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IntroductionDespite the significant stroke burden in the region, the RESILIENT trial remains the only randomized controlled trial (RCT) for stroke treatment in Latin America. Imbalances in baseline factors typically hamper comparisons between stroke populations. The Latin American Stroke Registry (LASE) is a registry of patients receiving tPA and thrombectomy from 17 centers across 9 countries. We compared the outcomes of LASE and RESILIENT at each cohort’s baseline characteristics against models derived from other RCTs.MethodsA systematic search identified RCTs that provided median NIHSS, mean age, percentage of patients receiving tPA, time-to-randomization, 90-day mRS0-2, and mortality. Akaike Information Criterion (AIC) was used to select the best model amongst 31 combinations of 5 variables. 90-day outcomes of LASE and RESILIENT were compared at their baseline values against the selected model.Results35 RCTs encompassing 8376 subjects were identified. Models based on baseline NIHSS and the percentage of intravenous thrombolysis (IVT) were considered the most optimum in terms of AIC. The LASE registry included 950 patients receiving IVT alone, 127 that received IVT and mechanical thrombectomy (MT), and 101 receiving only MT. LASE & RESILIENT outcomes were plotted onto the models at their baseline values. LASE IVT alone group outcomes were in line with the RCT-informed model. LASE MT alone and MT + IVT, and the RESILIENT MT arm (68.5% IVT) demonstrated superior efficacy compared to no-MT. The RESILIENT control arm (71.8% tPA) had higher-than-expected mortality, while mortality of all other arms was within the predicted range.ConclusionFunctional outcomes and mortality of patients from the LASE and RESILIENT trial receiving MT and MT+IVT compared favorably to the 90-day functional and mortality outcomes predicted in a model derived from no-MT data from other stroke RCTs, indicating Latin American MT systems of care are comparable to those of more resourceful regions. Higher mortality from IVT in the RESILIENT trial requires further investigation.

Introduction: As acute stroke therapies expand to less well-resourced regions, it is imperative to study real-world data to assess outcomes and the quality of stroke care. The present study analyzes clinical, and imaging outcomes after acute IV thrombolysis (IV-tPA) compared to mechanical thrombectomy (MT) or combined therapy in the LASE. Methods: A retrospective analysis of consecutive acute ischemic stroke cases in 17 centers from 9 Latin American (LA) countries since 2012 was performed using weighted Euclidean matching of nearest neighbors in 3-D space of baseline NIHSS, age, and glucose. Results: 950 patients receiving only IV-tPA were matched to 127 treated with MT+IV-tPA. Matching resulted in 97 pairs well balanced for age (69.1 vs. 69.3), baseline NIHSS (17 vs. 17), and glucose (124.3 vs. 124.5), all p>0.2. 3-month mRS 0-1 (38.3% vs 29.8%, p=0.23) and mRS 0-2 (46.8% vs 41.5%, p=0.54) were non-significantly higher in the MT+IV-tPA group, with higher hemorrhage (26.6% vs 15.5%, p=0.05) and trends for higher death (15.1% vs 9.5%, p=0.40) and symptomatic hemorrhage (7.4% vs 6.2%, p=1.0). One hundred one patients receiving only MT were matched to 127 patients with MT+IV-tPA, resulting in 61 pairs; MT+IV-tPA showed trends for higher rates of 3-month mRS 0-1 (45.0% vs 35.6%, p=0.31), mRS 0-2 (48.3% vs 42.4%, p=0.54); with trends for lower rates of death (16.9% vs 20.0%, p=1.0) and symptomatic hemorrhage (8.3% vs 11.1%, p=0.75). Conclusions: In this real-world LA sample, trends for better functional outcomes were demonstrated with MT+IV-tPA compared to either treatment alone, as in non-LA populations. A trend for higher adverse events in the combined group requires further investigation.

Objective To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). Methods We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. Results The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). Conclusion BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

Background and objectivesStructured and systematised checklists have been shown to prevent complications and improve patient care. We evaluated the implementation of systematic safety checklists in our neurocritical care unit (NCCU) and assessed its effect on patient outcomes.Design/methodsThis quality improvement project followed a Plan–Do–Study–Act (PDSA) methodology. A checklist for medication reconciliation, thromboembolic prophylaxis, glycaemic control, daily spontaneous awakening, breathing trial, diet, catheter/lines duration monitoring and antibiotics de-escalation was implemented during daily patient rounds. Main outcomes included the rate of new infections, mortality and NCCU-length of stay (LOS). Intervened patients were compared with historical controls after propensity score and Euclidean distance matching to balance baseline covariates.ResultsAfter several PDSA iterations, we applied checklists to 411 patients; the overall average age was 61.34 (17.39). The main reason for admission included tumour resection (31.39%), ischaemic stroke (26.76%) and intracerebral haemorrhage (10.95%); the mean Sequential Organ Failure Assessment (SOFA) score was 2.58 (2.68). At the end of the study, the checklist compliance rate throughout the full NCCU stays reached 97.11%. After controlling for SOFA score, age, sex and primary admitting diagnosis, the implementation of systematic checklists significantly correlated with a reduced LOS (ß=−0.15, 95% CI −0.24 to −0.06), reduced rate of any new infections (OR 0.59, 95% CI 0.40 to 0.87) and reduced urinary tract infections (UTIs) (OR 0.23, 95% CI 0.09 to 0.55). Propensity score and Euclidean distance matching yielded 382 and 338 pairs with excellent covariate balance. After matching, outcomes remained significant.DiscussionThe implementation of safety checklists in the NCCU proved feasible, easy to incorporate into the NCCU workflow, and a helpful tool to improve adherence to practice guidelines and quality of care measurements. Furthermore, our intervention resulted in a reduced NCCU-LOS, rate of new infections and rate of UTIs compared with propensity score and Euclidean distance matched historical controls.

Although first line therapies for essential tremor have been identified from small clinical trials, responses are variable. We conducted a survey of tremor management in a large sample of ET cases.The Movement Disorders Clinical Case Registry within a US Veterans Health Administration medical center was used to identify 1468 patients with ET.Of 1468 charts reviewed, 1074 (73.19%) met criteria for ET with characterization of temporal course and treatment; 291/1074 subjects (27.1%) did not receive any treatment. Almost half (500/1074; 46.6%) of the patients received monotherapy, 196/1074 (18.2%) two, 66/1074 (6.1%) three, and 21/1074 (2.0%) four or more medications. Of all prescriptions, primidone was the most used (546/1172; 46.6%), followed by propranolol (419; 35.8%), topiramate (122; 10.4%) and gabapentin (35; 3.0%). Medication response was available for a total of 1030 prescriptions, of which 138 (13.4%) were discontinued due to side effects; 180 (17.5%) prescriptions were ineffective. Furthermore, 52/1074 patients (4.8%) were treated with botulinum toxin injections and 41/1074 (3.8%) underwent deep brain stimulation surgery.Our data suggest that more widespread recognition of limitations underlying conventional approaches, as well as increased referrals for nonpharmacological therapies, may be necessary to achieve improved outcomes in ET populations.

