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The need for advances in the management/treatment options for ischemic stroke patients requires that upcoming preclinical research uses animals with more human-like brain characteristics. The porcine brain is considered appropriate, although the presence of the rete mirabile (RM) prevents direct catheterization of the intracranial arteries to produce focal cerebral ischemia. To develop a reproducible minimally invasive porcine stroke model, a guide catheter and guide wire were introduced through the femoral artery until reaching the left RM. Using the pressure cooker technique, Squid-12 embolization material was deposited to fill, overflow, and occlude the left RM, the left internal carotid artery, and left circle of Willis wing up to the origins of the middle cerebral arteries (MCAs), mimicking the occlusion produced in the filament model in rodents. Longitudinal multimodal cerebral MRI was conducted to assess the brain damage and cerebral blood supply. The technique we describe here occluded up to the origins of the MCAs in 7 of 8 swine, inducing early damage 90 minutes after occlusion that later evolved to a large cerebral infarction and producing no mortality during the intervention. This minimally invasive ischemic stroke model in swine produced reproducible infarcts and shows translational features common to human stroke.

Background: We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020., Methods: We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time: daytime (8:00 am-8:59 pm) and nighttime (9:00 pm-7:59 am). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated., Results: We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio [acOR], 1.620 [95% CI, 1.020-2.551]); no significant difference between trial groups was present during daytime (acOR, 0.890 [95% CI, 0.680-1.163]; P interaction <0.01); no heterogeneity was observed for other stroke subtypes ( P >0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers.interaction <0.01); no heterogeneity was observed for other stroke subtypes ( P interaction >0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers., Conclusions: Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02795962.

Background: Age and infarct volume are strong predictors of outcome in patients with ischemic stroke who underwent endovascular therapy (EVT). We aimed to investigate the impact of ischemic core volume (ICV) on stroke outcome after EVT in elderly., Methods: Using the HERMES (Highly Effective Reperfusion Using Multiple Endovascular Devices) collaboration, a patient-level meta-analysis of 7 randomized trials in which patients were enrolled from December 2010 to April 2015) dataset, we categorized patients into those aged <75 and ≥75 years. ICV was calculated on computed tomography perfusion or magnetic resonance diffusion-weighted imaging. The association between ICV and the benefit of EVT over best medical treatment on outcome (modified Rankin Scale [mRS] at 90 days) and an ICV threshold for high likelihood (≥90%) of very poor outcome (mRS score ≥5) after EVT were investigated., Results: A total of 899 patients who had baseline ICV data, 247 patients aged ≥75 years, of which 118 were randomized in the EVT arm. Patients aged ≥75 years required smaller ICV to achieve mRS score ≤3 than those aged <75 years in the EVT arm (median 10.7 mL versus 23.9 mL, P <0.001). In patients aged ≥75 years, modeling of outcome in both treatment arms revealed potential loss of effect for EVT at ICV of ≥50 mL or ≥85 mL for achieving mRS score ≤3 or ≤4, respectively. Treatment effect of EVT was significant in ICV <50 mL for mRS ≤3 (odds ratio 2.38, 95% confidence interval 1.35-4.22). ICV ≥132 mL was a threshold for high likelihood of very poor outcome after EVT. However, EVT still predicted at least 30% rate of mRS ≤3 at 150 mL ICV if near-complete or complete reperfusion was achieved., Conclusions: Baseline ICV has an impact on stroke outcome after EVT in the elderly, but elderly patients with large ICV may still benefit from EVT if near-complete or complete reperfusion is achieved. Young patients seem to benefit from EVT regardless of ICV status.

Background: We aim to compare the outcome of patients from urban areas, where the referral center is able to perform thrombectomy, with patients from nonurban areas enrolled in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion)., Methods: Patients with suspected large vessel occlusion stroke, as evaluated by a Rapid Arterial Occlusion Evaluation score of ≥5, from urban catchment areas of thrombectomy-capable centers during RACECAT trial enrollment period were included in the Stroke Code Registry of Catalonia. Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with an ischemic stroke. Secondary outcomes included mortality at 90 days, rate of thrombolysis and thrombectomy, time from onset to thrombolysis, and thrombectomy initiation. Propensity score matching was used to assemble a cohort of patients with similar characteristics., Results: The analysis included 1369 patients from nonurban areas and 2502 patients from urban areas. We matched 920 patients with an ischemic stroke from urban areas and nonurban areas based on their propensity scores. Patients with ischemic stroke from nonurban areas had higher degrees of disability at 90 days (median [interquartle range] modified Rankin Scale score, 3 [2-5] versus 3 [1-5], common odds ratio, 1.25 [95% CI, 1.06-1.48]); the observed average effect was only significant in patients with large vessel stroke (common odds ratio, 1.36 [95% CI, 1.08-1.65]). Mortality rate was similar between groups(odds ratio, 1.02 [95% CI, 0.81-1.28]). Patients from nonurban areas had higher odds of receiving thrombolysis (odds ratio, 1.36 [95% CI, 1.16-1.67]), lower odds of receiving thrombectomy(odds ratio, 0.61 [95% CI, 0.51-0.75]), and longer time from stroke onset to thrombolysis (mean difference 38 minutes [95% CI, 25-52]) and thrombectomy(mean difference 66 minutes [95% CI, 37-95])., Conclusions: In Catalonia, Spain, patients with large vessel occlusion stroke triaged in nonurban areas had worse neurological outcomes than patients from urban areas, where the referral center was able to perform thrombectomy. Interventions aimed at improving organizational practices and the development of thrombectomy capabilities in centers located in remote areas should be pursued., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02795962.

Introduction: Ischaemic stroke is the most common neurological complication of cardiac catheterisation. This study aims to analyse the clinical and prognostic differences between post-catheterisation stroke code (SC) and all other in-hospital and prehospital SC., Methods: We prospectively recorded SC activation at our centre between March 2011 and April 2016. Patients were grouped according to whether SC was activated post-catheterisation, in-hospital but not post-catheterisation, or before arrival at hospital; groups were compared in terms of clinical and radiological characteristics, therapeutic approach, functional status, and three-month mortality., Results: The sample included 2224 patients, of whom 31 presented stroke post-catheterisation. Baseline National Institutes of Health Stroke Scale score was lower for post-catheterisation SC than for other in-hospital SC and pre-hospital SC (5, 10, and 7, respectively; P=.02), and SC was activated sooner (50, 100, and 125minutes, respectively; P<.001). Furthermore, post-catheterisation SC were more frequently due to transient ischaemic attack (38%, 8%, and 9%, respectively; P<.001) and less frequently to proximal artery occlusion (17.9%, 31.4%, and 39.2%, respectively; P=.023). The majority of patients with post-catheterisation strokes (89.7%) did not receive reperfusion therapy; 60% of the patients with proximal artery occlusion received endovascular treatment. The mortality rate was 12.95% for post-catheterisation strokes and 25% for all other in-hospital strokes. Although patients with post-catheterisation stroke had a better functional prognosis, the adjusted analysis showed that this effect was determined by their lower initial severity., Conclusions: Post-catheterisation stroke is initially less severe, and presents more often as transient ischaemic attack and less frequently as proximal artery occlusion. Most post-catheterisation strokes are not treated with reperfusion; in case of artery occlusion, mechanical thrombectomy is the preferred treatment., (Copyright © 2019 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objective: We aimed to evaluate the safety and outcomes of thrombectomy in anterior circulation acute ischaemic stroke recorded in the SITS-International Stroke Thrombectomy Register (SITS-ISTR) and compare them with pooled randomized controlled trials (RCTs) and two national registry studies., Methods: We identified centres recording ≥10 consecutive patients in the SITS-ISTR with at least 70% of available modified Rankin Scale (mRS) at 3 months during 2014-2019. We defined large artery occlusion as intracranial internal carotid artery, first and second segment of middle cerebral artery and first segment of anterior cerebral artery. Outcome measures were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial haemorrhage (SICH) per modified SITS-MOST., Results: Results are presented in the following order: SITS-ISTR, RCTs, MR CLEAN Registry and German Stroke Registry (GSR). Median age was 73, 68, 71 and 75 years; baseline NIHSS score was 16, 17, 16 and 15; prior intravenous thrombolysis was 62%, 83%, 78% and 56%; onset to reperfusion time was 289, 285, 267 and 249 min; successful recanalization (mTICI score 2b or 3) was 86%, 71%, 59% and 83%; functional independence at 3 months was 45.5% (95% CI: 44-47), 46.0% (42-50), 38% (35-41) and 37% (35-41), respectively; death was 19.2% (19-21), 15.3% (12.7-18.4), 29.2% (27-32) and 28.6% (27-31); and SICH was 3.6% (3-4), 4.4% (3.0-6.4), 5.8% (4.7-7.1) and not available., Conclusion: Thrombectomy in routine clinical use registered in the SITS-ISTR showed safety and outcomes comparable to RCTs, and better functional outcomes and lower mortality than previous national registry studies., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background and Purpose: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice., Methods: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0–2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic., Results: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72–0.77) in HERMES and, after model updating, 0.80 (0.78–0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%–14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at www.mrpredicts.com., Conclusions: Because of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center.

