The prognosis of delirium in older outpatients.

BACKGROUND: Delirium is a common and serious neuropsychiatric disorder. The prognosis of delirium in older patients living at home has not been studied often before. The aim of this study is to examine the prognosis of delirium in patients attending a memory clinic of a psychiatric hospital. METHOD: The study population consisted of 85 outpatients diagnosed with delirium between October 2013 and October 2014. Seventeen patients had already been diagnosed as having dementia. Three months after the diagnosis, consenting patients underwent a follow-up visit. We recorded delirium status (remitted or not), new dementia diagnosis, subjective cognitive functioning compared to baseline and to before delirium, level of daily functioning, and place of residence. RESULTS: After 3 months, 45 (53%) had recovered from delirium, 19 (22,4%) had persistent/recurrent delirium, 12 (14%) patients had died, and another nine (11%) could not be revisited for other reasons than death. None of the 64 re-examined patients reported that their cognitive functioning had recovered to the pre-delirium level, and the mean level of daily functioning did not substantially improve either. The rate of diagnosed dementia increased to 63.8%, and 18 patients (28.1%) had moved to a nursing home. CONCLUSIONS: Delirium in older outpatients has a poor prognosis. A larger study on the risk factors of the prognosis of delirium in older persons living at home is advised.

Soundscape Awareness Intervention Reduced Neuropsychiatric Symptoms in Nursing Home Residents With Dementia: A Cluster-Randomized Trial With MoSART.

OBJECTIVES: Auditory environments as perceived by an individual, also called soundscapes, are often suboptimal for nursing home residents. Poor soundscapes have been associated with neuropsychiatric symptoms (NPS). We evaluated the effect of the Mobile Soundscape Appraisal and Recording Technology sound awareness intervention (MoSART+) on NPS in nursing home residents with dementia. DESIGN: A 15-month, stepped-wedge, cluster-randomized trial. Every 3 months, a nursing home switched from care as usual to the use of the intervention. INTERVENTION: The 3-month MoSART+ intervention involved ambassador training, staff performing sound measurements with the MoSART application, meetings, and implementation of microinterventions. The goal was to raise awareness about soundscapes and their influence on residents. SETTING AND PARTICIPANTS: We included 110 residents with dementia in 5 Dutch nursing homes. Exclusion criteria were palliative sedation and deafness. METHODS: The primary outcome was NPS severity measured with the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) by the resident's primary nurse. Secondary outcomes were quality of life (QUALIDEM), psychotropic drug use (ATC), staff workload (workload questionnaire), and staff job satisfaction (Maastricht Questionnaire of Job Satisfaction). RESULTS: The mean age of the residents (n = 97) at enrollment was 86.5 ± 6.7 years, and 76 were female (76.8%). The mean NPI-NH score was 17.5 ± 17.3. One nursing home did not implement the intervention because of staff shortages. Intention-to-treat analysis showed a clinically relevant reduction in NPS between the study groups (-8.0, 95% CI -11.7, -2.6). There was no clear effect on quality of life [odds ratio (OR) 2.8, 95% CI -0.7, 6.3], psychotropic drug use (1.2, 95% CI 0.9, 1.7), staff workload (-0.3, 95% CI -0.3, 0.8), or staff job satisfaction (-0.2, 95% CI -1.2, 0.7). CONCLUSIONS AND IMPLICATIONS: MoSART+ empowered staff to adapt the local soundscape, and the intervention effectively reduced staff-reported levels of NPS in nursing home residents with dementia. Nursing homes should consider implementing interventions to improve the soundscape.

Soundscape Optimization in Nursing Homes Through Raising Awareness in Nursing Staff With MoSART.

