Search

Background: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging., Methods: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed., Findings: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed p non-inferiority =0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed p non-inferiority =0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05])., Interpretation: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible., Funding: Australian National Health Medical Research Council; Boehringer Ingelheim., Competing Interests: Declaration of interests MWP is on a Boehringer-Ingelheim Advisory Board for metalyse in stroke. FCN has received grants from the National Health and Medical Research Council of Australia and the National Heart Foundation of Australia. AM participates on an advisory board for Boehringer Ingelheim and is a World Stroke Organisation board member. HSM reports grants from the British Heart Foundation, the Medical Research Council, the Alzheimer's Society, and the Stroke Association UK, and is the editor-in-chief of the World Stroke Organisation journal, International Journal of Stroke. HM has received speaking fees from the Indonesian Stroke Society and reports travel support for investigator meetings. TGP has received speaking fees from Bayer, Boehringer Ingelheim, Pfizer, and BMS. JFA reports consulting fees from Amgen, Medtronic, and BMS-Pfizer, reports speaking fees from Medtronic and BMS–Pfizer, reports travel support from Daiichi–Sankyo, participates on the advisory board for the WE-TRUST trial, and reports research grants from the Spanish Ministry of Science, the European Commission, and Astra Zeneca. RSG has received travel support from Boehringer Ingelheim. SA has received funding from the UK Stroke Clinical Research Network. KSB is in a spousal relationship with an employee of Boehringer Ingelheim and has received speaking fees from Boehringer Ingelheim and AstraZeneca. All other authors report no disclosures., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aims: We reprocessed the Extending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) perfusion imaging with a different automated software with the aim of comparing mismatch eligibility and outcomes., Methods: EXTEND baseline perfusion imaging data were reprocessed using autoMIStar software to identify patients who were eligible based on the same target mismatch criteria as per the original trial., Results: From the 225 patients fulfilling RAPID-based mismatch criteria randomized in the EXTEND study, 196 (87%) patients met the revised mismatch criteria. Most common reasons for not meeting revised criteria were core >70 ml (n = 9), and no perfusion lesion/lack of penumbral tissue (n = 20). The revised perfusion lesion volumes were significantly smaller compared to the original RAPID volumes (median 68 ml IQR 34-102 ml vs. 42 ml 16-92 ml, p = 0.036). Of the patients who met the revised mismatch criteria, 40% receiving alteplase had modified Rankin Scale (mRS) 0-1 at 3-month compared to 28% with placebo (Adjusted Odds Ratio (OR) = 2.23, CI 1.08-4.58, p = 0.028). In contrast, in the original mismatch cohort, 35% receiving alteplase had mRS 0-1 at 3-month compared to 30% with placebo (adjusted OR = 1.88, p = 0.056)., Conclusions: These data reinforce the benefit of alteplase in the later time window, and suggest that differences in automated perfusion imaging software outputs may be clinically relevant., (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO)., Methods: To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion >50% or absence of retrievable thrombus at the time of the initial angiogram was evaluated., Results: We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years; median NIH Stroke Scale score 16 [interquartile range (IQR) 7-32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion >50% occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3-12; p = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40-71] minutes) vs alteplase-treated patients (110 [IQR 51-185] minutes; p = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase; p = 0.9)., Conclusions: TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted., Clinicaltrialsgov Identifiers: NCT02388061 and NCT03340493., Classification of Evidence: This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO., (© 2021 American Academy of Neurology.)

