Background The effects of intravenous thrombolytic agents on fibrinogen differ due to structural differences among the agents. Using data from the RAISE (Reteplase Versus Alteplase for Acute Ischemic Stroke) trial, we aimed to investigate the impact of differences in baseline plasma fibrinogen levels on the efficacy and safety of reteplase versus alteplase within 4.5 hours of acute ischemic stroke symptom onset. Methods This post hoc subgroup analysis of the multicenter RAISE trial categorized participants by baseline fibrinogen levels: low (<2 g/L), normal (2–4 g/L), and high (>4 g/L). The primary efficacy outcome was excellent functional outcome at 90 days (modified Rankin scale score of 0 or 1). The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours. Results A total of 1373 patients with acute ischemic stroke were included. Ninety‐two in the low fibrinogen group (<2 g/L), 1178 in the normal fibrinogen group (2–4 g/L), and 103 in the high fibrinogen group (>4 g/L). Adjusted risk ratios of primary efficacy outcome were 1.13 (95% CI, 0.97–1.32) for the low fibrinogen group, 1.13 (95% CI, 1.04–1.23) for the normal fibrinogen group, and 1.09 (95% CI, 0.84–1.42) for the high fibrinogen group. The primary safety outcome showed no difference between reteplase and alteplase in the 3 fibrinogen subgroups. Conclusions Among patients with acute ischemic stroke who were treated with either reteplase or alteplase within 4.5 hours after symptom onset, there was no difference observed in the relative efficacy and safety between the 2 groups across the 3 fibrinogen subgroups. However, these findings should be interpreted cautiously and require validation in larger, adequately powered prospective studies. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05295173.

Acute ischemic stroke remains a major public health challenge due to its high incidence and limited effective treatment options. Reperfusion therapies, including thrombolysis and endovascular intervention, help restore blood flow in some patients but often fall short due to ineffective recanalization or reperfusion injury, emphasizing the urgent need for adjunctive neuroprotective strategies. BXOS110, a novel neuroprotective agent, targets PSD-95, a postsynaptic density protein that mediates excitotoxic damage by interacting with N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase. In this study, BXOS110 demonstrated a higher binding affinity for PSD-95 than its predecessor, nerinetide (NA-1). Our data further confirmed that BXOS110 directly binds to PSD-95 and mitigates NMDA-induced neurotoxicity in vitro. In vivo, BXOS110 exhibited robust brain penetration and sustained localization in ischemic brain regions of rats, as well as significant neuroprotective effects in both rat and primate models of ischemic stroke when administered within 1 h of ischemia onset. Additionally, we determined that BXOS110 administration must be carefully timed with thrombolytic agents to prevent its degradation, identifying optimal dosing intervals to maximize therapeutic efficacy. These findings highlight the potential of BXOS110 as an integrated stroke therapeutic agent, which combines vascular recanalization with targeted neuroprotection to enhance patient outcomes.

Background and aims Loberamisal is a small-molecule agent that inhibits the nNOS-postsynaptic density protein 95 coupling and enhances α2-containing γ-aminobutyric acid type A receptor, which has been shown effective in animal studies. This trial aimed to investigate its safety and therapeutic efficacy in patients with acute ischaemic stroke (AIS) within 48 hours of symptom onset.Methods Patients were randomly assigned in a 1:1:1:1 ratio to one of four groups: a low-dose loberamisal group (20 mg/dose), a medium-dose group (40 mg/dose), a high-dose group (60 mg/dose) or a placebo group. All patients received a continuous intravenous infusion treatment once a day for 10 days (60±10 min/dose). The primary efficacy outcome was the proportion of patients achieving an excellent functional outcome (a modified Rankin Scale score of 0–1 at 90 days). The primary safety outcome was the incidence of adverse events (AEs).Results A total of 240 patients were randomised, of whom 224 received study treatment from 4 June 2023 to 18 November 2023. The proportion of patients with excellent functional outcome was highest in the medium-dose group (76.7%, 46/60), followed by the high-dose group (70.0%, 42/60), the low-dose group (67.8%, 40/59) and the placebo group (60.7%, 37/61) (p=0.164). Regarding safety, 210 patients experienced at least one AE, with incidences of 80.0% (48/60), 88.3% (53/60) and 91.5% (54/59) in the high, medium and low-dose loberamisal groups, respectively, and 90.2% (55/61) in the placebo group (p=0.260).Conclusions Loberamisal injection was well tolerated in patients with AIS within 48 hours of symptom onset in China. The efficacy and optimal dosage of loberamisal for AIS need prospective validation.Trial registration number ChiCTR2400081662, NCT06429384.

