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BACKGROUND: Although aggregate data (AD) from randomised clinical trials (RCTs) are used in the majority of network meta-analyses (NMAs), other study designs (e.g., cohort studies and other non-randomised studies, NRS) can be informative about relative treatment effects. The individual participant data (IPD) of the study, when available, are preferred to AD for adjusting for important participant characteristics and to better handle heterogeneity and inconsistency in the network. RESULTS: We developed the R package crossnma to perform cross-format (IPD and AD) and cross-design (RCT and NRS) NMA and network meta-regression (NMR). The models are implemented as Bayesian three-level hierarchical models using Just Another Gibbs Sampler (JAGS) software within the R environment. The R package crossnma includes functions to automatically create the JAGS model, reformat the data (based on user input), assess convergence and summarize the results. We demonstrate the workflow within crossnma by using a network of six trials comparing four treatments. CONCLUSIONS: The R package crossnma enables the user to perform NMA and NMR with different data types in a Bayesian framework and facilitates the inclusion of all types of evidence recognising differences in risk of bias.
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Teorema de Bayes , Metaanálisis en Red , Programas Informáticos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación , Algoritmos , Metaanálisis como AsuntoRESUMEN
Autologous hematopoietic stem cell transplantation (AHSCT) is emerging as a potent treatment for highly active relapsing remitting multiple sclerosis (RRMS), potentially surpassing the efficacy of traditional disease-modifying therapies (DMTs). Phase II and III randomized controlled trials (RCTs) have demonstrated AHSCT's superiority in reducing relapse rates and delaying disability progression compared to standard DMTs. Despite the evolution of treatment guidelines, questions persist regarding patient selection criteria and optimal conditioning regimens. Notably, ongoing clinical trials in the United Kingdom, the United States, Italy, and Norway aim to address these uncertainties by evaluating the safety, efficacy, and long-term outcomes of AHSCT vs. high efficacy DMTs in both DMT-experienced and treatment-naïve patients with active RRMS or aggressive multiple sclerosis (MS). These trials promise to provide valuable insights into the positioning of AHSCT within the treatment landscape of MS.
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Trasplante de Células Madre Hematopoyéticas , Esclerosis Múltiple , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Esclerosis Múltiple/terapia , Trasplante Autólogo/métodosRESUMEN
BACKGROUND: Simulation is an important tool for assessing the performance of statistical methods for the analysis of data and for the planning of studies. While methods are available for the simulation of correlated binary random variables, all have significant practical limitations for simulating outcomes from longitudinal cluster randomised trial designs, such as the cluster randomised crossover and the stepped wedge trial designs. For these trial designs as the number of observations in each cluster increases these methods either become computationally infeasible or their range of allowable correlations rapidly shrinks to zero. METHODS: In this paper we present a simple method for simulating binary random variables with a specified vector of prevalences and correlation matrix. This method allows for the outcome prevalence to change due to treatment or over time, and for a 'nested exchangeable' correlation structure, in which observations in the same cluster are more highly correlated if they are measured in the same time period than in different time periods, and where different individuals are measured in each time period. This means that our method is also applicable to more general hierarchical clustered data contexts, such as students within classrooms within schools. The method is demonstrated by simulating 1000 datasets with parameters matching those derived from data from a cluster randomised crossover trial assessing two variants of stress ulcer prophylaxis. RESULTS: Our method is orders of magnitude faster than the most well known general simulation method while also allowing a much wider range of correlations than alternative methods. An implementation of our method is available in an R package NestBin. CONCLUSIONS: This simulation method is the first to allow for practical and efficient simulation of large datasets of binary outcomes with the commonly used nested exchangeable correlation structure. This will allow for much more effective testing of designs and inference methods for longitudinal cluster randomised trials with binary outcomes.