Rationale: The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials., Aim: The CHemical OptImization of Cerebral Embolectomy trial aims to establish whether rescue intraarterial thrombolysis is more effective than placebo in improving suboptimal reperfusion scores in patients with large vessel occlusion stroke treated with mechanical thrombectomy., Sample Size Estimates: A sample size of 200 patients allocated 1:1 to intraarterial thrombolysis or intraarterial placebo will have >95% statistical power for achieving the primary outcome (5% in the control versus 60% in the treatment group) for a two-sided (5% alpha, and 5% lost to follow-up)., Methods and Design: We conducted a multicenter, randomized, placebo-controlled, double blind, phase 2b trial. Eligible patients are 18 or older with symptomatic large vessel occlusion treated with mechanical thrombectomy resulting in a modified treatment in cerebral ischemia score 2b at end of the procedure. Patients will receive 20-30 min intraarterial infusion of recombinant tissue plasminogen activator or placebo (0.5 mg/ml, maximum dose limit 22.5 mg)., Study Outcome(s): The primary outcome is the proportion of patients with an improved modified treatment in cerebral ischemia score 10 min after the end of the study treatment. Secondary outcomes include the shift analysis of the modified Rankin Scale, the infarct expansion ratio, the proportion of excellent outcome (modified Rankin Scale 0-1), the proportion of infarct expansion, and the infarction volume. Mortality and symptomatic intracerebral bleeding will be assessed., Discussion: The study will provide evidence whether rescue intraarterial thrombolysis improves brain reperfusion in patients with large vessel occlusion stroke and incomplete reperfusion (modified treatment in cerebral ischemia 2b) at the end of mechanical thrombectomy.

In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed.

New reperfusion therapies have improved the clinical recovery rates of acute ischemic stroke patients (AISP), but it is not known whether other factors, such as the ability to cope, might also have an effect. The aim of this study was to evaluate the effect of endovascular treatment (EVT) on coping strategies, quality of life, and neurological and functional outcomes in AISP at 3 months and 1 year post-stroke. A multicenter, prospective, longitudinal, and comparative study of a sub-study of the participants in the Endovascular Revascularization with Solitaire Device versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours (REVASCAT) clinical trial was conducted after recruiting from two stroke centers in Catalonia, Spain. The cohort consisted of 82 ischemic stroke patients ( n = 42 undergoing EVT and n = 40 undergoing standard best medical treatment (BMT) as a control group), enrolled between 2013-2015. We assessed the coping strategies using the Brief Coping Questionnaire (Brief-COPE-28), the health-related quality of life (HRQoL) with the EQ-5D questionnaire, and the neurological and functional status using the National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), modified Rankin Scale (mRS), and Stroke Impact Scale-16 (SIS-16). Bivariate analyses and multivariate linear regression models were used. EVT patients were the ones that showed better neurological and functional outcomes, and more patients presented reporting no pain/discomfort at 3 months; paradoxically, problem-focused coping strategies were found to be significantly higher in patients treated with BMT at 1 year.

Aims: To determine the sensitivity of stroke detection by emergency medical services (EMS) and to analyse the clinical characteristics of unidentified patients with suspected stroke., Patients and Methods: Prospective register of patients with suspected stroke in our area (850,000 inhabitants) from 2011 to 2017. The population that notified the EMS was selected. Of this population, patients with and without stroke code activation by the EMS were compared (EMS+ versus EMS-). Demographics, time to progression, clinical characteristics of the episode and reperfusion therapy administered were recorded., Results: Of a total of 5,497 patients with suspected stroke, 2,087 alerted the EMS: 1,611 (77%) EMS+ and 476 (33%) EMS-. The EMS- patients presented lower scores on the National Institute of Health Stroke Scale (8 vs. 11) and a greater frequency of clinical features of the vertebrobasilar territory (14.1% vs. 8.7%) and partial hemispheric clinical features (23.5% vs. 18.4%), especially in the left hemisphere (78.1% vs. 48.4%). Reperfusion treatment was administered in 29% of EMS+ and 23% of EMS-. The time from symptom onset to treatment was 42 minutes longer in the EMS group (175 versus 133 minutes)., Conclusions: The sensitivity of EMS to detect stroke patients in our series is 77%. We have identified clinical features associated with lack of sensitivity, such as vertebrobasilar territory symptoms or isolated language disorder.

Introduction: Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures., Methods: We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures., Results: Mean ± standard deviation (SD) age was 72.3 ± 13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%)., Conclusion: Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. This article is part of the Special Issue "Seizures & Stroke"., Competing Interests: Declaration of competing interest L. Abraira has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve laboratorios. E. Fonseca has received travel support from UCB Pharma. M. Toledo has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve laboratorios. E. Santamarina has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve Laboratorios. The other authors declare no conflicts of interest. The following are the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.yebeh.2019.106549., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- Stroke Risk Analysis (SRA) comprises an algorithm for automated analysis of ECG monitoring, enabling the detection of paroxysmal atrial fibrillation (pxAF) and identifying patterns indicating a high risk of atrial fibrillation (R&#95;AF). We compared Holter-enabled continuous ECG monitoring in combination with SRA (hSRA) with standard continuous ECG monitoring for pxAF detection in patients with acute ischemic stroke. Also, we sought to identify whether the detection of R&#95;AF patterns during the first cycle (first 2 hours) of hSRA recording was associated with the detection of pxAF during the Stroke Unit stay. Methods- We enrolled 524 consecutive patients admitted in the Stroke Unit with acute ischemic stroke or transient ischemic attack with neither history of AF nor AF at admission into a prospective multicentric observational analytic clinical study with intrapatient comparison, who received both continuous ECG monitoring as well as hSRA up to 7 days. Investigators were blinded to hSRA results unless pxAF was detected on SRA. Results- Of the 524 consecutive acute stroke patients (median age, 70.0 years; 60% male; acute ischemic stroke 93%, transient ischemic attack 7%), 462 were eligible and included in the study. Among 462 patients with hSRA available for 66 hours, AF was documented by hSRA in 79 patients (17.1%). From this group, 45 AF cases (9.7%) were confirmed after review by an independent and blinded cardiologist. continuous ECG monitoring detected 21 AF cases (4.3%; P <0.0001). hSRA detected R&#95;AF patterns in 92 patients. 35 out of the 92 R&#95;AF patients showed an episode of AF during the Stroke Unit stay. Predictive values of R&#95;AF patterns within the first cycle of hSRA were: sensitivity 71%, specificity 86%, positive predictive value 38%, and negative predictive value 96%. Conclusions- Automated analysis using SRA technology strongly improves pxAF detection in acute ischemic stroke patients compared with continuous ECG monitoring. The predictive value of a R&#95;AF pattern, as detected by hSRA during the first few hours after admission, deserves further investigation.

