Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Combining Early Ischemic Change and Collateral Extent for Functional Outcomes After Endovascular Therapy: An Analysis From AcT Trial.

BACKGROUND: Early ischemic change and collateral extent are colinear with ischemic core volume (ICV). We investigated the relationship between a combined score using the Alberta Stroke Program Early Computed Tomography Score and multiphase computed tomography angiography (mCTA) collateral extent, named mCTA-ACE score, on functional outcomes in endovascular therapy-treated patients. METHODS: We performed a post hoc analysis of a subset of endovascular therapy-treated patients from the Alteplase Compared to Tenecteplase trial which was conducted between December 2019 and January 2022 at 22 centers across Canada. Ten-point mCTA collateral corresponding to M2 to M6 regions of the Alberta Stroke Program Early Computed Tomography Score grid was evaluated as 0 (poor), 1 (moderate), or 2 (normal) and additively combined with the 10-point Alberta Stroke Program Early Computed Tomography Score to produce a 20-point mCTA-ACE score. We investigated the association of mCTA-ACE score with modified Rankin Scale score ≤2 and return to prestroke level of function at 90 to 120 days using mixed-effects logistic regression. In the subset of patients who underwent baseline computed tomography perfusion imaging, we compared the mCTA-ACE score and ICV for outcome prediction. RESULTS: Among 1577 intention-to-treat population in the trial, 368 (23%; 179 men; median age, 73 years) were included, with Alberta Stroke Program Early Computed Tomography Score, mCTA collateral, and combination of both (mCTA-ACE score: median [interquartile range], 8 [7-10], 9 [8-10], and 17 [16-19], respectively). The probability of modified Rankin Scale score ≤2 and return to prestroke level of function increased for each 1-point increase in mCTA-ACE score (odds ratio, 1.16 [95% CI, 1.06-1.28] and 1.22 [95% CI, 1.06-1.40], respectively). Among 173 patients in whom computed tomography perfusion data was assessable, the mCTA-ACE score was inversely correlated with ICV (ρ=-0.46; P<0.01). The mCTA-ACE score was comparable to ICV to predict a modified Rankin Scale score ≤2 and return to prestroke level of function (C statistics 0.71 versus 0.69 and 0.68 versus 0.64, respectively). CONCLUSIONS: The mCTA-ACE score had a significant positive association with functional outcomes after endovascular therapy and had a similar predictive performance as ICV.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Effect of Needle-To-Puncture Time on Reperfusion Outcome in Acute Ischemic Stroke.

INTRODUCTION: The aim of the study was to investigate the impact of time interval between start of intravenous thrombolysis (IVT) to start of endovascular thrombectomy (EVT) on stroke outcomes. METHODS: Data from the Quality Improvement and Clinical Research (QuICR) provincial stroke registry from Alberta, Canada, were used to identify stroke patients who received IVT and EVT from January 2015 to December 2019. We assessed the impact of the time interval between IVT bolus to EVT puncture (needle-to-puncture times [NPT]) on outcomes. Radiological outcomes included successful initial recanalization (revised Arterial Occlusive Lesion 2b-3), successful initial and final reperfusion (modified thrombolysis in cerebral infarction 2b-3). Clinical outcomes were 90-day modified Rankin Scale (mRS) and mortality. RESULTS: Of the 680 patients, 233 patients (median age: 73, 41% females) received IVT + EVT. Median NPT was 38 min (IQR, 24-60). Arrival during working hours was independently associated with shorter NPT (p < 0.001). Successful initial recanalization and initial and final reperfusion were observed in 12%, 10%, and 83% of patients, respectively. NPT was not associated with initial successful recanalization (OR 0.97 for every 10-min increase of NPT, 95% CI: 0.91-1.04), initial successful reperfusion (OR 1.01, 95% CI: 0.96-1.07), or final successful reperfusion (OR: 1.03, 95% CI: 0.97-1.08). Every 10-min delay in NPT was associated with lower odds of functional independence at 90 days (mRS ≤2; OR: 0.93; 95% CI, 0.88-0.97). Patients with shorter NPT (≤38 min) had lower 90-day mRS scores (median 1 vs. 3; OR: 0.54 [0.31-0.91]) and had lower mortality (6.1% vs. 21.2%; OR, 0.23 [0.10-0.57]) than the longer NPT group. CONCLUSION: Shorter NPT did not impact reperfusion outcomes but was associated with better clinical outcome.

