Xingquan Zhao

Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack

BACKGROUND Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone. METHODS In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect. RESULTS Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group. CONCLUSIONS Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the Peoples Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).

The China National Stroke Registry for patients with acute cerebrovascular events: design, rationale, and baseline patient characteristics

Background As a leading cause of severe disability and death, stroke places an enormous burden on the health care system in China. There are limited data on the pattern of current medical practice and quality of care delivery for stroke patients at the national level. Aim The nation-wide prospective registry, China National Stroke Registry, will be considered with regard to its design, progress, geographic coverage, and hospital and patient characteristics. Methods Between September 2007 and August 2008, the China National Stroke Registry recruited consecutive patients with diagnoses of acute cerebrovascular events from 132 hospitals that cover all 27 provinces and four municipalities (including Hong Kong region) in China. Clinical data were collected prospectively using paper-based registry forms. Patients were followed for clinical and functional outcomes through phone interviews at three, six, 12, 18, and 24 months after disease onset. Results These patients (n = 21 902) were 63·8 years of age on average, and 39% were females. Ischaemic stroke was predominant (66·4%), and the other subtypes were intracerebral haemorrhage (23·4%), subarachnoid haemorrhage (3·4%), and transient ischaemic attack (6·2%). Conclusions The China National Stroke Registry is a large-scale nationwide registry in China. Rich data collected from this prospective registry may provide the opportunity to evaluate the quality of care for stroke patients in China.

Using Recombinant Tissue Plasminogen Activator to Treat Acute Ischemic Stroke in China Analysis of the Results From the Chinese National Stroke Registry (CNSR)

Background and Purpose— Little is known about intravenous recombinant tissue plasminogen activator (rtPA) use in China. By accessing the Chinese National Stroke Registry (CNSR), the rate of intravenous rtPA use was reviewed. We specifically examined the issues of prehospital and in-emergency department delay and compared them with the published data from developed countries. Methods— Funded by Chinese government, CNSR is the only nationwide stroke registry that includes 132 urban hospitals. All patients eligible for intravenous rtPA were included for analysis. We then compared the onset-to-needle time and door-to-needle time in the emergency department in China with those in developed countries. Results— From September 2007 to August 2008, 14 702 patients with ischemic stroke were entered into CNSR. Among 11 675 patients with known time of stroke onset, 2514 (21.5%) presented to the emergency department within 3 hours, 1469 (12.6%) were eligible for thrombolytic treatment, and 284 (2.4%) were finally treated, 181 (1.6%) of them with intravenous rtPA. The median onset-to-needle time was 180 (interquartile range, 150 to 228) minutes; the median door-to-needle time was 116 (interquartile range, 70 to 150) minutes; the median imaging-to-needle time was 90 (interquartile range, 60 to 129) minutes. Patients who were younger, presented to the emergency department quicker, with higher National Institutes of Health Stroke Scale scores, having higher income, and better education had a better chance of receiving intravenous rtPA. Conclusions— Approximately 1 in 5 patients with stroke presenting within 3 hours received thrombolytic therapy. The onset-to-needle time, door-to-needle time, and especially imaging-to-needle time were significantly longer than those in developed countries. Reducing prehospital and in-emergency department response time would help increase intravenous rtPA use in China.

Ideal Cardiovascular Health Metrics and the Risks of Ischemic and Intracerebral Hemorrhagic Stroke

