A conceptual model for the development process of confirmatory adaptive clinical trials within an emergency research network.

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.

Protocol Deviations before and after Treatment with Intravenous Tissue Plasminogen Activator in Community Hospitals.

BACKGROUND: Protocol deviations before and after tissue plasminogen activator (tPA) treatment for ischemic stroke are common. It is unclear if patient or hospital factors predict protocol deviations. We examined predictors of protocol deviations and the effects of protocol violations on symptomatic intracerebral hemorrhage (sICH). METHODS: We used data from the Increasing Stroke Treatment through Interventional Behavior Change Tactics trial, a cluster-randomized, controlled trial evaluating the efficacy of a barrier assessment and educational intervention to increase appropriate tPA use in 24 Michigan community hospitals, to review tPA treatments between 2007 and 2010. Protocol violations were defined as deviations from the standard tPA protocol, both before and after treatment. Multilevel logistic regression models were fitted to determine if patient and hospital variables were associated with pretreatment or post-treatment protocol deviations. RESULTS: During the study, 557 patients (mean age 70, 52% male, median National Institutes of Health Stroke Scale score 12) were treated with tPA. Protocol deviations occurred in 233 (42%) patients: 16% had pretreatment deviations, 35% had post-treatment deviations, and 9% had both. The most common protocol deviations included elevated post-treatment blood pressure, antithrombotic agent use within 24 hours of treatment, and elevated pretreatment blood pressure. Protocol deviations were not associated with sICH, stroke severity, or hospital factors. Older age was associated with pretreatment protocol deviations (adjusted odds ratio [OR], .52; 95% confidence interval [CI], .30-.92). Pretreatment deviations were associated with post-treatment deviations (adjusted OR, 3.20; 95% CI, 1.91-5.35). CONCLUSIONS: Protocol deviations were not associated with sICH. Aside from age, patient and hospital factors were not associated with protocol deviations.

Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis.

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.

Prevention of emergency physician migratory contamination in a cluster randomized trial to increase tissue plasminogen activator use in stroke (the INSTINCT trial).

OBJECTIVES: Cluster randomized trials (CRTs) are increasingly used to evaluate quality improvement interventions aimed at health care providers. In trials testing emergency department (ED) interventions, migration of emergency physicians (EPs) between hospitals is an important concern, as contamination may affect both internal and external validity. We hypothesized that geographically isolating EDs would prevent migratory contamination in a CRT designed to increase ED delivery of tissue plasminogen activator (tPA) in stroke (the INSTINCT trial). METHODS: INSTINCT was a prospective, cluster randomized, controlled trial. Twenty-four Michigan community hospitals were randomly selected in matched pairs for study. Contamination was defined at the cluster level, with substantial contamination defined a priori as greater than 10% of EPs affected. Nonadherence, total crossover (contamination+nonadherence), migration distance, and characteristics were determined. RESULTS: Three hundred seven EPs were identified at all sites. Overall, 7 (2.3%) changed study sites. One moved between control sites, leaving 6 (2.0%) total crossovers. Of these, 2 (0.7%) moved from intervention to control (contamination); and 4 (1.3%) moved from control to intervention (nonadherence). Contamination was observed in 2 of 12 control sites, with 17% and 9% contamination of the total site EP workforce at follow-up, respectively. Average migration distance was 42 miles for all EPs moving in the study and 35 miles for EPs moving from intervention to control sites. CONCLUSION: The mobile nature of EPs should be considered in the design of quality improvement CRTs. Increased reporting of contamination in CRTs is encouraged to clarify thresholds and facilitate CRT design.

Antihypertensive treatment prolongs tissue plasminogen activator door-to-treatment time: secondary analysis of the INSTINCT trial.

