Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).

Treatment strategies and prognosis for moderate stroke patients in China.

INTRODUCTION: Moderate stroke patients with National Institutes of Health Stroke Scale (NIHSS) score of 4-10 and without intravenous thrombolysis or endovascular treatment are basically excluded from current secondary prevention trials. We aimed to explore the effectiveness of mono- vs. dual-antiplatelet (DAPT) treatment strategies against subsequent stroke for these patients in a nationwide cohort. METHODS: Data were derived from the Third China National Stroke Registry (CNSR-Ш). In this prospective nationwide cohort, moderate ischemic stroke patients with NIHSS 4-10 and without intravenous thrombolysis or endovascular treatment were included and categorized into mono- or dual-antiplatelet groups. Demographics, medical history, NIHSS score, imaging and laboratory data were collected. The outcomes were stroke recurrence and all-cause mortality at 3 months and at 1 year, respectively. Cox proportional-hazards models were utilized to investigate the association of treatment strategies and prognosis. RESULTS: Of a total of 2 414 patients enrolled in the study, 1 633 (67.6%) received clopidogrel or aspirin and 781 (32.4%) received DAPT. Recurrent stroke occurred in 108 (6.6%) patients of the mono-antiplatelt group and 40 (5.1%) patients of the DAPT group ( adjusted hazard ratio [aHR] 0.73, 95% confidential interval [CI] 0.47-1.13, P=0.16) at 3 months, and the rate of stroke recurrence was 10.7% in the mono-antiplatelet group and 8.6% in the DAPT group ( aHR 0.81, 95% CI 0.58-1.13, P=0.22) at 12 months. The DAPT paradigm was not significantly associated with death at 3 months (0.6% vs 0.3%, a HR 0.28, 95%CI 0.04-2.25) but significantly reduced the mortality at 12 months (2.3% vs 1.0%, aHR 0.41, 95% CI 0.17-0.98, P=0.046). CONCLUSIONS: In moderate stroke patients presenting within 24 hours of symptom onset, the addition of clopidogrel 75 mg to aspirin might not be associated with lower risk of recurrent stroke than aspirin or clopidogrel alone.

Intravenous thrombolysis for mild stroke: NIHSS 3-5 Versus NIHSS 0-2.

BACKGROUND AND PURPOSE: Studies have shown that mild stroke patients with National Institutes of Health Stroke Scale (NIHSS) score 3-5 but not 0-2 may benefit from the intravenous thrombolysis when compared with antiplatelet therapy. We aimed to compare the safety and effectiveness of thrombolysis in mild stroke with NIHSS score of 0-2 vs. 3-5 and identify the predictors of an excellent functional outcome in a real world longitudinal registry. METHODS: In a prospective thrombolysis registry, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had initial NIHSS scores ≤ 5. Demographic data, medical history, pre-stroke medications, imaging data, and laboratory measures were collected. The outcome of interest was modified Rankin Scale score of 0 to 1 at discharge. Safety outcome was evaluated by syptomatic intracrerebral hemorrhage defined as any decline in neurologic status due to hemorrhage within 36 h. Multivariable regression models were performed to explore the safety and effectiveness in the alteplase-treated patients with admission NIHSS 0-2 vs. 3-5 and identify factors independently associated with an excellent functional outcome. RESULTS: Of a total of 236 eligible patients, those with an admission NIHSS score of 0-2 (n=80) had a better functional outcome at discharge compared with NIHSS 3-5 group (n=156) (81.3% vs. 48.7%, adjusted odds ratio [aOR] 0.40, 95% confidential interval [CI] 0.17 - 0.94, P=0.04) without increasing the rate of symptomatic intracerebral hemorrhage and mortality. Non-disabling stroke (Model 1: aOR 0.06, 95%CI 0.01-0.50, P=0.01; Model 2: aOR 0.06, 95% CI 0.01-0.48, P=0.01) and prior statin therapy (Model 1: aOR 3.46, 95% CI 1.02-11.70, P=0.046; Model 2: aOR 3.30, 95% CI 0.96-11.30, P=0.06) were independent predictors of excellent outcomes. CONCLUSIONS: Acute ischemic stroke patients with admission NIHSS 0-2 was associated with better functional outcomes at discharge compared with NIHSS 3-5 within the 4.5-hour time window. Minor stroke severity, non-disabling stroke and prior statin therapy were independent predictors for funcitonal outcomes at discharge. Further studies with large sample size are needed to confirm the findings.

Comprehensive Review of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

Although intravenous thrombolysis with alteplase remains the primary treatment for acute ischemic stroke, tenecteplase has shown potential advantages over alteplase. Animal studies have demonstrated the favorable pharmacokinetics and pharmacodynamics of tenecteplase. Moreover, it is easier to administer. Clinical trials have demonstrated that tenecteplase is not inferior to alteplase and may even be superior in cases of acute ischemic stroke with large vessel occlusion. Current evidence supports the time and cost benefits of tenecteplase, suggesting that it could potentially replace alteplase as the main option for thrombolytic therapy, especially in patients with large vessel occlusion.

