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In this Decade of the Brain, research is changing the approach to stroke: No longer something to wait out, it's becoming amenable to intervention. This puts a premium on asking the right questions early. [ABSTRACT FROM AUTHOR]

Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research., (© 2024 John Wiley & Sons Ltd.)

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction., (© 2023 John Wiley & Sons Ltd.)

Background/aims: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy., Methods: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios., Results: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis., Conclusion: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Importance: Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, a barrier to the uptake of bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared with a frequentist design., Objective: To compare the performance of a bayesian and a frequentist adaptive clinical trial design., Design, Setting, and Participants: This prospective cohort study compared 2 trial designs for a completed multicenter acute stroke trial conducted within a National Institutes of Health neurologic emergencies clinical trials network, with individual patient-level data, including the timing and order of enrollments and outcome ascertainment, from 1151 patients with acute stroke and hyperglycemia randomized to receive intensive or standard insulin therapy. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses at 90 days after randomization for 500, 700, 900, and 1100 patients. The bayesian alternative used predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients and subsequent interims after every 100 randomizations., Main Outcomes and Measures: The main outcome was the sample size at end of study, which was defined as the sample size at which each of the studies stopped accrual of patients., Results: Data were collected from 1151 patients. As conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the bayesian alternative crossed the futility boundary approximately 3 months earlier after 800 participants were randomized., Conclusions and Relevance: Both trial designs stopped for futility before reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial's primary question earlier. The common feature across the 2 designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how these analyses were implemented between the 2 trials resulted in the differences in early stopping.

Objective: Alterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS., Approach: The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin-antithrombin (TAT) complex; D-dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor-1 (PAI-1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two-way analysis of variance., Results: A total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA ( P  = 0.02) and PAI-1 ( P  = .04) and FVIIa ( P  = .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes ( P  = .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes ( P  = .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome ( P  = .006)., Conclusions: Intensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

Importance: The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown., Objective: To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg., Design, Setting, and Participants: This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included., Interventions: Intravenous nicardipine infusion titrated to goals., Main Outcomes and Measures: Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge., Results: A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events., Conclusions and Relevance: The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points., Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points., Design, Setting, and Participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018., Main Outcomes and Measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated., Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%., Conclusions and Relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial., Trial Registration: ClinicalTrials.gov identifier: NCT00991029.

Background: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone., Methods: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models., Results: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset., Conclusions: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example., (© 2019 John Wiley & Sons, Ltd.)

In 2005, the American Stroke Association published recommendations for the establishment of stroke systems of care and in 2013 expanded on them with a statement on interactions within stroke systems of care. The aim of this policy statement is to provide a comprehensive review of the scientific evidence evaluating stroke systems of care to date and to update the American Stroke Association recommendations on the basis of improvements in stroke systems of care. Over the past decade, stroke systems of care have seen vast improvements in endovascular therapy, neurocritical care, and stroke center certification, in addition to the advent of innovations, such as telestroke and mobile stroke units, in the context of significant changes in the organization of healthcare policy in the United States. This statement provides an update to prior publications to help guide policymakers and public healthcare agencies in continually updating their stroke systems of care in light of these changes. This statement and its recommendations span primordial and primary prevention, acute stroke recognition and activation of emergency medical services, triage to appropriate facilities, designation of and treatment at stroke centers, secondary prevention at hospital discharge, and rehabilitation and recovery.