BACKGROUND AND PURPOSE: Identifying modifiable tissue plasminogen activator treatment delays may improve stroke outcomes. We hypothesized that prethrombolytic antihypertensive treatment (AHT) may prolong door-to-treatment time (DTT). METHODS: We performed an analysis of consecutive tissue plasminogen activator-treated patients at 24 randomly selected community hospitals in the Increasing Stroke Treatment through Interventional Behavior Change Tactics (INSTINCT) trial between 2007 and 2010. DTT among stroke patients who received prethrombolytic AHT were compared with those who did not receive prethrombolytic AHT. We then calculated a propensity score for the probability of receiving prethrombolytic AHT using logistic regression with demographics, stroke risk factors, home medications, stroke severity (National Institutes of Health Stroke Scale), onset-to-door time, admission glucose, pretreatment blood pressure, emergency medical service transport, and location at time of stroke as independent variables. A paired t test was performed to compare the DTT between the propensity-matched groups. RESULTS: Of 534 tissue plasminogen activator-treated stroke patients analyzed, 95 received prethrombolytic AHT. In the unmatched cohort, patients who received prethrombolytic AHT had a longer DTT (mean increase, 9 minutes; 95% confidence interval, 2-16 minutes) than patients who did not. After propensity matching, patients who received prethrombolytic AHT had a longer DTT (mean increase, 10.4 minutes; 95% confidence interval, 1.9-18.8) than patients who did not receive prethrombolytic AHT. CONCLUSIONS: Prethrombolytic AHT is associated with modest delays in DTT. This represents a potential target for quality-improvement initiatives. Further research evaluating optimum prethrombolytic hypertension management is warranted.

An overview of the adaptive designs accelerating promising trials into treatments (ADAPT-IT) project.

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.

Provider perceptions of barriers to the emergency use of tPA for acute ischemic stroke: a qualitative study.

BACKGROUND: Only 1-3% of ischemic stroke patients receive thrombolytic therapy. Provider barriers to adhering with guidelines recommending tPA delivery in acute stroke are not well known. The main objective of this study was to describe barriers to thrombolytic use in acute stroke care. METHODS: Twenty-four hospitals were randomly selected and matched into 12 pairs. Barrier assessment occurred at intervention sites only, and utilized focus groups and structured interviews. A pre-specified taxonomy was employed to characterize barriers. Two investigators independently assigned themes to transcribed responses. Seven facilitators (three emergency physicians, two nurses, and two study coordinators) conducted focus groups and interviews of emergency physicians (65), nurses (62), neurologists (15), radiologists (12), hospital administrators (12), and three others (hospitalists and pharmacist). RESULTS: The following themes represented the most important external barriers: environmental and patient factors. Important barriers internal to the clinician included familiarity with and motivation to adhere to the guidelines, lack of self-efficacy and outcome expectancy. The following themes were not substantial barriers: lack of awareness of the existence of acute stroke guidelines, presence of conflicting guidelines, and lack of agreement with the guidelines. CONCLUSIONS: Healthcare providers perceive environmental and patient-related factors as the primary barriers to adherence with acute stroke treatment guidelines. Interventions focused on increasing physician familiarity with and motivation to follow guidelines may be of highest yield in improving adherence. Improving self-efficacy in performing guideline concordant care may also be useful.

Lack of association between pretreatment neurology consultation and subsequent protocol deviation in tissue plasminogen activator-treated patients with stroke.

BACKGROUND AND PURPOSE: We evaluated the hypothesis that consultation with neurology would be associated with fewer protocol deviations in tissue plasminogen activator-treated patients with stroke. METHODS: A retrospective analysis of consecutive tissue plasminogen activator-treated patients with acute patients was performed. Using chi(2) tests, the proportion of patients with a protocol deviation was calculated and compared between those with evidence of a neurology consultation and those without. Logistic regression was then used to determine the OR for protocol deviation at the same time as controlling for clinical presentation covariates. RESULTS: Two hundred seventy-three subjects were included. Protocol deviation rates did not significantly differ between those with (44%) and those without (41%) a consultation. The adjusted OR for deviation comparing any consultation versus nonconsultation was 1.25 (95% CI: 0.58 to 2.68). There was no statistically significant difference between symptomatic intracranial hemorrhage and in-hospital mortality rates between the groups. The proportion of patients with pretreatment deviations not related to timing was low in both the consultation (9.7%) and nonconsultation groups (8.1%). CONCLUSIONS: Neurological consultation was not found to be associated with decreased protocol deviations in this cohort, although the high proportion of deviations with and without consultation suggests that quality improvement is needed. Most observed pretreatment deviations were attributable to timing. As acute stroke care becomes more efficient and additional methods in reducing door-to-treatment times are sought, models in which emergency physicians direct the initial phase of treatment may merit further consideration.