We sought to compare thrombolysis outcomes from the Costa Rican Stroke Registry Program (CRSRP) with published individual patient data from NINDS and CLOTBUST-ER trials using matching and outcome modeling from randomized clinical trials (RCTs).A retrospective observational study matching subjects on baseline characteristics, from the CRSRP, the control arm of CLOTBUST-ER, and the interventional arm of NINDS trials. Day 7-10/discharge modified Rankin Score (mRS), and early mortality was compared between matched subjects. A mortality model derived from RCTs was developed, and outcomes were compared at similar baseline NIHSS scores. CRSRP symptomatic hemorrhage (SICH) rate was compared with an Ibero-American cohort (IAC).Of 540 CRSRP patients, 351 received rt-PA under 3 hours and were matched with NINDS subjects yielding 292 pairs; 161 CRSRP subjects treated within 4.5 hours were matched with CLOTBUST-ER subjects resulting in 151 pairs. The proportion of patients achieving excellent outcomes (mRS 0-1) did not differ between CRSRP and either NINDS or CLOTBUST-ER (CRSRP vs NINDS: 36.6% vs 32.9%, p=0.3; CRSRP vs CLOTBUST-ER: 26.5% vs 24.5%, p=0.8). Mortality was higher for CRSRP vs CLOTBUST-ER (7.3% vs 0.7%, p=0.006), but not vs NINDS (6.5% vs 4.5%, p=0.4). A pooled mortality model derived from 15 RCTs representing 4410 patients (RFunctional outcomes and SICH of thrombolysed Costa Rican patients compared favorably with published datasets, with a potential increase in early mortality.

Background: More than 70% of strokes occur in resource-poor countries. Outcomes are often not well documented. rt-PA for acute ischemic stroke was approved in 2012 for use in Costa Rica (CR). A hub and spoke model was initiated and a dataset established, the CR Stroke Registry Program (CRSRP) for conditional- and post-approval monitoring. Here, we compared CRSRP rt-PA outcomes to similarly treated subjects from the 1995 NINDS rt-PA trial and the 2019 CLOTBUST-ER control arm. Methods: Subjects were matched using a published pairing methodology and day 7-10/discharge modified Rankin Score (mRS), symptomatic intracerebral hemorrhages (SICH) and early mortality compared. A mortality model was generated from 15 randomized controlled trials (RCTs) and outcomes compared at similar baselines. SICH rates were compared with other cohorts: Get With The Guidelines (GWTG), a combined international IV thrombolysis trial pool, and 2 Ibero-American populations. Results: Of 424 CRSRP patients, 284 receiving rt-PA under 3 hrs were matched with 308 NINDS subjects. 131 non-diabetic CRSRP subjects, treated within 4.5 hrs, NIHSS 10 - 24 and Alberta Stroke Program Early CT Score (ASPECTS)>7, were matched with 300 CLOTBUST-ER subjects. Percent achieving either mRS 0-1 or 0-2 did not differ between CRSRP and either NINDS or CLOTBUST-ER (mRS 0-1: CRSRP:33.9% vs NINDS:33.6%; CRSRP:23.8% vs CLOTBUST-ER:27.0%, all p>=.05 / mRS 0-2: CRSRP:40.0% vs NINDS:41.4%; CRSRP:31.1% vs CLOTBUST-ER:36.1%, all p=>.05). Mortality was higher for CRSRP vs CLOTBUST-ER (6.6% vs 0.8%; p=0.05) but not vs NINDS (6.8% vs 4.3%; p=0.3). A predictive model (R 2 =0.39) showed neither cohort exceeded expected pooled mortality, with CLOTBUST-ER the lowest mortality. SICH rate was higher in CRSRP vs CLOTBUST-ER (7.3% vs 0.0% p=0.008) but not vs NINDS (5.7% vs 6.8% p=0.7)). SICH rates were not higher when compared with 4 international cohorts. Conclusion: Functional outcomes of Costa Rican patients receiving rt-PA compared favorably with 2 RCTs (NINDS and CLOTBUST-ER). SICH and mortality were higher than CLOTBUST-ER, although both were within expected range compared to other international cohorts. Systems of care development in order to further lower SICH and participate in the endovascular era are underway.

Background: Application of Machine Learning (ML) techniques in the prediction of Neurological Disorders has been growing rapidly. ML techniques require novel computer programming skills along with domain knowledge to produce a useful tool. We used Google Auto ML and Google ML Tables, a Cloud based front-end tools to develop, validate and deploy a prognostic model for Intracerebral Hemorrhage (ICH) without a single line of programming code. Methods: Data from Kasturba Medical College (KMC) Hospital ICH Stroke Registry between January 2015 and May 2019 was accessed. Google Auto ML Tables splits the dataset into training, validation and testing sets. 80% of the dataset was used for training, 10% for validation, and 10% for testing. Cramers V correlation statistic ( ϕ c ) between 30 variables and outcome was used to select 20 variables to predict the dichotomous outcome of good (mRS 0-3) vs bad outcome (mRS 4-6). The ML model generated was evaluated using Area Under the Curve (AUC) and Receiver Operating Characteristic (ROC) measures and by confusion/error matrix. Logistic Regression model was developed in parallel using Wizard Pro with the same set of 20 variables. Results: 1000 patients from KMC Registry were analysed. Cramers V correlation was highest for Glasgow Coma Scale (GCS) on admission ( ϕ c =0.6), followed by hematoma volume ( ϕ c =0.57). The AUC ROC of the model for good and bad outcome was 0.89 with an accuracy of 85.6%. Confusion matrix predicted 84% patients with good outcome and 87% with poor outcome. Feature importance chart showed that GCS had the highest relative importance at 25.7, followed by hematoma volume and age. A similar model created with simple logistic regression yielded a ROC of 0.87 with comparable results to the machine learning platform. Conclusion: Useful ML models can be easily developed and implemented by clinicians possessing domain expertise using Google Auto ML without computer programming experience.

Background and Purpose: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. Methods: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. Results: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03–4.54]; adjusted OR, 2.33 [95% CI, 1.02–5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68–6.11]; adjusted OR, 2.55 [95% CI, 0.76–8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. Conclusions: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Introduction: The etiology and significance of diffusion weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. We evaluated which factors were associated with DWI lesions, whether associated factors differed by ICH location, and whether DWI lesions were associated with functional outcomes. Methods: We pooled individual patient data from the MISTIE III trial, the ATACH-II trial, the i-DEF trial, and the ERICH study. We included only patients who underwent protocolized magnetic resonance imaging (MRI) of the brain. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 4-6 at 3-6 months. We used mixed effects logistic regression with the study database as a random effect. Results: Among 1,775 ICH patients, there were 621 (35.6%) lobar, 978 (55.9%) deep, and 148 (8.5%) infratentorial ICHs. Median time to MRI scan was 1.5 days (IQR, 1-4). DWIHLs occurred in 559 (31.5%) patients, with 190 (34.3%) in lobar ICH and 320 (57.8%) in deep ICHs. In mixed effects regression models, factors associated with DWIHLs included younger age factors associated with DWIHLs after acute ICH included younger age (OR, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.59; 95% CI, 1.18-2.16), admission systolic blood pressure (SBP per 10 mm Hg, OR, 1.13; 95% CI, 1.05-1.22), cerebral microbleeds (OR, 1.71, 95% CI, 1.24-2.35), and leukoaraiosis (OR, 1.60; 95% CI, 1.14-2.25). Patients with DWIHLs had higher odds of mRS 4-6 (OR, 1.57; 95% CI, 1.24-1.99) compared to those without, after adjustment for demographics and ICH severity. In subgroup analyses, similar factors influenced DWIHLs in deep ICH. However, in lobar ICH, younger age, admission SBP, and leukoaraiosis were associated with DWIHLs. Presence of DWIHLs was independently associated with poor mRS in deep ICH but not in lobar ICH. There was no relationship between acute BP lowering and DWIHLs, regardless of location. Conclusions: In a large, heterogeneous cohort of ICH patients, our results are consistent with the hypothesis that DWIHLs represent the effects of chronic hypertensive vasculopathy and acute blood pressure elevation. Furthermore, DWIHLs portend poor prognosis after ICH, particularly in deep hemorrhages.