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Simulación por Computador , Estudios Cruzados , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Estudios Longitudinales , Análisis por Conglomerados , Proyectos de Investigación/estadística & datos numéricos , Modelos Estadísticos , Interpretación Estadística de Datos , AlgoritmosRESUMEN
BACKGROUND: The ideal blood pressure (BP) target in patients who undergo endovascular thrombectomy (EVT) with successful reperfusion is uncertain. Observational studies show that elevated BP during this period is associated with a higher risk of intracranial hemorrhage (ICH) and worse clinical outcomes. Several randomized controlled trials (RCTs) have explored whether intensive BP lowering improves clinical outcomes in these patients. AIMS: This review aims to summarize the recent RCTs that compare intensive and conventional BP management strategies following EVT and discuss the innovative directions to improve. RESULT: The recently published RCTs failed to demonstrate the benefit of intensive BP control on the functional outcome and decreasing the risk of ICH. The complex mechanism in cerebral blood flow regulation and the inappropriate BP range chosen in RCTs may be the reasons behind the inconsistent results between observational studies and RCTs. Individualized BP management, reducing BP variability, and multi-stage BP management should be paid more attention in future exploration. CONCLUSION: Intensive BP target did not improve clinical outcomes after successful EVT as compared with a conventional BP target. Further research is required to identify the optimal BP management strategy after reperfusion.
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Presión Sanguínea , Procedimientos Endovasculares , Ensayos Clínicos Controlados Aleatorios como Asunto , Trombectomía , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Trombectomía/métodos , Procedimientos Endovasculares/métodos , Presión Sanguínea/fisiología , Presión Sanguínea/efectos de los fármacosRESUMEN
BACKGROUND: Mediation analysis, often completed as secondary analysis to estimating the main treatment effect, investigates situations where an exposure may affect an outcome both directly and indirectly through intervening mediator variables. Although there has been much research on power in mediation analyses, most of this has focused on the power to detect indirect effects. Little consideration has been given to the extent to which the strength of the mediation pathways, i.e., the intervention-mediator path and the mediator-outcome path respectively, may affect the power to detect the total effect, which would correspond to the intention-to-treat effect in a randomized trial. METHODS: We conduct a simulation study to evaluate the relation between the mediation pathways and the power of testing the total treatment effect, i.e., the intention-to-treat effect. Consider a sample size that is computed based on the usual formula for testing the total effect in a two-arm trial. We generate data for a continuous mediator and a normal outcome using the conventional mediation models. We estimate the total effect using simple linear regression and evaluate the power of a two-sided test. We explore multiple data generating scenarios by varying the magnitude of the mediation paths whilst keeping the total effect constant. RESULTS: Simulations show the estimated total effect is unbiased across the considered scenarios as expected, but the mean of its standard error increases with the magnitude of the mediator-outcome path and the variability in the residual error of the mediator, respectively. Consequently, this affects the power of testing the total effect, which is always lower than planned when the mediator-outcome path is non-trivial and a naive sample size was employed. Analytical explanation confirms that the intervention-mediator path does not affect the power of testing the total effect but the mediator-outcome path. The usual effect size consideration can be adjusted to account for the magnitude of the mediator-outcome path and its residual error. CONCLUSIONS: The sample size calculation for studies with efficacy and mechanism evaluation should account for the mediator-outcome association or risk the power to detect the total effect/intention-to-treat effect being lower than planned.
