Intra-arterial tenecteplase after successful endovascular therapy (ANGEL-TNK): protocol of a multicentre, open-label, blinded end-point, prospective, randomised trial.

BACKGROUND: Despite successful reperfusion after thrombectomy for large vessel occlusion (LVO) stroke, up to half of patients are dependent or dead at 3-month follow-up.The aim of the current study is to demonstrate safety and efficacy of administering adjunct intra-arterial (IA) tenecteplase in anterior circulation LVO patients who have achieved successful reperfusion defined as eTICI 2b50 to 3. METHODS: ANGEL-TNK is a multicentre, open-label, assessor-blinded endpoint, prospective randomised, controlled trial that will enrol up to 256 patients. Patients who meet inclusion criteria with anterior circulation LVO stroke and successful reperfusion will be randomised to receive IA tenecteplase or best medical management at 1:1 ratio. RESULTS: The primary endpoint is a 90-day excellent outcome defined as modified Rankin Scale (mRS) 0-1. The primary safety endpoint is symptomatic intracranial haemorrhage within 48 hours from randomisation. Secondary endpoints include 90-day ordinal mRS, mRS 0-2, mRS 0-3, all-cause mortality and any intracranial haemorrhage. CONCLUSION: In patients with anterior circulation LVO stroke, the ANGEL-TNK trial will inform whether adjunct IA tenecteplase administered after successful thrombectomy reperfusion improves patient outcomes. TRIAL REGISTRATION NUMBER: NCT05624190.

Glycated albumin levels are associated with adverse stroke outcomes in patients with acute ischemic stroke in China.

BACKGROUND AND AIM: Glycated albumin (GA) is a biomarker monitoring glycemia 2-4 weeks before stroke onset. This study was designed to explore the association between GA levels with poststroke outcomes in patients with acute ischemic stroke or transient ischemic attack (TIA). METHOD: Participants with ischemic stroke or TIA who had a baseline GA measurement were included in the Third China National Stroke Registry study. The effect of GA on stroke recurrence, poor functional outcomes, and combined vascular events was examined during the 1-year follow-up period. Multivariate Cox and logistic regression models were performed to evaluate the association. Discrimination tests were used to examine the incremental predictive value of GA when incorporating it into the conventional model. RESULTS: A total of 3861 participants were enrolled. At the 3-month follow-up, the elevated GA level was associated with an increased risk of poor functional outcomes (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.01-2.09). A similar increase was observed for stroke recurrence (adjusted hazard ratio [HR], 1.56; 95% CI, 1.09-2.24), poor functional outcomes (adjusted OR, 1.62; 95% CI, 1.07-2.45), and combined vascular events (adjusted HR, 1.55; 95% CI, 1.09-2.20) at the 1-year follow-up. In nondiabetic patients, the association between GA and poor functional outcomes was more pronounced (adjusted OR, 1.62; 95% CI, 1.05-2.50). Adding GA into the conventional model resulted in slight improvements in predicting poor functional outcomes (net reclassification improvement [NRI]: 12.30% at 1 year). CONCLUSION: This study demonstrated that elevated GA levels in serum were associated with stroke adverse outcomes, including stroke recurrence, poor functional outcomes, and combined vascular events, in patients with ischemic stroke or TIA.

Neutrophil-to-Lymphocyte Ratio, Lymphocyte-to-Monocyte Ratio and Platelet-to-Lymphocyte Ratio as Predictors of Short- and Long-Term Outcomes in Ischemic Stroke Patients with Atrial Fibrillation.