Introduction: Soundscapes in nursing homes are often suboptimal for residents. This can cause them feeling anxious and unsafe, or develop behavioral and psychological problems. Residents with dementia cannot adapt nursing home environments to their needs due to cognitive and physical limitations. It is up to the staff of psycho-geriatric wards to improve the soundscape. We evaluated the effect of the sound awareness intervention Mobile Soundscape Appraisal and Recording Technology (MoSART+) on soundscapes in nursing homes. Methods: The MoSART+ intervention was carried out in four nursing homes and took three months in each home. The MoSART+ intervention involved training ambassadors, assessing the soundscape with the MoSART application by the nursing staff to raise their sound awareness on random time points, discussing the measurements, and implementing micro-interventions. Soundscapes were assessed from 0 to 100 on four attributes: pleasantness, eventfulness, complexity, and range of affordances. Based on these scores, soundscapes were classified in four dimensions: calm, lively, boring, and chaotic. Nursing staff graded the environment on a scale of 0 to 10. T-test and Z-tests were used to analyze data. Results: Staff recorded 1882 measurements with the MoSART app. "People," "music, TV, and radio," and "machines and appliances" were the most prevalent sound sources before and after the implementation of micro-interventions. Post-implementation of micro-interventions, soundscapes were pleasant (median 69.0; IQR 54.0-81.0), of low complexity (33.0; 18.0-47.0), uneventful (27.0; 14.0-46.5), and gave moderate affordances (50.0; 35.0-67.0). Changes in attributes were statistically significant (p < 0.01). The proportion of the dimension calm increased (z = 12.7, p < 0.01), the proportion of chaotic decreased (z = 15.0, p < 0.01), and the proportion of lively decreased not statically significant (z = 0.68, p = 0.79). The proportion of boring was unchanged. The proportion of grades ≥6 increased after implementation of the micro-interventions (z = 15.3, p < 0.01). The micro-interventions focused on removing or reducing disturbing sounds and were unique for each nursing home. Discussion: The MoSART+ intervention resulted in a statistically significantly improvement of soundscapes, and more favorable evaluations of the nursing staff. The intervention empowered staff to adapt soundscapes. Nursing homes can improve soundscapes by raising sound awareness among staff. Trial Registration: Netherlands National Trial Register (NL6831).

Evolocumab's Long-Term Mortality Risk Unclear Due to Shortened Follow-Up of FOURIER.

The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 inhibition in Subjects with Elevated Risk) trial was conducted to study cardiovascular outcomes of treatment with evolocumab. The trial was terminated after a median follow-up of 2.2 years instead of the planned 3.6 years. We question this decision. According to the investigators, the event rate was 50% higher than expected. However, the accrued number of key secondary events (1829) was only 12% higher than the targeted number (1630). Also, around one-third of the events consisted of non-atherosclerotic myocardial infarctions, hemorrhagic strokes, and cardiovascular deaths unrelated to myocardial infarction or stroke. Moreover, halfway through the trial, the sample size changed from 22,500 to 27,500, even though the accrual of the targeted number of events was on track. Finally, the rate of all-cause mortality had started to diverge in favor of placebo after 2 years of follow-up. It was 4.8% for evolocumab and 4.3% for placebo in participants with > 2.5 years of follow-up. A long-term follow-up would have yielded more events and thus more power to evaluate the effect of evolocumab on all-cause mortality. We conclude that adaptive designs carry a recognized risk of false-positive efficacy results, but the risk of false-negative safety results is underappreciated.

Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia.

