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.

Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions: The ESCAPE-MeVO trial.

RATIONALE: Clinical outcomes in acute ischemic stroke due to medium vessel occlusion (MeVO) are often poor when treated with best medical management. Data from non-randomized studies suggest that endovascular treatment (EVT) may improve outcomes in MeVO stroke, but randomized data on potential benefits and risks are hitherto lacking. Thus, there is insufficient evidence to guide endovascular treatment decision-making in MeVO stroke. AIM: The primary aim of the ESCAPE-MeVO trial is to demonstrate that acute, rapid EVT in patients with acute ischemic stroke due to MeVO results in better clinical outcomes compared to best medical management. Secondary outcomes are to demonstrate the safety of EVT, its impact on self-reported health-related quality of life, and cost-effectiveness. SAMPLE SIZE ESTIMATES: Based on previously published data, we estimate a sample size of 500 subjects to achieve a power of 85% with a two-sided alpha of 0.05. To account for potential loss to follow-up, 530 subjects will be recruited. METHODS AND DESIGN: ESCAPE-MeVO is a multicenter, prospective, randomized, open-label study with blinded endpoint evaluation (PROBE design), clinicaltrials.gov: NCT05151172. Subjects with acute ischemic stroke due to MeVO meeting the trial eligibility criteria will be allocated in a 1:1 ratio to best medical care plus EVT vs. best medical care only. Patients will be screened only at comprehensive stroke centers to determine if they are eligible for the trial, regardless of whether they were previously treated at a primary care center. Key eligibility criteria are 1) acute ischemic stroke due to MeVO that is clinically and technically eligible for EVT, 2) last-known well within the last 12 hours, 3) National Institutes of Health Stroke Scale >5 or 3-5 with disabling deficit, 4) high likelihood of salvageable tissue on non-invasive neuroimaging. STUDY OUTCOMES: The primary outcome is the modified Rankin scale 90 days after randomization (shift analysis), whereby modified Rankin Score 5 and 6 will be collapsed into one category. Secondary outcomes include dichotomizations of the modified Rankin Score at 90 days, 24-hour National Institutes of Health Stroke Score, difference between 24-hour and baseline National Institutes of Health Stroke Score, mortality at 90 days, health-related quality of life (EQ-5D-5L), Lawton scale of instrumental activities of daily living score, reperfusion quality (MeVO expanded Thrombolysis in Cerebral Infarction Score) and infarct volume at 24 hours, and cost-effectiveness of endovascular recanalization. Safety outcomes include symptomatic and asymptomatic intracranial hemorrhage and procedural complications. DISCUSSION: The ESCAPE-MeVO trial will demonstrate the effect of endovascular thrombectomy in addition to best medical management vis-à-vis best medical management in patients with acute ischemic stroke due to MeVO and provide data for evidence-based treatment decision-making in acute MeVO stroke.

Optimizing Triage: Assessing Shock Index, Pediatric Age-Adjusted as an Adjunct to Improve Emergency Severity Index Mistriage.

