A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer's disease and agitated behaviours: the HTA-SYMBAD trial.

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting: Twenty-six UK secondary care centres. Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration: This trial is registered as ISRCTN17411897/NCT03031184. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

It is common for people with Alzheimer's disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer's disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer's disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer's disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia.

Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.

OBJECTIVES: To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up. DESIGN: Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo. SETTING: Community settings and care homes in 26 UK centers. PARTICIPANTS: People with probable or possible Alzheimer's disease and agitation. MEASUREMENTS: Primary outcome included incremental cost of participants' health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants' and unpaid carers' gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives. RESULTS: One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment. CONCLUSIONS: On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.

Cost-Effectiveness of an Online Intervention for Caregivers of People Living With Dementia.

OBJECTIVES: Little evidence exists on costs or cost-effectiveness of online interventions for caregivers of people living with dementia. We aimed to assess cost-effectiveness of online cognitive behavioral therapy (CBT) for dementia caregivers with mild-to-moderate depression/anxiety, with or without telephone support, relative to a psychoeducational control treatment. DESIGN: Cost-effectiveness study of data from 3-armed randomized controlled trial comparing computerized CBT (cCBT) or telephone-supported cCBT (cCBT+Telephone) to modular online educational program on dementia (Psychoeducation). SETTING AND PARTICIPANTS: UK-resident adult dementia caregivers with mild-to-moderate anxiety/depression. COST-EFFECTIVENESS ANALYSIS: We calculated health and social care costs, from participant-reported data collected at baseline, 12, 26 weeks, costs of intervention delivery. We examined 3 outcomes: cost of one-point reduction in General Health Questionnaire-12 (GHQ-12) rating at 26-weeks, cost of prevented "caseness" on GHQ-12 at 26 weeks, and cost per quality-adjusted life year (QALY) based on Short Form-6 Dimensions (SF-6D) over 26 weeks. RESULTS: Data from 176 participants (44 cCBT, 91 cCBT+Telephone, 41 Psychoeducation) were analyzed. Costs did not differ between cCBT and Psychoeducation; costs were £125 higher in cCBT+Telephone. Control and intervention groups did not differ on GHQ-12. Caseness was lower in cCBT+Telephone than Psychoeducation; cost of preventing a case was £610, and probability of cost-effectiveness on this outcome reached 98.5% at willingness to pay (WTP) of £12,900. Mean QALY did not differ between cCBT+Telephone and Psychoeducation. QALY gain in cCBT was 0.01 (95% CI 0.001, 0.021). Cost per QALY was £8130. Although base case probability of cost-effectiveness of cCBT was 93% at WTP-per-QALY of £27,600, sensitivity analyses suggested cCBT+Telephone was the more cost-effective. CONCLUSIONS AND IMPLICATIONS: We report preliminary evidence for adopting telephone-supported online CBT. This may be cost-effective in preventing a case of mental health disorder if, absent a societally accepted WTP threshold for this outcome, payers are willing to pay £12,900. Future research should investigate whether supported/unsupported online CBT improves health-related quality of life.

PERFECTED enhanced recovery pathway (PERFECT-ER) versus standard acute hospital care for people after hip fracture surgery who have cognitive impairment: a feasibility cluster randomised controlled trial.