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.

Background: Stroke guidelines recommend intravenous thrombolysis (IVT) within 4.5 hours of symptom onset for patients with minor acute ischemic stroke (AIS) but disabling symptoms. However, such patients are often overlooked for treatment, increasing their risk of stroke-related disability. Tenecteplase is endorsed as an alternative to alteplase for IVT in patients with AIS. More evidence is required regarding its efficacy and safety in the minor stroke population. Methods: This post hoc analysis of the ORIGINAL randomized clinical trial aimed to evaluate the efficacy and safety of tenecteplase versus alteplase in the patient subgroup with minor (National Institutes of Health Stroke Scale [NIHSS] 5) disabling stroke. Primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 at Day 90. Results: Data were analyzed for 299 patients treated with tenecteplase 0.25 mg/kg and 297 patients treated with alteplase 0.9 mg/kg. At Day 90, 86.3% of tenecteplase recipients and 82.8% of alteplase recipients achieved a mRS score of 0 or 1 (risk ratio=1.04 [95% confidence interval 0.971?1.114]; non-significant). No heterogeneity of treatment effect was observed across predefined subgroups according to baseline NIHSS score, time to drug administration, sex, age, presence (yes/no) of atrial fibrillation and diabetes and thrombectomy performed. No statistically significant differences were observed between tenecteplase and alteplase across secondary efficacy and safety outcomes. Conclusions: The comparable efficacy and safety of tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg in the minor stroke population of the ORIGINAL randomized clinical trial suggests that tenecteplase is a suitable alternative to alteplase in this setting. Trial registration: ClinicalTrials.gov [NCT04915729][1] (ORIGINAL randomized clinical trial; https://clinicaltrials.gov/study/[NCT04915729][1]). Submitted 4 June 2021. Key words: acute ischemic stroke, alteplase, intravenous thrombolysis, minor stroke, tenecteplase ### Competing Interest Statement Conflict of Interest Disclosures: Shuhong Xu, Hongguo Dai, Guozhi Lu, Weiwei Wang, Fengyuan Che, Yu Geng, Shuya Li and Yongjun Wang have nothing to disclose. Xiaolong Bao and Shijia Yan are employees of Boehringer Ingelheim, Shanghai, China. ### Clinical Trial ClinicalTrials.gov [NCT04915729][1] (ORIGINAL randomized clinical trial; https://clinicaltrials.gov/study/[NCT04915729][1]). ### Funding Statement Funding/Support: This post hoc analysis was funded by Boehringer Ingelheim (China). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ORIGINAL randomized clinical trial ([NCT04915729][1]), from which the data for this post hoc analysis were derived, was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University. All patients provided written informed consent for the original trial, which included the use of data for future research purposes. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Sharing Statement: To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the International Committee of Medical Journal Editors (ICMJE) criteria, Boehringer Ingelheim grants all external authors access to relevant material, including participant-level clinical study data. In adherence with Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data (see https://www.mystudywindow.com/msw/transparencypolicy), scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, providing regulatory activities are complete and other criteria met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/ for further information. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04915729&atom=%2Fmedrxiv%2Fearly%2F2026%2F03%2F20%2F2026.03.17.26348663.atom