Background and Purpose: Tenecteplase improved functional outcomes and reduced the requirement for endovascular thrombectomy in ischemic stroke patients with large vessel occlusion in the EXTEND-IA TNK randomized trial. We assessed the cost-effectiveness of tenecteplase versus alteplase in this trial., Methods: Post hoc within-trial economic analysis included costs of index emergency department and inpatient stroke hospitalization, rehabilitation/subacute care, and rehospitalization due to stroke within 90 days. Sources for cost included key study site complemented by published literature and government websites. Quality-adjusted life-years were estimated using utility scores derived from the modified Rankin Scale score at 90 days. Long-term modeled cost-effectiveness analysis used a Markov model with 7 health states corresponding to 7 modified Rankin Scale scores. Probabilistic sensitivity analyses were performed., Results: Within the 202 patients in the randomized controlled trial, total cost was nonsignificantly lower in the tenecteplase-treated patients (40 997 Australian dollars [AUD]) compared with alteplase-treated patients (46 188 AUD) for the first 90 days( P =0.125). Tenecteplase was the dominant treatment strategy in the short term, with similar cost (5412 AUD [95% CI, -13 348 to 2523]; P =0.181) and higher benefits (0.099 quality-adjusted life-years [95% CI, 0.001-0.1967]; P =0.048), with a 97.4% probability of being cost-effective. In the long-term, tenecteplase was associated with less additional lifetime cost (96 357 versus 106 304 AUD) and greater benefits (quality-adjusted life-years, 7.77 versus 6.48), and had a 100% probability of being cost-effective. Both deterministic sensitivity analysis and probabilistic sensitivity analyses yielded similar results., Conclusions: Both within-trial and long-term economic analyses showed that tenecteplase was highly likely to be cost-effective for patients with acute stroke before thrombectomy. Recommending the use of tenecteplase over alteplase could lead to a cost saving to the healthcare system both in the short and long term. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388061.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers., Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903., Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I 2 =27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024)., Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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: 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., Results: 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., Conclusions: 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.

Background: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging., Methods: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline., Results: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days., Conclusions: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: 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. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

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.

Goal: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on non-contrast computed tomography (NCCT) is dependent on the visibility of early ischemic change. The goal of our study was to evaluate whether time from ischemic stroke onset to initial NCCT influences the inter-rater variability and prognostic accuracy of ASPECTS for a 3-month functional outcome., Materials and Methods: Ischemic stroke patients treated with intravenous tissue plasminogen activator (IV-tPA) from 2007 to 2014 at the Royal Melbourne Hospital were included. ASPECTS were blindly assessed by 2 independent raters with inter-rater agreement determined by weighted kappa. Onset time to computed tomography time was dichotomized at the median (≤100 and >100 minutes). Outcome was assessed using the modified Rankin Scale. Logistic regression and receiver operating characteristic analysis were used to assess the prognostic utility of ASPECTS in the early and later time periods., Results: There were 379 patients included. Inter-rater agreement was significantly lower in the early time period: kappa = .75 (95% confidence interval (CI), .59-.84) ≤ 100 minutes versus .92 (95% CI, .91-.93) > 100 minutes, P < .001. The distributions of absolute inter-rater differences in ASPECTS differed significantly between time epochs (P = .03). The prognostic accuracies of ASPECTS across time epochs were area under the receiver operating characteristic curve ≤ 100 minutes = .57 (95% CI, .50-.64) and >100 minutes = .66 (95% CI, .59-.73), P = .055., Conclusions: This study demonstrated a significantly lower inter-rater agreement and a trend toward reduced prognostic accuracy of ASPECTS in earlier time periods. The use of ASPECTS to select patients for revascularization in early time windows may be unreliable., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to evaluate early recanalization postintravenous (i.v.) tissue plasminogen activator (t-PA) by digital subtraction angiography (DSA) in acute ischemic stroke (AIS) with large vessel occlusion (LVO)., Methods: We performed baseline CT angiography to identify LVO in AIS. Recanalization pre- and post-intra-arterial therapy (IAT) was categorized to none, partial, and global recanalization (GR). Modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome., Results: Among 1610 patients with AIS, 286 received IV t-PA. Of these, 55 patients with LVO were included. The median time from IV t-PA to DSA was 120 min (interquartile range, 79-152). Recanalization post-IV t-PA was observed in seven patients (12.7%). By occlusion sites, the recanalization rates were as follows: extracranial internal carotid artery 2 of 14 (14.3%); intracranial internal carotid artery 3 of 24 (12.5%); M1 of middle cerebral artery 3 of 39 (7.7%); M2 of middle cerebral artery 1 of 40 (2.5%); vertebral artery 0 of 4; and basilar artery 0 of 7. GR post-IAT was associated with favorable outcomes (odds ratio: 8.6; 95% confidence interval, 1.5-48.0; P = 0.014)., Conclusion: Early recanalization assessed by DSA post-IV t-PA is rarely observed in acute ischemic stroke patients with LVO., (© 2016 John Wiley & Sons Ltd.)