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Simulación por Computador , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Tamaño de la Muestra , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Análisis de Mediación , Análisis de Intención de Tratar , Resultado del Tratamiento , Interpretación Estadística de Datos , Modelos Lineales , Modelos EstadísticosRESUMEN
BACKGROUND: The effectiveness of telemedicine in aiding rehabilitation exercises among patients with rotator cuff (RC) disorders remains unknown. Therefore, this meta-analysis aimed to assess the effectiveness of telemedicine in patients with RC disorders. METHODS: Randomized clinical trials (RCTs) on the effectiveness of telemedicine in patients with RC disorders were summarized through a meta-analysis. A systematic search for these RCTs was conducted in PubMed, Cochrane, Embase, and Web of Science databases up to July 2024. Statistical analysis was performed using Stata 16. Publication bias was estimated with the funnel plot and Egger's test. RESULTS: Ten studies involving 497 participants (telemedicine group = 248 and conventional group = 249) were enrolled, with follow-up durations ranging from 8 weeks to 48 weeks. Functional outcomes measured by the Constant-Murley score were markedly improved after treatment in the telemedicine group compared to the conventional group. Moreover, compared to conventional treatment, telemedicine significantly improved shoulder function evaluated by Quick Disabilities of the Arm, Shoulder, and Hand Score, relieved pain assessed by visual analog scale pain score, and improved range of motion after treatment and in the final follow-up period. CONCLUSION: Telemedicine has demonstrated potential in alleviating pain and enhancing shoulder function and motion in patients with RC injuries. It may be a feasible intervention for rehabilitation exercises. Further research with a large sample size and standardized treatment is warranted to validate these findings.
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Ensayos Clínicos Controlados Aleatorios como Asunto , Rango del Movimiento Articular , Lesiones del Manguito de los Rotadores , Dolor de Hombro , Telemedicina , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Lesiones del Manguito de los Rotadores/terapia , Lesiones del Manguito de los Rotadores/rehabilitación , Lesiones del Manguito de los Rotadores/fisiopatología , Dolor de Hombro/terapia , Dolor de Hombro/rehabilitación , Dolor de Hombro/etiología , Resultado del Tratamiento , Terapia por Ejercicio/métodos , Masculino , Femenino , Manguito de los Rotadores/fisiopatología , Persona de Mediana Edad , Adulto , Dimensión del Dolor/métodosRESUMEN
BACKGROUND: This study compares the effect of positive end-expiratory pressure (PEEP) on postoperative pulmonary complications (PPCs) in patients with obesity undergoing laparoscopic bariatric surgery (LBS) under general anesthesia with mechanical ventilation. METHODS: A comprehensive search was conducted in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Internet, Wanfang database, and Google Scholar for studies published up to July 29, 2023, without time or language restrictions. The search terms included "PEEP," "laparoscopic," and "bariatric surgery." Randomized controlled trials comparing different levels of PEEP or PEEP with zero-PEEP (ZEEP) in patients with obesity undergoing LBS were included. The primary outcome was a composite of PPCs, and the secondary outcomes were intraoperative oxygenation, respiratory compliance, and mean arterial pressure (MAP). A fixed-effect or random-effect model was selected for meta-analysis based on the heterogeneity of the included studies. RESULTS: Thirteen randomized controlled trials with a total of 708 participants were included for analysis. No statistically significant difference in PPCs was found between the PEEP and ZEEP groups (risk ratio = 0.27, 95% CI: 0.05-1.60; p = 0.15). However, high PEEP ≥ 10 cm H2O significantly decreased PPCs compared with low PEEP < 10 cm H2O (risk ratio = 0.20, 95% CI: 0.05-0.89; p = 0.03). The included studies showed no significant heterogeneity (I2 = 20% & 0%). Compared with ZEEP, PEEP significantly increased intraoperative oxygenation and respiratory compliance (WMD = 74.97 mm Hg, 95% CI: 41.74-108.21; p < 0.001 & WMD = 9.40 ml cm H2O- 1, 95% CI: 0.65-18.16; p = 0.04). High PEEP significantly improved intraoperative oxygenation and respiratory compliance during pneumoperitoneum compared with low PEEP (WMD = 66.81 mm Hg, 95% CI: 25.85-107.78; p = 0.001 & WMD = 8.03 ml cm H2O- 1, 95% CI: 4.70-11.36; p < 0.001). Importantly, PEEP did not impair hemodynamic status in LBS. CONCLUSIONS: In patients with obesity undergoing LBS, high PEEP ≥ 10 cm H2O could decrease PPCs compared with low PEEP < 10 cm H2O, while there was a similar incidence of PPCs between PEEP (8-10 cm H2O) and the ZEEP group. The application of PEEP in ventilation strategies increased intraoperative oxygenation and respiratory compliance without affecting intraoperative MAP. A PEEP of at least 10 cm H2O is recommended to reduce PPCs in patients with obesity undergoing LBS. REGISTRATION NUMBER: CRD42023391178 in PROSPERO.
