NPI) were significantly worse in people receiving cholinesterase inhibitors compared with placebo, but moderate-quality evidence found they could not be differentiated when measured by the NPI-12.

Moderate- to high-quality evidence found global assessment (measured by the Clinician’s Global Impression of Change, Clinical Dementia Rating-sum of boxes) was significantly better in people receiving cholinesterase inhibitors compared with placebo, but could not be differentiated when measured by the Vascular Dementia Assessment Scale or Global Deterioration Scale.

High-quality evidence found functional ability (measured by the Alzheimer’s Disease Functional Assessment and Change Scale) was significantly better in people receiving cholinesterase inhibitors compared with placebo, but very low- to moderate-quality evidence found it could not be differentiated when measured by the ADCS-ADL, Instrumental Activities of Daily Living, Functional Assessment Battery or the Disability assessment for Dementia.

High-quality evidence found the numbers of adverse events and discontinuations due to adverse events were significantly higher in people receiving cholinesterase inhibitors compared with placebo, but low- to moderate-quality evidence could not differentiate the numbers of deaths or serious adverse events.

11.4.4.1.2. Memantine versus placebo

High-quality evidence found global cognition (measured by the MMSE, ADAS-Cog) was significantly better in people receiving memantine compared with placebo.

Moderate-quality evidence could not differentiate behavioural symptoms (measured by the Nurses’ Observational Scale for Geriatric Patients) between people receiving memantine compared with placebo.

Moderate-quality evidence could not differentiate global assessment (measured by the Gottfries-Bråne-Steen scale or CIGIC) between people receiving memantine compared with placebo.

Low- to high-quality evidence could not differentiate the numbers of adverse events or serious adverse events between people receiving memantine compared with placebo.

11.4.4.1.3. Network meta-analyses

Moderate- to high-quality evidence found cognition (measured by the MMSE, ADAS-Cog) was significantly better in people receiving either cholinesterase inhibitors or memantine compared with placebo, but could not differentiate scores between cholinesterase inhibitors and memantine.

Moderate-quality evidence found the numbers of adverse events was higher in people receiving cholinesterase inhibitors than placebo, but could not differentiate numbers between memantine and placebo or cholinesterase inhibitors and memantine.

Moderate-quality evidence could not differentiate the numbers of serious adverse events between cholinesterase inhibitors, memantine and placebo.

11.4.4.2. Behavioural variant frontotemporal dementia

11.4.4.2.1. Cholinesterase inhibitors versus placebo

Low-quality evidence could not differentiate global cognition (measured by the MMSE or DRS), functional ability (measured by the Functional Assessment Battery or ACDS-ADL) or neuropsychiatric symptoms (measured by the NPI) between people receiving cholinesterase inhibitors compared with placebo.

Low-quality evidence could not differentiate the numbers of adverse events or discontinuations due to adverse events between people receiving cholinesterase inhibitors compared with placebo.

11.4.4.3. Memantine versus placebo

Low- to moderate-quality evidence could not differentiate global cognition (measured by the MMSE, Mattis Dementia Rating Scale, EXIT-25), neuropsychiatric symptoms (measured by the NPI), global assessment (measured by CIBIC, CGIC, CDR-SB), motor function (measured by the Unified Parkinson’s disease rating scale) or carer burden (measured by the ZBI) between people receiving memantine compared with placebo.

Very low to low-quality evidence could not differentiate the numbers of adverse events, serious adverse events, deaths or discontinuations due to adverse events between people receiving memantine compared with placebo.

11.4.4.4. Network meta-analyses

Moderate-quality evidence could not differentiate global cognition (measured by the MMSE), neuropsychiatric symptoms (measured by the NPI) or the numbers of adverse events or discontinuations due to adverse events between cholinesterase inhibitors, memantine and placebo.

11.4.4.5. Semantic variant frontotemporal dementia

11.4.4.5.1. Memantine versus placebo

Low-quality evidence could not differentiate global cognition (measured by the MMSE, EXIT-25), neuropsychiatric symptoms (measured by the NPI), global assessment (measured by the CIBIC, CGIC, CDR-SB) or motor function (measured by the Unified Parkinson’s disease rating scale) between people receiving memantine compared with placebo.

Low-quality evidence could not differentiate the number of serious adverse events between people receiving memantine compared with placebo.

