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Background Tenecteplase (TNK) is a genetically modified variant of alteplase (TPA) and has been established as a non-inferior alternative to TPA in acute ischemic stroke (AIS). Whether TNK exerts distinct benefits in large vessel occlusion (LVO) AIS is still being investigated. Objective To describe our first-year experience after a healthcare system-wide transition from TPA to TNK as the primary thrombolytic. Methods Patients with AIS who received intravenous thrombolytics between January 2020 and August 2022 were retrospectively reviewed. All patients with LVO considered for mechanical thrombectomy (MT) were included in this analysis. Spontaneous recanalization (SR) after TNK/TPA was a composite variable of reperfusion >50% of the target vessel territory on cerebral angiography or rapid, significant neurological recovery averting MT. Propensity score matching (PSM) was performed to compare SR rates between TNK and TPA. results A total of 148 patients were identified; 51/148 (34.5%) received TNK and 97/148 (65.5%) TPA. The middle cerebral arteries M1 (60.8%) and M2 (29.7%) were the most frequent occlusion sites. Baseline demographics were comparable between TNK and TPA groups. Spontaneous recanalization was significantly more frequently observed in the TNK than in the TPA groups (unmatched: 23.5% vs 10.3%, P=0.032). PSM substantiated the observed SR rates (20% vs 10%). Symptomatic intracranial hemorrhage, 90-day mortality, and functional outcomes were similar. Conclusions The preliminary experience from a realworld setting demonstrates the effectiveness and safety of TNK before MT. The higher spontaneous recanalization rates with TNK are striking. Additional studies are required to investigate whether TNK is superior to TPA in LVO AIS. [ABSTRACT FROM AUTHOR]