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Background and Purpose: This study aimed to explore whether the therapeutic benefit of endovascular thrombectomy (EVT) was mediated by core growth rate., Methods: This retrospective cohort study identified acute ischemic stroke patients with large vessel occlusion and receiving reperfusion treatment, either EVT or intravenous thrombolysis (IVT), within 4.5 hours of stroke onset. Patients were divided into 2 groups: EVT versus IVT only patients (who had no access to EVT). Core growth rate was estimated by the acute core volume on perfusion computed tomography divided by the time from stroke onset to perfusion computed tomography. The primary clinical outcome was good outcome defined by 3-month modified Rankin Scale score of 0-2. Tissue outcome was the final infarction volume., Results: A total of 806 patients were included, 429 in the EVT group (recanalization rate of 61.6%) and 377 in the IVT only group (recanalization rate of 44.7%). The treatment effect of EVT versus IVT only was mediated by core growth rate, showing a significant interaction between EVT treatment and core growth rate in predicting good clinical outcome (interaction odds ratio=1.03 [1.01-1.05], P =0.007) and final infarct volume (interaction odds ratio=-0.44 [-0.87 to -0.01], P =0.047). For patients with fast core growth of >25 mL/h, EVT treatment (compared with IVT only) increased the odds of good clinical outcome (adjusted odds ratio=3.62 [1.21-10.76], P =0.021) and resulted in smaller final infarction volume (37.5 versus 73.9 mL, P =0.012). For patients with slow core growth of <15 mL/h, there were no significant differences between the EVT and the IVT only group in either good clinical outcome (adjusted odds ratio=1.44 [0.97-2.14], P =0.070) or final infarction volume (22.6 versus 21.9 mL, P =0.551)., Conclusions: Fast core growth was associated with greater benefit from EVT compared with IVT in the early <4.5-hour time window.

Background and Purpose: Distal clot migration is a recognized event following intravenous thrombolysis (IVT) in the setting of acute ischemic stroke. Of note, clots that were initially retrievable by endovascular thrombectomy may migrate to a distal nonretrievable location and compromise clinical outcome. We investigated the incidence of clot migration leading to clot inaccessibility following IVT in the time window of 4.5 to 9 hours., Methods: We performed a retrospective analysis of the EXTEND trial (Extending the Time for Thrombolysis in Emergency Neurological Deficits) data. Baseline and 12- to 24-hour follow-up clot location was determined on computed tomography angiogram or magnetic resonance angiogram. The incidence of clot migration leading to a change from retrievable to nonretrievable location was identified and compared between the two treatment groups (IVT versus placebo)., Results: Two hundred twenty patients were assessed. Clot migration from a retrievable to nonretrievable location occurred in 37 patients: 21 patients (19.3%) in the placebo group and 16 patients (14.4%) in the IVT group. No significant difference was identified in the incidence of clot migration leading to inaccessibility between groups ( P =0.336)., Conclusions: Our results did not show increased clot migration leading to clot inaccessibility in patients treated with IVT.

Importance: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain., Objective: To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials., Design, Setting, and Participants: Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020., Exposures: Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds' lesion volume at 24- to 72-hour follow-up., Main Outcomes and Measures: Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more., Results: Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P < .001). The median (interquartile range) age was 76 (66-81) years in the reperfusion group vs 74 (64.5-81.0) years in the group with no reperfusion. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (7-15) in the reperfusion group vs 12 (8.0-17.5) in the no reperfusion group. Overall, reperfusion was associated with improved functional outcome (common odds ratio, 7.7; 95% CI, 4.6-12.8; P < .001). Reperfusion was associated with significantly improved functional outcome in each of the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata, with no evidence of association between time to randomization and beneficial effect of reperfusion (P = .63). Symptomatic hemorrhage, assessed in all 294 patients, occurred in 3 of 51 (5.9%) in the 4.5- to 6-hours group, 2 of 28 (7.1%) in the 6- to 9-hours group, and 4 of 73 (5.5%) in the wake-up stroke in patients treated with alteplase (Fisher P = .91)., Conclusions and Relevance: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the consistent treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5- to 9-hours and wake-up stroke time window.

