https://www.nejm.org/doi/full/10.1056/NEJMoa2310392

Effectiveness of Tenecteplase in Ischemic Stroke Patients 4.5 to 24 Hours After Symptom Onset

• Background:
  • Thrombolytic agents, such as tenecteplase, are typically used within 4.5 hours after the onset of stroke symptoms.
  • Limited information available on the benefits of tenecteplase beyond 4.5 hours.
• Methods:
  • Multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke.
  • Comparison between tenecteplase and placebo administered 4.5 to 24 hours after the patient was last known to be well.
• Results:
  • 458 patients enrolled, with 77.3% subsequently undergoing thrombectomy.
  • No significant difference in clinical outcomes between tenecteplase and placebo at 90 days.
• Conclusions:
  • Tenecteplase therapy initiated 4.5 to 24 hours after stroke onset did not result in better clinical outcomes than placebo.
  • Similar incidence of symptomatic intracerebral hemorrhage in both groups.
• Quick Take:
  • Intravenous thrombolytic therapy with alteplase has been the standard care for eligible patients within 4.5 hours after the onset of ischemic stroke.
  • Previous trials of thrombolytic therapy have shown benefit when reperfusion can be obtained in patients with salvageable brain tissue.
• Trial Design and Oversight:
  • Multicenter, double-blind, randomized, placebo-controlled trial conducted at 112 centers in the US and Canada.
  • Trial sponsored by Genentech and designed by a steering committee in conjunction with the sponsor.
• Patients:
  • Eligible patients were at least 18 years of age with independent function before the stroke.
  • Could receive tenecteplase or placebo 4.5 to 24 hours after the time they were last known to be well.
• Patients Selection:
  • Patients with a NIHSS score of at least 5 were selected for the trial.
  • They needed to have evidence of salvageable brain tissue as determined by specific imaging criteria.
• Trial Interventions:
  • Patients were randomly assigned to receive either tenecteplase or placebo.
  • All patients received medical care in accordance with specific protocols and guidelines.
• Outcomes:
  • The primary outcome was the ordinal score on the modified Rankin scale at day 90.
  • Secondary outcomes included functional independence, recanalization of the implicated vessel, reperfusion, median NIHSS score, Barthel Index score, and good recovery according to the Glasgow Outcome Scale.
• Statistical Analysis:
  • The target sample size was estimated to be 456 with specific assumptions.
  • Efficacy analyses were adjusted for baseline factors, and missing data were handled according to protocol.
• Sensitivity Analyses:
  • Several sensitivity analyses of the primary outcome were conducted to assess the consistency of the primary analysis result.
  • The primary outcome was analyzed in prespecified subgroups defined according to specific criteria.
• Safety Outcomes:
  • Safety outcomes included death and symptomatic intracranial hemorrhage.
  • Trained assessors collected data on 30-day and 90-day outcomes.
• Patients Demographics:
  • A total of 458 patients underwent randomization at 108 centers in the United States and at 4 centers in Canada.
  • The baseline demographic and clinical characteristics of the patients were similar in the two groups.
• Clinical Outcomes:
  • There was no significant difference favoring the tenecteplase group over the placebo group in the overall distribution of scores on the Modified Rankin Scale at 90 days.
  • Functional independence at 90 days was observed in 104 patients (46.0%) in the tenecteplase group and in 97 (42.4%) in the control group.
• Safety Outcomes:
  • Mortality at 90 days did not differ appreciably between the two trial groups, with similar rates in both groups.
  • The incidence of adverse events, serious adverse events, and withdrawal from the trial due to adverse events did not differ appreciably between the groups.
• Imaging Outcomes:
  • Complete recanalization as assessed on 24-hour angiography by MRI or CT occurred in 76.7% of the patients in the tenecteplase group and in 63.9% of those in the placebo group.
  • The mean final infarct volume appeared to be lower in the tenecteplase group than in the placebo group.
• Subgroup Analyses:
  • The trial was not powered for conclusions from this analysis, and they are not adjusted for multiplicity.
  • The adjusted common odds ratio for the modified Rankin scale scores among patients with an occlusion of the M1 segment of the middle cerebral artery was 1.59 (95% CI, 1.00 to 2.52).