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Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis., Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis., Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed., Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90)., Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome., Results: A total of 11 431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively., Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis., Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

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., Competing Interests: Declaration of interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from National Key R&D Program of China, the 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; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Inflammation is associated with vascular events. We aimed to investigate the relationship between high-sensitivity C-reactive protein (hsCRP) levels with and without intracranial arterial stenosis (ICAS) and the prognosis of patients with minor stroke or transient ischemic attack., Methods: We used data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial (derivation cohort) and the Third China National Stroke Registry (validation cohort). Patients were divided into four groups according to the dichotomy of hsCRP level and ICAS status. The primary outcome was new ischemic stroke within 90 days, and the secondary outcome was dependence or death (Modified Rankin Scale score of 3-6) at 90 days. The associations between hsCRP level with and without ICAS and risk of outcomes were analyzed using multivariate Cox regression and logistic regression models., Results: In the derivation cohort, compared with patients with nonelevated hsCRP levels and no ICAS, those with both elevated hsCRP levels and ICAS had increased risk of recurrent stroke (adjusted hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.28-5.34; p=0.008) and dependence or death (adjusted odds ratio [OR], 7.58; 95% CI, 1.30-44.13; p=0.02). Consistent relationships of elevated hsCRP levels and presence of ICAS with recurrent stroke (adjusted HR, 1.67; 95% CI, 1.13-2.45; p=0.009) and dependence or death (adjusted OR, 1.87; 95% CI, 1.23-2.84; p=0.003) were observed in the validation cohort., Conclusion: Concomitant presence of increased hsCRP levels and ICAS was associated with increased risk of stroke recurrence and dependence or death in patients with minor ischemic stroke or transient ischemic attack.

Introduction: It remains unclear whether enlarged perivascular spaces (EPVS) predict poor clinical outcomes in patients with acute ischaemic stroke (AIS) or transient ischaemic attack (TIA)., Method: Data were obtained from the Third China National Stroke Registry study. We estimated EPVS in basal ganglia (BG) and centrum semiovale (CSO) using a semiquantified scale (Grade from 0 to 4). Using Cox and logistic regression analyses, the associations of EPVS with 3-month and 1-year adverse outcomes (including recurrent stroke, ischaemic stroke, haemorrhagic stroke, combined vascular event, disability and mortality) were explored. Sensitivity analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion (SAO) were conducted., Result: Among 12 603 patients with AIS/TIA, median age was 61.7±11.6 years, and 68.2% were men. After adjusting for all potential confounders, frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke (HR 0.71, 95% CI 0.55 to 0.92, p=0.01) but an increased risk of haemorrhagic stroke (HR 1.99, 95% CI 1.11 to 3.58, p=0.02) at 1 year after AIS/TIA, compared with none-to-mild BG-EPVS. Patients with frequent-to-severe CSO-EPVS had a decreased risk of disability (OR 0.76, 95% CI 0.62 to 0.92, p=0.004) and all-cause death (HR 0.55, 95% CI 0.31 to 0.98, p=0.04) within 3-month but not 1-year follow-ups, compared with those with none-to-mild BG-EPVS. Sensitivity analyses showed that both BG-EPVS (HR 0.43, 95% CI 0.21 to 0.87, p=0.02) and CSO-EPVS (HR 0.58, 95% CI 0.35 to 0.95, p=0.03) were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year follow-up., Conclusion: BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 year. Therefore, caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who were carriers of CYP2C19 loss-of-function alleles, dual-antiplatelet therapy with ticagrelor-aspirin reduced the 90-day risk of stroke without increased severe or moderate bleeding compared with clopidogrel-aspirin. However, whether dual-antiplatelet therapy with ticagrelor was superior to clopidogrel beyond the 90 days of follow-up remained unclear. In this study, we reported 1-year follow-up outcomes of the CHANCE-2 trial., Methods: The CHANCE-2 trial is a randomized, double-blind, placebo-controlled trial at 202 centers in China. Patients with a minor stroke or TIA who carried CYP2C19 loss-of-function alleles were randomized within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor and placebo clopidogrel or to receive clopidogrel and placebo ticagrelor for 90 days; both groups received aspirin for the first 21 days. After day 90, treatment was as per the choice of the clinician and the patient., Results: Among 6,412 patients, the proportion of patients on ticagrelor plus aspirin, clopidogrel plus aspirin, ticagrelor alone, clopidogrel alone, aspirin alone, other antiplatelet, and no antiplatelet beyond month 3 to 1 year was 0.09%, 1.56%, 0.13%, 2.66%, 73.65%, 0.78%, and 21.13% in the ticagrelor-aspirin group and 0.03%, 1.63%, 0.19%, 2.60%, 72.83%, 0.66%, and 22.06% in the clopidogrel-aspirin group, respectively. The primary outcome of new stroke occurred in 252 patients (7.91%) in the ticagrelor-aspirin group and 310 patients (9.73%) in the clopidogrel-aspirin group by 1 year of follow-up (hazard ratio 0.80; 95% CI 0.68-0.95; p = 0.007); new stroke beyond 3 months to 1 year occurred in 61 patients (2.07%) and 67 patients (2.32%) ( p = 0.48), respectively. Primary safety outcome of severe or moderate bleeding occurred in 17 patients (0.53%) in the ticagrelor-aspirin group and 20 patients (0.63%) in the clopidogrel-aspirin group ( p = 0.61)., Discussion: For CYP2C19 loss-of-function allele carriers, early dual-antiplatelet therapy with ticagrelor is superior to clopidogrel at 1 year in reducing recurrent stroke., Trial Registration Information: URL: clinicaltrials.gov. Unique identifier: NCT04078737., Classification of Evidence: This study provides Class II evidence that for patients with minor stroke or TIA with TIACYP2C19 loss-of-function, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin in reducing the 1-year risk of recurrent stroke.

Background: Elevated homocysteine levels are associated with increased blood coagulation and platelet activity and may modulate the response to antiplatelet therapies. We aimed to investigate the effects of homocysteine levels on the efficacy and safety of ticagrelor-acetylsalicylic acid (ASA) versus clopidogrel-ASA among patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles., Methods: We conducted a post hoc analysis of the CHANCE-2 (The Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial. Participants were randomly assigned to treatment with ticagrelor-ASA or clopidogrel-ASA. We categorized participants into groups with elevated and non-elevated homocysteine levels, based on the median level. The primary efficacy outcome was recurrent stroke within 90-day follow-up. The primary safety outcome was severe or moderate bleeding within 90 days., Results: A total of 2740 participants were randomly assigned to receive ticagrelor-ASA and 2700 to receive clopidogrel-ASA. Use of ticagrelor-ASA was associated with a reduced risk of recurrent stroke among participants with elevated homocysteine levels (74 [5.3%] v. 119 [8.5%]; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.45-0.81), but not among those with non-elevated levels (86 [6.4%] v. 87 [6.7%]; HR 0.97, 95% CI 0.71-1.32; p = 0.04 for interaction). When analyzed as a continuous variable, the benefits of ticagrelor-ASA with regard to recurrent stroke increased as homocysteine levels increased ( p = 0.04 for interaction). No significant interaction between homocysteine levels and treatment with regard to severe or moderate bleeding was observed ( p = 0.7 for interaction). We found a significant interaction between homocysteine levels and therapy with regard to recurrent stroke in females ( p = 0.04 for interaction) but not males., Interpretation: In comparison with clopidogrel-ASA, ticagrelor-ASA conferred more benefit to patients with elevated homocysteine levels, particularly to female patients, in this secondary analysis of a randomized controlled trial involving patients with minor ischemic stroke or TIA., Trial Registration: ClinicalTrials.gov, no. NCT04078737., Competing Interests: Competing interests: Philip Bath reports study grants from the British Heart Foundation and National Institute for Health and Care Research Health Technology Assessment; consulting fees from CoMind, DiaMedica, Phagenesis, and Roche; support for attending meetings or travel from Brainomix; and participation on a board for European Carotid Surgery Trial 2 and AVRT (atrioventricular reciprocating tachycardia) Dose. Dr. Bath reports being co-chair of the Industry Committee of the World Stroke Organisation and receipt of trial devices from Phagenesis for the Pharyngeal Electrical stimulation for Acute Stroke dysphagia Trial. No other competing interests declared., (© 2024 CMA Impact Inc. or its licensors.)