Background: Multiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)" study, which aimed to improve rates of intravenous thrombolysis in Australia., Methods: A posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups., Results: There was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-and post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56-2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active- (odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52)., Conclusion: The TIPS multi-component implementation approach was not effective in reducing the odds of post-treatment severe disability at 90 days, or post-thrombolysis hemorrhage., Trial Registration: Clinical Trial Registration-URL: http://www.anzctr.org.au/ Unique Identifier: ACTRN12613000939796 .

Aims: Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre-including noncontrast CT, CT perfusion, and CT angiography-may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis., Methods: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria., Results: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group., Conclusion: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To assess whether complete reperfusion after IV thrombolysis (IVT-R) would result in similar clinical outcomes compared to complete reperfusion after endovascular thrombectomy (EVT-R) in patients with a large vessel occlusion (LVO)., Methods: EVT-R patients were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to IVT-R patients from the International Stroke Perfusion Imaging Registry (INSPIRE). Only patients with complete reperfusion on follow-up imaging were included. The excellent clinical outcome rates at day 90 on the modified Rankin Scale (mRS) were compared between EVT-R vs IVT-R patients within quintiles of increasing baseline ischemic core and penumbral volumes., Results: From INSPIRE, there were 141 EVT-R patients and 141 matched controls (IVT-R) who met the eligibility criteria. In patients with a baseline core <30 mL, EVT-R resulted in a lower odds of achieving an excellent outcome at day 90 compared to IVT-R (day 90 mRS 0-1 odds ratio 0.01, p < 0.001). The group with a baseline core <30 mL contained mostly patients with distal M1 or M2 occlusions, and good collaterals ( p = 0.01). In patients with a baseline ischemic core volume >30 mL (internal carotid artery and mostly proximal M1 occlusions), EVT-R increased the odds of patients achieving an excellent clinical outcome (day 90 mRS 0-1 odds ratio 1.61, p < 0.001) and there was increased symptomatic intracranial hemorrhage in the IVT-R group with core >30 mL (20% vs 3% in EVT-R, p = 0.008)., Conclusion: From this observational cohort, LVO patients with larger baseline ischemic cores and proximal LVO, with poorer collaterals, clearly benefited from EVT-R compared to IVT-R alone. However, for distal LVO patients, with smaller ischemic cores and better collaterals, EVT-R was associated with a lower odds of favorable outcome compared to IVT-R alone., (© 2019 American Academy of Neurology.)

Background: Stroke thrombolysis with alteplase is currently recommended 0-4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis., Methods: In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036., Findings: We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81-2·96, p=0·66)., Interpretation: Patients with ischaemic stroke 4·5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The use of multimodal computed tomography imaging (MMCT) in routine clinical assessment of stroke patients improves the identification of patients with large regions of salvageable brain tissue, lower risk for haemorrhagic transformation, or a large vessel occlusion requiring endovascular therapy., Aim: To evaluate the cost-effectiveness of using MMCT compared to usual practice for determining eligibility for reperfusion therapy with alteplase using real world data from the International Stroke Perfusion Imaging Registry (INSPIRE)., Methods: We performed a cost-utility analysis. Mean costs and quality-adjusted life years (QALYs) per patient for two alternative screening protocols were calculated. Protocol 1 represented usual practice, while Protocol 2 reflected treatment targeting using multimodal imaging. Cost-effectiveness was assessed using the net-benefit framework., Results: Protocol 1 had a total mean per patient cost of $2,013 USD and 0.148 QALYs. Protocol 2 had a total mean per patient cost of $1,519 USD and 0.153 QALYs. For a range of willingness-to-pay values, representing implicit thresholds of cost-effectiveness, the lower bound of the incremental net monetary benefit statistic was consistently greater than zero, indicating that MMCT is cost- effective compared to usual practice. The results were most sensitive to variation in the mean number of alteplase vials administered., Conclusion: In a healthcare setting where multimodal imaging technologies are available and reimbursed, their use in screening patients presenting with acute stroke to determine eligibility for alteplase treatment is cost-effective given a range of willingness-to-pay thresholds and warrants consideration as an alternative to routine practice., Competing Interests: The authors have declared that no competing interests exist.