Introduction: Conflicting evidence has been published regarding the safety and efficacy of ultrasound-enhanced thrombolysis (sonothrombolysis) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). Methods: We conducted an individual participant data meta-analysis of available randomized controlled trials (RCTs) comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in AIS patients with LVO. Results: We included 6 in total RCTs that enrolled 1077 AIS patients. A total of 138 and 134 confirmed LVO patients were randomized to treatment and control groups respectively (median age 68 years, 58% men, median baseline NIHSS score 16). Patients randomized to sonothrombolysis had increased odds of complete recanalization compared to patients receiving intravenous thrombolysis alone (40.3% vs. 22.4%; OR=2.30, 95%CI: 1.05-5.02; adjusted OR=2.33, 95%CI: 1.02-5.34). They also tended to have increased odds of any (complete or partial recanalization (66.4% vs. 53.0%; OR=1.78, 95%CI: 0.95-3.33; adjusted OR=1.85, 95%CI: 0.97-3.53). The likelihood of symptomatic intracranial hemorrhage did not differ between the two groups (7.3% vs. 3.7%, OR=2.52, 95%CI: 0.77-8.29; adjusted OR=2.55, 95%CI: 0.76-8.52). No differences in the likelihood of asymptomatic intracranial hemorrhage (adjusted OR: 1.30, 95%CI: 0.38-4.39), three-month mortality (adjusted OR: 1.23, 95%CI: 0.25-6.05), three-month favorable functional outcome (mRS-scores of 0-1; adjusted OR: 1.43, 95%CI: 0.64-3.19) and three-month functional independence (mRS-scores of 0-2; adjusted OR: 1.43, 95%CI: 0.77-2.64) were documented. Conclusion: Sonothrombolysis was associated with a two-fold increase in the odds of complete recanalization compared to intravenous thrombolysis alone in AIS patients with LVOs. Further study of the safety and efficacy of sonothrombolysis is warranted.

Background: Patients suffering from subarachnoid hemorrhage (SAH) have poor long-term outcomes. There are predictive models for ischemic and hemorrhagic stroke. However, there is paucity of models for SAH. Machine learning concepts were applied to build multi-stage Neural Networks (NN), Support Vector Machines (SVM) and Keras/Tensor Flow models to predict SAH outcomes. Methods: A database of ~800 aneurysmal SAH patients from Kasturba Medical College was utilized. Baseline variables of World Federation of Neurosurgeons 5-point scale (WFNS 1-5), age, gender, and presence/absence of hypertension and diabetes were considered in Stage 1. Stage 2 included all Stage 1 variables along with presence/absence of radiologic signs vasospasm and ischemia. Stage 3 includes earlier 2 stages and discharge Glasgow Outcome Scale (GOS 1-5). GOS at 3 months was predicted using 2-layer NN/SVM/Keras-TensorFlow models on the five point categorical scale as well as dichotomized to dead/alive and favorable (GOS 4-5) or unfavorable (GOS 1-3). Prediction accuracy of models was compared to the recorded GOS. Results: Prediction accuracy shown as percentages (See Table) for all three stages was similar for SVM, NN and Keras/TensorFlow models. Accuracy was remarkably higher with dichotomization compared to the complete five point GOS categorical scale. Conclusions: SVM, NN, and Keras-TensorFlow based machine learning models can be used to predict SAH outcomes to a high degree of accuracy. These powerful predictive models can be used to prognosticate and select patients into trials.

Background and Purpose— Observational data suggest that antiplatelet therapy after intracerebral hemorrhage (ICH) alleviates thromboembolic risk without increasing the risk of recurrent ICH. Given the paucity of data on the relationship between antiplatelet therapy after ICH and functional outcomes, we aimed to study this association in a multicenter cohort. Methods— We meta-analyzed data from (1) the Massachusetts General Hospital ICH registry (n=1854), (2) the Virtual International Stroke Trials Archive database (n=762), and (3) the Yale stroke registry (n=185). Our exposure was antiplatelet therapy after ICH, which was modeled as a time-varying covariate. Our primary outcomes were all-cause mortality and a composite of major disability or death (modified Rankin Scale score 4–6). We used Cox proportional regression analyses to estimate the hazard ratio of death or poor functional outcome as a function of antiplatelet therapy and random-effects meta-analysis to pool the estimated HRs across studies. Additional analyses stratified by hematoma location (lobar and deep ICH) were performed. Results— We included a total of 2801 ICH patients, of whom 288 (10.3%) were started on antiplatelet medications after ICH. Median times to antiplatelet therapy ranged from 7 to 39 days. Antiplatelet therapy after ICH was not associated with mortality (hazard ratio, 0.85; 95% CI, 0.66–1.09), or death or major disability (hazard ratio, 0.83; 95% CI, 0.59–1.16) compared with patients not started on antiplatelet therapy. Similar results were obtained in additional analyses stratified by hematoma location. Conclusions— Antiplatelet therapy after ICH appeared safe and was not associated with all-cause mortality or functional outcome, regardless of hematoma location. Randomized clinical trials are needed to determine the effects and harms of antiplatelet therapy after ICH.

Background Mobile stroke units (MSUs), equipped with an integrated computed tomography scanner, can shorten time to thrombolytic treatment and may improve outcome in patients with acute ischemic stroke. Original (German) MSUs are staffed by neurologists trained as emergency physicians, but patient assessment and treatment decisions by a remote neurologist may offer an alternative to neurologists aboard MSU. Methods and Results Remote neurologists examined and assessed emergency patients treated aboard the MSU in Berlin, Germany. Audiovisual quality was rated by the remote neurologist from 1 (excellent) to 6 (insufficient), and duration of video examinations was assessed. We analyzed interrater reliability of diagnoses, scores on the National Institutes of Health Stroke Scale and treatment decisions (intravenous thrombolysis) between the MSU neurologist and the remote neurologist. We included 90 of 103 emergency assessments (13 patients were excluded because of either failed connection, technical problems, clinical worsening during teleconsultation, or missing data in documentation) in this study. The remote neurologist rated audiovisual quality with a median grade for audio quality of 3 (satisfactory) and for video quality of 2 (good). Mean time for completion of teleconsultations was about 19±5 minutes. The interrater reliabilities between the onboard and remote neurologist were high for diagnoses (Cohen's κ=0.86), National Institutes of Health Stroke Scale sum scores (intraclass correlation coefficient, 0.87) and treatment decisions (16 treatment decisions agreed versus 2 disagreed; Cohen's κ=0.93). Conclusions Remote assessment and treatment decisions of emergency patients are technically feasible with satisfactory audiovisual quality. Agreement on diagnoses, neurological examinations, and treatment decisions between onboard and remote neurologists was high., See Editorial by Derry et al

Introduction: High mortality is associated with aneurysmal subarachnoid hemorrhage (SAH). Despite years of studies and translational research, only a few health and lifestyle factors have been found to definitively associate with an increased risk of SAH incidence and mortality. Prior studies have provided some evidence that environmental factors play a role in the incidence of SAH, but the available data is not often consistent or applicable to the United States of America (USA). Here we provide support that there is a temporal differences in SAH mortality by month of the year and day of the week. Methods: The Centers for Disease Control (CDC) and Prevention public health database (wonder.cdc.gov) was accessed. Mortality events for the years 1999-2016 were obtained for deaths attributed to SAH from a named vessel distribution with accounting for day of week and month of year as well as gender from year to year. ANOVA was used to test for differences by week or month. Results: Mortality for week day variations found no significant differences (p = 0.13) in women, while men demonstrated a significant difference (p = 0.003) with the most common day of death being Monday. Mortality for monthly variation found a significant difference (p = 0.01) in total with January being the most common month of SAH mortality. However, divided by gender women (p = 0.06) and men (p = 0.10) did not meet predefined statistical significance. Conclusion: Mortality from SAH appears to have a variation in time of day of week in men and by month for both genders but this has unclear significance at this time.

