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Background and Purpose: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. Method(s): Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. Result(s): Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0-61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-pe

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage. Method(s): We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4.5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4.5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636). Finding(s): Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14.6 mL (7.9

Background: EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) is a randomized, multicenter, double-blinded, placebo-controlled phase 3 trial to test the hypothesis of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke (WUS) patients. Objective(s): To formulate the detailed statistical analysis plan for the EXTEND trial prior to database lock. This statistical analysis plan is based on the published and registered EXTEND trial protocol and is developed by the blinded steering committee and management team. Result(s): The developed EXTEND statistical analysis plan is transparent, verifiable, and predetermined before the database lock. It is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusion(s): Publication of a statistical analysis plan serves to reduce potential trial analysis and reporting bias and outlines pre-specified analyses to quantify the benefits and harms of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke patients. Trial registration: ClinicalTrials.gov number NCT00887328 registered 23/Apr/2009 and NCT01580839 (EXTEND International) registered 19/Apr/2012.Copyright © 2018 World Stroke Organization.

Background: Pre-existing comorbidities can compromise recovery post-stroke. However, the association between comorbidity burden and patient-rated perceived impact has not been systematically investigated. To date, only observer-rated outcome measures of function, disability, and dependence have been used, despite the complexity of the impact of stroke on an individual. Aim(s): Our aim was to explore the association between comorbidity burden and patient-rated perceived impact and overall recovery, within the first-year post-stroke, after adjusting for stroke severity, age, and sex. Method(s): The sample comprised 177 stroke survivors from 18 hospitals throughout Australia and New Zealand. Comorbidity burden was calculated using the Charlson Comorbidity Index. Perceived impact and recovery were measured by the Stroke Impact Scale index and Stroke Impact Scale overall recovery scale. Quantile regression models were applied to investigate the association between comorbidity burden and perceived impact and recovery. Result(s): Significant negative associations between the Charlson Comorbidity Index and the Stroke Impact Scale index were found at three months. At the.25 quantile, a one-point increase on the Charlson Comorbidity Index was associated with 6.80-points decrease on the Stroke Impact Scale index (95%CI: -11.26, -2.34; p =.003). At the median and.75 quantile, a one-point increase on the Charlson Comorbidity Index was associated, respectively, with 3.58-points decrease (95%CI: -5.62, -1.54; p =.001) and 1.76-points decrease (95%CI: -2.80, -0.73; p =.001) on the Stroke Impact Scale index. At 12 months, at the.25 and.75 quantiles, a one-point increase on the Charlson Comorbidity Index was associated, respectively, with 6.47-points decrease (95%CI: -11.05, -1.89; p =.006) and 1.26-points decrease (95%CI: -2.11, -0.42; p =.004) on the Stroke Impact Scale index. For the Stroke Impact Scale overall recovery measure, significant negative associations were found only at

Background and Purpose-Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods-Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results-In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes (P<0.001) for dispatch to hospital arrival and 15 minutes (P<0.001) for hospital arrival to thrombolysis. The calculated overall time saving from dispatch to thrombolysis was 42.5 minutes (95% CI, 36.0-49.0). In the same period, 41 MSU patients received EVT (mean age, 76 years; 61% men) with median dispatch-to-treatment time saving of 51 minutes ([95% CI, 30.1-71.9], P<0.001). This included a median time saving of 17 minutes ([95% CI, 7.6-26.4], P=0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions-The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful i

Item does not contain fulltext, 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 mum(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

Background and Purpose-Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke.Methods-Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration [highly effective reperfusion using multiple endovascular devices]). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0-6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level.Results-Median (interquartile range) serum glucose on admission was 120 (104-140) mg/dL (6.6 mmol/L [5.7-7.7] mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69-2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P=0.019 for interaction; acOR, 3.81; 95% CI, 1.73-8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53-2.19 for patients >90 mg/dL), and glucose < or > 100 mg/dL (5.5 mmol/L; P=0.004 for interaction; acOR, 3.17; 95% CI, 2.04-4.93 versus acOR, 1.72; 95% CI, 1.42-2.08) but not between subgroups above these levels of glucose.Conclusions-EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment e

Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset.Copyri

It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of "good" outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach.Copyright © 2017, © 2017 World Stroke Organization.

