Thirty years of intravenous thrombolysis for acute ischemic stroke: Historical perspectives, evidence from randomized trials, and emerging directions.

Intravenous thrombolysis (IVT) remains a cornerstone in the management of acute ischemic stroke (AIS). Since the landmark NINDS and ECASS III trials, numerous randomized controlled trials (RCTs) have expanded IVT indications beyond the initial 4.5-h window. Advanced imaging modalities, including perfusion-based and diffusion/fluid-attenuated inversion recovery (FLAIR) mismatch, have enabled individualized patient selection, leading to positive outcomes in trials such as WAKE-UP, EXTEND, and EXPECTS. Despite these advances, key challenges remain. Patients with large ischemic cores, those on direct oral anticoagulants (DOACs), and those with minor non-disabling strokes lack robust evidence supporting IVT use. Moreover, while alternative thrombolytics like tenecteplase have shown promise, additional data are needed to redefine the standard of care. Adjunctive pharmacologic therapies (e.g., glycoprotein IIb/IIIa or thrombin inhibitors) have yet to demonstrate consistent benefit. This review highlights the progress, limitations, and future directions of IVT, emphasizing a shift from rigid temporal thresholds toward physiology-based, patient-centered stroke reperfusion strategies.