Yuesong Pan

Prevalence and Outcomes of Symptomatic Intracranial Large Artery Stenoses and Occlusions in China The Chinese Intracranial Atherosclerosis (CICAS) Study

Background and Purpose— We aimed to establish the prevalence, characteristics, and outcomes of intracranial atherosclerosis (ICAS) in China by a large, prospective, multicenter study. Methods— We evaluated 2864 consecutive patients who experienced an acute cerebral ischemia <7 days after symptom onset in 22 Chinese hospitals. All patients underwent magnetic resonance angiography, with measurement of diameter of the main intracranial arteries. ICAS was defined as ≥50% diameter reduction on magnetic resonance angiography. Results— The prevalence of ICAS was 46.6% (1335 patients, including 261 patients with coexisting extracranial carotid stenosis). Patients with ICAS had more severe stroke at admission and stayed longer in hospitals compared with those without intracranial stenosis (median National Institutes of Health Stroke Scale score, 3 versus 5; median length of stay, 14 versus 16 days; both P<0.0001). After 12 months, recurrent stroke occurred in 3.27% of patients with no stenosis, in 3.82% for those with 50% to 69% stenosis, in 5.16% for those with 70% to 99% stenosis, and in 7.27% for those with total occlusion. Cox proportional hazards regression analyses showed that the degree of arterial stenosis, age, family history of stroke, history of cerebral ischemia or heart disease, complete circle of Willis, and National Institutes of Health Stroke Scale score at admission were independent predictors for recurrent stroke at 1 year. The highest rate of recurrence was observed in patients with occlusion with the presence of ≥3 additional risk factors. Conclusions— ICAS is the most common vascular lesion in patients with cerebrovascular disease in China. Recurrent stroke rate in our study was lower compared with those of previous clinical trials but remains unacceptably high in a subgroup of patients with severe stenosis.

Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack

IMPORTANCE Data are limited regarding the association between CYP2C19 genetic variants and clinical outcomes of patients with minor stroke or transient ischemic attack treated with clopidogrel. OBJECTIVE To estimate the association between CYP2C19 genetic variants and clinical outcomes of clopidogrel-treated patients with minor stroke or transient ischemic attack. DESIGN, SETTING, AND PARTICIPANTS Three CYP2C19 major alleles (*2, *3, *17) were genotyped among 2933 Chinese patients from 73 sites who were enrolled in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) randomized trial conducted from January 2, 2010, to March 20, 2012. INTERVENTIONS Patients with acute minor ischemic stroke or transient ischemic attack in the trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone. MAIN OUTCOMES AND MEASURES The primary efficacy outcome was new stroke. The secondary efficacy outcome was a composite of new composite vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death). Bleeding was the safety outcome. RESULTS Among 2933 patients, 1948 (66.4%) were men, with a mean age of 62.4 years. Overall, 1207 patients (41.2%) were noncarriers and 1726 patients (58.8%) were carriers of loss-of-function alleles (*2, *3). After day 90 follow-up, clopidogrel-aspirin reduced the rate of new stroke in the noncarriers but not in the carriers of the loss-of-function alleles (P = .02 for interaction; events among noncarriers, 41 [6.7%] with clopidogrel-aspirin vs 74 [12.4%] with aspirin; hazard ratio [HR], 0.51 [95% CI, 0.35-0.75]; events among carriers, 80 [9.4%] with clopidogrel-aspirin vs 94 [10.8%] with aspirin; HR, 0.93 [95% CI, 0.69 to 1.26]). Similar results were observed for the secondary composite efficacy outcome (noncarriers: 41 [6.7%] with clopidogrel-aspirin vs 75 [12.5%] with aspirin; HR, 0.50 [95% CI, 0.34-0.74]; carriers: 80 [9.4%] with clopidogrel-aspirin vs 95 [10.9%] with aspirin; HR, 0.92 [95% CI, 0.68-1.24]; P = .02 for interaction). The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the clopidogrel-aspirin group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin only group; P = .78 for interaction). CONCLUSIONS AND RELEVANCE Among patients with minor ischemic stroke or transient ischemic attack, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. These findings support a role of CYP2C19 genotype in the efficacy of this treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00979589.

Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial One-Year Outcomes

Background— The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone, but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination. We report the 1-year follow-up outcomes of this trial. Methods and Results— The trial was a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China. We randomly assigned 5170 patients within 24 hours after onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy (loading dose of 300 mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day for 90 days, plus 75 mg of aspirin per day for the first 21 days) or to the aspirin-alone group (75 mg/d for 90 days). The primary outcome was stroke event (ischemic or hemorrhagic) during 1-year follow-up. Differences in outcomes between groups were assessed by using the Cox proportional hazards model. Stroke occurred in 275 (10.6%) patients in the clopidogrel-aspirin group, in comparison with 362 (14.0%) patients in the aspirin group (hazard ratio, 0.78; 95% confidence interval, 0.65–0.93; P=0.006). Moderate or severe hemorrhage occurred in 7 (0.3%) patients in the clopidogrel-aspirin group and in 9 (0.4%) patients in the aspirin group (P=0.44). Conclusions— The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

