Abstract Background and aims The risks and benefits of tenecteplase for very old patients with acute ischaemic stroke (AIS) who were treated 4.5 to 24 hours after stroke onset are still unknown. We aimed to investigate the efficacy and safety of tenecteplase for AIS patients aged ≥ 80 years. Methods We performed a post hoc analysis of TRACE-III trial. Patients with anterior large vessel occlusion (LVO) and no access to endovascular thrombectomy were randomized (1:1) to receive either 0.25 mg/kg tenecteplase or standard medical treatment. The primary outcome was modified Rankin scale (mRS) score 0-1 at 90 days. Safety outcomes were symptomatic intracranial haemorrhage (sICH) within 36 hours and all-cause mortality within 90 days. Results Among the 516 patients in the TRACE-III trial, 67 (13.0%) aged ≥ 80 years. The percentage of mRS score of 0 or 1 at 90 days were similar between the tenecteplase and standard treatment groups in patients aged ≥ 80 years (21.4% vs. 10.3%; OR, 2.39; 95% CI, 0.61-9.42) and patients aged < 80 years (34.3% vs. 26.8%; OR, 1.43; 95% CI, 0.95-2.15), with a non-significant interaction value of 0.48. The sICH (10.7% vs. 0.0% in aged ≥ 80 years group) and and all-cause mortality (28.6% vs. 20.5% in aged ≥ 80 years group) were similar between the two treatment therapies across age categories. Conclusions In patients with LVO who were not eligible for thrombectomy within 4.5 to 24 hours of onset, tenecteplase was comparable with standard medical treatment for efficacy and safety outcomes in patients aged ≥ 80 years. Conflict of interest All authors have nothing to disclose.

Large vessel occlusion (LVO) is a severe subtype of acute ischaemic stroke, for which endovascular therapy significantly improves clinical outcomes. Expediting time to reperfusion is critical; however, conventional in-hospital workflows based on CT or MRI are frequently hindered by treatment delays. Direct Transfer to the Angiography Suite (DTAS) is an emerging care strategy in which patients with suspected or confirmed LVO bypass the emergency department and standard imaging. Using flat-panel CT or sliding-gantry CT combined with digital subtraction angiography, the DTAS workflow facilitates rapid diagnosis and prompt reperfusion therapy, thereby significantly reducing door-to-reperfusion time. Drawing on evidence from international and domestic studies, the Chinese Stroke Association convened an expert panel to develop this guideline, which systematically delineates the DTAS strategy, infrastructure requirements, diagnostic and therapeutic workflows and quality control indicators.

Abstract Background and aims We aimed to assess the effect of time to treatment on clinical outcomes in patients who received intravenous tenecteplase versus standard medical treatment between 4.5 and 24 hours after last known well (LKW). Methods This secondary analysis of the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial explored the association of LKW-to treatment time, analyzed as both categorical (4.5-9, 9-16, and 16-24 hours) and continuous variables, with 90-day functional outcomes and safety outcomes including symptomatic intracranial hemorrhage and mortality. Results Among 516 patients, 134 were treated within 4.5-9 hours, 232 within 9-16 hours, and 150 within 16-24 hours after LKW. The primary outcome (mRS 0-1) occurred in 31.9% versus 23.1% of patients receiving tenecteplase and standard medical treatment within 4.5-9 hours (adjusted odds ratio [aOR], 1.37; 95% confidence interval [CI], 0.59 to 3.17; adjusted P=0.470); 30.6% versus 21.3% within 9-16 hours (aOR, 1.69; 95%CI, 0.88 to 3.25; adjusted P=0.115); and 38.0% versus 29.1% within 16-24 hours (aOR, 1.98; 95%CI, 0.92 to 4.29; adjusted P=0.081). There was no statistically significant association between each 1-hour treatment delay and efficacy outcomes or symptomatic intracranial hemorrhage in either treatment arm, whereas mortality exhibited an inverse trend, with lower rates observed with longer treatment delays. Overall, no significant interaction between LKW-to-treatment time and treatment assignments was discovered (all p for interaction >0.1). Conclusions Collectively, these findings support the use of tenecteplase in TRACE-III-qualified patients throughout the entire 4.5-24-hour window and highlight the potential for extending the therapeutic window beyond 24 hours. Conflict of interest