11.4.4.6. Cognitive impairment in people with multiple sclerosis

11.4.4.6.1. Cholinesterase inhibitors versus placebo

Moderate-quality evidence could not differentiate global cognition (measured by the Selective Reminding Test, Multiple Sclerosis Inventarium Cognition Score), domain-specific cognition (measured by the Symbol Digit Modalities Test, Paced Auditory Serial Addition Test, Faces Symbol Test) or depressive symptoms (measured by the Montgomery-Åsberg Depression Rating Scale) between people receiving cholinesterase inhibitors compared with placebo.

Low to moderate-quality evidence could not differentiate the numbers of adverse events, serious adverse events, discontinuations due to adverse events or multiple sclerosis relapses between people receiving cholinesterase inhibitors compared with placebo.

11.4.4.6.2. Memantine versus placebo

Moderate-quality evidence could not differentiate domain-specific cognition (measured by the Paced Auditory Serial Addition Test) or multiple sclerosis progression (measured by the Expanded Disability Status Scale) between people receiving memantine compared with placebo.

High-quality evidence found the number of adverse events was significantly higher in people receiving memantine compared with placebo, but low-quality evidence could not differentiate the number of serious adverse events.

11.4.4.6.3. Network meta-analyses

High-quality evidence found significantly higher numbers of adverse events in people receiving memantine compared with either cholinesterase inhibitors or placebo, but moderate-quality evidence could not differentiate cognition (measured by the Paced Auditory Serial Addition Test) or the numbers of discontinuations due to adverse events.

11.4.4.7. Huntington’s disease

11.4.4.7.1. Cholinesterase inhibitors versus placebo

Moderate-quality evidence found domain-specific cognition (measured by the Tower of London total times score) was worse in people receiving cholinesterase inhibitors compared with placebo, but low-quality evidence found it could not be differentiated when measured by the Symbol Digit Modalities Test, Tower of London total moves score, Rey Complex Figure Test - delayed recall, Rey Complex Figure Test - immediate recall or Ruff Figural Fluency Test - unique designs.

11.4.4.8. Health economic evidence

No health economic evidence was identified for this review question.