Introduction: The aim of this study was to investigate the impact of smoking on dual antiplatelet therapy in patients with minor stroke or transient ischemic attack (TIA) under different glycated albumin (GA) levels., Methods: We analyzed data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. A subgroup of 3,044 patients with baseline GA levels was included and categorized by smoking status and GA levels. The primary efficacy outcome was a new stroke within 90 days. The safety outcome was any bleeding event at 90 days. The interaction of smoking status with antiplatelet therapy was calculated by Cox proportional hazards regression model., Results: In patients with GA levels ≤15.5%, the proportion of smokers was 37.7% (719/1,908), while in patients with GA levels >15.5%, it was 51.6% (586/1,136). During the 3-month follow-up period, 299 (9.9%) patients had a new stroke occurrence. In patients with elevated GA levels, both smokers and nonsmokers could not benefit from dual antiplatelet therapy (smokers, adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI]: 0.42-1.17; nonsmokers, adjusted HR 0.82, 95% CI: 0.57-1.18). In patients with normal GA levels, dual antiplatelet therapy reduced the risk of stroke recurrence in smokers by 72% (adjusted HR 0.28, 95% CI: 0.14-0.56) and in nonsmokers by 53% (adjusted HR 0.47, 95% CI: 0.26-0.86). However, whether the GA level was elevated or normal, there was no significant interaction between smoking status and antiplatelet therapy., Conclusions: Smokers with elevated GA levels could not benefit from dual antiplatelet therapy after minor stroke or TIA., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Intracranial atherosclerotic disease (ICAD) is a common cause of ischaemic stroke and transient ischaemic attack (TIA) with a high recurrence rate. It is often referred to as intracranial atherosclerotic stenosis (ICAS), when the plaque has caused significant narrowing of the vessel lumen. The lesion is usually considered 'symptomatic ICAD/ICAS' (sICAD/sICAS) when it has caused an ischaemic stroke or TIA. The severity of luminal stenosis has long been established as a prognostic factor for stroke relapse in sICAS. Yet, accumulating studies have also reported the important roles of plaque vulnerability, cerebral haemodynamics, collateral circulation, cerebral autoregulation and other factors in altering the stroke risks across patients with sICAS. In this review article, we focus on cerebral haemodynamics in sICAS. We reviewed imaging modalities/methods in assessing cerebral haemodynamics, the haemodynamic metrics provided by these methods and application of these methods in research and clinical practice. More importantly, we reviewed the significance of these haemodynamic features in governing the risk of stroke recurrence in sICAS. We also discussed other clinical implications of these haemodynamic features in sICAS, such as the associations with collateral recruitment and evolution of the lesion under medical treatment, and indications for more individualised blood pressure management for secondary stroke prevention. We then put forward some knowledge gaps and future directions on these topics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We sought to investigate whether the prognostic value of intracranial arterial stenosis (ICAS) is consistent across different risk stratifications using the Essen Stroke Risk score (ESRS)., Methods: We derived data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial. Patients without complete baseline brain imaging data were excluded. Participants were categorized into different risk groups based on ESRS (low risk, 0-2, and high risk ≥ 3). The main outcome was stroke recurrence within 3 and 12 months. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) of ICAS, and other factors associated with stroke recurrence within 3 and 12 months were estimated using the Cox regression method., Results: During the 3-month follow-up, 54 patients (7.9%) had recurrent stroke in the low-risk group, and 39 patients (9.6%) had recurrent stroke in the high-risk group. ICAS was associated with a higher risk of stroke within 3 months (HR = 2.761; 95%CI = 1.538-4.957; P  < 0.001) in the low-risk group, but not in the high-risk group (HR = 1.501; 95%CI = 0.701-3.213; P  = 0.296). ICAS was independently associated with higher recurrent risk in the low-risk group (HR = 2.540; 95%CI = 1.472-4.381; P  < 0.001), but not in the high-risk group (HR = 1.951; 95%CI = 0.977-3.893; P  = 0.058) within 12 months., Conclusion: ICAS was an independent predictor of both 3- and 12-month stroke recurrence in low-risk but not high-risk patients with minor ischemic stroke or transient ischemic attack according to ESRS stratification.

Background This study aimed to investigate the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in Chinese patients by the presence and clinical presentation of intracranial artery stenosis (ICAS) using randomized trial data from the CHANCE-2 (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II) trial. Methods and Results A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were randomized to either the ticagrelor-aspirin or clopidogrel-aspirin group. Patients without imaging of the intracranial artery were excluded from the nonprespecified subgroup analysis of CHANCE-2. All patients included were classified into the following groups: without ICAS, symptomatic ICAS, or asymptomatic ICAS. The primary efficacy outcome was new strokes within 90 days. There were 5893 patients (median age, 64.8 years; 33.9% women) included, and 172 (4.9%), 171 (10.5%), and 57 (7.7%) cases of new strokes occurred within 90 days in the without ICAS, with symptomatic ICAS, and with asymptomatic ICAS groups, respectively. Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without ICAS (62 [3.5%] versus 110 [6.3%]; hazard ratio [HR], 0.57 [95% CI, 0.41-0.78]) but not in those with symptomatic ICAS (HR, 0.77 [95% CI, 0.56-1.05]) or in those with asymptomatic ICAS (HR, 0.77 [95% CI, 0.43-1.38]) compared with clopidogrel-aspirin ( P for interaction=0.14). There were no significant differences in the proportion of severe or moderate bleeding events among different ICAS groups. Conclusions Patients without ICAS received a significantly greater benefit from ticagrelor-aspirin than clopidogrel-aspirin after minor ischemic stroke or transient ischemic attack, and there was no statistically significant difference between treatments in patients with symptomatic ICAS or asymptomatic ICAS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Aims: We aimed to investigate the association of the left ventricular ejection fraction (LVEF) spectrum with 1-year clinical outcomes in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA)., Methods: In a prospective registry for the Third China National Stroke Registry (CNSR-III), AIS or TIA patients with echocardiography records during hospitalization were recruited. All LVEFs were categorized into intervals of 5% in width. The lowest and highest intervals are ≤40% and >70%, respectively. The primary outcome was all-cause death at 1 year. Cox proportional hazards regression analysis was performed to investigate the association between baseline LVEF and clinical outcomes., Results: This analysis included a total of 14,053 patients. In total, 418 patients died during 1-year follow-up. Overall, LVEF ≤60% was associated with a higher risk of all-cause death compared to LVEF >60%, independent of demographic and clinical characteristics (aHR 1.29 [95% CI 1.06-1.58]; p = 0.01). The cumulative incidence of all-cause death was significantly different among the eight LVEF groups that survival declined successively with the decrease of LVEF (log-rank p ≤ 0.0001)., Conclusions: Patients with AIS or TIA with decreased LVEF (≤60%) had a lower 1-year survival rate after onset. LVEF 50%-60% even within the normal range, may still contribute to poor outcomes in AIS or TIA. Comprehensive evaluation of cardiac function after acute ischemic cerebrovascular disease should be strengthened., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: It is unclear whether patients with different stroke/transient ischemic attack etiologies benefit differently from gene-directed dual antiplatelet therapy. This study explored the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in transient ischemic attack or minor stroke with different causes in the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II)., Methods: This was a prespecified analysis of the CHANCE-2 trial, which enrolled 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles. Patients with centralized evaluation of TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification of large-artery atherosclerosis, small-vessel occlusion, and stroke of undetermined cause were included. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. Cox proportional hazards models were used to assess the interaction of TOAST classification with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin., Results: A total of 6336 patients were included in this study. In patients administered ticagrelor-aspirin and clopidogrel-aspirin, respectively, stroke recurred in 85 (9.8%) and 88 (10.7%) patients with large-artery atherosclerosis (hazard ratio, 0.86 [95% CI, 0.63-1.18]; P =0.34); 32 (3.6%) and 61 (7.0%) patients with small-vessel occlusion (hazard ratio, 0.51 [95% CI, 0.33-0.79]; P =0.002); and 68 (4.8%) and 87 (5.9%) patients with stroke of undetermined cause (hazard ratio, 0.80 [95% CI, 0.58-1.10]; P =0.17), with P =0.08 for the treatment×cause subtype interaction effect. There were no significant differences in severe or moderate bleeding events in patients with different cause and different treatment., Conclusions: In this prespecified analysis of the CHANCE-2 trial, the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing new stroke were consistent in patients with different causes. The influence of stroke cause on benefit of gene-guided antiplatelet therapy should be explored by further trials., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04078737., Competing Interests: Disclosures P.M. Bath has consulted for DiaMedica, Moleac, Phagenesis, and Roche. Dr Claiborne Johnston’s institution has received support from AstraZeneca for research and consulting related to the THALES trial (Ticagrelor and ASA [Acetylsalicylic Acid] for Prevention of Stroke and Death) and from Johnson and Johnson/Bristol-Myers Squibb for research planning. The other authors report no conflicts.

Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease., Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD 2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat., Trial Registry Name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356.

Background: Body mass index (BMI) may affect the response to platelet P2Y 12 receptor inhibitors. We aimed to explore whether BMI influenced the efficacy and safety of ticagrelor and clopidogrel for secondary prevention of minor ischemic stroke or transient ischemic attack (TIA) among patients enrolled in the CHANCE-2 (Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial., Methods: In a multicentre, randomized, double-blind, placebo-controlled trial, conducted in China, we randomized patients with minor stroke or TIA who carried the CYP2C19 loss-of-function allele to receive either ticagrelor-acetylsalicylic acid (ASA) or clopidogrel-ASA. We classified patients into obese (BMI ≥ 28) or nonobese (BMI < 28) groups. The primary efficacy outcome was stroke within 90 days, and the primary safety outcome was severe or moderate bleeding within 90 days., Results: Among 6412 patients, 876 were classified as obese and 5536 were classified as nonobese. Compared with clopidogrel-ASA, ticagrelor-ASA was associated with a significantly lower rate of stroke within 90 days among patients with obesity (25 [5.4%] v. 47 [11.3%]; hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.87), but not among those in the nonobese group (166 [6.0%] v. 196 [7.0%]; HR 0.84, 95% CI 0.69-1.04) The interaction of treatment and BMI group was significant ( p for interaction = 0.04). We did not observe any difference by BMI group in rates of severe or moderate bleeding (9 [0.3%] v. 10 [0.4%] in the nonobese group; 0 [0.0%] v. 1 [0.2%] in the obese group; p for interaction = 0.99)., Interpretation: In this secondary analysis of a randomized controlled trial involving patients with minor ischemic stroke or TIA, compared with clopidogrel-ASA, patients with obesity received more clinical benefit from ticagrelor-ASA therapy than those without obesity., Trial Registration: Clinicaltrials.gov, no. NCT04078737., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: There is a close brain-kidney interaction following ischemic cerebrovascular disease. The new-onset kidney injury after stroke leads to severe neurological deficits and poor functional outcomes. We aimed to validate the Nelson equation for predicting the new-onset and long-term kidney function decline in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA)., Methods: A total of 3169 patients were enrolled in the Third China National Stroke Registry, whose baseline estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m 2 . The outcome of interest was the incident eGFR< 60 mL/min/1.73 m 2 at 3 months. The prediction equation of participants with or without diabetes was validated respectively. The receiver operating characteristic curve (AUC) evaluated prediction performance. The Delong test compared the Nelson equation performance with the O'Seaghdha equation and the Chien equation. Continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were determined to evaluate the incremental effect., Results: During the 3-mo follow-up period, among 1151 patients with diabetes, there were 31 cases (2.7%) of reduced eGFR. Meanwhile, among 2018 non-diabetic patients, there were 23 cases (1.1%) of reduced eGFR. The Nelson equation showed good discrimination and was well-calibrated in patients with diabetes (AUC 0.82, Hosmer-Lemeshow test p = 0.67) or without diabetes (AUC 0.82, Hosmer-Lemeshow test p = 0.09). The performance of the Nelson equation was superior to other equation, as increased continuous NRI (diabetic, 0.64; non-diabetic, 1.13) and IDI (diabetic, 0.10; non-diabetic, 0.13) to the Chien equation., Conclusion: The Nelson equation reliably predicted the risks of the new-onset and long-term kidney function decline in patients with AIS or TIA, which could help clinicians screen high-risk patients and improve clinical care., Competing Interests: The authors declare that they do not have a conflict of interest., (© 2023 Zhou et al.)