Attitudes and beliefs of Michigan emergency physicians toward tissue plasminogen activator use in stroke: baseline survey results from the INcreasing Stroke Treatment through INteractive behavioral Change Tactic (INSTINCT) trial hospitals.

BACKGROUND AND PURPOSE: The objective of this study was to determine the baseline proportion of emergency physicians with favorable attitudes and beliefs toward intravenous tissue plasminogen activator (tPA) use in a cohort of randomly selected Michigan hospitals. METHODS: Two hundred seventy-eight emergency physicians from 24 hospitals were surveyed. A confidential, self-administered, pilot-tested survey assessing demographics, practice environment, attitudes, and beliefs regarding tPA use in stroke was used. Main outcome measures assessed belief in a legal standard of care, likelihood of use in an ideal setting, comfort in use without a specialist consultation, and belief that science on tPA use is convincing. ORs with robust 95% CIs (adjusted for clustering) were calculated to quantify the association between responses and physician- and hospital-level characteristics. RESULTS: One hundred ninety-nine surveys completed (gross response rate 71.6%). Ninety-nine percent (95% CI: 97.8 to 100) indicated use of tPA in eligible patients represented either acceptable or ideal patient care. Twenty-seven percent (95% CI: 21.7 to 32.3) indicated use of tPA represented a legal standard of care. Eighty-three percent (95% CI: 78.5 to 87.5) indicated they were "likely" or "very likely" to use tPA given an ideal setting. When asked about using tPA without a consultation, 65% (95% CI: 59.3 to 70.7) indicated they were uncomfortable. Forty-nine percent (95% CI: 43.0 to 55.0) indicated the science regarding use of tPA in stroke is convincing with 30% remaining neutral. Characteristics associated with favorable attitudes included non-emergency medicine board certification; older age, and a smaller hospital practice environment. CONCLUSIONS: In this cohort, emergency physician attitudes and beliefs toward intravenous tPA use in stroke are considerably more favorable than previously reported.

Characteristics of a mild head injury subgroup with extreme, persisting distress on the Rivermead Postconcussion Symptoms questionnaire.

UNLABELLED: Kirsch NL, de Leon MB, Maio RF, Millis SR, Tan-Schriner CU, Frederiksen S. Characteristics of a mild head injury subgroup with extreme, persisting distress on the Rivermead Postconcussion Symptoms Questionnaire. OBJECTIVE: To examine baseline variables and identify characteristics of participants with extremely high reports of symptoms (ie, outliers) 12 months after mild head injury (MHI). DESIGN: A prospective cohort study of MHI with and without loss of consciousness (LOC) and/or posttraumatic amnesia (PTA) recruited from and interviewed at the emergency department (ED), with a follow-up telephone interview at 12 months. SETTING: Level II community hospital ED. PARTICIPANTS: Participants (n=58) with MHI and LOC less than or equal to 30 minutes and/or PTA less than 24 hours and participants (n=173) with MHI but no PTA/LOC. INCLUSION CRITERIA: age greater than or equal to 18 years, less than or equal to 24 hours after injury, Glasgow Coma Scale score greater than or equal to 13, and discharge from the ED. Fourteen (6%) participants had extremely high scores on the Rivermead Postconcussion Symptoms Questionnaire (RPQ). MAIN OUTCOME MEASURES: RPQ and questions on health services use and litigation. RESULTS: Characterizing the outlier cases are prior head injury, preinjury disability, history of substance use, unemployment, and elevated somatic symptoms at the ED. At 12 months, outliers had higher use of health services and litigation. CONCLUSIONS: The existence of a subgroup with a distinctive pattern of baseline characteristics in combination with elevated somatic symptoms at the time of presentation to the ED suggests that further taxonomic distinctions may be warranted for the MHI population, each requiring appropriately targeted interventions for addressing symptomatic complaints.