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Cirugía Bariátrica , Laparoscopía , Respiración con Presión Positiva , Complicaciones Posoperatorias , Humanos , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/métodos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/prevención & control , Obesidad/cirugía , Respiración con Presión Positiva/métodos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
Critical care trials evaluate the effect of interventions in patients with diverse personal histories and causes of illness, often under the umbrella of heterogeneous clinical syndromes, such as sepsis or acute respiratory distress syndrome. Given this variation, it is reasonable to expect that the effect of treatment on outcomes may differ for individuals with variable characteristics. However, in randomized controlled trials, efficacy is typically assessed by the average treatment effect (ATE), which quantifies the average effect of the intervention on the outcome in the study population. Importantly, the ATE may hide variations of the treatment's effect on a clinical outcome across levels of patient characteristics, which may erroneously lead to the conclusion that an intervention does not work overall when it may in fact benefit certain patients. In this review, we describe methodological approaches for assessing heterogeneity of treatment effect (HTE), including expert-derived subgrouping, data-driven subgrouping, baseline risk modeling, treatment effect modeling, and individual treatment rule estimation. Next, we outline how insights from HTE analyses can be incorporated into the design of clinical trials. Finally, we propose a research agenda for advancing the field and bringing HTE approaches to the bedside.
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Cuidados Críticos , Medicina de Precisión , Humanos , Cuidados Críticos/métodos , Medicina de Precisión/métodos , Proyectos de Investigación , Estudios Observacionales como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
BACKGROUND: Spillover of effect, whether positive or negative, from intervention to control group patients invalidates the Stable Unit Treatment Variable Assumption (SUTVA). SUTVA is critical to valid causal inference from randomized concurrent controlled trials (RCCT). Spillover of infection prevention is an important population level effect mediating herd immunity. This herd effect, being additional to any individual level effect, is subsumed within the overall effect size (ES) estimate derived by contrast-based techniques from RCCT's. This herd effect would manifest only as increased dispersion among the control group infection incidence rates above background. METHODS AND RESULTS: The objective here is to explore aspects of spillover and how this might be visualized and diagnosed. I use, for illustration, data from 190 RCCT's abstracted in 13 Cochrane reviews of various antimicrobial versus non-antimicrobial based interventions to prevent pneumonia in ICU patients. Spillover has long been postulated in this context. Arm-based techniques enable three approaches to identify increased dispersion, not available from contrast-based techniques, which enable the diagnosis of spillover within antimicrobial versus non-antimicrobial based infection prevention RCCT's. These three approaches are benchmarking the pneumonia incidence rates versus a clinically relevant range, comparing the dispersion in pneumonia incidence among the control versus the intervention groups and thirdly, visualizing the incidence dispersion within summary receiver operator characteristic (SROC) plots. By these criteria there is harmful spillover effects to concurrent control group patients. CONCLUSIONS: Arm-based versus contrast-based techniques lead to contrary inferences from the aggregated RCCT's of antimicrobial based interventions despite similar summary ES estimates. Moreover, the inferred relationship between underlying control group risk and ES is 'flipped'.
