Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment within 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered within 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).

Tenecteplase versus alteplase for acute ischaemic stroke in the elderly patients: a post hoc analysis of the TRACE-2 trial.

BACKGROUND: The benefit-risk profile of tenecteplase in the elderly patients with acute ischaemic stroke (AIS) is uncertain. We sought to investigate the efficacy and safety of 0.25 mg/kg tenecteplase compared with alteplase for AIS patients aged ≥80 years. METHODS: We performed a post hoc analysis of the Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-2 Trial, a randomised, phase 3, non-inferiority clinical trial. Disabling AIS patients aged ≥80 years who initiated intravenous thrombolytics within 4.5 hours of symptom onset were enrolled from June 2021 to May 2022 across 53 centres in China and were randomly allocated to receive 0.25 mg/kg tenecteplase or 0.9 mg/kg alteplase. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Symptomatic intracranial haemorrhage (sICH) within 36 hours was the safety outcome. RESULTS: Of 137 participants, mRS 0-1 at 90 days occurred in 37 (49.3%) of 75 in the tenecteplase group vs 20 (33.9%) of 59 in the alteplase group (risk ratio (RR) 1.47, 95% CI 0.96 to 2.23). sICH within 36 hours was observed in 3 (4.0%) of 76 in the tenecteplase group and two (3.3%) of 61 in the alteplase group (RR 1.30, 95% CI 0.20 to 8.41). CONCLUSIONS: The risk-benefit profile of tenecteplase thrombolysis was preserved in the elderly patients, which lends further support to intravenous 0.25 mg/kg tenecteplase as an alternative to alteplase in these patients.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial.

BACKGROUND: The incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI remain limited. Anaemia or low haemoglobin was found as an independent risk factor for adverse outcomes after acute stroke. Anaemia or low haemoglobin was possibly associated with an increased risk of poststroke cognitive impairment. Whether supplement of ferrous iron to correct anaemia reduces the risk of VCI and improves adverse outcomes in patients with ischaemic cerebrovascular disease remains uncertain. AIM: We aim to introduce the design and rationale of the safety and efficacy of Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA (FAVORITE) trial. DESIGN: FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial that compares supplement of ferrous iron with placebo for recent minor stroke/TIA patients complicated with mild anaemia or iron deficiency: Ferrous succinate sustained-release tablet 0.2 g (corresponding to 70 mg of elemental iron) once daily after or during breakfast for 12 weeks or placebo with much the same colour, smell and size as ferrous iron once daily during or after breakfast for 12 weeks. All paticipants will be followed within the next year. STUDY OUTCOMES: The primary effective outcome is the incidence of VCI at 3 months after randomisation and the primary safety outcome includes any gastrointestinal adverse event during 3 months. DISCUSSION: The FAVORITE trial will clarify whether supplement of ferrous iron to correct low haemoglobin reduces the risk of VCI in patients with recent ischaemic stroke or TIA complicated with mild anaemia or iron deficiency compared with placebo. TRIAL REGISTRATION NUMBER: NCT03891277.

The FAITHS2 Model Predicts Functional Disability in Patients With Acute Ischemic Stroke.

The present study aimed to develop a model to predict functional disability at 3 months in patients with acute ischemic stroke (AIS) (n = 5,406). The primary outcome was functional disability (modified Rankin Scale [mRS] >2) at 3 months. A prediction model including blood biomarkers was developed based on a multivariable logistic regression model, which was internally validated by the 100-time bootstrap method. A nomogram and a web-based calculator were developed for usage in clinical practice. At 3 months, 11% (638/5,406) of the patients had functional disability. Seven independent predictors of functional disability at 3 months were incorporated into the FAITHS2 model (fasting plasma glucose, age, interleukin-6, stroke history, National Institute of Health Stroke Scale [NIHSS] at admission, sex, and systolic blood pressure). The Area Under Curves (AUCs) were 0.814 (95% confidence interval [CI] 0.796-0.832) and 0.808 (95% CI 0.806-0.810), and the Brier scores were 0.088 ± 0.214 and 0.089 ± 0.003 for the derivation cohort and internal validation, respectively, showing optimal performance of the model. The FAITHS2 model has excellent potential to be a dependable application for individualized clinical decision making.