Background: Intra-arterial therapy has improved recanalization rates compared with intravenous thrombolysis for acute ischemic stroke; however, superior clinical efficacy has not been convincingly demonstrated. Time to recanalization is postulated as a mechanism hindering the efficacy of intra-arterial therapy., Aim: To investigate the effects of time to recanalization on clinical outcome postintra-arterial therapy for acute ischemic stroke., Methods: Clinical data were collected prospectively for consecutive patients undergoing intra-arterial therapy for acute ischemic stroke at a single center between 2009 and 2013. Ninety-day functional outcome was assessed by the modified Rankin scale. Univariate analyses identified candidate clinical variables for inclusion in the multivariable model; multivariable logistic regression analyses identified variables independently associated with good outcome, defined as modified Rankin scale 0-2., Results: One hundred and seven patients were included in the analysis. Median (interquartile range) age was 67 (54-77) years, 41 (38%) were female, and median (interquartile range) baseline National Institute of Health Stroke Severity score was 18 (13-22). Median time from symptom onset to recanalization was 330 min (interquartile range 277-397). Fifty-four (50%) patients achieved a favorable modified Rankin scale at 90 days. Age, successful recanalization, and time to recanalization were independently associated with good outcome at 90 days in multivariable logistic regression analysis. For every 15 min delay in recanalization, the odds of good outcome decreased by 10%., Conclusions: Longer time to recanalization was associated with poorer functional outcome post intra-arterial therapy. We recommend that a systematic approach to minimize time delay to treatment is warranted in intra-arterial therapy for acute ischemic stroke., (© 2015 World Stroke Organization.)

Background: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes., Methods: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days., Results: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage., Conclusions: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.).

