Comparative Safety of Tenecteplase and Alteplase in Direct Oral Anticoagulant‐Pretreated Patients With Acute Ischemic Stroke

Pretreatment with direct oral anticoagulants (DOACs) may increase bleeding risk after intravenous thrombolysis (IVT) for acute ischemic stroke, but the comparative safety of tenecteplase vs. alteplase remains uncertain. We conducted a real-world retrospective cohort study using the TriNetX Global Network (queried October 2025). Patients with acute ischemic stroke who received IVT were identified and matched 1:1 by propensity scores. Cox proportional hazard models estimated hazard ratios (HRs); a time-split Cox model assessed time-varying effects. The primary composite outcome comprised nontraumatic intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), transfusion, gastrointestinal bleeding, and mortality; secondary outcomes were the individual components. Outcomes were assessed from the day of IVT through days 1, 7, 14, and 21. A total of 1636 patients receiving tenecteplase and 25,370 receiving alteplase were identified, yielding 1634 matched patients per group. Tenecteplase was associated with higher risks of composite outcomes (Day 1: 13.6% vs. 7.4%; HR 1.87, P < 0.001; Day 21: HR 1.36, P = 0.002), ICH (Day 1: 9.1% vs 2.8%; HR 3.26, P < 0.001; Day 21: HR 3.23, P < 0.001), SAH (Day 1: 3.2% vs 1.1%; HR 2.84, P < 0.001; Day 21: HR 2.78, P < 0.001). Mortality was greater with tenecteplase at Day 1 (2.6% vs 1.3%; HR 2.01, P = 0.009) and Day 7 (HR 1.38, P = 0.020). Time-split Cox analysis confirmed that excess risk was confined to the first 24 hours. Among patients pretreated with DOACs, tenecteplase was associated with higher early risk of hemorrhagic transformation and mortality than alteplase, underscoring the need for vigilance during the first 24 hours after treatment.