BACKGROUND: Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials have yielded negative results and effectiveness may be outweighed by harms. OBJECTIVES: To assess the efficacy and safety of antipsychotics for the treatment of agitation and psychosis in people with Alzheimer's disease and vascular dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, and the International Clinical Trials Registry Portal on 7 January 2021. Two review authors independently screened the title and abstract of the hits, and two review authors assessed the full text of studies that got through this screening. SELECTION CRITERIA: We included randomised, placebo-controlled, parallel-arm trials comparing the effects of antipsychotics and placebo for the treatment of agitation or psychosis in people with dementia due to Alzheimer's disease or vascular dementia, or both, irrespective of age, severity of cognitive impairment, and setting. (The majority of) participants had to have clinically significant agitation (including aggression) or psychosis or both at baseline. We excluded studies about antipsychotics that are no longer available in the USA or EU, or that are used for emergency short-term sedation. We also excluded head-to-head trials and antipsychotic withdrawal trials. DATA COLLECTION AND ANALYSIS: The primary outcomes were (1) reduction in agitation or psychosis in participants with agitation or psychosis, respectively at baseline, and (2) the number of participants with adverse events: somnolence, extrapyramidal symptoms, any adverse event, any serious adverse event (SAE), and death. Two review authors independently extracted the necessary data and assessed risk of bias with the Cochrane risk of bias tool. We calculated the pooled effect on agitation and psychosis for typical and atypical antipsychotics separately, and the pooled risk of adverse effects independent of the target symptom (agitation or psychosis). We used RevMan Web for the analyses. MAIN RESULTS: The search yielded 8233 separate hits. After assessing the full-text of 35 studies, we included 24 trials that met the eligibility criteria. Six trials tested a typical antipsychotic, four for agitation and two for psychosis. Twenty trials tested an atypical antipsychotic, eight for agitation and 12 for psychosis. Two trials tested both drug types. Seventeen of 26 comparisons were performed in patients with Alzheimer's disease specifically. The other nine comparisons also included patients with vascular dementia or mixed dementia. Together, the studies included 6090 participants (12 to 652 per study). The trials were performed in institutionalised, hospitalised and community-dwelling patients, or a combination of those. For typical antipsychotics (e.g. haloperidol, thiothixene), we are uncertain whether these drugs improve agitation compared with placebo (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.57 to -0.15, 4 studies, n = 361); very low-certainty evidence, but typical antipsychotics may improve psychosis slightly (SMD -0.29, 95% CI -0.55 to -0.03, 2studies, n= 240; low-certainty evidence) compared with placebo. These drugs probably increase the risk of somnolence (risk ratio (RR) 2.62, 95% CI 1.51 to 4.56, 3 studies, n = 466; moderate-certainty evidence) and increase extrapyramidal symptoms (RR 2.26, 95% CI 1.58 to 3.23, 3 studies, n = 467; high-certainty) evidence. There was no evidence regarding the risk of any adverse event. The risks of SAEs (RR 1.32, 95% CI 0.65 to 2.66, 1 study, n = 193) and death (RR 1.46, 95% CI 0.54 to 4.00, 6 studies, n = 578) may be increased slightly, but these estimates were very imprecise, and the certainty was low. The effect estimates for haloperidol from five trials were in line with those of the drug class. Atypical antipsychotics (e.g. risperidone, olanzapine, aripiprazole, quetiapine) probably reduce agitation slightly (SMD -0.21, 95% CI -0.30 to -0.12, 7 studies, n = 1971; moderate-certainty evidence), but probably have a negligible effect on psychosis (SMD -0.11, 95% CI -0.18 to -0.03, 12 studies, n = 3364; moderate-certainty evidence). These drugs increase the risk of somnolence (RR 1.93, 95% CI 1.57 to 2.39, 13 studies, n - 3878; high-certainty evidence) and are probably also associated with slightly increased risk of extrapyramidal symptoms (RR 1.39, 95% CI 1.14 to 1.68, 15 studies, n = 4180; moderate-certainty evidence), serious adverse events (RR 1.32, 95% CI 1.09 to 1.61, 15 studies, n= 4316; moderate-certainty evidence) and death (RR 1.36, 95% CI 0.90 to 2.05, 17 studies, n= 5032; moderate-certainty evidence), although the latter estimate was imprecise. The drugs probably have a negligible effect on the risk of any adverse event (RR 1.05, 95% CI 1.02 to 1.09, 11 studies, n = 2785; moderate-certainty evidence). The findings from seven trials for risperidone were in line with those for the drug class. AUTHORS' CONCLUSIONS: There is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia. Atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible. The apparent effectiveness of the drugs seen in daily practice may be explained by a favourable natural course of the symptoms, as observed in the placebo groups. Both drug classes increase the risk of somnolence and other adverse events. If antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative.

A short delirium caregiver questionnaire for triage of elderly outpatients with cognitive impairment: a development and test accuracy study.

OBJECTIVES: Delirium is often missed in older outpatients. Caregivers can give valuable information that might improve identification rates. The aim of this study was to develop a short and sensitive delirium caregiver questionnaire (DCQ) for triage of elderly outpatients with cognitive impairment by telephone. DESIGN, SETTING, AND PARTICIPANTS: The pilot questionnaire was administered to 112 caregivers of patients who were referred for dementia screening to our clinic for geriatric psychiatry, and the final DCQ to 234 other caregivers. MEASUREMENTS: In phase I (2013-2014), we tested a pilot questionnaire with 17 items. Health professionals who established delirium diagnoses were blinded to the results. We then used the results and other information available at referral to construct the final DCQ with seven items. During phase II (2015-2016), we investigated the test accuracy of the final DCQ in a subsequent cohort. In both phases, the patients received a structured diagnostic workup. Time between referral and first visit was a secondary outcome. RESULTS: The final DCQ consisted of the following items: emergency visit required, sleeping disorder, fluctuating course, hallucinations, suspicious thoughts, previous delirium, and recent discharge from hospital. DCQ results indicated that urgent intake was required in 85 of 234 patients. Sensitivity was 73.5% (95% CI: 58.9-85.1%) and specificity 73.5% (95% CI: 66.5-79.7%). The mean number of days to first visit dropped from 31.6 to 11.2 in delirious patients (p = 0.001). CONCLUSIONS: Triage with the easy-to-use DCQ among patients referred for cognitive screening leads to earlier assessment and higher detection rates of delirium.