Background: Large vessel occlusion (LVO) is associated with poor functional outcome in acute ischemic stroke. Given the uncertainty whether LVO has the same significance in mild and severe stroke, we compared functional outcomes after intravenous thrombolysis, based on severity and LVO., Methods: Ischemic stroke patients were thrombolyzed in less than 4.5 hours after onset between 2007 and 2013. LVO was defined as occlusion of one of the following arteries: internal carotid, middle cerebral (M1/M2), anterior cerebral (A1), posterior cerebral (P1), basilar, or vertebral (V4) arteries on prethrombolysis computed tomography angiography. Mild stroke was defined as baseline National Institutes of Health Stroke Scale (NIHSS) score 0-6. Favorable outcome was defined as modified Rankin Scale (mRS) score 0-1 at 3 months or equal to the prestroke mRS., Results: There were 175 acute stroke patients, median age 74 years (interquartile range [IQR], 64-83), median baseline NIHSS = 11 (IQR, 5-16), and 63 of 175 patients (36%) with mild stroke. LVO was associated with worse outcome in severe stroke (age-adjusted odds ratio [OR] of favorable outcome, .42; 95% confidence interval [CI], .19-.93; P = .033) and mortality (age-adjusted OR, 3.52; 95% CI, 1.08-11.48; P = .037). Although the difference in favorable outcome between mild stroke patients with and without LVO was not significant (55.6% vs. 74.1%, P = .262; age-adjusted OR of favorable outcome, .42; 95% CI, .1-1.84; P = .251), the similarity of effects across both subgroups cannot be excluded (LVO-by-stroke severity interaction test, P = .906)., Conclusions: LVO is associated with worse functional outcome and mortality in severe stroke after intravenous thrombolysis. Although significant association between LVO and outcome in mild stroke was not found, there were similar effects on outcome and a larger study might well confirm a relationship., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The currently proven time window for thrombolysis in ischemic stroke is 4.5 h. Beyond this, the risks and benefits of thrombolysis are uncertain., Aims: To determine whether thrombolysis and reperfusion were beneficial after 4.5 h, we examined clinical and radiological outcomes in patients treated with tissue plasminogen activator or placebo within 4.5-6 h, using data from the Echoplanar Imaging Thrombolytic Evaluation Trial., Methods: In the Echoplanar Imaging Thrombolytic Evaluation Trial, ischemic stroke patients presenting three to six-hours after stroke onset were randomized to tissue plasminogen activator or placebo, without knowledge of magnetic resonance imaging results. This analysis was restricted to patients treated between 4.5 and 6 h. The effect of tissue plasminogen activator and reperfusion on infarct growth between baseline diffusion-weighted imaging and day 90 T2 imaging was assessed, along with good neurological outcome (≥8 point reduction or reaching 0-1 at 90 days on National Institutes of Health Stroke Scale) and functional outcome (modified Rankin scale). The effect of tissue plasminogen activator on reperfusion was also analyzed., Results: Sixty-nine patients were treated 4.5-6 h after onset, and infarct growth was assessed in 63. Tissue plasminogen activator was associated with lower relative growth (94% vs. 168%, P = 0.03) and a trend to lower absolute growth (-0.17 ml versus 9.6 ml, P = 0.07). Reperfusion was increased in the tissue plasminogen activator group (58% versus 25%, P = 0.03) and was associated with increased rates of good neurological (86% versus 28% P < 0.001) and functional (modified Rankin scale 0-2 73% versus 34%, P = 0.01) outcomes. Reperfusion was strongly associated with lower relative (80% versus 189%, P < 0.001) and absolute (-2.5 ml versus 40 ml, P < 0.001) infarct growth., Conclusions: Thrombolysis 4.5-6 h after stroke onset reduced infarct growth and increased the rate of reperfusion, which was associated with good neurological and functional outcome., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

Introduction: Previous studies on the impact of nonworking hours (NWH) have produced conflicting results. We aimed to compare the time to treatment with thrombolysis between NWH and working hours (WH) at an Australian comprehensive stroke center., Materials and Methods: All acute ischemic stroke patients treated with intravenous alteplase (IV-alteplase) from January 2003 to December 2011 at the Royal Melbourne Hospital were included. Data collected included demographics, serial time points (including onset, presentation to emergency department, neuroimaging, and thrombolysis), and clinical outcomes (modified Rankin Scale [mRS] and death) at 3 months. NWH were defined as weekdays 5 PM-8 AM, weekends, and public holidays. Comparisons were made in the door-to-computed tomography (CT) time, the door-to-needle time, mRS, and mortality within 3 months between the NWH group and WH group., Results: We recruited 388 consecutive patients who received IV-alteplase, 226 patients were in NWH and 162 patients in WH. The median age was 71 years (Interquartile range [IQR] = 60-79), 54.1% of patients were male, and the median National Institutes of Health Stroke Scale score was 13 (IQR = 8-18). No significant differences were observed at baseline between the NWH and WH groups except for prior stroke. There was a 15-minute increase in the median door-to-needle time (80 minutes in the NWH group versus 64.5 minutes in the WH group, 95% confidence interval [CI]: 6.36-23.64, P = .001). No significant differences were noted in the median door-to-CT time (95% CI: -1.16 to 9.16, P = .128) and clinical outcomes at 3 months (P > .05). Both the door-to-CT time and the door-to-needle time became shorter over the period of the study (P < .001)., Conclusions: Our study showed that the "NWH effect" increased the door-to-needle time. The patients treated out of hours did not have a worse outcome., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Renal dysfunction is associated with poor outcomes in ischaemic stroke but remains unproven post intravenous thrombolysis. We studied the renal function in stroke patients treated with intravenous tissue plasminogen activator (IV tPA)., Methods: We retrospectively analysed consecutive ischaemic stroke patients treated with IV tPA (0.9 mg/kg) from January 2003 to December 2011. Collected data included demographics, medical histories, stroke severity measured by National Institutes of Health Stroke Scale (NIHSS), serum urea, creatinine, estimated glomerular filtration rate (eGFR), platelet, white cell count and international normalised ratio (INR) at baseline. Poor clinical outcome was defined as modified Rankin Scale (mRS) of 2 to 6 at 3 months. Logistic regression analysis was performed to test the association between renal function and clinical outcomes adjusted for confounders., Results: In the 378 patients included, the median age was 72 (IQR=62-81) years, 54.2% were male. Median baseline NIHSS was 12 (IQR=8-18). There was a statistically significant association between all three renal function markers. After adjustments for confounding factors, baseline urea was significantly associated with poor outcome (OR=1.100; 95% CI 1.010-1.198 per mmol/L; p=0.028) and mortality (OR=1.117; 95% CI 1.027-1.213 per mmol/L; p=0.009), eGFR was associated with mortality (OR=0.984; 95% CI 0.970-0.998 per mL/min/1.73 m(2); p=0.026) but not poor outcome (OR=0.994; 95% CI 0.983-1.004 per mL/min/1.73m(2); p=0.230), and serum creatinine was not significant for poor outcome (OR=1.037; 95% CI 0.967-1.113 per 10 μmol/L; p=0.306) or mortality (OR=1.032; 95% CI 0.979-1.088 per 10 μmol/L; p=0.238). No association was observed between ICH and any renal function test., Conclusions: Elevated serum urea was independently associated with poor clinical outcome and mortality in acute ischaemic stroke patients treated with IV tPA., (© 2013 Elsevier B.V. All rights reserved)