Importance:Whether intravenous tenecteplase prior to endovascular treatment (EVT) for ischemic stroke reduces disability in the late time window is unclear. Objective:To investigate the adverse events and efficacy of tenecteplase prior to EVT in patients 4.5 to 24 hours after ischemic stroke onset due to proximal middle cerebral artery (MCA) occlusion. Design, Setting, and Participants:Multicenter, phase 3, randomized, open-label, blinded end point, superiority trial conducted at 40 centers in China. Adult (≥18 years) patients with acute ischemic stroke 4.5 to 24 hours after last known to be well due to MCA-M1 or proximal M2 occlusion with salvageable brain tissue (ischemic core volume <70 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL) identified on computed tomography-perfusion or magnetic resonance-perfusion-diffusion imaging were enrolled from January 25, 2024, through July 21, 2025, and followed up for 90 days. Final follow-up occurred on October 14, 2025. Interventions:Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous tenecteplase (0.25 mg/kg; maximum dose, 25 mg) before EVT (n = 199) or EVT alone (n = 192). Main Outcomes and Measures:The primary outcome was functional independence, defined as a score of 0 to 2 on the modified Rankin Scale (range, 0-6, with higher scores indicating greater disability) at 90 days. Adverse events outcomes included symptomatic intracranial hemorrhage and death. Results:All of the 391 patients enrolled (median age, 68 years [IQR, 59-75]; 155 [39.6%] females) completed the trial. Functional independence at 90 days occurred in 88 patients (44.2%) in the tenecteplase before EVT group and 83 patients (43.2%) in the EVT alone group (adjusted relative rate, 1.01 [95% CI, 0.83-1.24]; P = .89; risk difference, 0.99% [95% CI, -8.84% to 10.83%]). Mortality within 90 days was 12.7% (25/197) in the tenecteplase before EVT group and 14.2% (27/190) in the EVT alone group. Symptomatic intracranial hemorrhage within 36 hours was 5.1% (10/197) and 2.6% (5/190), respectively. Conclusions and Relevance:In patients presenting to EVT-capable centers 4.5 to 24 hours after stroke onset with proximal MCA occlusion, intravenous tenecteplase before EVT did not improve clinical outcomes vs EVT alone. Trial Registration:ClinicalTrials.gov Identifier: NCT06221371.

Abstract Background and aims Neutrophil extracellular traps (NETs) contribute to microvascular dysfunction, which may be associated with poor functional outcomes in patients with acute ischemic stroke (AIS) and successful recanalization after endovascular treatment (EVT). We aimed to investigate dynamic changes in NETs biomarkers (Myeloperoxidase-associated DNA complexes [MPO-DNA] and citrullinated Histone H3 [CitH3]) pre and post-recanalization and the prognostic significance for non-ambulatory functional outcome. Methods In this prospective multicenter cohort, 114 anterior-circulation AIS patients undergoing EVT with successful recanalization (defined as eTICI 2b-3) underwent serial serum measurements of NETs biomarkers before reperfusion therapy, at 24 hours after EVT and at 7days/discharge. Primary outcome was non-ambulatory functional outcome (mRS 4-6 at 90 days in patients with successful recanalization). Univariate and multivariable logistic regression were used to determine the relationship of non-ambulatory functional outcome with NET biomarkers. Results MPO-DNA levels peaked at 24h post-EVT (median 472.29 [IQR 386.35-571.09]), significantly increased from baseline (341.34 [280.72-442.81]; P<0.001) and declined by 7 days/discharge (327.74 [268.17-397.99]; P<0.001). CitH3 showed a non-significant increase at 24h (14.022 [9.322-25.783] vs baseline 12.107 [8.810-21.327]; P=0.164), followed by a significant decrease at 7 days (11.302 [2.824-21.540]; P=0.011). NET clearance kinetics (Elevated CitH3 7 days/24 hours ratio) was independently associated with non-ambulatory functional outcome after multivariable adjustment (aOR 1.48, 95% CI 1.04-2.10, P=0.03) with age, baseline National Institutes of Health Stroke Scale (NIHSS), ischemic core volume, MPO-DNA 7 days/24h ratio, and hemoglobin A1c (HbA1c) >6.0%, as covariates. Conclusions NETs clearance deficiency during 24 hours to 7 days is independently associated with post-EVT non-ambulatory functional outcome. Conflict of interest All authors have nothing to disclose.