Novel Risk Score to Predict Pneumonia After Acute Ischemic Stroke

Background and Purpose— To develop and validate a risk score (acute ischemic stroke-associated pneumonia score [AIS-APS]) for predicting in-hospital stroke-associated pneumonia (SAP) after AIS. Methods— The AIS-APS was developed based on the China National Stroke Registry, in which eligible patients were randomly classified into derivation (60%) and internal validation cohort (40%). External validation was performed using the prospective Chinese Intracranial Atherosclerosis Study. Independent predictors of in-hospital SAP after AIS were obtained using multivariable logistic regression, and &bgr;-coefficients were used to generate point scoring system of the AIS-APS. The area under the receiver operating characteristic curve and the Hosmer–Lemeshow goodness-of-fit test were used to assess model discrimination and calibration, respectively. Results— The overall in-hospital SAP after AIS was 11.4%, 11.3%, and 7.3% in the derivation (n=8820), internal (n=5882) and external (n=3037) validation cohort, respectively. A 34-point AIS-APS was developed from the set of independent predictors including age, history of atrial fibrillation, congestive heart failure, chronic obstructive pulmonary disease and current smoking, prestroke dependence, dysphagia, admission National Institutes of Health Stroke Scale score, Glasgow Coma Scale score, stroke subtype (Oxfordshire), and blood glucose. The AIS-APS showed good discrimination (area under the receiver operating characteristic curve) in the internal (0.785; 95% confidence interval, 0.766–0.803) and external (0.792; 95% confidence interval, 0.761–0.823) validation cohort. The AIS-APS was well calibrated (Hosmer–Lemeshow test) in the internal (P=0.22) and external (P=0.30) validation cohort. When compared with 3 prior scores, the AIS-APS showed significantly better discrimination with regard to in-hospital SAP after AIS (all P<0.0001). Conclusions— The AIS-APS is a valid risk score for predicting in-hospital SAP after AIS.

Dual antiplatelet therapy in stroke and ICAS Subgroup analysis of CHANCE

Objective: We aimed to investigate whether the efficacy and safety of clopidogrel plus aspirin vs aspirin alone were consistent between patients with and without intracranial arterial stenosis (ICAS), in the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. Methods: We assessed the interaction of the treatment effects of the 2 antiplatelet therapies among patients with and without ICAS, identified by magnetic resonance angiography (MRA) in CHANCE (ClinicalTrials.gov identifier NCT00979589). Results: Overall, 1,089 patients with MRA images available in CHANCE were included in this subanalysis, 608 patients (55.8%) with ICAS and 481 (44.2%) without. Patients with ICAS had higher rates of recurrent stroke (12.5% vs 5.4%; p < 0.0001) at 90 days than those without. But there was no statistically significant treatment by presence of ICAS interaction on either the primary outcome of any stroke (hazard ratio for clopidogrel plus aspirin vs aspirin alone: 0.79 [0.47–1.32] vs 1.12 [0.56–2.25]; interaction p = 0.522) or the safety outcome of any bleeding event (interaction p = 0.277). Conclusions: The results indicated higher rate of recurrent stroke in minor stroke or high-risk TIA patients with ICAS than in those without. However, there was no significant difference in the response to the 2 antiplatelet therapies between patients with and without ICAS in the CHANCE trial. Classification of evidence: This study provides Class II evidence that for patients with acute minor stroke or TIA with and without ICAS identified by MRA, clopidogrel plus aspirin is not significantly different than aspirin alone in preventing recurrent stroke.

Interrelationship Among Common Medical Complications After Acute Stroke Pneumonia Plays an Important Role

Background and Purpose— Medical complications are common among patients with stroke. However, little is known about the potential interrelationship among them. In the present study, we aimed to investigate the association between common in-hospital medical complications after acute ischemic stroke (AIS) and spontaneous intracerebral hemorrhage (ICH). Methods— We analyzed patients enrolled in the China National Stroke Registry from 2007 to 2008. The occurrence of 11 common stroke-associated medical complications during acute hospitalization was prospectively registered. Multivariable analysis using generalized estimation equation was performed to assess association between medical complications in AIS and ICH cohort, respectively. Results— A total of 14 702 patients with AIS and 5221 patients with ICH were enrolled. The median age was 65 years (interquartile range, 55–74 years), and 38.1% were female. The median length of hospital stay was 14 days (interquartile range, 10–20 days) for AIS and 18 days (interquartile range, 11–26 days) for ICH. Pneumonia was the most common medical complication after AIS (11.4%) and ICH (16.8%). In the AIS cohort, after adjusting for potential confounders, pneumonia was significantly associated with development of gastrointestinal bleeding (adjusted odds ratio [OR], 8.35; 95% confidence interval [CI], 6.27–11.1; P<0.001), decubitus ulcer (adjusted OR, 5.31; 95% CI, 3.39–8.31; P<0.001), deep vein thrombosis (adjusted OR, 4.27; 95% CI, 2.41–7.59; P<0.001), epileptic seizure (adjusted OR, 3.96; 95% CI, 2.67–5.88; P<0.001), urinary tract infection (adjusted OR, 3.34; 95% CI, 2.73–4.10; P<0.001), atrial fibrillation/flutter (adjusted OR, 3.17; 95% CI, 2.58–3.90; P<0.001), and recurrent stroke (adjusted OR, 2.65; 95% CI, 2.07–3.40; P<0.001). Similar significant association between pneumonia and development of several nonpneumonia medical complications was verified in ICH cohort as well. Conclusions— Pneumonia is closely associated with the development of several nonpneumonia medical complications after AIS and ICH.