OBJECTIVES: Assess feasibility of a cluster randomised controlled trial (RCT) to measure clinical and cost-effectiveness of an enhanced recovery pathway for people with hip fracture and cognitive impairment (CI). DESIGN: Feasibility trial undertaken between 2016 and 2018. SETTING: Eleven acute hospitals from three UK regions. PARTICIPANTS: 284 participants (208 female:69 male). INCLUSION CRITERIA: aged >60 years, confirmed proximal hip fracture requiring surgical fixation and CI; preoperative AMTS ≤8 in England or a 4AT score ≥1 in Scotland; minimum of 5 days on study ward; a 'suitable informant' able to provide proxy measures, recruited within 7 days of hip fracture surgery. EXCLUSION CRITERIA: no hip surgery; not expected to survive beyond 4 weeks; already enrolled in a clinical trial. INTERVENTION: PERFECT-ER, an enhanced recovery pathway with 15 quality targets supported by a checklist and manual, a service improvement lead a process lead and implemented using a plan-do-study-act model. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility outcomes: recruitment and attrition, intervention acceptability, completion of participant reported outcome measures, preliminary estimates of potential effectiveness using mortality, EQ-5D-5L, economic and clinical outcome scores. RESULTS: 282 participants were consented and recruited (132, intervention) from a target of 400. Mean recruitment rates were the same in intervention and control sites, (range: 1.2 and 2.7 participants/month). Retention was 230 (86%) at 1 month and 54%(144) at 6 months. At 3 months a relatively small effect (one quarter of an SD) was observed on health-related quality of life of the patient measured with EQ-5D-5L proxy in the intervention group. CONCLUSION: This trial design was feasible with modifications to recruitment. Mechanisms for delivering consistency in the PERFECT-ER intervention and participant retention need to be addressed. However, an RCT may be a suboptimal research design to evaluate this intervention due to the complexity of caring for people with CI after hip fracture. TRIAL REGISTRATION NUMBER: ISRCTN99336264.

Development and assessment of a brief screening tool for psychosis in dementia.

INTRODUCTION: Hallucinations and delusions (H+D) are common in dementia, but screening for these symptoms-especially in busy clinical practices-is challenging. METHODS: Six subject matter experts developed the DRP3™ screen, a novel valid tool to detect H+D in dementia, assessed its content validity through alignment with DRP reference assessments (Scale for the Assessment of Positive Symptoms-Hallucinations + Delusions, Neuropsychiatric Inventory-Questionnaire, International Psychogeriatric Association Criteria), and retrospectively investigated its ability to detect H+D in HARMONY trial (NCT03325556) enrollees. RESULTS: All items from three reference assessments demonstrated significant agreement with the DRP3 screen among raters (P < .0001). Retrospectively applying the DRP3 screen to HARMONY identified all (N = 392) trial enrollees. DISCUSSION: The DRP3 screen, comprising three yes/no questions, is a content-valid tool for detecting H+D in dementia that aligned with current reference assessments and successfully identified trial participants when retrospectively applied to a completed trial. Within busy practice constraints, the DRP3 screen provides a brief tool for sensitive detection of H+D in patients with dementia.

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia: a series of cohort studies.

BACKGROUND: Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. OBJECTIVES: To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. DESIGN: A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. DATA SOURCES: Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. SETTING: Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England. PARTICIPANTS: Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. INTERVENTIONS: The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. MAIN OUTCOME MEASURES: Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. RESULTS: The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. LIMITATIONS: Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. CONCLUSIONS: We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. FUTURE WORK: More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. STUDY REGISTRATION: This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.

WHAT WAS THE PROBLEM?: Poor sleep is common in people living with dementia. It can worsen their own and their carer's quality of life. Sleeping tablets called Z-drugs (zolpidem, zopiclone and zaleplon) are often given to people with dementia. Some studies suggest that Z-drugs may be harmful, but no studies have looked into the effects of Z-drugs for people with dementia. Good sleep is important, but we need to understand if Z-drugs cause harm. WHAT DID WE DO?: Using existing medical records, we compared the quality of life, memory and number of falls, infections, strokes, broken bones and deaths for a group of people living with dementia taking a Z-drug, with those for a group not taking any sleep drug. WHAT DID WE FIND?: Z-drug users were no more likely to suffer falls, infection or stroke, but they were more likely to break a bone. We also found that Z-drug users died earlier, but we could not be sure that this was as a result of taking the Z-drug. Using Z-drugs did not appear to affect quality of life or memory. We talked to carers and health-care practitioners, who told us that decisions about Z-drugs need to balance a range of complicated health and social factors. WHAT DOES THIS MEAN?: We found that people living with dementia who take Z-drugs are more likely to break a bone or to die sooner than similar people with dementia who are not taking Z-drugs. However, we cannot be certain that these problems are caused by Z-drugs, as many other factors can also lead to broken bones and death. Further work is needed to clarify the risk of broken bones, but if sleep problems can be managed in other ways then this may be preferable. Patients and family carers should be involved in decisions about Z-drugs, so that they can balance the possible harms against the benefits.