Background and Purpose- Computed tomographic perfusion (CTP) thresholds associated with follow-up brain infarction may differ by time from symptom onset to imaging and reperfusion. We confirm CTP thresholds over time to imaging and reperfusion in patients with acute ischemic stroke from the HERMES collaboration (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) data. Methods- Patients with occlusion on CT angiography were acutely imaged with CTP. Noncontrast CT and magnetic resonance-diffusion weighted imaging at 24 to 48 hours defined follow-up infarction. Reperfusion was assessed on conventional angiogram. Tmax, cerebral blood flow (CBF), and cerebral blood volume maps were derived from delay-insensitive CTP postprocessing. These parameters were analyzed using receiver operator characteristics to derive optimal thresholds based on time from stroke onset-to-CTP or to reperfusion. ANOVA and linear regression were used to test whether the derived CTP thresholds were different by time. Results- One hundred thirty-seven patients were included. Tmax thresholds of >15.7 s and >15.8 s and absolute CBF thresholds of <8.9 and <7.5 mL·min -1 ·100 g -1 for gray matter and white matter respectively were associated with infarct if reperfusion was achieved <90 minutes from CTP with stroke onset-to-CTP <180 minutes. The discriminative ability of cerebral blood volume was modest. There were no statistically significant relationships between stroke onset-to-CTP time and Tmax, CBF, and cerebral blood volume thresholds (all P >0.05). A statistically significant relationship was observed between CTP-to-reperfusion time and the optimal thresholds for Tmax ( P <0.001) and CBF ( P <0.001). Similar but more modest relationship was noted for onset-to-reperfusion time and optimal thresholds for CBF ( P ≤0.01). Conclusions- CTP thresholds based on stroke onset and imaging time and taking into account time needed for reperfusion may improve infarct prediction in patients with acute ischemic stroke.

Rationale: Optimal pre-hospital delivery pathways for acute stroke patients suspected to harbor a large vessel occlusion have not been assessed in randomized trials., Aim: To establish whether stroke subjects with rapid arterial occlusion evaluation scale based suspicion of large vessel occlusion evaluated by emergency medical services in the field have higher rates of favorable outcome when transferred directly to an endovascular center (endovascular treatment stroke center), as compared to the standard transfer to the closest local stroke center (local-SC)., Design: Multicenter, superiority, cluster randomized within a cohort trial with blinded endpoint assessment., Procedure: Eligible patients must be 18 or older, have acute stroke symptoms and not have an immediate life threatening condition requiring emergent medical intervention. They must be suspected to have intracranial large vessel occlusion based on a pre-hospital rapid arterial occlusion evaluation scale of ≥5, be located in geographical areas where the default health authority assigned referral stroke center is a non-thrombectomy capable hospital, and estimated arrival at a thrombectomy capable stroke hospital in less than 7 h from time last seen well. Cluster randomization is performed according to a pre-established temporal sequence (temporal cluster design) with three strata: day/night, distance to the endovascular treatment stroke center, and week/week-end day., Study Outcome: The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is mortality at 90 days., Analysis: The primary endpoint based on the modified intention-to-treat population is the distribution of modified Rankin Scale scores at 90 days analyzed under a sequential triangular design. The maximum sample size is 1754 patients, with two planned interim analyses when 701 (40%) and 1227 patients have completed follow-up. Hypothesized common odds ratio is 1.35.

Background and Purpose- Previous studies have reported less favorable outcome and less effect of endovascular treatment (EVT) after ischemic stroke in women than in men. Our aim was to study the influence of sex on outcome and on the effect of EVT for ischemic stroke in recent randomized trials on EVT. Methods- We used data from 7 randomized controlled trials on EVT within the HERMES collaboration. The primary outcome was 90-day functional outcome (modified Rankin Scale). We compared baseline characteristics and outcomes between men and women. With ordinal logistic regression, we evaluated the association between EVT and 90-day functional outcome for men and women separately, adjusted for potential confounders. We tested for interaction between sex and EVT. Results- We included 1762 patients in the analyses, of whom 833 (47%) were women. Women were older (median, 70 versus 66 years; P<0.001), were smoking less often (30% versus 44%; P<0.001), and had higher collateral grades (grade 3: 46% versus 35%; P<0.001) than men. Functional independence (modified Rankin Scale score, 0-2) at 90 days was reached by 318 women (39%) and 364 men (39%). The effect of EVT on the ordinal modified Rankin Scale was similar in women (adjusted common odds ratio [acOR], 2.13; 95% CI, 1.47-3.07) and men (acOR, 2.16; 95% CI, 1.59-2.96), with a P for interaction of 0.926. Conclusions- Sex does not influence clinical outcome after EVT and does not modify treatment effect of EVT. Therefore, sex should not be a consideration in the selection of patients for EVT.

Background: Revascularization after endovascular therapy for acute ischemic stroke is measured by the Thrombolysis In Cerebral Infarction (TICI) scale, yet variability exists in scale definitions. We examined the degree of reperfusion with the expanded TICI (eTICI) scale and association with outcomes in the HERMES collaboration of recent endovascular trials., Methods: The HERMES Imaging Core, blind to all other data, evaluated angiography after endovascular therapy in HERMES. A battery of TICI scores (mTICI, TICI, TICI2C) was used to define reperfusion of the initial target occlusion defined by non-invasive imaging and conventional angiography., Results: Angiography of 801 subjects was available, including 797 defined by non-invasive imaging (154 internal carotid artery (ICA), 583 M1, 60 M2) and 748 by conventional angiography (195 ICA, 459 M1, 94 M2). Among 729 subjects in whom the reperfusion grade could be established, using eTICI (3=100%, 2C=90-99%, 2b67=67-89%, 2b50=50-66%) of the conventional angiography target occlusion, there were 63 eTICI 3 (9%), 166 eTICI 2c (23%), 218 eTICI 2b67 (30%), 103 eTICI 2b50 (14%), 100 eTICI 2a (14%), 19 eTICI 1 (3%), and 60 eTICI 0 (8%). Modified Rankin Scale shift analyses from baseline to 90 days showed that increasing TICI grades were linked with better outcomes, with significant distinctions between TICI 0/1 versus 2a (p=0.028), 2a versus 2b50 (p=0.017), and 2b50 versus 2b67 (p=0.014)., Conclusions: The benefit of endovascular therapy in HERMES was strongly associated with increasing degrees of reperfusion defined by eTICI. The eTICI metric identified meaningful distinctions in clinical outcomes and may be used in future studies and routine practice., Competing Interests: Competing interests: DSL reports having received grant funding from NINDS and consulting fees as an imaging core laboratory from Stryker and Medtronic. RJ reports consulting with Medtronic. CBLMM reports having received grant funding from the Dutch Heart Foundation and European Commission and an unrestricted grant from Stryker. AvdL reports consulting fees from Stryker and grant funding from the Dutch Heart Foundation, AngioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO, Penumbra, Top Medical/Concentric, and Stryker, received by the Erasmus University Medical Center. LSR proctors for Stryker and Medtronic. PW discloses institutional research grant support within the last 2 years from Microvention Terumo. He declares the following relevant professional relationships: Chair of the European Society of Minimally Invasive Neurotherapeutics Guidelines Committee, sits on the Policy Working Group for Thrombectomy of NHS England and represents the Royal College of Radiologists on the UK Intercollegiate Stroke Working party (none of these are associated with financial reimbursement). He reports the following modest consultancy work: member of Stryker’s Global Hemorrhagic Stroke Advisory Board and educational consultancy work for Microvention Terumo. He has no other interests to declare. MG reports being the principal investigator of an unrestricted research grant to the University of Calgary for the HERMES collaboration by Medtronic. He also reports consulting services with Medtronic, Stryker, Microvention, Cerenovus and a licensing agreement with GE Healthcare re systems of acute stroke diagnosis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Objectives: Recent real-world data studies on the use of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation, provide data on the use of different DOAC according to patient characteristics. The objective of this work was to elaborate on the suggestions on the use of DOAC based on evidence and clinical experience., Materials and Methods: A multidisciplinary panel of 8 experts developed the agreed content. The document was completed in 10 regional meetings with experts from different specialties. According to these contributions, the panel prepared the final suggestions., Results: The final document includes the contributions generated throughout the entire process in 3 sections. The general conclusions / suggestions on the use of DOAC are detailed. Specific tips on the use of each DOAC are proposed, based on the specific clinical profiles of the patients. Finally, the limitations on the use of DOAC are defined, and a group of actions are proposed to improve the management of anticoagulation., Conclusions: It is necessary to overcome the clinical and administrative barriers that hinder the optimal use of DOAC, in order to improve the treatment of patients with non-valvular atrial fibrillation who require anticoagulation., (Copyright © 2018 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

