Intra-Arterial Urokinase After Endovascular Reperfusion for Acute Ischemic Stroke: The POST-UK Randomized Clinical Trial

Abstract

Importance: Persisting or new thrombi in the distal arteries and the microcirculation have been reported to limit the benefits of successful endovascular thrombectomy for patients with acute ischemic stroke. It remains uncertain whether intra-arterial thrombolysis by urokinase following near-complete to complete reperfusion by thrombectomy improves outcomes among patients with ischemic stroke due to large vessel occlusion.

Objective: To assess the efficacy and adverse events of intra-arterial urokinase after near-complete to complete reperfusion by thrombectomy for acute ischemic stroke due to large vessel occlusion.

Design, setting, and participants: This investigator-initiated, randomized, open-label, blinded-end point trial was implemented at 35 hospitals in China, enrolling 535 patients with proximal intracranial large vessel occlusion presenting within 24 hours of time last known well, who achieved near-complete or complete reperfusion by endovascular thrombectomy and did not receive intravenous thrombolysis prior to the procedure. Recruitment took place between November 15, 2022, and March 29, 2024, with final follow-up on July 4, 2024.

Interventions: Eligible patients were randomly assigned to the intra-arterial urokinase group (a single dose of intra-arterial 100 000 IU urokinase injected in the initial target territory; n = 267) or control group (without intra-arterial thrombolysis; n = 267).

Main outcomes and measures: The primary efficacy outcome was the percentage of patients achieving survival without disability (modified Rankin Scale score of 0 or 1) at 90 days. The primary safety outcomes were mortality at 90 days and incidence of symptomatic intracranial hemorrhage within 48 hours.

Results: A total of 535 patients were enrolled (median age, 69 years; 223 [41.8%] female) and 532 (99.6%) completed the trial. The percentage of patients with survival without disability at 90 days was 45.1% (120/266) in the intra-arterial urokinase group and 40.2% (107/266) in the control group (adjusted risk ratio, 1.13 [95% CI, 0.94-1.36]; P = .19). Mortality at 90 days (18.4% vs 17.3%, respectively; adjusted hazard ratio, 1.06 [95% CI, 0.71-1.59]; P = .77) and incidence of symptomatic intracranial hemorrhage (4.1% vs 4.1%, respectively; adjusted risk ratio, 1.05 [95% CI, 0.45-2.44]; P = .91) were not significantly different between groups.

Conclusions and relevance: Among patients with acute ischemic stroke due to large vessel occlusion, adjunct intra-arterial urokinase after near-complete to complete reperfusion by endovascular thrombectomy did not significantly increase the likelihood of survival without disability at 90 days.

Trial registration: ChiCTR.org.cn Identifier: ChiCTR2200065617.

Figure 1.. Flow of Patients in the POST-UK Trial

CT indicates computed tomography; CTP, computed tomography perfusion; eTICI, expanded Thrombolysis in Cerebral Infarction; MRI, magnetic resonance imaging; and mRS, modified Rankin Scale. ^aBaseline Alberta Stroke Program Early CT Score (ASPECTS) of ≥6 based on noncontrast computed tomography if the onset time was within 6 hours; ASPECTS of ≥7; or met the DEFUSE 3 study criteria or the DAWN study criteria. ^bOne patient in each group was lost to follow-up at 90 days. ^ceFigure 1 in Supplement 3 provides detailed explanations of protocol violations.

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

Scores on the mRS of all included patients with available 90-day follow-up data. The primary analysis set included all patients who provided consent; patients were included in the analysis according to their assigned trial group. Data were missing for 1 patient in each group. mRS scores range from 0 to 6, with 0 indicating no symptoms or disability after stroke; 1, no clinically relevant disability; 2, slight disability; 3, moderate disability; 4, moderate to severe disability; 5, severe disability (complete dependence on daily care); and 6, death. Percentages do not total 100% because of rounding. Treatment with intra-arterial urokinase was associated with an adjusted risk ratio of 1.13 (95% CI, 0.94-1.36; P = .19) for the primary outcome of survival without disability. The adjusted generalized odds ratio for a favorable shift in mRS distribution was 1.07 (95% CI, 0.84-1.35; P = .59).

Figure 3.. Subgroup Analyses

Prespecified subgroup analyses for the RR of survival without disability (defined as a score on the mRS of 0 to 1) at 90 days. The widths of the CIs were not adjusted for multiple comparisons and the reported CIs should not be used for hypothesis testing. One patient in each group without valid assessment due to loss to follow-up were not included in the chart. The age, baseline NIHSS score, baseline ASPECTS, and time from last known well to randomization were divided at the median of the whole population as prespecified in the statistical analysis plan. The size of the squares corresponds to the number of patients in each subgroup. The arrow indicates that the 95% CI was beyond the scale. ASPECTS indicates Alberta Stroke Program Early Computed Tomography Score; eTICI, expanded Thrombolysis in Cerebral Infarction; M1, first middle cerebral artery segment; M2, second middle cerebral artery segment; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; RR, risk ratio; TIA, transient ischemic attack; TOAST, Trial of ORG 10172 in Acute Stroke Treatment. ^aScores on the NIHSS range from 0 to 42, with higher scores indicating worse neurological deficits. ^bScores on the mRS of functional disability range from 0 (no symptoms) to 6 (death). Four patients had an mRS score higher than 1 prior to enrollment, including 1 patient who was lost to follow-up (not shown). ^cASPECTS ranges from 0 to 10, with higher scores indicating a smaller infarct core. ^dThe TOAST classification system is a widely used method for classifying ischemic stroke and TIA. It divides ischemic stroke and TIA into 5 subtypes based on their likely causes: large artery atherosclerosis, cardioembolism, small artery occlusion, other determined etiology, and undetermined etiology. ^eFive patients with an eTICI grade lower than 2c, including 1 patient who was lost to follow-up, are not shown.