Comprehensive Review of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

Although intravenous thrombolysis with alteplase remains the primary treatment for acute ischemic stroke, tenecteplase has shown potential advantages over alteplase. Animal studies have demonstrated the favorable pharmacokinetics and pharmacodynamics of tenecteplase. Moreover, it is easier to administer. Clinical trials have demonstrated that tenecteplase is not inferior to alteplase and may even be superior in cases of acute ischemic stroke with large vessel occlusion. Current evidence supports the time and cost benefits of tenecteplase, suggesting that it could potentially replace alteplase as the main option for thrombolytic therapy, especially in patients with large vessel occlusion.

Assessment of Perfusion Volumes by a New Automated Software for Computed Tomography Perfusion.

INTRODUCTION: To compare the perfusion volumes assessed by a new automated CT perfusion (CTP) software iStroke with the circular singular value decomposition software RAPID and determine its predictive value for functional outcome in patients with acute ischaemic stroke (AIS) who underwent endovascular treatment (EVT). METHODS: Data on patients with AIS were collected from four hospitals in China. All patients received CTP followed by EVT with complete recanalisation within 24 hours of symptom onset. We evaluated the agreement of CTP measures between the two softwares by Spearman's rank correlation tests and kappa tests. Bland-Altman plots were used to evaluate the agreement of infarct core volume (ICV) on CTP and ground truth on diffusion-weighted imaging (DWI). Logistic regression models were used to test the association between ICV on these two softwares and functional outcomes. RESULTS: Among 326 patients, 228 had DWI examinations and 40 of them had infarct volume >70 mL. In all patients, the infarct core and hypoperfusion volumes on iStroke had a strong correlation with those on RAPID (ρ=0.68 and 0.66, respectively). The agreement of large infarct core (volume >70 mL) was substantial (kappa=0.73, p<0.001) between these two softwares. The ICV measured by iStroke and RAPID was significantly correlated with independent functional outcome at 90 days (p=0.009 and p<0.001, respectively). In patients with DWI examinations and those with an ICV >70 mL, the ICV of iStroke and RAPID was comparable on individual agreement with ground truth. CONCLUSION: The automatic CTP software iStroke is a reliable tool for assessing infarct core and mismatch volumes, making it clinically useful for selecting patients with AIS for acute reperfusion therapy in the extended time window.

Clinical significance of the Microbleed Anatomical Rating Scale score in ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Conflicting results were shown on the relationship between cerebral microbleeds (CMBs) burden and functional outcomes in patients treated with intravenous tissues plasminogen activator (IV tPA). We aimed to investigate the relationship between CMBs burden and functional outcomes using the Microbleed Anatomical Rating Scale (MARS) and determine its optimal cutoff value. METHODS: A retrospective study was conducted to include patients treated with IV tPA in our stroke center, and the MARS was used to assess the CMBs burden. Other clinical data including demographic factors, stroke severity, vascular risk factors, and clinical outcomes were also documented. Another mediation analysis was performed to investigate whether early neurological improvement could mediate the association between MARS and functional outcomes. RESULTS: A total of 408 patients were included. A cutoff value of 1.5 could predict functional outcomes in patients treated with IV tPA. Based on that cutoff value, MARS showed an independent relationship with functional outcomes [adjusted OR (Odds Ratio) 0.841, 95% confidence interval (CI) 0.720-0.982, P = .029]. A shift analysis showed that higher MARS score (MARS ≥1.5) was related with poor functional outcome according to mRS score distribution (OR = 0.519, 95% CI 0.336-0.803, P = .003). Total effect (indirect + direct effect) was calculated and showed in figure. Early neurological improvement mediated 24% of the effect of MARS score on functional outcomes. CONCLUSION: Our study showed that MARS could be a potential method to assess the functional outcome based on CMBs in patients treated with IV tPA, and MARS score ≥ 1.5 might be an optimal threshold for poor functional outcome.