See Saver (doi:10.1093/awx020) for a scientific commentary on this article.Stroke shortens an individual's disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion computed tomography imaging variables (e.g. ischaemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. We used data from a prospectively collected international, multicentre, observational registry of acute ischaemic stroke patients who had perfusion computed tomography and computed tomography angiography before treatment with intravenous alteplase. Baseline perfusion computed tomography and follow-up magnetic resonance imaging were analysed to derive the baseline penumbra volume, baseline ischaemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on Disability-Adjusted Life Year. Clinical variables were age, sex, National Institutes of Health Stroke Scale score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate disability-adjusted life-year due to stroke, such that 1 year of disability-adjusted life-year equates to 1 year of healthy life lost due to stroke. There were 772 patients receiving alteplase therapy. The number of disability-adjusted life-year days lost per 1 ml of baseline ischaemic core volume was 17.5 (95% confidence interval, 13.2-21.9 days, P < 0.001). For every millilitre of penumbra salvaged, 7.2 days of disability-adjusted life-year days were saved (β = -7.2, 95% confidence interval, -10.4 to -4.1 days, P < 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3-7.5 days, P = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in disability-adjusted life-year days. Pretreatment perfusion computed tomography can (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra, particularly when the ischaemic core is not too large., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.)

Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p=0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score⩽5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54minutes, p=0.0355) and imaging-to-needle time (34 versus 27minutes, p=0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies., (Copyright © 2016. Published by Elsevier Ltd.)

Background and Purpose: The Stroke Imaging Research (STIR) group, the Imaging Working Group of StrokeNet, the American Society of Neuroradiology, and the Foundation of the American Society of Neuroradiology sponsored an imaging session and workshop during the Stroke Treatment Academy Industry Roundtable (STAIR) IX on October 5 to 6, 2015 in Washington, DC. The purpose of this roadmap was to focus on the role of imaging in future research and clinical trials., Methods: This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the US Food and Drug Administration to discuss STIR priorities in the light of an unprecedented series of positive acute stroke endovascular therapy clinical trials., Results: The imaging session summarized and compared the imaging components of the recent positive endovascular trials and proposed opportunities for pooled analyses. The imaging workshop developed consensus recommendations for optimal imaging methods for the acquisition and analysis of core, mismatch, and collaterals across multiple modalities, and also a standardized approach for measuring the final infarct volume in prospective clinical trials., Conclusions: Recent positive acute stroke endovascular clinical trials have demonstrated the added value of neurovascular imaging. The optimal imaging profile for endovascular treatment includes large vessel occlusion, smaller core, good collaterals, and large penumbra. However, equivalent definitions for the imaging profile parameters across modalities are needed, and a standardization effort is warranted, potentially leveraging the pooled data resulting from the recent positive endovascular trials., (© 2016 American Heart Association, Inc.)