Background: Acute stroke management is a dynamic field. Treatment with recombinant tissue plasminogen activator is standard care in Australia, but there are no evidence-based practice guidelines about first out of bed activity (mobilization) after recombinant tissue plasminogen activator., Aims: To identify factors influencing clinicians' decisions to delay or allow mobilization., Methods: Case-crossover design. Using hypothetical case vignettes, we explored the factors that clinicians consider when deciding to first mobilize a patient after recombinant tissue plasminogen activator. Acute stroke physicians and nurses from Australian hospitals known to treat with recombinant tissue plasminogen activator participated. Information about hospital recombinant tissue plasminogen activator protocols and perceived benefits and harms of mobilization after recombinant tissue plasminogen activator were also captured., Results: Fifty-four clinicians, 52% senior nurses, and 48% senior physicians from all states of Australia participated. Of the factors influencing decisions about mobilization after recombinant tissue plasminogen activator, neurological decline (0.29; confidence interval 0.12, 0.46; P = 0.001), neurological decline with symptomatic intracerebral hemorrhage (0.41; confidence interval 0.24, 0.59; P < 0.0001), infection of uncertain cause (0.32; confidence interval 0.14, 0.50; P = 0.001), severe chest infection (0.35; confidence interval 0.16, 0.53; P = 0.0004), severe stroke (0.29; confidence interval 0.12, 0.46; P = 0.001), drowsiness (0.47; confidence interval 0.29, 0.63; P < 0.0001), and confusion (0.31; confidence interval 0.15, 0.47; P = 0.0001) significantly influenced decisions. Falls risk was a common concern (85%)., Conclusion: Growing interest in development of clear protocols that guide first mobilization after recombinant tissue plasminogen activator prompted this study. We have identified factors that may influence decisions about when to allow patients to mobilize after recombinant tissue plasminogen activator. These, combined with emerging evidence of risks and benefits of early mobilization, should help protocol development in the future., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