Risk factors and Outcomes of Dysphagia Among Patients Hospitalized with Acute Intracerebral Hemorrhage: Findings from the Chinese Stroke Center Alliance.

Objective: Dysphagia is a common and severe symptom of acute stroke; however, few studies investigated the prevalence of and risk factors of dysphagia among intracerebral hemorrhage (ICH) patients. We aimed to determine the prevalence and risk factors for dysphagia among acute ICH patients, and assess its impact on outcome of hospitalization. Methods: We collected data of ICH patients from the Chinese Stroke Center Alliance (CSCA) from August 2015 to July 2019 retrospectively. Univariate analysis and multivariable analysis were conducted to identify the factors associated with dysphagia and the outcomes of hospitalization. Results: 32 581 eligible ICH patients were included in the final analysis. According to the results of the swallowing function assessment, patients were divided into 24 084 (73.9%) non-dysphagia group and 8497 (26.1%) dysphagia group. Compared with the non-dysphagia group, the dysphagia group had poor outcomes, including higher incidence of pneumonia (60.2% vs 17.3%, OR 4.82, 95% CI 4.53-5.13) and in-hospital mortality (3.5% vs 0.3%, OR 5.96, 95% CI 4.41-8.06), longer length of stay (P < .01), higher hospitalization cost (P < .01), and higher medicine cost (P < .01). In multivariable analysis, the incidence of dysphagia was independently associated with older age (OR 1.10, 95% CI 1.09-1.11), male sex (OR 1.13, 95% CI 1.06-1.20), arrival at the hospital by emergency medical services (OR 2.11, 95% CI 1.99-2.24), lower Glasgow Coma Scale (GCS) score (per point decrease) (OR 0.78, 95% CI 0.77-0.78), history of ICH (OR 1.25, 95% CI 1.17-1.35), and higher glucose level (OR 1.09, 95% CI 1.07-1.10). Conclusions: More than one-quarter of acute ICH patients were diagnosed with dysphagia, which was associated with poor hospital outcomes. The early identification and management of dysphagia may reduce the possibility of stroke-associated pheumonia, shorten the length of hospital stay, and reduce medical cost.

Outcomes associated to the time to treatment with intravenous tenecteplase for acute ischaemic stroke: subgroup analysis of the TRACE-2 randomised controlled clinical trial.

BACKGROUND: The benefit of intravenous alteplase in acute ischaemic stroke (AIS) is time-dependent. Tenecteplase is non-inferior to alteplase among patients with AIS. We aimed to delineate the association of the stroke onset to treatment time (OTT) with tenecteplase compared with alteplase on therapeutic benefit and clinical risks. METHODS: This is a post hoc analysis of the Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-2 an open-label, randomised, controlled, non-inferior trial. A total of 1430 AIS within 4.5 hours onset at 53 sites in China from 12 June 2021 to 29 May 2022 were randomly assigned (1:1) to receive either tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale score of 0-1 at 90 days. A post hoc subgroup analysis was conducted with the OTT divided into three intervals (0-90 min, 91-180 min and 181-270 min). The primary safety outcome was symptomatic intracranial haemorrhage within 36 hours post-thrombolytic treatment. RESULTS: Treatment was initiated within 270 min of stroke onset in 1412 patients who were randomly allocated to either tenecteplase (n=707) or alteplase (n=705). The OR of primary efficacy outcome was similar as OTT increased (p=0.84). Adjusted odds of an excellent functional outcome were 0.99 (95% CI 0.37 to 2.67) for 0-90 min, 1.23 (95% CI 0.88 to 1.71) for 91-180 min and 1.21 (95% CI 0.88 to 1.65) for 181-270 min. All were in favour of the tenecteplase group. Meta-analysis of 2949 patients yielded a pooled risk difference of 5.54 (95% CI -0.18 to 11.26; p=0.82) in favour of tenecteplase for more than 180 min and 1.77 (95% CI -2.66 to 6.20; p=0.58) for 0-180 min. CONCLUSIONS: In AIS patients who were treated with either tenecteplase or alteplase within 4.5 hours onset, there was no difference observed in the efficacy and safety between the two groups at the three different OTT time intervals.