11.4.5. Evidence to recommendations

Relative value of different outcomesThe committee agreed that the following measures (where available) would be prioritised across the various outcome domains:
  • Global cognition (MMSE, ASAS-cog)
  • Global assessment (Clinical Dementia Rating scale)
  • Functional ability (Disability Assessment for Dementia)
  • Neuropsychiatric symptoms (NPI)
  • Dementia-specific quality of life (DEMQOL)
  • Generic health-related quality of life (EQ-5D)
No outcome was prioritised for domain-specific cognition, as it was agreed that the different outcome measures were often measuring different aspects of cognition, and therefore it would not be appropriate to prioritise 1 measure.
Trade-off between benefits and harmsVascular dementia
The committee recognised there was some evidence of cognitive benefits with treatment, although these were small and often below levels considered clinically significant, such as 1.4 points on the MMSE. Additionally, information on how these differences affect functional ability or quality of life was limited, and the group noted that NPI scores were worse with cholinesterase inhibitors. It was noted that many of the studies (those using a definition of possible or probable vascular dementia) may have included people with underlying Alzheimer’s disease, and the committee agreed any effect is likely to be greater in this population than in people with pure vascular dementia, a finding supported by 1 study reporting data on Alzheimer’s disease with cerebrovascular legions (which showed an improvement of 3.2 points in the ADAS-cog with treatment, compared with a 1.6 point improvement in people with pure vascular dementia). The committee agreed therefore that it was only clinically justified to consider these drugs in groups of people with vascular dementia where there is clinical suspicion of there also being the presence of another form of dementia where these drugs have been shown to be effective and are recommended by NICE (Alzheimer’s disease, Parkinson’s disease dementia, dementia with Lewy Bodies). This recommendation was agreed to be important as people may initially be diagnosed with one form of dementia (such as vascular dementia), and then not receive a formal diagnosis of another dementia subtype at a later date. The committee discussed the evidence base and agreed that it was not sufficiently robust to enable making any recommendations about the comparative effectiveness of cholinesterase inhibitors and memantine.
Frontotemporal dementia
The committee noted the evidence base for this population was far smaller than in the population with vascular dementia, and there was no biological hypothesis as to why these treatments would be expected to provide a benefit (there is not usually a cholinergic deficit in people with frontotemporal dementia). No evidence was found of benefit for the use of cholinesterase inhibitors or memantine in behavioural variant or semantic variant frontotemporal dementia, and therefore the committee agreed that, owing to the potential adverse effects associated with these drugs, their use could not be justified in this group. Hence a ‘do not use’ recommendation was made; however, the committee recognised that it was unlikely that cholinesterase inhibitors or memantine were commonly used in this group, and that the drugs are not licensed for frontotemporal dementia. The committee agreed it was appropriate to extend the recommendation to the third subtype of frontotemporal dementia (progressive non-fluent aphasia) as there is also no underlying cholinergic deficit in this group, and therefore there is no reason to expect that the drugs would be more effective in this group than the other subtypes of frontotemporal dementia.
Multiple sclerosis
The committee discussed whether cognitive impairment associated with multiple sclerosis should be included in this section of the guideline. The committee recognised that the definition of cognitive impairment may not be as clearly defined as in other conditions. They noted there were additional challenges in interpreting the evidence due to the physical impairments associated with the condition when symptoms of cognitive impairment appear. The committee noted that the population in the included studies was younger than other subtypes but agreed it was important to include people with multiple sclerosis because the evidence associated with adverse events meant it was important to prevent clinicians from prescribing treatment with cholinesterase inhibitors or memantine to people in this group. They therefore agreed to make a ‘do not use’ recommendation.
Huntington’s disease
The committee noted that the evidence was drawn from a small pilot study and therefore agreed that it would not be appropriate to make any recommendations for this population.
Trade-off between net health benefits and resource useNo economic evidence was identified for this review question and health economic modelling was not prioritised. The committee noted that all of the named drugs are now generic and off patent and therefore it is unlikely that any significant resource implications would arise from the recommendations made for their use. They also noted that cholinesterase inhibitors and memantine have been found to be cost effective in Alzheimer’s disease, Parkinson’s Disease dementia and dementia with Lewy Bodies, where they have shown clinical benefit. Therefore, it is reasonable to infer that, in any cases where using cholinesterase inhibitors is clinically effective, the cost of the drugs will be justified.
Quality of evidenceThe committee considered making a research recommendation around vascular dementia (now we are better able to diagnose the subtype of people with pure vascular dementia). However, large RCTs have already been conducted in this group (even if these did not always measure the outcomes we would want nowadays - functional ability and quality of life) so it was felt unlikely that such studies would be conducted.
The committee agreed the quality of evidence for vascular dementia was based upon a number of large clinical trials but recognised the evidence was poor for other subtypes, mainly due to the size of the studies.
Other considerationsThe committee agreed that there is generally a need for more research in vascular dementia, but felt the focus is now more on disease modifying agents rather than symptom focused and therefore agreed this was not the forum to pursue such research, as there is not yet sufficient evidence to know which medicines are worth testing for disease modifying purposes.

11.4.6. Recommendations

75.

Only consider AChE inhibitorse or memantinef to people with vascular dementia if they have suspected comorbid Alzheimer’s disease, Parkinson’s disease dementia or dementia with Lewy bodies.

76.

Do not offer AChE inhibitors or memantine for people with frontotemporal dementia. g

77.

Do not offer AChE inhibitors or memantine to people with cognitive impairment caused by multiple sclerosis.

Footnotes

a

At the time of publication (June 2018), donepezil and rivastigmine did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information

b

At the time of publication (June 2018), galantamine did not have a UK marketing authorisation for this indication.

The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information

c

At the time of publication (June 2018), memantine did not have a UK marketing authorisation for this indication.

The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.

d

At the time of publication (June2018), the AChE inhibitors donepezil, rivastigmine and galantamine did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information

e

At the time of publication (June 2018), the AChE inhibitors donepezil, rivastigmine and galantamine did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.

f

At the time of publication (June 2018), memantine did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.

g

Note that logopenic aphasia, which has previously been included in some diagnostic guidelines for frontotemporal dementia, has now been shown to most commonly be caused by Alzheimer’s disease.

Copyright © NICE 2018.
Bookshelf ID: NBK536484
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