Resource utilization and outcome at a university versus a community teaching hospital in tPA treated stroke patients: a retrospective cohort study.

BACKGROUND: Comparing patterns of resource utilization between hospitals is often complicated by biases in community and patient populations. Stroke patients treated with tissue plasminogen activator (tPA) provide a particularly homogenous population for comparison because of strict eligibility criteria for treatment. We tested whether resource utilization would be similar in this homogenous population between two hospitals located in a single Midwestern US community by comparing use of diagnostic testing and associated outcomes following treatment with t-PA. METHODS: Medical records from 206 consecutive intravenous t-PA-treated stroke patients from two teaching hospitals (one university, one community-based) were reviewed. Patient demographics, clinical characteristics and outcome were analyzed, as were the frequency of use of CT, MRI, MRA, echocardiography, angiography, and EEG. RESULTS: Seventy-nine and 127 stroke patients received t-PA at the university and community hospitals, respectively. The two patient populations were demographically similar. There were no differences in stroke severity. All outcomes were similar at both hospitals. Utilization of CT scans, and non-invasive carotid and cardiac imaging studies were similar at both hospitals; however, brain MR, TEE, and catheter angiography were used more frequently at the university hospital. EEG was obtained more often at the community hospital. CONCLUSIONS: Utilization of advanced brain imaging and invasive diagnostic testing was greater at the university hospital, but was not associated with improved clinical outcomes. This could not be explained on the basis of stroke severity or patient characteristics. This variation of practice suggests substantial opportunities exist to reduce costs and improve efficiency of diagnostic resource use as well as reduce patient exposure to risk from diagnostic procedures.

Baseline predictors of fatigue 1 year after mild head injury.

OBJECTIVE: To compare reports of fatigue 12 months after minor trauma by participants with mild head injury (MHI) with those with other injury, and identify injury and baseline predictors of fatigue. DESIGN: An inception cohort study of participants with MHI and other nonhead injuries recruited from and interviewed at the emergency department (ED), with a follow-up telephone interview at 12 months. SETTING: Level II community hospital ED. PARTICIPANTS: Participants (n=58) with MHI and loss of consciousness (LOC) of 30 minutes or less and/or posttraumatic amnesia (PTA) less than 24 hours, 173 with MHI but no PTA/LOC, and 128 with other mild nonhead injuries. INCLUSION CRITERIA: age 18 years or older, within 24 hours of injury, Glasgow Coma Scale score of 13 or higher, and discharge from the ED. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Medical Outcomes Study 36-Item Short-Form Health Survey Vitality subscale. RESULTS: Significant predictors of fatigue severity at 12 months were baseline fatigue, having seen a counselor for a mental health issue, medical disability, marital status, and in some stage of litigation. Injury type was not a significant predictor. CONCLUSIONS: Fatigue severity 12 months after injury is associated with baseline characteristics and not MHI. Clinicians should be cautious about attributing persisting fatigue to MHI without comprehensive consideration of other possible etiologic factors.

Health status, not head injury, predicts concussion symptoms after minor injury.

OBJECTIVE: Postconcussion (PC) syndrome etiology remains poorly understood. We sought to examine predictors of persistent PC symptoms after minor injury. METHODS: Health status, symptom, and injury information were obtained on a sample of patients presenting to the emergency department after minor injury. Postconcussion and cognitive symptoms were assessed at 1, 3, and 12 months. RESULTS: Among 507 patients enrolled, 339 had head injury. Repeated-measures logistic regression modeling of PC and cognitive symptom presence across time indicated that baseline mental health status and physical health status were most predictive of persistent symptoms. In contrast, head injury presence did not predict persistent PC syndrome. DISCUSSION: Baseline mental health status and physical health status were associated with persistent PC syndrome after minor injury, but head injury status was not. Further studies of PC syndrome pathogenesis are needed.