Importance: The Clopidogrel With Aspirin in High-Risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that ticagrelor-aspirin combination therapy reduced the risk of stroke compared with a clopidogrel-aspirin combination among carriers of CYP2C19 loss-of-function (LOF) alleles after a transient ischemic attack (TIA) or minor ischemic stroke. However, the association between the degree of CYP2C19 LOF and ideal treatment allocation remains unknown., Objective: To investigate whether the efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin are consistent with the expected degree of CYP2C19 LOF after TIA or minor stroke., Design, Setting, and Participants: CHANCE-2 was a multicenter, double-blind, double-dummy, placebo-controlled randomized clinical trial. Patients were enrolled at 202 centers in China from September 23, 2019, through March 22, 2021. Patients with at least two *2 or *3 alleles (*2/*2, *2/*3, or *3/*3) according to point-of-care genotyping were classified as "poor metabolizers," and those with one *2 or *3 allele (*1/*2 or *1/*3) were classified as "intermediate metabolizers.", Interventions: Patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or clopidogrel (300-mg loading dose on day 1 followed by 75 mg/d for days 2-90). All patients received aspirin (75- to 300-mg loading dose followed by 75 mg/d for 21 days)., Main Outcomes and Measures: The primary efficacy outcome was a new ischemic or hemorrhagic stroke. The secondary efficacy outcome was a composite of new clinical vascular events and individual ischemic stroke events within 3 months. The primary safety outcome was severe or moderate bleeding. Analyses were performed according to the intention-to-treat principle., Results: Of the 6412 patients enrolled, the median age was 64.8 years (IQR, 57.0-71.4 years), and 4242 patients (66.2%) were men. Of the 6412 patients, 5001 (78.0%) were intermediate metabolizers, and 1411 (22.0%) were poor metabolizers. The primary outcome occurred less often with ticagrelor-aspirin vs clopidogrel-aspirin, irrespective of metabolizer status (6.0% [150 of 2486] vs 7.6% [191 of 2515]; hazard ratio [HR], 0.78 [95% CI, 0.63-0.97] among intermediate metabolizers and 5.7% [41 of 719] vs 7.5% [52 of 692]; HR, 0.77 [95% CI, 0.50-1.18] among poor metabolizers; P = .88 for interaction). Patients taking ticagrelor-aspirin had a higher risk of any bleeding event compared with those taking clopidogrel-aspirin, irrespective of metabolizer status: 5.4% (134 of 2486) vs 2.6% (66 of 2512) (HR, 2.14 [95% CI, 1.59-2.89]) among intermediate metabolizers and 5.0% (36 of 719) vs 2.0% (14 of 692) (HR, 2.99 [95% CI, 1.51-5.93]) among poor metabolizers (P = .66 for interaction)., Conclusions and Relevance: This prespecified analysis of a randomized clinical trial found no difference in treatment effect between poor and intermediate CYP2C19 metabolizers. The relative clinical efficacy and safety of ticagrelor-aspirin vs clopidogrel-aspirin were consistent across CYP2C19 genotypes., Trial Registration: ClinicalTrials.gov Identifier: NCT04078737.

Background: It remains unclear if intensive antiplatelet and statin treatments begun within 24-72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe., Methods: The Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial is a randomised, double-blind, placebo-controlled, multicentre and 2×2 factorial trial. 6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack (TIA) within the previous 72 hours that is attributed to ≥50% atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial. Eligible subjects will be randomised 1:1:1:1 to one of four groups: (1) intensive antiplatelet therapy (combined clopidogrel and aspirin for days 1-21, then aspirin placebo and clopidogrel for days 22-90) plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days, then 40 mg daily for days 22-90); (2) intensive antiplatelet therapy plus delayed intensive statin therapy (atorvastatin placebo for days 1-3, followed by 40 mg per day of atorvastatin for days 4-90); (3) standard antiplatelet therapy (combination of clopidogrel placebo with aspirin for 90 days) plus immediate intensive statin therapy and (4) standard antiplatelet therapy plus delayed intensive statin therapy. The primary efficacy endpoint is any new stroke (ischaemic or haemorrhagic) within 90 days after randomisation. The primary safety endpoint is moderate to severe bleeding at 90 days., Conclusion: The INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin., Trial Registration Number: NCT03635749., Competing Interests: Competing interests: YiW received support from Sanofi and Beijing Jialin Pharmaceuticals for the INSPIRES trial. All of the sponsors for the INSPIRES trial do not play any role in the design, implementation and interpretation of the study. Dr. Johnston’s institution received support from AstraZeneca for research and consulting related to the THALES trial. PMB is Stroke Association Professor of Stroke Medicine an emeritus NIHR Senior Investigator. YoW received support from Shenzhen Salubris Pharmaceuticals for the CHANCE-2 trial., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study was performed to investigate whether ticagrelor/aspirin versus clopidogrel/aspirin can further reduce the residual risk of stroke recurrence in patients with positive diffusion-weighted imaging (DWI) in the High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial., Methods: Patients with DWI data in the CHANCE-2 trial were included and divided into those with and without acute infarction according to their DWI findings. The primary efficacy outcome and safety outcome were stroke recurrence and moderate to severe bleeding within 3 months of follow-up, respectively., Results: Of the 6,412 patients enrolled in the CHANCE-2 trial, 5,796 (90.4%) patients with DWI data were included in the subgroup analysis. A total of 4,369 patients (75.4%) had an acute infarction on DWI. Patients with positive DWI had higher risk of recurrent stroke (8.1%) than those without infarction (2.2%) within 3-month follow-up. Compared with clopidogrel/aspirin, ticagrelor/aspirin was associated with lower risk of stroke in patients with positive DWI (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.52-0.80, p < 0.001) than in those negative DWI (HR = 1.22, 95% CI = 0.55-2.72, p = 0.63), with a significant interaction association (p for interaction = 0.049). The risk of moderate to severe bleeding was similar between ticagrelor/aspirin and clopidogrel/aspirin treatment in the different groups., Interpretation: Our study demonstrates that imaging evaluation should be emphasized before targeting the best candidates for genotype-guided dual antiplatelet therapy in future clinical research and practice. ANN NEUROL 2023;93:783-792., (© 2022 American Neurological Association.)