Intravenous alteplase versus tenecteplase in patients with acute posterior circulation strokes: A secondary analysis from the AcT randomized controlled trial.

OBJECTIVES: There are limited data available demonstrating the safety and efficacy of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke in the posterior circulation. MATERIALS AND METHODS: This is a post-hoc analysis of the Alteplase compared to Tenecteplase (AcT) pragmatic, phase 3, registry-linked randomized controlled trial. Patients with any posterior circulation vessel occlusion on baseline imaging were included. Study outcomes included 90-day modified Rankin Scale (mRS) 0-1, mRS 0-2, ordinal mRS, death within 90 days, 24 h symptomatic intracerebral haemorrhage (sICH) and successful reperfusion/recanalization. Mixed effects regression adjusting for age, sex and stroke severity was used to analyze differences in outcomes between patients administered tenecteplase vs. alteplase. Further, sensitivity analysis was conducted for basilar artery occlusion (BAO) alone. RESULTS: Of 1577 patients, 136 (8.6 %, 77:alteplase, 59:tenecteplase) had posterior circulation stroke. Baseline characteristics were similar[median age 71 (IQR 60-81) vs. 72 (IQR 65-82) years, 57.1 % vs. 67.8 % males, median baseline NIHSS 7 (IQR 4-12) vs. 7 (IQR 4-16) in alteplase vs. tenecteplase arms, respectively]. 28 patients (20.6 %, 16:alteplase, 12:tenecteplase arm) underwent EVT. The median 90-120 days mRS was 2 (IQR 1-4). There were no differences between alteplase and tenecteplase for 90-d mRS 0-1 (adjRR 0.93;95 %CI 0.63-1.36), 90-day mRS 0-2 (adjRR 0.95; 95 %CI 0.72-1.26), sICH (RR 0.65; 95 %CI 0.06-7.02) and mortality (RR 1.21; 95 %CI 0.61-2.38). Successful reperfusion eTICI 2b-3 and successful recanalization rAOL 2b-3 was achieved in 23/28 (82 %, 12:alteplase, 11:tenecteplase) and in 16/28 (57 %, 14:alteplase, 12:tenecteplase), respectively. Similar results were seen in 31 patients (22.8 %) with BAO. CONCLUSION: Intravenous tenecteplase has a similar effect on outcome as alteplase, without increased safety concerns in patients with acute posterior circulation strokes.

Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. FUNDING: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Vertebral to Basilar Thrombus Migration Post Intravenous Thrombolysis.

Recombinant tissue plasminogen activator improves outcomes in acute ischemic stroke. Alteplase may result in thrombus migration (TM) distally to a critical arterial supply that can worsen perfusion to eloquent brain tissue. Alteplase-related stroke recanalization and clot migration in vertebral artery (VA) occlusion whereby the clot migrates to the basilar artery (BA) may be harmful. We identified seven subjects with isolated symptomatic vertebral occlusion. Two cases suffered early neurologic deterioration due to TM from VA to BA following alteplase. Precautionary transfer to thrombectomy centers may be warranted in alteplase-treated symptomatic VA occlusions in case of migration to basilar occlusion.

Thrombus Migration and Fragmentation After Intravenous Alteplase Treatment: The INTERRSeCT Study.