Purpose: Inflammatory response plays essential roles in the pathophysiology of both ischemic stroke and atrial fibrillation (AF). We aimed to investigate whether composite inflammatory markers, including neutrophil to lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR), can serve as early predictors of short- and long-term outcomes in ischemic stroke patients with AF. Patients and Methods: Ischemic stroke patients with AF were enrolled in this cohort study. The primary outcome was 1-year functional dependence or death (modified Rankin scale (mRS) score 3-6). Secondary outcomes included hemorrhagic transformation (HT) and early neurological deterioration (END, increase in the National Institutes of Health Stroke Scale (NIHSS) ≥4 within 7 days). Partial correlations were performed to assess the correlation between systemic inflammation markers and admission NIHSS scores. Univariate and multivariate logistic analyses were performed to investigate whether systemic inflammatory markers were independent predictors of adverse outcomes. Results: A total of 408 patients were included. Partial correlation analysis revealed statistically significant but weak correlations between the NLR (r = 0.287; P < 0.001), PLR (r = 0.158; P = 0.001) and admission NIHSS score. Compared with patients without HT or END, patients who developed HT or END had higher NLR and PLR, and lower LMR. Patients in the functional dependence or death group had significantly higher NLR and PLR, and lower LMR than those in the functional independence group (all P < 0.001). Multivariate logistic analysis indicated that NLR, LMR and PLR were independent predictors of HT (OR = 1.069, 0.814 and 1.003, respectively), END (OR = 1.100, 0.768 and 1.006, respectively) and adverse 1-year functional outcome (OR = 1.139, 0.760 and 1.005, respectively). Conclusion: NLR, LMR and PLR were independent predictors for in-hospital HT, END and long-term functional outcome in ischemic stroke patients with AF. Close monitoring of these inflammatory markers may help guide risk stratification and clinical treatment strategies.

Association between the C-reactive protein to albumin ratio and poor clinical outcome in patients with spontaneous intracerebral hemorrhage.

BACKGROUND: The C-reactive protein-to-albumin ratio (CAR) is a novel prognostic biomarker of systemic inflammation and nutritional status. The association between CAR and the long-term outcome of spontaneous intracerebral hemorrhage (ICH) remains unclear. METHODS: From January 2014 to September 2016, 497 patients with spontaneous ICH were enrolled in our study from 13 hospitals in Beijing. According to the CAR quartiles, patients were classified into four groups (Q1-Q4). Logistic regression was applied to analyze the relationship between different CAR levels and main outcome (90-day and 1-year mRS 4-6). Restricted cubic splines and receiver operating characteristic (ROC) curves of CAR for poor clinical outcomes were assessed. RESULTS: In the multivariate logistic regression model, compared with the lowest quartile of CAR, the adjusted odds ratios of the Q2, Q3, and Q4 group for 90-day mRS score of 4-6 were 3.64 (1.61-8.23), 3.83 (1.67-8.77), and 8.91 (3.85-20.64). In terms of 1-year mRS score of 4-6, compared with the lowest quartile of CAR, the adjusted odds ratios of the Q3 and Q4 group were 3.31 (1.33-8.22) and 6.87 (2.81-16.78). CONCLUSIONS: A high CAR level was associated with a high risk of long-term adverse prognosis in patients with ICH, and the risk of ICH poor outcome increased steadily with CAR rising in a certain range, and maintained in a high level thereafter.

Balloon Angioplasty vs Medical Management for Intracranial Artery Stenosis: The BASIS Randomized Clinical Trial.