Background:Endovascular treatment has emerged as a cornerstone intervention for acute ischaemic stroke caused by large-vessel occlusion. However, a subset of patients experience futile recanalisation, correlating with unfavourable long-term outcomes. We aimed to investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) in ischaemic stroke patients with endovascular treatment. Methods:This randomised, double-blind, double-dummy, placebo-controlled phase 2 trial in 33 centres in China prospectively enrolled patients aged 35-80 years, who had ischaemic stroke with large vessel occlusion in the anterior circulation within 24 h of onset, with an NIHSS score 7-25 at randomisation. Participants were randomly assigned (1:1:1:1:1) to the Y-6 high-dose group, Y-6 low-dose group, cilostazol high-dose group, cilostazol low-dose group, and placebo group for 28 days. The modified intention-to-treat analysis included the patients receiving at least one dose of the intervention. The primary efficacy outcome was the 90-day mRS 0-1 score, and the primary safety outcome was symptomatic intracranial haemorrhage at 28 days. The trial has been registered on ClinicalTrials.govNCT06138834. Findings:Between Dec 14, 2023, and Dec 25, 2024, of 300 enrolled Chinese patients, 294 patients were included in the intention-to-treat analysis with 213 (72.4%) male. A favourable functional outcome (mRS 0-1) at 90 days occurred in 25 patients (44.6%) in the Y-6 high-dose group (RR 1.25, 95% confidence interval [CI] 0.79-1.97; p = 0.34), 29 patients (46.0%) in the Y-6 low-dose group (RR 1.29, 95% CI 0.83-2.00; p = 0.25), 25 patients (41.7%) in the cilostazol high-dose group (RR 1.17, 95% CI 0.74-1.85; p = 0.51), 22 patients (37.3%) in the cilostazol low-dose group (RR 1.04, 95% CI 0.64-1.69; p = 0.86), and 20 patients (35.7%) in the placebo group. Symptomatic intracranial haemorrhage at 28 days occurred in 1 patient (1.8%) in the Y-6 high-dose group, 3 patients (4.8%) in the Y-6 low-dose group, 2 patients (3.3%) in the cilostazol high-dose group, 4 patients (6.8%) in the cilostazol low-dose group, and 2 patients (3.6%) in the placebo group. No significant differences in efficacy and safety outcomes were found compared with that in the placebo group. Serious adverse events within 90 days occurred in 14 patients (25.0%) in the Y-6 high-dose group, 18 patients (28.6%) in the Y-6 low-dose group, 18 patients (30.0%) in the cilostazol high-dose group, 24 patients (40.7%) in the cilostazol low-dose group, and 14 patients (25.0%) in the placebo group. Interpretation:Our findings indicate that, for patients with ischaemic stroke undergoing endovascular treatment for large vessel occlusion, Y-6 sublingual tablets (cilostazol and dexborneol) were safe with tolerance. Although the trial did not demonstrate statistically significant efficacy on the primary outcome, the signal toward improved functional outcomes without haemorrhage risk supports the biological plausibility of the intervention and justifies further investigation. Large-scale phase 3 clinical trials are warranted to further this research. Funding:The National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Beijing Municipal Science & Technology Commission; Capital's Funds for Health Improvement and Research; National Key R&D Program of China.

Background and objectives Loberamisal, a novel agent that dissociates the post-synaptic density protein 95/neuronal nitric oxide synthase complex and potentiates the α2-containing γ-aminobutyric acid type A receptors, is a potential neuroprotectant that is effective in preclinical studies for acute ischaemic stroke. This trial aims to demonstrate the efficacy and safety of intravenous loberamisal in patients with acute ischaemic stroke (AIS) within 48 hours of onset.Methods and design The LAIS (Loberamisal for Acute Ischaemic Stroke) trial is a multicentre, prospective, randomised, double-blind, placebo-controlled phase 3 trial. A total of 998 eligible patients will be randomly assigned to receive either loberamisal or placebo in a 1:1 ratio.Outcomes The primary efficacy outcome is proportion of individuals achieving an excellent functional outcome, defined as modified Rankin Scale (mRS) 0–1 at 90 days. Secondary efficacy outcomes include favourable functional outcome (defined as an mRS score of 0 in patients with a baseline NIHSS score of 4 to 7; an mRS score of 0 to 1 in patients with a baseline NIHSS score of 8 to 14; and an mRS score of 0 to 2 in patients with a baseline NIHSS score of 15 to 25), distribution of mRS at 90 days, patients with ≥4 points reduction in National Institutes of Health Stroke Scale score from baseline at 10 days and 30 days, and Barthel Index ≥95 at 90 days. Safety outcomes were adverse events. Exploratory outcomes include the incidence of depressive and anxiety symptoms at 90 days.Discussion The LAIS trial will evaluate the potential of loberamisal as a novel neuroprotectant in acute ischaemic stroke.Trial registration number NCT06517173.