Background and Purpose— Previous studies showed an inverse association between ideal cardiovascular health (CVH) metrics and the total risk of cardiovascular diseases and stroke. This study aimed to investigate the relationship between ideal CVH metrics and the risks of ischemic and hemorrhagic stroke, respectively. Methods— We collected information on the 7 ideal CVH metrics (including smoking status, body mass index, dietary intake, physical activity, blood pressure, total cholesterol, and fasting blood glucose) among 91  698 participants from the Kailuan study, China (72 826 men and 18 872 women between the ages of 18 and 98 years), free of myocardial infarction and stroke at baseline (2006–2007). Cox proportional hazards models were used to estimate stroke risk. Results— During the 4-year follow-up, we identified 1486 incident stroke events (1057 ischemic, 386 intracerebral hemorrhagic, and 43 subarachnoid hemorrhagic). The hazard ratios (95% confidence interval) for total stroke with adherence to 0 (reference), 1, 2, 3, 4, 5, and 6/7 ideal CVH metrics were: 1, 0.92 (0.69–1.23), 0.69 (0.52–0.92), 0.52 (0.39–0.68), 0.38 (0.28–0.51), 0.27 (0.18–0.40), and 0.24 (0.11–0.54), respectively (P trend <0.01), after adjusting for age, sex, education, income, and hospital. Similar inverse associations were observed for both ischemic and intracerebral hemorrhagic stroke (both P trend <0.01). Conclusions— We observed a clear inverse gradient relationship between the number of ideal CVH metrics and the risk of stroke in a Chinese population, supporting the importance of ideal health behaviors and factors in stroke prevention.

Diabetes and Poor Outcomes Within 6 Months After Acute Ischemic Stroke The China National Stroke Registry

Background and Purpose— Diabetes mellitus (DM) is an independent risk factor for ischemic stroke. However, controversy exists with regard to the impact of DM on prognosis after ischemic stroke in the Chinese population. We investigated the associations between DM and death, dependency, and stroke recurrence in patients after ischemic stroke onset in a nationwide, prospective registry, the China National Stroke Registry. Methods— The China National Stroke Registry consecutively recruited patients hospitalized for acute ischemic stroke in 2007 to 2008 and who were prospectively followed up for clinical and functional outcomes (death, dependency, and stroke recurrence) at 3 and 6 months after disease onset. Multivariable logistic regression was performed to analyze the association between DM and stroke outcomes after adjusting for potential confounding including age, sex, National Institutes of Health Stroke Scale score, glucose level at admission, hypertension, coronary heart disease, smoking, urinary tract infection, and other factors. Results— DM was identified in 3483 (27.0%) of stroke patients. Compared with stroke patients without DM, patients with DM had a significantly higher incidence of death or dependency and of recurrent stroke at 3 and 6 months after stroke onset. DM was an independent risk factor for death or dependency (adjusted odds ratio=1.23; 95% confidence interval, 1.10 to 1.37) in patients with ischemic stroke at 6 months after onset. Conclusions— DM independently predicted poor outcomes in Chinese patients after acute ischemic stroke.

Contrast Extravasation on Computed Tomography Angiography Predicts Clinical Outcome in Primary Intracerebral Hemorrhage: A Prospective Study of 139 Cases

Background and Purpose— Several retrospective studies suggested that contrast extravasation on CT angiography predicts hematoma expansion, poor outcome, and mortality in primary intracerebral hemorrhage. We aimed to determine the predictive value of contrast extravasation on multidetector CT angiography for clinical outcome in a prospective study. Methods— In 160 consecutive patients with spontaneous intracerebral hemorrhage admitted within 6 hours of symptom onset, noncontrast CT and multidetector CT angiography were performed on admission. A follow-up noncontrast CT was done at 24 hours. Multidetector CT angiography images were analyzed to identify the presence of contrast extravasation. Clinical outcome was assessed by modified Rankin Scale on discharge and at 90 days. Results— A total of 139 patients with primary intracerebral hemorrhage were included in the final analysis. Contrast extravasation occurred in 30 (21.6%) patients. The presence of contrast extravasation was associated with increased hematoma expansion (P<0.0001), in-hospital mortality (P=0.008), prolonged hospital stay (P=0.006), poor outcome on discharge (P=0.025), increased 3-month mortality (P=0.009), and poor clinical outcome (P<0.0001). In multivariate analysis, contrast extravasation was a promising independent predictor (OR, 10.5; 95% CI, 3.2–34.7; P<0.0001) for 90-day poor clinical outcome followed by the presence of intraventricular hemorrhage (OR, 3.4; 95% CI, 1.5–7.7; P=0.003) and initial hematoma volume (OR, 1.0; 95% CI, 1.0–1.1; P=0.013). Conclusions— The presence of contrast extravasation on multidetector CT angiography in patients with hyperacute-stage intracerebral hemorrhage is an independent and strong factor associated with poor outcome. Any patient with intracerebral hemorrhage with such sign on multidetector CT angiography should be monitored intensely and treated accordingly.