Background: A predictive outcome model for intracranial hemorrhage (ICH) from patient level data would be of interest in planning clinical trials. Despite decades of effort and several different types of models attempted, there is no universally accepted model. Here, we sought to apply Information Theory precepts to select the optimum set of baseline variables that can predict outcomes using data from the control arm of ATACH-II, a recently concluded ICH trial that tested the effects of control of systolic BP (SBP). Methods: Sixty-three logistic regression models of mortality and good outcome (modified Rankin Score of 0-3 at 90 days) were generated based on all possible combination of 6 baseline variables: NIH Stroke Scale (NIHSS), Glasgow Coma Scale (GCS), age, hematoma volume (Hem Vol), intraventricular hematoma volume (IVH Vol), and SBP. Akaike Information Criterion (AIC) a measure of information content in a model was calculated. Those with the lowest AIC are considered best. Results: ATACH-II had 405 subjects with non-lobar hemorrhages that reported all six baseline variables and long-term outcomes. The best model of good outcome was based on NIHSS, age, Hem Vol, IVH Vol (R 2 = 0.33; p <2 = 0.18; p < Conclusion: We show that Information Theory constructs can be used to select the best set of variables to model outcomes in ICH. While we found generally better predictive ability for good outcome compared to mortality, the best model predicted only 57% of the outcome variance. While additional types of data fitting might yield additional predictive value, the relatively modest results seen here suggest that there remain additional factors related to outcome not typically measured in ICH trials. Additional data points from other trails are being pooled to see if predictive ability improves.

Background and Aims: Spontaneous subarachnoid hemorrhage (sSAH) is a rare stroke event with a relatively high rate of mortality. There are a number of risk factors, including gender and race, for sSAH. However, it is unclear whether these risk factors are associated with the age of mortality due to sSAH. Methods: We utilized the CDC Wonder dataset (wonder.cdc.gov) “Underlying Cause of Mortality 1999-2016” to query for sSAH mortality in named arterial distributions. Age, race and other demographic data from the entire United States was available. Statistical differences between populations of different races including Caucasian African American, Asian, or Native American or between genders were assessed using a Chi-squared test of independence and unpaired Student’s t tests. Results: Our analysis detected an association between race and age range of mortality due to sSAH (χ 2 = 414.00, df = 51, p -value = 1.6E-58). Further analyses revealed a younger age of mortality due to sSAH in males as compared to females, with an average age of mortality at 53.3 and 60.0 years old respectively ( p < 0.0001). Notably, race differences were greater in females than in males, whereby black females exhibited the youngest age of mortality due to sSAH with an average age of mortality at 51.8 years as compared to 61.6 for non-black females ( p < 0.0001). Conclusion: These findings suggest that underlying differences in race and gender have an effect on age of mortality due to sSAH.

Supplemental Material for Ayurvedic Treatment of Acute Ischemic Stroke: A Prospective Observational Study by J Aarthi Harini BAMS Avineet Luthra BPT, MSc Shrey Madeka MSc Prasan Shankar BAMS, MD (Ayu.) Pitchaiah Mandava MD, PhD, MSEE Ravishankar Pervaje BAMS, MS (Ayu.) Sanjith Aaron MBBS, MD, DM Archana Purushotham MD, PhD in Global Advances in Health and Medicine

Importance The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. Objective To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. Design, Setting, and Participants This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. Main Outcomes and Measures The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. Results After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10–mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. Conclusions and Relevance In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

High-profile failures in stroke clinical trials have discouraged clinical translation of neuroprotectants. While there are several plausible explanations for these failures, we believe that the fundamental problem is the way clinical and pre-clinical studies are designed and analyzed for heterogeneous disorders such as stroke due to innate biological and methodological variability that current methods cannot capture. Recent efforts to address pre-clinical rigor and design, while important, are unable to account for variability present even in genetically homogenous rodents. Indeed, efforts to minimize variability may lessen the clinical relevance of pre-clinical models. We propose a new approach that recognizes the important role of baseline stroke severity and other factors in influencing outcome. Analogous to clinical trials, we propose reporting baseline factors that influence outcome and then adapting for the pre-clinical setting a method developed for clinical trial analysis where the influence of baseline factors is mathematically modeled and the variance quantified. A new therapy's effectiveness is then evaluated relative to the pooled outcome variance at its own baseline conditions. In this way, an objective threshold for robustness can be established that must be overcome to suggest its effectiveness when expanded to broader populations outside of the controlled environment of the PI's laboratory. The method is model neutral and subsumes sources of variance as reflected in baseline factors such as initial stroke severity. We propose that this new approach deserves consideration for providing an objective method to select agents worthy of the commitment of time and resources in translation to clinical trials.

Background: In the near future, a majority of strokes are projected to occur in developing countries. However, population-level information on the prevalence of stroke from rural areas of developing countries, including India, is rare. We estimated the prevalence of stroke in a rural area of one of the most underdeveloped districts of India. Methods: Trained surveyors conducted a house-to-house survey using a validated screening questionnaire in a well-defined population of 45,053 living in 39 villages in a demographic surveillance site in Gadchiroli district. A trained physician and a neurologist evaluated screen-positive patients and diagnosed stroke using the World Health Organization's criteria. Results: In the screened population, 175 patients had stroke. The mean age of patients with stroke was 60.9 ± 14.7 years and 32.5% were women. The crude prevalence rate of stroke was 388.43 (95% CI 335.04-450.33) and the age-standardized prevalence rate of stroke was 535.58 (95% CI 492.41-583.01) per 100,000 population. The crude prevalence rate of stroke was significantly higher among men than among women (520 vs. 255/100,000 population, p < 0.05). Conclusion: In this prevalence study, conducted after a gap of 20 years in rural India, the prevalence of stroke was high and was more than twice the prevalence reported from the previous study. The prevalence was double among men compared to women. Stroke is emerging as a public health priority in rural India.

Introduction While oxidative stress can be measured during transient cerebral ischemia, antioxidant therapies for ischemic stroke have been clinically unsuccessful. Many antioxidants are limited in their range and/or capacity for quenching radicals and can generate toxic intermediates overwhelming depleted endogenous protection. We developed a new antioxidant class, 40 nm × 2 nm carbon nanoparticles, hydrophilic carbon clusters, conjugated to poly(ethylene glycol) termed PEG-HCCs. These particles are high-capacity superoxide dismutase mimics, are effective against hydroxyl radical, and restore the balance between nitric oxide and superoxide in the vasculature. Here, we report the effects of PEG-HCCs administered during reperfusion after transient middle cerebral artery occlusion (tMCAO) by suture in the rat under hyperglycemic conditions. Hyperglycemia occurs in one-third of stroke patients and worsens clinical outcome. In animal models, this worsening occurs largely by accelerating elaboration of reactive oxygen species (ROS) during reperfusion. Methods PEG-HCCs were studied for their protective ability against hydrogen peroxide in b.End3 brain endothelial cell line and E17 primary cortical neuron cultures. In vivo, hyperglycemia was induced by streptozotocin injection 2 days before tMCAO. 58 Male Sprague-Dawley rats were analyzed. They were injected IV with PBS or PEG-HCCs (4 mg/kg 2×) at the time of recanalization after either 90- or 120-min occlusion. Rats were survived for up to 3 days, and infarct volume characteristics and neurological functional outcome (modified Bederson Score) were assessed. Results PEG-HCCs were protective against hydrogen peroxide in both culture models. In vivo improvement was found after PEG-HCCs with 90-min ischemia with reduction in infarct size (42%), hemisphere swelling (46%), hemorrhage score (53%), and improvement in Bederson score (70%) (p = 0.068–0.001). Early high mortality in the 2-h in the PBS control group precluded detailed analysis, but a trend was found in improvement in all factors, e.g., reduction in infarct volume (48%; p = 0.034) and a 56% improvement in Bederson score (p = 0.055) with PEG-HCCs. Conclusion This nano-antioxidant showed some improvement in several outcome measures in a severe model of tMCAO when administered at a clinically relevant time point. Long-term studies and additional models are required to assess potential for clinical use, especially for patients hyperglycemic at the time of their stroke, as these patients have the worst outcomes.

