Since the landmark NINDS trial (National Institute of Neurological Disorders and Stroke) in 1995, alteplase (tissue plasminogen activator (tPA)) has remained the only fibrinolytic agent for the treatment of acute ischemic stroke (AIS) approved by the Food and Drug Administration.1 However, tenecteplase (TNK), a genetically modified variant of tPA, has emerged as a promising alternative due to its higher fibrin specificity, longer half-life, and ease of administration via a single bolus.2 These properties allow for rapid clot exposure to high enzyme concentrations, facilitating faster fibrinolysis.2

TNK became the preferred thrombolytic agent in the early 2000s for treating myocardial infarction, favored for its simplicity of use, comparable efficacy, and cost-effectiveness over tPA.3 These advantages quickly garnered attention for potential use in stroke treatment. Over recent years, increasing evidence from randomized controlled trials (RCTs) and real-world studies has confirmed TNK’s safety and efficacy in patients with AIS.4 As a result, TNK has seen growing off-label adoption as the preferred agent for intravenous thrombolysis (IVT) in AIS.

This commentary aims to examine the expanding body evidence supporting TNK use in patients with AIS, particularly in those undergoing endovascular thrombectomy (EVT). Additionally, it assesses the potential for intra-arterial (IA) TNK as an emerging approach for improving stroke outcomes.

EVT has become the standard of care for appropriately selected patients with AIS due to large vessel occlusion (LVO).5 Although current guidelines recommend IVT with tPA before EVT in patients with LVO who meet criteria, clinical trials have shown inconclusive results, as non-inferiority of thrombectomy alone has not been consistently demonstrated.6 A recent meta-analysis found that the benefit of IVT decreases with time, with no statistically significant advantage observed when IVT is administered beyond 2 hours 20 min after onset of symptoms in patients undergoing EVT.7 Pooled data also revealed …