Rationale and design of ProUrokinase in Mild IsChemic strokE (PUMICE): a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial.

BACKGROUND AND PURPOSE: Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, that is non-inferior to alteplase in acute ischemic stroke. We aimed to investigate the efficacy and safety of rhPro-UK compared with standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset. METHODS AND DESIGN: Prourokinase in mild ischemic stroke is a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Patients who had an acute ischemic stroke within 4.5 hours from symptom onset and with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 will be recruited. Patients will be randomly assigned (1:1) to receive intravenous rhPro-UK (35 mg) or standard medical treatment. The follow-up duration will be 90 days. The calculated sample size is 1446. STUDY OUTCOMES: Primary efficacy outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score ≤ 1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, mRS score ≤ 2 at 90 days, early neurological improvement at 24 hours (a decrease of NIHSS score ≥ 4 points compared with baseline or NIHSS score ≤ 1 point), Barthel index of 75-100 points at 90 days, quality of life at 90 days, and activities of daily living at 90 days. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, mortality at 90 days, moderate and severe systematic bleeding at 90 days, and adverse events/serious adverse events within 90 days. DISCUSSION: This large phase III randomised clinical trial will answer the question of whether thrombolysis is beneficial for acute mild ischemic stroke, and may provide evidence for rhPro-UK in patients had an acute mild ischemic stroke within 4.5 hours of symptom onset. TRIAL REGISTRATION NUMBER: NCT05507645.

Tenecteplase versus alteplase for acute ischaemic stroke in the elderly patients: a post hoc analysis of the TRACE-2 trial.

BACKGROUND: The benefit-risk profile of tenecteplase in the elderly patients with acute ischaemic stroke (AIS) is uncertain. We sought to investigate the efficacy and safety of 0.25 mg/kg tenecteplase compared with alteplase for AIS patients aged ≥80 years. METHODS: We performed a post hoc analysis of the Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-2 Trial, a randomised, phase 3, non-inferiority clinical trial. Disabling AIS patients aged ≥80 years who initiated intravenous thrombolytics within 4.5 hours of symptom onset were enrolled from June 2021 to May 2022 across 53 centres in China and were randomly allocated to receive 0.25 mg/kg tenecteplase or 0.9 mg/kg alteplase. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Symptomatic intracranial haemorrhage (sICH) within 36 hours was the safety outcome. RESULTS: Of 137 participants, mRS 0-1 at 90 days occurred in 37 (49.3%) of 75 in the tenecteplase group vs 20 (33.9%) of 59 in the alteplase group (risk ratio (RR) 1.47, 95% CI 0.96 to 2.23). sICH within 36 hours was observed in 3 (4.0%) of 76 in the tenecteplase group and two (3.3%) of 61 in the alteplase group (RR 1.30, 95% CI 0.20 to 8.41). CONCLUSIONS: The risk-benefit profile of tenecteplase thrombolysis was preserved in the elderly patients, which lends further support to intravenous 0.25 mg/kg tenecteplase as an alternative to alteplase in these patients.

Assessment of Perfusion Volumes by a New Automated Software for Computed Tomography Perfusion.

INTRODUCTION: To compare the perfusion volumes assessed by a new automated CT perfusion (CTP) software iStroke with the circular singular value decomposition software RAPID and determine its predictive value for functional outcome in patients with acute ischaemic stroke (AIS) who underwent endovascular treatment (EVT). METHODS: Data on patients with AIS were collected from four hospitals in China. All patients received CTP followed by EVT with complete recanalisation within 24 hours of symptom onset. We evaluated the agreement of CTP measures between the two softwares by Spearman's rank correlation tests and kappa tests. Bland-Altman plots were used to evaluate the agreement of infarct core volume (ICV) on CTP and ground truth on diffusion-weighted imaging (DWI). Logistic regression models were used to test the association between ICV on these two softwares and functional outcomes. RESULTS: Among 326 patients, 228 had DWI examinations and 40 of them had infarct volume >70 mL. In all patients, the infarct core and hypoperfusion volumes on iStroke had a strong correlation with those on RAPID (ρ=0.68 and 0.66, respectively). The agreement of large infarct core (volume >70 mL) was substantial (kappa=0.73, p<0.001) between these two softwares. The ICV measured by iStroke and RAPID was significantly correlated with independent functional outcome at 90 days (p=0.009 and p<0.001, respectively). In patients with DWI examinations and those with an ICV >70 mL, the ICV of iStroke and RAPID was comparable on individual agreement with ground truth. CONCLUSION: The automatic CTP software iStroke is a reliable tool for assessing infarct core and mismatch volumes, making it clinically useful for selecting patients with AIS for acute reperfusion therapy in the extended time window.

Outcomes in minor stroke patients treated with intravenous thrombolysis.