Validation of a modified ambiance scale in nursing homes.

OBJECTIVES: We translated and modified an ambiance scale for use by (in)formal caregivers in Dutch nursing homes. We tested validity and reliability of the modified Ambiance Scale. METHOD: Convenience sampling was used to enrol (in)formal caregivers in three nursing homes in the Netherlands. 104 questionnaires were filled in; 45 by informal caregivers, 46 by formal caregivers. Ten caregivers filled in the questionnaire twice for test-retest purposes. Three original items were used, and seven newly were added to form the modified Ambiance Scale. Each item consisted of an adjective pair assessing an aspect of ambiance on a scale of 1 (homelike) to 5 (institutional). Caregivers filled in the questionnaire on two different days to assess intra rater reliability. Differences in scoring between formal and informal caregivers and between original and new items were analyzed. RESULTS: The questionnaire was easy to comprehend and fill in. Internal consistency was good (a = 0.93). Validity was found to be good. Factor analysis demonstrated that eight items identified as one factor. No differences in scoring between the first and second assessment were found (p<.001). Formal caregivers scored ambiance more chaotic than informal caregivers did (p<.01). No differences in scoring between original and new items were found (p =.06). CONCLUSION: This study demonstrated that the modified Ambiance Scale had good internal consistency, moderate replicability and both informal and formal caregivers' overall ratings were comparable. The modified Ambiance Scale is a valid, reliable and easy to use tool to assess ambiance in nursing home settings.

Prevalence and risk factors of delirium in psychogeriatric outpatients.

BACKGROUND: Delirium is a serious neuropsychiatric syndrome, which requires timely treatment. However, it is easily missed, especially in older patients with premorbid cognitive disorders. OBJECTIVES: The aim of this study is to investigate the prevalence and risk factors of delirium in older outpatients with and without dementia. METHOD: We assessed 444 patients referred to the memory clinic of a psychiatric hospital between March 2013 and March 2014. Demographic information, medical history, impairments in daily living activities and referral information were registered. Patients underwent a psychiatric examination using the Delirium Rating Scale-Revised-98 and cognitive tests, a physical examination and laboratory tests. We recorded medication use and changes before and after the onset of symptoms. RESULTS: Among the 444 outpatients, 85 had probable delirium (prevalence of 19%), and 10 had subsyndromal delirium (2%). The most common triggers were infection (42%), drug-intoxication or withdrawal (22%), and metabolic/endocrine disturbance (12%). Age (OR 1.07, 95% CI 1.02-1.11) and prior delirium (OR 3.34, 95% CI 1.28-8.69) were independent non-modifiable factors associated with an increased risk of delirium. The only independent modifiable risk factor was infection (OR 17.31, 95% CI 8.44-35.49). CONCLUSIONS: A delirium was detected in one of five patients referred for dementia screening. Most patients could be treated at home. Age and prior delirium were predictive of an increased risk of delirium.

Sounds in nursing homes and their effect on health in dementia: a systematic review.

OBJECTIVES: Nursing home residents with dementia are sensitive to detrimental auditory environments. This paper presents the first literature review of empirical research investigating (1) the (perceived) intensity and sources of sounds in nursing homes, and (2) the influence of sounds on health of residents with dementia and staff. DESIGN: A systematic review was conducted in PubMed, Web of Science and Scopus. Study quality was assessed with the Mixed Methods Appraisal Tool. We used a narrative approach to present the results. RESULTS: We included 35 studies. Nine studies investigated sound intensity and reported high noise intensity with an average of 55-68 dB(A) (during daytime). In four studies about sound sources, human voices and electronic devices were the most dominant sources. Five cross-sectional studies focused on music interventions and reported positives effects on agitated behaviors. Four randomized controlled trials tested noise reduction as part of an intervention. In two studies, high-intensity sounds were associated with decreased nighttime sleep and increased agitation. The third study found an association between music and less agitation compared to other stimuli. The fourth study did not find an effect of noise on agitation. Two studies reported that a noisy environment had negative effects on staff. CONCLUSIONS: The need for appropriate auditory environments that are responsive to residents' cognitive abilities and functioning is not yet recognized widely. Future research needs to place greater emphasis on intervention-based and longitudinal study design.

