IMPORTANCE: Tenecteplase is an alternative to alteplase for emergency treatment of acute ischemic stroke. However, limited data are available comparing their clinical effectiveness in routine clinical practice. OBJECTIVE: To compare short-term effectiveness and safety outcomes for patients with ischemic stroke treated with intravenous tenecteplase vs alteplase. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study used data prospectively collected from July 1, 2020, through June 30, 2022, from the Get With The Guidelines-Stroke registry. EXPOSURE: Consecutive patients with ischemic stroke treated with either tenecteplase or alteplase within 4.5 hours from last known well time were included. MAIN OUTCOMES AND MEASURES: The primary end point was functional independence on discharge (modified Rankin Scale [mRS] score, 0-2). Secondary effectiveness end points included disability free at discharge (mRS score, 0-1), discharge home, and independent ambulation at discharge. Safety end points included symptomatic intracranial hemorrhage (sICH) within 36 hours and combined in-hospital mortality or hospice discharge. Generalized linear mixed models were fit to evaluate associations between exposure to tenecteplase (vs alteplase) and end points after adjustment for demographic, clinical, and hospital-level variables. Adjusted odds ratios (AORs) with 95% CIs were computed. RESULTS: Among 79 550 patients treated with intravenous thrombolysis, the mean (SD) age was 68.6 (14.8) years, 38 596 (48.5%) were female, and the median National Institutes of Health Stroke Scale (NIHSS) score was 7 (IQR, 4-13). Of these patients, 9465 (11.9%) received tenecteplase (mean [SD] age, 69.6 [14.7] years
median NIHSS score, 7 [IQR, 4-14]
4504 [47.6%] female) and 70 085 (88.1%) received alteplase (mean [SD] age, 68.5 [14.8] years
median NIHSS score, 7 [IQR, 4-13]
34 092 [48.6%] female). After adjustment for covariates, no significant differences were found between tenecteplase and alteplase in effectiveness or safety outcomes for the overall cohort, including functional independence at discharge (AOR, 1.00
95% CI, 0.93-1.07), sICH (AOR, 0.96
95% CI, 0.83-1.11), and in-hospital mortality or hospice discharge (AOR, 0.98
95% CI, 0.89-1.07), but significant improvement was found in discharge home (AOR, 1.26
95% CI, 1.03-1.53), in-hospital mortality (AOR, 0.63
95% CI, 0.47-0.85), and composite in-hospital mortality or hospice discharge (AOR, 0.78
95% CI, 0.62-0.97) among those who were eligible for but did not undergo endovascular thrombectomy. CONCLUSIONS AND RELEVANCE: This large, nationwide comparative effectiveness study using data from routine clinical practice demonstrated similar effectiveness and safety outcomes with tenecteplase compared with alteplase in patients with acute ischemic stroke. This study supports tenecteplase as a reasonable alternative to alteplase.