Importance: Previous randomized clinical trials did not demonstrate the superiority of endovascular stenting over aggressive medical management for patients with symptomatic intracranial atherosclerotic stenosis (sICAS). However, balloon angioplasty has not been investigated in a randomized clinical trial. Objective: To determine whether balloon angioplasty plus aggressive medical management is superior to aggressive medical management alone for patients with sICAS. Design, Setting, and Participants: A randomized, open-label, blinded end point clinical trial at 31 centers across China. Eligible patients aged 35 to 80 years with sICAS defined as recent transient ischemic attack (<90 days) or ischemic stroke (14-90 days) before enrollment attributed to a 70% to 99% atherosclerotic stenosis of a major intracranial artery receiving treatment with at least 1 antithrombotic drug and/or standard risk factor management were recruited between November 8, 2018, and April 2, 2022 (final follow-up: April 3, 2023). Interventions: Submaximal balloon angioplasty plus aggressive medical management (n = 249) or aggressive medical management alone (n = 252). Aggressive medical management included dual antiplatelet therapy for the first 90 days and risk factor control. Main Outcomes and Measures: The primary outcome was a composite of any stroke or death within 30 days after enrollment or after balloon angioplasty of the qualifying lesion or any ischemic stroke in the qualifying artery territory or revascularization of the qualifying artery after 30 days through 12 months after enrollment. Results: Among 512 randomized patients, 501 were confirmed eligible (mean age, 58.0 years; 158 [31.5%] women) and completed the trial. The incidence of the primary outcome was lower in the balloon angioplasty group than the medical management group (4.4% vs 13.5%; hazard ratio, 0.32 [95% CI, 0.16-0.63]; P < .001). The respective rates of any stroke or all-cause death within 30 days were 3.2% and 1.6%. Beyond 30 days through 1 year after enrollment, the rates of any ischemic stroke in the qualifying artery territory were 0.4% and 7.5%, respectively, and revascularization of the qualifying artery occurred in 1.2% and 8.3%, respectively. The rate of symptomatic intracranial hemorrhage in the balloon angioplasty and medical management groups was 1.2% and 0.4%, respectively. In the balloon angioplasty group, procedural complications occurred in 17.4% of patients and arterial dissection occurred in 14.5% of patients. Conclusions and Relevance: In patients with sICAS, balloon angioplasty plus aggressive medical management, compared with aggressive medical management alone, statistically significantly lowered the risk of a composite outcome of any stroke or death within 30 days or an ischemic stroke or revascularization of the qualifying artery after 30 days through 12 months. The findings suggest that balloon angioplasty plus aggressive medical management may be an effective treatment for sICAS, although the risk of stroke or death within 30 days of balloon angioplasty should be considered in clinical practice. Trial Registration: ClinicalTrials.gov Identifier: NCT03703635.

Safety and efficacy of GD-11 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: GD-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). METHODS: A 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. RESULTS: From 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). CONCLUSION: GD-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.

A Deep Learning-Based Framework for Predicting Intracerebral Hemorrhage Hematoma Expansion Using Head Non-contrast CT Scan.

RATIONALE AND OBJECTIVES: Hematoma expansion (HE) in intracerebral hemorrhage (ICH) is a critical factor affecting patient outcomes, yet effective clinical tools for predicting HE are currently lacking. We aim to develop a fully automated framework based on deep learning for predicting HE using only clinical non-contrast CT (NCCT) scans. MATERIALS AND METHODS: A large retrospective dataset (n = 2484) was collected from 84 centers, while a prospective dataset (n = 500) was obtained from 26 additional centers. Baseline NCCT scans and follow-up NCCT scans were conducted within 6 h and 48 h from symptom onset, respectively. HE was defined as a volume increase of more than 6 mL on the follow-up NCCT. The retrospective dataset was divided into a training set (n = 1876) and a validation set (n = 608) by patient inclusion time. A two-stage framework was trained to predict HE, and its performance was evaluated on both the validation and prospective sets. Receiver operating characteristics area under the curve (AUC), sensitivity, and specificity were leveraged. RESULTS: Our two-stage framework achieved an AUC of 0.760 (95% CI 0.724-0.799) on the retrospective validation set and 0.806 (95% CI 0.750-0.859) on the prospective set, outperforming the commonly used BAT score, which had AUCs of 0.582 and 0.699, respectively. CONCLUSION: Our framework can automatically and robustly identify ICH patients at high risk of HE using admission head NCCT scans, providing more accurate predictions than the BAT score.

Association between PPARγ polymorphisms and neurological functional disability of ischemic stroke.

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, Pinteraction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

Association and temporal sequence of pneumonia and gastrointestinal bleeding after acute ischemic stroke.