Rationale and design of ProUrokinase in Mild IsChemic strokE (PUMICE): a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial.

BACKGROUND AND PURPOSE: Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, that is non-inferior to alteplase in acute ischemic stroke. We aimed to investigate the efficacy and safety of rhPro-UK compared with standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset. METHODS AND DESIGN: Prourokinase in mild ischemic stroke is a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Patients who had an acute ischemic stroke within 4.5 hours from symptom onset and with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 will be recruited. Patients will be randomly assigned (1:1) to receive intravenous rhPro-UK (35 mg) or standard medical treatment. The follow-up duration will be 90 days. The calculated sample size is 1446. STUDY OUTCOMES: Primary efficacy outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score ≤ 1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, mRS score ≤ 2 at 90 days, early neurological improvement at 24 hours (a decrease of NIHSS score ≥ 4 points compared with baseline or NIHSS score ≤ 1 point), Barthel index of 75-100 points at 90 days, quality of life at 90 days, and activities of daily living at 90 days. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, mortality at 90 days, moderate and severe systematic bleeding at 90 days, and adverse events/serious adverse events within 90 days. DISCUSSION: This large phase III randomised clinical trial will answer the question of whether thrombolysis is beneficial for acute mild ischemic stroke, and may provide evidence for rhPro-UK in patients had an acute mild ischemic stroke within 4.5 hours of symptom onset. TRIAL REGISTRATION NUMBER: NCT05507645.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Rationale and design of Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events III (TRACE III): a randomised, phase III, open-label, controlled trial.

BACKGROUND AND PURPOSE: Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) was not inferior to alteplase for ischaemic stroke within 4.5 hours. Our study aimed to investigate the efficacy and safety of rhTNK-tPA in patients who had an ischaemic stroke due to large vessel occlusion (LVO) of anterior circulation beyond 4.5 hours. METHODS AND DESIGN: Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III (TRACE III) is a multicentre, prospective, randomised, open-label, blind endpoint, controlled clinical trial. Patients who had an ischaemic stroke due to anterior circulation LVO (internal carotid artery, middle cerebral artery M1 and M2 segments) within 4.5-24 hours from last known well (including wake-up stroke and no witness stroke) and with salvageable tissue (ischaemic core volume <70 mL, mismatch ratio ≥1.8 and mismatch volume ≥15 mL) based on CT perfusion or MRI perfusion-weighted imaging (PWI) were included and randomised to rhTNK-tPA 0.25 mg/kg (single bolus) to a maximum of 25 mg or standard medical therapy. Specially, we will exclude patients who are intended for direct thrombectomy. All will be followed up for 90 days. STUDY OUTCOMES: Primary efficacy outcome is modified Rankin Scale (mRS) score ≤1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, major neurological improvement defined by a decrease ≥8 points compared with the initial deficit or a score ≤1 on the National Institutes of Health Stroke Scale (NIHSS) at 72 hours, mRS score ≤2 at 90 days, the rate of improvement on Tmax >6 s at 24 hours and NIHSS score change from baseline at 7 days. Safety outcomes are symptomatic intracerebral haemorrhage within 36 hours and mortality at 90 days. DISCUSSION: TRACE III will provide evidence for the efficacy and safety of rhTNK-tPA in patients who had an ischaemic strokes due to anterior circulation LVO beyond 4.5 hours. TRIAL REGISTRATION NUMBER: NCT05141305.

Short- and long-term outcomes of patients with minor stroke and nonvalvular atrial fibrillation.