OBJECTIVE: We investigated the diagnostic value of shock index, pediatric age-adjusted (SIPA) in predicting Emergency Severity Index level 3 patients' outcomes. Secondary objectives included exploring the impact of fever and participant variables on SIPA's predictive ability. METHODS: A retrospective chart review identified children aged 1 to 15 years triaged as a level 3 in the emergency department between January 2018 and December 2021. Shock index, pediatric age-adjusted thresholds based on age, 1 to 6 years (>1.2), 7 to 12 years (>1.0), and 13 to 17 years (>0.9), were used. We assessed elevated SIPA and SIPA corrected for fever to evaluate associations with outcomes and interventions. RESULTS: Our findings, involving 192 patients, revealed that elevated SIPA demonstrated enhanced discrimination relative to nonelevated SIPA. Patients with elevated SIPA had more average interventions: 1.14 versus 0.74, P < 0.016; average interventions using SIPA corrected for fever: 1.14 versus 0.77, P < 0.006; average interventions controlling for race and sex: 1.15 versus 0.71, P < 0.001; hospital admission: 64.4% versus 42.9%, P = 0.004; hospital length of stay (LOS): 3.06 days (SE, 0.42) versus 1.46 days (SE, 0.23); hospital LOS using SIPA corrected for fever: 2.75 days (SE, 0.44) versus 1.72 days (SE, 0.24); ventilatory support: 16.44% versus 3.36%, P < 0.002; fluid bolus: 28.77% versus 14.29%, P < 0.015; intravenous medications (antibiotics, antiepileptics, immune globulin, albumin): 45.21% versus 30.25%, P < 0.036. There was no difference between other interventions, pediatric intensive care admission, and LOS between the 2 groups. Importantly, SIPA was unaffected by fever, race, or sex. CONCLUSIONS: Shock index, pediatric age-adjusted identifies level 3 Emergency Severity Index pediatric patients more likely to require hospital admission, longer LOS, and a lifesaving intervention especially ventilatory support, intravenous fluids, or specific intravenous medications. Shock index, pediatric age-adjusted's predictive ability remained unaffected by fever, race, or sex, making it a valuable tool in preventing mistriage and justifying inclusion in the Emergency Severity Index danger zone vitals criteria for up-triage.

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.

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.

CT Perfusion Map Synthesis from CTP Dynamic Images Using a Learned LSTM Generative Adversarial Network for Acute Ischemic Stroke Assessment.

Computed tomography perfusion (CTP) is a dynamic 4-dimensional imaging technique (3-dimensional volumes captured over approximately 1 min) in which cerebral blood flow is quantified by tracking the passage of a bolus of intravenous contrast with serial imaging of the brain. To diagnose and assess acute ischemic stroke, the standard method relies on summarizing acquired CTPs over the time axis to create maps that show different hemodynamic parameters, such as the timing of the bolus arrival and passage (Tmax and MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). However, producing accurate CTP maps requires the selection of an arterial input function (AIF), i.e. a time-concentration curve in one of the large feeding arteries of the brain, which is a highly error-prone procedure. Moreover, during approximately one minute of CT scanning, the brain is exposed to ionizing radiation that can alter tissue composition, and create free radicals that increase the risk of cancer. This paper proposes a novel end-to-end deep neural network that synthesizes CTP images to generate CTP maps using a learned LSTM Generative Adversarial Network (LSTM-GAN). Our proposed method can improve the precision and generalizability of CTP map extraction by eliminating the error-prone and expert-dependent AIF selection step. Further, our LSTM-GAN does not require the entire CTP time series and can produce CTP maps with a reduced number of time points. By reducing the scanning sequence from about 40 to 9 time points, the proposed method has the potential to minimize scanning time thereby reducing patient exposure to CT radiation. Our evaluations using the ISLES 2018 challenge dataset consisting of 63 patients showed that our model can generate CTP maps by using only 9 snapshots, without AIF selection, with an accuracy of 84.37 % .

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT: Data will be available upon reasonable request.

Concurrent Outbreaks of Hepatitis A, Invasive Meningococcal Disease, and Mpox, Florida, USA, 2021-2022.

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March--June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Prevalence of "Ghost Infarct Core" after Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: Baseline CTP sometimes overestimates the size of the infarct core ("ghost core" phenomenon). We investigated how often CTP overestimates infarct core compared with 24-hour imaging, and aimed to characterize the patient subgroup in whom a ghost core is most likely to occur. MATERIALS AND METHODS: Data are from the randomized controlled ESCAPE-NA1 trial, in which patients with acute ischemic stroke undergoing endovascular treatment were randomized to intravenous nerinetide or placebo. Patients with available baseline CTP and 24-hour follow-up imaging were included in the analysis. Ghost infarct core was defined as CTP core volume minus 24-hour infarct volume > 10 mL). Clinical characteristics of patients with versus without ghost core were compared. Associations of ghost core and clinical characteristics were assessed by using multivariable logistic regression. RESULTS: A total of 421 of 1105 patients (38.1%) were included in the analysis. Forty-seven (11.2%) had a ghost core > 10 mL, with a median ghost infarct volume of 13.4 mL (interquartile range 7.6-26.8). Young patient age, complete recanalization, short last known well to CT times, and possibly male sex were associated with ghost infarct core. CONCLUSIONS: CTP ghost core occurred in ∼1 of 10 patients, indicating that CTP frequently overestimates the infarct core size at baseline, particularly in young patients with complete recanalization and short ischemia duration.