Effectiveness of Dementia Care Mapping™ to reduce agitation in care home residents with dementia: an open-cohort cluster randomised controlled trial.

OBJECTIVES: Agitation is common and problematic in care home residents with dementia. This study investigated the (cost)effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation in this population. METHOD: Pragmatic, cluster randomised controlled trial with cost-effectiveness analysis in 50 care homes, follow-up at 6 and 16 months and stratified randomisation to intervention (n = 31) and control (n = 19). Residents with dementia were recruited at baseline (n = 726) and 16 months (n = 261). Clusters were not blinded to allocation. Three DCM cycles were scheduled, delivered by two trained staff per home. Cycle one was supported by an external DCM expert. Agitation (Cohen-Mansfield Agitation Inventory (CMAI)) at 16 months was the primary outcome. RESULTS: DCM was not superior to control on any outcomes (cross-sectional sample n = 675: 287 control, 388 intervention). The adjusted mean CMAI score difference was -2.11 points (95% CI -4.66 to 0.44, p = 0.104, adjusted ICC control = 0, intervention 0.001). Sensitivity analyses supported the primary analysis. Incremental cost per unit improvement in CMAI and QALYs (intervention vs control) on closed-cohort baseline recruited sample (n = 726, 418 intervention, 308 control) was £289 and £60,627 respectively. Loss to follow-up at 16 months in the original cohort was 312/726 (43·0%) mainly (87·2%) due to deaths. Intervention dose was low with only a quarter of homes completing more than one DCM cycle. CONCLUSION: No benefits of DCM were evidenced. Low intervention dose indicates standard care homes may be insufficiently resourced to implement DCM. Alternative models of implementation, or other approaches to reducing agitation should be considered.

LIVE@Home.Path-innovating the clinical pathway for home-dwelling people with dementia and their caregivers: study protocol for a mixed-method, stepped-wedge, randomized controlled trial.

BACKGROUND: The global health challenge of dementia is exceptional in size, cost and impact. It is the only top ten cause of death that cannot be prevented, cured or substantially slowed, leaving disease management, caregiver support and service innovation as the main targets for reduction of disease burden. Institutionalization of persons with dementia is common in western countries, despite patients preferring to live longer at home, supported by caregivers. Such complex health challenges warrant multicomponent interventions thoroughly implemented in daily clinical practice. This article describes the rationale, development, feasibility testing and implementation process of the LIVE@Home.Path trial. METHODS: The LIVE@Home.Path trial is a 2-year, multicenter, mixed-method, stepped-wedge randomized controlled trial, aiming to include 315 dyads of home-dwelling people with dementia and their caregivers, recruited from 3 municipalities in Norway. The stepped-wedge randomization implies that all dyads receive the intervention, but the timing is determined by randomization. The control group constitutes the dyads waiting for the intervention. The multicomponent intervention was developed in collaboration with user-representatives, researchers and stakeholders to meet the requirements from the national Dementia Plan 2020. During the 6-month intervention period, the participants will be allocated to a municipal coordinator, the core feature of the intervention, responsible for regular contact with the dyads to facilitate L: Learning, I: Innovation, V: Volunteering and E: Empowerment (LIVE). The primary outcome is resource utilization. This is measured by the Resource Utilization in Dementia (RUD) instrument and the Relative Stress Scale (RSS), reflecting that resource utilization is more than the actual time required for caring but also how burdensome the task is experienced by the caregiver. DISCUSSION: We expect the implementation of LIVE to lead to a pathway for dementia treatment and care which is cost-effective, compared to treatment as usual, and will support high-quality independent living, at home. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04043364. Registered on 15 March 2019.