BACKGROUND: Stroke-associated pneumonia (SAP) and gastrointestinal bleeding (GIB) are common medical complications after stroke. The previous study suggested a strong association between SAP and GIB after stroke. However, little is known about the time sequence of SAP and GIB. In the present study, we aimed to verify the association and clarify the temporal sequence of SAP and GIB after ischemic stroke. METHODS: Patients with ischemic stroke from in-hospital Medical Complication after Acute Stroke study were analyzed. Data on occurrences of SAP and GIB during hospitalization and the intervals from stroke onset to diagnosis of SAP and GIB were collected. Multiple logistic regression was used to evaluate the association between SAP and GIB. Kruskal-Wallis test was used to compare the time intervals from stroke onset to diagnosis of SAP and GIB. RESULTS: A total of 1129 patients with ischemic stroke were included. The median length of hospitalization was 14 days. Overall, 86 patients (7.6%; 95% CI, 6.1-9.2%) developed SAP and 47 patients (4.3%; 95% CI, 3.0-5.3%) developed GIB during hospitalization. After adjusting potential confounders, SAP was significantly associated with the development of GIB after ischemic stroke (OR = 5.13; 95% CI, 2.02-13.00; P < 0.001). The median time from stroke onset to diagnosis of SAP was shorter than that of GIB after ischemic stroke (4 days vs. 5 days; P = 0.039). CONCLUSIONS: SAP was associated with GIB after ischemic stroke, and the onset time of SAP was earlier than that of GIB. It is imperative to take precautions to prevent GIB in stroke patients with SAP.

DNMT3A dysfunction promotes neuroinflammation and exacerbates acute ischemic stroke.

Somatic mutations related to clonal hematopoiesis of indeterminate potential (CHIP) are risk factors for stroke. The impact of DNMT3A, the most mutated gene in CHIP, on clinical functional outcomes of acute ischemic stroke (AIS) remains unclear. In a well-characterized cohort of 8524 ischemic stroke patients, we demonstrated that DNMT3A-driven CHIP was significantly associated with neurological disability in these patients. With a stroke mouse model of transient middle cerebral artery occlusion (tMCAO), we demonstrated that DNMT3A protein levels in the brain penumbra increased. The DNMT3A inhibitor RG108 administration amplified neutrophil proliferation in the blood, promoted neutrophil infiltration into the brain penumbra, and exaggerated proinflammatory activation in tMCAO male mice. DNMT3A inhibition also significantly increased infarct volume and worsened neurobehavioral function in tMCAO male mice. In conclusion, DNMT3A somatic mutations are associated with worsened neurological disability in some patients with AIS, potentially through increased neutrophil proliferation and infiltration in the ischemic brain region. These findings suggest a possible mechanism for proinflammatory activation and tissue damage in the affected brain tissue, highlighting the need for further research in this area.

Therapeutic effect and mechanisms of traditional Chinese medicine compound (Qilong capsule) in the treatment of ischemic stroke.