Infarct Evolution on MR-DWI After Thrombectomy in Acute Stroke Patients Randomized to Nerinetide or Placebo: The REPERFUSE-NA1 Study

BACKGROUND AND OBJECTIVES: The neuroprotectant nerinetide has shown promise in reducing infarct volumes in primate models of ischemia reperfusion. We hypothesized that early secondary infarct growth after endovascular therapy (EVT) (1) may be a suitable surrogate biomarker for testing neuroprotective compounds, (2) is feasible to assess in the acute setting using sequential MRI, and (3) can be modified by treatment with nerinetide. METHODS: REPERFUSE-NA1 was a prospective, multisite MRI substudy of the randomized controlled trial ESCAPE-NA1 (ClinicalTrials.gov NCT02930018) that involved patients with acute disabling large vessel occlusive stroke undergoing EVT within 12 hours of onset who were randomized to receive intravenous nerinetide or placebo. Patients enrolled in REPERFUSE-NA1 underwent sequential MRI <5 hours post-EVT (day 1) and at 24 hours (day 2). The primary outcome was total diffusion-weighted MRI infarct growth early after EVT, defined as the lesion volume difference between day 2 and day 1. The secondary outcome was region-specific infarct growth in different brain tissue compartments. Statistical analyses were performed using the Mann-Whitney U test and multiple linear regression. RESULTS: Sixty-seven of 71 patients included had MRI of sufficient quality. The median infarct volume post-EVT was 12.98 mL (IQR, 5.93-28.08) in the nerinetide group and 10.80 mL (IQR, 3.11-24.45) in the control group (p = 0.59). Patients receiving nerinetide showed a median early secondary infarct growth of 5.92 mL (IQR, 1.09-21.30) compared with 10.80 mL (interquartile range [IQR], 2.54-21.81) in patients with placebo (p = 0.30). Intravenous alteplase modified the effect of nerinetide on region-specific infarct growth in white matter and basal ganglia compartments. In patients with no alteplase, the infarct growth rate was reduced by 120% (standard error [SE], 60%) in the white matter (p = 0.03) and by 340% (SE, 140%) in the basal ganglia (p = 0.02) in the nerinetide group compared with placebo after adjusting for confounders. DISCUSSION: This study highlights the potential of using MR imaging as a biomarker to estimate the effect of a neuroprotective agent in acute stroke treatment. Patients with acute large vessel occlusive stroke exhibited appreciable early infarct growth both in the gray matter and the white matter after undergoing EVT. Acknowledging relatively small overall infarct volumes in this study, treatment with nerinetide was associated with slightly reduced percentage infarct growth in the white matter and basal ganglia compared with placebo in patients not receiving intravenous alteplase and had no effect on the total early secondary infarct growth. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02930018. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute large vessel ischemic stroke undergoing EVT, nerinetide did not significantly decrease early post-EVT infarct growth compared with placebo.

Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke.

Importance: Age is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely considered in acute decision-making or trials, is unknown. Objectives: To explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT). Design, Setting, and Participants: This cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy [subcortical or cortical], white matter disease [periventricular or deep], and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023. Exposures: All patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management. Main Outcome and Measures: The primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment. Results: Among a total of 1105 patients enrolled in the study, 1102 (median age, 71 years [IQR, 61-80 years]; 554 [50.3%] male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (ß coefficient, 0.04 per year [95% CI, 0.02-0.06 per year]; P < .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (ß coefficient, 0.07 per year [95% CI, 0.03-0.10 per year]; P = .001). Conclusions and Relevance: In this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.

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.

Direct to Angiosuite in Acute Stroke with Mobile Stroke Unit.