Dementia Care Mapping™ to reduce agitation in care home residents with dementia: the EPIC cluster RCT.

BACKGROUND: The quality of care for people with dementia in care homes is of concern. Interventions that can improve care outcomes are required. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation and improving care outcomes for people living with dementia in care homes, versus usual care. DESIGN: A pragmatic, cluster randomised controlled trial with an open-cohort design, follow-up at 6 and 16 months, integrated cost-effectiveness analysis and process evaluation. Clusters were not blinded to allocation. The primary end point was completed by staff proxy and independent assessors. SETTING: Stratified randomisation of 50 care homes to the intervention and control groups on a 3 : 2 ratio by type, size, staff exposure to dementia training and recruiting hub. PARTICIPANTS: Fifty care homes were randomised (intervention, n = 31; control, n = 19), with 726 residents recruited at baseline and a further 261 recruited after 16 months. Care homes were eligible if they recruited a minimum of 10 residents, were not subject to improvement notices, had not used DCM in the previous 18 months and were not participating in conflicting research. Residents were eligible if they lived there permanently, had a formal diagnosis of dementia or a score of 4+ on the Functional Assessment Staging Test of Alzheimer's Disease, were proficient in English and were not terminally ill or permanently cared for in bed. All homes were audited on the delivery of dementia and person-centred care awareness training. Those not reaching a minimum standard were provided training ahead of randomisation. Eighteen homes took part in the process evaluation. INTERVENTION: Two staff members from each intervention home were trained to use DCM and were asked to carry out three DCM cycles; the first was supported by an external expert. MAIN OUTCOME MEASURES: The primary outcome was agitation (Cohen-Mansfield Agitation Inventory), measured at 16 months. Secondary outcomes included resident behaviours and quality of life. RESULTS: There were 675 residents in the final analysis (intervention, n = 388; control, n = 287). There was no evidence of a difference in agitation levels between the treatment arms. The adjusted mean difference in Cohen-Mansfield Agitation Inventory score was -2.11 points, being lower in the intervention group than in the control (95% confidence interval -4.66 to 0.44; p = 0.104; adjusted intracluster correlation coefficient: control = 0, intervention = 0.001). The sensitivity analyses results supported the primary analysis. No differences were detected in any of the secondary outcomes. The health economic analyses indicated that DCM was not cost-effective. Intervention adherence was problematic; only 26% of homes completed more than their first DCM cycle. Impacts, barriers to and facilitators of DCM implementation were identified. LIMITATIONS: The primary completion of resident outcomes was by staff proxy, owing to self-report difficulties for residents with advanced dementia. Clusters were not blinded to allocation, although supportive analyses suggested that any reporting bias was not clinically important. CONCLUSIONS: There was no benefit of DCM over control for any outcomes. The implementation of DCM by care home staff was suboptimal compared with the protocol in the majority of homes. FUTURE WORK: Alternative models of DCM implementation should be considered that do not rely solely on leadership by care home staff. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82288852. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 16. See the NIHR Journals Library website for further project information.

Agitation is common in care home residents and may result from care that does not meet individual needs. Dementia Care Mapping™ (DCM) is a tool used within care homes to improve the delivery of person-centred care, which may help reduce agitation. This randomised controlled trial aimed to understand whether or not DCM is better than usual care at reducing resident agitation, behaviours that staff may find difficult to support and the use of antipsychotic medicines, as well as at improving residents' quality of life and staff communication. It also assessed its value for money. We recruited 726 residents with dementia from 50 care homes. After initial data collection, care homes were randomly assigned to DCM (31/50) or told to continue with usual care (19/50) and data were collected again after 6 and 16 months. A further 261 residents were recruited after 16 months. We also interviewed staff, relatives and residents about the use of DCM after the final data collection had taken place. Two staff members in each DCM home were trained to use DCM and were helped by an expert to use it for the first time. They were asked to use it again a further two times without support. Results showed that DCM was no better than usual care in relation to any of the outcomes. It was also not shown to be value for money. Only one-quarter of care homes used DCM more than once. The care staff who were interviewed said that the benefits of using DCM included reduced resident boredom and increased staff confidence. There were also many challenges, including the time needed to complete DCM, a lack of managerial support and problems with staffing levels. Putting DCM into practice in care homes was difficult, even with expert support, and most care homes did not complete three DCM cycles. Future research should explore models of implementing DCM that do not rely on care home staff to lead them.