The use of perfusion imaging to guide selection of patients for stroke thrombolysis remains controversial because of lack of supportive phase three clinical trial evidence. We aimed to measure the outcomes for patients treated with intravenous recombinant tissue plasminogen activator (rtPA) at a comprehensive stroke care facility where perfusion computed tomography was routinely used for thrombolysis eligibility decision assistance. Our overall hypothesis was that patients with 'target' mismatch on perfusion computed tomography would have improved outcomes with rtPA. This was a prospective cohort study of consecutive ischaemic stroke patients who fulfilled standard clinical/non-contrast computed tomography eligibility criteria for treatment with intravenous rtPA, but for whom perfusion computed tomography was used to guide the final treatment decision. The 'real-time' perfusion computed tomography assessments were qualitative; a large perfusion computed tomography ischaemic core, or lack of significant perfusion lesion-core mismatch were considered relative exclusion criteria for thrombolysis. Specific volumetric perfusion computed tomography criteria were not used for the treatment decision. The primary analysis compared 3-month modified Rankin Scale in treated versus untreated patients after 'off-line' (post-treatment) quantitative volumetric perfusion computed tomography eligibility assessment based on presence or absence of 'target' perfusion lesion-core mismatch (mismatch ratio >1.8 and volume >15 ml, core <70 ml). In a second analysis, we compared outcomes of the perfusion computed tomography-selected rtPA-treated patients to an Australian historical cohort of non-contrast computed tomography-selected rtPA-treated patients. Of 635 patients with acute ischaemic stroke eligible for rtPA by standard criteria, thrombolysis was given to 366 patients, with 269 excluded based on visual real-time perfusion computed tomography assessment. After off-line quantitative perfusion computed tomography classification: 253 treated patients and 83 untreated patients had 'target' mismatch, 56 treated and 31 untreated patients had a large ischaemic core, and 57 treated and 155 untreated patients had no target mismatch. In the primary analysis, only in the target mismatch subgroup did rtPA-treated patients have significantly better outcomes (odds ratio for 3-month, modified Rankin Scale 0-2 = 13.8, P < 0.001). With respect to the perfusion computed tomography selected rtPA-treated patients (n = 366) versus the clinical/non-contrast computed tomography selected rtPA-treated patients (n = 396), the perfusion computed tomography selected group had higher adjusted odds of excellent outcome (modified Rankin Scale 0-1 odds ratio 1.59, P = 0.009) and lower mortality (odds ratio 0.56, P = 0.021). Although based on observational data sets, our analyses provide support for the hypothesis that perfusion computed tomography improves the identification of patients likely to respond to thrombolysis, and also those in whom natural history may be difficult to modify with treatment., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: Intracerebral hemorrhage is a serious potential complication of stroke thrombolysis. We investigated the optimal computed tomography perfusion (CTP) parameter to predict cerebral parenchymal hematoma (PH) in acute ischemic stroke., Methods: Patients with hyperacute ischemic stroke had whole-brain CTP and follow-up computed tomography/MRI to identify hemorrhagic transformation. The association of the 3 parameters relative cerebral blood flow, relative cerebral blood volume, and time to maximum (Tmax) with PH was examined using receiver operating characteristic analysis and multivariate logistic regression., Results: Of 132 patients, 70 were treated with thrombolysis, and 14 (10.6%) developed PH on follow-up imaging. Baseline National Institutes of Health Stroke Scale score (P=0.033) and thrombolysis (P=0.003) were both predictive of PH. Receiver operating characteristic analysis revealed that Tmax>14 s (area under the curve=0.748; P=0.002) and relative cerebral blood flow <30% of contralateral mean (area under the curve=0.689, P=0.021) were the optimal thresholds, and the Bayesian information criterion (+2.6) indicated that Tmax was more strongly associated with PH than relative cerebral blood flow. Tmax >14 s volumes of >5 mL allowed prediction of PH with sensitivity of 79%, specificity of 68%, and negative likelihood ratio of 3.16. Tmax>14 s volume and thrombolysis were both independently predictive of PH in a multivariate logistic regression model (P<0.05)., Conclusions: Tmax >14 s was the CTP parameter most strongly associated with PH. This outperformed relative cerebral blood flow <30%, which closely equates to CTP estimates of ischemic core volume. Although ischemic core volume on CTP is useful in the pretreatment prediction of PH, severe hypoperfusion on Tmax is more strongly associated and may allow better prediction of the likely anatomic location of hemorrhage.

Currently, imaging is predominantly used to exclude patients for thrombolysis, rather than identify patients most likely to benefit. This means that patients are being selected for treatment without reference to tissue pathophysiology. Imaging of specific stroke pathophysiology may be the key to selecting patients most likely to benefit from thrombolysis, and could revolutionize acute stroke assessment and treatment. The technology is available to identify the acute infarct core and possibly the penumbra, via magnetic resonance diffusion-weighted imaging, and both magnetic resonance- and computed tomography-perfusion imaging techniques. However, these modalities require fine tuning before they can be reliably implemented in a routine clinical setting.