Attitudes and opinions regarding confirmatory adaptive clinical trials: a mixed methods analysis from the Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT) project.

BACKGROUND: Adaptive designs have been increasingly used in the pharmaceutical and device industries, but adoption within the academic setting has been less widespread - particularly for confirmatory phase trials. We sought to understand perceptions about understanding, acceptability, and scientific validity of adaptive clinical trials (ACTs). METHODS: We used a convergent mixed methods design using survey and mini-focus group data collection procedures to elucidate attitudes and opinions among "trial community" stakeholders regarding understanding, acceptability, efficiency, scientific validity, and speed of discovery with adaptive designs. Data were collected about various aspects of ACTs using self-administered surveys (paper or Web-based) with visual analog scales (VASs) with free text responses and with mini-focus groups of key stakeholders. Participants were recruited as part of an ongoing NIH/FDA-funded research project exploring the incorporation of ACTs into an existing NIH network that focuses on confirmatory phase clinical trials in neurological emergencies. "Trial community" representatives, namely, clinical investigators, biostatisticians, NIH officials, and FDA scientists involved in the planning of four clinical trials, were eligible to participate. In addition, recent and current members of a clinical trial-oriented NIH study section were also eligible. RESULTS: A total of 76 stakeholders completed the survey (out of 91 who were offered it, response rate 84 %). While the VAS attitudinal data showed substantial variability across respondents about acceptability and understanding of ACTs by various constituencies, respondents perceived clinicians to be less likely to understand ACTs and that ACTs probably would increase the efficiency of discovery. Textual and focus group responses emerged into several themes that enhanced understanding of VAS attitudinal data including the following: acceptability of adaptive designs depends on constituency and situation; there is variable understanding of ACTs (limited among clinicians, perceived to be higher at FDA); views about the potential for efficiency depend on the situation and implementation. Participants also frequently mentioned a need for greater education within the academic community. Finally, the empiric, non-quantitative selection of treatments for phase III trials based on limited phase II trials was highlighted as an opportunity for improvement and a potential explanation for the high number of neutral confirmatory trials. CONCLUSIONS: These data show considerable variations in attitudes and beliefs about ACTs among trial community representatives. For adaptive trials to be fully considered when appropriate and for the research enterprise to realize the full potential of adaptive designs will likely require extensive experience and trust building within the trial community.

Prospective performance assessment of an out-of-hospital protocol for selective spine immobilization using clinical spine clearance criteria.

STUDY OBJECTIVE: We determine whether the use of an emergency medical services (EMS) protocol for selective spine immobilization would result in appropriate immobilization without spinal cord injury associated with nonimmobilization. METHODS: A 4-year prospective study examined EMS and hospital records for patients after the implementation of an EMS protocol for selective spine immobilization. EMS personnel were trained to perform and document a spine injury assessment for out-of-hospital trauma patients with a mechanism of injury judged sufficient to cause a spine injury. The assessment included these clinical criteria: altered mental status, evidence of intoxication, neurologic deficit, suspected extremity fracture, and spine pain or tenderness. The protocol required immobilization for patients with a positive assessment on any of those criteria. Outcome characteristics included the presence or absence of spine injury and spine injury management. RESULTS: The study collected data on 13,483 patients; 126 of the patients were subsequently excluded from the study because of incomplete data, leaving a study sample of 13,357 patients with complete data. Spine injuries were confirmed in the hospital records for 3% (n=415) of patients, including 50 patients with cord injuries and 128 patients with cervical injuries. Sensitivity of the EMS protocol was 92% (95% confidence interval [CI] 89.4 to 94.6%) resulting in nonimmobilization of 8% of the patients with spine injuries (33 of 415). None of the nonimmobilized patients sustained cord injuries. The specificity was 40% (95% CI 38.9 to 40.5%). CONCLUSION: The use of our selective immobilization protocol resulted in spine immobilization for most patients with spine injury without causing harm in cases in which spine immobilization was withheld.

Prevalence of atrial fibrillation and antithrombotic prophylaxis in emergency department patients.