Cost-Effectiveness of Dementia Care Mapping in Care-Home Settings: Evaluation of a Randomised Controlled Trial.

BACKGROUND: Behaviours such as agitation impact on the quality of life of care-home residents with dementia and increase healthcare use. Interventions to prevent these behaviours have little evidence supporting their effectiveness or cost-effectiveness. We conducted an economic evaluation alongside a trial assessing Dementia Care Mapping™ (DCM) versus usual care for reducing agitation, and highlight methodological challenges of conducting evaluations in this population and setting. METHODS: RCT data over 16 months from English care-home residents with dementia (intervention n = 418; control n = 308) were analysed. We conducted a cost-utility analysis from the healthcare provider perspective. We gathered resource use and utility (EQ-5D-5L and DEMQoL-Proxy-U) from people living with dementia and proxy informants (staff and relatives). Data were analysed using seemingly unrelated regression, accounting for care-home clustering and bootstrapping used to capture sampling uncertainty. RESULTS: Costs were higher in the intervention arm than in the control arm (incremental = £1479) due in part to high cost outliers. There were small QALY gains (incremental = 0.024) in favour of DCM. The base-case ICER (£64,380 per QALY) suggests DCM is not cost-effective versus usual care. With the exception of analyses excluding high cost outliers, which suggested a potential for DCM to be cost-effective, sensitivity analyses corroborated the base-case findings. Bootstrapped estimates suggested DCM had a low probability (< 0.20 where λ = £20,000) of being cost-effective versus control. CONCLUSION: DCM does not appear to be a cost-effective intervention versus usual care in this group and setting. The evaluation highlighted several methodological challenges relating to validity of utility assessments, loss to follow-up and compliance. Further research is needed on handling high-cost individuals and capturing utility in this group. ISRCTN reference 82288852.

Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer's Disease and Related Dementias and Strategic Implications for Stakeholders.

While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

Improving the quality of life of care home residents with dementia: Cost-effectiveness of an optimized intervention for residents with clinically significant agitation in dementia.

INTRODUCTION: To examine whether an optimized intervention is a more cost-effective option than treatment as usual (TAU) for improving agitation and quality of life in nursing home residents with clinically significant agitation and dementia. METHODS: A cost-effectiveness analysis within a cluster-randomized factorial study in 69 care homes with 549 residents was conducted. Each cluster was randomized to receive either the Well-being and Health for people with Dementia (WHELD) intervention or TAU for nine months. Health and social care costs, agitation, and quality of life outcomes were evaluated. RESULTS: Improvements in agitation and quality of life were evident in residents allocated to the WHELD intervention group. The additional cost of the WHELD intervention was offset by the higher health and social care costs incurred by TAU group residents (mean difference, £2103; 95% confidence interval, -13 to 4219). DISCUSSION: The WHELD intervention has clinical and economic benefits when used in residents with clinically significant agitation.

Protocol for the IDEAL-2 longitudinal study: following the experiences of people with dementia and their primary carers to understand what contributes to living well with dementia and enhances active life.

