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

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

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

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

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

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)

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