BACKGROUND AND PURPOSE: The emergency department (ED), as the point of first medical contact for many complaints referable to atrial fibrillation (AF) and a common source of primary care, occupies a unique position to identify AF patients at risk of stroke. This study evaluates that potential by determining the prevalence of AF in an ED population and assessing antithrombotic use in those patients with recurrent AF. METHODS: This was a multicenter, retrospective, cross-sectional study of consecutive records of ED patients with AF identified by ECG between January and June 1998. American Heart Association and modified Stroke Prevention in Atrial Fibrillation criteria established high-risk patients and contraindications to anticoagulation, respectively. RESULTS: We identified 866 records with ECG-proven AF in 78 787 patient visits for an estimated prevalence of 1.10% (95% CI, 1.03 to 1.17). We found that 556 records had a prior history of AF; of these, 221 (40%) used warfarin alone, 155 (28%) had antiplatelet therapy alone, 28 (5%) used both, and 152 (27%) had no antithrombotic therapy identified. Sixty-eight patients (12%; 95% CI, 0.10 to 0.15) were warfarin eligible and without antithrombotic therapy. An additional 64 (12%; 95% CI, 0.09 to 0.14) had antiplatelet therapy alone. In warfarin-eligible patients, no differences were identified between the anticoagulated and nonanticoagulated groups on the basis of age, sex, or race. Of patients on warfarin with a measured international normalized ratio, 61% (95% CI, 0.55 to 0.67) were outside the AHA-recommended range of 2.0 to 3.0. CONCLUSIONS: AF is a common finding in an ED population. Many are warfarin eligible and untreated or undertreated. Methods to increase anticoagulant use in this at-risk population warrant further investigation.

Does preexisting antiplatelet treatment influence postthrombolysis intracranial hemorrhage in community-treated ischemic stroke patients? An observational study.

OBJECTIVES: Intracranial hemorrhage (ICH) after acute stroke thrombolysis is associated with poor outcomes. Previous investigations of the relationship between preexisting antiplatelet use and the safety of intravenous (IV) thrombolysis have been limited by low event rates. The objective of this study was to determine whether preexisting antiplatelet therapy increased the risk of ICH following acute stroke thrombolysis. The primary hypothesis was that antiplatelet use would not be associated with radiographic evidence of ICH after controlling for relevant confounders. METHODS: Consecutive cases of thrombolysis patients treated in the emergency department (ED) were identified using multiple methods. Retrospective data were collected from four hospitals from 1996 to 2004 and 24 other hospitals from 2007 to 2010 as part of a cluster-randomized trial. The same chart abstraction tool was used during both time periods, and data were subjected to numerous quality control checks. Hemorrhages were classified using a prespecified methodology: ICH was defined as presence of hemorrhage in radiographic interpretations of follow-up imaging (primary outcome). Symptomatic ICH (sICH) was defined as radiographic ICH with associated clinical worsening. A multivariable logistic regression model was constructed to adjust for clinical factors previously identified to be related to postthrombolysis ICH. Sensitivity analyses were conducted where the unadjusted and adjusted results from this study were combined with those of previously published external studies on this topic via meta-analytic techniques. RESULTS: There were 830 patients included, with 47% having documented preexisting antiplatelet treatment. The mean (± standard deviation [SD]) age was 69 (± 15) years, and the cohort was 53% male. The unadjusted proportion of patients with any ICH was 15.1% without antiplatelet use and 19.3% with antiplatelet use (absolute risk difference = 4.2%, 95% confidence interval [CI] = -1.2% to 9.6%); for sICH this was 6.1% without antiplatelet use and 9% with antiplatelet use (absolute risk difference = 3.1%, 95% CI = -1% to 6.7%). After adjusting for confounders, antiplatelet use was not significantly associated with radiographic ICH (odds ratio [OR] = 1.1, 95% CI = 0.8 to 1.7) or sICH (OR = 1.3, 95% CI = 0.7 to 2.2). In patients 81 years and older, there was a higher risk of radiographic ICH (absolute risk difference = 11.9%, 95% CI = 0.1% to 23.6%). The meta-analyses combined the findings of this investigation with previous similar work and found increased unadjusted risks of radiographic ICH (absolute risk difference = 4.9%, 95% CI = 0.7% to 9%) and sICH (absolute risk difference = 4%, 95% CI = 2.3% to 5.6%). The meta-analytic adjusted OR of sICH for antiplatelet use was 1.6 (95% CI = 1.1 to 2.4). CONCLUSIONS: The authors did not find that preexisting antiplatelet use was associated with postthrombolysis ICH or sICH in this cohort of community treated patients. Preexisting tobacco use, younger age, and lower severity were associated with lower odds of sICH. The meta-analyses demonstrated small, but statistically significant increases in the absolute risk of radiographic ICH and sICH, along with increased odds of sICH in patients with preexisting antiplatelet use.