BACKGROUND: There is a major need for longitudinal research examining the experiences of people with dementia and their primary carers, as relatively little is known about how the factors associated with capability to 'live well' vary over time. The main aim of the IDEAL-2 study is to investigate how and why, over time, people with dementia and their primary carers might vary in their capability to live well with dementia, whilst exploring both their use of health and care services and their unmet needs. METHODS: IDEAL-2 will build on the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort of 1547 people (who, at recruitment between July 2014 and July 2016, had mild-to-moderate dementia), and their 1283 primary carers in Great Britain. The existing cohort will be enriched with additional participants with mild-to-moderate dementia (and their primary carers where available and willing) from the following groups: people with rarer forms of dementia, and/or those who are ≥90 years or < 65 years of age at time of recruitment. We will assess the primary outcome, capability to live well with dementia, and the factors influencing it using questionnaires at yearly intervals for 3 years. Additionally, we will seek to link the cohort data with administrative data to obtain information about health service use. Some participants will be invited for in-depth face-to-face interviews. The cohort study will be supplemented by linked research focusing on: the co-production of new measures of living well; including the perspectives of people with advanced dementia living in residential care settings; including people with dementia from black, Asian, and minority ethnic groups; and understanding the experience of people living with undiagnosed dementia. DISCUSSION: IDEAL-2 will provide evidence about the key indicators of, and factors associated with, living well over the course of dementia and how these differ for particular subgroups. It will tell us which combinations of services and support are most beneficial and cost-effective. Moreover, the IDEAL-2 study will gather evidence from under-researched groups of people with dementia, who are likely to have their own distinct perceptions of living well.

Hospitalization in people with dementia with Lewy bodies: Frequency, duration, and cost implications.

INTRODUCTION: Increased hospitalization is a major component of dementia impact on individuals and cost, but has rarely been studied in dementia with Lewy bodies (DLB). Our aim was to describe the risk and duration of hospital admissions in patients with DLB, and compare these to those in Alzheimer's disease (AD) and the general population. METHODS: A large database of mental health and dementia care in South London was used to assemble a cohort of patients diagnosed with DLB. These were 1:4 matched with patients diagnosed with AD on age, gender, and cognitive status. RESULTS: Rates of hospital admissions in the year after dementia diagnosis were significantly higher in 194 patients with DLB than in 776 patients with AD (crude incidence rate ratio 1.50; 95% confidence interval: 1.28-1.75) or the catchment population (indirectly standardized hospitalization rate 1.22; 95% confidence interval: 1.06-1.39). Patients with DLB had on average almost four additional hospital days per person-year than patients with AD. Multivariate Poisson regression models indicated poorer physical health early in the disease course as the main driver of this increased rate of hospitalization, whereby neuropsychiatric symptoms additionally explained the higher number of hospital days. DISCUSSION: Patients with DLB are more frequently admitted to general hospitals and utilize inpatient care to a substantially higher degree than patients with AD or the general elderly population. These data highlight an opportunity to reduce hospital days by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay.

A roadmap to advance dementia research in prevention, diagnosis, intervention, and care by 2025.

OBJECTIVE: National and global dementia plans have focused on the research ambition to develop a cure or disease-modifying therapy by 2025, with the initial focus on investment in drug discovery approaches. We set out to develop complementary research ambitions in the areas of prevention, diagnosis, intervention, and care and strategies for achieving them. METHODS: Alzheimer's Society facilitated a taskforce of leading UK clinicians and researchers in dementia, UK funders of dementia research, people with dementia, and carer representatives to develop, using iterative consensus methodology, goals and recommendations to advance dementia research. RESULTS: The taskforce developed 5 goals and 30 recommendations. The goals focused on preventing future cases of dementia through risk reduction, maximising the benefit of a dementia diagnosis, improving quality of life, enabling the dementia workforce to improve practice, and optimising the quality and inclusivity of health and social care systems. Recommendations addressed gaps in knowledge and limitations in research methodology or infrastructure that would facilitate research in prioritised areas. A 10-point action plan provides strategies for delivering the proposed research agenda. CONCLUSIONS: By creating complementary goals for research that mirror the need to find effective treatments, we provide a framework that enables a focus for new investment and initiatives. This will support a broader and more holistic approach to research on dementia, addressing prevention, surveillance of population changes in risk and expression of dementia, the diagnostic process, diagnosis itself, interventions, social support, and care for people with dementia and their families.

Impact of person-centred care training and person-centred activities on quality of life, agitation, and antipsychotic use in people with dementia living in nursing homes: A cluster-randomised controlled trial.