Assessing risk of bias: a proposal for a unified framework for observational studies and randomized trials.

BACKGROUND: Evidence based medicine aims to integrate scientific evidence, clinical experience, and patient values and preferences. Individual health care professionals need to appraise the evidence from randomized trials and observational studies when guidelines are not yet available. To date, tools for assessment of bias and terminologies for bias are specific for each study design. Moreover, most tools appeal only to methodological knowledge to detect bias, not to subject matter knowledge, i.e. in-depth medical knowledge about a topic. We propose a unified framework that enables the coherent assessment of bias across designs. METHODS: Epidemiologists traditionally distinguish between three types of bias in observational studies: confounding, information bias, and selection bias. These biases result from a common cause, systematic error in the measurement or common effect of the intervention and outcome respectively. We applied this conceptual framework to randomized trials and show how it can be used to identify bias. The three sources of bias were illustrated with graphs that visually represent researchers' assumptions about the relationships between the investigated variables (causal diagrams). RESULTS: Critical appraisal of evidence started with the definition of the research question in terms of the population of interest, the compared interventions and the main outcome. Next, we used causal diagrams to illustrate how each source of bias can lead to over- or underestimated treatment effects. Then, we discussed how randomization, blinded outcome measurement and intention-to-treat analysis minimize bias in trials. Finally, we identified study aspects that can only be appraised with subject matter knowledge, irrespective of study design. CONCLUSIONS: The unified framework encompassed the three main sources of bias for the effect of an assigned intervention on an outcome. It facilitated the integration of methodological and subject matter knowledge in the assessment of bias. We hope that graphical diagrams will help clarify debate among professionals by reducing misunderstandings based on different terminology for bias.

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

PURPOSE: Run-in periods are used to identify placebo-responders and washout. Our aim was to assess the association of run-in periods with clinical outcomes of antipsychotics in dementia. METHODS: We searched randomized placebo-controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run-in period, use of placebo/investigated drug during run-in (versus washout only), and run-in duration (1 week or more) and (b) the reduction in NPS, number of participants with somnolence, extrapyramidal symptoms (EPS), and deaths per treatment group. We pooled clinical outcomes comparing antipsychotic and placebo groups in trials with and without run-in. RESULTS: We identified 35 trials. Twenty-nine trials used run-in. The pooled standardized mean difference in the reduction of NPS was -0.170 (95% CI, -0.227 to -0.112) in trials with run-in and -0.142 (95% CI, -0.331 to 0.047) in trials without run-in. The pooled odds ratio for somnolence was 2.8 (95% CI, 2.3-3.5) in trials with run-in and 3.5 (95% CI, 1.2-10.7) in trials without run-in; for EPS, these ORs were 1.8 (95% CI, 1.4-2.2) and 2.0 (95% CI, 1.3-3.1) respectively, and for mortality 1.4 (95% CI, 1.0-2.0) and 1.6 (95% CI, 0.7-3.4). The use of placebo/investigated drug during run-in and run-in duration did not affect the estimates in a consistent way. CONCLUSIONS: The use of run-in in trials might have led to overestimated efficacy and especially underestimated risks of side effects of antipsychotics compared with placebo for NPS in dementia.

Subjective Versus Objective Outcomes of Antipsychotics for the Treatment of Neuropsychiatric Symptoms Associated with Dementia.