Background and purpose There is a scarcity of evidence of tenecteplase administered within the 24-hour window of acute ischaemic stroke due to basilar artery occlusion (BAO). We sought to assess whether intravenous tenecteplase within 24 hours of stroke onset, with or without endovascular treatment (EVT), leads to superior outcomes compared with standard care in acute BAO.Methods and design Tenecteplase Reperfusion therapy in Acute ischaemic Cerebrovascular Events-5 (TRACE-5), using a prospective, randomised, open-label, blinded-endpoint design, will enrol patients with acute ischaemic stroke due to BAO within 24 hours of the time they were last known well. Patients will be randomised to either intravenous tenecteplase (0.25 mg/kg, maximum 25 mg) or standard care. EVT is allowed in both groups.Study outcomes Modified Rankin Scale (mRS) of 0–1 or return to baseline mRS at 90 days is the primary outcome. Secondary outcomes include mRS 0–2 or return to baseline, mRS 0–3 and mRS distribution at 90 days, early neurological improvement within 72 hours and substantial reperfusion at initial angiogram. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, death within 90 days and mRS 5–6 at 90 days.Discussion The TRACE-5 trial will address whether extended-time window thrombolysis with a potentially more effective thrombolytic agent tenecteplase±EVT is superior to standard care in BAO.Trial registration number NCT06196320.

Alteplase is synthesized as a single-chain protease that requires plasmin-mediated conversion to its fully active two-chain form for maximal thrombolysis. Tenecteplase (TNK), an alteplase variant, is widely regarded as being more fibrin-selective and more resistant to plasminogen activator inhibitor-1 (PAI-1) than alteplase. However, the PAI-1 sensitivity of TNK after two-chain conversion, and that of newly available TNK formulations, has not been evaluated. Alteplase and four TNK formulations: Metalyse (Boehringer Ingelheim), Tenectase (Gennova, India), GenetPA (BioApower, China) and Mingfule (CSPC, China) were compared in their native state and after two-chain conversion. Proteolytic activity, PAI-1 resistance and binding were evaluated using amidolytic assay, fibrinolysis assays and Western blotting. Alteplase, but not Metalyse was converted into its two-chain form in plasma in a fibrinogen-dependent manner, resulting in off-target fibrinogenolysis. When directly reconstituted from the manufacturers vial (native form), TNK was ~4-fold more resistant to PAI-1 than alteplase; however, two-chain conversion significantly reduced PAI-1 resistance by ~40%, concomitant with increased PAI-1 binding. Native Metalyse contained ~3-fold more pre-existing two-chain species than the other TNK formulations, explaining its higher amidolytic activity. However, after two-chain conversion, all TNK formulations showed similar fibrinolytic activity albeit with substantially reduced PAI-1 resistance. Metalyse and all new TNK formulations display similar fibrinolytic activity in their fully active two-chain states, but this is associated with substantial loss of PAI-1 resistance, challenging the view that the fully active two-chain form of TNK maintains PAI-1 resistance during thrombolysis.