Background Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. Methods In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). Results Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). Conclusions Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality. [ABSTRACT FROM AUTHOR]

Rationale: Alteplase is the only approved thrombolytic agent for acute stroke. An alternative plasminogen activator, tenecteplase, has been previously shown to increase early biological effectiveness (reperfusion) resulting in early clinical recovery in acute stroke patients with target mismatch on perfusion imaging; however, phase III data are lacking. Aim and hypothesis: In this study, we assess the efficacy and safety of tenecteplase compared to alteplase in acute stroke patients with target mismatch on perfusion imaging. Methods and Design: Tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) for Stroke Thrombolysis Evaluation (TASTE) is a multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase III non-inferiority trial (2 arms with 1:1 randomization) with an adaptive sample size re-estimation in patients with acute ischemic stroke meeting target mismatch criteria on perfusion imaging. Sample size estimates: Recruiting 728 patients (1:1 tenecteplase vs alteplase) would yield 90% power (two-sided alpha 0.05) to detect a treatment effect of 8% (26% modified Rankin scale (mRS) 0–1 in alteplase arm and 34% mRS 0–1 in tenecteplase arm), with an absolute non-inferiority margin of 3%. Following the pre-planned "promising zone" adaptive sample size re-estimation, the final sample size was set at 832 patients. Study outcomes: The primary outcome measure is the proportion of patients with an mRS score of 0–1 at 3 months. Secondary outcomes include the categorical shift in mRS at 3 months; the proportion of patients with: mRS 0–2, 5–6, and 6; reduction of the National Institutes of Health Stroke Scale (NIHSS) by 8 or more points or reaching 0–1 at 24 h; symptomatic intracerebral hemorrhage within 36 h; and death. Discussion: This pivotal trial will provide important data on the role of tenecteplase in acute ischemic stroke, and the use of imaging-based treatment decision-making for stroke thrombolysis. Clinical trial protocol: Trial Registration: ACTRN12613000243718, EudraCT 2015-002657-36 [ABSTRACT FROM AUTHOR]

Rationale: More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success. Hypothesis: We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early. Methods: This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders. Outcomes: The primary outcome will be time to recanalization detected by TCD (defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ~120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study. Discussion: If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients. [ABSTRACT FROM AUTHOR]

Objective: To explore the association of poststroke baseline blood pressure with cerebral collateral flow and functional outcome in acute ischemic patients with large vessel occlusion/stenosis.Methods: Patients identified with large vessel occlusion/stenosis with baseline multimodal computed tomography, follow-up imaging, and complete clinical profiles were included. A 90-day modified Rankin Scale of 0-1 was defined as an excellent functional outcome. Cerebral collateral flow was quantified by the volume ratio of tissue within the delay time >3 seconds perfusion lesion with severely delayed contrast transit (delay time >3 seconds/delay time >6 seconds).Results: There were 306 patients included in this study. With every increase of 10 mmHg in baseline systolic blood pressure, the odds of achieving an excellent functional outcome decreased by 12% in multivariate analysis (odds ratio = 0.88, p = 0.048). Conversely, increased baseline blood pressure was associated with better collateral flow. In subgroup analysis of patients with major reperfusion, higher blood pressure was associated with decreased infarct growth and a better clinical outcome, and vice versa in patients without reperfusion.Interpretation: Higher baseline blood pressure in acute ischemic stroke patients with large vessel occlusion/stenosis was associated with better collateral flow. However, for patients without reperfusion, higher baseline blood pressure was associated with increased infarct growth, leading to an unfavorable clinical outcome. The relationship between blood pressure and outcomes is highly dependent on reperfusion, and active blood pressure-lowering treatment may be inappropriate in acute ischemic stroke patients prior to reperfusion treatment. ANN NEUROL 2019;85:331-339. [ABSTRACT FROM AUTHOR]

