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Background: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. Methods: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. Results: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2–2.6). Median time from baseline CT to study drug was 62.5 (55–80) minutes, and from study drug to early post-dose CT was 19 (14.5–30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (−0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8–8.3) in the placebo arm ( P =0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (−2.6 to 8.3) in the rFVIIa arm and 0.7 mL (−1.6 to 2.1) in the placebo arm ( P =0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71–1.43]; P =0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994–1.003]; P =0.50; Table 3). Conclusions: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01359202.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Introduction: First-pass effect (FPE), i.e., achieving reperfusion with a single thrombectomy device pass, is associated with better clinical outcomes in patients with acute stroke. FPE is therefore increasingly being used as a marker of device and procedural efficacy. We evaluated the ability of thrombus-based radiomics models to predict FPE in patients undergoing endovascular thrombectomy (EVT) and compare performance to experts and non-radiomics thrombus characteristics. Methods: Patients with thin-slice non-contrast CT and CT angiography from The Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke (ESCAPE-NA1) trial were included. Thrombi were manually segmented on all images. Data was randomly split into a derivation set that included a training and a validation subset and an independent test set. Radiomics features were extracted from the derivation data set. Three expert stroke physicians reviewed baseline imaging and clinical data for the test set. The machine learning (ML) models were compared to the three experts in predicting the primary outcome (FPE) in the test set using area under the receiver operating characteristic curves (AUC-ROC). Results: A total of 554 patients with available thin-slice images comprised of a derivation set (training subset [n=388, 70%]), validation subset [n=55, 10%]), and a test set (n=111, 20%). FPE was seen in 31.8% in the derivation set and 31.5 % in the test set. AUC of the best radiomics model was 0.74 (95% CI: 0.64, 0.84), which was higher than the mean AUC of the three experts 0.60 (95% CI: 0.50, 0.71) ( P =0.009). Specificity of radiomics was better than the mean specificity of the three experts, 46 of 76 (60%) vs. 35 of 76 (46.4%), P =0.004, whereas sensitivity was not significantly different between radiomics (28 of 35 [79%]) and experts (27 of 35 [77%]). Moreover, radiomics features performed better than non-radiomics features such as thrombus volume and permeability measurements in predicting FPE ( P Conclusion: A radiomics-based ML model of thrombus characteristics on non-contrast CT and CT angiography performs better than experts and non-radiomics image characteristics in predicting FPE in patients with acute stroke treated with EVT.

Endovascular treatment (EVT) is a powerful treatment for large vessel occlusion (LVO) stroke if reperfusion can be achieved, while in cases with failed reperfusion, EVT may cause harm, as procedure-related complications may occur. We hypothesized that EVT with failed recanalization does not result in worse outcomes compared to best medical management and compared clinical outcomes of LVO stroke patients who underwent EVT with failed reperfusion to those who were treated with best medical management.We included patients with failed reperfusion from the control (EVT-only) arm of the ESCAPE-NA1 trial and the EVT arm of the ESCAPE trial and patients of the ESCAPE control arm who were treated with best medical management. Failed reperfusion following EVT was defined as modified thrombolysis in cerebral infarction score 0-2a. Proportions of good outcome (modified Rankin scale 0-2) were compared between patients who did and did not undergo EVT, and adjusted effect size estimates for EVT on outcomes were obtained.We included 260 patients (110 failed EVT and 150 non-EVT patients). Proportions of good outcome were 38/110 (34.6%) with failed EVT vs.43/147 (29.3%) without EVT (adjusted odds ratio[aOR]: 1.48 [95%CI: 0.81-2.68]). Mortality and proportions of sICH in the failed EVT group vs. patients treated with best medical management were 26/110 (23.6%) vs. 28/147 (19.1%), aOR: 1.12 (95%CI: 0.56-2.24), and 7/110 (6.4%) vs. 4/150 (2.7%), aOR: 2.34 (95%CI: 0.00-22.97).Clinical outcomes of EVT patients with failed reperfusion did not differ significantly from patients treated with best medical management.