Background Qilong capsule (QLC) is a well-known traditional Chinese medicine compound extensively used in clinical practice. It has been approved by the China's FDA for the treatment of ischemic stroke (IS). In our clinical trial involving QLC (ClinicalTrials.gov identifier: NCT03174535), we observed the potential of QLC to improve neurological function in IS patients at the 24th week, while ensuring their safety. However, the effectiveness of QLC beyond the initial 12-week period remains uncertain, and the precise mechanisms underlying its action in IS have not been fully elucidated. Purpose In order to further explore the clinical efficacy of QLC in treating IS beyond the initial 12-week period and systematically elucidate its underlying mechanisms. Study Design This study employed an interdisciplinary integration strategy that combines post hoc analysis of clinical trials, transcriptome sequencing, integrated bioinformatics analysis, and animal experiments. Methods In this study, we conducted a post-hoc analysis with 2302 participants to evaluate the effectiveness of QLC at the 12th week. The primary outcome was the proportion of patients achieving functional independence at the 12th week, defined as a score of 0-2 on the modified Rankin Scale (mRS), which ranges from 0 (no symptoms) to 6 (death). Subsequently, we employed RNA sequencing (RNA-Seq) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) techniques in the QLC trial to investigate the potential molecular mechanisms underlying the therapeutic effect of QLC in IS. Simultaneously, we utilized integrated bioinformatics analyses driven by external multi-source data and algorithms to further supplement the exploration and validation of QLC's therapeutic mechanism in treating IS. This encompassed network pharmacology analysis and analyses at the mRNA, cellular, and pathway levels focusing on core targets. Additionally, we developed a disease risk prediction model using machine learning. By identifying differentially expressed core genes (DECGs) between the normal and IS groups, we quantitatively predicted IS occurrence. Furthermore, to assess its protective effects and determine the key regulated pathway, we conducted experiments using a middle cerebral artery occlusion and reperfusion (MACO/R) rat model. Results Our findings demonstrated that the combination of QLC and conventional treatment (CT) significantly improved the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week compared to CT alone (n = 2,302, 88.65 % vs 87.33 %, p = 0.3337; n = 600, 91.33 % vs 84.67 %, p = 0.0165). Transcriptome data revealed that the potential underlying mechanism of QLC for IS is related to the regulation of the NF-κB inflammatory pathway. The RT-qPCR results demonstrated that the regulatory trends of key genes, such as MD-2, were consistent with those observed in the RNA-Seq analysis. Integrated bioinformatics analysis elucidated that QLC regulates the NF-κB signaling pathway by identifying core targets, and machine learning was utilized to forecast the risk of IS onset. The MACO/R rat model experiment confirmed that QLC exerts its anti-CIRI effects by inhibiting the MD-2/TLR-4/NF-κB signaling axis. Conclusion: Our interdisciplinary integration study has demonstrated that the combination of QLC with CT exhibits significant superiority over CT alone in improving functional independence in patients at the 12th week. The potential mechanism underlying QLC's therapeutic effect in IS involves the inhibition of the MD-2/TLR4/NF-κB inflammatory signaling pathway, thereby attenuating cerebral ischemia/reperfusion inflammatory injury and facilitating neurofunctional recovery. The novelty and innovative potential of this study primarily lie in the novel finding that QLC significantly enhances the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week. Furthermore, employing a "multilevel-multimethod" integrated research approach, we elucidated the potential mechanism underlying QLC's therapeutic effect in IS.

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial.

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.

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.).

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Data-Driven Analysis Reveals Cortical Infarction Patterns Correlated With Inflammation and Prognosis: A Retrospective, Multicenter Cohort Study.

BACKGROUND: We aim to identify the distinct lesion patterns and regions associated with functional outcome and inflammation in patients with acute ischemic stroke, and investigate whether the association between lesion patterns and functional outcome was mediated by inflammation. METHODS AND RESULTS: We performed nonnegative matrix factorization to derived low-dimensional lesion patterns (atoms), and Bayesian linear regression models were applied to explore the associations of lesion patterns with inflammatory factors including high-sensitivity C-reactive protein and interleukin-6, as well as functional outcome (defined as modified Rankin Scale score at 3 months). The difference distribution mean and 95% highest probability density interval (HPDI) were calculated. Mediation analysis was used to examine the mediating effects of inflammation on the relationships between lesion patterns and functional outcome. Seven lesion patterns were derived from 5914 patients with acute ischemic stroke. Lesion patterns distributed in the cortical regions were associated with inflammatory response, including atom 1 (interleukin-6: mean, 0.113 [95% HPDI, 0.073-0.162]; high-sensitivity C-reactive protein: mean, 0.082 [95% HPDI, 0.038-0.123]) and atom 4 (interleukin-6: mean, 0.113 [95% HPDI, 0.071-0.167]; high-sensitivity C-reactive protein: mean, 0.108 [95% HPDI, 0.058-0.165]). These lesion patterns were also significantly associated with functional outcome (atom 1: mean, 1.958 [95% HPDI, 1.538-2.383]; atom 4: mean, 2.245 [95% HPDI, 1.773-2.741]). Mediation analysis suggested that interleukin-6 explained 15.34% and 7.47% in the association of atom 1 and atom 4 with functional outcome, respectively. CONCLUSIONS: Certain lesion patterns that are associated with both inflammation and functional outcome of acute ischemic stroke, especially cortical infarction, may play a role in functional outcome through modulating inflammatory reactions.