Importance: The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke., Objective: To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke., Design, Setting, and Participants: Patient data from 7 randomized multicenter trials were pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography or magnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017., Main Outcome and Measure: The 90-day functional outcome via the modified Rankin Scale (mRS)., Results: Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P = .007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; P < .001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95% CI, 1.52-3.21; P < .001). Treatment-reduced FIV explained 12% (95% CI, 1-19) of the relationship between EVT and functional outcome., Conclusions and Relevance: In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome., Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date., Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10 -9 )., Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Background: In-hospital stroke death rate is an important sanitary issue. Despite advances in the acute phase management of stroke patients, mortality and disability rates remain high. In aging populations and with different mortality between the sexes in general, the study of sex- and age-related differences becomes increasingly relevant for optimization of post-acute clinical care of stroke patients., Methods: We designed a cohort follow-up study with 13,932 consecutive ischemic stroke (IS) patients from 19 Spanish hospitals. Data was obtained from the Spanish Stroke Registry; transient ischemic attacks and ages <18 years were excluded. Patients were organised by age group and sex. We compared female and male patient cohorts within and across age groups univariately and used multivariable logistic regression to adjust for confounders in differential in-hospital mortality., Results: The median (percentiles 2.5 and 97.5%) age was 78 (41-92) years old for women and 71 (41-92) for men. IS women were more likely to be older, to exhibit cardio-embolic aetiology, and less likely to have been admitted to a stroke unit or to have had a stroke code activated. Both pre-stroke modified Rankin Scale and National Institute of Health Stroke Scale (NIHSS) scores at admission increased significantly with age and were higher in women than those in men. Differences in distributions of common risk factors for IS and of in-hospital outcomes between women and men actually changed with patient's age. It is to be noted here that although there were no statistically significant differences (p > 0.05) between the sexes within any age group, in-hospital mortality appeared significantly higher in women than that in men when analysed overall, due to confounding. Death was more closely related to stroke in women than in men and occurred earlier. Although there were some age-specific sex differences between the predictors for in-hospital mortality, stroke severity measured by NIHSS was the main predictor of in-hospital mortality for both sexes. Topographic classifications - partial anterior circulatory infarct and total anterior circulatory infarct - were significant prognostic factors for men aged <60 years and for those in the 60-69 years range respectively., Conclusion: Although most of our findings were consistent with previous studies, it is important to take into account and highlight differences in in-hospital mortality between the sex and age group. Not to account for age-related differences between the sexes can give false results that may mislead management decisions. As most deaths in women were related to stroke, it is important to improve their early management, stroke code activation, access to stroke units and/or revascularisation therapies, especially in the older age groups., (© 2019 S. Karger AG, Basel.)

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome., Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm 2 /s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered., Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, p interaction =0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, p interaction =0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low., Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions., Funding: Medtronic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Evidence regarding whether imaging can be used effectively to select patients for endovascular thrombectomy (EVT) is scarce. We aimed to investigate the association between baseline imaging features and safety and efficacy of EVT in acute ischaemic stroke caused by anterior large-vessel occlusion., Methods: In this meta-analysis of individual patient-level data, the HERMES collaboration identified in PubMed seven randomised trials in endovascular stroke that compared EVT with standard medical therapy, published between Jan 1, 2010, and Oct 31, 2017. Only trials that required vessel imaging to identify patients with proximal anterior circulation ischaemic stroke and that used predominantly stent retrievers or second-generation neurothrombectomy devices in the EVT group were included. Risk of bias was assessed with the Cochrane handbook methodology. Central investigators, masked to clinical information other than stroke side, categorised baseline imaging features of ischaemic change with the Alberta Stroke Program Early CT Score (ASPECTS) or according to involvement of more than 33% of middle cerebral artery territory, and by thrombus volume, hyperdensity, and collateral status. The primary endpoint was neurological functional disability scored on the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included symptomatic intracranial haemorrhage, parenchymal haematoma type 2 within 5 days of randomisation, and mortality within 90 days. For the primary analysis, we used mixed-methods ordinal logistic regression adjusted for age, sex, National Institutes of Health Stroke Scale score at admission, intravenous alteplase, and time from onset to randomisation, and we used interaction terms to test whether imaging categorisation at baseline modifies the association between treatment and outcome. This meta-analysis was prospectively designed by the HERMES executive committee but has not been registered., Findings: Among 1764 pooled patients, 871 were allocated to the EVT group and 893 to the control group. Risk of bias was low except in the THRACE study, which used unblinded assessment of outcomes 90 days after randomisation and MRI predominantly as the primary baseline imaging tool. The overall treatment effect favoured EVT (adjusted common odds ratio [cOR] for a shift towards better outcome on the mRS 2·00, 95% CI 1·69-2·38; p<0·0001). EVT achieved better outcomes at 90 days than standard medical therapy alone across a broad range of baseline imaging categories. Mortality at 90 days (14·7% vs 17·3%, p=0·15), symptomatic intracranial haemorrhage (3·8% vs 3·5%, p=0·90), and parenchymal haematoma type 2 (5·6% vs 4·8%, p=0·52) did not differ between the EVT and control groups. No treatment effect modification by baseline imaging features was noted for mortality at 90 days and parenchymal haematoma type 2. Among patients with ASPECTS 0-4, symptomatic intracranial haemorrhage was seen in ten (19%) of 52 patients in the EVT group versus three (5%) of 66 patients in the control group (adjusted cOR 3·94, 95% CI 0·94-16·49; p interaction =0·025), and among patients with more than 33% involvement of middle cerebral artery territory, symptomatic intracranial haemorrhage was observed in 15 (14%) of 108 patients in the EVT group versus four (4%) of 113 patients in the control group (4·17, 1·30-13·44, p interaction =0·012)., Interpretation: EVT achieves better outcomes at 90 days than standard medical therapy across a broad range of baseline imaging categories, including infarcts affecting more than 33% of middle cerebral artery territory or ASPECTS less than 6, although in these patients the risk of symptomatic intracranial haemorrhage was higher in the EVT group than the control group. This analysis provides preliminary evidence for potential use of EVT in patients with large infarcts at baseline., Funding: Medtronic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS., Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups., Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus., Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe., Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron-loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca 2+ -calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke-induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The study aimed to evaluate the impact of a telestroke network on acute stroke care in Catalonia, by measuring thrombolysis rates, access to endovascular treatment, and clinical outcome of telestroke patients in a population-based study., Methods: Telestroke network was implemented on March 2013 and consists of 12 community hospitals and 1 expert stroke neurologist 24 h/7 day, covering a population of 1.3 million inhabitants. Rest of the population (6.2 million) of Catalonia is covered by 8 primary stroke centers (PSC) and 6 comprehensive stroke centers (CSC). After a 2-way videoconference and visualization of neuroimaging on a web platform, the stroke neurologist decides the therapeutic approach and/or to transfer the patient to another facility, entering these data in a mandatory registry. Simultaneously, all patients treated with reperfusion therapies in all centers of Catalonia are prospectively recorded in a mandatory and audited registry., Results: From March 2013 to December 2015, 1,206 patients were assessed by telestroke videoconference, of whom 322 received intravenous thrombolysis (IVT; 33.8% of ischemic strokes). Baseline and 24 h NIHSS, rate of symptomatic hemorrhage, mortality, and good outcome at 3 months were similar compared to those who received IVT in PSC or CSC (2,897 patients in the same period). The door-to-needle time was longer in patients treated through telestroke, but was progressively reduced from 2013 to 2015. Percentage of patients receiving thrombectomy after IVT was similar in patients treated through telestroke circuit, compared to those treated in PSC or CSC (conventional circuit). Population rates of IVT*100,000 inhabitants in Catalonia increased from 2011 to 2015, especially in areas affected by the implementation of telestroke network, achieving rates as high as 16 per 100,000 inhabitants. Transfers to another facility were avoided after telestroke consultation in 46.8% of ischemic, 76.5% of transient ischemic attacks, and 23.5% of hemorrhages., Conclusions: Telestroke favors safe and effective thrombolysis, helps to increase the population rate of IVT, and avoids a large number of interhospital transfers., (© 2018 S. Karger AG, Basel.)

