Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection

N Engl J Med. 2024 Feb 22;390(8):701-711. doi: 10.1056/NEJMoa2310392. Epub 2024 Feb 8.


Background: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited.

Methods: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage.

Results: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively.

Conclusions: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Publication types

  • Randomized Controlled Trial
  • Multicenter Study

MeSH terms

  • Brain / blood supply
  • Brain / diagnostic imaging
  • Brain Ischemia* / diagnostic imaging
  • Brain Ischemia* / drug therapy
  • Brain Ischemia* / mortality
  • Brain Ischemia* / surgery
  • Carotid Artery Diseases / diagnostic imaging
  • Carotid Artery Diseases / drug therapy
  • Carotid Artery Diseases / surgery
  • Double-Blind Method
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / adverse effects
  • Fibrinolytic Agents / therapeutic use
  • Humans
  • Infarction, Middle Cerebral Artery / diagnostic imaging
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / surgery
  • Intracranial Hemorrhages / chemically induced
  • Intracranial Hemorrhages / diagnostic imaging
  • Ischemic Stroke* / diagnostic imaging
  • Ischemic Stroke* / drug therapy
  • Ischemic Stroke* / mortality
  • Ischemic Stroke* / surgery
  • Perfusion
  • Perfusion Imaging* / methods
  • Stroke / diagnostic imaging
  • Stroke / drug therapy
  • Stroke / mortality
  • Stroke / surgery
  • Tenecteplase* / administration & dosage
  • Tenecteplase* / adverse effects
  • Tenecteplase* / therapeutic use
  • Thrombectomy* / adverse effects
  • Thrombectomy* / methods
  • Time-to-Treatment
  • Tissue Plasminogen Activator* / administration & dosage
  • Tissue Plasminogen Activator* / adverse effects
  • Tissue Plasminogen Activator* / therapeutic use
  • Treatment Outcome


  • Fibrinolytic Agents
  • Tenecteplase
  • Tissue Plasminogen Activator

Associated data

  • ClinicalTrials.gov/NCT03785678