Thrombolysis Experience in Costa Rica Compared Against Individual Patient Data from two Randomized Controlled Trials.

OBJECTIVES: 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). MATERIALS AND METHODS: 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). RESULTS: 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 (R2=0.39) showed CRSRP and NINDS within expected mortality, while CLOTBUST-ER showed lower than expected mortality. CRSRP SICH rate equaled IAC (5.7% vs 5.7%; p=0.9). CONCLUSIONS: Functional outcomes and SICH of thrombolysed Costa Rican patients compared favorably with published datasets, with a potential increase in early mortality.

Treatment Patterns in Essential Tremor: A Retrospective Analysis.

Background: 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. Methods: The Movement Disorders Clinical Case Registry within a US Veterans Health Administration medical center was used to identify 1468 patients with ET. Results: 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. Discussion: 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.

Implementation of systematic safety checklists in a neurocritical care unit: a quality improvement study.

BACKGROUND AND OBJECTIVES: Structured 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/METHODS: This 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. RESULTS: After 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. DISCUSSION: The 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.

Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

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.

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

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.

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage.

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.

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

BACKGROUND: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. METHODS: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. RESULTS: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04). CONCLUSION: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

Ayurvedic Treatment of Acute Ischemic Stroke: A Prospective Observational Study.

BACKGROUND: The western medical arsenal for treating stroke is rather limited, and the only treatments shown to improve outcomes are not accessible to most in the third world. Even in the developed world, many patients present too late to receive thrombolysis or thrombectomy. Stroke patients in India commonly use Ayurvedic therapies, but there are no published data regarding the efficacy or safety of these therapies, the latter being of particular concern in acute ischemic stroke (AIS). OBJECTIVE: To obtain preliminary data on the safety and efficacy of stand-alone whole-system Ayurvedic treatment in AIS. METHODS: We present here an observational study prospectively comparing outcomes in 2 cohorts of AIS patients treated with whole-system classical Ayurveda (n = 13) or conservative (nonthrombolytic, noninterventional) western biomedicine (n = 20). RESULTS: Pooled analysis of outcomes did not show statistically significant differences in mortality (15.38% vs 15%, P = 1.00), nonfatal adverse event rates (15.38% vs 30%, P = .4), or functional disability measures. A paired analysis performed using a matching algorithm to reduce baseline disparities between the cohorts also showed no statistically significant differences in outcomes. CONCLUSIONS: The safety profiles of classical Ayurveda and conservative western biomedicine in AIS are similar. This is the first ever report of stand-alone Ayurvedic therapy in AIS. Our results support the conduct of a randomized controlled trial to study the efficacy of Ayurvedic treatment of AIS.

Pooled analysis suggests benefit of catheter-based hematoma removal for intracerebral hemorrhage.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: Fourteen 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 R 2 = 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. CONCLUSIONS: We 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.

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.

Telemedicine in Prehospital Acute Stroke Care: An Expanding Infrastructure for Treatment and Research.

See Article by Geisler et al.

Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage and Functional Outcomes.

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.

Efficacy of Novel Carbon Nanoparticle Antioxidant Therapy in a Severe Model of Reversible Middle Cerebral Artery Stroke in Acutely Hyperglycemic Rats.

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.

Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis.

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 <0.001). No significant publication bias was detected in our analyses. 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.

Embracing Biological and Methodological Variance in a New Approach to Pre-Clinical Stroke Testing.

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.

High Prevalence of Stroke in Rural Gadchiroli, India: A Community-Based Study.

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.

An Outcome Model for Intravenous rt-PA in Acute Ischemic Stroke.

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 < 0.001), and mortality (r(2) = 0.54; p = 0.001). We confirmed better outcomes compared to no IVT and mixed use IVT models across the range of baseline factors. It was possible to generate an expected outcome model for IVT from existing literature. We confirmed benefit compared to placebo. This model should be useful to compare to new agents without the need for statistical manipulation.

Improving early clinical trial phase identification of promising therapeutics.

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.

Hyperglycemia worsens outcome after rt-PA primarily in the large-vessel occlusive stroke subtype.

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.

Exploratory analysis of glyburide as a novel therapy for preventing brain swelling.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.