Background and Purpose: We compared the rates of death or disability, defined by modified Rankin Scale score of 4 to 6, at 3 months in patients with intracerebral hemorrhage according to post-treatment systolic blood pressure (SBP)-attained status., Methods: We divided 1000 subjects with SBP ≥180 mm Hg who were randomized within 4.5 hours of symptom onset as follows: SBP <140 mm Hg achieved or not achieved within 2 hours; subjects in whom SBP <140 mm Hg was achieved within 2 hours were further divided: SBP <140 mm Hg for 21 to 22 hours (reduced and maintained) or SBP was ≥140 mm Hg for at least 2 hours during the period between 2 and 24 hours (reduced but not maintained)., Results: Compared with subjects without reduction of SBP <140 mm Hg within 2 hours, subjects with reduction and maintenance of SBP <140 mm Hg within 2 hours had a similar rate of death or disability (relative risk of 0.98; 95% confidence interval, 0.74-1.29). The rates of neurological deterioration within 24 hours were significantly higher in reduced and maintained group (10.4%; relative risk, 1.98; 95% confidence interval, 1.08-3.62) and in reduced but not maintained group (11.5%; relative risk, 2.08; 95% confidence interval, 1.15-3.75) compared with reference group. The rates of cardiac-related adverse events within 7 days were higher among subjects with reduction and maintenance of SBP <140 mmHg compared to subjects without reduction (11.2% versus 6.4%)., Conclusions: No decline in death or disability but higher rates of neurological deterioration and cardiac-related adverse events were observed among intracerebral hemorrhage subjects with reduction with and without maintenance of intensive SBP goals., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565., (© 2018 American Heart Association, Inc.)

Objectives: Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed., Methods: To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations., Results: The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies., Conclusion: Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Berry reported that he is a part owner of Berry Consultants LLC, a statistical consulting firm that specializes in the design, implementation, and analysis of Bayesian adaptive clinical trials for pharmaceutical manufacturers, medical device companies, and academic institutions; Dr Lewis reported that he is the senior medical scientist of Berry Consultants LLC; both Dr Lewis and the Los Angeles Biomedical Research Institute are compensated for his time.

Background: Adaptive clinical trials use accumulating data from enrolled subjects to alter trial conduct in pre-specified ways based on quantitative decision rules. In this research, we sought to characterize the perspectives of key stakeholders during the development process of confirmatory-phase adaptive clinical trials within an emergency clinical trials network and to build a model to guide future development of adaptive clinical trials., Methods: We used an ethnographic, qualitative approach to evaluate key stakeholders' views about the adaptive clinical trial development process. Stakeholders participated in a series of multidisciplinary meetings during the development of five adaptive clinical trials and completed a Strengths-Weaknesses-Opportunities-Threats questionnaire. In the analysis, we elucidated overarching themes across the stakeholders' responses to develop a conceptual model., Results: Four major overarching themes emerged during the analysis of stakeholders' responses to questioning: the perceived statistical complexity of adaptive clinical trials and the roles of collaboration, communication, and time during the development process. Frequent and open communication and collaboration were viewed by stakeholders as critical during the development process, as were the careful management of time and logistical issues related to the complexity of planning adaptive clinical trials., Conclusion: The Adaptive Design Development Model illustrates how statistical complexity, time, communication, and collaboration are moderating factors in the adaptive design development process. The intensity and iterative nature of this process underscores the need for funding mechanisms for the development of novel trial proposals in academic settings.

Background: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage., Methods: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments., Results: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002)., Conclusions: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Context: The context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials., Objectives: The purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development., Materials and Methods: We conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials., Results: The qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community., Discussion and Conclusions: While participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials.

Background: In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts' views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs., Methods: We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20)., Results: The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns., Conclusions: Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.