BACKGROUND AND PURPOSE: There is interest in what happens over time to the thrombus after intravenous alteplase. We study the effect of alteplase on thrombus structure and its impact on clinical outcome in patients with acute stroke. METHODS: Intravenous alteplase treated stroke patients with intracranial internal carotid artery or middle cerebral artery occlusion identified on baseline computed tomography angiography and with follow-up vascular imaging (computed tomography angiography or first run of angiography before endovascular therapy) were enrolled from INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography). Thrombus movement after intravenous alteplase was classified into complete recanalization, thrombus migration, thrombus fragmentation, and no change. Thrombus migration was diagnosed when occlusion site moved distally and graded according to degrees of thrombus movement (grade 0-3). Thrombus fragmentation was diagnosed when a new distal occlusion in addition to the primary occlusion was identified on follow-up imaging. The association between thrombus movement and clinical outcome was also evaluated. RESULTS: Among 427 patients in this study, thrombus movement was seen in 54% with a median time of 123 minutes from alteplase administration to follow-up imaging, and sub-classified as marked (thrombus migration grade 2-3 + complete recanalization; 27%) and mild to moderate thrombus movement (thrombus fragmentation + thrombus migration grade 0-1; 27%). In patients with proximal M1/internal carotid artery occlusion, marked thrombus movement was associated with a higher rate of good outcome (90-day modified Rankin Scale, 0-2) compared with mild to moderate movement (52% versus 27%; adjusted odds ratio, 5.64 [95% CI, 1.72-20.10]). No difference was seen in outcomes between mild to moderate thrombus movement and no change. In M1 distal/M2 occlusion, marked thrombus movement was associated with improved 90-day good outcome compared with no change (70% versus 56%; adjusted odds ratio, 2.54 [95% CI, 1.21-5.51]). CONCLUSIONS: Early thrombus movement is common after intravenous alteplase. Marked thrombus migration leads to good clinical outcomes. Thrombus dynamics over time should be further evaluated in clinical trials of acute reperfusion therapy.

Total intracranial hemorrhage volume measurement summating all compartments best in traumatic and nontraumatic intracranial bleeding.

BACKGROUND AND PURPOSE: The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume. METHODS: Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4. RESULTS: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. CONCLUSION: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes.

Co-localization of NCCT hypodensity and CTA spot sign predicts substantial intracerebral hematoma expansion: The Black-&-White sign.

BACKGROUND: Existing radiological markers of hematoma expansion (HE) show modest predictive accuracy. We aim to investigate a novel radiological marker that co-localizes findings from non-contrast CT (NCCT) and CT angiography (CTA) to predict HE. METHODS: Consecutive acute intracerebral hemorrhage patients admitted at Foothills Medical Centre in Calgary, Canada, were included. The Black-&-White sign was defined as any visually identified spot sign on CTA co-localized with a hypodensity sign on the corresponding NCCT. The primary outcome was hematoma expansion (⩾6 mL or ⩾33%). Secondary outcomes included absolute (<3, 3-6, 6-12, ⩾12 mL) and relative (0%, <25%, 25%-50%, 50%-75%, or >75%) hematoma growth scales. RESULTS: Two-hundred patients were included, with 50 (25%) experiencing HE. Forty-four (22%) showed the spot sign, 69 (34.5%) the hypodensity sign, and 14 (7%) co-localized both as the Black-&-White sign. Those with the Black-&-White sign had higher proportions of HE (100% vs 19.4%, p < 0.001), greater absolute hematoma growth (23.37 mL (IQR = 15.41-30.27) vs 0 mL (IQR = 0-2.39), p < 0.001) and relative hematoma growth (120% (IQR = 49-192) vs 0% (0-15%), p < 0.001). The Black-&-White sign had a specificity of 100% (95%CI = 97.6%-100%), a positive predictive value of 100% (95%CI = 76.8%-100%), and an overall accuracy of 82% (95%CI = 76%-87.1%). Among the 14 patients with the Black-&-White sign, 13 showed an absolute hematoma growth ⩾12 mL, and 10 experienced a HE exceeding 75% of the initial volume. The inter-rater agreement was excellent (kappa coefficient = 0.84). CONCLUSION: The Black-&-White sign is a robust predictor of hematoma expansion occurrence and severity, yet further validation is needed to confirm these compelling findings.

