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Introduction Tenecteplase (TNK) has emerged as an alternative intravenous thrombolytic for acute ischemic stroke (AIS). Multiple randomized phase III noninferiority trials, including AcT and TRACE-2, have demonstrated that TNK 0.25 mg/kg is noninferior to alteplase 0.9 mg/kg for 90-day functional outcomes, with comparable safety profiles. Additional data from EVT-bridging trials such as EXTEND-IA TNK suggest favorable early reperfusion signals with TNK in large-vessel occlusion. However, randomized studies primarily report short-term (90-day) outcomes, and long-term comparative effectiveness and safety beyond this time horizon remain incompletely characterized. We therefore evaluated 6-month, 1-year, and 3-year outcomes following AIS treated with TNK versus alteplase using a large federated electronic health record network.Methods Using the TriNetX Research network, we identified adults (≥18 years) with AIS (ICD-10 I63) from 2018-2025 who received alteplase or TNK within 1 day of AIS. Cohorts were mutually exclusive by thrombolytic exposure and excluded patients with hemorrhagic stroke (I61/I62) on or before thrombolysis and those with pulmonary embolism, acute myocardial infarction, or cardiac arrest. Outcomes were assessed for patients with 6 months, 1 year, and 3 years follow up, excluding patients with the outcome prior to the time window. Propensity-score matching balanced demographics and baseline characteristics including age, sex, race/ethnicity, hypertension, diabetes, atrial fibrillation, prior TIA/stroke, ischemic heart disease, heart failure, kidney disease, nicotine dependence, hyperlipidemia, peripheral vascular disease, antithrombotic therapy (warfarin, DOACs, aspirin, clopidogrel, ticagrelor), and endovascular thrombectomy.Results After propensity-score matching, 9,832 matched pairs were included in the 6-month analysis, 9,601 matched pairs in the 1-year analysis, and 2,120 matched pairs in the 3-year analysis comparing alteplase and TNK. At 6 months, alteplase was associated with higher mortality than TNK (9.5% vs 6.6%; OR 1.47, 95% CI 1.32-1.63) without a significant difference in intracerebral hemorrhage (2.3% vs 2.5%; OR 0.91, 95% CI 0.76-1.09). Cognitive impairment occurred more frequently after alteplase (9.9% vs 8.8%; OR 1.15, 95% CI 1.03-1.28). At 1 year, alteplase remained associated with higher mortality (11.9% vs 7.8%; OR 1.59, 95% CI 1.44-1.75) with no difference in intracerebral hemorrhage (2.7% vs 2.8%; OR 0.99, 95% CI 0.84-1.18). Cognitive impairment was higher after alteplase at 1 year (11.9% vs 10.7%; OR 1.13, 95% CI 1.02-1.25). At 3 years, alteplase remained associated with higher mortality (14.8% vs 12.2%; OR 1.25, 95% CI 1.05-1.50), while intracerebral hemorrhage incidence was not significantly different (2.8% vs 2.4%; OR 1.19, 95% CI 0.81-1.74). Cognitive impairment was similar by 3 years (15.1% vs 14.7%; OR 1.03, 95% CI 0.84-1.26).Conclusions In this large propensity-matched federated EHR analysis, TNK exposure was associated with lower mortality at 6 months, 1 year, and 3 years compared with alteplase, without increased intracerebral hemorrhage. Early cognitive impairment diagnoses were more frequent after alteplase but converged over longer follow-up. While randomized trials have established noninferiority of TNK relative to alteplase for 90-day functional outcomes, these real-world longitudinal findings extend comparative data beyond the traditional trial horizon. Prospective studies incorporating long-term endpoints may further clarify durability of outcomes between thrombolytic strategies.Disclosures M. Costa: None. S. O’Leary: None. C. Young: None.