Standard-Dose Tenecteplase vs Low-Dose Alteplase for Acute Ischemic Stroke From Large-Vessel Occlusion: A Randomized Clinical Trial.

Importance: Tenecteplase has advantages over standard-dose alteplase for acute ischemic stroke. A low-dose alteplase regimen (0.6 mg/kg) remains the standard in Japan and is commonly used in several Asian countries. Objective: To determine whether standard-dose tenecteplase at 0.25 mg/kg achieves a higher rate of recanalization on the initial angiogram than low-dose alteplase at 0.6 mg/kg in patients scheduled for mechanical thrombectomy. It is inevitable to generate evidence required to support potential regulatory approval of tenecteplase in Japan. Design, Setting, and Participants: This investigator-initiated, multicenter, randomized, controlled, open-label, superiority trial was conducted from August 19, 2022, through March 13, 2025, with 3-month follow-up and was the first ever to compare tenecteplase (0.25 mg/kg) with alteplase (0.6 mg/kg) for acute ischemic stroke. Participants included patients with large-vessel-occlusion stroke eligible for intravenous thrombolysis within 4.5 hours of symptom onset followed by mechanical thrombectomy. A total of 221 patients were randomized and 218 who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). These data were analyzed from July 2025 to December 2025. Interventions: Patients were randomly assigned in a 1:1 ratio to receive either intravenous tenecteplase or alteplase. Main outcomes and measures: The primary outcome was substantial reperfusion (modified Treatment in Cerebral Ischemia grade 2b to 3 or no retrievable thrombus) on the initial angiogram. Secondary outcomes included the 90-day modified Rankin Scale. Safety outcomes were symptomatic intracranial hemorrhage within 24 to 36 hours and mortality at 90 days. Results: A total of 218 patients (mean [SD] age, 77.1 [12.0] years; 92 female and 126 male) who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). Substantial reperfusion occurred in 10.3% of the standard-dose tenecteplase group vs 3.6% of the low-dose alteplase group (absolute difference, 6.5 percentage points; 90% CI, 0.89-12.1), meeting the prespecified success criterion. The estimated common odds ratio for a shift toward better 90-day functional outcome with tenecteplase was 1.47 (95% CI, 0.92-2.35). Rates of symptomatic intracranial hemorrhage (2.8% vs 1.8%) and mortality (6.5% vs 9.9%) were similar between tenecteplase and alteplase groups. Conclusions and relevance: In this study, standard-dose tenecteplase (0.25 mg/kg) prior to thrombectomy resulted in a higher rate of early substantial reperfusion compared with low-dose alteplase (0.6 mg/kg), with comparable functional and safety outcomes. Standard-dose tenecteplase is a promising thrombolytic option in regions where low-dose alteplase is currently the standard of care. Trial Registration: Japan Registry of Clinical Trials Identifier: 051210055.