Background and Purpose: The residual recurrent risk of stroke, which cannot be entirely explained by the traditional ABCD2 score, still existed. Heart rate variability (HRV), a method for reflecting the function of automatic nervous system (ANS), was a novel predictor of secondary stroke events. We aimed to investigate the relationships of combined HRV and ABCD 2 score with adverse outcomes after acute minor stroke (MS) or transient ischemic attack (TIA), and further investigate the independent associations between HRV and adverse outcomes after MS/TIA stratified by ABCD 2 score., Methods: Data were obtained from the Third China National Stroke Registry (CNSR-III) study. We assessed the activity of ANS using standard deviation of NN intervals (SDNN), a time domain index of HRV. Trained investigators collected clinical characteristics and estimated ABCD 2 score for each participant. All enrolled patients were categorized into different risk groups based on SDNN level and ABCD 2 score. The clinial outcomes included recurrent stroke, recurrent ischemic stroke, and disability within 1-year follow-up. We evaluated whether combined SDNN and ABCD 2 score were associated with recurrent events using multivariable Cox regression models, and those with disability using multivariable logistic regression models. The independent associations between SDNN and diverse outcomes stratified by ABCD 2 score were explored using multivariable Cox and logistic regression analyses., Results: A total of 5,743 participants [3,316 (70.02) males, 62.0 (54.0-69.0) years] were included. Patients with low SDNN and ABCD 2  ≥ 4 were associated with higher risk of recurrent stroke within 1 year (10.8% versus 4.9%; [HR] 1.31, 95% [CI] 0.92-1.88, P = 0.14) compared to patients with high SDNN with ABCD 2 < 4. Lower SDNN was associated with higher recurrent stroke in patients with ABCD 2 0-3 score ([HR] 0.73, 95% [CI] 0.57-0.947, P = 0.01) and ABCD 2 4-5 score ([HR] 0.85, 95% [CI] 0.74-0.97, P = 0.02), but not in patients with ABCD 2 6-7 score., Conclusion: The combination of HRV and ABCD 2 score might efficiently stratify the risk of 1-year recurrent stroke after MS/TIA. Moreover, lower SDNN was independently related to recurrent stroke in patients with MS/TIA, especially for those with low-to-moderate traditional vascular risk factors., Competing Interests: Declaration of Competing Interest Authors report no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background and Objective: Genotype data of the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial showed that efficacy of clopidogrel aspirin depended on CYP2C19 genotype and risk profile. A stratification of patients who carried CYP2C19 loss-of-function (LOF) alleles according to the risk of recurrent stroke may be important for selecting optimal antiplatelet therapy. We aimed to compare the efficacy and safety of ticagrelor aspirin with clopidogrel aspirin in CYP2C19 LOF carriers with minor stroke or transient ischemic attack (TIA) stratified by risk profile., Methods: Data were obtained from Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial. Low-risk and high-risk profiles were defined by Essen Stroke Risk Score (ESRS) (<3 [low risk] and ≥3 [high risk], respectively)., Results: A total of 6,412 CYP2C19 LOF carriers were enrolled; ticagrelor aspirin was associated with a reduced risk of primary outcome (new stroke within 90-day follow-up) in patients at low risk (hazard ratio [HR], 0.65; 95% CI, 0.48-0.82), but not in those at high risk (HR, 0.97; 95% CI, 0.73-1.29), compared with clopidogrel aspirin ( p = 0.02 for interaction). Secondary outcomes generally went in the same direction as the primary outcome. The primary safety outcome of severe or moderate bleeding did not differ based on risk profile ( p = 0.24 for interaction), although the incidence of total bleeding was greater with ticagrelor aspirin than with clopidogrel aspirin among patients at low risk ( p < 0.01 for interaction). Analysis in the per-protocol population yielded similar results., Discussion: This post hoc analysis of CHANCE-2 trial showed that CYP2C19 LOF carriers with minor stroke or TIA at low risk of recurrent stroke received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin., Classification of Evidence: This study provides Class II evidence that CYP2C19 LOF carriers with minor stroke or TIA at low risk, but not at high risk, of recurrent stroke (by the ESRS) received a greater benefit from ticagrelor aspirin than from clopidogrel aspirin., Trial Registration Information: URL: www., Clinicaltrials: gov. Unique identifier: NCT04078737., (© 2022 American Academy of Neurology.)

Introduction: This study was intended to evaluate whether the safety and efficacy of dual antiplatelet treatment in patients with minor ischemic stroke (MIS) or transient ischemic attack (TIA) could be modified by the aminotransferase level. Also, we sought to assess the interaction between aminotransferase level and CYP2C19 loss-of-function status on the efficacy of dual antiplatelet therapy., Methods: This study is a post hoc analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) study, a double-blinded randomized control trial. We included 5,133 patients with a complete workup of baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The primary outcome is stroke or TIA recurrence within 90 days. Cox proportional hazard models were used in the evaluation of the efficacy of antiplatelet treatment in patients with different aminotransferase levels and subgroups categorized by the aminotransferase level × CYP2C19 loss-of-function status., Results: The median age of all the included patients was 62 years; 66.3% of the patients were male. More recurrent stroke or TIA occurred in patients with elevated ALT and AST levels within 90 days compared to patients with normal ALT and AST levels (14.5 vs. 11.2%, p = 0.029). Dual antiplatelet treatment with aspirin and clopidogrel reduced recurrence compared with aspirin alone in patients with both normal (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.72 [0.60-0.86], p < 0.001) and elevated (adjusted HR [95% CI]: 0. 57 [0. 35-0. 92], p = 0. 020) ALT and AST levels (p = 0.64 for interaction). No significant difference in treatment efficacy on 90-day all-cause death or bleeding events was found., Conclusions: Dual antiplatelet treatment was safe for minor stroke or high-risk TIA patients with mildly elevated aminotransferase. Mild elevation of ALT or AST did not undermine the protective efficacy of the dual antiplatelet regimen in reducing recurrent stroke or TIA within 90 days after MIS or TIA. The interaction between the CYP2C19 loss-of-function allele carrier status and aminotransferase level on the efficacy of dual antiplatelet treatment was not observed., (© 2022 S. Karger AG, Basel.)

Background: Evidence on the risk-benefit ratio of dual antiplatelet therapies among patients with stroke and impaired renal function is limited and inconsistent., Objective: To investigate the effect of renal function on the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin treatment., Design: Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04078737)., Setting: 202 centers in China., Patients: CYP2C19 loss-of-function allele carriers with minor stroke or transient ischemic attack., Intervention: Ticagrelor-aspirin and clopidogrel-aspirin., Measurements: Renal function was evaluated by estimated glomerular filtration rate (eGFR) levels. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days, respectively., Results: Among 6378 patients, 4050 (63.5%) had normal (eGFR ≥90 mL/min/1.73 m 2 ), 2010 (31.5%) had mildly decreased (eGFR 60 to 89 mL/min/1.73 m 2 ), and 318 (5.0%) had moderately to severely decreased (eGFR <60 mL/min/1.73 m 2 ) renal function. The corresponding differences in recurrent stroke between ticagrelor-aspirin and clopidogrel-aspirin for normal, mildly decreased, and moderately to severely decreased renal function was -2.8 percentage points (95% CI, -4.4 to -1.3 percentage points) (hazard ratio [HR], 0.63 [CI, 0.49 to 0.81]), -0.2 percentage point (CI, -2.4 to 2.0 percentage points) (HR, 0.98 [CI, 0.69 to 1.39]), and 3.7 percentage points (CI, -2.3 to 10.1 percentage points) (HR, 1.31 [CI, 0.48 to 3.55]), respectively. Rates of severe or moderate bleeding did not substantially differ by treatment assignments across eGFR categories., Limitation: Renal function was only evaluated by using eGFR, and the proportion of patients with severely decreased renal function was low., Conclusion: Patients with normal, rather than impaired, renal function received greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin., Primary Funding Source: Ministry of Science and Technology of the People's Republic of China.

Background and Purpose: Previous studies demonstrated that discontinuation of clopidogrel in patients after ACS was associated with a rebound increase in risk of recurrent events. In this study, we aimed to investigate the rebound effect after discontinuation of clopidogrel therapy in patients with TIA or stroke., Methods: All patients with minor stroke or TIA were recruited from the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Patients were divided into two groups: patients who discontinued clopidogrel and switched to aspirin therapy   (Clopidogrel Discontinuation Group) and patients who continued one mono-antiplatelet therapy (non-Clopidogrel Discontinuation Group) during 90-180  days. The outcomes included risks of recurrent ischemic stroke, recurrent TIA, and composite events during 90-180  days. The prevalence of each outcome was compared between two groups for every 30 days. Further subgroup analysis was conducted in patients with and without CYP2C19 loss-of-function alleles., Results: Among the 3456 patients included, a total of 10 patients in the Clopidogrel Discontinuation Group and 11 patients in the non-Clopidogrel Discontinuation Group presented ischemic stroke recurrence during the 90-180-day period. The inter-group comparisons were not significant in each 30 days. Similar results were found for recurrent stroke, recurrent TIA, and composite events in these two groups, which were also found in CYP2C19 subgroup analysis., Conclusions: No rebound increase in the risk of ischemic stroke and composite events was found during the 90 days after discontinuation of clopidogrel therapy in patients with TIA or minor stroke in the CHANCE trial., Trial Registration: clinicaltrials.gov Identifier: NCT00979589.

Background and Purpose: To explore the relationship between baseline levels of matrix metalloproteinase 9 (MMP9) in peripheral blood and the outcomes in patients with acute minor stroke and transient ischemic attack (TIA)., Methods: We assessed data from patients with acute minor ischemic stroke or TIA who were included in the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial. Baseline level of MMP9 in peripheral blood is classified into five quintiles. We assessed the relationship between the baseline MMP9 and outcomes of stroke recurrence, composite vascular events, and poor functional outcomes within 90 days after stroke onset., Results: Of the 3014 patients included, 295 (9.79%) had recurrent stroke, 289 (9.59%) had recurrent ischemic stroke, 297 (9.85%) had combined vascular events, and 199 (6.64%) had poor functional outcomes within 90 days. We used MMP9 concentrations near hazard ratio (HR) = 1 (Q3) in restricted cubic splines as the reference. The result showed that, compared to patients in the Q3 group, patients in the highest quintile (Q5 group) had an increased risk of poor functional outcomes at 90 days after adjusting the risk factors and confounders (p = 0.030), which may be associated with an increased risk of combined vascular events (p = 0.052). Using Cox regression models or logistic regression models with restricted cubic spline, we also observed that higher MMP9 ratios were associated with an increased risk of stroke recurrence, combined events, and poor functional outcomes at a range of concentrations., Conclusions: For patients with acute minor stroke or TIA, higher baseline MMP9 level was associated with an increased risk of poor functional outcomes, which might be related to stroke recurrence and combined vascular events., (© 2022 European Academy of Neurology.)