The TRACE-3 trial established the efficacy of intravenous tenecteplase for patients with acute ischemic stroke and large vessel occlusion in the late time window. It remains unclear whether intravenous tenecteplase confers clinical benefits specifically in the subpopulation of patients who did not achieve successful large vessel recanalization. This is a post-hoc analysis of the TRACE-3 trial, a multicenter randomized controlled trial comparing tenecteplase with standard medical therapy in patients with large vessel occlusion between 4.5 and 24 h of symptom onset. The analysis included participants who had failed recanalization (defined as an Arterial Occlusive Lesion [AOL] score of 0) on follow-up angiography at 24 h. Primary outcome of current study was functional independence (modified Rankin Scale [mRS] score 0–2) at 90 days. We assessed effect modification by baseline characteristics, including stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and collateral circulation status. Among 288 patients with failed recanalization (123 in the tenecteplase group and 165 in the control group), tenecteplase was associated with a significantly higher rate of functional independence at 90 days compared with standard medical therapy (42.3

Abstract Background and aims The efficacy and safety of tenecteplase at different fibrinogen levels remains uncertain. Methods We performed a post hoc analysis of the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) Trial. Patients with anterior large vessel occlusion, salvageable brain tissue, and no access to endovascular thrombectomy were randomized (1:1) to receive either 0.25 mg/kg tenecteplase or standard medical treatment. We categorized patients into groups with non-elevated fibrinogen (≤4.0 g/L) and elevated fibrinogen levels (>4.0 g/L). The primary outcome was the absence of disability, which was defined as a score of 0 to 1 on the modified Rankin scale (mRS) at 90 days. The safety outcomes were symptomatic intracranial hemorrhage (sICH) within 36 hours and all-cause mortality within 90 days. Results We included 498 of the 516 patients in the TRACE-III trial who had baseline fibrinogen data. Among them, 426 (85.5%) had non-elevated fibrinogen, and 72 (14.5%) had elevated fibrinogen. Compared with standard medical treatment, tenecteplase significantly increased the proportion of mRS scores of 0 to 1 at 90 days among patients with non-elevated fibrinogen (35.0% vs. 25.7%; relative rate [RR], 1.55; 95% confidence interval [CI], 1.03-2.37; P =0.04). No significant difference was observed in those with elevated fibrinogen (16.7% vs. 11.1%; RR, 1.60; 95% CI, 0.42-6.78; P =0.50). Safety outcomes were similar between the two treatment groups across fibrinogen categories. Conclusions Patients with non-elevated fibrinogen levels may receive greater benefit from tenecteplase in reducing disability risk without increasing the incidence of sICH, compared to those with elevated fibrinogen levels. Conflict of interest

Fibrinogen levels may influence the effect of intravenous thrombolysis. We aimed to investigate the efficacy and safety of tenecteplase across different baseline fibrinogen levels in acute ischaemic stroke due to large vessel occlusion (LVO) in the extended time window. We performed a post hoc analysis of the Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-III (TRACE-III) trial. Patients who presented within 4.5 to 24 h after symptom onset with anterior LVO, salvageable brain tissue, and no access to endovascular thrombectomy were randomised (1:1) to receive either 0.25 mg/kg tenecteplase or standard medical treatment. We categorised patients into groups with non-elevated fibrinogen (≤ 4.0 g/L) and elevated fibrinogen levels (> 4.0 g/L). The primary outcome was the absence of disability, which was defined as a score of 0 to 1 on the modified Rankin scale (mRS) at 90 days. The safety outcomes were symptomatic intracranial haemorrhage (sICH) within 36 h and all-cause mortality within 90 days. We included 498 of the 516 patients in the TRACE-III trial who had baseline fibrinogen data. Among them, 426 (85.5