The efficacy of intravenous thrombolysis is time-dependent. Reteplase has been shown to be superior to alteplase in certain acute ischemic stroke patients. The authors aimed to delineate the associations of stroke onset-to-treatment time (OTT) on the therapeutic benefits and clinical risks with reteplase in comparison to alteplase. This is a post hoc analysis of the RAISE (Reteplase versus Alteplase for Acute Ischemic Stroke) trial. Patients were divided into 3 groups based on their onset-to-treatment times: 0 to 90, 91 to 180, and 181 to 270 minutes. The primary efficacy outcome was the proportion of participants with a modified Rankin scale score of 0 to 1 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours post-thrombolytic treatment. A total of 1,399 patients (99.1%) with OTT (median 180 minutes; Q1-Q3: 135-222 minutes) were included. Adjusted risk ratios of primary efficacy outcome were 1.16 (95% CI: 0.70-1.91) for the 0 to 90 minutes group, 1.14 (95% CI: 0.97-1.35) for 91 to 180 minutes group, and 1.12 (95% CI: 0.93-1.18) for 181 to 270 minutes group. The primary safety outcome had no difference between reteplase and alteplase in the 3 OTT intervals. Among patients with ischemic stroke within 4.5 hours after symptom onset, there was no significant difference in the efficacy profile between reteplase and alteplase for achieving excellent functional outcomes at 3 different OTT intervals. (A Study of r-PA Treating Patients With Acute Ischemic Stroke [RAISE]; NCT05295173).

BackgroundGD-11, a novel brain cytoprotective drug, was designed to be actively taken up and transported across the blood-brain barrier via the glucose transporter. This study aimed to evaluate the safety and efficacy of GD-11 for improving the recovery of patients with acute ischaemic stroke (AIS).MethodsA double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 15 clinical sites in China. Patients aged 18–80 years with AIS within 48 hours were randomly assigned (1:1:1) to receive 160 mg GD-11, 80 mg GD-11 and placebo, two times a day for 10 days. The primary endpoint was a modified Rankin Scale (mRS) score of 0–1 at 90 days after treatment. The safety outcome was any adverse events within 90 days.ResultsFrom 17 November 2022 to 22 March 2023, a total of 80 patients in the 160 mg GD-11 group, 79 patients in the 80 mg GD-11 group and 80 patients in the placebo group were included. The proportion of an mRS score of 0–1 at day 90 was 77.5% in the 160 mg GD-11 group, 72.2% in the 80 mg GD-11 group and 67.5% in the placebo group. Though no significant difference was found (p=0.3671), a numerically higher proportion was observed in the GD-11 group, especially in the 160 mg GD-11 group. The incidence of adverse events was similar across the three groups (p=0.1992).ConclusionGD-11 was safe and well-tolerated. A dosage of GD-11 160 mg two times a day was recommended for a large trial to investigate the efficacy.

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.