Background: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI., Methods: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score., Results: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes., Conclusions: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Acute stroke is an important focus of quality improvement efforts. There are many organizations involved in quality measurement for acute stroke, and a complex landscape of quality measures exists. Our objective is to describe and evaluate existing US quality measures for the emergency care of acute ischemic stroke patients in the emergency department (ED) setting. We performed a systematic review of the literature to identify the existing quality measures for the emergency care of acute ischemic stroke. We then convened a panel of experts to appraise how well the measures satisfy the American College of Cardiology/American Heart Association (ACC/AHA) criteria for performance measure development (strength of the underlying evidence, clinical importance, magnitude of the relationship between performance and outcome, and cost-effectiveness). We identified 7 quality measures relevant to the emergency care of acute ischemic stroke that fall into 4 main categories: brain imaging, thrombolytic administration, dysphagia screening, and mortality. Three of the 7 measures met all 4 of the ACC/AHA evaluation criteria: brain imaging within 24 hours, thrombolytic therapy within 3 hours of symptom onset, and thrombolytic therapy within 60 minutes of hospital arrival. Measures not satisfying all evaluation criteria were brain imaging report within 45 minutes, consideration for thrombolytic therapy, dysphagia screening, and mortality rate. There remains room for improvement in the development and use of measures that reflect high-quality emergency care of acute ischemic stroke patients in the United States., (Copyright © 2014 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Effective treatments for acute neurologic illness and injury are lacking, particularly for spinal cord injury (SCI). The very structure of clinical trials may be contributing to this because assumptions made during trial planning preclude additional learning within residual important areas of uncertainty, such as dose, timing, and duration of treatment. Adaptive clinical trials offer potential solutions to some of the factors that may be slowing the pace of discovery. Broadly defined, one can consider an adaptive clinical trial as any sort of clinical trial that makes use of information from within the trial to make decisions about how the trial is conducted going forward; however, it is important to emphasize that regardless of the degree of flexibility or complexity of an adaptive clinical trial design, the types of designs being described are only those in which all potential changes to the conduct of the trial are prospectively defined before the first patient is enrolled. Within this review, we describe the structure of flexible adaptive clinical trial designs, the process by which they are developed and conducted, and potential opportunities and drawbacks of these approaches. We must accept that there are some uncertainties that remain when both exploratory and confirmatory trials are designed. The process by which teams carefully consider which uncertainties are most important and most likely to potentially compromise the ability to detect an effective treatment can lead to trial designs that are more likely to find the right treatment for the right population of patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The telemedicine intervention in chronic disease management promises to involve patients in their own care, provides continuous monitoring by their healthcare providers, identifies early symptoms, and responds promptly to exacerbations in their illnesses. This review set out to establish the evidence from the available literature on the impact of telemedicine for the management of three chronic diseases: congestive heart failure, stroke, and chronic obstructive pulmonary disease. By design, the review focuses on a limited set of representative chronic diseases because of their current and increasing importance relative to their prevalence, associated morbidity, mortality, and cost. Furthermore, these three diseases are amenable to timely interventions and secondary prevention through telemonitoring. The preponderance of evidence from studies using rigorous research methods points to beneficial results from telemonitoring in its various manifestations, albeit with a few exceptions. Generally, the benefits include reductions in use of service: hospital admissions/re-admissions, length of hospital stay, and emergency department visits typically declined. It is important that there often were reductions in mortality. Few studies reported neutral or mixed findings.

Rationale: Patients with acute ischemic stroke and hyperglycemia have worse outcomes than those without hyperglycemia. Intensive glucose control during acute stroke is feasible and can be accomplished safely but has not been fully assessed for efficacy., Aims: The Stroke Hyperglycemia Insulin Network Effort trial aims to determine the safety and efficacy of standard vs. intensive glucose control with insulin in hyperglycemic acute ischemic stroke patients., Design: This is a randomized, blinded, multicenter, phase III trial of approximately 1400 hyperglycemic patients who receive either standard sliding scale subcutaneous insulin (blood glucose range 80-179 mg/dL, 4·44-9·93 mmol/L) or continuous intravenous insulin (target blood glucose 80-130 mg/dL, 4·44-7·21 mmol/L) for up to 72 h, starting within 12 h of stroke symptom onset. The acute treatment phase is single blind (for the patients), but the final outcome assessment is double blind. The study is powered to detect a 7% absolute difference in favorable outcome at 90 days., Study Outcomes: The primary outcome is a baseline severity adjusted 90-day modified Rankin Scale score, defined as 0, 0-1, or 0-2, if the baseline National Institutes of Health Stroke Scale score is 3-7, 8-14, or 15-22, respectively. The primary safety outcome is the rate of severe hypoglycemia (<40 mg/dL, <2·22 mmol/L)., Discussion: This trial will provide important novel information about preferred management of acute ischemic stroke patients with hyperglycemia. It will determine the potential benefits and risks of intensive glucose control during acute stroke., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