A multilevel intervention to increase community hospital use of alteplase for acute stroke (INSTINCT): a cluster-randomised controlled trial.

BACKGROUND: Use of alteplase improves outcome in some patients with stroke. Several types of barrier frequently prevent its use. We assessed whether a standardised, barrier-assessment, multicomponent intervention could increase alteplase use in community hospitals in Michigan, USA. METHODS: In a cluster-randomised controlled trial, we selected adult, non-specialty, acute-care community hospitals in the Lower Peninsula of Michigan, USA. Eligible hospitals discharged at least 100 patients who had had a stroke per year, had less than 100 000 visits to the emergency department per year, and were not academic comprehensive stroke centres. Using a computer-generated randomisation sequence, we selected 12 matched pairs of eligible hospitals. Within pairs, the hospitals were allocated to intervention or control groups with restricted randomisation in January, 2007. Between January, 2007, and December, 2007, intervention hospitals implemented a multicomponent intervention that included qualitative and quantitative assessment of barriers to alteplase use and ways to address the findings, and provided additional support. The primary outcome was change in alteplase use in patients with stroke in emergency departments between the pre-intervention period (January, 2005, to December, 2006) and the post-intervention period (January, 2008, to January, 2010). Physicians in participating hospitals and the coordinating centre could not be masked to group assignment, but were masked to progress made in paired control hospitals. External medical reviewers who were masked to group assignment assessed outcomes. We did intention-to-treat (ITT) and target-population (without one pair that was excluded after randomisation) analyses. This trial is registered at ClinicalTrials.gov, number NCT00349479. FINDINGS: All 24 hospitals completed the study. Overall, 745 of 40 823 patients with stroke received intravenous alteplase treatment. In the ITT analysis, the proportion of patients with stroke who were admitted and treated with alteplase increased between the pre-intervention and post-intervention periods in intervention hospitals (89 [1·25%] of 7119 patients to 235 [2·79%] of 8419) to a greater extent than in control hospitals (99 [1·25%] of 7946 to 194 [2·10%] of 9222), but the difference between groups was not significant (relative risk [RR] 1·37, 95% CI 0·96-1·93; p=0·08). In the target-population analysis, the increase in alteplase use in intervention hospitals (59 [1·00%] of 5882 to 191 [2·62%] of 7288) was significantly greater than in control hospitals (65 [1·09%] of 5957 to 120 [1·72%] of 6989; RR 1·68, 95% CI 1·09-2·57; p=0·02), but was still clinically modest. INTERPRETATION: The intervention did not significantly increase alteplase use in patients with ischaemic stroke. The increase in use of alteplase in the target population was significant, but smaller than the effect to which the study was powered. Additional strategies to increase acute stroke treatment are needed. FUNDING: National Institutes of Health National Institute of Neurological Disorders and Stroke.

The impact of emergency physician turnover on planning for prospective clinical trials.