Background and Purpose: Endovascular therapy has become the standard of care for patients with disabling anterior circulation ischemic stroke due to proximal intracranial thrombi. Our aim was to determine whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in posttreatment infarct volume in the Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT) trial., Materials and Methods: The REVASCAT trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 206 enrolled subjects (endovascular treatment, n = 103; control, n = 103), posttreatment infarct volume was measured in 204 subjects. Posttreatment infarct volumes were compared with treatment assignment and recanalization status. Appropriate statistical models were used to assess the relationship among baseline clinical and imaging variables, posttreatment infarct volume, the 24-hour NIHSS score, and functional status with the 90-day modified Rankin Scale score., Results: The median posttreatment infarct volume in all subjects was 23.7 mL (interquartile range = 68.9 mL) and 16.3 mL (interquartile range = 50.2 mL) in the endovascular treatment arm and 38.6 mL (interquartile range = 74.9 mL) in the control arm ( P = .02 for endovascular treatment versus control subjects). Baseline NIHSS ( P < .01), site of occlusion ( P < .03), baseline NCCT ASPECTS ( P < .01), and recanalization status ( P = .02) were independently associated with posttreatment infarct volume. Baseline NIHSS ( P < .01), time from symptom onset to randomization ( P = .02), treatment type ( P = .04), and recanalization status ( P < .01) were independently associated with the 24-hour NIHSS scores. The 24-hour NIHSS score strongly mediated the relationship between treatment type and 90-day mRS ( P < .01 for indirect effect when adjusted for age), while posttreatment infarct volume did not ( P = .26)., Conclusions: Endovascular treatment saves brain and improves 90-day clinical outcomes primarily through a beneficial effect on the 24-hour stroke severity., (© 2018 by American Journal of Neuroradiology.)

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care., Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered., Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14-2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low., Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons., Funding: Medtronic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the study was to confirm the safety and effectiveness of using intravenous thrombolysis (IVT) with individuals aged 80 and older in routine practice in different hospital settings., Design: Observasional registry., Setting: Prospective multicenter population-based registry of acute stroke patients treated with reperfusion therapies in Catalonia, Spain (Sistema Online d'Informació de l'Ictus Agut)., Participants: Individuals treated only with IVT (N = 3,231; 1,189 (36.8%) aged ≥80)., Measurements: Symptomatic intracranial hemorrhage, mortality, and favorable outcome (modified Rankin Scale (mRS) score = 0-2) at 3 months were evaluated according to hospital characteristics. Treating hospitals were classified in three categories: comprehensive stroke centers (CSCs), primary stroke centers (PSCs), and community hospitals operating a telestroke system (TS). First individuals aged 80 and older were compared with those younger than 80, and then participants aged 80 and older were focused on., Results: Participants aged 80 and older had significantly higher baseline National Institute of Health Stroke Scale (NIHSS) scores, longer onset to treatment times, and worse outcomes than younger participants. For participants aged 80 and older, 90-day mortality was 23.2%, with 38.7% having favorable outcomes at 3 months. Symptomatic intracranial hemorrhage (SICH; Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition) was observed in 4.7% of subjects. None of the risk factors differed significantly between participants treated in different types of hospitals. Basal stroke severity measured according to NIHSS score was not significantly different either. The three different types of hospitals achieved similar outcomes, although the TS and PSC hospitals had significantly higher proportions of SICH (6.3% and 6.3%, respectively) than the CSC (3.2%)., Conclusion: Older adults with acute stroke treated with IVT had similar outcomes regardless of hospital characteristics., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background and Purpose: Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase., Methods: The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21-biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves., Results: From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P <0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P =0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%., Conclusions: The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke., (© 2017 American Heart Association, Inc.)

Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition, etiology, physical properties and neurovascular interactions may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Advances in imaging techniques may enhance clot characterization and inform therapeutic decision-making prior to treatment and reveal stroke etiology to guide secondary prevention. Current imaging techniques can provide some information about thrombi, but there remains much to evaluate about relationships that may exist among thrombus composition, occlusion characteristics and treatment outcomes. Improved pathophysiological characterization of clot types, their properties and how these properties change over time, together with clinical correlates from ongoing studies, may facilitate revascularization with thrombolysis and thrombectomy. Interdisciplinary approaches covering clinical, engineering and scientific aspects of thrombus research will be key to advancing the understanding of thrombi and improving acute ischemic stroke therapy. This consensus statement integrates recent research on clots and thrombi retrieved from cerebral arteries and provides a rationale for further analyses, including current opportunities and limitations.