BACKGROUND: Early reperfusion has the best likelihood for a favorable outcome in acute ischemic stroke (AIS) with large vessel occlusion (LVO). Our experience with mobile stroke unit (MSU) for direct to angiosuite (DTAS) transfer in AIS patients with suspected LVO is presented. METHODS: Retrospective review of prospectively collected data from November 2019 to August 2022, of patients evaluated and transferred by the University of Alberta Hospital MSU and moved to angiosuite for endovascular thrombectomy (EVT). RESULT: A total of 41 cases were included. Nine were chosen for DTAS and 32 were shifted to angiosuite after stopping for computed tomography (CT) angiography of the head and neck (no-DTAS). Stroke severity measured by NIHSS (median with interquartile range (IQR)) was higher in patients of DTAS, 22 (14-24) vs 14.5 (5-25) in no-DTAS (p = 0.001). The non-contrast CT head in MSU showed hyperdense vessels in 8 (88.88%) DTAS vs 11 (34.35%) no-DTAS patients (p = 0.003). The EVT timelines (median with IQR, 90th percentile) including "door to artery puncture time" were 31 (23-50, 49.2) vs 79 (39-264, 112.8) minutes, and "door to recanalization time" was 69 (49-110, 93.2) vs 105.5 (52-178, 159.5) minutes in DTAS vs no-DTAS group, respectively. The workflow times were significantly shorter in the DTAS group (p < 0.001). Eight (88.88%) out of 9 DTAS patients had LVO and underwent thrombectomy. CONCLUSIONS: MSU for DTAS in patients with high NIHSS scores, cortical signs, and CT showing hyperdense vessel is an effective strategy to reduce the EVT workflow time.

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.

Endovascular treatment of cerebral sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

INTRODUCTION: There is little data on the role of endovascular treatment (EVT) of cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe clinical characteristics and outcomes of CVST-VITT patients who were treated with EVT. PATIENTS AND METHODS: We report data from an international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 6 March 2023. VITT was defined according to the Pavord criteria. RESULTS: EVT was performed in 18/136 (13%) patients with CVST-VITT (92% aspiration and/or stent retrieval, 8% local thrombolysis). Most common indications were extensive thrombosis and clinical or radiological deterioration. Compared to non-EVT patients, those receiving EVT had a higher median thrombus load (4.5 vs 3). Following EVT, local blood flow was improved in 83% (10/12, 95% confidence interval [CI] 54-96). One (6%) asymptomatic sinus perforation occurred. Eight (44%) patients treated with EVT also underwent decompressive surgery. Mortality was 50% (9/18, 95% CI 29-71) and 88% (8/9, 95% CI 25-66) of surviving EVT patients achieved functional independence with a modified Rankin Scale score of 0-2 at follow-up. In multivariable analysis, EVT was not associated with increased mortality (adjusted odds ratio, 0.66, 95% CI 0.16-2.58). DISCUSSION AND CONCLUSION: We describe the largest cohort of CVST-VITT patients receiving EVT. Half of the patients receiving EVT died during hospital admission, but most survivors achieved functional independence.

Tensor-valued diffusion MRI of human acute stroke.

PURPOSE: Tensor-valued diffusion encoding can disentangle orientation dispersion and subvoxel anisotropy, potentially offering insight into microstructural changes after cerebral ischemia. The purpose was to evaluate tensor-valued diffusion MRI in human acute ischemic stroke, assess potential confounders from diffusion time dependencies, and compare to Monte Carlo diffusion simulations of axon beading. METHODS: Linear (LTE) and spherical (STE) b-tensor encoding with inherently different effective diffusion times were acquired in 21 acute ischemic stroke patients between 3 and 57 h post-onset at 3 T in 2.5 min. In an additional 10 patients, STE with 2 LTE yielding different effective diffusion times were acquired for comparison. Diffusional variance decomposition (DIVIDE) was used to estimate microscopic anisotropy (µFA), as well as anisotropic, isotropic, and total diffusional variance (MKA , MKI , MKT ). DIVIDE parameters, and diffusion tensor imaging (DTI)-derived mean diffusivity and fractional anisotropy (FA) were compared in lesion versus contralateral white matter. Monte Carlo diffusion simulations of various cylindrical geometries for all b-tensor protocols were used to interpret parameter measurements. RESULTS: MD was ˜40% lower in lesions for all LTE/STE protocols. The DIVIDE parameters varied with effective diffusion time: higher µFA and MKA in lesion versus contralateral white matter for STE with longer effective diffusion time LTE, whereas the shorter effective diffusion time LTE protocol yielded lower µFA and MKA in lesions. Both protocols, regardless of diffusion time, were consistent with simulations of greater beading amplitude and intracellular volume fraction. CONCLUSION: DIVIDE parameters depend on diffusion time in acute stroke but consistently indicate neurite beading and larger intracellular volume fraction.

