Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection:the umbrella phase IIa CHABLIS-T randomised clinical trial

Background The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/ medium vessel occlusion beyond 4.5- hour time window. Methods The CHinese Acute tissue- Based imaging selection for Lysis In Stroke- Tenecteplase was an investigator- initiated, umbrella phase IIa, open- label, blinded- endpoint, Simon’s two- stage randomised clinical trial in 13 centres across China's Mainland. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/ kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. Results A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon’s two- stage design. Discussion Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety.

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study

Background The optimal time to commence anticoagulation in patients with atrial fibrillation(AF)after ischaemic stroke or transient ischaemic attack(TIA)is unclear,with guidelines differing in recommendations.A limitation of previous studies is the focus on clinically overt stroke,rather than radiologically obvious diffusion-weighted imaging ischaemic lesions.We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1month in patients commenced on early(<4days)vs late(≥4days)anticoagulation.We hypothesised that there would be fewer ischaemic lesions and more haemorrhages in the early anticoagulant group at 1-month MRI.Methods A prospective multicentre,observational cohort study was performed at 11 Australian stroke centres.Clinical and MRI data were collected at baseline and follow-up,with blinded imaging assessment performed by two authors.Timing of commencement of anticoagulation was at the discretion of the treating stroke physician.Results We recruited 276 patients of whom 208 met the eligibility criteria.The average age was 74.2 years(SD±10.63),and 79(38%)patients were female.Median National Institute of Health Stroke Scale score was 5(IQR 1–12).Median baseline ischaemic lesion volume was 5mL(IQR 2–17).There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation≥4days after index event(17%vs 8%,p=0.04),but no difference in haemorrhage rates(22%vs 32%,p=0.10).Baseline ischaemic lesion volume of≤5mL was less likely to have a new haemorrhage at 1month(p=0.02).There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of>5mL,regardless of anticoagulation timing.Conclusion Commencing anticoagulation<4days after stroke or TIA is associated with fewer ischaemic lesions at 1month in AF patients.There is no increased rate of haemorrhage with early anticoagulation.These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe,but randomised controlled studies are needed to inform clinical practice.WHAT IS ALREADY KNOWN ON THIS TOPIC⇒Early anticoagulation after ischaemic stroke associ-ated with atrial fibrillation(AF)may reduce the rate of recurrent diffusion-weighted imaging ischaemic lesions and increase the rate of new haemorrhage.⇒It is unknown whether early anticoagulation also re-duces the rate of new silent ischaemic lesions.WHAT THIS STUDY ADDS⇒Early anticoagulation(<4days)after ischaemic stroke due to AF reduces the rate of new silent isch-aemic lesions at 1month without increasing the rate of new haemorrhage.HOW THIS STUDY MIGHT AFFECT RESEARCH,PRACTICE OR POLICY⇒Early anticoagulation after mild-to-moderate acute ischaemic stroke due to AF might be safe,howev-er,the results require further validation with ran-domised trials.

CHinese Acute Tissue-Based Imaging Selection for Lysis In Stroke TenecteplaseⅡ(CHABLIS-TⅡ):rationale and design

Background and purpose Tenecteplase(TNK)has demonstrated non-­inferiority to alteplase in patients who had an acute ischaemic stroke presenting within 4.5 hours from symptom onset.The trial is aimed to explore the efficacy and safety of TNK in Chinese patients who had an acute ischaemic stroke with large/medium vessel occlusion in an extended time window.Methods and design Chinese Acute Tissue-­Based Imaging Selection for Lysis In Stroke TenecteplaseⅡ(CHABLIS-­TⅡ)is a multicentre,prospective,block-­randomised,open-­label,blinded-­endpoint,phaseⅡb study.Eligible patients are 1:1 randomised into two groups:0.25 mg/kg TNK versus best medical management(excluding TNK).The safety and efficacy of 0.25 mg/kg TNK are assessed through reperfusion status and presence of symptomatic intracranial haemorrhage(sICH).Study outcomes The primary outcome is major reperfusion without sICH at 24–48 hours after randomisation.Major reperfusion is defined as restoration of blood flow to greater than 50%of the involved ischaemic territory assessed by catheter angiography or repeated perfusion imaging.Secondary outcomes include post-­thrombolytic recanalisation,neurological improvements,change in the National Institutes of Health Stroke Scale score,haemorrhagic transformation at 24–48 hours,systematic bleeding at discharge,modified Rankin Scale(mRS)0–1,mRS 0–2,mRS 5–6,mRS distribution and Barthel index at 90 days.Discussion CHABLIS-­TⅡwill provide important evidence of intravenous thrombolysis with TNK for patients who had an acute stroke in an extended time window.