Tenecteplase Versus Alteplase in Medium Vessel Occlusion Ischemic Stroke: A Secondary Analysis of the Alteplase Compared to Tenecteplase Randomized Trial.

BACKGROUND AND PURPOSE: The safety and efficacy of tenecteplase in patients with ischemic stroke due to medium vessel occlusion (MeVO) are not well studied. We aimed to compare tenecteplase with alteplase in stroke due to MeVO. METHODS: Patients with baseline M2-middle cerebral artery (MCA), M3/M4-MCA, P2/P3/P4-posterior cerebral artery (PCA), A2/A3/A4-anterior cerebral artery (ACA) occlusions from the Alteplase Compared to Tenecteplase (AcT) trial were included. Primary outcome was the proportion of 90-day modified Rankin Scale (mRS) 0-1. Secondary outcomes were 90-day mRS 0-2, ordinal mRS, mortality, quality of life measures (EuroQol 5-Dimension 5-Level, EuroQol visual analog scale), and symptomatic intracerebral hemorrhage (sICH). Initial and final successful reperfusion were reported in patients undergoing endovascular thrombectomy (EVT). RESULTS: Among 1,558 patients with available baseline computed tomography angiography; 455 (29.2%) had MeVO of which 27.5% (125/455) were proximal M2; 16.3% (74/455) were distal M2; 35.2% (160/455) were M3/M4; 7.5% (34/455) were A2/A3/A4; and 13.6% (62/455) were P2/P3/P4 occlusions. EVT was performed in 87/455 (19.1%) patients. mRS 0-1 at 90 days was achieved in 37.9% in the tenecteplase versus 34.7% in the alteplase group (adjusted risk ratio [aRR] 1.07; 95% confidence interval [CI] 0.91-1.25). Rates of 90-day mRS 0-2, sICH, and mortality were similar in both groups. No statistical difference was noted in initial successful reperfusion rates (13.0% vs. 7.5%) among the 87 patients who underwent endovascular thrombectomy. However, final successful reperfusion was higher in the tenecteplase group (71.7% vs. 60.0%, aRR 1.29, 95% CI 1.04-1.61). CONCLUSION: Intravenous tenecteplase had comparable safety, functional outcomes and quality of life compared to intravenous alteplase among patients with MeVO. Among those treated with EVT, tenecteplase was associated with higher successful reperfusion rates than alteplase.

Timing of Spot Sign Appearance, Spot Sign Volume, and Leakage Rate among Phases of Multiphase CTA Predict Intracerebral Hemorrhage Growth.

BACKGROUND AND PURPOSE: The presence of spot sign is associated with a high risk of hematoma growth. Our aim was to investigate the timing of the appearance, volume, and leakage rate of the spot sign for predicting hematoma growth in acute intracerebral hemorrhage using multiphase CTA. MATERIALS AND METHODS: In this single-center retrospective study, multiphase CTA in 3 phases was performed in acute intracerebral hemorrhage (defined as intraparenchymal ± intraventricular hemorrhages). Phases of the spot sign first appearance, spot sign volumes (microliter), and leakage rates among phases (microliter/second) were measured. Associations between baseline clinical and imaging variables including spot sign volume parameters (volume and leakage rate divided by median) and hematoma growth (>6 mL) were investigated using regression models. Receiver operating characteristic analysis was used as appropriate. RESULTS: Two hundred seventeen patients (131 men; median age, 70 years) were included. The spot sign was detected in 21.7%, 30.0%, and 29.0% in the first, second, and third phases, respectively, with median volumes of 19.7, 31.4, and 34.8 µl in these phases. Hematoma growth was seen in 44 patients (20.3%). By means of modeling, the following variables, namely the spot sign appearing in the first phase, first phase spot sign volume, spot sign appearing in the second or third phase, and spot sign positive and negative leakage rates, were associated with hematoma growth. Among patients with a spot sign, the absolute leakage rate accounting for both positive and negative leakage rates was also associated with hematoma growth (per 1-µl/s increase; OR, 1.26; 95% CI, 1.04-1.52). Other hematoma growth predictors were stroke history, baseline NIHSS score, onset-to-imaging time, and baseline hematoma volume (all P values < .05). CONCLUSIONS: The timing of the appearance of the spot sign, volume, and leakage rate were all associated with hematoma growth. Development of automated software to generate these spot sign volumetric parameters would be an important next step to maximize the potential of temporal intracerebral hemorrhage imaging such as multiphase CTA for identifying those most at risk of hematoma growth.