The whole day matters after stroke: Study protocol for a randomized controlled trial investigating the effect of a 'sit less, move more, sleep better' program early after stroke.

BACKGROUND: Movement-related behaviours, including prolonged sedentary behaviour, physical inactivity, and poor sleep, are associated with worse functional outcomes poststroke. Addressing these co-dependent behaviours early after stroke may help to optimize recovery and improve overall quality of life for individuals with stroke. OBJECTIVE: This study aims to determine the feasibility and effect of a 'sit less, move more, sleep better' program early after stroke on functional mobility and global disability outcomes, while also exploring imaging and behavioural markers that may influence walking recovery. METHODS: The study is an assessor-blinded, single-center, parallel-group, randomized controlled trial to be completed within 24 months from July 12, 2023 to June 30, 2025. We will enroll 50 patients with acute ischemic stroke within 7 days from symptom onset, aged 18 years or older, and with ongoing walking goals. Demographic and stroke characteristics, including stroke risk factors, neuroimaging, and acute stroke treatments, will be determined and documented. All participants will wear an accelerometer for one week at three different time-points (baseline, 6, and 12 weeks) to assess movement-related behaviours. Following randomization, participants in the intervention arm will receive a 'sit less, move more, sleep better' program for up to 1 hour/day, 5 days/week, for 6 weeks to enhance self-efficacy for change. Participants in the control arm will receive usual inpatient and early supported stroke discharge care. The feasibility outcomes will include reach (enrolled/eligible), retention (completed/enrolled), adverse events, and program adherence. Other outcomes at 6 and 12 weeks include the modified Rankin Scale, Timed-Up and Go, movement-related behaviours, walking endurance, gait speed, cognition, stroke severity and quality of life. Mixed-effects models will assess changes in outcomes over time. Compositional associations between movement-related behaviours and outcomes will consider covariates such as imaging markers. DISCUSSION: Adopting a whole-day approach to poststroke rehabilitation will provide valuable insights into the relationship between optimizing movement-related behaviours early after stroke and their impact on functional outcomes. Through exploring person-specific behavioural and imaging markers, this study may inform precision rehabilitation strategies, and guide clinical decision making for more tailored interventions. TRIAL REGISTRATION: Clinical Trial registration (ClinicalTrials.gov Identifier: NCT05753761, March 3, 2023).

Effect of Time to Thrombolysis on Clinical Outcomes in Patients With Acute Ischemic Stroke Treated With Tenecteplase Compared to Alteplase: Analysis From the AcT Randomized Controlled Trial.