BACKGROUND:Acute ischaemic stroke, due to its high mortality and disability rates, imposes a significant economic and social burden worldwide. Typically, endovascular treatment within the therapeutic window is provided to salvage the ischaemic penumbra; however, even when recanalisation is successful during endovascular treatment, the clinical outcomes may still be disappointing. This highlights the necessity of further research, so as to discover better solutions to futile recanalisation and improve patient outcomes. OBJECTIVE:To investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) compared with a placebo in the treatment of patients with acute ischaemic stroke caused by large vessel occlusion. METHOD:The efficacy and safety of Y-6 sublingual tablets in patients with acute ischaemic stroke are evaluated in a phase II, randomised, double-blind, double-dummy, placebo-controlled, parallel clinical trial. Eligible patients having provided informed consent are randomised into five groups for a 28-day treatment period. The primary outcome is the percentage of patients achieving the modified Rankin Scale score of 0-1 at 90 days. DISCUSSION:The EFfects of Y-6 SUblingual Tablets for PaTients with AcUte Ischemic StRokE trial assesses whether Y-6 sublingual tablets are effective and safe in improving the clinical outcomes of patients with acute ischaemic stroke caused by large vessel occlusion. TRIAL REGISTRATION NUMBER:NCT06138834.

Background:The effect of colchicine on subsequent stroke among patients with and without symptomatic intracranial artery stenosis (sICAS) and whether age modifies such effect are not known. Methods:In this prespecified subgroup analysis of CHANCE-3, a randomized, double-blind, placebo-controlled clinical trial conducted at 244 centers in China between 11 August 2022 and 13 April 2023 (ClinicalTrials.gov number, NCT05439356), we included 7567 patients with ischemic stroke or transient ischemic attack and assessments of intracranial arteries at baseline. The primary efficacy outcome was a new stroke at 90 days. The main secondary outcome was a combined vascular event including ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, and vascular death. The primary safety outcome was any serious adverse event within 90 days. Findings:In patients with sICAS, 141 (10.5%) patients on colchicine and 115 (8.5%) on placebo had recurrent stroke within 90 days (adjusted HR 1.30, 95% CI 1.01-1.69; p = 0.04); in patients without sICAS, the corresponding event rates were 4.2% and 5.2% (adjusted HR 0.80, 95% CI 0.62-1.05; p = 0.10) (adjusted interaction p = 0.01). A significant interaction was also observed between sICAS status and the effect of colchicine on the secondary outcome of combined vascular events (adjusted p = 0.02). The interaction was more apparent in the elderly patients (adjusted p < 0.001). In the elderly patients with sICAS (n = 1648), the risk of stroke was higher in the colchicine group (n = 829, 50.3%) compared to the placebo group (n = 819, 49.7%) (adjusted HR 1.58, 95% CI 1.13-2.20; p < 0.001). There was no interaction of status of sICAS with treatment groups on primary safety outcome of any serious adverse event (p = 0.54). In patients with sICAS, 24 (1.8%) patients on colchicine and 7 (0.5%) on placebo had diarrhea within 90 days (p = 0.002). In patients without sICAS, diarrhea occurred in 43 (1.8%) patients on colchicine and in 20 (0.8%) patients on placebo (p = 0.004). Interpretation:The effect of colchicine on subsequent stroke within 90 days may differ according to the presence of sICAS. Aging might be associated with an increased risk of early recurrent stroke in the patients with sICAS receiving colchicine treatment. Future prospective studies are needed to confirm these results. Funding:National Key R&D Program of China, National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. China Kunming Pharmaceuticals supplied colchicine and placebo. Guangdong Wesail Biotech Co. provided assistance in measurement of hsCRP levels.