Background: In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome., Methods: We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495., Findings: 422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 0·96, 95% CI 0·84-1·10, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%., Interpretation: Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome., Funding: National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Randomized clinical trials, which aim to determine the efficacy and safety of drugs and medical devices, are a complex enterprise with myriad challenges, stakeholders, and traditions. Although the primary goal is scientific discovery, clinical trials must also fulfill regulatory, clinical, and ethical requirements. Innovations in clinical trials methodology have the potential to improve the quality of knowledge gained from trials, the protection of human subjects, and the efficiency of clinical research. Adaptive clinical trial methods represent a broad category of innovations intended to address a variety of long-standing challenges faced by investigators, such as sensitivity to previous assumptions and delayed identification of ineffective treatments. The implementation of adaptive clinical trial methods, however, requires greater planning and simulation compared with a more traditional design, along with more advanced administrative infrastructure for trial execution. The value of adaptive clinical trial methods in exploratory phase (phase 2) clinical research is generally well accepted, but the potential value and challenges of applying adaptive clinical trial methods in large confirmatory phase clinical trials are relatively unexplored, particularly in the academic setting. In the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) project, a multidisciplinary team is studying how adaptive clinical trial methods could be implemented in planning actual confirmatory phase trials in an established, National Institutes of Health-funded clinical trials network. The overarching objectives of ADAPT-IT are to identify and quantitatively characterize the adaptive clinical trial methods of greatest potential value in confirmatory phase clinical trials and to elicit and understand the enthusiasms and concerns of key stakeholders that influence their willingness to try these innovative strategies., (Copyright © 2012. Published by Mosby, Inc.)

Stroke is a major public health concern afflicting an estimated 795,000 Americans annually. The associated morbidity and mortality is staggering. Early treatment with thrombolytics is beneficial. The window for treatment is narrow and minimization of the time from symptom onset to treatment is vital. The general population is not well informed as to the warning signs or symptoms of stroke, leading to substantial delays in emergency medical services (EMS) activation. Ambulance transport of stroke patients to the hospital has demonstrated improvements in key benchmarks such as door to physician evaluation, door to CT initiation, and increased thrombolytic treatment. Pre-hospital notification of the impending arrival of a stroke patient allows for vital preparation in the treating emergency department, and improving timely evaluation and treatment upon arrival of the stroke patient. EMS systems are a vital component of the management of stroke patients, and resources used to improve these systems are beneficial., (© 2012 New York Academy of Sciences.)

Background: Although many global health programs focus on providing clinical care or medical education, improving clinical operations can have a significant effect on patient care delivery, especially in developing health systems without high-level operations management. Lean manufacturing techniques have been effective in decreasing emergency department (ED) length of stay, patient waiting times, numbers of patients leaving without being seen, and door-to-balloon times for ST-elevation myocardial infarction in developed health systems, but use of Lean in low to middle income countries with developing emergency medicine (EM) systems has not been well characterized., Objectives: To describe the application of Lean manufacturing techniques to improve clinical operations at Komfo Anokye Teaching Hospital (KATH) in Ghana and to identify key lessons learned to aid future global EM initiatives., Methods: A 3-week Lean improvement program focused on the hospital admissions process at KATH was completed by a 14-person team in six stages: problem definition, scope of project planning, value stream mapping, root cause analysis, future state planning, and implementation planning., Results: The authors identified eight lessons learned during our use of Lean to optimize the operations of an ED in a global health setting: 1) the Lean process aided in building a partnership with Ghanaian colleagues; 2) obtaining and maintaining senior institutional support is necessary and challenging; 3) addressing power differences among the team to obtain feedback from all team members is critical to successful Lean analysis; 4) choosing a manageable initial project is critical to influence long-term Lean use in a new environment; 5) data intensive Lean tools can be adapted and are effective in a less resourced health system; 6) several Lean tools focused on team problem-solving techniques worked well in a low-resource system without modification; 7) using Lean highlighted that important changes do not require an influx of resources; and 8) despite different levels of resources, root causes of system inefficiencies are often similar across health care systems, but require unique solutions appropriate to the clinical setting., Conclusions: Lean manufacturing techniques can be successfully adapted for use in developing health systems. Lessons learned from this Lean project will aid future introduction of advanced operations management techniques in low- to middle-income countries., (© 2012 by the Society for Academic Emergency Medicine.)