ObjectiveTo develop models of outcome for intracerebral hemorrhage (ICH) to identify promising and futile interventions based on their early phase results without need for correction for baseline imbalances.MethodsWe developed a pooled outcome model from the control arms of randomized control trials and tested different interventions against the model at comparable baseline conditions. Eligible clinical trials and large case series were identified from multiple library databases. Models based on baseline factors reported in the control arms were tested for the ability to predict functional outcome (modified Rankin Scale score) and mortality. Interventions were grouped into blood pressure control, fibrinolytic-assisted hematoma evacuation, hemostatic medications, and neuroprotective agents. Statistical intervals around the model were generated at the p = 0.1 level to screen how each trial's outcome compared to expected outcome.ResultsFourteen control arms with 3,386 patients were used to develop 7 alternate models for functional outcome. The model incorporating baseline NIH Stroke Scale, age, and hematoma volume yielded the best fit (adjusted R2 = 0.89). All early phase treatments that eventually resulted in negative late phase trials were identified as negative by this method. Early phase fibrinolytic-assisted hematoma evacuation studies showed the most promise trending toward improved functional outcome with no suggestion of an increase in mortality, supporting its further study.ConclusionsWe successfully developed an outcome model for ICH that identified interventions destined to be negative while identifying a promising one. Such an approach may assist in prioritizing resources prior to multicenter trial.

Introduction: Many randomized clinical trials (RCTs) have been conducted for subarachnoid hemorrhage (SAH), yet no treatment definitively improves outcome. Predictive ability of early phase trials is uncertain because outcome is strongly related to baseline severity factors, yet imbalances are common in these trials. We previously developed a method for ischemic stroke to identify promising treatments at early phase using a pooled model constructed from the control arms of RCTs and comparing trial outcomes at their own baselines. We applied this method to SAH. Methods: SAH predictive models for functional outcome and mortality were developed based on published variables (eg, WFNS, Fisher, age). The outcome model is the best fit 3-d surface bounded on either side by p=±0.1 prediction interval (PI) surfaces. These surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome of a pooled sample. Treatment arms from RCTs and single arm trials for SAH are then visually compared against the pooled controlled arm to see if they surpassed the prediction surfaces at their own baseline conditions. Results: The best model fit was for good outcome (modified Rankin Score 0-2) based on WFNS grade 4-5% and age (26 RCTs, 5200 subjects; R 2 =0.54; p Conclusions: Outcome models based on percentage of high grade WFNS and age were successfully developed. This approach may be useful to prioritize treatments worthy of further study.

Background and Purpose— The safety and efficacy of restarting anticoagulation therapy after intracranial hemorrhage (ICH) remain unclear. We performed a systematic review and meta-analysis to summarize the associations of anticoagulation resumption with the subsequent risk of ICH recurrence and thromboembolism. Methods— We searched published medical literature to identify cohort studies involving adults with anticoagulation-associated ICH. Our predictor variable was resumption of anticoagulation. Outcome measures were thromboembolic events (stroke and myocardial infarction) and recurrence of ICH. After assessing study heterogeneity and publication bias, we performed a meta-analysis using random-effects models to assess the strength of association between anticoagulation resumption and our outcomes. Results— Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25–0.45; Q =5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58–1.77; Q =24.68, P for heterogeneity Conclusions— In observational studies, reinstitution of anticoagulation after ICH was associated with a lower risk of thromboembolic complications and a similar risk of ICH recurrence. Randomized clinical trials are needed to determine the true risk–benefit profile of anticoagulation resumption after ICH.

Introduction: Many stroke patients do not fully respond to intravenous rt-PA, possibly due to factors that increase clot resistance or impede reperfusion. GPIb receptors on the platelet surface initiate vessel occlusion through an interaction with subendothelium-bound von Willebrand Factor and the interaction transduces signals resulting in further activation. An increase in GPIb availability may result in macro or micro-vascular thrombosis. We report the effect of rt-PA on a potential compensatory conformational response of platelet GPIb. Methods: 5 subjects with large artery stroke and treated with rt-PA within 4.5 hours of onset were enrolled after consent. Blood was obtained immediately before and 1.3 hours post rt-PA bolus. Blood was incubated with 3 monoclonal antibodies (mABs: AN51, 6D1 and SZ2) and control antibody. AN51 and 6D1 are conformation sensitive and SZ2 is relatively less conformation sensitive. Flow cytometry was performed to assess fluorescent intensity of platelets pre and post-treatment and corrected for non-specific staining with control IgG. Blood from healthy donors subjected to appropriate concentrations of rt-PA in vitro was tested for conformational changes with AN51 and 6D1. Results: Compared to pre-treatment, 4 of 5 patients showed increased GPIb or binding with AN51 and 6D1 post treatment, with an overall median percentage increase with AN51 of 40.6% and 60.3% with 6D1. SZ2 showed a smaller increase (30.7%). The 1 subject who showed no change had the only hemorrhagic transformation. Blood from healthy donors showed an increase of 21.4% with AN51 and 41.3% with 6D1 after rt-PA. Conclusion: These results indicate for the first time rt-PA induced conformation changes on platelet GPIb in acute ischemic stroke in vivo despite that GPIb is not the direct target. These changes were also seen with rt-PA in vitro. It is possible that up-regulation of GPIb receptors plays a protective role in preventing hemorrhages but also may mediate increased propensity for clot resistance or downstream thrombosis. If confirmed in a larger ongoing sample, measuring GPIb binding may provide a rational approach to post-rt-PA antiplatelet therapy and identify a risk for hemorrhagic transformation.

Introduction: Failures to translate pre-clinical results have been discouraging. We have contended that stroke is too heterogeneous with respect to factors influencing outcome to expect small studies to be balanced. It is not only difficult to control for biological and methodological variability but efforts to improve homogeneity, such as minimizing physiological variability, may render results less applicable to humans. Here, we report a predictive outcome model in experimental stroke which incorporates baseline variability and provides statistical thresholds a treatment must exceed to be efficacious in a broad population. Methods: We generated a mathematical model to predict outcome using transient MCA occlusion in 23 unfasted rats. To create baseline variability, we varied occlusion times from 90-120 min, altered baseline glucose with streptozotocin, and assessed neurological outcome 3 days later with a modified Bederson Score (BS; 0-6 functional measure, 7 death). Statistical surfaces in 3 dimensions were generated using Jacobian matrices flanking the model to provide a screening threshold (1 SD) for comparing new therapies against this model. Results: We successfully generated an outcome model from occlusion time, glucose and BS (Fig; R 2 =.49, p=.0003; middle surface is the model surrounded by ±SD surfaces). Outcome was sensitive to change in glucose and time, suggesting small imbalances in these factors between groups may influence outcome, and hence the perceived efficacy of a new therapeutic intervention. At normoglycemia and 90 mins, the lower surface overlapped with no deficit, indicating it would be difficult to reliably demonstrate benefit under those conditions. Conclusions: These results indicate it is feasible to incorporate biological variability to generate more clinically relevant conditions. The method will be tested with other stroke models and modifiers towards a generalized model to screen for therapies worthy of further study.