The Influence of Non-High-Density Lipoprotein Cholesterol on the Efficacy of Genotype-Guided Dual Antiplatelet Therapy in Preventing Stroke Recurrence.

BACKGROUND AND PURPOSE: Non-high-density lipoprotein cholesterol (non-HDL-C), which represents the total cholesterol content of all pro-atherogenic lipoproteins, has recently been included as a new target for lipid-lowering therapy in high-risk atherosclerotic patients in multiple guidelines. Herein, we aimed to explore the relationship between non-HDL-C level and the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing stroke recurrence. METHODS: This study comprised a post hoc analysis of the CHANCE-2 (Ticagrelor or Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial, from which 5,901 patients with complete data on non-HDL-C were included and categorized by median non-HDL-C levels, using a cutoff of 3.5 mmol/L. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days. RESULTS: Ticagrelor-aspirin significantly reduced the risk of recurrent stroke in patients with low non-HDL-C (71 [4.8%] vs. 119 [7.7%]; adjusted hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.40-0.74), but not in those with high non-HDL-C (107 [7.3%] vs. 108 [7.6%]; adjusted HR, 0.88; 95% CI, 0.67-1.16), compared with clopidogrel-aspirin (P for interaction=0.010). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin for recurrent stroke decreased as non-HDL-C levels increased. No significant differences in the treatment assignments across the non-HDL-C groups were observed in terms of the rate of severe or moderate bleeding (5 [0.3%] vs. 8 [0.5%] in the low non-HDL-C group; 4 [0.3%] vs. 2 [0.1%] in the high non-HDL-C group; P for interaction=0.425). CONCLUSION: CHANCE-2 participants with low non-HDL-C levels received more clinical benefit from ticagrelor-aspirin versus clopidogrel-aspirin compared to those with high non-HDL-C, following minor ischemic stroke or transient ischemic attack.

Hemodynamic Impairment of Blood Pressure and Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Hemodynamic impairment of blood pressure may play a crucial role in determining the mechanisms of stroke in symptomatic intracranial atherosclerotic stenosis). We aimed to elucidate this issue and assess the impacts of modifications to blood pressure on hemodynamic impairment. METHODS: From the Third China National Stroke Registry III, computed fluid dynamics modeling was performed using the Newton-Krylov-Schwarz method in 339 patients with symptomatic intracranial atherosclerotic stenosis during 2015 to 2018. The major exposures were translesional systolic blood pressure (SBP) drop and poststenotic mean arterial pressure (MAP), and the major study outcomes were cortex-involved infarcts and borderzone-involved infarcts, respectively. Multivariate logistic regression models and the bootstrap resampling method were utilized, adjusting for demographics and medical histories. RESULTS: In all, 184 (54.3%) cortex-involved infarcts and 70 (20.6%) borderzone-involved infarcts were identified. In multivariate logistic model, the upper quartile of SBP drop correlated with increased cortex-involved infarcts (odds ratio, 1.92 [95% CI, 1.03-3.57]; bootstrap analysis odds ratio, 2.07 [95% CI, 1.09-3.93]), and the lower quartile of poststenotic MAP may correlate with increased borderzone-involved infarcts (odds ratio, 2.07 [95% CI, 0.95-4.51]; bootstrap analysis odds ratio, 2.38 [95% CI, 1.04-5.45]). Restricted cubic spline analysis revealed a consistent upward trajectory of the relationship between translesional SBP drop and cortex-involved infarcts, while a downward trajectory between poststenotic MAP and borderzone-involved infarcts. SBP drop correlated with poststenotic MAP negatively (rs=-0.765; P<0.001). In generating hemodynamic impairment, simulating blood pressure modifications suggested that ensuring adequate blood pressure to maintain sufficient poststenotic MAP appears preferable to the reverse approach, due to the prolonged plateau period in the association between the translesional SBP drop and cortex-involved infarcts and the relatively short plateau period characterizing the correlation between poststenotic MAP and borderzone-involved infarcts. CONCLUSIONS: This research elucidates the role of hemodynamic impairment of blood pressure in symptomatic intracranial atherosclerotic stenosis-related stroke mechanisms, underscoring the necessity to conduct hemodynamic assessments when managing blood pressure in symptomatic intracranial atherosclerotic stenosis.