INTRODUCTION: Emergency physician (EP) turnover is a significant issue that can have strong economic impact on hospital systems, as well as implications on research efforts to test and improve clinical practice. This work is particularly important to researchers planning randomized trials directed toward EPs because a large degree of turnover within a physician group would attenuate the effectiveness of the desired intervention. We sought to determine the incidence and factors associated with EP workforce changes. METHODS: In an attempt to determine EP turnover and workforce change, data from the INSTINCT (INcreasing Stroke Treatment through INterventional behavior Change Tactics) trial were used. The INSTINCT trial is a prospective, cluster-randomized, controlled trial evaluating a targeted behavioral intervention to increase appropriate use of tissue plasminogen activator in acute ischemic stroke. Individual EPs staffing each of the study hospitals were identified at baseline and 18 months. Surveys were sent to EPs at both intervals. Models were constructed to investigate relationships between physician/hospital characteristics and workforce change. RESULTS: A total of 278 EPs were identified at baseline. Surveys were sent to all EPs at baseline and 18 months with a response rate of 72% and 74%, respectively. At 18 months, 37 (15.8%) had left their baseline hospital and 66 (26.3%) new EPs were working. Seven EPs switched hospitals within the sample. The total number of EPs at 18 months was 307, a 10.8% overall increase. Among the 24 hospitals, 6 had no EP departures and 5 had no new arrivals. The median proportion of EP workforce departing by hospital was 16% (interquartile range [IQR] = 4%-25%; range = 0%-73%), and the median proportion added was 21% (IQR = 7%-41%; range = 0%-120%). None of the evaluated covariates investigating relationships between physician/hospital characteristics and workforce change were significant. CONCLUSION: EP workforce changes over an 18-month period were common. This has implications for emergency department directors, researchers, and individual EPs. Those planning research involving interventions upon EPs should account for turnover as it may have an impact when designing clinical trials to improve performance on healthcare delivery metrics for time-sensitive medical conditions such as stroke, acute myocardial infarction, or trauma.

Observational study of telephone consults by stroke experts supporting community tissue plasminogen activator delivery.

OBJECTIVES: Barriers to intravenous (IV) tissue plasminogen activator (tPA) use in ischemic stroke include limited treatment experience of community physicians. Models of acute stroke care have been designed to address these limitations by providing community support. These include support by telephone or televideo, with or without subsequent transport to tertiary care centers. The authors describe the frequency, characteristics, and effect of community phone consultations to a 24/7 stroke "hotline" staffed by stroke physicians at an academic stroke center using such a model. METHODS: Twelve intervention hospitals participating in the INcreasing Stroke Treatment through Interventional behavior Change Tactics (INSTINCT) trial were provided a single-access number ("hotline") for expert consultation on tPA use. Experts consisted of stroke-trained physicians at an academic medical center. Hotline use was not mandated by the study protocol, nor was patient transfer required. Consultants were required to record all treatment questions in a Web-based log. All patients discussed over the hotline and/or treated with tPA in an INSTINCT hospital underwent multilevel chart review by trained nurse coordinators. Cases were linked to logged hotline calls, based on the time of treatment and the initial treating hospital. Physician adjudicators assessed appropriateness of tPA treatment, presence of deviation from standard guidelines, and treatment complications (intracranial hemorrhage [ICH], systemic hemorrhage, or death). RESULTS: Over 27 months, there were a total of 204 hotline calls regarding 116 patients. Ninety-one percent of calls were between 8 a.m. and midnight, and 77% of questions explored issues of eligibility for IV tPA, particularly for minor stroke or improving stroke (26%). A total of 243 patients were treated with IV tPA at the 12 intervention hospitals, 54 of which were following hotline consult. Seventy-six percent of hotline patients in whom tPA was recommended actually received tPA, while 2% of those in whom tPA was not recommended received the medication. There were no differences in protocol deviations (27.8% hotline group vs. 23.8% nonhotline group), incidence of symptomatic ICH (5.6% vs. 7.3%), or in-hospital mortality (5.6% vs. 13.2%). No medico-legal issues have been reported for any case in the study. CONCLUSIONS: Providing tPA decision-making support via telephone consult to community physicians is feasible and safe. Consultants may play a more prominent role in determining tPA ineligibility than acceptance. Future work should include a real-time survey of physician providers to ascertain such potential qualitative benefits of a stroke hotline.