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

Abstract

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 4·5 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.