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Objective To investigate the safety outcomes in acute ischemic stroke patients who received tenecteplase versus alteplase within 4.5 hours of symptom onset.Background Acute ischemic strokes (AIS) are a leading cause of morbidity worldwide. Alteplase (tPA) is the gold standard, FDA-approved thrombolytic administered within 4.5 hours of stroke symptoms. Tenecteplase (TNK) is FDA-approved for STEMI, but its off-label use for AIS is rising due to its greater fibrin specificity and longer half-life. The proportion of adverse safety outcomes in AIS patients who received either thrombolytic has been reported across trials, however the overall bleeding risk in adult AIS patients given TNK has not been well established.Methods Using PRIMA guidelines, a systematic review was conducted examining safety outcomes of TNK versus tPA in treating AIS. The PubMed database was searched using keywords including ‘tenecteplase’, ‘bleeding’, ‘acute ischemic stroke’, ‘adults’, ‘safety’, and others up until January 23, 2026. Then, two independent reviewers conducted a manual review to include only studies which directly compared TNK versus tPA with at least 1 primary safety outcome.Results 18 studies met the inclusion criteria, with 7,894 total AIS patients. Of these, 8 were randomized control trials and 10 were subsequent post-hoc analyses. Neither incidence of symptomatic intracerebral hemorrhage (sICH), 90-day mortality rate, or serious adverse events differed significantly between TNK and tPA treatment groups. The incidence of sICH ranged from 1-3.4% in AIS patients given TNK and 1-4% in those given tPA within 4.5 hours. 90-day mortality ranged from 4.6-15.3% in TNK groups and 5-18% in tPA groups. The incidence of serious adverse events ranged from 5-42% in TNK groups and 8-31% tPA groups. Post hoc analyses showed TNK and tPA safety outcomes to not differ significantly in the following subsets of AIS patients: minor stroke (NIHSS <= 5), posterior circulation stroke, large vessel occlusion stroke, no visible occlusion, patients < 80 years old and >= 80 years old, diabetics and those with admission hyperglycemia, and those given TNK or tPA in the 3-4.5 hour window. In comparing moderate to severe AIS cases, sICH incidence was similar in TNK and tPA groups however 90-day mortality rate was significantly increased in severe AIS treated with TNK (26.3%) versus tPA (9.1%).Discussion These results provide evidence of comparable safety outcomes in AIS patients administered TNK versus tPA, the current gold standard, building on well-established evidence that TNK has superior efficacy in treating AIS. However, there is a need for future studies to focus on more at-risk populations. The lack of statistically significant differences in bleeding risk, specifically sICH, in this systematic review supports the use of TNK over tPA given that TNK is has high affinity towards fibrin and may be given in a single bolus, especially in mild to moderate stroke.Disclosures S. Hyland: None. C. Carr: None. L. Jones: None. H. David: None. K. Asher: None. L. Debs: None. L. Kaoutzani: None. D. Giurgiutiu: None. S. Rahimi: None.