Background: The REVASCAT trial and other studies have shown that the neurovascular thrombectomy improves outcomes at 90 days post stroke. However, whether the observed benefit is sustained in the long term remains unknown. We report the results of the prespecified 12-month analysis of the REVASCAT trial., Methods: Patients with acute ischaemic stroke who could be treated within 8 h of symptom onset were randomly assigned to medical therapy (including intravenous alteplase when eligible) and neurovascular thrombectomy with Solitaire FR or medical therapy alone. The main secondary outcome measure at 1 year follow-up was disability, measured using the modified Rankin Scale (mRS), ranging from 0 (no symptoms) to 6 (death) with categories 5 (severe disability) and 6 (death) collapsed into one category (severe disability or death), analysed as the distribution of the mRS. Additional prespecified secondary outcome measures included health-related quality of life measured with the EuroQol five dimensions questionnaire (EQ-5D) utility index (ranging from -0·3 to 1, higher values indicate better quality of life), the rate of functional independence (mRS 0-2), and cognitive function measured with the Trail Making Test (reported elsewhere). Treatment allocation was open label but endpoints at 12 months were assessed by masked investigators. The trial was registered at ClinicalTrials.gov, number NCT01692379., Findings: From Nov 24, 2012, to Dec 12, 2014, 206 patients were randomly assigned to medical therapy plus endovascular treatment (n=103) or medical treatment alone (n=103), at four centres in Catalonia, Spain. At 12 months post randomisation, based on 205 of 206 outcomes available at 12 months, thrombectomy reduced disability over the range of the mRS (common adjusted odds ratio [aOR] 1·80, 95% CI 1·09-2·99), and improved functional independence (mRS=0-2; 45 [44%] of 103 patients vs 31 [30%] of 103 patients; aOR 1·86, 95% CI 1·01-3·44). Health-related quality of life was superior in the thrombectomy group (mean EQ-5D utility index score, 0·46 [SD 0·38] in the thrombectomy group vs 0·33 [0·33] in the control group, difference 0·12 [95% CI 0·03-0·22]; p=0·01). 1-year mortality was 23% (24 of 103 patients) in the thrombectomy group versus 24% (25 of 103 patients) in the control group., Interpretation: At 12 months follow-up, neurovascular thrombectomy reduced post-stroke disability and improved health-related quality of life, indicating sustained benefit. These findings have important clinical and public health implications for evaluating the cost-effectiveness of the intervention in the long term., Funding: Fundació Ictus Malaltia Vascular through an unrestricted grant from Medtronic., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Purpose: Stroke patients with unknown onset (UKO) are excluded from thrombolytic therapy. We aim to study the safety and efficacy of intravenous alteplase in ischemic stroke patients with UKO of symptoms compared with those treated within 4.5 hours in a large cohort., Methods: Data were analyzed from 47 237 patients with acute ischemic stroke receiving intravenous tissue-type plasminogen activator in hospitals participating in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry between 2010 and 2014. Two groups were defined: (1) patients with UKO (n=502) and (2) patients treated within 4.5 hours of stroke onset (n=44 875). Outcome measures were symptomatic intracerebral hemorrhage per Safe Implementation of Treatment in Stroke on the 22 to 36 hours post-treatment neuroimaging and mortality and functional outcome assessed by the modified Rankin Scale at 3 months., Results: Patients in UKO group were significantly older, had more severe stroke at baseline, and longer door-to-needle times than patients in the ≤4.5 hours group. Logistic regression showed similar risk of symptomatic intracerebral hemorrhage (adjusted odds ratio, 1.09; 95% confidence interval, 0.44-2.67) and no significant differences in functional independency (modified Rankin Scale score of 0-2; adjusted odds ratio, 0.79; 95% confidence interval, 0.56-1.10), but higher mortality (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.41) in the UKO group compared with the ≤4.5 hours group. Patients treated within 4.5 hours showed reduced disability over the entire range of modified Rankin Scale compared with the UKO group (common adjusted odds ratio, 1.29; 95% confidence interval, 1.01-1.65)., Conclusions: Our data suggest no excess risk of symptomatic intracerebral hemorrhage but increased mortality and reduced favorable outcome in patients with UKO stroke compared with patients treated within the approved time window., (© 2017 American Heart Association, Inc.)

Importance: Mechanical thrombectomy (MT) improves clinical outcomes in patients with acute ischemic stroke (AIS) caused by a large vessel occlusion. However, it is not known whether intravenous thrombolysis (IVT) is of added benefit in patients undergoing MT., Objective: To examine whether treatment with IVT before MT with a stent retriever is beneficial in patients undergoing MT., Design, Setting, and Participants: This post hoc analysis used data from 291 patients treated with MT included in 2 large, multicenter, prospective clinical trials that evaluated MT for AIS (Solitaire With the Intention for Thrombectomy performed from January 1, 2010, through December 31, 2011, and Solitaire Flow Restoration Thrombectomy for Acute Revascularization from January 1, 2010, through December 31, 2012). An independent core laboratory scored the radiologic outcomes in each trial., Interventions: Patients were treated with IVT with tissue plasminogen activator followed by MT (IVT and MT group) with the use of a stent retriever or MT with a stent retriever alone (MT group)., Main Outcomes and Measures: Successful reperfusion, functional independence (modified Rankin Scale score of 0-2) and mortality at 90 days, symptomatic intracranial hemorrhage, emboli to new territory, and vasospasm were compared., Results: Of 291 patients included in the analysis, 160 (55.0%) underwent IVT and MT (mean [SD] age, 67 [13] years; 97 female [60.6%]), and 131 (45.0%) underwent MT alone (mean [SD] age, 69 [12] years; 71 [55.7%] female). Median Alberta Stroke Program Early CT Score at baseline was lower in the IVT and MT group (8 vs 9, P = .04). There was no statistically significant difference in the duration from symptom onset to groin puncture (254 minutes for the IVT and MT group vs 262 minutes for the MT group, P = .10). The number of passes, rate of successful reperfusion, functional independence at 90 days, mortality at 90 days, and emboli to new territory were also similar among groups. Symptomatic intracranial hemorrhage (1% vs 4%) and parenchymal hemorrhages type 1 (1% vs 3%) or type 2 (1% vs 2%) did not differ significantly (P = .25). Vasospasm occurred more often in patients who received IVT and MT vs MT alone (27% vs 14%, P = .006). In multivariate analysis, no statistically significant association was observed between IVT and MT vs MT alone for any of the outcomes., Conclusions and Relevance: The results indicate that treatment of patients experiencing AIS due to a large vessel occlusion with IVT before MT does not appear to provide a clinical benefit over MT alone. A randomized clinical trial seems warranted., Trial Registration: clinicaltrials.gov Identifiers: NCT01054560 and NCT01327989.

Introduction: Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms., Methods: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Prestroke PhA was evaluated with the International Physical Activity Questionnaire (metabolic equivalent of minutes/week). We studied several circulating angiogenic and neurogenic factors at different time points: vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and brain-derived neurotrophic factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (modified Rankin scale  ≤ 2) as primary end point, and final infarct volume as secondary outcome., Results: We studied 83 patients with at least 2 time point serum determinations (mean age 69.6 years, median National Institutes of Health Stroke Scale 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum VEGF on the seventh day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of prestroke PhA nor with stroke outcomes., Conclusions: Although there are probably more molecular mechanisms by which PhA exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial., Methods: REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded., Results: From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51-6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60-8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life., Conclusions: Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery., Clinicaltrialsgov Identifier: NCT01692379., Classification of Evidence: This study provides Class I evidence that for patients with stroke from acute anterior circulation proximal arterial occlusion, thrombectomy improves performance on the TMT at 3 months., (© 2016 American Academy of Neurology.)

Vascular neuroimaging plays a decisive role in selecting the best therapy in patients with acute ischaemic stroke. However, compared with the arterial system, the role of veins has not been thoroughly studied. In this review, we present the major venous imaging-based biomarkers in ischaemic stroke. First, the presence of hypodense veins in the monophasic CT angiography ipsilateral to the arterial occlusion. Second, the asymmetry of venous drainage in the pathological cerebral hemisphere on CT and MRI dynamic angiography. Finally, the presence of hypodense veins on T2* -based MRI. From the physiological point of view, the venous imaging-based biomarkers would detect the alteration of brain perfusion (flow), as well as the optimisation of extraction oxygen mechanisms (misery perfusion). Several studies have correlated the venous imaging-based biomarkers with grade of collateral circulation, the ischaemic penumbra and clinical functional outcome. Although venous imaging-based biomarkers still have to be validated, growing evidence highlights a potential complementary role in the acute stroke clinical decision-making process., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Prehospital clinical scales to identify patients with acute stroke with a large vessel occlusion (LVO) and direct them to an endovascular-capable stroke center are needed. We evaluated whether simplification of the Rapid Arterial oCclusion Evaluation (RACE) scale, a 5-item scale previously validated in the field, could maintain its high performance to identify patients with LVO., Methods: Using the original prospective validation cohort of the RACE scale, 7 simpler versions of the RACE scale were designed and retrospectively recalculated for each patient. National Institutes of Health Stroke Scale score and proximal LVO were evaluated in hospital. Receiver operating characteristic analysis was performed to test performance of the simplified versions to identify LVO. For each version, the threshold with sensitivity closest to the original scale (85%) was used, and the variation in specificity and correct classification were assessed., Results: The study included 341 patients with suspected stroke; 20% had LVO. The 7 simpler versions of the RACE scale had slightly lower area under the curve for detecting LVO because of lower specificity at the chosen sensitivity level. Correct classification rate decreased 9% if facial palsy was simplified or if eye or gaze deviation was removed, and decreased 4.5% if the aphasia or agnosia cortical sign was removed., Conclusions: We recommend the original RACE scale for prehospital assessment of patients with suspected stroke for its ease of use and its high performance to predict the presence of a LVO. The use of simplified versions would reduce its predictive value., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window., Methods: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events., Results: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms., Conclusions: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661., (© 2016 American Heart Association, Inc.)