Intravenous tenecteplase compared with alteplase for minor ischaemic stroke: a secondary analysis of the AcT randomised clinical trial.

BACKGROUND: In ischaemic stroke, minor deficits (National Institutes of Health Stroke Scale (NIHSS) ≤5) at presentation are common but often progress, leaving patients with significant disability. We compared the efficacy and safety of intravenous thrombolysis with tenecteplase versus alteplase in patients who had a minor stroke enrolled in the Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT) trial. METHODS: The AcT trial included individuals with ischaemic stroke, aged >18 years, who were eligible for standard-of-care intravenous thrombolysis. Participants were randomly assigned 1:1 to intravenous tenecteplase (0.25 mg/kg) or alteplase (0.9 mg/kg). Patients with minor deficits pre-thrombolysis were included in this post-hoc exploratory analysis. The primary efficacy outcome was the proportion of patients with a modified Rankin Score (mRS) of 0-1 at 90-120 days. Safety outcomes included mortality and symptomatic intracranial haemorrhage (sICH). RESULTS: Of the 378 patients enrolled in AcT with an NIHSS of ≤5, the median age was 71 years, 39.7% were women; 194 (51.3%) received tenecteplase and 184 (48.7%) alteplase. The primary outcome (mRS score 0-1) occurred in 100 participants (51.8%) in the tenecteplase group and 86 (47.5 %) in the alteplase group (adjusted risk ratio (RR) 1.14 (95% CI 0.92 to 1.40)). There were no significant differences in the rates of sICH (2.9% in tenecteplase vs 3.3% in alteplase group, unadjusted RR 0.79 (0.24 to 2.54)) and death within 90 days (5.5% in tenecteplase vs 11% in alteplase group, adjusted HR 0.99 (95% CI 0.96 to 1.02)). CONCLUSION: In this post-hoc analysis of patients with minor stroke enrolled in the AcT trial, safety and efficacy outcomes with tenecteplase 0.25 mg/kg were not different from alteplase 0.9 mg/kg.

The treatment effect across ASPECTS in acute ischemic stroke: Analysis from the AcT trial.

BACKGROUND: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication. AIMS: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase and Alteplase. METHODS: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-h symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed-effects logistic regression was used to assess the association of ASPECTS (continuous and categorical (0-4 vs 5-7 vs 8-10)) with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity. RESULTS: Of the 1577 patients in the trial, 901 patients (56.3%; median age 75 years (IQR 65-84), 50.8% females, median National Institute of Health Stroke Scale (NIHSS) 14 (IQR 17-19)) with anterior circulation stroke were included. mRS 0-1 at 90 days was achieved in 1/14 (0.3%), 43/160 (14.7%), and 252/726 (85.1%) in the ASPECTS 0-4, 5-7, and 8-10 groups respectively. Every one-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in endovascular thrombectomy (EVT)-treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P-interaction 0.75). There was no significant interaction by thrombolytic type with any other outcomes. CONCLUSION: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase. DATA ACCESS STATEMENT: Data shall made available on reasonable request from the PI (BMM).

Safety and efficacy of tenecteplase versus alteplase in stroke patients with carotid tandem lesions: Results from the AcT trial.