There are few data on the prevalence and impact of isolated deep grey matter infarction in acute stroke. In this study, we aimed to investigate the prevalence of isolated deep grey matter infarcts and their impact on the outcome.Infarcts on 24-h follow-up imaging (non-contrast head CT or diffusion-weighted MRI) in the ESCAPE-NA1 trial were categorized into predominantly deep grey matter infarcts vs. infarcts involving additional territories ("other infarcts"). Total infarct volume was manually segmented. Baseline characteristics and proportions of good outcome (primary outcome, defined as modified Rankin Score [mRS] 0-2 at 90 days), excellent outcome (mRS 0-1) and mortality were compared between patients with and without predominantly deep grey matter infarcts. Multivariable logistic regression with adjustment for baseline variables and total infarct volume was used to determine a possible association of predominantly deep grey matter infarcts and clinical outcome.Predominantly deep grey matter infarcts were seen in 316/1026 patients (30.8%). Compared to other patients, their ASPECTS was higher, collateral status and reperfusion quality were better and time to treatment was shorter. Good outcome was seen in 239/316 (75.6%) with vs. 374/704 (53.1%) without predominantly deep grey matter infarcts. After adjusting for baseline variables and total infarct volume, predominantly deep grey matter infarcts were independently associated with excellent outcome (

BACKGROUNDPatients with acute stroke due to tandem occlusion, the benefit of immediate revascularisation (stenting) of the cervical internal carotid artery (ICA) lesion during the endovascular thrombectomy (EVT) procedure is uncertain. We sought to determine current practice patterns and whether equipoise existed in a community of physicians with stroke expertise.METHODWe distributed an online survey to stroke experts affiliated with the Canadian Stroke Consortium, the Canadian Interventional Neuro Group, the Society of Vascular and Interventional Neurology and international ESCAPE trial collaborators. Questions were based on clinical scenarios and multiple-choice questions across a Likert-type scale were provided. The survey was sent out in September 2017. After two months, data were extracted and then analyzed using descriptive statistics. RESULTSResponses from 162 stroke experts, primarily stroke physicians (N=65, 40.1%) and neuro-interventionalists (N=74, 45.7%), from Canada (N=95, 58.6%), the United States (N=42, 25.9%) and other countries (N=25, 15.4%) were analyzed. Over half (N=96, 59.7%) of respondents consider acute stenting of the cervical ICA as a treatment option (either rarely, occasionally, usually or always) versus 40,3% (N=66) who would never use it. Most respondents (N=113, 75%) agree that there exists equipoise or uncertainty regarding the optimal acute management of patients with tandem occlusion. A majority (N=88, 58.2%) of physicians surveyed would include patients in a trial addressing this question.CONCLUSIONThis survey shows high variability in practice regarding acute management of tandem lesions. The existence of community equipoise underscores the importance of a randomized clinical trial evaluating the benefit of acute ICA stenting in patients with tandem occlusion undergoing EVT.

Background: Until recently, clinical benefits of endovascular stroke treatment remained unproven. Care trials can be used to simultaneously offer yet-to-be validated interventions and verify treatment outcomes. Our aim was to implement care trial methodology for patients with severe acute ischemic stroke. Methods: The study was offered to all patients considered for endovascular management of acute ischemic stroke in one Canadian hospital. Inclusion criteria were broad: onset of symptoms ≤ 5h or at any time in the presence of clinical-imaging mismatch; suspected anterior or posterior circulation large vessel occlusion; patients eligible or ineligible for intravenous thrombolysis. Exclusion criteria were few: established infarction or hemorrhagic transformation of the target symptomatic territory; poor 3-month prognosis from comorbidities. The primary outcome was mRS ≤ 2 at three months. Patients were randomly allocated to standard care (control) or standard care plus endovascular treatment (intervention group). Analyses were by intention-to-treat. (Identifier NCT02157532) Findings: Seventy-seven patients were recruited in 19 months (March 2013 - October 2014) at a single center. Randomized allocation was interrupted when other trials showed the benefits of endovascular therapy. At three months, 20 of 40 patients (50·0 %; 95% C.I.: 35%-65%) in the intervention group had reached the primary outcome, compared to 14 of 37 patients (37·8%; 95% C.I.: 24%-54%) in the control group arm (P=0·36). Eleven patients in the intervention arm died within 3 months compared to 9 patients in the standard care arm. Interpretation: EASI met all the characteristics of a care trial: inclusion of all eligible patients, no extra risk, no extra test, no extra cost, simple case report forms filled by care personnel, normal follow-up, involvement of all regular practitioners, and flexible care. The trial was prematurely interrupted, but this approach offers a promising means to manage clinical dilemmas and guide uncertain practices in the care of patients. Funding: There was no funding source for this study.