Background Acute stroke care represents a challenge for decision makers. Recent randomized trials showed the benefits of endovascular therapy. Our goal was to provide a visual aid tool to guide clinicians in the decision process of endovascular intervention in patients with acute ischemic stroke. Methods We created visual plots (Cates' plots; www.nntonline.net ) representing benefits of standard of care vs. endovascular thrombectomy from the pooled analysis of five RCTs using stent retrievers. These plots represent the following clinically relevant outcomes (1) functionally independent state (modified Rankin scale (mRS) 0 to 2 at 90 days) (2) excellent recovery (mRS 0-1) at 90 days, (3) NIHSS 0-2 (4) early neurological recovery, and (5) revascularization at 24 h. Subgroups visually represented include time to treatment and baseline stroke severity strata. Results Overall, 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control were included to create the visual plots. Cates' visual plots revealed that for every 100 patients with acute ischemic stroke and large vessel occlusion, 27 would achieve independence at 90 days (mRS 0-2) in the control group compared to 49 (95% CI 43-56) in the intervention group. Similarly, 21 patients would achieve early neurological recovery at 24 h compared to 54 (95% CI 45-63) out of 100 for the intervention group. Conclusion Cates' plots may assist clinicians and patients to visualize and compare potential outcomes after an acute ischemic stroke. Our results suggest that for every 100 treated individuals with an acute ischemic stroke and a large vessel occlusion, endovascular thrombectomy would provide 22 additional patients reaching independency at three months and 33 more patients achieving ENR compared to controls.

Background and Purpose: Previous studies have suggested that advanced age predicts worse outcome following mechanical thrombectomy. We assessed outcomes from 2 recent large prospective studies to determine the association among TICI, age, and outcome., Materials and Methods: Data from the Solitaire FR Thrombectomy for Acute Revascularization (STAR) trial, an international multicenter prospective single-arm thrombectomy study and the Solitaire arm of the Solitaire FR With the Intention For Thrombectomy (SWIFT) trial were pooled. TICI was determined by core laboratory review. Good outcome was defined as an mRS score of 0-2 at 90 days. We analyzed the association among clinical outcome, successful-versus-unsuccessful reperfusion (TICI 2b-3 versus TICI 0-2a), and age (dichotomized across the median)., Results: Two hundred sixty-nine of 291 patients treated with Solitaire in the STAR and SWIFT data bases for whom TICI and 90-day outcome data were available were included. The median age was 70 years (interquartile range, 60-76 years) with an age range of 25-88 years. The mean age of patients 70 years of age or younger was 59 years, and it was 77 years for patients older than 70 years. There was no significant difference between baseline NIHSS scores or procedure time metrics. Hemorrhage and device-related complications were more common in the younger age group but did not reach statistical significance. In absolute terms, the rate of good outcome was higher in the younger population (64% versus 44%, P < .001). However, the magnitude of benefit from successful reperfusion was higher in the 70 years of age and older group (OR, 4.82; 95% CI, 1.32-17.63 versus OR 7.32; 95% CI, 1.73-30.99)., Conclusions: Successful reperfusion is the strongest predictor of good outcome following mechanical thrombectomy, and the magnitude of benefit is highest in the patient population older than 70 years of age., (© 2016 by American Journal of Neuroradiology.)

Background and Purpose: Since demonstration of the benefit of endovascular treatment (EVT) in acute ischemic stroke patients with proximal arterial occlusion, stroke care systems need to be reorganized to deliver EVT in a timely and equitable way. We analyzed differences in the access to EVT by geographical areas in Catalonia, a territory with a highly decentralized stroke model., Methods: We studied 965 patients treated with EVT from a prospective multicenter population-based registry of stroke patients treated with reperfusion therapies in Catalonia, Spain (SONIIA). Three different areas were defined: (A) health areas primarily covered by Comprehensive Stroke Centers, (B) areas primarily covered by local stroke centers located less than hour away from a Comprehensive Stroke Center, and (C) areas primarily covered by local stroke centers located more than hour away from a Comprehensive Stroke Center. We compared the number of EVT×100 000 inhabitants/year and time from stroke onset to groin puncture between groups., Results: Baseline characteristics were similar between groups. Throughout the study period, there were significant differences in the population rates of EVT across geographical areas. EVT rates by 100 000 in 2015 were 10.5 in A area, 3.7 in B, and 2.7 in C. Time from symptom onset to groin puncture was 82 minutes longer in group B (312 minutes [245-435]) and 120 minutes longer in group C (350 minutes [284-408]) compared with group A (230 minutes [160-407]; P<0.001)., Conclusions: Accessibility to EVT from remote areas is hampered by lower rate and longer time to treatment compared with areas covered directly by Comprehensive Stroke Centers., (© 2016 American Heart Association, Inc.)

Background: In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included., Methods: We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation., Findings: We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations., Interpretation: Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion., Funding: Medtronic., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Polycythemia vera (PV) is a blood disorder in which the first expression may be an ischemic stroke. Stroke mechanism in PV is usually attributed to a hypercoagulability state and blood stasis. We report a case of a patient with PV presenting with recurrent ischemic stroke associated with the development of large intracranial stenosis in a period of 1 month. Stenosis was associated with microembolic signals detected by transcranial Doppler. One year later and after hematocrit control, stenosis persisted but microembolic signals disappeared. We discuss similar reports in the literature and the possible pathophysiological mechanism of large-vessel damage in these patients., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: For the STroke Imaging Research (STIR) and VISTA-Imaging Investigators The purpose of this study was to collect precise information on the typical imaging decisions given specific clinical acute stroke scenarios. Stroke centers worldwide were surveyed regarding typical imaging used to work up representative acute stroke patients, make treatment decisions, and willingness to enroll in clinical trials., Methods: STroke Imaging Research and Virtual International Stroke Trials Archive-Imaging circulated an online survey of clinical case vignettes through its website, the websites of national professional societies from multiple countries as well as through email distribution lists from STroke Imaging Research and participating societies. Survey responders were asked to select the typical imaging work-up for each clinical vignette presented. Actual images were not presented to the survey responders. Instead, the survey then displayed several types of imaging findings offered by the imaging strategy, and the responders selected the appropriate therapy and whether to enroll into a clinical trial considering time from onset, clinical presentation, and imaging findings. A follow-up survey focusing on 6 h from onset was conducted after the release of the positive endovascular trials., Results: We received 548 responses from 35 countries including 282 individual centers; 78% of the centers originating from Australia, Brazil, France, Germany, Spain, United Kingdom, and United States. The specific onset windows presented influenced the type of imaging work-up selected more than the clinical scenario. Magnetic Resonance Imaging usage (27-28%) was substantial, in particular for wake-up stroke. Following the release of the positive trials, selection of perfusion imaging significantly increased for imaging strategy., Conclusions: Usage of vascular or perfusion imaging by Computed Tomography or Magnetic Resonance Imaging beyond just parenchymal imaging was the primary work-up (62-87%) across all clinical vignettes and time windows. Perfusion imaging with Computed Tomography or Magnetic Resonance Imaging was associated with increased probability of enrollment into clinical trials for 0-3 h. Following the release of the positive endovascular trials, selection of endovascular only treatment for 6 h increased across all clinical vignettes., (© 2016 World Stroke Organization.)