BACKGROUND: Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed to evaluate the efficacy of a person-centred care and psychosocial intervention incorporating an antipsychotic review, WHELD, on QoL, agitation, and antipsychotic use in people with dementia living in nursing homes, and to determine its cost. METHODS AND FINDINGS: This was a randomised controlled cluster trial conducted between 1 January 2013 and 30 September 2015 that compared the WHELD intervention with treatment as usual (TAU) in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person-centred care and social interaction and education regarding antipsychotic medications (antipsychotic review), followed by ongoing delivery through a care staff champion model. The primary outcome measure was QoL (DEMQOL-Proxy). Secondary outcomes were agitation (Cohen-Mansfield Agitation Inventory [CMAI]), neuropsychiatric symptoms (Neuropsychiatric Inventory-Nursing Home Version [NPI-NH]), antipsychotic use, global deterioration (Clinical Dementia Rating), mood (Cornell Scale for Depression in Dementia), unmet needs (Camberwell Assessment of Need for the Elderly), mortality, quality of interactions (Quality of Interactions Scale [QUIS]), pain (Abbey Pain Scale), and cost. Costs were calculated using cost function figures compared with usual costs. In all, 847 people were randomised to WHELD or TAU, of whom 553 completed the 9-month randomised controlled trial. The intervention conferred a statistically significant improvement in QoL (DEMQOL-Proxy Z score 2.82, p = 0.0042; mean difference 2.54, SEM 0.88; 95% CI 0.81, 4.28; Cohen's D effect size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68, p = 0.0076; mean difference 4.27, SEM 1.59; 95% CI -7.39, -1.15; Cohen's D 0.23) and overall neuropsychiatric symptoms (NPI-NH Z score 3.52, p < 0.001; mean difference 4.55, SEM 1.28; 95% CI -7.07,-2.02; Cohen's D 0.30). Benefits were greatest in people with moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94; 95% CI 2.12, 37.16, p = 0.03; Cohen's D 0.55). There were no statistically significant differences between WHELD and TAU for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL-Proxy, CMAI, and NPI-NH outcomes with the WHELD intervention. Antipsychotic drug use was at a low stable level in both treatment groups, and the intervention did not reduce use. The WHELD intervention reduced cost compared to TAU, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group. CONCLUSIONS: These findings suggest that the WHELD intervention confers benefits in terms of QoL, agitation, and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented in nursing homes. Future work should consider how to facilitate sustainability of the intervention in this setting. TRIAL REGISTRATION: ISRCTN Registry ISRCTN62237498.

Feasibility of a staff training and support programme to improve pain assessment and management in people with dementia living in care homes.

OBJECTIVES: The objective of this study was to establish the feasibility and initial effectiveness of training and support intervention for care staff to improve pain management in people with dementia living in care homes (PAIN-Dem). METHODS: PAIN-Dem training was delivered to care staff from three care homes in South London, followed by intervention support and resources to encourage improved pain management by staff over 4 weeks. Feasibility was assessed through fidelity to intervention materials and qualitative approaches. Focus group discussions with staff explored the use of the PAIN-Dem intervention, and interviews were held with six residents and family carers. Pain was assessed in all residents at baseline, 3 and 4 weeks, and goal attainment scaling was assessed at 4 weeks. RESULTS: Delivery of training was a key driver for success and feasibility of the PAIN-Dem intervention. Improvements in pain management behaviour and staff confidence were seen in homes where training was delivered in a care home setting across the care team with good manager buy-in. Family involvement in pain management was highlighted as an area for improvement. Goal attainment in residents was significantly improved across the cohort, although no significant change in pain was seen. CONCLUSIONS: This study shows good initial feasibility of the PAIN-Dem intervention and provides valuable insight into training and support paradigms that deliver successful learning and behaviour change. There is a need for a larger trial of PAIN-Dem to establish its impact on resident pain and quantifiable staff behaviour measures. Copyright © 2017 John Wiley & Sons, Ltd.