Geographic and Sex Difference in the Distribution of Intracranial Atherosclerosis in China

Background and Purpose— Geographic variation and sex difference in the distribution of intracranial atherosclerosis (ICAS) have not been fully discussed before in Chinese patients with cerebral ischemia. We performed this study with the aim to investigate geographic and sex difference in the distribution of ICAS in China. Methods— In this prospective multicenter study, we evaluated 2864 consecutive patients who experienced an acute cerebral ischemia within 7 days of symptom onset in 22 hospitals in China. All the inclusive patients underwent 3-dimensional time-of-flight MR angiography and duplex color Doppler ultrasound or contrast-enhanced MR angiography to document the presence of intracranial or extracranial stenosis. Intracranial large-artery atherosclerosis was defined as ≥50% diameter reduction on MR angiography. Results— The proportion of patients with ICAS was significantly higher in north China than in south China (50.22% versus 41.88%; P<0.0001). Patients in the north were likely to consume more alcohol and smoke more cigarettes and had significantly higher proportion of diabetes mellitus, family history of stroke, history of cerebral ischemia, heart disease, and higher body mass index. In patients aged >63 years, the percentage of ICAS in women was notably higher than in men (51.51% versus 45.40%; P=0.028). In elderly patients, women had higher proportion of diabetes mellitus, hypertension, hyperlipidemia, and heart disease than men. Conclusions— There exists geographic and sex difference in the distribution of symptomatic ICAS in China. Public health measures should strengthen improving social determinants of health and risk factor prevention/control in high-risk populations for decreasing stroke risk.

Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Stroke Is Better Than Low Doses

Background and Purpose— It remains uncertain whether lower dose intravenous tissue-type plasminogen activator (tPA) for stroke is as effective and safe as the standard dose. Methods— We analyzed data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China). Patients who were treated within 4.5 hours after symptom onset were included. These patients were divided into 5 groups according to tPA doses given: <0.5, 0.5 to 0.7, 0.7 to 0.85, 0.85 to 0.95, and ≥0.95 mg/kg. Symptomatic intracranial hemorrhage, mortality, and 90-day outcome assessed by modified Rankin scale were analyzed. Results— A total of 919 patients were enrolled. Among them, 9 had <0.5 mg/kg, 75 had 0.5 to 0.7 mg/kg, 131 had 0.7 to 0.85 mg/kg, 678 had 0.85 to 0.95 mg/kg, and 26 had ≥0.95 mg/kg. Because of sample sizes, only 0.5 to 0.7, 0.7 to 0.85, and 0.85 to 0.95 mg/kg groups were compared. Median tPA doses were 0.64, 0.79, and 0.90 mg, respectively. After adjustment for the baseline variables, there were no significant differences in mortality(5.41% versus 8.66% versus 7.36%; P=0.695) and symptomatic intracranial hemorrhage (0% versus 3.82% versus 1.46%; P=0.106). The 0.5 to 0.7 mg/kg group had less excellent recovery outcome (modified Rankin scale, 0–1) than 0.85 to 0.95 mg/kg group (41.89% versus 53.83%; odds ratio=0.58; P=0.031) at 90 days. The 0.70 to 0.85 mg/kg group had less functional independence outcome (modified Rankin scale, 0–2) than 0.85 to 0.95 mg/kg group (54.33% versus 64.51%; odds ratio=0.66; P=0.036) at 90 days. Conclusions— Our study suggests that standard-dose intravenous tPA for stroke had more favorable outcome without increasing the risk of symptomatic intracranial hemorrhage than low-dose tPA. For Asian people, 0.9 mg/kg should be the optimal dose of tPA to treat acute ischemic stroke.

Implementation and Outcome of Thrombolysis with Alteplase 3 to 4.5 h After Acute Stroke in Chinese Patients

The European Cooperative Acute Stroke Study (ECASS) III showed that intravenous recombinant tissue plasminogen activator (rtPA) administered in the 3 to 4.5 h after symptom onset significantly improved clinical outcomes in patients with acute ischemic stroke (AIS). But little is known regarding the safety and efficacy of intravenous rtPA treatment within this extended time window in Chinese patients with AIS.

Use of Statin During Hospitalization Improves the Outcome After Intracerebral Hemorrhage

To examine the relationship between statin use in Chinese patients with intracerebral hemorrhage (ICH) during their hospitalization and the outcomes.