BACKGROUND AND PURPOSE: Nonvalvular atrial fibrillation (NVAF) is a risk factor for stroke. This study was undertaken to determine the influence of NVAF on the mortality and recurrent stroke after a minor stroke event. METHODS: Data were derived from the Third China National Stroke Registry (CNSR-III) which enrolled 15,166 subjects during August 2015 through March 2018 in China. Patients with minor stroke (NIHSS ≤ 5) within 24 h after onset were included. Clinical outcomes including all-cause mortality, cardiovascular death, recurrent ischemic stroke, and recurrent hemorrhagic stroke were collected. The Cox proportional hazards models were used to determine the association between NVAF and clinical outcomes. RESULTS: A total of 4,753 patients were included in our study. Of them, 222 patients had NVAF (4.7%) (mean age, 71.1 years) and 4,531 patients were without AF (95.3%) (mean age, 61.4 years). NVAF was associated with 12-month cardiovascular mortality in both univariate (hazards ratio [HR], 4.13; 95% confidence interval [CI], 1.84 to 9.31; P < 0.001) and multivariate analyses (HR, 4.66; 95% CI, 1.79 to 12.15; P = 0.001). There was no difference in the in-hospital ischemic stroke recurrence rate between the two groups (HR, 0.45 [95% CI, 0.19 to 1.05] P = 0.07 at discharge). However, patients with NVAF had a lower rate of recurrent ischemic stroke at medium- (3 months and 6 months) and long-term (12 months) follow-up (HR, 0.33 [95% CI, 0.16 to 0.68] P = 0.003 at 3 months; 0.49 [95% CI, 0.27 to 0.89] P = 0.02 at 6 months; 0.55 [95% CI, 0.32 to 0.94] P = 0.03 at 12 months, respectively) compared with those without. There was no difference in all-cause mortality and hemorrhagic stroke between the two groups during follow-up. CONCLUSIONS: Minor stroke patients with NVAF were at higher risk of cardiovascular death but had a lower rate of recurrent ischemic stroke compared to those without during the subsequent year after stroke event. A more accurate stroke risk prediction model for NVAF is warranted for optimal patient care strategies.

Treatment strategies and prognosis for moderate stroke patients in China.

INTRODUCTION: Moderate stroke patients with National Institutes of Health Stroke Scale (NIHSS) score of 4-10 and without intravenous thrombolysis or endovascular treatment are basically excluded from current secondary prevention trials. We aimed to explore the effectiveness of mono- vs. dual-antiplatelet (DAPT) treatment strategies against subsequent stroke for these patients in a nationwide cohort. METHODS: Data were derived from the Third China National Stroke Registry (CNSR-Ш). In this prospective nationwide cohort, moderate ischemic stroke patients with NIHSS 4-10 and without intravenous thrombolysis or endovascular treatment were included and categorized into mono- or dual-antiplatelet groups. Demographics, medical history, NIHSS score, imaging and laboratory data were collected. The outcomes were stroke recurrence and all-cause mortality at 3 months and at 1 year, respectively. Cox proportional-hazards models were utilized to investigate the association of treatment strategies and prognosis. RESULTS: Of a total of 2 414 patients enrolled in the study, 1 633 (67.6%) received clopidogrel or aspirin and 781 (32.4%) received DAPT. Recurrent stroke occurred in 108 (6.6%) patients of the mono-antiplatelt group and 40 (5.1%) patients of the DAPT group ( adjusted hazard ratio [aHR] 0.73, 95% confidential interval [CI] 0.47-1.13, P=0.16) at 3 months, and the rate of stroke recurrence was 10.7% in the mono-antiplatelet group and 8.6% in the DAPT group ( aHR 0.81, 95% CI 0.58-1.13, P=0.22) at 12 months. The DAPT paradigm was not significantly associated with death at 3 months (0.6% vs 0.3%, a HR 0.28, 95%CI 0.04-2.25) but significantly reduced the mortality at 12 months (2.3% vs 1.0%, aHR 0.41, 95% CI 0.17-0.98, P=0.046). CONCLUSIONS: In moderate stroke patients presenting within 24 hours of symptom onset, the addition of clopidogrel 75 mg to aspirin might not be associated with lower risk of recurrent stroke than aspirin or clopidogrel alone.

Insulin resistance estimated by estimated glucose disposal rate predicts outcomes in acute ischemic stroke patients.