aim: The relative prognostic importance of modern imaging profles compared with standard clinical characteristics is uncertain in acute stroke patients. In this study, we aimed to compare baseline multimodal CT imaging measures with known clinical predictors of patient outcome at 3 months [modifed Rankin scale (mRS)]. Methods: We collected baseline, 24 h, and day 90 clinical and imaging data from acute ischemic stroke patients being assessed for thrombolytic therapy between 2010 and 2015 at a single center as part of a retrospective analysis. results: 561 patients presenting within 4.5 h of ischemic stroke onset who were eligible for thrombolysis based on standard clinical criteria were assessed. Acute infarct core volume on CTP was the strongest univariate predictor of patient outcome (mRS 0-2, R² 0.497, p < 0.001), followed by collateral grade (mRS 0-2, R#178; 0.281, p < 0.001). The strongest baseline clinical predictor of outcome was National Institutes of Health Stroke Scale (NIHSS) (mRS 0-2, R#178; = 0.203, p < 0.001). Time to treatment (mRS 0-2, R#178; 0.096, p = 0.01) and age (mRS 0-2, R#178; 0.027, p = 0.013) were relatively weak univariate baseline clinical predictors of 3-month outcome. In multivariate analysis, acute infarct core volume and collateral grade were the only signifcant baseline predictors of 3-month disability (both p < 0.001). conclusion: In patients assessed for thrombolysis by combined clinical and multimodal CT criteria within 4.5 h of onset, the size of the CTP infarct core and collateral grade on multimodal CT were highly predictive of patient outcome. Standard clinical variables, including time to treatment and NIHSS, were not as strongly predictive as multimodal CT variables. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to identify whether acute ischemic stroke patients with known complete reperfusion after thrombectomy had the same baseline computed tomography perfusion (CTP) ischemic core threshold to predict infarction as thrombolysis patients with complete reperfusion.Methods: Patients who underwent thrombectomy were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to patients who were treated with intravenous alteplase alone from the International Stroke Perfusion Imaging Registry. A pixel-based analysis of coregistered pretreatment CTP and 24-hour diffusion-weighted imaging (DWI) was then undertaken to define the optimum CTP thresholds for the ischemic core.Results: There were 132 eligible thrombectomy patients and 132 matched controls treated with alteplase alone. Baseline National Institutes of Health Stroke Scale (median, 15; interquartile range [IQR], 11-19), age (median, 65; IQR, 59-80), and time to intravenous treatment (median, 153 minutes; IQR, 82-315) were well matched (all p > 0.05). Despite similar baseline CTP ischemic core volumes using the previously validated measure (relative cerebral blood flow [rCBF], <30%), thrombectomy patients had a smaller median 24-hour infarct core of 17.3ml (IQR, 11.3-32.8) versus 24.3ml (IQR, 16.7-42.2; p = 0.011) in alteplase-treated controls. As a result, the optimal threshold to define the ischemic core in thrombectomy patients was rCBF <20% (area under the curve [AUC], 0.89; 95% CI, 0.84, 0.94), whereas in alteplase controls the optimal ischemic core threshold remained rCBF <30% (AUC, 0.83; 95% CI, 0.77, 0.85).Interpretation: Thrombectomy salvaged tissue with lower CBF, likely attributed to earlier reperfusion. For patients who achieve rapid reperfusion, a stricter rCBF threshold to estimate the ischemic core should be considered. Ann Neurol 2017;82:995-1003. [ABSTRACT FROM AUTHOR]

See Saver (doi:10.1093/awx020) for a scientific commentary on this article.Stroke shortens an individual's disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion computed tomography imaging variables (e.g. ischaemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. We used data from a prospectively collected international, multicentre, observational registry of acute ischaemic stroke patients who had perfusion computed tomography and computed tomography angiography before treatment with intravenous alteplase. Baseline perfusion computed tomography and follow-up magnetic resonance imaging were analysed to derive the baseline penumbra volume, baseline ischaemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on Disability-Adjusted Life Year. Clinical variables were age, sex, National Institutes of Health Stroke Scale score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate disability-adjusted life-year due to stroke, such that 1 year of disability-adjusted life-year equates to 1 year of healthy life lost due to stroke. There were 772 patients receiving alteplase therapy. The number of disability-adjusted life-year days lost per 1 ml of baseline ischaemic core volume was 17.5 (95% confidence interval, 13.2-21.9 days, P < 0.001). For every millilitre of penumbra salvaged, 7.2 days of disability-adjusted life-year days were saved (β = -7.2, 95% confidence interval, -10.4 to -4.1 days, P < 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3-7.5 days, P = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in disability-adjusted life-year days. Pretreatment perfusion computed tomography can (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra, particularly when the ischaemic core is not too large. [ABSTRACT FROM AUTHOR]