Neutrophil extracellular traps (NETs) contribute to microvascular dysfunction and may predict poor outcomes after successful endovascular treatment (EVT) for acute ischemic stroke (AIS). We investigated dynamic changes in NETs biomarkers (myeloperoxidase-associated DNA complexes (MPO-DNA) and citrullinated histone H3 (CitH3)) and their prognostic value for non-ambulatory functional outcome. In this prospective multicenter cohort, 114 AIS patients with successful recanalization after EVT underwent serial biomarkers measurement at baseline, at 24 h post-EVT and at 7 days/discharge. Primary outcome was non-ambulatory functional outcome (90 days modified Rankin Scale (mRS) 4-6). Generalized estimating equation (GEE) assessed trajectory differences between outcome groups. Logistic regression identified independent predictors. MPO-DNA increased from baseline (341.34 (280.72-442.81)) to 24 h (472.29 (386.35-571.09); p < 0.01) and decline at 7 days/discharge (327.74 (268.17-397.99); p < 0.01 vs at 24 h). CitH3 showed non-significant increase at 24 h (14.022 (9.322-25.783)) vs baseline (12.107 (8.810-21.327); p = 0.16) but significant decrease at 7 days/discharge (11.302 (2.824-21.540); p = 0.01 vs at 24 h post-EVT). GEE revealed a significant time-by-group interaction for CitH3 (p = 0.01), but not for MPO-DNA (p = 0.18). Elevated CitH3 7 days/24 h ratio was independently associated with non-ambulatory functional outcome after multivariable adjustment (aOR = 1.99, 95% CI: 1.06-3.72, p = 0.03) with age, baseline National Institutes of Health Stroke Scale (NIHSS), ischemic core volume, and hemoglobin A1c (HbA1c) >6.0% as covariates. Persistent elevation of NETs during 24 h to 7 days is independently associated with post-EVT non-ambulatory functional outcome.

INTRODUCTION:The hypoperfusion intensity ratio (HIR) was significantly correlated with the futile reperfusion (FR) and National Institutes of Health Stroke Scale (NIHSS) score. We aimed to quantify the direct and indirect effect of HIR on FR. METHODS:We analyzed acute ischemic stroke patients with large vessel occlusion who underwent endovascular treatment at seven comprehensive stroke centers between 2017 and 2022 in China. HIR was automatically calculated on baseline perfusion imaging as the ratio of brain volume with time-to-max (Tmax) delay >10 s over volume with Tmax >6 s. The established threshold HIR >0.4 was regarded as poor tissue-level collaterals (TLCs). FR was defined as the modified Rankin Scale score of 4-6 at 90 days despite successful recanalization. Mediation analysis using the "mediation" package in R 4.2.2 was performed to examine the potential causal chain. RESULTS:Among the 891 included patients, FR was observed in 320 (35.9%) patients. Inadequate TLC was significantly associated with a higher NIHSS score (adjusted common odds ratio [OR], 1.47; 95% confidence interval [CI], 1.12-1.93; p = 0.006) and higher rates of FR (aOR, 1.87; 95% CI, 1.31-2.68; p = 0.001) within 90 days. The baseline NIHSS score was a predictor of FR (aOR, 1.13; 95% CI, 1.10-1.16; p < 0.001). Causal mediation analyses revealed that 20.4% (95% CI, 5.5%-40.9%) of the relationship between HIR and FR was mediated by the baseline NIHSS score. CONCLUSION:Higher NIHSS score partially mediates the association between poorer HIR and FR at 90 days among patients after EVT. Our study provided primarily mechanistic and prognostic findings about the effect of HIR on FR.

BACKGROUND:We aimed to explore whether the benefits of tenecteplase within 4.5 to 24 h would be modified by the infarct growth rate (IGR). METHODS:This study is a secondary analysis of the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events-III (TRACE-III) trial, a Phase 3, multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial. In the TRACE-III trial, patients with large-vessel occlusion at 4.5 to 24 h without thrombectomy were enrolled at 58 centers in China and randomly assigned to receive 0.25 mg/kg tenecteplase or standard medical treatment. Of these, patients with witnessed stroke onset time were analyzed. The IGR was calculated as baseline ischemic core volume divided by time since onset. The primary outcome was the modified Rankin Scale (mRS) 0-1 at 90 days. The treatment effect of tenecteplase versus standard medical treatment was assessed in two groups based on the median IGR cut point. A multiplicative interaction term for IGR*treatment was used to test for effect modification. RESULTS:In 292 eligible patients, the median IGR was 1.4 ml/h. A total of 146 patients with IGR < 1.4 ml/h were classified as ultraslow IGR (Tenecteplase, 70; Standard medical treatment, 76), and 146 patients with IGR ⩾ 1.4 ml/h were classified as slow IGR (Tenecteplase, 73; Standard medical treatment, 73). The rate of no disability (mRS ⩽ 1) was significantly increased with tenecteplase in slow progressors (34.2% vs 15.1%; OR = 2.94, 95% CI 1.32 to 6.55; P = 0.009). The functional status was similar in ultraslow progressors (mRS 0-1: 37.1% vs 35.5%; OR = 1.07, 95% CI 0.55 to 2.11; P = 0.84). A P value for the interaction between IGR and treatment was 0.06. The incidence of sICH and mortality did not differ significantly between the two treatment regimens in the IGR groups. CONCLUSION:Patients with late-window ischemic stroke who are not eligible for endovascular thrombectomy may derive greater benefit from tenecteplase compared with standard medical treatment among those with relatively faster infarct growth, although this finding should be considered exploratory.

