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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Campbell reported receiving grants from the National Health and Medical Research Council and the National Heart Foundation during the conduct of the study. Dr Mitchell reported receiving travel support from Stryker and Microvention and institutional research support from Stryker and Medtronic. Dr Thijs reported receiving personal fees and travel support from Boehringer Ingelheim, Bayer, Pfizer/Bristol-Myers Squibb, Amgen, and Medtronic outside the submitted work. Dr Brooks reported receiving grant support from Stryker and personal fees from Microvention outside the submitted work. Dr Shah reported receiving personal fees and travel support from Boehringer Ingelheim and personal fees from Bayer and Medtronic outside the submitted work. Dr Zhao reported receiving travel support from Boehringer Ingelheim outside the submitted work. Dr Bailey reported receiving travel support from Boehringer Ingelheim. Dr Miteff reported receiving grants from John Hunter Hospital during the conduct of the study. Dr Cloud reported receiving travel support from Boehringer Ingelheim and speaker fees from Medtronic. Dr Levi reported receiving travel support from Boehringer Ingelheim and the Australian National Health and Medical Research Partnership and project grant support from Boehringer Ingelheim and Apollo Medical Imaging. Dr Wong reported receiving travel support from Boehringer Ingelheim and Medtronic. Dr Parsons reported receiving travel support from Boehringer Ingelheim and research collaboration with Apollo Medical Imaging outside the submitted work. Dr Donnan reported receiving grants from the Australian National Health and Medical Research Council and personal fees from Allergan, Amgen, Bayer, Boehringer Ingelheim, Pfizer, and Servier outside the submitted work. Dr Davis reported receiving personal fees from Bayer, Boehringer Ingelheim, Tide Pharmaceuticals, and Medtronic and grants from the National Health and Medical Research Council of Australia outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Enrollment, Randomization, and Follow-up of Patients in a Study of the Effect of Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke

The number of patients assessed for eligibility is unknown because screening logs were not maintained. One patient in each group received the 0.50 mg/kg of tenecteplase dose recommended for myocardial infarction. Neither patient achieved reperfusion at the time of the initial angiogram and neither developed hemorrhagic transformation. In 25 of 300 (8%) patients, the primary outcome was assessed using computed tomographic perfusion imaging rather than catheter angiography (8 received 0.40 mg/kg and 17 received 0.25 mg/kg of tenecteplase) either due to re-imaging after transfer showing substantial reperfusion (6 who received 0.40 mg/kg and 8 who received 0.25 mg/kg tenecteplase), neurointerventionist decision not to attempt endovascular thrombectomy due to poor clinical state (2 who received 0.40 mg/kg and 6 who received 0.25 mg/kg ), or mild clinical deficit (3 who received 0.25 mg/kg of tenecteplase).

Figure 2.. Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population in a Study of the Effect of Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke

No significant differences were observed between the 0.40 mg/kg and 0.25 mg/kg tenecteplase groups in ordinal analysis of the modified Rankin Scale (mRS) score, adjusted for age and clinical severity (National Institutes of Health Stroke Scale score) (adjusted generalized odds ratio, 0.96 [95% CI, 0.74-1.24]). mRS score ranges from 0 to 6, with 0 indicating no symptoms; 1, no clinically significant disability; 2, slight disability (the patient is able to look after their own affairs without assistance but is unable to carry out all previous activities); 3, moderate disability (requiring some help [eg, with shopping, cleaning, finances] but is able to walk unassisted); 4, moderately severe disability (unable to attend to bodily needs without assistance and unable to walk unassisted); 5, severe disability (requiring constant nursing care and attention); and 6, death.