Background: Hypertension is a risk factor of poor stroke outcomes and associated with antiplatelet resistance. This study aimed to explore the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in patients with different hypertension status, using randomized trial data from the CHANCE-2 trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II)., Methods: A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were enrolled and randomized to either ticagrelor-aspirin or clopidogrel-aspirin group. Hypertension status were classified into no, newly diagnosed, and previously diagnosed hypertension according to medical history, blood pressure, and antihypertensive medications during hospitalization. The primary efficacy and safety outcomes were stroke recurrence and moderate to severe bleeding risk within 90-day follow-up., Results: Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without hypertension (32 [4.8%] versus 60 [7.2%]; hazard ratio, 0.55 [95% CI, 0.35-0.86]), but not in those with a newly diagnosed hypertension (20 [5.3%] versus 36 [9.1%]; hazard ratio 0.59 [95% CI, 0.33-1.07]), or those with a previously diagnosed hypertension (139 [7.0%] versus 147 [7.4%]; hazard ratio, 0.93 [95% CI, 0.74-1.18]) compared with clopidogrel-aspirin ( P =0.04 for interaction). The risk of bleeding for ticagrelor-aspirin was not associated with hypertension status (0.1% versus 0.4%; 0.3% versus 0.5%, 0.4% versus 0.3%, P =0.50 for interaction). All the efficacy and safety outcomes between treatments did not differ by blood pressure levels on admission., Conclusions: In the CHANCE-2 trial, patients without hypertension received a significantly greater benefit from ticagrelor- aspirin than those with previous hypertension after minor stroke or transient ischemic attack, and a similar benefit trend was observed in those with newly diagnosed hypertension., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04078737.

Objective: Whether aspirin platelet reactivity affects platelet function and clinical outcomes with different antiplatelet therapies in patients with mild stroke or transient ischemic attack (TIA) remains unclear. We conducted a subgroup analysis of the PRINCE trial., Materials and Methods: Patients with mild stroke or TIA were randomized into aspirin+ticagrelor, or aspirin+clopidogrel groups; aspirin reaction units (ARU) were measured at the baseline and after 7 ± 2 days to assess response to treatment. High on-treatment platelet reactivity (HPR) was defined as ≥550 ARU (poor response to aspirin). The platelet functions of ticagrelor and clopidogrel were measured using the VerifyNow P2Y 12 assay for P2Y 12 reaction units (PRU); HPR to P2Y 12 was defined as >208 PRU (poor response to P2Y 12 ). Clinical outcomes included stroke and clinical vascular and bleeding events after 90 days., Results: Among 628 enrolled patients, 69 (11%) were poor aspirin responders. After 7 ± 2 days, the proportion of poor P2Y 12 responders for ticagrelor versus clopidogrel significantly reduced in poor (2.6% versus 27.4%) and good (14.3% versus 29.4%) aspirin responders. There were significant interactions between treatment groups, and between treatment groups and aspirin platelet reactivity for poor P2Y 12 responders (P = 0.01). After 90 ± 7 days, there were no significant interactions between treatment groups and aspirin platelet reactivity for new stroke risk (good aspirin responders: 5.5% versus 8.8%, hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.32 to 1.16; P = 0.13; poor aspirin responders: 8.6% versus 8.8%, HR: 0.97, 95% CI: 0.20-4.81; P = 0.97; P for interaction = 0.60). Major bleeding was less frequent in poor than good aspirin responders (ticagrelor/aspirin: 0.4%/0%; clopidogrel/aspirin: 1.4%/0%)., Conclusions: In patients with minor stroke or TIA, clopidogrel, and particularly ticagrelor, decreased platelet function in poor versus good aspirin responders. The poor platelet reactivity of aspirin could not sufficiently reduce the risk of recurrent stroke with ticagrelor or clopidogrel; however, HPR (poor aspirin response) may have a protective effect on clinically relevant major bleeding., Competing Interests: Disclosure of Competing Interest The authors declare no financial or other conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to validate the predictive value of the ABCD3-I score for short-term and long-term stroke risk after transient ischemic attack (TIA) and to evaluate the influence of symptomatic intracranial artery stenosis (sICAS) on the performance of ABCD3-I., Methods: We recruited TIA patients from the Third China National Stroke Registry study. Outcome parameters were stroke events during the 14-day, 3-month, 6-month, and 12-month points. The area under the curve (AUC) was calculated as a measure of predictive ability. A multivariable-adjusted Cox proportional hazards model was used to assess the hazard ratio of risk factors for stroke., Results: Among 986 patients, 3.9%, 5.1%, 6.5 %, and 8.2% of participants experienced a stroke event during the 14-day, 3-month, 6-month, and 12-month points post TIA, respectively. The AUCs of ABCD3-I score for the prediction of stroke were 0.786, 0.732, 0.715, and 0.699 at the 14-day, 3-month, 6-month, and 12-month points, respectively. The AUCs were 0.774, 0.690, 0.617, and 0.611 in patients with sICAS, 0.789, 0.748, and 0.758 and 0.734 in those without sICAS. P values of the interaction between ABCD3-I categories and sICAS were 0.0618 for 14-day, 0.0098 for 3-month, 0.0318 for 6-month, and 0.0294 for 12-month., Conclusions: ABCD3-I score performed well in predicting short-term risk of a stroke after an index TIA in patients with or without sICAS. However, the predictive power decayed with the prolonged period, and the decayed extent was more pronounced among those with sICAS. The assessment of sICAS is a non-ignorable item when using the ABCD3-I score for long-term stroke risk prediction in patients with TIA.

Background and Purpose: To investigate the association of different status of cerebral small vessel disease (CSVD) and infarction number with recurrence after acute minor stroke and transient ischaemic attack (TIA)., Methods: This study was a post hoc analysis of the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, and includes 886 patients with acute minor stroke and TIA. The status of CSVD and infarction number was recorded for each individual. Infarction number were classified as multiple acute infarctions (MAIs≥2), single acute infarction (SAI =1), and non-acute infarction (NAI =0). The CSVD burden were grouped into non-CSVD (0 score) and CSVD (1-4 score). The primary outcome was a recurrent stroke at the 1-year follow-up. The secondary outcomes were recurrent ischaemic stroke, composite vascular event (CVE), and TIA. We analyzed the relationships between different status of CSVD burden and infarction pattern with the risk of outcomes using multivariable Cox regression models., Results: Among all 886 patients included in present analysis, recurrent stroke was occurred in 93 (10.5%) patients during 1-year follow-up. After adjusted for all potential covariates, compared with patients with non-CSVD and NAI, patients with CSVD and MAIs were associated with approximately 9.5-fold increased risk of recurrent stroke at 1 year (HR 9.560, 95% CI 1.273-71.787, p=0.028). Similar results observed in ischaemic stroke and CVE., Conclusion: The status of CSVD and infarction number predicted recurrent stroke in patients with acute minor stroke and TIA, especially for those with coexistent CSVD and MAIs., (© 2022. The Author(s).)

Importance: Dual antiplatelet therapy (DAPT) with ticagrelor and aspirin has been found to be effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA) in individuals who carry CYP2C19 loss-of-function (LOF) alleles; however, uncertainties remain about the time course of benefit and risk with ticagrelor and aspirin in these patients., Objective: To obtain time-course estimates of efficacy and risk with ticagrelor and aspirin after minor stroke or TIA in individuals with CYP2C19 LOF alleles., Design, Setting, and Participants: The Ticagrelor or Clopidogrel With Aspirin in High-risk Patients With Acute Nondisabling Cerebrovascular Events II (CHANCE-2) randomized clinical trial enrolled patients 40 years and older from 202 hospitals in China with acute minor stroke or TIA who carried CYP2C19 LOF alleles between September 23, 2019, and March 22, 2021, and were followed up for 90 days. All 6412 patients enrolled in the CHANCE-2 trial were included in this secondary analysis. Data were analyzed in October 2021., Interventions: Ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2-90) or clopidogrel (300 mg on day 1 followed by 75 mg daily on days 2-90). All patients received aspirin (75-300 mg on day 1 followed by 75 mg daily for 21 days)., Main Outcomes and Measures: The efficacy outcome was major ischemic event, defined as the composite of ischemic stroke or nonhemorrhagic death. Safety outcomes included moderate to severe bleeding and any bleeding., Results: A total of 6412 patients were included (3205 in the ticagrelor and aspirin group and 3207 in the clopidogrel and aspirin group). The median (IQR) age was 65 (57-71) years, and 4242 patients (66%) were men. The reduction of major ischemic events with ticagrelor and aspirin predominately occurred in the first week (absolute risk reduction, 1.34%; 95% CI, 0.29 to 2.39) and attenuated but remained in the next 3 weeks (absolute risk reduction in the second week, 0.11%; 95% CI, -0.24 to 0.45; absolute risk reduction in the third week, 0.14%; 95% CI, -0.11 to 0.38; absolute risk reduction in the fourth week, 0.04%; 95% CI, -0.18 to 0.25). The risk of moderate to severe bleeding was consistently low in the ticagrelor and aspirin group. The absolute increase in any bleeding seen in the first week (0.87%; 95% CI, 0.25 to 1.50) remained in the next 3 weeks (absolute increase in the second week, 1.21%; 95% CI, 0.75 to 1.68; absolute increase in the third week, 0.33%; 95% CI, -0.05 to 0.72; absolute increase in the fourth week, 0.23%; 95% CI, -0.03 to 0.49)., Conclusion and Relevance: Among patients with minor stroke or TIA who carried CYP2C19 LOF alleles, benefit with ticagrelor and aspirin was present predominately in the first week, with additional small benefit accruing in the next 2 weeks.