Background and Purpose: Two phase 2 studies of alteplase in acute ischemic stroke 3 to 6 hours after onset, Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; a randomized, controlled, double-blinded trial), and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE; open-label, treatment only) using MR imaging-based outcomes have been conducted. We have pooled individual patient data from these to assess the response to alteplase. The primary hypothesis was that alteplase would significantly attenuate infarct growth compared with placebo in mismatch-selected patients using coregistration techniques., Methods: The EPITHET-DEFUSE study datasets were pooled while retaining the original inclusion and exclusion criteria. Significant hypoperfusion was defined as a Tmax delay >6 seconds), and coregistration techniques were used to define MR diffusion-weighted imaging/perfusion-weighted imaging mismatch. Neuroimaging, parameters including reperfusion, recanalization, symptomatic intracerebral hemorrhage, and clinical outcomes were assessed. Alteplase and placebo groups were compared for the primary outcome of infarct growth as well for secondary outcome measures., Results: From 165 patients with adequate MR scans in the EPITHET-DEFUSE pooled data, 121 patients (73.3%) were found to have mismatch. For the primary outcome analysis, 60 patients received alteplase and 41 placebo. Mismatch patients receiving alteplase had significantly attenuated infarct growth compared with placebo (P=0.025). The reperfusion rate was also increased (62.7% vs 31.7%; P=0.003). Mortality and clinical outcomes were not different between groups., Conclusions: The data provide further evidence that alteplase significantly attenuates infarct growth and increases reperfusion compared with placebo in the 3- to 6- hour time window in patients selected based on MR penumbral imaging.

Background and Hypothesis: Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo., Study Design: EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4-26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo., Study Outcome: The primary outcome measure will be modified Rankin Scale 0-1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0-1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

Objective: Recanalization of arterial obstruction is associated with improved clinical outcomes. There are no controlled data demonstrating whether arterial obstruction status predicts the treatment effect of intravenous (IV) tissue plasminogen activator (tPA). We aimed to determine if the presence of arterial obstruction improves the treatment effect of IV tPA over placebo in attenuating infarct growth., Methods: We analyzed 175 ischemic stroke patients treated in the 3-6 hour time window from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) trial (randomized to IV tPA or placebo) and Diffusion and perfusion imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study (all treated with IV tPA). Infarct growth was calculated as the difference between baseline diffusion-weighted imaging (DWI) and final T2 lesion volumes. Baseline arterial obstruction of large intracranial arteries was graded on magnetic resonance angiography (MRA)., Results: Among the 116 patients with adequate baseline MRA and final lesion assessment, 72 had arterial obstruction (48 tPA, 24 placebo) and 44 no arterial obstruction (33 tPA, 11 placebo). Infarct growth was lower in the tPA than placebo group (median difference 26ml, 95% confidence interval [CI], 1-50) in patients with arterial obstruction, but was similar in patients with no arterial obstruction (median difference 5ml, 95%CI, -3 to 9). Infarct growth attenuation with tPA over placebo treatment was greater among patients with arterial obstruction than those without arterial obstruction by a median of 32ml (95%CI, 21-43, p < 0.001)., Interpretation: The treatment effect of IV tPA over placebo was greater with baseline arterial obstruction, supporting arterial obstruction status as a consideration in selecting patients more likely to benefit from IV thrombolysis., (Copyright © 2011 American Neurological Association.)

Background and Purpose: the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated., Methods: patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥ 10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch., Results: of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33-0.99; P=0.0459)., Conclusions: when using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.

Cerebral amyloid angiopathy (CAA) may be an important predisposing factor for the hemorrhagic complications of recombinant tissue-type plasminogen activator (rt-PA) therapy. We studied patients treated within 3 hours of onset of ischemic stroke with rt-PA using positron emission tomography to compare Pittsburgh compound B (PiB) (a cerebral β-amyloid ligand) retention in those with and without parenchymal hemorrhage (PH) and normal controls. Neocortical PiB retention was higher among patients with PH compared with patients without PH and normal controls, suggesting underlying CAA as a predisposing factor for rt-PA-related hemorrhage. This finding may provide an impetus for the development of a more practical rapid pretreatment screening technique.