BACKGROUND: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. METHODS: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. RESULTS: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0-1: odds ratio, 1.77; 95% confidence interval, 0.89-3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0-1: odds ratio, 2.33; 95% confidence interval, 1.13-5.94; P=0.032) than those treated with alteplase. CONCLUSIONS: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion-defined target mismatch. [ABSTRACT FROM AUTHOR]

Objective: Although commonly used in clinical practice, there remains much uncertainty about whether perfusion computed tomography (CTP) should be used to select stroke patients for acute reperfusion therapy. In this study, we tested the hypothesis that a small acute perfusion lesion predicts good clinical outcome regardless of thrombolysis administration.Methods: We used a prospectively collected cohort of acute ischemic stroke patients being assessed for treatment with IV-alteplase, who had CTP before a treatment decision. Volumetric CTP was retrospectively analyded to identify patients with a small perfusion lesion (<15ml in volume). The primary analysis was excellent 3-month outcome in patients with a small perfusion lesion who were treated with alteplase compared to those who were not treated.Results: Of 1526 patients, 366 had a perfusion lesion <15ml and were clinically eligible for alteplase (212 being treated and 154 not treated). Median acute National Institutes of Health Stroke Scale score was 8 in each group. Of the 366 patients with a small perfusion lesion, 227 (62%) were modified Rankin Scale (mRS) 0 to 1 at day 90. Alteplase-treated patients were less likely to achieve 90-day mRS 0 to 1 (57%) than untreated patients (69%; relative risk [RR] = 0.83; 95% confidence interval [CI], 0.71-0.97; p = 0.022) and did not have different rates of mRS 0 to 2 (72% treated patients vs 77% untreated; RR, 0.93; 95% CI, 0.82-1.95; p = 0.23).Interpretation: This large observational cohort suggests that a portion of ischemic stroke patients clinically eligible for alteplase therapy with a small perfusion lesion have a good natural history and may not benefit from treatment. Ann Neurol 2016;80:286-293. [ABSTRACT FROM AUTHOR]

Background: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging.Methods: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group.Results: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0-1: odds ratio, 1.77; 95% confidence interval, 0.89-3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0-1: odds ratio, 2.33; 95% confidence interval, 1.13-5.94; P=0.032) than those treated with alteplase.Conclusions: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion-defined target mismatch.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347. [ABSTRACT FROM AUTHOR]

Alteplase is currently the only approved thrombolytic agent for treatment of acute ischaemic stroke, but interest is burgeoning in the development of new thrombolytic agents for systemic reperfusion with an improved safety profile, increased efficacy, and convenient delivery. Tenecteplase has emerged as a potential alternative thrombolytic agent that might be preferred over alteplase because of its ease of administration and reported efficacy in patients with large vessel occlusion. Ongoing research efforts are also looking at potential improvements in recanalisation with the use of adjunct therapies to intravenous thrombolysis. New treatment strategies are also emerging that aim to reduce the risk of vessel reocclusion after intravenous thrombolysis administration. Other research endeavors are looking at the use of intra-arterial thrombolysis after mechanical thrombectomy to induce tissue reperfusion. The growing implementation of mobile stroke units and advanced neuroimaging could boost the number of patients who can receive intravenous thrombolysis by shortening onset-to-treatment times and identifying patients with salvageable penumbra. Continued improvements in this area will be essential to facilitate the ongoing research endeavors and to improve delivery of new interventions. [ABSTRACT FROM AUTHOR]