Background and hypothesis: Intravenous thrombolysis with alteplase remains standard care prior to thrombectomy for eligible patients within 4.5 h of ischemic stroke onset. However, alteplase only succeeds in reperfusing large vessel arterial occlusion prior to thrombectomy in a minority of patients. We hypothesized that tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design: EXTEND-IA TNK is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint non-inferiority study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale<=3 (no upper age limit), large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal computed tomography and absence of contraindications to intravenous thrombolysis. Patients are randomized to either IV alteplase (0.9 mg/kg, max 90 mg) or tenecteplase (0.25 mg/kg, max 25 mg) prior to thrombectomy. Study outcomes: The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified treatment in cerebral infarction 2 b/3 or the absence of retrievable thrombus. Secondary outcomes include modified Rankin Scale at day 90 and favorable clinical response (reduction in National Institutes of Health Stroke Scale by >=8 points or reaching 0-1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT02388061.Copyright © 2017, © 2017 World Stroke Organization.

There is mounting evidence that the width of the tropics has increased over the last few decades, but there are large differences in reported expansion rates. This is, likely, in part due to the wide variety of metrics that have been used to define the tropical width. Here we perform a systematic investigation into the relationship among nine metrics of the zonal-mean tropical width using preindustrial control and abrupt quadrupling of CO2 simulations from a suite of coupled climate models. It is shown that the latitudes of the edge of the Hadley cell, the midlatitude eddy-driven jet, the edge of the subtropical dry zones, and the Southern Hemisphere subtropical high covary interannually and exhibit similar long-term responses to a quadrupling of CO2. However, metrics based on the outgoing longwave radiation, the position of the subtropical jet, the break in the tropopause, and the Northern Hemisphere subtropical high have very weak covariations with the above metrics and/or respond differently to increases in CO2 and thus are not good indicators of the expansion of the Hadley cell or subtropical dry zone. The differing variability and responses to increases in CO2 among metrics highlights that care is needed when choosing metrics for studies of the width of the tropics and that it is important to make sure the metric used is appropriate for the specific phenomena and impacts being examined.

Background and aim: The availability and access of hospital administrative data [coding for Charlson comorbidity index (CCI)] in large data form has resulted in a surge of interest in using this information to predict mortality from stroke. The aims of this study were to determine the minimum clinical data set to be included in models for predicting disability after ischemic stroke adjusting for CCI and clinical variables and to evaluate the impact of CCI on prediction of outcome. Method(s): We leverage anonymized clinical trial data in the Virtual International Stroke Trials Archive. This repository contains prospective data on stroke severity and outcome. The inclusion criteria were patients with available stroke severity score such as National Institutes of Health Stroke Scale (NIHSS), imaging data, and outcome disability score such as 90-day Rankin Scale. We calculate CCI based on comorbidity data in this data set. For logistic regression, we used these calibration statistics: Nagelkerke generalised R2 and Brier score; and for discrimination we used: area under the receiver operating characteristics curve (AUC) and integrated discrimination improvement (IDI). The IDI was used to evaluate improvement in disability prediction above baseline model containing age, sex, and CCI. Result(s): The clinical data among 5,206 patients (55% males) were as follows: mean age 69 +/- 13 years, CCI 4.2 +/- 0.8, and median NIHSS of 12 (IQR 8, 17) on admission and 9 (IQR 5, 15) at 24 h. In Model 2, adding admission NIHSS to the baseline model improved AUC from 0.67 (95% CI 0.65-0.68) to 0.79 (95% CI 0.78-0.81). In Model 3, adding 24-h NIHSS to the baseline model resulted in substantial improvement in AUC to 0.90 (95% CI 0.89-0.91) and increased IDI by 0.23 (95% CI 0.22-0.24). Adding the variable recombinant tissue plasminogen activator did not result in a further change in AUC or IDI to this regression model. In Model 3, the variable NIHSS at 24 h explains 87.3% of the variance of