Objective: Contribution of individual and combined inflammatory markers in prognosis after stroke was still undefined. We aimed to investigate the association of systemic and local vascular inflammatory markers and recurrent stroke as well as impact on poor functional outcome., Methods: In this pre-specified substudy of the Third China National Stroke Registry (CNSR-III), 10,472 consecutive acute ischemic stroke or TIA patients with available centralized-measured levels of Interleukin-6 (IL-6), high sensitive C-reactive protein (hsCRP), IL-1 receptor antagonist (IL-1Ra), lipoprotein-associated phospholipase A 2 mass (Lp-PLA 2 ) and activity (Lp-PLA 2 -A), and YKL-40 from 171 sites were enrolled. The primary outcomes consisted of stroke recurrence and poor functional outcome defined as modified Rankin Scale (mRS) score of 2-6 within 1 year., Results: There were 1026 (9.8%) and 2395 (23.4%) patients with recurrent stroke and poor functional outcome within 1 year. The highest quartiles of IL-6 (adjusted HR, 1.36; 95% CI 1.13-1.64; P = 0.001), hsCRP (adjusted HR, 1.41; 95% CI 1.17-1.69; P = 0.0003) and YKL-40 (adjusted HR, 1.28; 95% CI 1.06-1.56; P = 0.01) were associated with increased risk of recurrent stroke; and the highest quartiles of IL-6 (adjusted OR 1.93; 95% CI 1.64-2.27; P < 0.0001), IL-1Ra (adjusted OR 1.60; 95% CI 1.37-1.87; P < 0.0001), hsCRP (adjusted OR 1.60; 95% CI 1.37-1.86; P < 0.0001) and YKL-40 (adjusted OR 1.21; 95% CI 1.03-1.42; P = 0.02) were correlated with increased risk of poor functional outcome. In the multivariate stepwise regression analysis including all markers with backward selection, elevated levels of IL-6 or YKL-40 were associated with recurrent stroke (IL6: OR, 1.34; 95% CI 1.19-1.52; P < 0.0001; YKL-40: OR, 1.01; 95% CI 1.01-1.03; P = 0.004) and poor functional outcome (IL6: OR, 1.68; 95% CI 1.46-1.93; P < 0.0001; YKL-40: OR, 1.02; 95% CI 1.01-1.03; P = 0.0001). Adding IL-6 and YKL-40 significantly increased the area under the receiver operating characteristic curves for the prediction models of Essen Stroke Risk Score (0.03, P < 0.0001) and Totaled Health Risks in Vascular Events Score (0.07, P < 0.0001), and yielded continuous net reclassification improvement (19.0%, P < 0.0001; 33.0, P < 0.0001)., Conclusions: In the patients with ischemic stroke or TIA, IL-6 and YKL-40 were independently associated with recurrent stroke and poor functional outcome, and improved risk classification of clinical risk algorithms., (© 2022. The Author(s).)

Background and Purpose: We aimed to explore the frequencies, risk factors, and natural history of embolic stroke of undetermined source (ESUS) through a national prospective registry in China., Methods: Between August 2015 and March 2018, the Third China National Stroke Registry recruited consecutive patients with ischemic stroke or transient ischemic attack in China. The baseline characteristics, risks of stroke, and prognosis in patients with embolic stroke of undetermined source were described and compared with that in patients with other causative subtypes., Results: A total of 15,166 transient ischemic attack and ischemic stroke patients were enrolled in the Third China National Stroke Registry. Among 8528 ischemic stroke with standard diagnostic work-up, 2415 (28.3%) patients were diagnosed with embolic stroke of undetermined source. The mean age was 61 years and 70% of them were male. Compared to patients with cardioembolic strokes and small vessel disease, patients with embolic stroke of undetermined source had higher prevalence of nonstenosing large artery atherosclerosis (37.93% vs. 31.26%, P  = 0.008 and 37.93% vs. 34.40%, P  = 0.044 respectively). The cumulative probability of stroke recurrence in patients with embolic stroke of undetermined source at three months and one year was 5.59% and 8.74%. Compared with embolic stroke of undetermined source patients (0.70% and 1.99%), patients with the large artery atherosclerosis and cardioembolic strokes had higher cumulative probability of death at three months (1.94% and 3.22%) and one year (4.17% and 7.39%)., Conclusions: Embolic stroke of undetermined source is a common cause of ischemic stroke in Chinese population with a higher stroke recurrence than previously reported. It was more likely to have nonstenosing large artery atherosclerosis in patients with embolic stroke of undetermined source than with cardioembolic strokes and small vessel disease.

Objective: This study was undertaken to identify the risk of bleeding events and potential risk factors within 90 days in patients who carried CYP2C19 loss-of-function alleles and received dual antiplatelet therapy after minor stroke or transient ischemic attack., Methods: A total of 6,412 patients were enrolled from the CHANCE-2 (Clopidogrel with Aspirin in High-Risk Patients with Acute Non-disabling Cerebrovascular Events II) trial. The main outcome was any bleeding within 90 days defined by the criteria from GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)., Results: A total of 250 (3.9%) bleeding events were reported, which occurred mainly within the 21 days of dual antiplatelet therapy (200 cases, 3.1%). Minor bleeding of the skin bruises, epistaxis, and gum bleeding were most frequent. Multivariate analysis showed that treatment with ticagrelor-aspirin compared with clopidogrel-aspirin was associated with increased bleeding (hazard ratio [HR] = 2.21, 95% confidence interval [CI] = 1.68-2.89, p < 0.001). Current smoking was associated with a lower risk of bleeding (HR = 0.70, 95% CI = 0.52-0.95, p = 0.02). Additionally, ticagrelor-aspirin compared with clopidogrel-aspirin was associated with higher risk of bleeding in patients aged <65 years (HR = 2.87, 95% CI = 1.95-4.22) and those without diabetes mellitus (HR = 2.65, 95% CI = 1.88-3.73; p for interaction = 0.04 and 0.03, respectively)., Interpretation: Bleeding events mostly occurred within the 21-day dual antiplatelet therapy stage and were generally mild. The risk of bleeding was greater in nonsmoking patients, and was associated with treatment with ticagrelor-aspirin compared with clopidogrel-aspirin, particularly in patients aged <65 years and nondiabetic patients. ANN NEUROL 2022;91:380-388., (© 2021 American Neurological Association.)

Background: Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function carriers have not been extensively performed., Methods: We conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor; both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days., Results: A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively., Conclusions: Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Purpose: It is still unclear whether the residual cholesterol and inflammatory risk in the acute phase is associated with prognosis of stroke. We aimed to investigate the proportion and relative contribution of residual cholesterol and inflammatory risk, determined by baseline low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels, to the risk of recurrent stroke and poor functional outcome at 1 year., Methods: In this prospective multicenter cohort study, 10 499 consecutive acute ischemic stroke and transient ischemic attack patients with levels of LDL-C and hsCRP were enrolled. Patients were divided into 4 groups: residual cholesterol risk only (LDL-C ≥2.6 mmol/L and hsCRP <3 mg/L), residual inflammatory risk (RIR) only (LDL-C <2.6 mmol/L and hsCRP ≥3 mg/L), both risk (LDL-C ≥2.6 mmol/L and hsCRP ≥3 mg/L), and neither risk (LDL-C <2.6 mmol/L and hsCRP <3 mg/L). The primary outcomes consisted of stroke recurrence and a modified Rankin Scale score of 2 to 6 within 1 year., Results: The relative proportions of patients with RIR only, residual cholesterol risk only, both risk, and neither were 21.3%, 23.7%, 14.4%, and 40.6%, respectively. RIR only was independently associated with recurrent stroke (adjusted hazard ratio, 1.18 [95% CI, 1.00–1.40]; P=0.05). The association was slightly attenuated after further adjusting for usage of antiplatelet agent and statin during 1-year follow-up in addition to the traditional risk factors (hazard ratio, 1.31 [95% CI, 0.99–1.76]; P=0.07). When applying the LDL-C cutoff value of 1.8 mmol/L in the sensitivity analyses, such association in large-artery atherosclerosis subtype was more significant (adjusted hazard ratio, 1.69 [95% CI, 1.06–2.67]; P=0.03). Patients with RIR only also had increased risk of poor functional outcome (adjusted odds ratio, 1.43 [95% CI, 1.24–1.64]; P<0.0001)., Conclusions: In the patients with acute ischemic stroke or transient ischemic attack, RIR only could be predictive for recurrent stroke, especially for those with large-artery atherosclerosis, and poor functional outcome.

Background and Purpose: Whether imaging parameters would independently predict stroke recurrence in low-risk minor ischemic stroke (MIS) or transient ischemic attack (TIA) according to traditional score system (such as ABCD 2 score, which was termed on the basis of the initials of the five factors: age, blood pressure, clinical features, duration, diabetes) remains unclear. We sought to evaluate the association between imaging parameters and 1-year stroke recurrence in patients with TIA or MIS in different risk stratum stratified by ABCD 2 score., Methods: We included patients with TIA and MIS (National Institutes of Health Stroke Scale score ≤3) with complete baseline vessel and brain imaging data from the Third China National Stroke Registry III. Patients were categorized into different risk groups based on ABCD 2 score (low risk, 0-3; moderate risk, 4-5; and high risk, 6-7). The primary outcome was stroke recurrence within 1 year. Multivariable Cox proportional-hazards regression models were used to assess whether imaging parameters (large artery stenosis, infarction number) were independently associated with stroke recurrence., Results: Of the 7140 patients included, 584 patients experienced stroke recurrence within 1 year. According to the ABCD 2 score, large artery stenosis was associated with higher stroke recurrence in both low-risk (adjusted hazard ratio, 1.746 [95% CI, 1.200-2.540]) and moderate-risk group (adjusted hazard ratio, 1.326 [95% CI, 1.042-1.687]) but not in the high-risk group ( P >0.05). Patients with multiple acute infarctions or single acute infarction had a higher risk of recurrent stroke than those with no infarction in both low- and moderate-risk groups, but not in the high-risk group., Conclusions: Large artery stenosis and infarction number were independent predictors of 1-year stroke recurrence in low-moderate risk but not in high-risk patients with TIA or MIS stratified by ABCD 2 score. This finding emphasizes the importance of early brain and vascular imaging evaluation for risk stratification in patients with TIA or MIS.

