Intra-Arterial Tenecteplase Following Endovascular Reperfusion for Large Vessel Occlusion Acute Ischemic Stroke: The POST-TNK Randomized Clinical Trial

Abstract

Importance: The impact of adjunctive intra-arterial tenecteplase administration following near-complete to complete reperfusion by endovascular thrombectomy (EVT) for acute ischemic stroke is unknown.

Objective: To assess the efficacy and adverse events of adjunctive intra-arterial tenecteplase in patients with large vessel occlusion stroke who had achieved near-complete to complete reperfusion (defined as a score on the expanded Thrombolysis in Cerebral Infarction [eTICI] scale of 2c to 3) after EVT.

Design, setting, and participants: Investigator-initiated, randomized, open-label, blinded outcome assessment trial implemented at 34 hospitals in China among 540 patients with stroke due to proximal intracranial large vessel occlusion within 24 hours of the time they were last known to be well, with an eTICI score of 2c to 3 after EVT, and without prior intravenous thrombolysis. Recruitment took place between October 26, 2022, and March 1, 2024, with final follow-up on June 3, 2024.

Interventions: Eligible patients were randomly assigned to receive intra-arterial tenecteplase (n = 269) at 0.0625 mg/kg or no intra-arterial thrombolysis (control group; n = 271).

Main outcomes and measures: The primary efficacy outcome was freedom from disability, defined as a score of 0 or 1 on the modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) at 90 days. The primary safety outcomes were death at 90 days and symptomatic intracranial hemorrhage within 48 hours.

Results: A total of 539 participants (99.8%) completed the trial (median age, 69 years; 221 female [40.9%]). The proportion with a modified Rankin Scale score of 0 or 1 at 90 days was 49.1% (132/269) in the intra-arterial tenecteplase group and 44.1% (119/270) in the control group (adjusted risk ratio, 1.15 [95% CI, 0.97-1.36]; P = .11). Ninety-day mortality was 16.0% and 19.3% (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.13]; P = .16), respectively. The proportions of symptomatic intracranial hemorrhage were 6.3% and 4.4% (adjusted risk ratio, 1.43 [95% CI, 0.68-2.99]; P = .35), respectively.

Conclusions and relevance: In patients with acute ischemic stroke due to large vessel occlusion presenting within 24 hours of time last known to be well and who had achieved near-complete to complete reperfusion after EVT, adjunctive intra-arterial tenecteplase did not significantly increase the likelihood of freedom from disability at 90 days.

Trial registration: ChiCTR.org.cn Identifier: ChiCTR2200064809.

Figure 1.. Flow of Participants Through the POST-TNK Trial

eTICI indicates expanded Thrombolysis in Cerebral Infarction. ^aBaseline Alberta Stroke Program Early CT Score (ASPECTS) ≥6 based on noncontrast computed tomography within 6 hours of time last known to be well, or ASPECTS of ≥7 or meets the DEFUSE 3 or DAWN study criteria between 6 and 24 hours after time last known to be well. ^beFigure 1 in Supplement 3 provides detailed explanations of protocol violations.

Figure 2.. Distribution of Scores on the Modified Rankin Scale at 90 Days

Scores range from 0 to 6, with 0 indicating no symptoms; 1, no clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. Numbers are rounded proportions. One patient in the control group without valid assessment due to loss to follow-up was excluded. Treatment with intra-arterial tenecteplase was associated with an adjusted risk ratio of 1.15 (95% CI, 0.97-1.36; P = .11) for the primary efficacy outcome of a modified Rankin Scale score of 0 or 1 at 90 days. The overall distribution of scores was not statistically significant in the ordinal logistic analysis (adjusted generalized odds ratio, 1.22 [95% CI, 0.96-1.55]; P = .10).

Figure 3.. Subgroup Analysis of the Primary Efficacy Outcome of Modified Rankin Scale Score of 0 or 1 at 90 Days

ASPECTS indicates Alberta Stroke Program Early CT Score; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale. Age, baseline NIHSS score, baseline ASPECTS, and time from last known to be well to randomization were divided at the median of the full population as prespecified in the statistical analysis plan. Widths of 95% CIs were not adjusted for multiple comparisons; 95% CIs should not be used for hypothesis testing. One patient in the control group without valid assessment due to loss to follow-up was excluded. Sizes of boxes in the plot correspond to number of patients in each subgroup. ^aNIHSS scores range from 0 to 42; higher scores indicate more severe neurological deficits. ^bFunctional disability scores on the mRS range from 0 (no symptoms) to 6 (death). Five patients had mRS scores of ≥2 prior to enrollment and were not included in the test of interaction for prestroke mRS score subgroup analysis. P value for interaction was not calculated because no treatment estimation was generated due to insufficient number of patients with prestroke mRS scores ≥1. ^cASPECTS ranges from 0 to 10; lower values indicate larger infarction. ^dTOAST classifies ischemic stroke and transient ischemic attack into 5 subtypes based on likely causes: large artery atherosclerosis, cardioembolism, small artery occlusion, other determined etiology, and undetermined etiology. ^eThe expanded Thrombolysis in Cerebral Infarction (eTICI) scale measures reperfusion based on digital subtraction angiography (range, 0 [no reperfusion] to 3 [complete reperfusion]). One patient in the intra-arterial tenecteplase group and 2 in the control group had eTICI scores <2c and were not included in the test of interaction for eTICI subgroup analysis.