Background: Ischemic cerebrovascular accidents remain a leading cause of morbidity and mortality. Thrombolytic therapy for acute ischemic stroke within 3h of symptom onset of highly select patients has been advocated by some groups since 1995, but trials have yielded inconsistent outcomes. One recent trial demonstrated significant improvement when the therapeutic window was extended to 4.5h., Clinical Question: Does the intravenous systemic administration of tPA within 4.5h to select patients with acute ischemic stroke improve functional outcomes?, Evidence Review: All randomized controlled trials enrolling patients within 4.5h were identified, in addition to a meta-analysis of these trial data., Results: The National Institute of Neurological Disorders and Stroke (NINDS) and European Cooperative Acute Stroke Study III (ECASS III) clinical trials demonstrated significantly improved outcomes at 3 months, with increased rates of intracranial hemorrhage, whereas ECASS II and the Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study showed increased hemorrhagic complications without improving outcomes. Meta-analysis of trial data from all ECASS trials, NINDS, and ATLANTIS suggest that thrombolysis within 4.5h improves functional outcomes., Conclusion: Ischemic stroke tPA treatment within 4.5h seems to improve functional outcomes and increases symptomatic intracranial hemorrhage rates without significantly increasing mortality., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Study Objective: The National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. The NIH Trauma Research Roundtable was convened on June 22 to 23, 2009. The objectives of the roundtable are to identify key research questions essential to advancing the scientific underpinnings of emergency trauma care and to discuss the barriers and best means to advance research by exploring the role of trauma research networks and collaboration between NIH and the emergency trauma care community., Methods: Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. During and after the conference, the lists were circulated among the participants and revised to reach a consensus., Results: Emergency trauma care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype of patients on the time spectrum of acuity and severity after injury and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency trauma research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical injuries, and the development of treatments capable of halting or reversing them; the need for novel experimental models of acute injury; the need to assess the effect of development and aging on the postinjury response; and the need to understand why there are regional differences in outcomes after injury. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles., Conclusion: The science of emergency trauma care may be advanced by facilitating the following: (1) development of an acute injury template for clinical research; (2) developing emergency trauma clinical research networks; (3) integrating emergency trauma research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving acute trauma and emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; (7) performing research to address ethical and regulatory issues; and (8) training emergency care investigators with research training programs., (Copyright © 2010 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Study Objective: The Institute of Medicine Committee on the Future of Emergency Care in the United States Health System (2003) identified a need to enhance the research base for emergency care. As a result, a National Institutes of Health (NIH) Task Force on Research in Emergency Medicine was formed to enhance NIH support for emergency care research. Members of the NIH Task Force and academic leaders in emergency care participated in 3 Roundtable discussions to prioritize current opportunities for enhancing and conducting emergency care research. We identify key research questions essential to advancing the science of emergency care and discuss the barriers and strategies to advance research by exploring the collaboration between NIH and the emergency care community., Methods: Experts from emergency medicine, neurology, psychiatry, and public health assembled to review critical areas in need of investigation, current gaps in knowledge, barriers, and opportunities. Neurologic emergencies included cerebral resuscitation, pain, stroke, syncope, traumatic brain injury, and pregnancy. Mental health topics included suicide, agitation and delirium, substances, posttraumatic stress, violence, and bereavement., Results: Presentations and group discussion firmly established the need for translational research to bring basic science concepts into the clinical arena. A coordinated continuum of the health care system that ensures rapid identification and stabilization and extends through discharge is necessary to maximize overall patient outcomes. There is a paucity of well-designed, focused research on diagnostic testing, clinical decisionmaking, and treatments in the emergency setting. Barriers include the limited number of experienced researchers in emergency medicine, limited dedicated research funding, and difficulties of conducting research in chaotic emergency environments stressed by crowding and limited resources. Several themes emerged during the course of the roundtable discussion, including the need for development of (1) a research infrastructure for the rapid identification, consent, and tracking of research subjects that incorporates innovative informatics technologies, essential for future research; (2) diagnostic strategies and tools necessary to understand key populations and the process of medical decisionmaking, including the investigation of the pathobiology of symptoms and symptom-oriented therapies; (3) collaborative research networks to provide unique opportunities to form partnerships, leverage patient cohorts and clinical and financial resources, and share data; (4) formal research training programs integral for creating new knowledge and advancing the science and practice of emergency medicine; and (5) recognition that emergency care is part of an integrated system from emergency medical services dispatch to discharge. The NIH Roundtable "Opportunities to Advance Research on Neurological and Psychiatric Emergencies" created a framework to guide future emergency medicine-based research initiatives., Conclusion: Emergency departments provide the portal of access to the health care system for most patients with acute neurologic and psychiatric illness. Emergency physicians and colleagues are primed to investigate neurologic and psychiatric emergencies that will directly improve the delivery of care and patient outcomes., (Copyright © 2010. Published by Mosby, Inc.)