Objective: To report Australian outcomes from the Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR)., Design: Observational study using data collected prospectively from December 2002 to December 2008., Setting: Centres administering thrombolysis for acute stroke in Australia and worldwide., Patients: All patients treated with recombinant tissue plasminogen activator for acute stroke in participating centres, regardless of stroke severity, time of treatment and other clinical factors., Intervention: Thrombolysis for acute stroke, administered according to local protocol., Main Outcome Measures: Functional outcome as 3-month modified Rankin score (mRS), and frequency of symptomatic intracerebral haemorrhage (ICH)., Results: During the study period, a total of 32 countries participated, and confirmed baseline data were available for 581 Australian patients and 20 953 patients in the rest of the world. Australian patients were older (median age, 73 v 69 years; P < 0.001), were less independent before stroke (premorbid mRS of 0-1, 87.5% v 91.2%; P < 0.005), and had more comorbidities and more severe strokes. Comparing the Australian cohort with the rest of the world, the odds ratio of 3-month mRS of 0-2 was 0.98 (95% CI, 0.88-1.08; P = 0.63), the odds ratio of symptomatic ICH was 0.98 (95% CI, 0.83-1.16; P = 0.85 [by the definition used by the National Institute of Neurological Disorders]) and the odds ratio of death was 1.04 (95% CI, 0.91-1.19; P = 0.54). Good outcome in the Australian cohort was predicted by younger age, presence of hyperlipidaemia, lower premorbid mRS, absence of infarct on early brain imaging, less severe stroke, and lower baseline blood glucose level., Conclusion: Clinical outcomes after thrombolysis in Australia were similar to those worldwide.

Background and hypothesis: Intravenous thrombolysis with tenecteplase is more effective than alteplase in achieving substantial reperfusion at initial angiographic assessment and improves functional outcome. However, the optimal dose of tenecteplase remains uncertain. We hypothesized that 0.40 mg/kg tenecteplase is superior to 0.25 mg/kg tenecteplase 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 part 2 is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale (mRS)≤3 (no upper age limit), absence of contraindications to intravenous thrombolysis, and large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal CT. Patients are randomized to IV tenecteplase at either 0.40 mg/kg (max 40 mg) or 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 (mTICI) 2b/3, or the absence of retrievable intracranial thrombus. Secondary outcomes include mRS at day 90 and early neurological improvement (reduction in National Institutes of Health Stroke Scale (NIHSS) by ≥8 points or reaching 0–1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT03340493 [ABSTRACT FROM AUTHOR]