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Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Neumonía/diagnóstico , Incidencia , Pruebas Diagnósticas de Rutina/métodos , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Unidades de Cuidados Intensivos/estadística & datos numéricosRESUMEN
A dynamic treatment regime (DTR) is a mathematical representation of a multistage decision process. When applied to sequential treatment selection in medical settings, DTRs are useful for identifying optimal therapies for chronic diseases such as AIDs, mental illnesses, substance abuse, and many cancers. Sequential multiple assignment randomized trials (SMARTs) provide a useful framework for constructing DTRs and providing unbiased between-DTR comparisons. A limitation of SMARTs is that they ignore data from past patients that may be useful for reducing the probability of exposing new patients to inferior treatments. In practice, this may result in decreased treatment adherence or dropouts. To address this problem, we propose a generalized outcome-adaptive (GO) SMART design that adaptively unbalances stage-specific randomization probabilities in favor of treatments observed to be more effective in previous patients. To correct for bias induced by outcome adaptive randomization, we propose G-estimators and inverse-probability-weighted estimators of DTR effects embedded in a GO-SMART and show analytically that they are consistent. We report simulation results showing that, compared to a SMART, Response-Adaptive SMART and SMART with adaptive randomization, a GO-SMART design treats significantly more patients with the optimal DTR and achieves a larger number of total responses while maintaining similar or better statistical power.
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Simulación por Computador , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Modelos Estadísticos , Resultado del Tratamiento , SesgoRESUMEN
BACKGROUND: Benefits of different types of family-centred care (FCC) interventions in neonatal intensive care units (NICUs) have been reported. However, a comprehensive review of existing FCC intervention studies was lacking. OBJECTIVE: This review aimed at synthesising the characteristics of FCC interventions, related outcomes and measurement methods in randomised controlled trials (RCTs) in NICU, and providing menus of options to favour implementation and further research. METHODS: We searched PubMed, EMBASE, Web of Science and the Cochrane Library up to 31 January 2022. Interventions were mapped according to five categories as defined by a previous Cochrane review. We described outcome types, measurement populations, measurement methods and timelines. Subgroup analyses were also performed. RESULTS: Out of 6583 studies identified, 146 met eligibility criteria. Overall, 52 (35.6%) RCTs tested more than one category of intervention, with a large variety of combinations, with the most frequent category of intervention being the educational (138 RCTs, 94.5%). We identified a total of 77 different intervention packages, and RCTs comparing the same interventions were lacking. The 146 RCTs reported on 425 different outcomes, classified in 13 major categories with parental mental health (61 RCTs, 41.8% of total RCTs) being the most frequent category in parents, and neurobehavioural/developmental outcomes being the most frequent category in newborns (62 RCTs, 42.5%). For several categories of outcomes almost every RCT used a different measurement method. Educational interventions targeting specifically staff, fathers, siblings and other family members were lacking or poorly described. Only one RCT measured outcomes in health workers, two in siblings and none considered other family members. CONCLUSIONS: A large variety of interventions, outcomes and measurement methods were used in FCC studies in NICU. The derived menus of options should be helpful for researchers and policy makers to identify interventions most suitable in each setting and to further standardise research methods.
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Unidades de Cuidado Intensivo Neonatal , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Recién NacidoRESUMEN
BACKGROUND: Pre-frailty is associated with increased healthcare utilization. Over the past decade, public health interventions such as community-based exercises to target pre-frailty have been increasingly studied. However, the effects of community-based exercises on clinical outcome measures amongst community-dwelling older adults with pre-frailty remain unclear. This review aims to better understand the effects of community-based exercise on physical function, cognition, quality of life and frailty status in community-dwelling pre-frail older adults. A secondary objective was to investigate the optimal exercise parameters on clinical outcomes. METHODS: Searches of MEDLINE, CINAHL, Google Scholar and Web of Science databases were conducted. Articles were included if they were randomized controlled trials (RCTs), and excluded if the participants consist of less than 50% pre-frail community-dwelling older adults. Meta-analyses (where possible) with either a fixed- or random- effect(s) model, standardized mean difference (SMD), odds ratio (OR) and tests of heterogeneity were performed. Multivariable meta-regression was performed to identify predictors of statistically significant outcome measures. The risk of bias was assessed using the modified Cochrane Risk-of-Bias tool. RESULTS: Twenty-two RCTs with 900 participants in the experimental group and 1015 participants in the control group were included. When compared to minimal intervention, community-based exercises significantly improved lower limb strength (10 RCTs, 384 participants in the experimental group and 482 participants in the control group) with SMD 0.67 (95% CI 0.29 to 1.04), and lower limb function (5 RCTs, 120 participants in the experimental group and 219 participants in the control group) with SMD 0.27 (95% CI 0.03 to 0.51). Those who have received community-based exercises were more likely to reverse from pre-frailty to healthy state (OR = 2.74, 95% CI 1.36 to 5.51) (6 RCTs, 263 participants in the experimental group and 281 participants in the control group). The frequency of exercise sessions was a significant predictor of the effect size for gait speed (P<0.05). CONCLUSIONS: Community-based exercise intervention is superior to minimal intervention for improving health status in pre-frail older adults. This has implications on the implementation of community-based exercise intervention by healthcare providers and policymakers. OTHER: Nil funding for this review. PROSPERO registration number CRD42022348556.
