Reference: Albers GW et al. TIMELESS Investigators. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. NEJM Feb 2024 Date: April 12, 2024 Guest Skeptic: Dr. Vasisht Srinivasan is an Emergency Medicine physician and neurointensivist at the University of Washington and Harborview Medical Center in Seattle, WA. He is an assistant professor in Emergency Medicine, Neurology, and Neurosurgery at the School of Medicine at the University of Washington. Case: A 70-year-old woman was brought into the emergency department by EMS after her family reported she was having trouble talking.  They noticed this earlier in the day and let her rest, but when she had trouble moving her right arm, they called 911.  Initial evaluation by medics revealed right hemiplegia, a right facial droop, left gaze deviation, and aphasia.  When she arrives in your ED, her family tells you she was last seen normal about 12 hours ago.  A code stroke is activated, and the initial CT head shows no signs of hemorrhage or early ischemic changes.  A CT angiogram shows a proximal middle cerebral artery occlusion.  CT perfusion showed a 10 mL core and 189 mL penumbra.  As you speak to your stroke team, the question of thrombolysis comes up, as her core is quite small, and the stroke may still be very early in its time course. Background: The question of thrombolysis for acute ischemic stroke dates back nearly 30 years to the initial NINDS trial published in 1995 [1].  Since that time, numerous studies and analyses have been undertaken to categorize the potential benefits and potential harms associated with thrombolysis in stroke [2-8]. We have discussed this issue multiple times on the SGEM including: SGEM#29: Stroke Me, Stroke Me SGEM#70: The Secret of NINDS SGEM Xtra:Thrombolysis for Acute Stroke SGEM Xtra: Walk of Life SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up With the pentad of thrombectomy trials published in 2015 [9-13] and the extension of the thrombectomy window in 2018 following the publication of DAWN [13] and DEFUSE-3 [15], the standard of care has now shifted to mechanical thrombectomy for large vessel occlusion, though thrombolysis is still used up to 4.5 hours from onset of symptoms. We have looked at the issue of EVT with or without thrombolytics on the SGEM a few times. SGEM#137: A Foggy Day – Endovascular Treatment for Acute Ischemic Stroke SGEM#292: With or Without You – Endovascular Treatment with or without tPA for Large Vessel Occlusions SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up SGEM#333: Do you Gotta Be Starting Something – Like tPA before EVT? SGEM#349: Can tPA Be A Bridge Over Trouble Waters to Mechanical Thrombectomy? There have also been several SRMA on this issue [16-21] a few guidelines published on the topic [22-24] and ACEP is currently working on a clinical policy to address this question of EVT +/- thrombolytics. Following nearly a decade of research into Tenecteplase (TNK), beginning as early as 2012 [25], this agent has supplanted alteplase (tPA)as the preferred thrombolytic agent at both some large stroke centers as well as many community sites designated as primary stroke centers. SGEM#377 covered one of those trials comparing tPA to TNK. The AcT trial was a pragmatic, multicentre, open-label, registry-linked, randomized, controlled, non-inferiority trial [26]. This trial reported that TNK was non-inferior to tPA in stroke patients treated within 4.5 hours of symptom onset.  Studies from the UK [27], Australia and New Zealand [28, 29], and several studies from Norway [30, 31] have similarly shown that it is neither superior to alteplase nor is it inferior. Perfusion imaging allows more careful patient selection for therapies as it identifies those patients with salvageable ischemic tissue (penumbra) that can be “rescued” if reperfused versus those who have a large burden of infarct (core) that cannot be recovered wi...