Background and Purpose: The relationship of high-sensitive C-reactive protein (hs-CRP) levels and infarction numbers with the prognosis of stroke is uncertain. This study evaluated the association of different hs-CRP levels and infarction numbers with the prognosis of acute minor ischaemic stroke or transient ischaemic attack (TIA)., Methods: A subset of 807 patients with both hs-CRP measurement and baseline MRI was included from the Clopidogrel in High-risk Patients with Acute Non-disabling Cerebrovascular Events trial. The primary efficacy outcome was the occurrence of an ischaemic stroke at the 1-year follow-up. Infarction numbers were classified as multiple acute infarctions (MAIs), single acute infarction and no acute infarction (NAI). The association between different hs-CRP levels with different infarction numbers and the risk of any outcome was analysed using multivariable Cox regression models., Results: Among the 807 patients, 84 (10.4%) patients had a recurrent ischaemic stroke within 1 year. After adjustment for conventional confounding factors, patients with both elevated hs-CRP levels and MAIs were associated with approximately 4.7-fold of risk of ischaemic stroke within 1 year (16.7% vs 3.5%, HR 4.68, 95% CI 1.54 to 14.23, p=0.007), compared with those with non-elevated hs-CRP levels and NAI. Similar results were observed for the composite events., Conclusions: Combined elevated hs-CRP levels and MAIs may increase 1-year stroke risk stratification efficiency in patients with minor ischaemic stroke or TIA compared with using those markers alone, which indicated that the combination of inflammatory and imaging markers might improve the effectiveness of risk stratification concerning minor ischaemic stroke or TIA.ClinicalTrials.gov Registry (NCT00979589)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the association between protease-activated receptor-1 (PAR-1) gene F2R polymorphisms and efficacy of clopidogrel for minor stroke or TIA., Methods: Three single nucleotide polymorphisms ( CYP2C19*2 [681G>A, rs4244285], CYP2C19 * 3 [636G>A, rs4986893], and F2R [IVSn-14 A/T, rs168753]) were genotyped among 2,924 patients randomized to clopidogrel plus aspirin (n = 1,461) or aspirin alone (n = 1,463). The primary efficacy outcome was new stroke (ischemic or hemorrhagic) and the safety outcome was any bleeding., Results: Overall, 859 (29.4%) were AA homozygotes, 1,479 (50.6%) were AT heterozygotes, and 586 (20.0%) were TT homozygotes for F2R IVSn-14 polymorphisms; 1,716 (58.7%) were carriers of at least 1 CYP2C19 loss-of-function allele (*2 or *3). Compared with aspirin alone, patients with clopidogrel-aspirin treatment had a low risk of new stroke in patients with AT genotype (7.6% vs 11.3%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.44-0.89) and TT genotype (5.8% vs 11.6%; HR, 0.46; 95% CI, 0.25-0.82) but not in carriers of the AA genotype (10.8% vs 11.6%; HR, 0.95; 95% CI, 0.63-1.44) ( p = 0.03 for interaction). The association between F2R IVSn-14 A/T polymorphism and clopidogrel response was present regardless of the carrier status of the CYP2C19 loss-of-function alleles. The F2R IVSn-14 genotypes were not associated with the risk of any bleeding for clopidogrel-aspirin treatment ( p = 0.66 for interaction)., Conclusions: Among patients with minor ischemic stroke or TIA who were receiving clopidogrel and aspirin, those carrying the F2R IVSn-14 T allele had a lower rate of recurrent stroke than those who were not., Clinicaltrialsgov Identifier: NCT00979589., (© 2020 American Academy of Neurology.)

In this study, we tested the effect of ticagrelor versus clopidogrel on platelet reactivity in patients with minor stroke or transient ischemic attack (TIA). A pre-specified subgroup analysis of a randomized controlled trial was conducted. Platelet reactivity was assessed by thrombelastography (TEG) platelet mapping. Patients were divided into carriers and non-carriers according to the carrier status of CYP2C19 loss-of-function (LOF) alleles. The primary outcome was the proportion of patients with high on-treatment platelet reactivity (HOPR) (defined as maximum amplitude induced by adenosine diphosphate > 47mm) at 90±7 days. Clinical outcomes within 90±7 days were followed up. Among 339 patients, 170 were randomized to ticagrelor/aspirin and 169 to clopidogrel/aspirin. Compared with clopidogrel/aspirin, the proportion of HOPR at 90±7 days in ticagrelor/aspirin was significantly lower (12.2% versus 30.0%, P < 0.001). Ticagrelor/aspirin had a lower proportion of HOPR among carriers (11.0% versus 35.6%, P < 0.001), but not among non-carriers (13.5% versus 22.4%, P = 0.17). Ticagrelor was superior to clopidogrel in inhibiting platelet reactivity measured by TEG platelet mapping among patients with acute minor stroke or TIA, particularly in carriers of the CYP2C19 LOF alleles. Large randomised controlled trials are needed to confirm our findings.

Background: A single index of body mass index (BMI) may not fully address its impact on anti-platelet therapy. We aimed to elucidate the combined impact of BMI and dysglycemia expressed by glycated albumin (GA) on efficacy of clopidogrel-aspirin therapy among minor stroke (MS) or transient ischemic attack (TIA) patients., Results: Patients with overweight/obesity and low GA levels still benefited from clopidogrel-aspirin therapy for stroke recurrence (Hazard ratio [HR]: 0.48, 95 % confidence interval [CI]: 0.28-0.82), so did those with high GA levels but low/normal weight (HR: 0.67, 95 % CI: 0.45-0.99). However, patients with both overweight/obesity and high GA levels did not benefit from clopidogrel-aspirin therapy (HR: 0.89, 95 % CI: 0.59-1.33)., Conclusions: Compared with aspirin alone, efficacy of clopidogrel-aspirin therapy for stroke still exists in overweight/obesity patients with normal glycemic control., Methods: In Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial, 3044 patients with available baseline GA were recruited. Low/normal weight and overweight/obesity were defined as BMI < 25 kg/m 2 and ≥ 25 kg/m 2 , respectively. Elevated and low GA levels were defined as GA levels > 15.5 % and ≤ 15.5 %, respectively. The primary outcome was stroke recurrence during the 90-day follow-up.

Background: The effect of cerebral small vessel disease (CSVD) and intracranial arterial stenosis (ICAS) on stroke outcomes remains unclear., Methods: Data of 1045 patients with minor stroke or transient ischaemic attack (TIA) were obtained from 45 sites of the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. We assessed the associations of burdens of CSVD and ICAS with new strokes and bleeding events using multivariate Cox regression models and those with modified Rankin Scale (mRS) scores using ordinal logistic regression models., Results: Among the 1045 patients, CSVD was present in 830 cases (79.4%) and ICAS in 460 (44.0%). Patients with >1 ICAS segment showed the highest risk of new strokes (HR 2.03, 95% CI 1.15 to 3.56, p=0.01). No association between CSVD and the occurrence of new strokes was found. The presence of severe CSVD (common OR (cOR) 2.01, 95% CI 1.40 to 2.89, p<0.001) and >1 ICAS segment (cOR 2.15, 95% CI 1.57 to 2.93, p<0.001) was associated with higher mRS scores. Severe CSVD (HR 10.70, 95% CI 1.16 to 99.04, p=0.04), but not ICAS, was associated with a higher risk of bleeding events. Six-point modified CSVD score improved the predictive power for bleeding events and disability., Interpretation: CSVD is associated with more disability and bleeding events, and ICAS is associated with an increased risk of stroke and disability in patients with minor stroke and TIA at 3 months. CSVD and ICAS may represent different vascular pathologies and play distinct roles in stroke outcomes., Trial Registration Number: NCT00979589., Competing Interests: Competing interests: CJ is the principal investigator of the POINT trial, a NIH-sponsored trial with clopidogrel and placebo donated by Sanofi., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the relationship of homocysteine levels with the efficacy and safety of dual antiplatelet therapy in female and male patients. Approach and Results: The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized patients with acute minor ischemic stroke or high-risk transient ischemic attack to clopidogrel plus aspirin or aspirin alone from October 1, 2009, to July 30, 2012, in China. A subgroup of 3044 consecutive patients with baseline homocysteine levels from 73 (64%) prespecified clinical sites was analyzed. Participants were grouped by sex. Primary outcome was stroke recurrence within 90 days. Secondary outcomes consisted of composite vascular events and independent living or death. Safety outcome was any bleeding. Cox proportional-hazards models were used to assess the interaction of homocysteine levels with randomized antiplatelet therapy on efficacy and safety outcomes. A significant interaction between homocysteine levels and the randomized antiplatelet therapies was found on recurrent stroke after adjustment for confounding factors in women ( P =0.010) but not in men ( P =0.595). Compared with aspirin alone, clopidogrel plus aspirin significantly reduced the risk of recurrent stroke in women without elevated homocysteine levels (adjusted hazard ratio, 0.459 [95% CI, 0.271-0.776]; P =0.004). Such benefit disappeared in female patients with increased homocysteine level. No significant interaction on functional outcome or bleeding rate was observed., Conclusions: Homocysteine could be a potential biomarker to discriminate the effects of dual and single antiplatelet therapy in female patients with minor ischemic stroke or high-risk transient ischemic attack., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Importance: Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about the optimal duration of dual antiplatelet therapy for minor stroke or TIA., Objective: To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA., Design, Setting, and Participants: This analysis pooled individual patient-level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019., Interventions: In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset., Main Outcomes and Measures: The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage., Results: The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 [6.5%] vs 458 of 5035 [9.1%]; hazard ratio [HR], 0.70 [95% CI, 0.61-0.81]; P < .001), mainly within the first 21 days (263 of 5016 [5.2%] vs 391 of 5035 [7.8%]; HR, 0.66 [95% CI, 0.56-0.77]; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant., Conclusions and Relevance: In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.