Background and Purpose: The standard outcome measure in stroke research is modified Rankin scale (mRS) evaluated by local blinded investigators. We aimed to assess feasibility and reliability of 2 central adjudication methods of mRS in the setting of a randomized endovascular stroke trial., Methods: This is a secondary analysis derived from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REVASCAT) trial cohort. Primary outcome was distribution of mRS at 90 days. Local evaluation was done by certified investigators masked to treatment assignment using structured face-to-face interviews. In addition, central assessment was performed by 2 independent raters via structured phone interview (n=120) and via video recordings of the face-to-face interviews with local investigators (n=106). Interrater agreement was evaluated using kappa and discordance statistics. Sensitivity analyses for the primary end point using different adjudication approaches were performed. Correlation between mRS obtained with each modality and 24-hour follow-up infarct volumes was studied., Results: Using local evaluation as the reference, higher agreement rates were noted with central video than with central phone evaluations (kw 0.92 [0.88-0.96] versus 0.77 [0.72-0.83]). Discrepancies in mRS scoring between local and central raters (phone- and video-based) were similar in both treatment allocation arms. Sensitivity analyses showed benefit of endovascular treatment irrespective of adjudication method, but higher odds ratios were observed with local evaluations. Final infarct volume was similarly correlated with mRS across all 3 evaluation modalities., Conclusions: Central adjudication of mRS is feasible, reducing interrater variability and avoiding potential problems related to lack of blinding. Our findings may have implications in the planning of future randomized acute stroke trials, especially in those including nonpharmacological interventions., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379., (© 2015 American Heart Association, Inc.)

Background and Purpose: Recent trials have shown the superiority of endovascular thrombectomy (EVT) over medical therapy alone in certain stroke patients with proximal arterial occlusion. Using data from the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within 8-Hours of Symptom Onset (REVASCAT) and a parallel reperfusion treatment registry, we sought to assess the utilization of EVT in a defined patient population, comparing the outcomes of patients treated in and outside the REVASCAT trial., Methods: SONIIA [Sistema Online d'Informació de l'Ictus Agut], a population-based, government-mandated, prospective registry of reperfusion therapies for stroke encompassing the entire population of Catalonia, was used as data source. The registry documents 5 key inclusion criteria of the REVASCAT trial: age, stroke severity, time to treatment, baseline functional status, and occlusion site. We compared procedural, safety, and functional outcomes in patients treated inside and outside the trial., Results: From November 2012 to December 2014, out of 17596 ischemic stroke patients in Catalonia (population 7.5 million), 2576 patients received reperfusion therapies (17/100000 inhabitants-year), mainly intravenous thrombolysis only (2036). From the remaining 540 treated with EVT, 103 patients (out of 206 randomized) were treated within REVASCAT and 437 outside the trial. Of these, 399 did not fulfill some of the study criteria, and 38 were trial candidates (8 treated at REVASCAT centers and 30 at 2 non-REVASCAT centers). The majority of procedural, safety, and functional outcomes were similar in patients treated with EVT within and outside REVASCAT., Conclusions: REVASCAT enrolled nearly all eligible patients representing one third of all patients treated with EVT. Patients treated with EVT within and outside REVASCAT had similar outcomes, reinforcing the therapeutic value of EVT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379., (© 2015 American Heart Association, Inc.)

Background: Metabolic syndrome (MetS) has been associated with higher resistance to clot lysis at 24 hours after tissue plasminogen activator (tPA) administration in patients with acute ischemic stroke. We aimed to test this hypothesis at earlier time points, when neurointerventional rescue procedures may still be indicated to achieve arterial recanalization., Methods: This is a prospective and observational study in consecutive stroke patients with MCA occlusion treated with IV tPA. MetS was diagnosed following the unified criteria of the last Joint Interim Statement 2009 participating several major organizations. The primary outcome variable was resistance to thrombolysis, defined as the absence of complete middle cerebral artery recanalization 2 hours after tPA bolus assessed by transcranial color-coded duplex or when rescue mechanical thrombectomy after IV tPA was required. Secondary outcome variables were dramatic neurological improvement (decrease in ≥10 points, or a National Institutes of Health Stroke Scale [NIHSS] score of 0-1 at 24 hours), symptomatic intracerebral hemorrhage following European-Australasian Acute Stroke Study II criteria, infarct volume at 24 hours (calculated by using the formula for irregular volumes, ABC/2), and good outcome (modified Rankin Scale score < 3) at 3 months., Results: A total of 234 patients (median baseline NIHSS score 16 [10-20]) were included and 146 (62.4%) fulfilled MetS criteria. After multivariate analysis, MetS emerged as an independent predictor of resistance to thrombolysis (odds ratio = 2.2 [1.3-4.2], P = .01) and absence of dramatic neurological improvement (odds ratio = .5 [.28-.97], P = .04). In addition, MetS conferred poorer functional outcome, higher symptomatic intracerebral hemorrhage rate, and increased infarct volume, although these associations disappeared after adjustment for covariates., Conclusions: MetS predicts patients with middle cerebral artery occlusion refractory to early clot dissolution after IV tPA. This finding may help in acute clinical decision-making., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Rationale: Endovascular treatment has been shown to restore blood flow effectively. Second-generation medical devices such as stent retrievers are now showing overwhelming efficacy in clinical trials, particularly in conjunction with intravenous recombinant tissue plasminogen activator., Aims and Design: This statistical analysis plan utilizing a novel, sequential approach describes a prospective, individual patient data analysis of endovascular therapy in conjunction with intravenous recombinant tissue plasminogen activator agreed upon by the Thrombectomy and Tissue Plasminogen Activator Collaborative Group., Study Outcomes: This protocol will specify the primary outcome for efficacy, as 'favorable' outcome defined by the ordinal distribution of the modified Rankin Scale measured at three-months poststroke, but with modified Rankin Scales 5 and 6 collapsed into a single category. The primary analysis will aim to answer the questions: 'what is the treatment effect of endovascular therapy with intravenous recombinant tissue plasminogen activator compared to intravenous tissue plasminogen activator alone on full scale modified Rankin Scale at 3 months?' and 'to what extent do key patient characteristics influence the treatment effect of endovascular therapy?'. Key secondary outcomes include effect of endovascular therapy on death within 90 days; analyses of modified Rankin Scale using dichotomized methods; and effects of endovascular therapy on symptomatic intracranial hemorrhage. Several secondary analyses will be considered as well as expanding patient cohorts to intravenous recombinant tissue plasminogen activator-ineligible patients, should data allow., Discussion: This collaborative meta-analysis of individual participant data from randomized trials of endovascular therapy vs. control in conjunction with intravenous thrombolysis will demonstrate the efficacy and generalizability of endovascular therapy with intravenous thrombolysis as a concomitant medication., (© 2015 World Stroke Organization.)

Introduction: Cervical artery dissection (CAD) is the cause of 2% to 3% of ischaemic strokes and 10% to 25% of the ischaemic strokes in young people. Our objective is to evaluate whether implementation of a comprehensive stroke centre (CSC) improves the diagnosis and modifies the prognosis of patients with acute stroke due to CAD., Patients and Methods: Retrospective study of a registry of consecutive patients with acute stroke due to CAD. They were classified according to the period of care at our centre: pre-CSC (October 2004-March 2008, 42 months) or post-CSC (April 2008-June 2012, 51 months). We compared baseline characteristics, methods of diagnosis, treatment and outcome of these patients in both periods., Results: Nine patients were diagnosed with CAD in pre-CSC and 26 in post-CSC, representing 0.8% and 2.1% of all ischaemic strokes treated in each period, respectively. The diagnosis of CAD was made within the first 24 hours in 42.3% of the patients in post-CSC versus 0% in pre-CSC, by using urgent cerebral angiography as a diagnostic test in 46.2% of cases in the second period compared to 0% in the first. Both severity of stroke (median NIHSS score 11 vs. 3, P=.014) and time to neurological care (265 min vs 148, P=.056) were higher in the post-CSC period. Endovascular treatment was performed in 34.3%, and all treatments were post-CSC. The functional outcome was comparable for both periods., Conclusions: Implementation of a CSC increases the frequency of the diagnosis of CAD, as well as the treatment options for these patients in the acute phase of stroke., (Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)