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Terapia por Ejercicio , Vida Independiente , Humanos , Anciano , Terapia por Ejercicio/métodos , Estado de Salud , Calidad de Vida , Fragilidad , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Anciano Frágil , Anciano de 80 o más AñosRESUMEN
INTRODUCTION: Pakistan has significantly strengthened its capacity for active case finding (ACF) for tuberculosis (TB) that is being implemented at scale in the country. However, yields of ACF have been lower than expected, raising concerns on its effectiveness in the programmatic setting. Distribution of TB in communities is likely to be spatially heterogeneous and targeting of ACF in areas with higher TB prevalence may help improve yields. The primary aim of SPOT-TB is to investigate whether a policy change to use a geographically targeted approach towards ACF supported by an artificial intelligence (AI) software, MATCH-AI, can improve yields in Pakistan. METHODS AND ANALYSIS: SPOT-TB will use a pragmatic, stepped wedge cluster randomised design. A total of 30 mobile X-ray units and their field teams will be randomised to receive the intervention. Site selection for ACF in the intervention areas will be guided primarily through the use of MATCH-AI software that models subdistrict TB prevalence and identifies potential disease hotspots. Control areas will use existing approaches towards site selection that are based on staff knowledge, experience and analysis of historical data. The primary outcome measure is the difference in bacteriologically confirmed incident TB detected in the intervention relative to control areas. All remaining ACF-related procedures and algorithms will remain unaffected by this trial. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Health Services Academy, Islamabad, Pakistan (7-82/IERC-HSA/2022-52) and from the Common Management Unit for TB, HIV and Malaria, Ministry of Health Services, Regulation and Coordination, Islamabad, Pakistan (26-IRB-CMU-2023). Findings from this study will be disseminated through publications in peer-reviewed journals and stakeholder meetings in Pakistan with the implementing partners and public-sector officials. Findings will also be presented at local and international medical and public health conferences. TRIAL REGISTRATION NUMBER: NCT06017843.