BACKGROUND:The efficacy and safety of intravenous thrombolysis with tenecteplase within 24 h after stroke onset due to basilar artery occlusion are not well studied. We aimed to assess whether intravenous tenecteplase administered within 24 h after symptom onset improved functional outcome compared with standard medical treatment in patients with basilar artery occlusion. METHODS:TRACE-5 was a prospective, randomised, open-label, blinded-endpoint, superiority, phase 3 trial conducted at 66 stroke centres in China. We included patients aged 18 years or older with stroke due to basilar artery occlusion who were eligible for intravenous thrombolytics within 24 h of stroke onset or the time they were last known to be well and had a pre-stroke modified Rankin scale (mRS) score of 3 or less (scores range from 0 to 6, with higher scores indicating greater disability). Patients were randomly assigned to receive a single intravenous bolus of tenecteplase (0·25 mg/kg; maximum 25 mg) within 24 h after symptom onset or standard medical treatment (which could include intravenous alteplase at 0·9 mg/kg, maximum 90 mg, within 4·5 h of symptom onset; anticoagulation; or antiplatelets), with or without endovascular thrombectomy. The primary outcome was a score of 0-1 on the mRS or return to the baseline mRS score (if the baseline pre-stroke mRS score was 2-3) at 90 days. Safety outcomes were symptomatic intracranial haemorrhage and death. The primary outcome and safety outcomes were assessed in all randomly assigned participants included in their originally assigned groups. This trial is registered with ClinicalTrials.gov, NCT06196320. FINDINGS:Between Jan 24, 2024, and June 20, 2025, 452 patients were enrolled (mean age 66·4 years [SD 11·2], 321 [71%] males, and 131 [29%] females), of whom 222 (49%) subsequently underwent thrombectomy; 221 were randomly assigned to receive tenecteplase and 231 to receive standard medical treatment. Alteplase was used in 80 (35%) of the patients in the standard medical treatment group. An mRS score of 0-1 or return to the baseline mRS score occurred in 83 (38%) patients in the tenecteplase group and 66 (29%) patients in the standard medical treatment group (adjusted relative rate 1·50 [95% CI 1·09-2·08], p=0·014). Symptomatic intracranial haemorrhage within 36 h occurred in four (2%) patients in the tenecteplase group and seven (3%) patients in the standard medical treatment group (adjusted relative rate 0·58 [95% CI 0·17-1·99]). All-cause mortality at 90 days was similar between groups (65 [29%] patients in the tenecteplase group and 71 [31%] patients in the standard medical treatment group; adjusted relative rate 0·87 [95% CI 0·62-1·22]), as was the proportion of patients with an mRS score of 5-6 at 90 days (82 [37%] vs 89 [39%]; 0·87 [0·65-1·18]). INTERPRETATION:In this trial involving Chinese patients with ischaemic stroke due to basilar artery occlusion, tenecteplase within 24 h after stroke onset improved functional outcome compared with standard medical treatment. The incidence of symptomatic intracranial haemorrhage and death was similar. FUNDING:Noncommunicable Chronic Diseases-National Science and Technology Major Project, Beijing Municipal Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).

