Background and Objective:The safety and efficacy of tenecteplase in patients with tandem lesion stroke is unknown. We performed a comparative analysis of tenecteplase versus alteplase in patients with tandem lesions.Methods:We first compared the treatment effect of tenecteplase and alteplase in patients with tandem lesions using individual patient data from the EXTEND-IA TNK trials. We evaluated intracranial reperfusion at initial angiographic assessment and 90-day mRS with ordinal logistic and Firth regression models. Because two key outcomes, mortality and symptomatic intracranial hemorrhage, were few in number among those who received alteplase in the EXTEND-IA TNK trials, we generated pooled estimates for these outcomes by supplementing trial data with estimates of incidence obtained through a meta-analysis of studies identified in a systematic review. We then calculated unadjusted risk differences to compare the pooled estimates for those receiving alteplase with the incidence observed in the trial among those receiving tenecteplase.Results:Seventy-one of 483 patients (15%) in the EXTEND-IA TNK trials possessed a tandem lesion. In tandem lesion patients, intracranial reperfusion was observed in 11/56 (20%) of tenecteplase treated patients vs. 1/15 (7%) alteplase treated patients (aOR: 2.19; 95% CI:0.28-17.29). No significant difference in 90-day mRS was observed (adjusted common OR: 1.48; 95% CI: 0.44-5.00). A pooled study-level proportion of alteplase associated mortality and symptomatic intracranial hemorrhage was 0.14 (95% CI: 0.08-0.21) and 0.09 (95% CI: 0.04-0.16), respectively. Compared to a mortality rate of 0.09 (95% CI: 0.03-0.20) and a symptomatic intracranial hemorrhage rate of 0.07 (95% CI: 0.02-0.17) in tenecteplase treated patients, no significant difference was observed.Conclusions:Functional outcomes, mortality, and symptomatic intracranial hemorrhage did not significantly differ between tenecteplase and alteplase treated tandem lesion patients.Classification of Evidence:This study provides Class III evidence that tenecteplase is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and symptomatic intracranial hemorrhage compared with alteplase, in patients with acute stroke due to tandem lesions. However, the confidence intervals do not rule out clinically important differences.