BACKGROUND: Estimated glucose disposal rate (eGDR), a simple and noninvasive measure of insulin resistance, has been proven to be an independent risk factor for first-time stroke and all-cause mortality. In this study, we aimed to investigate the associations between eGDR and the stroke outcome in patients with first-time acute ischemic stroke (AIS). METHODS: We included first-time AIS patients with available data on eGDR in the China National Stroke Registry III (CNSR-III), and divided the subjects into lower eGDR group (eGDR ≤ 6 mg/kg/min) and higher eGDR group (eGDR > 6 mg/kg/min). The primary outcome was excellent functional outcome (modified Rankin Scale score 0-1) at 3 months. Secondary outcomes included stroke recurrence and favorable functional outcome (modified Rankin Scale score 0-2) at 3 months, and functional outcome and combined vascular event at one year. Univariate and multivariate analyses were performed to evaluate the association between eGDR and outcomes. RESULTS: A total of 6,271 patients with AIS were included in this study. The median values of eGDR in lower and higher eGDR group were 5.0 mg/kg/min (interquartile range, 4.2-5.6) and 7.6 mg/kg/min (interquartile range, 6.8-9.6), respectively. Patients with higher eGDR were significantly associated with higher incidence of excellent functional outcome (adjusted odds ratio, 1.24; 95% confidence interval, 1.06-1.45; P < 0.01) at 3 months and favorable (adjusted odds ratio, 1.55; 95% confidence interval, 1.24-1.93; P < 0.01) and excellent (adjusted odds ratio, 1.28; 95% confidence interval, 1.08-1.51; P < 0.01) functional outcome at one year. However, there was no significant difference in stroke recurrence between these two groups at 3 months (adjusted odds ratio, 0.81; 95% confidence interval, 0.61-1.06; P = 0.12) and one year (adjusted odds ratio, 0.91; 95% confidence interval, 0.73-1.14; P = 0.41). CONCLUSION: eGDR is a predictor of functional outcome in patients with AIS, independent of traditional cardiovascular predictors.

Tenecteplase versus alteplase for acute ischaemic stroke: a meta-analysis of phase III randomised trials.

BACKGROUND: Tenecteplase (TNK) was found non-inferior to alteplase in recent clinical trials. We aimed to elucidate the efficacy and safety of TNK versus alteplase for acute ischaemic stroke (AIS). METHODS: Systematic literature search and a meta-analysis of phase III clinical trials in ischaemic stroke patients with TNK use were conducted. The primary outcome was excellent functional outcome which was defined as modified Rankin Scale score of 0-1 at 90 days and safety outcomes included symptomatic intracerebral haemorrhage and death at 90 days. We used random-effects model to estimate the pooled risk difference and 95% CI in R package 'Meta'. The included trials were adapted to the non-inferiority analysis with a margin of -4%. RESULTS: Three trials enrolling 4094 patients were identified by systematic search. All trials included AIS patients within 4.5 hours time window. Meta-analysis indicated that 1089 (53.0%) of 2056 patients in the TNK arm and 1016 (50.5%) of 2012 in the alteplase arm had excellent functional outcome at 90 days (0.03 (95% CI -0.00 to 0.06); I2=0%), meeting the prespecified non-inferiority threshold. And TNK thrombolysis was not correlated with increased risk of symptomatic intracerebral haemorrhage (0.00 (95% CI -0.01 to 0.01); I2=0%) or death (0.01 (95% CI -0.01 to 0.02); I2=0%) at 90 days. The sensitivity analysis with the 0.25 mg/kg trials exclusively showed similar results to the main analysis. CONCLUSIONS: TNK was non-inferior to alteplase for achieving excellent functional outcome at 90 days without increasing the safety concern in treating patients with AIS. These findings suggest that TNK can be an alternative to alteplase. PROSPERO REGISTRATION NUMBER: CRD42022354342.

Mediation effect of stroke recurrence in the association between post-stroke interleukin-6 and functional disability.

