Sample size estimation in clinical trials using ventilator-free days as the primary outcome: a systematic review.

BACKGROUND: Ventilator-free days (VFDs) are a composite endpoint increasingly used as the primary outcome in critical care trials. However, because of the skewed distribution and competitive risk between components, sample size estimation remains challenging. This systematic review was conducted to systematically assess whether the sample size was congruent, as calculated to evaluate VFDs in trials, with VFDs' distribution and the impact of alternative methods on sample size estimation. METHODS: A systematic literature search was conducted within the PubMed and Embase databases for randomized clinical trials in adults with VFDs as the primary outcome until December 2021. We focused on peer-reviewed journals with 2021 impact factors greater than five. After reviewing definitions of VFDs, we extracted the sample size and methods used for its estimation. The data were collected by two independent investigators and recorded in a standardized, pilot-tested forms tool. Sample sizes were calculated using alternative statistical approaches, and risks of bias were assessed with the Cochrane risk-of-bias tool. RESULTS: Of the 26 clinical trials included, 19 (73%) raised "some concerns" when assessing risks of bias. Twenty-four (92%) trials were two-arm superiority trials, and 23 (89%) were conducted at multiple sites. Almost all the trials (96%) were unable to consider the unique distribution of VFDs and death as a competitive risk. Moreover, significant heterogeneity was found in the definitions of VFDs, especially regarding varying start time and type of respiratory support. Methods for sample size estimation were also heterogeneous, and simple models, such as the Mann-Whitney-Wilcoxon rank-sum test, were used in 14 (54%) trials. Finally, the sample sizes calculated varied by a factor of 1.6 to 17.4. CONCLUSIONS: A standardized definition and methodology for VFDs, including the use of a core outcome set, seems to be required. Indeed, this could facilitate the interpretation of findings in clinical trials, as well as their construction, especially the sample size estimation which is a trade-off between cost, ethics, and statistical power. Systematic review registration PROSPERO ID: CRD42021282304. Registered 15 December 2021 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021282304 ).

Prescription-free consultation in France and Europe: Rates' evolution, physicians' and patients' perceptions from 2005 to 2019, a systematic review.

BACKGROUND: In 2005, the rate of prescription-free consultations in Europe varied widely: 57% in the Netherlands, 28% in Germany, 17% in Spain and 10% in France. OBJECTIVES: To assess the number of prescription-free consultations in European countries since 2005 and to analyse the perceptions of patients and general practitioners (GPs). METHODS: This was a systematic review of the literature from 2005 to 2019, including both quantitative and qualitative studies on prescription-free consultations. RESULTS: Of 13,380 studies, 28 were included. The rates of prescription-free consultations were 30% in Belgium, 41% in Slovenia, 47% in the UK and 22% in France, according to the most recent figures. Swedish GPs estimated their prescription-free consultation rate at 70%. The only significant factor that decreased the number of prescription-free consultations was laboratory visits. According to the qualitative data, the main constraint was lack of time; the main facilitating factor was a shared medical decision. CONCLUSION: Medical visits decreased the number of prescription-free consultations. According to qualitative studies, the main barrier was lack of time. The countries with the highest drug consumption levels were those with the lowest number of prescription-free consultations. Achieving prescription-free consultations to combat overmedication and for the quality of care and the environment is a priority. To understand and analyse consultations without prescriptions, a quantitative observational study was launched in France in 2020.

Effectiveness of brief interventions in primary care for cannabis users aged from 12 to 25 years old: a systematic review.

INTRODUCTION: The aim of this systematic review was to assess the effectiveness of brief interventions realized in primary care in reducing cannabis use for adolescents and emerging adults. METHODS: PubMed, CINAHL, Embase, PsycInfo, and Central (Cochrane Library) were searched until December 2020. Randomized controlled trials conducted in primary care, concerning in-person brief interventions for non-medical cannabis users aged from 12 to 25 years old were eligible for inclusion. Brief interventions had to last 30 min or less. Patients with comorbid mental health disorder or very specific populations were not included. RESULTS: One thousand eighty hundred and fifty-five studies were identified through database searching; only 8 studies involving 2,199 patients were included for qualitative synthesis after double reading and data extraction. Randomized controlled trials selected were heterogeneous regarding screening tools, initial levels of cannabis use and cannabis outcomes measures. Brief interventions were all based on motivational interviewing techniques or personalized feedback. Seven studies consisted in a single session of brief intervention. Six studies involved also other substance users. No significant reduction of cannabis use after brief intervention was found for most studies, especially in the long term. A trend of decreased cannabis consequences, such as negative psychosocial repercussions, perception of cannabis use by peers, or driving under the influence of cannabis, was reported. CONCLUSION: The current state of knowledge does not allow us to say that the brief intervention is effective in reducing cannabis use among adolescents in primary care. We found a mild positive effect on cannabis consequences after brief intervention. Mixed qualitative and quantitative studies are need to better evaluate the impact of brief intervention and his faisability. PROSPERO (International Prospective Register of Systematic Reviews): n° CRD42016033080.

Benefits and adverse effects of sacubitril/valsartan in patients with chronic heart failure: A systematic review and meta-analysis.

This review aims to assess the benefits and adverse effects of sacubitril/valsartan in heart failure, with a focus on important patient outcomes. A systematic review was conducted of double-blind randomized controlled trials (RCTs) comparing sacubitril/valsartan versus a reference drug, in heart failure patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction, published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all-cause mortality and adverse events. From 2 082 articles analyzed, 5 were included. For all-cause mortality, the absolute numbers for HFrEF (2 RCTs, 4627 patients) were 16% on sacubitril/valsartan and 18% on enalapril, with a risk ratio (RR) of 0.85 [CI = 0.78, 0.93], and 13% vs 14% in with HFpEF (2 RCTs, 5097 patients), with no statistical difference. Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence for HFrEF patients was of moderate quality. For HFrEF patients, an increased risk of symptomatic hypotension and angioedema (low quality of evidence) was shown. There was no statistical difference for the risk of hyperkalemia or worsening renal function. There was a protective RR (0.50 [0.34, 0.75]) for worsening renal function for patients with HFpEF, with a high quality of evidence despite similar absolute numbers (1.4% vs. 2.8%). To keep in mind for shared decision-making, sacubitril/valsartan reduces all-cause mortality in HFrEF patients but for HFpEF further data are needed. Take into consideration the small number of studies to date to assess the risks.

Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis.

BACKGROUND: Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits. METHODS: We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects. DISCUSSION: This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (ID: CRD42019157236).