Background: Ischemic stroke is a leading cause of new-onset seizures. Cortical ischemia and large ischemic lesion size are among the most consistently reported risk factors for post-stroke seizures. Alberta Stroke Program Early CT Score (ASPECTS) is a simple and reliable tool for quantifying the extent of cerebral ischemia and may function as a screening tool for patients with high risk of seizure development. We investigated the association of post-stroke seizures with the extent of ischemia assessed by ASPECTS and with cortical involvement identified on non-contrast CT (NCCT). Methods: This cohort study was based on a prospectively maintained clinical database of acute ischemic stroke patients who were given intravenous tissue plasminogen activator treatment. We included patients with anterior circulation stroke admitted between January 2008 and October 2014. Patients with pre-stroke seizures were excluded. Clinical data and seizure follow-up data were collected. NCCT scans acquired both on stroke admission and at 24 h were analyzed. Logistic regression and cox regression were performed in statistical analysis. Results: A total of 348 patients (median age 73 years, interquartile range [IQR] 63-80, 55% male) were included. During follow-up (median duration 559 days, IQR 107.5-1188.5 days), 22 (6.3%) patients developed post-stroke seizures. Median time from stroke to seizure onset was 138 days (IQR 10-342 days). In univariate logistic regression, both ASPECTS on admission (OR 0.69 per 1-point increase; 95% CI 0.55-0.86; p = 0.001) and at 24 h (OR 0.80 per 1-point increase; 95% CI 0.70-0.92; p = 0.002) were significantly associated with post-stroke seizures. Cortical involvement at 24 h also correlated with seizure occurrence (OR 3.01; 95% CI 1.08-8.34; p = 0.03). Cox regression confirmed the higher risk of developing seizures at any time point in patients with lower ASPECTS value and cortical ischemia. Of note, ASPECTS was the only independent predictor for post-stroke seizures in multivariate logistic regression. Conclusion: The extent of ischemia assessed by ASPECTS and cortical involvement identified on NCCT were associated with the development of post-stroke seizures. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4·5 h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with 'dual target' vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging 'mismatch' within 4·5 h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0·9 mg/kg intravenous tissue plasminogen activator within 4·5 h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion : ischemic core mismatch ratio >1·2, absolute mismatch >10 ml, ischemic core volume <70 ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes The coprimary outcome measure will be reperfusion at 24 h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0-1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Background: CHADS2 and CHA2DS2-VASc scores are validated tools for assessing stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with 3-month stroke outcomes and evaluated the utility of these scores in stratifying 3-month stroke outcomes in both patients with and without AF. Methods: We analysed 6,612 acute ischaemic stroke patients from the Virtual International Stroke Trials Archive who received either placebo or ineffective active treatments not associated with significant cardiac complications. Outcomes included 3-month mortality, good functional outcomes defined as modified Rankin Scale score ≤1 and serious cardiac adverse events (SCAEs) defined as one of acute coronary syndrome, symptomatic heart failure, cardiopulmonary arrest, life-threatening arrhythmia and cardiac death. The association between the pre-stroke CHADS2 and CHA2DS2-VASc scores and 3-month stroke outcomes was assessed using binary logistic regression. The utility of the two scores in estimating 3-month stroke outcomes was assessed using area under the receiver operator characteristic curves (AUC) and compared using the χ2 test. Results: In this cohort, 26.5% had AF, 35.3% received IV tissue plasminogen activator (tPA), 17.7% died, 25.1% achieved good functional outcomes and 9.5% had ≥1 SCAE at 3 months. High-risk (≥2) pre-stroke CHADS2 and CHA2DS2-VASc scores are both associated with 3-month mortality (CHADS2: odds ratio, OR, 2.33, 95% confidence interval 1.81-3.00; CHA2DS2-VASc: OR 3.01, 2.00-4.80), good functional outcomes (CHADS2: OR 0.47, 0.39-0.57; CHA2DS2-VASc: OR 0.55, 0.42-0.71) and SCAEs (CHADS2: OR 1.76, 1.28-2.42; CHA2DS2-VASc: OR 2.69, 1.53-4.73) after adjusting for baseline differences in neurological impairment, tPA use and AF. The pre-stroke CHA2DS2-VASc score is better than the CHADS2 score in estimating 3-month stroke outcomes in both patients with and without AF (p ≤ 0.005 in all AUC comparisons). High-risk pre-stroke CHA2DS2-VASc score has high sensitivity for mortality (AF: 0.96, 0.94-0.98; no AF: 0.88, 0.86-0.91) and negative predictive value for SCAE (AF: 0.93, 0.87-0.96; no AF: 0.96, 0.95-0.97) within 3 months. Low risk pre-stroke CHA2DS2-VASc score has high specificity for good functional outcome (AF: 0.99, 0.98-0.994; no AF: 0.94, 0.93-0.95) at 3 months. Conclusions: The pre-stroke CHA2DS2-VASc score appears to be a simple tool for identifying patients at lower risk of poor outcomes and serious cardiac complications within 3 months following ischaemic stroke in patients with and without AF. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The authors reflect on several editorials in the October 2012 issue that were concerned with stroke thrombolysis in the light of the third international stroke trial (IST-3). They suggest that the editorials challenge the validity of stroke thrombolysis. They argue that future acute stroke research needs to be conducted in several areas, including the development of more effective thrombolytic agents, ways to decrease onset-treatment times and the development of recanalisation techniques.

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. [ABSTRACT FROM AUTHOR]