Manabu Inoue, Teruyuki Hirano, Mayumi Fukuda-Doi, Hiroyuki Kawano, Kenta Tanaka, Nobuyuki Sakai, Masatoshi Koga, Koji Iwasaki, Tomohide Yoshie, Naruhiko Kamogawa, Masafumi Ihara, Tsuyoshi Ohta, Masaki Chin, Naoto Kimura, Kazumi Kimura, Yohei Tateishi, Tadashi Terasaki, Taketo Hatano, Takahiro Kuwashiro, Shinichi Yoshimura, Toshihiro Ueda, Eiichiro Nagata, Yoshinari Nagakane, Shinichi Takahashi, Fumio Miyashita, Kazutaka Sonoda, Kenji Fukuda, Kanta Tanaka, Yoshiko Une, Shigetaka Kobari, Takehiko Nagao, Makoto Sasaki, Haruko Yamamoto, Kazunori Toyoda, T-FLAVOR trial Investigators
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.
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.