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Original Investigation
February 20, 2020

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  • 2The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia
  • 3Department of Radiology, the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
  • 4Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
  • 5Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
  • 6Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  • 7Department of Neurology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia
  • 8Department of Radiology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
  • 9Department of Radiology, Austin Hospital, Austin Health, Heidelberg, Victoria, Australia
  • 10School of Medicine, Faculty of Health, Deakin University, Victoria, Australia
  • 11Department of Neurology, Christchurch Hospital, Christchurch, New Zealand
  • 12Department of Neurology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  • 13Melbourne Medical School, Department of Medicine and Neurology, The University of Melbourne and Western Health, Sunshine Hospital, St Albans Victoria, Australia
  • 14Department of Neurology, Gold Coast University Hospital, Southport, Queensland, Australia
  • 15Department of Radiology, Gold Coast University Hospital, Southport, Queensland, Australia
  • 16Eastern Health and Eastern Health Clinical School, Department of Neurosciences, Monash University, Clayton, Victoria, Australia
  • 17Department of Radiology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  • 18Department of Radiology, Christchurch Hospital, Christchurch, New Zealand
  • 19Department of Medicine, Ballarat Base Hospital, Ballarat, Victoria, Australia
  • 20Department of Neurology, Royal North Shore Hospital and Kolling Institute, University of Sydney, St Leonards, New South Wales, Australia
  • 21Department of Neurology, Liverpool Hospital, Liverpool, New South Wales, Australia
  • 22Department of Neurology, Lyell McEwin Hospital, Adelaide, South Australia, Australia
  • 23School of Clinical Sciences, Department of Medicine, Monash University, Clayton, Victoria, Australia
  • 24Department of Neurology, Gosford Hospital, Gosford, New South Wales, Australia
  • 25Department of Neurology, University Hospital Geelong, Deakin University, Geelong, Victoria, Australia
  • 26Department of Neurology, Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital, University of Newcastle, Newcastle, New South Wales, Australia
  • 27Department of Medicine, Southwest Healthcare, Warrnambool, Victoria, Australia
  • 28Department of Neurology, Alfred Hospital, Prahran, Victoria, Australia
  • 29Department of Medicine, Northeast Health, Wangaratta, Victoria, Australia
  • 30Department of Medicine, Albury Base Hospital, Albury, New South Wales, Australia
  • 31Department of Medicine, Goulburn Valley Health, Shepparton, Victoria, Australia
  • 32Department of Medicine, Latrobe Regional Health, Traralgon, Victoria, Australia
  • 33Department of Medicine, Campbelltown Hospital, Campbelltown, New South Wales, Australia
  • 34Department of Aged Care and Rehabilitation, Bankstown-Lidcombe Hospital, Bankstown, New South Wales, Australia
  • 35Department of Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  • 36Department of Neurology, Royal Brisbane and Women’s Hospital and the University of Queensland, Brisbane, Queensland, Australia
  • 37Maridulu budyari gumal, The Sydney Partnership for Health Education Research & Enterprise (SPHERE), University of New South Wales, Sydney, Australia
  • 38Victorian Stroke Telemedicine service, Ambulance Victoria, Melbourne, Victoria, Australia
JAMA. 2020;323(13):1257-1265. doi:10.1001/jama.2020.1511
Key Points

Question  Does a 0.40-mg/kg dose of tenecteplase, compared with 0.25 mg/kg of tenecteplase, improve cerebral reperfusion prior to endovascular thrombectomy in patients with large vessel occlusion ischemic stroke?

Findings  In this randomized clinical trial that included 300 adults, the percentage who achieved substantial reperfusion prior to endovascular thrombectomy was 19.3% in each tenecteplase dose group, with no statistically significant difference.

Meaning  The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke.

Abstract

Importance  Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.

Objective  To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.

Design, Setting, and Participants  Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.

Interventions  Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.

Main Outcomes and Measures  The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.

Results  All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, −8.9% to −8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, −5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, −0.5% to 7.2%]).

Conclusions and Relevance  Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.

Trial Registration  ClinicalTrials.gov Identifier: NCT03340493

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