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 Alteplase compared to Tenecteplase (AcT) randomized controlled trial (RCT) showed that tenecteplase is non-inferior to alteplase in treating 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 RCT comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4{middle dot}5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin scale(mRS) 0-1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage (sICH) and 90-day mortality rates. Mixed effects logistic regression was used to assess a)the association of stroke symptom onset to needle time (ONT), b)door (hospital arrival) to needle time(DNT) with outcomes and c)if these associations were modified by type of thrombolytic administered( tenecteplase vs. 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, 555 alteplase] presented within 3 hours vs. 392 (25.5%)[196: TNK, 196 alteplase] who presented within 3-4.5 hours of symptom onset. Baseline patient characteristics in the 0-3 hour versus 3-4.5-hour time window were similar, except patients in the 3-to-4.5-hour window had lower median baseline NIHSS (10 vs 7 respectively) and lower proportion of patients with large vessel occlusion on baseline CT Angiography (26.9% vs 18.7% respectively). Type of thrombolytic agent ( tenecteplase vs. alteplase) did not modify the association between ONT(pinteraction = 0.161) or DNT(pinteraction = 0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-min reduction in ONT was associated with a 1.8% increase while every 10 min reduction in DNT was associated with a 0.2% increase in the probability of achieving 90-day mRS 0-1 respectively. Conclusion: The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes.

[1]  G. D. De Marchis,et al.  European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke , 2023, European stroke journal.

[2]  Y. Liu,et al.  Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial , 2023, The Lancet.

[3]  N. Foley,et al.  Canadian Stroke Best Practice Recommendations: Acute Stroke Management, 7th Edition Practice Guidelines Update, 2022. , 2022, The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques.

[4]  Alexander M. Fraser,et al.  Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial , 2022, The Lancet.

[5]  Nazia Darvesh,et al.  Systemic Thrombolysis by Alteplase for Acute Ischemic Stroke , 2022, Canadian Journal of Health Technologies.

[6]  R. Swartz,et al.  Ethical Justification for Deferral of Consent in the AcT Trial for Acute Ischemic Stroke , 2022, Stroke.

[7]  N. Lannin,et al.  Living clinical guidelines for stroke: updates, challenges and opportunities , 2022, The Medical journal of Australia.

[8]  Thalia Shoshana Field,et al.  Alteplase Compared to Tenecteplase in patients with Acute Ischemic Stroke (AcT) Trial: Protocol for a Pragmatic Registry linked Randomized Clinical Trial , 2022, Stroke: Vascular and Interventional Neurology.

[9]  Ana Catarina Fonseca,et al.  European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke , 2021, European stroke journal.

[10]  M. Krause,et al.  Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. , 2020, JAMA.

[11]  G. Donnan,et al.  Determining the optimal dose of tenecteplase before endovascular therapy for ischemic stroke (EXTEND-IA TNK Part 2): A multicenter, randomized, controlled study , 2020, International journal of stroke : official journal of the International Stroke Society.

[12]  W. Powers,et al.  Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. , 2019, Stroke.

[13]  K. Butcher,et al.  Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018 , 2018, International journal of stroke : official journal of the International Stroke Society.

[14]  A. Demchuk,et al.  The Heidelberg Bleeding Classification: Classification of Bleeding Events After Ischemic Stroke and Reperfusion Therapy. , 2015, Stroke.

[15]  P. Sandercock,et al.  Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials | NOVA. The University of Newcastle's Digital Repository , 2014 .

[16]  J. Brophy,et al.  Fibrinolysis or primary PCI in myocardial infarction. , 2013, The New England journal of medicine.

[17]  G. Donnan,et al.  A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. , 2012, The New England journal of medicine.

[18]  A. Rabinstein Acute ischemic stroke: Imaging-guided tenecteplase treatment in an extended time window , 2009 .

[19]  Frank E. Harrell,et al.  Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis , 2001 .