BACKGROUND: Carotid tandem lesions ((TL) ⩾70% stenosis or occlusion) account for 15-20% of acute stroke with large vessel occlusion. AIMS: We investigated the safety and efficacy of intravenous tenecteplase (0.25 mg/kg) versus intravenous alteplase (0.9 mg/kg) in patients with carotid TL. METHODS: This is a substudy of the alteplase compared with the tenecteplase trial. Patients with ⩾70% stenosis of the extracranial internal carotid artery (ICA) and concomitant occlusion of the intracranial ICA, M1 or M2 segments of the middle cerebral artery on baseline computed tomography angiography (CTA) were included. Primary outcome was 90-day-modified Rankin Scale (mRS) 0-1. Secondary outcomes were mRS 0-2, mortality, and symptomatic ICH (sICH). Angiographic outcomes were successful recanalization (revised Arterial Occlusive Lesion (rAOL) 2b-3) on first and successful reperfusion (eTICI 2b-3) on final angiographic acquisitions. Multivariable mixed-effects logistic regression was performed. RESULTS: Among 1577 alteplase versus tenecteplase randomized controlled trial (AcT) patients, 128 (18.8%) had carotid TL. Of these, 93 (72.7%) underwent intravenous thrombolysis plus endovascular thrombectomy (IVT + EVT), while 35 (27.3%) were treated with IVT alone. In the IVT + EVT group, tenecteplase was associated with higher odds of 90-day-mRS 0-1 (46.0% vs. 32.6%, adjusted OR (aOR) 3.21; 95% CI = 1.06-9.71) compared with alteplase. No statistically significant differences in rates of mRS 0-2 (aOR 1.53; 95% CI = 0.51-4.55), initial rAOL 2b-3 (16.3% vs. 28.6%), final eTICI 2b-3 (83.7% vs. 85.7%), and mortality (18.0% vs. 16.3%) were found. SICH only occurred in one patient. There were no differences in outcomes between thrombolytic agents in the IVT-only group. CONCLUSION: In patients with carotid TL treated with EVT, intravenous tenecteplase may be associated with similar or better clinical outcomes, similar angiographic reperfusion rates, and safety outcomes as compared with alteplase.

Prediction of 90 day home time among patients with low baseline ASPECTS undergoing endovascular thrombectomy: results from Alberta's Provincial Stroke Registry (QuICR).

BACKGROUND: The benefit of endovascular thrombectomy (EVT) in stroke patients with a low baseline Alberta Stroke Program Early CT Score (ASPECTS, ≤5) is uncertain. We aim to use random forest regression modeling to predict 90 day home time in patients with low ASPECTS. METHODS: We used the Quality Improvement and Clinical Research (QuICR) provincial stroke registry and administrative data from southern Alberta to identify patients who underwent EVT in our center from July 2015 to November 2020. Baseline ASPECTS on non-contrast CT and CT angiography data were scored by a two physician consensus. The primary outcome was the predicted 90 day home time (the number of nights a patient is back at their premorbid living situation without an increase in level of care within 90 days of the stroke) using random forests regression. Estimates were generated using 200 bootstrapped datasets. Covariate contribution to home time was determined using partial dependence plots. RESULTS: Of 657 EVT patients, 85 (12.9%) had baseline ASPECTS ≤5 (mean age 70.9 years, 44.7% women, 93.9% good-moderate collaterals, 60% M1-middle cerebral artery occlusion). Using partial dependence estimates, mean predicted home times were similar in the low ASPECTS (44.3 days) versus higher ASPECTS (43.1) groups. Factors predicting lower 90 day home time in this population were diabetes mellitus (-8.8 days), hypertension (-5.7 days), and atrial fibrillation (-3.6 days). There was no meaningful difference in predicted 90 day home time by sex, baseline National Institutes of Health Stroke Severity Scale score, occlusion site, tandem lesion, collateral grade or thrombolysis. CONCLUSIONS: Patients with low ASPECTS who are selected for EVT using demographic and clinical profiles similar to higher ASPECTS patients achieved comparable outcomes.