Objectives: The objective was to evaluate safety of intravenous (IV) tissue plasminogen activator (tPA) delivered without dedicated thrombolytic stroke teams., Methods: This was a retrospective, observational study of patients treated between 1996 and 2005 at four southeastern Michigan hospital emergency departments (EDs) with a prospectively defined comparison to the National Institute of Neurological Disorders and Stroke (NINDS) tPA stroke study cohort. Main outcome measures were mortality, intracerebral hemorrhage (ICH), systemic hemorrhage, neurologic recovery, and guideline violations., Results: A total of 273 consecutive stroke patients were treated by 95 emergency physicians (EPs) using guidelines and local neurology resources. One-year mortality was 27.8%. Unadjusted Cox model relative risk (RR) of mortality compared to the NINDS tPA treatment and placebo groups was 1.20 (95% confidence interval [CI] = 0.87 to 1.64) and 1.04 (95% CI = 0.76 to 1.41), respectively. The rate of significant ICH by computed tomography (CT) criteria was 6.6% (odds ratio [OR] = 1.03, 95% CI = 0.56 to 1.90 compared to the NINDS tPA treatment group). The proportions of symptomatic ICH by two other prespecified sets of clinical criteria were 4.8 and 7.0%. The rate of any ICH within 36 hours of treatment was 9.9% (RR = 0.94, 95% CI = 0.58 to 1.51 compared to the NINDS tPA group). The occurrence of major systemic hemorrhage (requiring transfusion) was 1.1%. Functional recovery by the modified Rankin Scale score (mRS = 0 to 2) at discharge occurred in 38% of patients with a premorbid disability mRS < 2. Guideline deviations occurred in the ED in 26% of patients and in 25% of patients following admission., Conclusions: In these EDs there was no evidence of increased risk with respect to mortality, ICH, systemic hemorrhage, or worsened functional outcome when tPA was administered without dedicated thrombolytic stroke teams. Additional effort is needed to improve guideline compliance., (© 2010 by the Society for Academic Emergency Medicine.)