Background: Endovascular thrombectomy improves functional outcome in large vessel occlusion ischemic stroke. We examined disability, quality of life, survival and acute care costs in the EXTEND-IA trial, which used CT-perfusion imaging selection. Method(s): Large vessel ischemic stroke patients with favorable CT-perfusion were randomized to endovascular thrombectomy after alteplase versus alteplase-only. Clinical outcome was prospectively measured using 90-day modified Rankin scale (mRS). Individual patient expected survival and net difference in Disability/Quality-adjusted life years (DALY/QALY) up to 15 years from stroke were modeled using age, sex, 90-day mRS, and utility scores. Level of care within the first 90 days was prospectively measured and used to estimate procedure and inpatient care costs (US$ reference year 2014). Result(s): There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15 (IQR 12-19). The median (IQR) disability-weighted utility score at 90 days was 0.65 (0.00-0.91) in the alteplase-only versus 0.91 (0.65-1.00) in the endovascular group (p = 0.005). Modeled life expectancy was greater in the endovascular versus alteplase-only group (median 15.6 versus 11.2 years, p = 0.02). The endovascular thrombectomy group had fewer simulated DALYs lost over 15 years [median (IQR) 5.5 (3.2-8.7) versus 8.9 (4.7-13.8), p = 0.02] and more QALY gained [median (IQR) 9.3 (4.2-13.1) versus 4.9 (0.3-8.5), p = 0.03]. Endovascular patients spent less time in hospital [median (IQR) 5 (3-11) days versus 8 (5-14) days, p = 0.04] and rehabilitation [median (IQR) 0 (0-28) versus 27 (0-65) days, p = 0.03]. The estimated inpatient costs in the first 90 days were less in the thrombectomy group (average US$15,689 versus US$30,569, p = 0.008) offsetting the costs of interhospital transport and the thrombectomy procedure (average US$10,515). The average saving per patient treated with thrombectomy was US$4,365. Conclusion(s): Thrombectomy patients with large vessel

Background: EXTEND is an investigator-initiated, randomised, double-blind and placebo-controlled Phase III trial of intravenous alteplase vs placebo in patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). The prevalence of intra-cranial vessel occlusion in WUS patients remains to be determined and can guide the development of optimal therapy for this unique group of stroke patients. Objective(s): To study the prevalence and characteristics of intra-cranial vessel occlusion in this WUS cohort. Method(s): Ischemic stroke patients within 4.5-9 hours from stroke onset or with WUS (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrollment. Criteria for entry into the trial include perfusion-diffusion mismatch using a perfusion threshold of Tmax>6sec and a perfusion:diffusion lesion volume ratio of >1.2. Diffusion lesion volume must be <70mL based on assessment by automated RAPID software. Intra-cranial vessel occlusion was assessed on MR or CT angiogram performed at randomisation and 24 later. Two expert readers assessed these images independently. Result(s): 97 patients had images with adequate quality, including 63 (65%) in the WUS group with median age of 77.0 yrs (IQR 67.0, 81.0) and NIHSS of 14.0 (9.0, 19.0). 62 of 63 patients (98%) had vessel occlusion with 44.4% involving M1 of the middle cerebral artery, 17.5% M2, 4.8% M3, 25.4% both internal carotid artery (ICA) and M1, 4.8% ICA alone and 3.1% the posterior cerebral artery. The median ischemic core volume was 15.0 ml (6.5, 31.5), Tmax>6 volume 88.5ml (58.0, 122.0), mismatch volume 65.5ml (42.8, 92.0), and ratio of 4.8 (2.5, 8.7). 19 patients (30%) demonstrated recanalization on follow-up imaging. Conclusion(s): In WUS patients there is a very high rate of intracranial vessel occlusion with relatively large volumes of salvageable penumbral tissue. Intravenous thrombolytic therapy followed by thrombectomy in s