Safety and Efficacy of Tenecteplase Compared With Alteplase in Patients With Large Vessel Occlusion Stroke: A Prespecified Secondary Analysis of the ACT Randomized Clinical Trial.

Importance: It is unknown whether intravenous thrombolysis using tenecteplase is noninferior or preferable compared with alteplase for patients with acute ischemic stroke. Objective: To examine the safety and efficacy of tenecteplase compared to alteplase among patients with large vessel occlusion (LVO) stroke. Design, Setting, and Participants: This was a prespecified analysis of the Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada (ACT) randomized clinical trial that enrolled patients from 22 primary and comprehensive stroke centers across Canada between December 10, 2019, and January 25, 2022. Patients 18 years and older with a disabling ischemic stroke within 4.5 hours of symptom onset were randomly assigned (1:1) to either intravenous tenecteplase or alteplase and were monitored for up to 120 days. Patients with baseline intracranial internal carotid artery (ICA), M1-middle cerebral artery (MCA), M2-MCA, and basilar occlusions were included in this analysis. A total of 1600 patients were enrolled, and 23 withdrew consent. Exposures: Intravenous tenecteplase (0.25 mg/kg) vs intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures: The primary outcome was the proportion of modified Rankin scale (mRS) score 0-1 at 90 days. Secondary outcomes were an mRS score from 0 to 2, mortality, and symptomatic intracerebral hemorrhage. Angiographic outcomes were successful reperfusion (extended Thrombolysis in Cerebral Infarction scale score 2b-3) on first and final angiographic acquisitions. Multivariable analyses (adjusting for age, sex, National Institute of Health Stroke Scale score, onset-to-needle time, and occlusion location) were carried out. Results: Among 1577 patients, 520 (33.0%) had LVO (median [IQR] age, 74 [64-83] years; 283 [54.4%] women): 135 (26.0%) with ICA occlusion, 237 (45.6%) with M1-MCA, 117 (22.5%) with M2-MCA, and 31 (6.0%) with basilar occlusions. The primary outcome (mRS score 0-1) was achieved in 86 participants (32.7%) in the tenecteplase group vs 76 (29.6%) in the alteplase group. Rates of mRS 0-2 (129 [49.0%] vs 131 [51.0%]), symptomatic intracerebral hemorrhage (16 [6.1%] vs 11 [4.3%]), and mortality (19.9% vs 18.1%) were similar in the tenecteplase and alteplase groups, respectively. No difference was noted in successful reperfusion rates in the first (19 [9.2%] vs 21 [10.5%]) and final angiogram (174 [84.5%] vs 177 [88.9%]) among 405 patients who underwent thrombectomy. Conclusions and Relevance: The findings in this study indicate that intravenous tenecteplase conferred similar reperfusion, safety, and functional outcomes compared to alteplase among patients with LVO.

Non-invasive Brain Temperature Measurement in Acute Ischemic Stroke.

Selective therapeutic hypothermia in the setting of mechanical thrombectomy (MT) is promising to further improve the outcomes of large vessel occlusion stroke. A significant limitation in applying hypothermia in this setting is the lack of real-time non-invasive brain temperature monitoring mechanism. Non-invasive brain temperature monitoring would provide important information regarding the brain temperature changes during cooling, and the factors that might influence any fluctuations. This review aims to provide appraisal of brain temperature changes during stroke, and the currently available non-invasive modalities of brain temperature measurement that have been developed and tested over the past 20 years. We cover modalities including magnetic resonance spectroscopy imaging (MRSI), radiometric thermometry, and microwave radiometry, and the evidence for their accuracy from human and animal studies. We also evaluate the feasibility of using these modalities in the acute stroke setting and potential ways for incorporating brain temperature monitoring in the stroke workflow.

MRI Diffusion-Weighted Imaging to Measure Infarct Volume: Assessment of Manual Segmentation Variability.