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.

Abnormal Glucose Regulation in Patients With Acute Stroke Across China: Prevalence and Baseline Patient Characteristics

Background and Purpose— The prevalence of diabetes is high among patients with ischemic stroke. However, the prevalence of abnormal glucose regulation and clinical characteristics among patients with stroke in the Chinese population is uncertain. We investigated the prevalence of prediabetes and diabetes in Chinese patients after stroke onset in a nationwide cohort study and investigated abnormal glucose regulation in patients with acute stroke across China (ACROSS-China). Methods— The ACROSS-China study consecutively recruited patients hospitalized for acute stroke in 2008 to 2009 and investigated the prevalence of impaired glucose tolerance and diabetes among the patients on day 14 after stroke onset. Oral glucose tolerance test was performed in the diagnosis of abnormal glucose regulation. Results— The prevalence of abnormal glucose regulation was 68.7% among all the patients with stroke. Diabetes was identified in 42.3% of all the patients (45.8% for patients with ischemic stroke, 31.2% for patients with intracerebral hemorrhage, and 26.4% for patients with subarachnoid hemorrhage, respectively). Prediabetes (impaired fasting glucose and impaired glucose tolerance) was identified in 26.4% of all the patients with stroke. The prevalence of diabetes and impaired glucose tolerance was the highest in the patients with atherothrombotic infarction (73.4%). Conclusions— The prevalence of abnormal glucose regulation was high in Chinese patients with acute stroke, especially in patients with atherothrombotic infarction. Oral glucose tolerance test identified a large percentage of patients with newly diagnosed diabetes or impaired glucose tolerance after stroke onset.

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.

Asymptomatic Polyvascular Abnormalities in Community (APAC) Study in China: Objectives, Design and Baseline Characteristics

Objective The population-based “Asymptomatic Polyvascular Abnormalities in Community (APAC) Study was designed to examine prevalence and associations of asymptomatic polyvascular abnormalities (APA) in a general population. In this report, the objectives, design and baseline data of the APAC study are described. Methods The study included 5,440 participants (40.1% women) with an age of 40+ years who were randomly selected from the population of the Kailuan Study which included 101,510 employees and retirees of the Kailuan Co. Ltd, a large coal mine industry located in Tangshan, Hebei, China. Exclusion criteria were previous cerebral stroke, transient ischemic attacks and coronary heart disease. In 2010 and 2011, information on potential cardiovascular risk factors was collected and all participants underwent transcranial Doppler sonography, measurement of the ankle brachial index, and bilateral carotid duplex sonography. In a first follow-up examination in 2012/2013, retinal photography and spectral-domain optical coherence tomography were additionally performed. In a planned long-term follow-up, data from clinical examinations and laboratory tests and the occurrence of cardiovascular or cerebrovascular events will be collected to build up a predicting model for the risk of ischemic events. Results At baseline, mean age of the participants was 55.2±11.8 years, and men showed a significantly (P<0.001) higher prevalence of arterial hypertension (55.5% vs. 36.5%) and hyperlipidemia (50.7% vs. 46.0%) and a higher blood homocysteine concentration (18.68±10.28µmol/L versus 11.69±6.40µmol/L). Conclusions The APAC is the first study to prospectively evaluate the relationship between intracranial arterial stenosis, retinal nerve fiber layer changes, retinal microvascular signs, and the eventual development of cerebrovascular or cardiovascular events.