Safety of pharmacologic interventions for neuropsychiatric symptoms in dementia: a systematic review and network meta-analysis.

BACKGROUND: Prescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is scarce. Our objective was to describe the comparative safety of pharmacologic interventions for treating neuropsychiatric symptoms in dementia. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, from inception to May 28, 2019, for studies of pharmacologic interventions used to treat neuropsychiatric symptoms in dementia. Dementia care partners selected fracture risk as our primary outcome. Pairs of reviewers, working independently, conducted all study screening, data abstraction, and risk of bias appraisal. We conducted Bayesian random-effects network meta-analyses (NMAs) using data from RCTs to derive odds ratios (ORs). In secondary analyses, we conducted frequentist random-effects NMAs using data from RCTs and Bayesian three-level hierarchical random-effects NMAs incorporating data from RCTs and non-randomized studies. RESULTS: Our systematic review included 209 randomized and non-randomized studies (889,378 persons with dementia). In NMAs of data from randomized trials, there were no increased odds of fracture associated with any intervention in primary analyses; however, data were sparse. We found increased odds of cerebrovascular events associated with antipsychotics (odds ratio [OR] 2.12, 95% credible interval [CrI] 1.29 to 3.62; number needed to harm [NNH] = 99) and increased odds of falls associated with dextromethorphan-quinidine (OR 4.16, 95% CrI 1.47 to 14.22; NNH = 55) compared to placebo in persons with dementia. In a subgroup of persons with Alzheimer disease, antipsychotics were associated with increased odds of fracture compared to anticonvulsants (OR 54.1, 95% CrI 1.15 to 38,300; NNH = 18). In older persons (mean age ≥ 80 years) with dementia, anticonvulsants were associated with increased odds of death compared to placebo (OR 8.36, 95% CrI 1.17 to 203.4; NNH = 35) and antipsychotics were associated with increased odds of death compared to antidepressants (OR 5.28, 95% CrI 1.06 to 3.51; NNH = 47). CONCLUSION: Although antipsychotics were associated with greater harm than antidepressants and anticonvulsants in subgroups of persons with dementia, medications used in lieu of antipsychotics for treating neuropsychiatric symptoms in dementia, such as anticonvulsants and dextromethorphan-quinidine, were also associated with harm. Decision-making concerning treatments prescribed in lieu of antipsychotics should include potential harms. PROSPERO REGISTRATION: CRD42017050130.

Effectiveness of interventions for managing multiple high-burden chronic diseases in older adults: a systematic review and meta-analysis.

INTRODUCTION: More than half of older adults (age ≥ 65 yr) have 2 or more high-burden multimorbidity conditions (i.e., highly prevalent chronic diseases, which are associated with increased health care utilization; these include diabetes [DM], dementia, depression, chronic obstructive pulmonary disease [COPD], cardiovascular disease [CVD], arthritis, and heart failure [HF]), yet most existing interventions for managing chronic disease focus on a single disease or do not respond to the specialized needs of older adults. We conducted a systematic review and meta-analysis to identify effective multimorbidity interventions compared with a control or usual care strategy for older adults. METHODS: We searched bibliometric databases for randomized controlled trials (RCTs) evaluating interventions for managing multiple chronic diseases in any language from 1990 to December 2017. The primary outcome was any outcome specific to managing multiple chronic diseases as reported by studies. Reviewer pairs independently screened citations and full-text articles, extracted data and assessed risk of bias. We assessed statistical and methodological heterogeneity and performed a meta-analysis of RCTs with similar interventions and components. RESULTS: We included 25 studies (including 15 RCTs and 6 cluster RCTs) (12 579 older adults; mean age 67.3 yr). In patients with [depression + COPD] or [CVD + DM], care-coordination strategies significantly improved depressive symptoms (standardized mean difference -0.41; 95% confidence interval [CI] -0.59 to -0.22; I2 = 0%) and reduced glycosylated hemoglobin (HbA1c) levels (mean difference -0.51; 95% CI -0.90 to -0.11; I2 = 0%), but not mortality (relative risk [RR] 0.79; 95% CI 0.53 to 1.17; I2 = 0%). Among secondary outcomes, care-coordination strategies reduced functional impairment in patients with [arthritis + depression] (between-group difference -0.82; 95% CI -1.17 to -0.47) or [DM + depression] (between-group difference 3.21; 95% CI 1.78 to 4.63); improved cognitive functioning in patients with [DM + depression] (between-group difference 2.44; 95% CI 0.79 to 4.09) or [HF + COPD] (p = 0.006); and increased use of mental health services in those with [DM + (CVD or depression)] (RR 2.57; 95% CI 1.90 to 3.49; I2 = 0%). INTERPRETATION: Subgroup analyses showed that older adults with diabetes and either depression or cardiovascular disease, or with coexistence of chronic obstructive pulmonary disease and heart failure, can benefit from care-coordination strategies with or without education to lower HbA1c, reduce depressive symptoms, improve health-related functional status, and increase the use of mental health services. PROTOCOL REGISTRATION: PROSPERO-CRD42014014489.

Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis.

OBJECTIVE: To describe the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia who experience depression as a neuropsychiatric symptom of dementia or have a diagnosis of a major depressive disorder. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Library, CINAHL, PsycINFO, and grey literature between inception and 15 October 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing drug or non-drug interventions with usual care or any other intervention targeting symptoms of depression in people with dementia. MAIN OUTCOME MEASURES: Pairs of reviewers screened studies, abstracted aggregate level data, and appraised risk of bias with the Cochrane risk of bias tool, which facilitated the derivation of standardised mean differences and back transformed mean differences (on the Cornell scale for depression in dementia) from bayesian random effects network meta-analyses and pairwise meta-analyses. RESULTS: Of 22 138 citations screened, 256 studies (28 483 people with dementia) were included. Missing data posed the greatest risk to review findings. In the network meta-analysis of studies including people with dementia without a diagnosis of a major depressive disorder who were experiencing symptoms of depression (213 studies; 25 177 people with dementia; between study variance 0.23), seven interventions were associated with a greater reduction in symptoms of depression compared with usual care: cognitive stimulation (mean difference -2.93, 95% credible interval -4.35 to -1.52), cognitive stimulation combined with a cholinesterase inhibitor (-11.39, -18.38 to -3.93), massage and touch therapy (-9.03, -12.28 to -5.88), multidisciplinary care (-1.98, -3.80 to -0.16), occupational therapy (-2.59, -4.70 to -0.40), exercise combined with social interaction and cognitive stimulation (-12.37, -19.01 to -5.36), and reminiscence therapy (-2.30, -3.68 to -0.93). Except for massage and touch therapy, cognitive stimulation combined with a cholinesterase inhibitor, and cognitive stimulation combined with exercise and social interaction, which were more efficacious than some drug interventions, no statistically significant difference was found in the comparative efficacy of drug and non-drug interventions for reducing symptoms of depression in people with dementia without a diagnosis of a major depressive disorder. Clinical and methodological heterogeneity precluded network meta-analysis of studies comparing the efficacy of interventions specifically for reducing symptoms of depression in people with dementia and a major depressive disorder (22 studies; 1829 patients). CONCLUSIONS: In this systematic review, non-drug interventions were found to be more efficacious than drug interventions for reducing symptoms of depression in people with dementia without a major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017050130.

Improving KT tools and products: development and evaluation of a framework for creating optimized, Knowledge-activated Tools (KaT).