AIM: Post-stroke inflammation increases the risk of functional disability through enlarged cerebral infarct size directly and follow-up stroke event indirectly. We aimed to use post-stroke proinflammatory cytokine interleukin-6 (IL-6) as a marker of inflammatory burden and quantify post-stroke inflammation's direct and indirect effect on functional disability. METHODS: We analyzed patients with acute ischemic stroke admitted to 169 hospitals in the Third China National Stroke Registry. Blood samples were collected within 24 h of admission. Stroke recurrence and functional outcome measured by the modified Rankin scale (mRS) were assessed via face-to-face interviews at 3 months. Functional disability was defined as an mRS score ≥2. Mediation analyses under the counterfactual framework were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between IL-6 and functional outcome. RESULTS: Among the 7053 analyzed patients, the median (interquartile range [IQR]) NIHSS score was 3 (1-5), and the median (IQR) level of IL-6 was 2.61 (1.60-4.73) pg/mL. Stroke recurrence was observed in 458 (6.5%) patients, and functional disability was seen in 1708 (24.2%) patients at the 90-day follow-up. Per stand deviation (4.26 pg/mL) increase in the concentration of IL-6 was associated with an increased risk of stroke recurrence (adjusted odds ratio [aOR], 1.19; 95% CI, 1.09-1.29) and disability (aOR, 1.22; 95% CI, 1.15-1.30) within 90 days. Mediation analyses revealed that 18.72% (95% CI, 9.26%-28.18%) of the relationship between IL-6 and functional disability was mediated by stroke recurrence. CONCLUSIONS: Stroke recurrence mediates less than 20% of the association between IL-6 and functional outcome at 90 days among patients with acute ischemic stroke. In addition to typical secondary prevention strategies for preventing stroke recurrence, more attention should be paid to novel anti-inflammatory therapy to improve functional outcomes directly.

Intravenous thrombolysis for acute ischemic stroke during two COVID-19 outbreaks in China: Wuhan pandemic and Beijing pandemic.

INTRODUCTION: The COVID-19 pandemic has had an impact on the emergency department (ED). Door-to-needle time (DNT) could be prolonged for intravenous thrombolysis (IVT) treatment. We aimed to investigate the impact of two COVID-19 pandemics on the workflow of IVT in our neurovascular ED. METHOD: We performed a retrospective analysis of patients who received IVT treatment in the neurovascular ED of Beijing Tiantan Hospital, Beijing, from January 20, 2020, to October 30, 2020, covering two COVID-19 pandemics in China. The time-based performances of IVT treatment including onset-to-arrival time, arrival-to-CT time, CT-to-needle time, door-to-needle time, and onset-to-needle time were recorded. Data on clinical characteristics and imaging information were also collected. RESULTS: Four hundred forty patients that received IVT were enrolled in this study. The number of patients admitted to our neurovascular ED began to decrease in December 2019 and was the lowest in April 2020 (n = 95). Longer DNT (Wuhan pandemic: 49.00 [35.00, 64.00] min; Beijing pandemic: 55.00 [45.50, 77.00] min) interval delays were observed during the two pandemics (p = .016). More patients admitted during the two pandemics had an 'unknown' subtype (Wuhan pandemic: 21.8%; Beijing pandemic: 31.4%. p = .008). The percentage of the cardiac embolism subtype was higher during the Wuhan pandemic (20.0%) than during other periods. The median admission NIHSS score increased during the Wuhan pandemic and the Beijing pandemic (8.00 [4.00, 12.00], 7.00 [4.50, 14.00], respectively, p < .001). CONCLUSION: The number of patients who received IVT decreased during the Wuhan pandemic. Higher admission NIHSS scores and prolonged DNT intervals were also observed during the Wuhan pandemic and the Beijing pandemic.

Indobufen versus aspirin in patients with acute ischaemic stroke in China (INSURE): a randomised, double-blind, double-dummy, active control, non-inferiority trial.