Introduction: While oxidative stress mediates many of the pathologies in stroke, antioxidant therapies have been unsuccessful. Current antioxidants are limited either by a narrow range of radicals quenched or by low capacity. Some can yield toxic intermediates. We developed a new class of antioxidant, highly modified carbon nanoparticles called PEGylated hydrophilic carbon clusters (PEG-HCCs). These 40 nM particles quench superoxide by a high capacity novel catalytic mechanism (PNAS 2015: 2343-8), are effective against - OH and recouple nitric oxide synthase. Here we report the effect of PEG-HCCs administered during reperfusion after transient MCA suture occlusion in the rat under varying glucose levels. Hyperglycemia occurs in 1/3 of stroke patients and worsens outcome in part by accelerating release of radicals during reperfusion. Methods: Variation in glucose was induced by streptozocin IP 2 days prior to MCAO. At 90 mins, 23 rats were injected IV with PBS or PEG-HCCs (4 mg/kg) and the suture removed. A second dose was given 2 hours later (dosing based on half-life and in-vitro efficacy). At 3 days, infarct size corrected for edema and neurological function (Bederson Score, BS) was obtained. An outcome curve was developed using a range of baseline glucose in controls and the effect of PEG-HCCs compared at rat’s baseline glucose values. Results: We found a strong sigmoidal relationship between infarct size and glucose level in control rats (Fig. R 2 =.93; p=.0001; blue curve: control arm ± 95% confidence intervals). All PEG-HCC treated rats showed infarct size below the confidence interval (red stars; p Conclusions: This novel, broadly active, high capacity antioxidant was able to improve outcome in a severe test of pre-clinical stroke at clinically relevant times. Studies are ongoing to assess the treatment window and longer term outcomes.

Hyperglycemia at the time of ischemic stroke has been associated with poorer outcomes. Preclinical literature suggests that hyperglycemia is an independent prognostic factor and the vasculature is more vulnerable to reperfusion injury. We applied a method to match subjects on important baseline factors to test whether, independent of stroke severity, stroke subtype influences the effect of hyperglycemia on outcome after recombinant tissue plasminogen activator (rt-PA). We reanalyzed the NINDS rt-PA dataset with respect to matching variables baseline NIHSS, age, and investigator-determined stroke subtypes small-vessel occlusive stroke (SVS), large-vessel occlusive stroke (LVS), and cardioembolic stroke (CES), above and below a glucose threshold of 150 mg/dl. Ninety-day outcomes were compared. Post hoc baseline matching was excellent in most cases. Hyperglycemia was associated with worsened functional outcome mostly in the LVS subtype with increased mortality in the placebo arm (15.3 % mortality normoglycemia vs. 30.6 % hyperglycemia; p = .046), worse functional outcome in the rt-PA arm (modified Rankin Score (mRS) 0–1; 46.3 vs. 22.0 %; p = .034), and no improvement in functional outcome with rt-PA compared to placebo (mRS 0–1; 25 % in both groups). Among hyperglycemic subjects, CES subjects showed significant improvement following rt-PA (p = .027). After matching for baseline severity, the influence of hyperglycemia on outcome was primarily in the LVS subtype, especially after rt-PA. This finding is consistent with a deleterious effect of hyperglycemia on ischemia/reperfusion of symptomatic large arteries. If confirmed, the particular vulnerability of the LVS subtype is important in understanding the role of stroke subtype in the mechanism of worsening and potential treatment of hyperglycemic stroke patients.

Background The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian population, but the results are often extrapolated onto non-Caucasians. A limited number of nonrandomized studies have proposed that non-Caucasian patients show differential response to tissue plasminogen activator. Aims and/or hypothesis We examined if non-Caucasian patients of mixed national origin within the Virtual International Stroke Trials Archives neuroprotection trials responded differently to tissue plasminogen activator compared with Caucasians. Methods We matched patients within each race-subtype for age, baseline National Institutes of Health Stroke Scales, and diabetes status, and excluded outliers. We tested for an interaction of race ethnicity with tissue plasminogen activator on predicting outcomes at α = 0·05. We compared 90-day ordinal outcome (modified Rankin Scale; primary analysis) and dichotomized outcomes (modified Rankin Scale 0–1; modified Rankin Scale 0–2; survival) within individual race ethnicity. Results One thousand nine hundred forty-six thrombolysed patients (125 Blacks, 39 Asians, and 1821 Caucasians) were matched with 1946 non-thrombolysed patients in each race ethnicity group. Postmatching, there were no imbalances in baseline National Institutes of Health Stroke Scales and age between the groups ( P > 0·05). The interaction of tissue plasminogen activator with race ethnicity was nonsignificant in ordinal ( P = 0·4) and in dichotomized outcome models ( P > 0·05). Ordinal odds for improved outcomes were 1·5 for all patients ( P < 0·05). Ordinal odds for Caucasians were 1·5 ( P < 0·05); for Blacks, 2·1 ( P < 0·05); and for Asians, 1·2 ( P > 0·05; 1·6 after 1:2 matching with nonthrombolysed, because of small numbers). Dichotomized functional outcomes improved after thrombolysis overall, in Caucasians, in Blacks (modified Rankin Scale 0–2 only), and in Asians (after 1:2 matching; P > 0·05). Odds for survival were consistent across all groups. Conclusions These results do not suggest a differential response to tissue plasminogen activator based on race ethnicity. Among Asians, data were particularly sparse, and results should be interpreted with caution.

Background and Purpose— Sex and race reportedly influence outcome after recombinant tissue-type plasminogen activator (rtPA). It is, however, unclear whether baseline imbalances (eg, stroke severity) or lack of response to thrombolysis is responsible. We applied balancing methods to test the hypothesis that race and sex influence outcome after rtPA independent of baseline conditions. Methods— We mapped group outcomes from the National Institute of Neurological Disorders and Stroke (NINDS) dataset based on race and sex onto a surrogate-control function to assess differences from expected outcomes at their respective National Institutes of Health Stroke Scale and age. Outcomes were also compared for subjects matched individually on key baseline factors using NINDS and 2 recent datasets from southeastern United States. Results— At similar National Institutes of Health Stroke Scale and age, 90-day good outcomes (modified Rankin Score, 0–2) in NINDS were similarly improved after rtPA for white men and women. There was a strong trend for improvement in black men. Conversely, black women treated with rtPA showed response rates no different from the controls. After baseline matching, there were nonsignificant trends in outcomes except for significantly fewer good outcomes in black versus matched white women (37% versus 63%; P =0.027). Pooling the 3 datasets showed a similar trend for poorer short-term outcome for black women ( P =0.054; modified Rankin Score, 0–1). Conclusions— Matching for key baseline factors indicated that race and sex influence outcome most strikingly in black women who demonstrated poorest outcomes after rtPA. This finding supports the hypothesis that poor response to rtPA, rather than differences in baseline conditions, contributes to the worse outcome. This finding requires prospective confirmation.