BACKGROUND:Although the clinical significance of lipidemic profiles has been reported in ischemic stroke, fewer studies reported the clinical significance of these lipidemic profiles in intracerebral hemorrhage. This study aimed to investigate the relationship between high-density lipoprotein to low-density lipoprotein ratios and long-term clinical outcomes including functional dependence and mortality. METHODS:Based on a multicenter, real-world registry, our study included patients with intracerebral hemorrhage hospitalized within 72 hours from symptoms onset. Divided into quartiles (Q1-Q4), the association between high-density lipoprotein to low-density lipoprotein ratios and poor functional outcomes (modified Rankin Scale scores 3-6) was investigated using multivariable logistic regression models. RESULTS:The final study included 869 intracerebral hemorrhage patients, with a median National Institutes of Health Stroke Scale score of 9 (3-16) and median hematoma volume of 13.4 mL (5.7-31). In the fully adjusted logistic model, where the high-density lipoprotein to low-density lipoprotein ratio was analyzed as a continuous variable, a higher ratio was significantly associated with an elevated odds of poor functional outcome at 90 days (adjusted odds ratio (OR), 4.57 [95% CI 1.70-12.29], P=0.003) and at 1 year (adjusted OR, 2.93 [95% CI 1.08-7.99], P=0.036). The sensitivity analyses confirmed that, compared with high-density lipoprotein or low-density lipoprotein separately, the high-density lipoprotein to low-density lipoprotein ratios emerged as a more robust and consistent predictor in patients with intracerebral hemorrhage without receiving surgical intervention. CONCLUSIONS:Our study delineated the association between high-density lipoprotein to low-density lipoprotein ratios and poor functional outcomes in patients with intracerebral hemorrhage.

Over the past three decades, thrombolytic therapy for acute ischaemic stroke has evolved dramatically since the landmark National Institute of Neurological Disorders and Stroke (NINDS) trial in 1995, which formally established recombinant tissue plasminogen activator as an effective treatment for stroke. This evolution has occurred along three key dimensions: (1) an expanding repertoire of thrombolytic agents, (2) a progressive broadening of the therapeutic window and (3) organisational and technological innovations aimed at minimizing prehospital and in-hospital treatment delays.In this review, we summarise the major milestones in the clinical evidence supporting thrombolytic therapy over the past 30 years, with particular emphasis on large phase III randomised clinical trials. Our goal is to delineate the trajectory of progress in stroke thrombolysis and to provide clinicians and researchers with a clear and coherent framework for understanding the field’s past achievements and future directions.

Abstract Background and aims Alteplase is produced as a single chain enzyme but is converted into a more active two-chain form by plasmin. Tenecteplase is structurally similar to alteplase and shows higher resistance to PAI-1. Factors influencing two-chain conversion of tenecteplase are poorly understood. Several formulations of TNK are now available. We compared two-chain conversion of alteplase and four tenecteplase formulations and downstream consequences on plasminogen activation, fibrinogenolysis, and PAI-1 resistance. Methods Alteplase and four tenecteplase formulations: Metalyse (Boehringer Ingelheim), Tenectase (Gennova, India), Mingfule (CSPC, China), GenetPA (BioApower, China) were compared. Two-chain conversion was achieved with plasmin and by western blotting. Proteolytic activity and the effect of PAI-1 was evaluated using amidolytic or fibrinolysis assays. Results Plasmin caused a dose-dependent conversion of alteplase and all tenecteplase formulations into their two-chain forms resulting in a ~2.5-fold increase in proteolytic activity. Two-chain conversion of alteplase, but not tenecteplase, occurred in plasma coinciding with off-target fibrinogen depletion. Metalyse contained ~3-fold more two-chain tenecteplase compared to other formulations, resulting in higher proteolytic activity in the absence of fibrin. However, all tenecteplase formulations showed similar activity in their two-chain form. Two-chain conversion of all tenecteplase formulations increased PAI-1 binding and a significant decrease in PAI-1 resistance. Conclusions Generation of two-chain tPA promotes fibrinogenolysis. Metalyse contains 3-fold more two-chain species and is more active in the absence of fibrin than other tenecteplase formulations. However, all tenecteplase formulations have similar proteolytic activity in their two-chain form but lose some resistance to PAI-1. Conflict of interest Liu: Nothing to disclose; Tippett: Nothing to disclose; McCutcheon: Nothing to disclose; Keragala: Nothing to disclose; Lin: Nothing to disclose; Xiong: Nothing to disclose; Wang: Nothing to disclose; Campbell: Nothing to disclose; Parsons: Nothing to disclose; Medcalf: Nothing to disclose