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Inteligencia Artificial , Tuberculosis , Humanos , Pakistán/epidemiología , Tuberculosis/epidemiología , Programas Informáticos , Prevalencia , Ensayos Clínicos Pragmáticos como Asunto , Tamizaje Masivo/métodos , Tuberculosis Pulmonar/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
Importance: The COVID-19 pandemic created unprecedented challenges for clinical trials worldwide, threatening premature closure and trial integrity. Every phase of research operations was affected, often requiring modifications to protocol design and implementation. Objectives: To identify the barriers, solutions, and opportunities associated with continuing critical care trials that were interrupted during the pandemic, and to generate suggestions for future trials. Design, Setting, and Participants: This mixed-methods study performed an explanatory sequential analysis involving a self-administered electronic survey and focus groups of principal investigators (PIs) and project coordinators (PCs) conducting adult and pediatric individual-patient randomized trials of the Canadian Critical Care Trials Group during the COVID-19 pandemic. Eligible trials were actively enrolling patients on March 11, 2020. Data were analyzed between September 2023 and January 2024. Main Outcomes and Measures: Importance ratings of barriers to trial conduct and completion, solutions employed, opportunities arising, and suggested strategies for future trials. Quantitative data examining barriers were analyzed using descriptive statistics. Data addressing solutions, opportunities, and suggestions were analyzed by qualitative content analysis. Integration involved triangulation of data sources and perspectives about 13 trials, synthesized by an interprofessional team incorporating reflexivity and member-checking. Results: A total of 13 trials run by 29 PIs and PCs (100% participation rate) were included. The highest-rated barriers (on a 5-point scale) to ongoing conduct during the pandemic were decisions to pause all clinical research (mean [SD] score, 4.7 [0.8]), focus on COVID-19 studies (mean [SD] score, 4.6 [0.8]), and restricted family presence in hospitals (mean [SD] score, 4.1 [0.8]). Suggestions to enable trial progress and completion included providing scientific leadership, implementing technology for communication and data management, facilitating the informed consent process, adapting the protocol as necessary, fostering site engagement, initiating new sites, streamlining ethics and contract review, and designing nested studies. The pandemic necessitated new funding opportunities to sustain trial enrollment. It increased public awareness of critical illness and the importance of randomized trial evidence. Conclusions and Relevance: While underscoring the vital role of research in society and drawing the scientific community together with a common purpose, the pandemic signaled the need for innovation to ensure the rigor and completion of ongoing trials. Lessons learned to optimize research procedures will help to ensure a vibrant clinical trials enterprise in the future.
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COVID-19 , Cuidados Críticos , Pandemias , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Canadá , Ensayos Clínicos como Asunto , Proyectos de Investigación , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Grupos Focales , AdultoRESUMEN
BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
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Fibrilación Atrial , Inhibidores del Factor Xa , Selección de Paciente , Pirazoles , Piridonas , Rivaroxabán , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificación , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/etiología , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Piridonas/efectos adversos , Piridonas/administración & dosificación , Rivaroxabán/administración & dosificación , Rivaroxabán/uso terapéutico , Masculino , Femenino , Anciano , Resultado del Tratamiento , Sistema de Registros , Administración Oral , Factores de Riesgo , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Medición de Riesgo/métodos , Anticoagulantes/uso terapéutico , Vitamina K/antagonistas & inhibidoresRESUMEN
BACKGROUND: Data on the effectiveness of erector spinae plane block (ESPB) for patients undergoing liver surgeries is limited and inconclusive. We hereby aimed to systematically review if ESPB can provide adequate analgesia after liver surgery. METHODS: PubMed, CENTRAL, Scopus, Embase, and gray literature were examined up to 25th April 2023 for randomized controlled trials (RCTs) comparing ESPB with control or spinal analgesia. RESULTS: Nine RCTs were included of which three compared ESPB with spinal analgesia. 24-hour opioid consumption did not differ significantly between ESPB vs. control (MD: -35.25 95% CI: -77.01, 6.52 I2 = 99%) or ESPB vs. spinal analgesia (MD: 2.32 95% CI: -6.12, 10.77 I2 = 91%). Comparing pain scores between ESPB and control, a small but significant effect favoring ESPB was noted at 12 h and 48 h, but not at 6-8 h and 24 h. Pain scores did not differ between ESPB and spinal analgesia. The risk of postoperative nausea and vomiting was also not significantly different between ESPB vs. control or spinal analgesia. GRADE assessment shows moderate certainty of evidence. CONCLUSION: ESPB may not provide any significant postoperative analgesia in liver surgery patients. There was a tendency of reduced opioid consumption with ESPB. Limited data also showed that ESPB and spinal analgesia had no difference in pain scores and 24-hour analgesic consumption.
Asunto(s)
Bloqueo Nervioso , Dolor Postoperatorio , Músculos Paraespinales , Humanos , Dolor Postoperatorio/prevención & control , Bloqueo Nervioso/métodos , Hígado/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS: A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS: The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION: These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.