Objective: Disability or death occurs more frequently in patients with hemorrhagic transformation (HT) after ischemic stroke. In rat models of stroke, sulfonylurea (SU) drugs such as glibenclamide (adopted US name, glyburide) confer protection against swelling and HT through actions on the novel SUR1-regulated NCCa-ATP channel. Here, we sought to determine whether the use of SU drugs in patients with diabetes mellitus (DM) presenting with acute ischemic stroke might influence the incidence of HT. Methods: We retrospectively analyzed data on 220 patients with DM who presented with acute ischemic stroke, 43 of whom were managed with and continued to receive SU drugs, and 177 of whom were managed without (controls). Results: During a median length of stay in hospital of 11 days, 20 control patients (11%) experienced symptomatic HT (sHT), whereas no patient in the SU group experienced sHT (p = 0.016). No patient in the SU group died, compared to 18 (10%) in the control group (p = 0.027). Similarly favorable outcomes were observed after matching for baseline imbalances and excluding outliers. In support of the proposed mechanism, we present a case of sHT in which an analysis of brain tissues obtained intraoperatively showed prominent upregulation of SUR1, the target of SU drugs, in microvessels and neurons. Interpretation: We conclude that, in diabetic patients with acute ischemic stroke, prior and continued use of SU drugs is associated with reduced sHT compared to those whose treatment regimen does not include SU drugs. ANN NEUROL 2012;72:799–806

Background: While stent-retriever randomized clinical trials (RCTs) were uniformly positive, their designs differed. Here, we assessed whether trials also differed in the magnitude of improvement and if factors could be identified that distinguished the best performers. Because % utilization of rt-PA in the control arms varied, we developed a multi-dimensional outcome model from the control arms of all IV tPA RCTs treating various % of subjects and their baseline stroke severity (NIHSS). This model was used to compare each trial’s functional outcome (mRS < 2) and mortality at their own baseline without need for statistical manipulation. We assessed factors that potentially distinguished the best performers. Methods: The model was developed from 54 RCT control arms representing >11,000 subjects treating between 0-100% with IV rt-PA. 3-D non-linear functions were fit to the 90-day mortality and mRS 0-2. This model includes ±95% statistical interval surfaces to assess whether a trial’s outcomes surpass the variability inherent in a sample of RCT subjects (Neurology 85:274-83, 2015). 6 stent retriever RCTs were compared. Results: The models showed excellent fit: mRS 0-2 (r 2 =0.83, p<2 =0.65, p< Conclusion: A new outcome model based on stroke severity and % IV rt-PA permitted analysis of stent-retriever therapy compared to a large population. Best outcomes were related to shorter treatment time and higher utilization of rt-PA, suggesting a treatment interaction between these modalities. Factors influencing mortality are being analyzed.

Background and Purpose— Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection). Methods— We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm 3 , whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127 ≤10 hours. Results— Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm 3 . There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm 3 . The proportion of 90-day modified Rankin Scale ≤4 was 90% (40% modified Rankin Scale, ≤3). Conclusions— RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01268683.

Most early phase trials in stroke and brain trauma have failed in phase 3, including efforts to improve acute ischemic stroke outcomes beyond that achieved by intravenous recombinant tissue plasminogen activator (t-PA) (IVT). With the exception of more recent stent retriever trials, most subsequent phase 3 trials failed. We previously showed that baseline imbalances, non-linear relationships of these factors to outcome, and unrepresentative control populations invalidate traditional statistical analysis in early trials of heterogeneous diseases such as stroke. We developed an alternative approach using a pooled outcome model derived from control arms of randomized clinical trial (RCTs). This model then permits comparing treatment trials to an expected outcome of a pooled population. Here, we hypothesized we could develop such a model for IVT and tested it against outcomes without IVT. We surveyed literature for all trials involving one arm with IVT reporting baseline National Institute Stroke Scale (NIHSS), age, and outcome. A non-linear fit was performed including multi-dimensional statistical intervals (±95 %) permitting visual comparison of outcomes at their own baselines. We compared models derived from non-IVT control arms. Models from 24 IVT RCTs representing 3195 subjects were successfully generated for functional outcome, modified Rankin Scale (mRS) 0-2 (r(2) = 0. 83, p

BACKGROUND: Outcome following ischemic stroke is strongly related to baseline severity. Differences in baseline balance between arms seen even in larger trials complicate analysis. We developed a method (pPREDICTS) that generates a pooled outcome model from baseline factors taken from randomized clinical trials (RCTs). It visualizes variability to assess whether an individual study treatment arm differs sufficiently from expected outcome to be considered positive if tested in a larger population, without need for any statistical corrections. Here we assessed whether intracerebral hemorrhage (ICH) could be similarly modeled and how blood pressure (BP) interventions fared considering between-trial variance. METHODS: pPREDICTS generates an outcomes and provides multi-dimensional ±p=.05 statistical surfaces to visualize the variance among these trials. ICH RCTs were selected that provided baseline NIHSS, age and 90 day outcomes. Individual results from 4 BP trials were tested against these models to determine whether outcomes surpassed the ±95% prediction interval surfaces. Mortality and mRS0-2, the most frequently reported outcomes were modeled. RESULTS: Outcome functions derived from 12 ICH RCTs representing 2766 subjects were generated (middle surface ± p=.05 surfaces; Fig 1a: Mortality: r 2 =0.84; Fig 1b:mRS0-2:r 2 =0.79; p≤0.005). Control management (green) and treatment arm (red) outcomes of ATACH, ICH-ADAPT, INTERACT and INTERACT2 were plotted (see Figs). No mortality or functional outcome different from control was seen as outcomes are mostly distributed along the middle surface. However, tier 3 of ATACH, BP goal of SBP 110-140 showed increased mortality (>+95%) and decreased mRS 0-2 outcome ( CONCLUSION: Outcome models for mortality and mRS 0-2 were successfully developed. No benefit was seen from any BP intervention. We suspect small differences in outcomes reported as positive are more likely random variation.

BACKGROUND: Although a phase 3 trial using cardiac dose of the GP IIb/IIIa inhibitor abciximab was halted, we previously reported that a 30% lower total intravenous (IV) abciximab dose achieved optimal platelet inhibition (92%) and showed benefit in patients ineligible for tPA when compared using a rigorous matching process to historical controls (Mandava et al, TSR 2010). Given lack of proven alternatives, we were interested in abciximab specifically in the posterior circulation. METHODS: 0.2 mg/kg IV bolus followed by 0.05 ug/kg/hr infusion over 12 hrs of abciximab was administered with suspected large vessel posterior circulation occlusion after informed consent and presentation of alternatives. Patients were ineligible for tPA mostly from time window (24 hrs, later changed to 12 hrs) or elevated INR < 2.5. A weight based heparin protocol was used in most patients to achieve PTT 46-70. Ninety day follow up was obtained. To assess benefit, patients’ baseline characteristics were compared to the NINDS control arms subjects restricted to large vessel and cardioembolic subtypes. Matching was performed for 5 hour baseline NINDS NIHSS, age, glucose, and posterior stroke. An excess of posterior strokes in the abciximab group permitted 2:1 matching with outlier elimination. McNemars test compared 90 day mRS 0-1/0-2, mortality, and hemorrhage RESULTS: 26 subjects were treated in 3 university centers. Post-match baseline variables were slightly more severe in the abciximab group and they were treated later (Table). 90-day functional outcomes were higher in the abciximab group (mRS 0-1:54.5% vs 23.1%, mRS 0-2: 63.6% vs 30.8%; p CONCLUSION: Low dose IV abciximab in extended time window for large vessel posterior stroke shows promise. Given lack of proven alternatives, these results need to be verified prospectively.