The "obesity paradox" was reported in patients with stroke. We aimed to evaluate the pattern and magnitude of association between body mass index (BMI) and prognosis of stroke in patients with minor ischemic stroke or transient ischemic attack (TIA). A total of 5163 patients with available BMI data from the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial were included. Patients were classified into three groups according to their BMI values: normal weight (< 23.9 kg/m 2 ), overweight (24-27.9 kg/m 2 ), and obese (≥ 28.0 kg/m 2 ). The efficacy outcomes included a new stroke (ischemic or hemorrhagic), poor functional outcome defined as modified Rankin scale ≥ 2 points and death from any cause within 90 days. The interaction effects were determined using multivariable Cox or logistic regression models. After 90 days of follow up, there were 513 new strokes. Overweight (BMI 24-27.9 kg/m 2 ) patients had a higher risk of recurrent strokes than those with normal weight (10.8% vs 8.8%; HR = 1.24, 95% CI 1.02-1.50) after adjusting for the baseline covariates, but no significant association was observed for those who were obese (P = 0.37). No significant association was found between being overweight or obese and poor functional outcome or death. For patients with a minor ischemic stroke or TIA, being overweight was associated with an increased risk of recurrent stroke compared to being of normal weight in our study.Trial registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00979589.

Background: In 2009, China launched ambitious healthcare reform plans to provide affordable and equitable basic healthcare for all patients, including the substantial number of patients who had a stroke. However, little is known about the pattern of evidence-based stroke care and outcomes across hospitals, regions and time during the last decade., Aims: The Patient-centered Retrospective Observation of Guideline-Recommended Execution for Stroke Sufferers in China (China PROGRESS) Study aims to use findings from a representative sample of Chinese hospitals over the last decade to improve future stroke care for patients hospitalised with ischaemic stroke (IS) or transient ischaemic attack (TIA)., Design: The China PROGRESS Study will use a two-stage cluster sampling method to identify over 32000 patient records from 208 hospitals across the Eastern, Central and Western geographical regions in China. To assess the temporal trends in patient characteristics, treatment and outcomes, study investigators will select records from 2005, 2010 and 2015. A double data reading/entry system will be developed to conduct this assessment. A central coordinating centre will monitor case ascertainment, data abstraction and data management. Analyses will examine patient characteristics, testing patterns, in-hospital treatment and outcomes, and variations across regions and across time., Conclusions: The China PROGRESS Study is the first nationally representative study that aims to better understand care quality and outcomes for patients with IS or TIA before and after the national healthcare reform in China. This initiative will translate findings into clinical practices that improve care quality for patients who had a stroke and policy recommendations that allow these changes to be implemented widely. Ethics approval This study has also been approved by the central institutional review board (IRB) at Beijing Tiantan Hospital., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Genetic variants of ABCB1 may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whether ABCB1 polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA)., Objectives: To investigate the association between ABCB1 polymorphisms and clopidogrel efficacy for minor stroke or TIA., Design, Setting, and Participants: In this prespecified secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, 3010 patients with minor stroke or TIA at 73 sites in China with experience in conducting genetic studies were included from October 1, 2009, to July 30, 2012. The analysis was conducted on March 20, 2018. Four single-nucleotide polymorphisms (ABCB1 -154T>C [rs4148727], ABCB1 3435C>T [rs1045642], CYP2C19*2 [681G>A, rs4244285], and CYP2C19*3 [636G>A, rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association of ABCB1 genetic variants (-154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context of CYP2C19 status, another gene associated with clopidogrel efficacy., Interventions: Patients in the CHANCE trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone., Main Outcomes and Measures: Primary efficacy outcome was stroke recurrence after 3 months. The safety outcome was any bleeding risk after 3 months., Results: Among 2836 patients, the median age was 61.8 years (interquartile range, 54.4-71.1 years) and 1887 patients (66.5%) were male. A total of 2146 (75.7%) patients were carriers of ABCB1 -154 TC/CC (570 [20.1%]) or 3435 CT/TT (1851 [65.3%]) genotype. Clopidogrel plus aspirin treatment was associated with reduced risk of new stroke in patients with ABCB1 -154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% CI, 0.26-0.71) but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03) compared with aspirin (P = .04 for interaction). A combined association of ABCB1 and CYP2C19 polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with the ABCB1 genotypes (2.3% and 1.3% vs 1.9% and 2.2%; P = .25 for interaction in patients with or without ABCB1 -154 TC/CC or 3435 CT/TT genotype)., Conclusions and Relevance: The ABCB1 polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism of ABCB1 should be considered when prescribing clopidogrel for these patients., Trial Registration: ClinicalTrials.gov identifier: NCT00979589.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare that the study was supported by grants from the Ministry of Science and Technology of the People’s Republic of China (2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2018YFC1311700 and 2018YFC1311706), and grants from Beijing Municipal Commission of Health and Family Planning (No 2016-1-2041, SML20150502).

Clopidogrel resistance is prevalent in chronic kidney disease (CKD) patients. Genetic polymorphism is considered to be the most important factor that influences clopidogrel resistance. Limited data exist as to the role of pharmacogenetics in prognosis of stroke patients with impaired renal function on clopidogrel. We sought to explore whether decreased kidney function alters the association between CYP2C19 genetic variants and clinical outcome in patients with minor stroke or transient ischemic attack (TIA) receiving clopidogrel therapy. A total of 1476 participants on clopidogrel-aspirin treatment with genotyping results in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were categorized by quintiles of renal function estimated by estimated glomerular filtration rate (eGFR), and were stratified according to the possession of CYP2C19 loss-of-function (LOF) alleles: carriers and non-carriers. Patients were followed up and clinical outcomes were evaluated. The primary efficacy outcome was new stroke. The secondary efficacy outcome was combined vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death). The safety outcome was bleeding event. CYP2C19 LOF carriers had higher odds of new stroke than non-carriers (10.4% versus 2.4 %, hazard ratio [HR], 5.30; 95% CI, 1.51-18.3, P = 0.009) in the lowest quintile of renal function group with eGFR < 75 ml/min/1.73 m 2 but not in the other four higher quintiles. Similar results were observed for the ischemic stroke and combined vascular events. There was no significant difference in the individual outcomes of bleeding in carriers compared with non-carriers in any renal function group. Among patients with minor stroke or TIA taking clopidogrel-aspirin treatment, CYP2C19 LOF carrier state was associated with higher risk of new stroke in those with eGFR < 75 ml/min/1.73 m 2 . This observation supports that the evaluation of CYP2C19 LOF carrier state may be useful for identification of the patients with kidney impairment with greater likelihood of having worse outcomes.

Background: In June 2015, the Chinese Stroke Association (CSA) initiated the Chinese Stroke Center Alliance (CSCA) to establish the national hospital-based stroke care quality assessment and improvement platform. This article outlines its objectives, operational structure, patient population, quality improvement (QI) intervention tools, data elements, data collection methodology and current patient and hospital data., Methods: The CSCA is a national, hospital-based, multicentre, voluntary, multifaceted intervention and continuous QI initiative. This multifaceted intervention includes stroke centre development, written care protocols, workshops and a monitoring/feedback system of evidence-based performance measures. The data coordinating centre of the CSCA resides at the China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital., Results: As of July 2017, 1576 hospitals in China have contributed detailed clinical information to serve as a benchmark for the stroke care quality of 433 264 patients with acute stroke/transient ischaemic attacks (TIA), including 352 572 (81.38%) acute ischaemic stroke, 30 362 (7.01%) TIA, 42 080 (9.71%) spontaneous intracranial haemorrhage, 5505 (1.27%) subarachnoid haemorrhage and 2745 (0.63%) not specified stroke., Conclusion: The CSCA programme is designed to establish a continuous national stroke registry and help healthcare providers develop stroke centres and treat patients in a consistent manner in accordance with accepted national guidelines and, ultimately, improve patient outcomes. It supports the CSA mission to reduce stroke burden in China., Competing Interests: Competing interests: None declared.

Objective: To investigate the association between oxidized low-density lipoprotein (oxLDL) and recurrent stroke in patients with minor stroke or TIA., Methods: In the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial, baseline oxLDL levels were blindly measured in plasma with the 4E6 antibody in the core laboratory. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year and ischemic stroke and combined vascular events within 90 days and 1 year. The associations of oxLDL with recurrent stroke were analyzed by Cox proportional hazards., Results: Among 3,019 patients included in this study, the median (interquartile range) of oxLDL was 13.96 (6.65-28.81) μg/dL. After adjustment for conventional confounding factors, patients in the highest oxLDL quartile (≥28.81 μg/dL) had a higher risk of recurrent stroke within 90 days (hazard ratio 1.43, 95% confidence interval 1.03-1.98) compared to those in the lowest oxLDL quartile (<6.65 μg/dL). Similar results were found for secondary outcomes. We also found a J-shaped association between oxLDL and risk of each outcome. There were no significant interactions between oxLDL and low-density lipoprotein and use of dual antiplatelet, antihypertensive, antidiabetic, and statins agents., Conclusions: Elevated oxLDL levels can independently predict recurrent stroke in patients with minor stroke or TIA., Clinicaltrialsgov Identifier: NCT00979589., (© 2018 American Academy of Neurology.)