BACKGROUND: The AcT (Alteplase Compared to Tenecteplase) randomized controlled trial showed that tenecteplase is noninferior to alteplase in treating patients with acute ischemic stroke within 4.5 hours of symptom onset. The effect of time to treatment on clinical outcomes with alteplase is well known; however, the nature of this relationship is yet to be described with tenecteplase. We assessed whether the association of time to thrombolysis treatment with clinical outcomes in patients with acute ischemic stroke differs by whether they receive intravenous tenecteplase versus alteplase. METHODS: Patients included were from AcT, a pragmatic, registry-linked, phase 3 randomized controlled trial comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4.5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin Scale score 0 to 1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage and 90-day mortality rates. Mixed-effects logistic regression was used to assess the following: (a) the association of stroke symptom onset to needle time; (b) door (hospital arrival) to needle time with outcomes; and (c) if these associations were modified by type of thrombolytic administered (tenecteplase versus alteplase), after adjusting for age, sex, baseline stroke severity, and site of intracranial occlusion. RESULTS: Of the 1538 patients included in this analysis, 1146 (74.5%; 591 tenecteplase and 555 alteplase) presented within 3 hours versus 392 (25.5%; 196: TNK and 196 alteplase) who presented within 3 to 4.5 hours of symptom onset. Baseline patient characteristics in the 0 to 3 hours versus 3- to 4.5-hour time window were similar, except patients in the 3- to 4.5-hour window had lower median baseline National Institutes of Health Stroke Severity Scale (10 versus 7, respectively) and lower proportion of patients with large vessel occlusion on baseline CT angiography (26.9% versus 18.7%, respectively). Type of thrombolytic agent (tenecteplase versus alteplase) did not modify the association between continuous onset to needle time (Pinteraction=0.161) or door-to-needle time (Pinteraction=0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-minute reduction in onset to needle time was associated with a 1.8% increase while every 10 minutes reduction in door-to-needle time was associated with a 0.2% increase in the probability of achieving 90-day modified Rankin Scale score 0 to 1, respectively. CONCLUSIONS: The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes. REGISTRATION: URL: https://classic. CLINICALTRIALS: gov; Unique identifier: NCT03889249.

Study of Rivaroxaban for Cerebral Venous Thrombosis: A Randomized Controlled Feasibility Trial Comparing Anticoagulation With Rivaroxaban to Standard-of-Care in Symptomatic Cerebral Venous Thrombosis.

BACKGROUND: Emerging data suggest that direct oral anticoagulants may be a suitable choice for anticoagulation for cerebral venous thrombosis (CVT). However, conducting high-quality trials in CVT is challenging as it is a rare disease with low rates of adverse outcomes such as major bleeding and functional dependence. To facilitate the design of future CVT trials, SECRET (Study of Rivaroxaban for Cerebral Venous Thrombosis) assessed (1) the feasibility of recruitment, (2) the safety of rivaroxaban compared with standard-of-care anticoagulation, and (3) patient-centered functional outcomes. METHODS: This was a phase II, prospective, open-label blinded-end point 1:1 randomized trial conducted at 12 Canadian centers. Participants were aged ≥18 years, within 14 days of a new diagnosis of symptomatic CVT, and suitable for oral anticoagulation; they were randomized to receive rivaroxaban 20 mg daily, or standard-of-care anticoagulation (warfarin, target international normalized ratio, 2.0-3.0, or low-molecular-weight heparin) for 180 days, with optional extension up to 365 days. Primary outcomes were annual rate of recruitment (feasibility); and a composite of symptomatic intracranial hemorrhage, major extracranial hemorrhage, or mortality at 180 days (safety). Secondary outcomes included recurrent venous thromboembolism, recanalization, clinically relevant nonmajor bleeding, and functional and patient-reported outcomes (modified Rankin Scale, quality of life, headache, mood, fatigue, and cognition) at days 180 and 365. RESULTS: Fifty-five participants were randomized. The rate of recruitment was 21.3 participants/year; 57% of eligible candidates consented. Median age was 48.0 years (interquartile range, 38.5-73.2); 66% were female. There was 1 primary event (symptomatic intracranial hemorrhage), 2 clinically relevant nonmajor bleeding events, and 1 recurrent CVT by day 180, all in the rivaroxaban group. All participants in both arms had at least partial recanalization by day 180. At enrollment, both groups on average reported reduced quality of life, low mood, fatigue, and headache with impaired cognitive performance. All metrics improved markedly by day 180. CONCLUSIONS: Recruitment targets were reached, but many eligible participants declined randomization. There were numerically more bleeding events in patients taking rivaroxaban compared with control, but rates of bleeding and recurrent venous thromboembolism were low overall and in keeping with previous studies. Participants had symptoms affecting their well-being at enrollment but improved over time. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03178864.