Obstructive thrombosis of left-sided mechanical prosthetic valves is a life-threatening complication. Intravenous thrombolytic therapy is contraindicated due to risk of clot embolization and surgical treatment is often required for hemodynamically unstable patients. We report for the first time the successful use of abciximab in the management of a patient in cardiogenic shock with multiple prosthetic valve obstructive thrombosis and evolving embolic stroke. Serial Doppler echocardiography and cinefluoroscopy demonstrated resolution of thrombi, improvements in transvalvular gradients and improvement in leaflet motion. This observation suggests abciximab should be considered as a therapeutic option in the treatment of obstructed prosthetic heart valves. (ECHOCARDIOGRAPHY, Volume 21, January 2004)

This review addresses decision-making underlying the frequent failure to confirm early-phase positive trial results and how to prioritize which early agents to transition to late phase. While unexpected toxicity is sometimes responsible for late-phase failures, lack of efficacy is also frequently found. In stroke as in other conditions, early trials often demonstrate imbalances in factors influencing outcome. Other issues complicate early trial analysis, including unequally distributed noise inherent in outcome measures and variations in natural history among studies. We contend that statistical approaches to correct for imbalances and noise, while likely valid for homogeneous conditions, appear unable to accommodate disease complexity and have failed to correctly identify effective agents. While blinding and randomization are important to reduce selection bias, these methods appear insufficient to insure valid conclusions. We found potential sources of analytical errors in nearly 90% of a sample of early stroke trials. To address these issues, we recommend changes in early-phase analysis and reporting: (1) restrict use of statistical correction to studies where the underlying assumptions are validated, (2) select dichotomous over continuous outcomes for small samples, (3) consider pooled samples to model natural history to detect early therapeutic signals and increase the likelihood of replication in larger samples, (4) report subgroup baseline conditions, (5) consider post hoc methods to restrict analysis to subjects with an appropriate match, and (6) increase the strength of effect threshold given these cumulative sources of noise and potential errors. More attention to these issues should lead to better decision-making regarding selection of agents to proceed to pivotal trials.

Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm(3) treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls.Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm(3). Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest.The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm(3). After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0-4-90% versus 50% in controls p = 0.049; with a similar trend in mRS 0-3 (40 vs. 25%; p = 0.43) and trend toward lower mortality (10 vs. 35%; p = 0.21).In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.

BACKGROUND: While intravenous thrombolysis (IVT) remains the only established therapy for ischemic stroke including beyond 3 hours, there is considerable room for improvement in IVT outcomes. Non-randomized series suggested better outcomes for add-on therapies; however randomized clinical trials (RCTs) were often equivocal. One reason for these discrepancies is that imbalances in important baseline factors between treatment and control arms affect all but the largest trials and can produce misleading results. We developed techniques to identify potentially efficacious therapies by generating a pooled outcome model. Here we tested RCTs attempting to improve upon IVT against this model at each treatment arm’s baseline NIHSS and age. METHODS: We generated outcome models (mortality, mRS 0-1, mRS 0-2) pooled from the thrombolytic arms of all IV tPA RCTs with the novel feature of multi-dimensional statistical intervals. A function was iteratively fitted and individual results of IV, add-on and endovascular arms tested against this model to determine whether outcomes surpassed the + p< .05 surface (see mRS0-2 Fig.). RESULTS: Functions derived from 19 IVT RCT thrombolytic arms representing 2748 subjects were generated (Mortality: r 2 =0.51; mRS0-1: r 2 =0.79; 0-2: r 2 =0.85). No treatment increased mortality. Three hour IVT/ultrasound with (TUCSON) or without (CLOTBUST) microspheres, the neuroprotectant Cerebrolysin and IA tPA alone (SYNTHESIS) had better functional outcomes, as did CTP-guided 6 hr. IV tenecteplase. Notably, 4.5 hour SYNTHESIS-EXPANSION (IA tPA) and IMS III (IV tPA + endovascular) did not. No extended window device showed benefit. CONCLUSION: We found that several treatments show the potential to improve outcome compared to our pooled IVT model, including 3 hour ultrasound, IA tPA and 6 hr. tenecteplase. Consistent with the cardiac experience, there remains little evidence that the 3 hour window can be extended other than by an IV thrombolytic.

Background and Objective: Thrombin inhibitors such as Argatroban in combination with full-dose IV-tPA are currently being tested in a series of clinical trials for acute ischemic stroke. A single-arm, phase IIa study (ARTSS-1) of 65 patients treated with low-dose Argatroban + IV-tPA in either the 3 or 4.5 hour treatment window demonstrated an overall sICH rate of 4.6% and 40% complete recanalization within 2-hours. The objective of the study was to assess safety in a matched group of IV-tPA alone patients. Methods: pPAIRS © performs a post-hoc Euclidean matching of subjects on factors of choice and excludes outliers when no close match is found. We applied these techniques to compare outcomes of Argatroban+tPA treated subjects from ARTSS-1 with tPA treated subjects from NINDS. Matching factors were NIHSS, age, glucose, race, gender, hemisphere, and subtype. Outcomes were sICH, death and mRS 0-1, 0-2 at day 7 and 90. Results: Of the 65 Argatroban+TPA patients, 55 and 44 had good NINDS matches at day 7 and 90, respectively. Rates of sICH were identical at both day 7 and 90 between ARTSS-1 and NINDS (3.6% and 2.3%). Mortality was not significantly different (5.5% vs. 3.6% at day 7; p=1.00; and 11.4% in each group at day 90). There was a non-significant trend for higher percent of mRS 0-1 (36.4% vs. 32.0%, p=0.814) and 0-2 (47.7% vs. 43.2%, p=0.823) at day 90 in the ARTSS-1 patients that was not present at day 7. The mRS 0-2 trend remained after excluding ARTSS-1 patients treated with tPA between 3-4.5 hours (see table). Conclusion: There is no evidence for significantly increased mortality or symptomatic hemorrhage after addition of low dose Argatroban compared to a NINDS population with similar baseline characteristics particularly in those tPA-treated within 3 hours. A non-significant trend emerged at 90 days for 14% relative improvement in functional outcomes. A larger, Phase IIb, randomized trial (ARTSS-2) is ongoing to determine whether these trends reflect a true treatment effect.

Thrombolysis remains a mainstay in the treatment of ischemic stroke. While not usually considered in the spectrum of clot lysis, experimental data show that inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor can reduce as well as reverse thrombus formation and improve microvascular flow in stroke models. However, a recent clinical trial of GP IIb/IIIa inhibition in stroke did not demonstrate clinical benefit and was associated with increased hemorrhage. Based on an understanding of the relationship between GP IIb/IIIa receptor inhibition, efficacy and hemorrhage, we hypothesized that a lower dose of abciximab would achieve a favorable range of platelet inhibition and potentially good clinical outcomes. Forty-four patients with suspected large vessel occlusion, who were not eligible for rt-PA were offered treatment with approximately 30% lower total dose of intravenous abciximab if within 6 h for anterior circulation or 24 h for posterior circulation stroke (later modified to 12 h). Concomitant anticoagulation, usually with unfractionated heparin was employed. The extent of platelet inhibition was measured in 21 patients. Hemorrhage rate and 90-day functional outcomes and mortality were obtained. A matching algorithm involving finding the nearest neighbor from individual subjects in the control arm of the NINDS rt-PA database was used to compare outcomes at similar baseline characteristics and gender. Mean platelet inhibition was 92.1 ± 6.7% vs inhibition reported with percutaneous coronary intervention (PCI) of 96 ± 10; p = 0.08. Successful matching to NINDS controls was accomplished: after outlier elimination, median and mean NIHSS of the abciximab subjects compared to NINDS controls was 16.5 vs 15.5 (p = 0.92) and 16.3 vs 16.0 (p = 0.86). Mean age was 67.2 vs 67.1 (p = 0.97). Mean glucose was 141 vs 142 (p = 0.92). There was one symptomatic hemorrhage; minor hemorrhages occurred in 9%. The percent of patients who achieved an mRS 0–2 or died in the treated vs matched NINDS control patients was 63 vs 38 (p = .02) and 23 vs 23 (p = 1.0). Our pilot results indicated that a lower dose of abciximab results in platelet inhibition similar to that achieved in the coronary vascular bed during PCI. Comparison to matched historical controls suggests that this lower dose in combination therapy may be safe and effective therapy for thrombotic stroke and a randomized trial is warranted.