BACKGROUND AND PURPOSE: Manual segmentation of infarct volume on follow-up MRI diffusion-weighted imaging (MRI-DWI) is considered the gold standard but is prone to rater variability. We assess the variability of manual segmentations of MRI-DWI infarct volume. METHODS: Consecutive patients (May 2018 to May 2019) with the anterior circulation stroke and endovascularly treated were enrolled. All patients underwent 24- to 32-hour follow-up MRI. Three users manually segmented DWI infarct volumes slice by slice twice. The reference standard of DWI infarct volume was generated by the STAPLE algorithm. Intra- and interrater reliability was evaluated using the intraclass correlation coefficient (ICC) by comparing manual segmentations with the reference standard. Spatial measurements were evaluated using metrics of the Dice similarity coefficient (DSC). Volumetric measurements were compared using the lesion volume. RESULTS: The dataset consisted of 44 patients, mean (SD) age was 70.1 years (±10.3), 43% were women, and median baseline NIHSS score was 16. Among three users, the mean DSC for MRI-DWI infarct volume segmentations ranged from 80.6% ± 11.7% to 88.6% ± 7.5%, and the mean absolute volume difference was 2.8 ± 6.8 to 13.0 ± 14.0 ml. Interrater ICC among the users for DSC and infarct volume was .86 (95% confidence interval [95% CI]: .78-.91) and .997 (95% CI: .995-.998). Intrarater ICC for the three users was .83 (95% CI: .69-.93), .84 (95% CI: .72-.91), and .80 (95% CI: .64-.89) for DSC, and .99 (95% CI: .987-.996), .991 (95% CI: .983-.995), and .996 (95% CI: .993-.998) for infarct volume. CONCLUSIONS: Manual segmentation of infarct volume on follow-up MRI-DWI shows excellent agreement and good spatial overlap with the reference standard, suggesting its usefulness for measuring infarct volume on 24- to 32-hour MRI-DWI.

Semi-automatic measurement of intracranial hemorrhage growth on non-contrast CT.

BACKGROUND: Manual segmentations of intracranial hemorrhage on non-contrast CT images are the gold-standard in measuring hematoma growth but are prone to rater variability. AIMS: We demonstrate that a convex optimization-based interactive segmentation approach can accurately and reliably measure intracranial hemorrhage growth. METHODS: Baseline and 16-h follow-up head non-contrast CT images of 46 subjects presenting with intracranial hemorrhage were selected randomly from the ANNEXA-4 trial imaging database. Three users semi-automatically segmented intracranial hemorrhage to measure hematoma volume for each timepoint using our proposed method. Segmentation accuracy was quantitatively evaluated compared to manual segmentations by using Dice similarity coefficient, Pearson correlation, and Bland-Altman analysis. Intra- and inter-rater reliability of the Dice similarity coefficient and intracranial hemorrhage volumes and volume change were assessed by the intraclass correlation coefficient and minimum detectable change. RESULTS: Among the three users, the mean Dice similarity coefficient, Pearson correlation, and mean difference ranged from 76.79% to 79.76%, 0.970 to 0.980 (p < 0.001), and -1.5 to -0.4 ml, respectively, for all intracranial hemorrhage segmentations. Inter-rater intraclass correlation coefficients between the three users for Dice similarity coefficient and intracranial hemorrhage volume were 0.846 and 0.962, respectively, and the corresponding minimum detectable change was 2.51 ml. Inter-rater intraclass correlation coefficient for intracranial hemorrhage volume change ranged from 0.915 to 0.958 for each user compared to manual measurements, resulting in an minimum detectable change range of 2.14 to 4.26 ml. CONCLUSIONS: We spatially and volumetrically validate a novel interactive segmentation method for delineating intracranial hemorrhage on head non-contrast CT images. Good spatial overlap, excellent volume correlation, and good repeatability suggest its usefulness for measuring intracranial hemorrhage volume and volume change on non-contrast CT images.