BACKGROUND:Malignant cerebral edema is a critical cause of poor outcomes in large hemispheric infarction and novel neuroprotective agents are urgently needed. We aimed to assess the safety and preliminarily explored the feasibility of YC-6 (5α-androst-3β,5,6β-triol for injection) in large hemispheric infarction. METHODS:This study was a prospective, randomized, double-blind, placebo-controlled, proof-of-concept trial. Patients with large hemispheric infarction in middle cerebral artery within 12 hours of symptom onset were enrolled. Patients were assigned to receive either 300 mg YC-6 or placebo twice a day for 10 days, randomly. The primary safety outcomes were serious adverse events and all-cause death. The primary efficacy outcome was the distribution of the modified Rankin Scale score at 90 days. RESULTS:The incidence of serious adverse events (52.2% and 43.5%) and all-cause death (39.1% and 40.0%) within 90 days were similar between YC-6 and placebo group. There was no statistical difference between the groups in the distribution of modified Rankin Scale score (common odds ratio 0.73, 95% CI: 0.25 to 2.18). The proportion of a modified Rankin Scale score of 0 to 4 was 56.5% in YC-6 group compared with 35.0% in placebo group (P=0.16). In addition, YC-6 treatment numerically alleviated edema volume at 72 hours and 10 days (RD -15.02, 95% CI: -40.94 to 10.90; RD -10.35, 95% CI: -46.69 to 25.98) and decreased midline shift at 10 days (RD -0.6, 95% CI: -4.17 to 2.97). CONCLUSIONS:This study preliminarily explored the safety and feasibility of YC-6 in patients with large hemispheric infarction. Based on this trial, the phase 2 trial of YC-6 was worthy of anticipation. REGISTRATION:http://www.chinadrugtrials.org.cn; Unique identifier: CTR20192127; http://www.chictr.org.cn; Unique identifier: ChiCTR2400088887.

BACKGROUND:The efficacy of intravenous thrombolysis is time-dependent. Reteplase has been shown to be superior to alteplase in certain acute ischemic stroke patients. OBJECTIVES:The authors aimed to delineate the associations of stroke onset-to-treatment time (OTT) on the therapeutic benefits and clinical risks with reteplase in comparison to alteplase. METHODS:This is a post hoc analysis of the RAISE (Reteplase versus Alteplase for Acute Ischemic Stroke) trial. Patients were divided into 3 groups based on their onset-to-treatment times: 0 to 90, 91 to 180, and 181 to 270 minutes. The primary efficacy outcome was the proportion of participants with a modified Rankin scale score of 0 to 1 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours post-thrombolytic treatment. RESULTS:A total of 1,399 patients (99.1%) with OTT (median 180 minutes; Q1-Q3: 135-222 minutes) were included. Adjusted risk ratios of primary efficacy outcome were 1.16 (95% CI: 0.70-1.91) for the 0 to 90 minutes group, 1.14 (95% CI: 0.97-1.35) for 91 to 180 minutes group, and 1.12 (95% CI: 0.93-1.18) for 181 to 270 minutes group. The primary safety outcome had no difference between reteplase and alteplase in the 3 OTT intervals. CONCLUSIONS:Among patients with ischemic stroke within 4.5 hours after symptom onset, there was no significant difference in the efficacy profile between reteplase and alteplase for achieving excellent functional outcomes at 3 different OTT intervals. (A Study of r-PA Treating Patients With Acute Ischemic Stroke [RAISE]; NCT05295173).

Background Stroke remains a major global health challenge, with China experiencing a significant burden due to its high incidence and severe outcomes. Reperfusion therapies, such as intravenous thrombolysis and endovascular thrombectomy, have shown substantial benefits in improving early outcomes for ischaemic stroke. Recent clinical trials have validated the safety and efficacy of a broader range of thrombolytic agents and expanded the eligible patient populations for both intravenous thrombolysis and mechanical thrombectomy. This guideline aims to provide the latest evidence-based insights in the field of reperfusion therapy.Methods The Chinese Stroke Association (CSA) established a writing group to develop updated guidelines on reperfusion therapy for acute ischaemic stroke. A comprehensive search of MEDLINE (via PubMed) was conducted up to 30 September 2024. Experts in the field of stroke engaged in extensive discussions, both online and offline, to evaluate the latest evidence. Each recommendation was graded using the CSA’s class of recommendation and level of evidence in the Guideline Development Manual of the CSA.Results This guideline, reviewed and approved by the CSA Guidelines Writing Group, outlines the criteria for patient selection for thrombolysis and thrombectomy and summarises the latest evidence on various thrombolytic drug options to support decision-making in reperfusion therapy. Additionally, the guideline includes green channel flow charts for intravenous thrombolysis and mechanical thrombectomy, designed to assist clinicians in optimising their clinical decisions.Conclusion This guideline updates the latest advancements in the field of reperfusion therapy for acute ischaemic stroke. It is anticipated that future clinical research will further advance areas such as innovative thrombolytic agents, expanded indications for thrombolysis and mechanical thrombectomy.