BACKGROUND: Positive impacts of quality improvement initiatives on health care and services have not been substantial. Knowledge translation (KT) strategies (tools, products and interventions) strive to facilitate the uptake of knowledge thereby the potential to improve care, but there is little guidance on how to develop them. Existing KT guidance or planning tools fall short in operationalizing all aspects of KT practice activities conducted by knowledge users (researchers, clinicians, patients, decision-makers), and most do not consider their variable needs or to deliver recommendations that are most relevant and useful for them. METHODS: We conducted a 3-phase study. In phase 1, we used several sources to develop a conceptual framework for creating optimized Knowledge-activated Tools (KaT) (consultation with our integrated KT team, the use of existing KT models and frameworks, findings of a systematic review of multimorbidity interventions and a literature review and document analysis on existing KT guidance tools). In phase 2, we invited KT experts to participate in a Delphi study to refine and evaluate the conceptual KaT framework. In phase 3, we administered an online survey to knowledge users (researchers, clinicians, decision-makers, trainees) to evaluate the potential usefulness of an online mock-up version of the KaT framework. RESULTS: We developed the conceptual KaT framework, and iteratively refined it with 35 KT experts in a 3-round Delphi study. The final framework represents the blueprint for what is needed to create KT strategies. Feedback from 201 researcher, clinician, decision-maker and trainee knowledge users on the potential need and usefulness of an online, interactive version of KaT indicated that they liked the idea of it (mean score 4.36 on a 5-point Likert scale) and its proposed features (mean score range 4.30-4.79). CONCLUSIONS: Our findings suggest that mostly Canadian KT experts and knowledge users perceived the KaT framework and the future development of an online, interactive version to be important and needed. We anticipate that the KaT framework will provide clarity for knowledge users about how to identify their KT needs and what activities can address these needs, and to help streamline the process of these activities to facilitate efficient uptake of knowledge.

Underlying mechanisms of complex interventions addressing the care of older adults with multimorbidity: a realist review.

OBJECTIVES: To understand how and why effective multi-chronic disease management interventions influence health outcomes in older adults 65 years of age or older. DESIGN: A realist review. DATA SOURCES: Electronic databases including Medline and Embase (inception to December 2017); and the grey literature. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We considered any studies (ie, experimental quasi-experimental, observational, qualitative and mixed-methods studies) as long as they provided data to explain our programme theories and effectiveness review (published elsewhere) findings. The population of interest was older adults (age ≥65 years) with two or more chronic conditions. ANALYSIS: We used the Realist And MEta-narrative Evidence Syntheses: Evolving Standards (RAMESES) quality and publication criteria for our synthesis aimed at refining our programme theories such that they contained multiple context-mechanism-outcome configurations describing the ways different mechanisms fire to generate outcomes. We created a 3-step synthesis process grounded in meta-ethnography to separate units of data from articles, and to derive explanatory statements across them. RESULTS: 106 articles contributed to the analysis. We refined our programme theories to explain multimorbidity management in older adults: (1) care coordination interventions with the best potential for impact are team-based strategies, disease management programmes and case management; (2) optimised disease prioritisation involves ensuring that clinician work with patients to identify what symptoms are problematic and why, and to explore options that are acceptable to both clinicians and patients and (3) optimised patient self-management is dependent on patients' capacity for selfcare and to what extent, and establishing what patients need to enable selfcare. CONCLUSIONS: To optimise care, both clinical management and patient self-management need to be considered from multiple perspectives (patient, provider and system). To mitigate the complexities of multimorbidity management, patients focus on reducing symptoms and preserving quality of life while providers focus on the condition that most threaten morbidity and mortality. PROSPERO REGISTRATION NUMBER: CRD42014014489.

Scoping review identifies significant number of knowledge translation theories, models, and frameworks with limited use.

OBJECTIVES: To conduct a scoping review of knowledge translation (KT) theories, models, and frameworks that have been used to guide dissemination or implementation of evidence-based interventions targeted to prevention and/or management of cancer or other chronic diseases. STUDY DESIGN AND SETTING: We used a comprehensive multistage search process from 2000 to 2016, which included traditional bibliographic database searching, searching using names of theories, models and frameworks, and cited reference searching. Two reviewers independently screened the literature and abstracted the data. RESULTS: We found 596 studies reporting on the use of 159 KT theories, models, or frameworks. A majority (87%) of the identified theories, models, or frameworks were used in five or fewer studies, with 60% used once. The theories, models, and frameworks were most commonly used to inform planning/design, implementation and evaluation activities, and least commonly used to inform dissemination and sustainability/scalability activities. Twenty-six were used across the full implementation spectrum (from planning/design to sustainability/scalability) either within or across studies. All were used for at least individual-level behavior change, whereas 48% were used for organization-level, 33% for community-level, and 17% for system-level change. CONCLUSION: We found a significant number of KT theories, models, and frameworks with a limited evidence base describing their use.