Reteplase versus Alteplase for Acute Ischemic Stroke.

BACKGROUND: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. METHODS: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. RESULTS: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). CONCLUSIONS: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).

Bailout intracranial angioplasty or stenting following thrombectomy for acute large vessel occlusion in China (ANGEL-REBOOT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: Unsuccessful recanalisation or reocclusion after thrombectomy is associated with poor outcomes in patients with large vessel occlusion (LVO) acute ischaemic stroke (LVO-AIS). Bailout angioplasty or stenting (BAOS) could represent a promising treatment for these patients. We conducted a randomised controlled trial with the aim to investigate the safety and efficacy of BAOS following thrombectomy in patients with LVO. METHODS: ANGEL-REBOOT was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, blinded-endpoint clinical trial conducted at 36 tertiary hospitals in 19 provinces in China. Participants with LVO-AIS 24 h after symptom onset were eligible if they had unsuccessful recanalisation (expanded Thrombolysis In Cerebral Infarction score of 0-2a) or risk of reocclusion (residual stenosis >70%) after thrombectomy. Eligible patients were randomly assigned by the minimisation method in a 1:1 ratio to undergo BAOS as the intervention treatment, or to receive standard therapy (continue or terminate the thrombectomy procedure) as a control group, both open-label. In both treatment groups, tirofiban could be recommended for use during and after the procedure. The primary outcome was the change in modified Rankin Scale score at 90 days, assessed in the intention-to-treat population. Safety outcomes were compared between groups. This trial was completed and registered at ClinicalTrials.gov (NCT05122286). FINDINGS: From Dec 19, 2021, to March 17, 2023, 706 patients were screened, and 348 were enrolled, with 176 assigned to the intervention group and 172 to the control group. No patients withdrew from the trial or were lost to follow-up for the primary outcome. The median age of patients was 63 years (IQR 55-69), 258 patients (74%) were male, and 90 patients (26%) were female; all participants were Chinese. After random allocation, tirofiban was administered either intra-arterially, intravenously, or both in 334 [96%] of 348 participants. No between-group differences were observed in the primary outcome (common odds ratio 0·86 [95% CI 0·59-1·24], p=0·41). Mortality was similar between the two groups (19 [11%] of 176 vs 17 [10%] of 172), but the intervention group showed a higher risk of symptomatic intracranial haemorrhage (eight [5%] of 175 vs one [1%] of 169), parenchymal haemorrhage type 2 (six [3%] of 175 vs none in the control group), and procedure-related arterial dissection (24 [14%] of 176 vs five [3%] of 172). INTERPRETATION: Among Chinese patients with unsuccessful recanalisation or who are at risk of reocclusion after thrombectomy, BAOS did not improve clinical outcome at 90 days, and incurred more complications compared with standard therapy. The off-label use of tirofiban might have affected our results and their generalisability, but our findings do not support the addition of BAOS for such patients with LVO-AIS. FUNDING: Beijing Natural Science Foundation, National Natural Science Foundation of China, National Key R&D Program Beijing Municipal Administration of Hospitals Incubating Program, Shanghai HeartCare Medical Technology, HeMo (China) Bioengineering, Sino Medical Sciences Technology.