The ability of emergency care research (ECR) to produce meaningful improvements in the outcomes of acutely ill or injured patients depends on the optimal configuration, infrastructure, organization, and support of emergency care research networks (ECRNs). Through the experiences of existing ECRNs, we can learn how to best accomplish this. A meeting was organized in Washington, DC, on May 28, 2008, to discuss the present state and future directions of clinical research networks as they relate to emergency care. Prior to the conference, at the time of online registration, participants responded to a series of preconference questions addressing the relevant issues that would form the basis of the breakout session discussions. During the conference, representatives from a number of existing ECRNs participated in discussions with the attendees and provided a description of their respective networks, infrastructure, and challenges. Breakout sessions provided the opportunity to further discuss the strengths and weaknesses of these networks and patterns of success with respect to their formation, management, funding, best practices, and pitfalls. Discussions centered on identifying characteristics that promote or inhibit successful networks and their interactivity, productivity, and expansion. Here the authors describe the current state of ECRNs and identify the strengths, weaknesses, and potential pitfalls of research networks. The most commonly cited strengths of population- or disease-based research networks identified in the preconference survey were access to larger numbers of patients; involvement of physician experts in the field, contributing to high-level study content; and the collaboration among investigators. The most commonly cited weaknesses were studies with too narrow a focus and restrictive inclusion criteria, a vast organizational structure with a risk of either too much or too little central organization or control, and heterogeneity of institutional policies and procedures among sites. Through the survey and structured discussion process involving multiple stakeholders, the authors have identified strengths and weaknesses that are consistent across a number of existing ECRNs. By leveraging the strengths and addressing the weaknesses, strategies can be adopted to enhance the scientific value and productivity of these networks and give direction to future ECRNs.

Introduction: The purpose of this study was to assess the agreement of Emergency Department (ED) attendings, ED residents, and neurology residents compared with stroke neurologists in the assessment of intravenous rt-PA eligibility., Methods: A convenience sample of patients presenting with possible stroke symptoms to the University of Michigan Hospital ED from June 2003 to July 2004 was identified. A physician from each of four groups: ED attending, ED resident, neurology resident, and stroke neurology attending independently evaluated each patient for eligibility for intravenous (i.v.) rt-PA. Accuracy, sensitivity, and positive predictive value (PPV) with 95% confidence intervals (CI) were calculated by physician type, compared with the stroke neurologist, for eligibility for i.v. rt-PA., Results: Exactly 36 (49%) out of the 73 evaluated patients were diagnosed with acute ischemic stroke and 11 were deemed eligible for treatment with i.v. tPA by the stroke neurologist. Agreement with the stroke neurologist for rt-PA eligibility was 93% [95% CI: 84%, 98%] (sensitivity = 82% [48%, 98%], PPV = 82% [48%, 99%]) for the ED attendings, 79% [65%, 90%] (sensitivity = 75% [35%, 97%], PPV = 43% [18% 71%]) for the ED residents, and 84% [73%, 92%] (sensitivity = 100% [74%, 100%], PPV = 52% [31%, 73%]) for the neurology residents. There were two false positive cases identified by ED attendings, eight, by ED residents, and 11 by neurology residents., Conclusions: This study suggests that the agreement between ED attendings and stroke neurologists for determination of rt-PA eligibility is good. There is room for improvement, however, in the determination of acute stroke therapy eligibility in the ED setting especially among trainees.

Many cardiovascular experts have called for the creation of specialized myocardial infarction centers and networks in the United States analogous to the current model for major trauma. Patients suffering ST-elevation myocardial infarction (STEMI) and trauma share an essential feature that makes the argument for regionalization persuasive: rapid triage and treatment by highly trained personnel improve survival in both conditions. Despite this similarity, however, the trauma system may be limited as a model for regionalizing STEMI care. First, the development of trauma systems has been hindered by the struggle for sufficient and stable funding, competing interests among individual stakeholders, and the overall lack of desire for state-sponsored healthcare planning in the United States. These same obstacles would need to be overcome if STEMI care is regionalized. Second, unique characteristics related to STEMI care, such as its varied clinical presentation and more lucrative reimbursement, will create new challenges. In this article, we briefly review the current status of trauma systems in the United States and describe why the regionalization of STEMI care may require different methods of healthcare organization.