BACKGROUND: Aspirin is recommended for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke but can lead to gastrointestinal intolerance and bleeding. Indobufen is used as an alternative antiplatelet agent in some countries, despite an absence of large-scale clinical trials for this indication. We tested the hypothesis that indobufen is non-inferior to aspirin in reducing the risk of new stroke at 90 days in patients with moderate-to-severe ischaemic stroke. METHODS: We conducted a randomised, double-blind, double-dummy, active control, non-inferiority trial at 163 tertiary and district general hospitals in China. Eligible participants were aged 18-80 years with acute moderate-to-severe ischaemic stroke (National Institutes of Health Stroke Scale score 4-18). We randomly assigned (1:1) participants within 72 h of the onset of symptoms to receive either indobufen (100 mg tablet twice per day) or aspirin (100 mg tablet once per day) for 90 days. The randomisation sequence was computer generated centrally and stratified by local participating centres. Masked local investigators assigned the random code to patients in ascending order and provided a treatment kit corresponding to the random code. The primary efficacy outcome was new stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. This primary efficacy outcome was assessed in all randomly assigned and consenting patients and in a per-protocol group (ie, all patients finishing the treatment without major violation of the trial protocol). Safety analyses were done in the safety-analysis population (ie, all patients who received at least one dose of the study drug and had a safety assessment available). We assessed the non-inferiority of indobufen versus aspirin using the one-sided upper limit of the 95% CI of the hazard ratio (HR) with a prespecified non-inferiority margin of 1·25. This trial is registered with ClinicalTrials.gov (NCT03871517). FINDINGS: This trial took place between June 2, 2019, and Nov 28, 2021. Of 84 093 patients screened, 5438 patients were randomly assigned to receive either indobufen (n=2715) or aspirin (n=2723), all of whom were included in the primary analyses. Median age was 64·2 years (IQR 56·1-70·6); 1921 (35·3%) were women and 3517 (64·7%) were men. Stroke occurred within 90 days in 213 (7·9%) patients in the indobufen group versus 175 (6·4%) in the aspirin group (HR 1·23, 95% CI 1·01-1·50; pnon-inferiority=0·44). Moderate or severe bleeding occurred in 18 (0·7%) patients in the indobufen group and in 28 (1·0%) in the aspirin group (0·63, 95% CI 0·35 to 1·15; p=0·13). Adverse events within 90 days occurred in 666 (24·5%) patients in the indobufen group and 679 (24·9%) patients in the aspirin group (p=0·73). INTERPRETATION: In patients with acute moderate-to-severe ischaemic stroke, indobufen was not non-inferior to aspirin because the upper limit of the 95% CI was greater than 1·25. Furthermore, indobufen seemed to be inferior to aspirin in reducing the risk of recurrent stroke at 90 days because the lower limit of the 95% CI was greater than 1·00. Although moderate or severe bleeding did not differ between groups, these findings do not support the use of indobufen for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke. FUNDING: Hangzhou Zhongmei Huadong Pharmaceutical and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Intravenous thrombolysis versus antiplatelet therapy in minor stroke patients with large vessel occlusion.

AIM: Our study aimed to explore the effectiveness and safety of intravenous t-PA compared with dual antiplatelet therapy (DAPT) and aspirin alone for minor stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5 and large vessel occlusion (LVO). METHODS: Patients with minor stroke harboring LVO within 4.5-h time window were included from the Third China National Stroke Registry (CNSR-III) between August 2015 and March 2018 in China. Clinical outcomes including modified Rankin scale (mRS) score, recurrent stroke, and all-cause mortality at 90 days and 36-h symptomatic intracerebral hemorrhage (sICH) were collected. Multivariable logistic regression models and propensity score matching analyses were used to determine the association between treatment groups and clinical outcomes. RESULTS: A total of 1401 minor stroke patients with LVO were included. Overall 251 patients (17.9%) received intravenous t-PA, 722 patients (51.5%) received DAPT, and 428 patients (30.5%) received aspirin alone. The intravenous t-PA was associated with greater proportions of mRS 0-1 (aspirin versus t-PA: adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.32 to 0.80; p = 0.004; DAPT versus t-PA: aOR, 0.76; 95% CI, 0.49 to 1.19; p = 0.23). Using propensity score matching analyses, the results were similar. There was no difference in 90-day recurrent stroke among the groups. The rates of all-cause mortality in intravenous t-PA, DAPT, and aspirin groups were 0%, 0.55%, 2.34%, respectively. No patient developed sICH within 36 h of intravenous t-PA. CONCLUSION: In patients with minor stroke harboring LVO within 4.5-h time window, intravenous t-PA was associated with higher odds for the excellent functional outcome, as compared with the aspirin alone. Further randomized controlled trials are warranted.