Background Intra-arterial prourokinase has been shown to be a promising thrombolytic agent in patients with acute ischaemic stroke. Given the global shortage of thrombolytics, we aimed to assess the non-inferiority of intravenous recombinant human prourokinase compared with alteplase in patients with acute ischaemic stroke who were ineligible for or who refused endovascular thrombectomy. Methods PROST-2 was a phase 3, open-label, non-inferiority, randomised controlled trial conducted at 61 hospitals in China. Patients older than 18 years with acute ischaemic stroke, who were ineligible for or who refused endovascular thrombectomy, were randomly assigned in a 1:1 ratio within 45 h of stroke onset to receive intravenous recombinant human prourokinase (15 mg bolus followed by 20 mg infusion within 30 min) or intravenous alteplase (09 mg per kg, maximum dose 90 mg; 10% bolus followed by remainder as infusion over 60 min). The primary efficacy outcome was the proportion of patients with a modified Rankin Scale score of 0 or 1 at 90 days, assessed via masked review in the intention-to-treat population, with a non-inferiority margin for the risk ratio of 093. The primary safety outcome was the incidence of symptomatic intracranial haemorrhage within 36 h. This trial is registered with ClinicalTrials.gov (NCT05700591) and is now completed. Findings Between Jan 29, 2023, and March 14, 2024, 1552 patients were randomly assigned: 775 received recombinant human prourokinase and 777 received alteplase. The primary outcome of a modified Rankin Scale score of 0 or 1 at 90 days was reached by 558 (720%) of 775 patients in the recombinant human prourokinase group versus 534 (687%) of 777 in the alteplase group (risk ratio 104 [95% CI 098 to 110]; p<00001 for non-inferiority). The frequency of symptomatic intracranial haemorrhage within 36 h was lower in the recombinant human prourokinase group than in the alteplase group (two [03%] of 770 patients vs ten [13%] of 775, risk difference -10 percentage points [95% CI -21 to -01]; p=0021), as was the incidence of major bleeding at 7 days (four [05%] vs 16 [21%]; -15 percentage points (-28 to -04); p=00072). All-cause mortality within 7 days did not differ between groups (five [06%] deaths in the recombinant human prourokinase group vs 13 [17%] in the alteplase group; risk difference -10 percentage points; 95% CI -23 to 01]; p=0060). Interpretation In our trial, recombinant human prourokinase was shown to be non-inferior to alteplase for achieving excellent functional outcome, with no difference between groups in safety endpoints. These findings support the use of recombinant human prourokinase as a viable alternative to alteplase for patients with ischaemic stroke who are eligible for intravenous thrombolysis therapy but ineligible for or who have refused endovascular thrombectomy.

Objective Limited evidence is available regarding the risk-benefit ratio of thrombolytic therapy in patients with stroke and renal impairment complications, particularly for the drug tenecteplase. Therefore, we examined the association of impaired renal function with the safety and efficacy of intravenous thrombolytic treatment (IVT) in patients with acute ischaemic stroke (AIS).Methods A post hoc analysis of a randomised controlled trial (ClinicalTrials gov. NCT04797013) was conducted. Participants who received IVT with tenecteplase and alteplase (0.25 and 0.9 mg/kg, respectively) within 4.5 hours of symptoms onset were categorised based on their estimated glomerular filtration rate as follows: (1) ≥90 mL/min/1.73 m2,normal renal function; (2) 60–89 mL/min/1.73 m2, mildly decreased renal function; and (3) <60 mL/min/1.73 m2, moderately to severely decreased renal function. Patients stratified based on the normal renal function were used as the references. The primary efficacy and safety outcome were the percentage of patients achieving a modified Rankin Scale score of 0–1 at 90 days and the symptomatic intracranial haemorrhage (sICH) occurrence within 36 hours, respectively.Results In intravenous tenecteplase-treated patients, mildly decreased renal function (OR 3.10; 95% CI: 1.41 to 6.78) and moderately to severely decreased renal function (OR: 8.03; 95% CI: 2.76 to 23.38) showed an association with a higher risk of all-cause mortality but not with sICH incidence compared with normal renal function. Among patients administered intravenous alteplase, those with a moderate-to-severe decrease in renal function exhibited an elevated risk of sICH (adjusted OR: 10.01; 95% CI: 1.61 to 62.15) and all-cause mortality (adjusted OR: 4.54; 95% CI: 1.48 to 13.91). Comparative treatment effects between tenecteplase and alteplase according to renal function grades showed no heterogeneity.Conclusions A significant correlation was noted between kidney dysfunction and unfavourable outcomes in individuals with AIS who received treatment with either tenecteplase or alteplase.