BACKGROUND: Knowledge about treatment status can influence effects measured in trials when subjective scales are used. OBJECTIVE: The aim of this study was to compare subjective outcomes with objective outcomes of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia. METHODS: We performed a meta-epidemiological study of 38 randomized, placebo-controlled trials. For effectiveness, we used change in NPS and response rate as subjective outcomes, while overall dropout and additional psychotropic use were used as objective outcomes. For side effects, extrapyramidal symptoms (EPS) and somnolence were used as subjective outcomes, while dropout due to adverse events, medication use for EPS, and participants falling were used as objective outcomes. RESULTS: Conventional antipsychotics reduced NPS more than placebo (standardized mean difference [SMD] - 0.36, 95% confidence interval [CI] - 0.49 to - 0.23), as did atypical antipsychotics (SMD - 0.14, 95% CI - 0.19 to - 0.08). Response rates in the drug groups were also higher. Overall dropout did not differ between conventional antipsychotics and placebo (odds ratio [OR] 1.03, 95% CI 0.77-1.37) or atypical antipsychotics and placebo (OR 1.01, 95% CI 0.89-1.14). Furthermore, additional psychotropic use did not differ. The risk of EPS was higher for conventional (OR 2.93, 95% CI 2.04-4.22) and atypical antipsychotics (OR 1.52, 95% CI 1.23-1.88) versus placebo, as was the risk of somnolence and dropout due to adverse events, but medication use for EPS, as well as risk of falls, was not. CONCLUSIONS: The effectiveness of antipsychotics for NPS in dementia based on subjective scales was not confirmed using objective outcomes, in contrast to the increased risk of side effects.

[Is the approach of delirium in Dutch nursing-homes in accordance with the national guideline?] / Is de aanpak van delier in Nederlandse verpleeghuizen conform de richtlijn?

INTRODUCTION: Delirium is a common disorder, affecting many patients in nursing-homes, with large impact on patients. Implementation of good care and treatment can potentially prevent development of a delirium or may reduce the severity or duration. This research was conducted to get an impression of delirium care in Dutch nursing homes, and of the implementation of the recommendations of the national guideline. OBJECTIVES: 1. How many Dutch nursing homes have a local protocol for delirium?2. To what extend do doctors, specialised in care for older people in nursing homes, screen, diagnose and treat delirium according to the Dutch guideline for delirium? METHODS: Between June and December 2016, Dutch nursing homes were approached with an online questionnaire. Data were collected in Survey Monkey and descriptive analyses were performed. RESULTS: 68 nursing homes were included. 32% of the nursing homes had a local delirium protocol. 48% of the doctors knew about the national guideline delirium, 60% used preventive measures, and screening instruments were used in 98%. 29% used diagnostic criteria. Non-medical interventions were applied by 96%. In 98%, haloperidol was the drug of first choice. Preventive antipsychotics were prescribed by 21%. CONCLUSIONS: Only a third of the organisations developed a local delirium protocol. Standardising delirium care by a local delirium protocol, with special attention for prevention, diagnostics and aftercare of delirium, can be an important step in improving the quality of care in nursing homes.

Large Sample Size Fallacy in Trials About Antipsychotics for Neuropsychiatric Symptoms in Dementia.

BACKGROUND: A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant. OBJECTIVE: To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size. STUDY DESIGN AND SETTING: We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively. RESULTS: We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6-179) in placebo-controlled trials testing conventional drugs, 107 (8-237) in such trials testing atypical drugs, and 104 (95-115) in such trials testing both drug types; it was 31 (10-88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size. CONCLUSION: Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered.

Baseline imbalances and clinical outcomes of atypical antipsychotics in dementia: A meta-epidemiological study of randomized trials.

OBJECTIVES: To assess baseline imbalances in placebo-controlled trials of atypical antipsychotics in dementia, and their association with neuropsychiatric symptoms (NPS), extrapyramidal symptoms (EPS), and mortality. METHOD: We searched for trials in multiple sources. Two reviewers extracted baseline characteristics and outcomes per treatment group. We calculated direction, range, pooled mean, and heterogeneity in the baseline differences, and used meta-regression for the relationship with the outcomes. RESULTS: We identified 23 trials. Baseline type of dementia, cognitive impairment and NPS were poorly reported. The drug group had a higher mean age than the placebo group in nine trials and lower mean age in three trials (p = 0.073). The difference in percentage men between the drug and placebo group ranged from -9.7% to 4.4%. There were no statistically significant pooled baseline differences, but heterogeneity was present for age. Higher mean age at baseline in the drug versus placebo group was significantly associated with greater reduction in NPS, and higher percentage of non-White persons with lower risk of EPS. Imbalances were not significantly associated with risk of mortality. CONCLUSION: Randomized trials of atypical antipsychotics in dementia showed baseline imbalances that were associated with higher efficacy and lower risk of EPS for atypical antipsychotics versus placebo.