AIMS: Our study aimed to describe the short-, medium-, and long-term outcomes of intravenous thrombolysis in minor stroke, and to explore the relationship between thrombolysis and clinical outcomes. METHODS: Our study included ischemic minor stroke patients (National Institutes of Health Stroke Scale score ≤ 5) within 4.5 h from symptom onset from the Third China National Stroke Registry (CNSR-III) between August 2015 and March 2018. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-1 at 3 months. The secondary outcomes included mRS score of 0-1 at discharge, 6 months, and 1 year. The safety outcomes were symptomatic intracerebral hemorrhage (sICH) at 24-36 h and all-cause mortality. The association between intravenous thrombolysis and clinical outcomes was studied using multivariable models. RESULTS: A total of 1905 minor ischemic stroke patients were included. Overall 527 patients (28%) received intravenous t-PA (IV t-PA) and 1378 patients (72%) in the non-IV t-PA group. Of them, 18.85% (359/1905) participants had a disabled outcome (defined as mRS score ≥ 2) at discharge, 12.8% (242/1885) at 3 months, 13.9% (262/1886) at 6 months, and 13.9% (260/1871) at 1 year. In multivariable analysis, IV t-PA was associated with favorable functional outcomes at discharge (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] 1.13-1.96; p = 0.004), 3 months (aOR 1.51; 95% CI 1.09-2.10; p = 0.01), 6 months (aOR 1.64; 95% CI 1.19-2.27; p = 0.003), and 1 year (aOR 1.52; 95% CI 1.10-2.10; p = 0.01). Symptomatic ICH occurred in 3 (0.6%) patients in IV t-PA versus 2 (0.1%) in the non-IV t-PA group. No significant differences were found in all-cause mortality between the two groups. CONCLUSIONS: Intravenous t-PA may be safe and effective in minor stroke (NIHSS ≤ 5) within a 4.5-h window and further randomized controlled trials are warranted.

Intravenous thrombolysis versus antiplatelet therapy in minor stroke patients with large vessel occlusion.

AIM: Our study aimed to explore the effectiveness and safety of intravenous t-PA compared with dual antiplatelet therapy (DAPT) and aspirin alone for minor stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5 and large vessel occlusion (LVO). METHODS: Patients with minor stroke harboring LVO within 4.5-h time window were included from the Third China National Stroke Registry (CNSR-III) between August 2015 and March 2018 in China. Clinical outcomes including modified Rankin scale (mRS) score, recurrent stroke, and all-cause mortality at 90 days and 36-h symptomatic intracerebral hemorrhage (sICH) were collected. Multivariable logistic regression models and propensity score matching analyses were used to determine the association between treatment groups and clinical outcomes. RESULTS: A total of 1401 minor stroke patients with LVO were included. Overall 251 patients (17.9%) received intravenous t-PA, 722 patients (51.5%) received DAPT, and 428 patients (30.5%) received aspirin alone. The intravenous t-PA was associated with greater proportions of mRS 0-1 (aspirin versus t-PA: adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.32 to 0.80; p = 0.004; DAPT versus t-PA: aOR, 0.76; 95% CI, 0.49 to 1.19; p = 0.23). Using propensity score matching analyses, the results were similar. There was no difference in 90-day recurrent stroke among the groups. The rates of all-cause mortality in intravenous t-PA, DAPT, and aspirin groups were 0%, 0.55%, 2.34%, respectively. No patient developed sICH within 36 h of intravenous t-PA. CONCLUSION: In patients with minor stroke harboring LVO within 4.5-h time window, intravenous t-PA was associated with higher odds for the excellent functional outcome, as compared with the aspirin alone. Further randomized controlled trials are warranted.

Tenecteplase versus alteplase for acute ischaemic stroke: a meta-analysis of phase III randomised trials.

BACKGROUND: Tenecteplase (TNK) was found non-inferior to alteplase in recent clinical trials. We aimed to elucidate the efficacy and safety of TNK versus alteplase for acute ischaemic stroke (AIS). METHODS: Systematic literature search and a meta-analysis of phase III clinical trials in ischaemic stroke patients with TNK use were conducted. The primary outcome was excellent functional outcome which was defined as modified Rankin Scale score of 0-1 at 90 days and safety outcomes included symptomatic intracerebral haemorrhage and death at 90 days. We used random-effects model to estimate the pooled risk difference and 95% CI in R package 'Meta'. The included trials were adapted to the non-inferiority analysis with a margin of -4%. RESULTS: Three trials enrolling 4094 patients were identified by systematic search. All trials included AIS patients within 4.5 hours time window. Meta-analysis indicated that 1089 (53.0%) of 2056 patients in the TNK arm and 1016 (50.5%) of 2012 in the alteplase arm had excellent functional outcome at 90 days (0.03 (95% CI -0.00 to 0.06); I2=0%), meeting the prespecified non-inferiority threshold. And TNK thrombolysis was not correlated with increased risk of symptomatic intracerebral haemorrhage (0.00 (95% CI -0.01 to 0.01); I2=0%) or death (0.01 (95% CI -0.01 to 0.02); I2=0%) at 90 days. The sensitivity analysis with the 0.25 mg/kg trials exclusively showed similar results to the main analysis. CONCLUSIONS: TNK was non-inferior to alteplase for achieving excellent functional outcome at 90 days without increasing the safety concern in treating patients with AIS. These findings suggest that TNK can be an alternative to alteplase. PROSPERO REGISTRATION NUMBER: CRD42022354342.