Background and Objectives:Hemostasis factors affecting clot patterns, particularly fibrinogen, may influence the effectiveness of intravenous thrombolysis (IVT). We aimed to investigate the impact of differences in fibrinogen plasma levels on the efficacy and safety of tenecteplase versus alteplase in an acute ischemic cerebrovascular events-II (TRACE-II) trial. Methods:In a multi-center, prospective, open-label, end-point blinded, randomized, controlled trial. Adults with acute ischemic stroke (AIS) were enrolled. Patients received intravenous tenecteplase (0-25 mg/kg) or alteplase (0-9 mg/kg) within 4-5 h. Patients were divided into three groups according to their plasma fibrinogen level: low fibrinogen level (< 2 g/L), normal fibrinogen level (2-4 g/L), and high fibrinogen level (> 4 g/L). The Modified Rankin Score (mRS) from 2 to 6 was used to define the efficacy outcome. The safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) within 36 h and 90 days, parenchymal hematoma 2 (PH2) within 36 h, any intracranial hemorrhage (ICH), other significant hemorrhagic events, and death at 3 months. SAS software version 9.4 was used for statistical analysis. Binary logistic regression was used to evaluate the efficacy and safety outcomes differences between tenecteplase and alteplase in the three fibrinogen groups. The interaction between treatment and fibrinogen subgroups was used to assess the effect of fibrinogen levels on the efficacy and safety of different treatments. All P-values are two-tailed and significance was defined as P < 0.05. Results:The trial enrolled 1409 patients with AIS. Among them, 705 patients received tenecteplase treatment and 704 patients received alteplase treatment. Six percent of all patients had a low plasma fibrinogen level ( < 2 g/L), 81% had a normal fibrinogen level (2-4 g/L), and 13% had a high plasma fibrinogen level ( > 4 g/L). The efficacy of tenecteplase compared to alteplase remained consistent across varying fibrinogen levels (interaction P = 0.30). Additionally, the safety outcomes were comparable between the two treatments across all fibrinogen levels [sICH at 36 h (interaction P = 0.94); sICH at 90 days (interaction P = 0.77); PH2ICH at 36 h (interaction P = 0.84); Other symptomatic hemorrhagic events within 90 days (interaction P = 0.54)]. Similarly, there was no significant difference in mortality rates between patients treated with tenecteplase and alteplase across different plasma fibrinogen levels (interaction P = 0.58). Conclusion:The results of the study suggest that the efficacy and safety of tenecteplase in treated AIS patients within 4.5 h are comparable to those of alteplase, regardless of plasma fibrinogen levels.

OBJECTIVES:To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3). DESIGN:Multicentre, double blind, randomised, placebo controlled trial. SETTING:244 hospitals in China between 11 August 2022 and 13 April 2023. PARTICIPANTS:8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled. INTERVENTIONS:Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days. MAIN OUTCOME MEASURES:The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. RESULTS:4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83). CONCLUSIONS:The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L. TRIAL REGISTRATION:ClinicalTrials.gov, NCT05439356.