Study Objective: The use of recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke is controversial among emergency physicians. We survey emergency physicians to determine (1) the proportion of emergency physicians resistant to using rt-PA in the ideal setting because of the risk of symptomatic intracerebral hemorrhage; (2) the proportion of emergency physicians resistant to using rt-PA in the ideal setting because of the perceived lack of benefit; (3) the highest acceptable symptomatic intracerebral hemorrhage risk; and (4) the lowest acceptable accompanying relative improvement in neurologic outcome., Methods: The American College of Emergency Physicians randomly selected 2,600 of its active members for anonymous Web-based or paper survey. The proportion of ED physicians resistant to rt-PA use because of symptomatic intracerebral hemorrhage risk and perceived lack of benefit, in addition to the mean acceptable symptomatic intracerebral hemorrhage risk and associated benefit, was calculated with 95% confidence intervals (CIs). Multivariable logistic regression was used to identify factors independently associated with willingness to use rt-PA in the ideal setting., Results: The median age of the 1,105 (43%) respondents was 44 years. Overall, the mean upper limit of symptomatic intracerebral hemorrhage tolerable was 3.4% (95% CI 3.2% to 3.5%), with associated lowest acceptable mean relative improvement of 40% (95% CI 39% to 41%). Forty percent (95% CI 37% to 44%) of physicians reported that they were not likely to use rt-PA. Of these, 65% (95% CI 61% to 69%) of physicians reported this was because of the risk of symptomatic intracerebral hemorrhage, 23% (95% CI 19% to 27%) reported the cause was the perceived lack of benefit, and 12% (95% CI 9% to 15%) reported both reasons were the cause. Independently associated with willingness to use rt-PA were female sex (odds ratio 2.30 [1.57, 3.36]) and previous use of rt-PA for stroke (3.13 [2.33, 4.17])., Conclusion: Symptomatic intracerebral hemorrhage risk is the factor most likely to preclude rt-PA use by emergency physicians. Of the 40% of physicians who would not use rt-PA, about two thirds reported this was due to symptomatic intracerebral hemorrhage risk, and about a quarter of physicians cited the relative lack of benefit. Treatment trials that aim to reduce symptomatic intracerebral hemorrhage risk to 2% to 3% are likely to stimulate the interest of emergency physicians in the use of thrombolytics for acute ischemic stroke.

Study Objective: We estimate the total number of physicians practicing clinical emergency medicine during a specified period, describe certain characteristics of those individuals to estimate the total number of full-time equivalents (FTEs) and the total number of individuals needed to staff those FTEs, and compare the data collected with those data collected in 1997., Methods: Data were gathered from a survey of a random sample of 2,153 hospitals drawn from a population of 5,329 hospitals reported by the American Hospital Association as having, or potentially having, an emergency department. The survey instrument addressed items such as descriptive data on the institution, enumeration of physicians in the ED, and the total number of physicians working during the period from June 6 to June 9, 1999. Demographic data on the individuals were also collected., Results: A total of 940 hospitals responded (a 44% return rate). These hospitals reported that a total of 6,719 physicians were working during the specified period, or an average of 7.85 persons scheduled per institution. The physicians were scheduled for a total of 347,702 hours. The average standard for FTE was 40 clinical hours per week. This equates to 4,346 FTEs or 5.29 FTEs per institution. The ratio of persons to FTEs was 1.48:1. With regard to demographics, 83% of the physicians were men, and 82% were white. Their average age was 42.6 years. As for professional credentials, 42% were emergency medicine residency trained, and 58% were board certified in emergency medicine; 50% were certified by the American Board of Emergency Medicine., Conclusion: Given that there are 5,064 hospitals with EDs and given that the data indicate that there are 5.35 FTEs per ED, the total number of FTEs is projected to be 27,067 (SE=500). Given further that the data indicate a physician/FTE ratio of 1.47:1, we conclude that there are 39,746 persons (SE=806) needed to staff those FTEs. When adjusted for persons working at more than one ED, that number is reduced to 31,797. When the 1999 data are compared with those collected in 1997, we note a statistically significant decline in the number of hospital EDs, from 5,126 in 1997 to 5,064 in 1999 (P =.02). The total number of emergency physicians remained the same over the 2-year period, whereas the number of FTEs per institution increased from 5.11 to 5.35. The physician/FTE ratio remained unchanged.