Abstract Background and aims Whether sex influence thrombolysis outcomes beyond 4.5 hours remains unclear. We aimed to investigate potential sex-based disparities in outcomes of late-window tenecteplase thrombolysis. Methods The Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events–III (TRACE-III) trial is a phase 3, multicenter, prospective, open-label, randomized, blinded-outcome-assessment trial, including patients with large-vessel occlusion at 4.5 to 24 hours without thrombectomy who were enrolled at 58 centers in China and randomly assigned to receive 0.25mg/kg tenecteplase or standard medical treatment. In this secondary analysis, we compared outcomes after tenecteplase versus control, stratified by sex. We also compared outcomes in female versus male patients treated with tenecteplase. The primary outcome was modified Rankin scale (mRS) 0-1 at 90 days. Sex-related effect modification was examined. Results Women accounted for 166 (32.2%) of 516 patients enrolled in the TRACE-III trial. Eighty-one (48.8%) of 166 women and 183 (52.3%) of 350 men received tenecteplase thrombolysis. Among male participants, the tenecteplase group achieved significantly higher rates of mRS 0-1 at 90 days compared with control (36.6% tenecteplase, 25.7% control, OR 1.67 [95% CI, 1.05–2.64]). Among female participants, the primary outcome was similar between groups (24.7% tenecteplase, 21.2% control, OR 1.22 [95% CI, 0.59–2.52]). No significant sex-based differences were observed for the primary outcome (P for interaction= 0.48) and other efficacy or safety outcomes. Conclusions Tenecteplase treatment benefit was maintained in both women and men without increasing safety concerns. Thrombolysis should be equally considered for patients of both sex meeting eligibility criteria in late-time windows. Conflict of interest All authors have nothing to disclose.

RATIONALE AND OBJECTIVES:Half of ischemic stroke patients are subject to futile reperfusion (FR) after endovascular treatment (EVT). The hypoperfusion intensity ratio (HIR) represents tissue-level collaterals (TLC). We aimed to evaluate the predictive performance of HIR in the assessment of FR. MATERIALS AND METHODS:Retrospective data were derived from a multicenter cohort study of patients with large vessel occlusion in the anterior circulation who underwent EVT in China. HIR was automatically calculated on baseline perfusion imaging as the ratio of brain volume with Tmax >10 s over volume with Tmax >6 s. Poor TLC was regarded as HIR >0.4. The primary outcome was FR, defined as modified Rankin Scale score of 4-6 at 90 days despite successful recanalization. Safety outcomes were symptomatic intracranial hemorrhage (sICH) within 36 h and all-cause mortality at 90 days. RESULTS:A total of 910 patients were included, and we observed FR in 325 (35.7%) patients after EVT. More frequent FR at 90 days was seen in patients with poor TLC (50.2% vs. 30.1%; odds ratio [OR], 2.34; 95% confidential interval [CI], 1.74-3.25; P<0.001). In multivariable regression, the higher HIR was independently associated with higher odds of FR (adjusted OR, 1.88; 95% CI, 1.31-2.68; P=0.001). The rates of sICH were not significantly different between the two groups. HIR>0.4 was correlated with higher rates of 90-day mortality even after adjusting covariates. CONCLUSION:Poorer HIR on admission perfusion imaging was strongly associated with FR occurrence after EVT. This automated and rapidly available perfusion parameter might help the identification of stroke patients at risk of FR.