Weiqi Chen

Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack

Background: The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA. Methods: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding. Results: Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57–2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10–2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58–1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study. Conclusions: Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.

Global Survey of the Frequency of Atrial Fibrillation-Associated Stroke: Embolic Stroke of Undetermined Source Global Registry.

Background and Purpose— Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. Methods— Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. Results— Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6–29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6–12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3–5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). Conclusions— This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF-associated stroke were typically elderly (>75 years old) and more often women.

Risks and benefits of clopidogrel–aspirin in minor stroke or TIA: Time course analysis of CHANCE

Objective: To investigate the short-term time course risks and benefits of clopidogrel with aspirin in minor ischemic stroke or TIA. Methods: Data were derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. The primary outcome was a new ischemic stroke. Safety outcomes included any bleeding and moderate to severe bleeding. Time course analyses were performed for the outcomes of both stroke and bleeding. Results: A total of 145 (71.1%), 13 (6.4%), and 12 (5.9%) of 204 new ischemic strokes in the clopidogrel–aspirin group vs 223 (75.6%), 19 (6.4%), and 8 (2.7%) of 295 in the aspirin alone group occurred at the first, second, and third week, respectively. A total of 23 (38.3%), 15 (25.0%), and 9 (15.0%) of 60 bleeding cases in the clopidogrel–aspirin group vs 15 (36.6%), 8 (19.5%), and 3 (7.3%) of 41 in the aspirin alone group occurred at the first, second, and third week, respectively. Clopidogrel–aspirin treatment numerically reduced the risk of ischemic stroke within the first 2 weeks. From the 10th day, the number of any bleeding cases caused by dual antiplatelets outweighed that of new stroke reduced by dual antiplatelets. Conclusions: Clopidogrel–aspirin treatment may have a benefit of reducing stroke risk outweighing the potential risk of increased bleeding especially within the first 2 weeks compared with aspirin alone in patients with minor stroke or TIA. Clinicaltrials.gov identifier: NCT00979589. Classification of evidence: This study provides Class II evidence that for patients with minor stroke or TIA, the reduction of stroke risk from clopidogrel plus aspirin within the first 2 weeks outweighs the risk of bleeding compared with aspirin alone.

Insulin Resistance and Prognosis of Nondiabetic Patients With Ischemic Stroke: The ACROSS-China Study (Abnormal Glucose Regulation in Patients With Acute Stroke Across China)

Background and Purpose— Insulin resistance was common in patients with stroke. This study investigated the association between insulin resistance and outcomes in nondiabetic patients with first-ever acute ischemic stroke. Methods— Patients with ischemic stroke without history of diabetes mellitus in the ACROSS-China registry (Abnormal Glucose Regulation in Patients With Acute Stroke Across China) were included. Insulin resistance was defined as a homeostatis model assessment–insulin resistance (HOMA-IR) index in the top quartile (Q4). HOMA-IR was calculated as fasting insulin (&mgr;U/mL)×fasting glucose (mmol/L)/22.5. Multivariable logistic regression or Cox regression was performed to estimate the association between HOMA-IR and 1-year prognosis (mortality, stroke recurrence, poor functional outcome [modified Rankin scale score 3–6], and dependence [modified Rankin scale score 3–5]). Results— Among the 1245 patients with acute ischemic stroke enrolled in this study, the median HOMA-IR was 1.9 (interquartile range, 1.1–3.1). Patients with insulin resistance were associated with a higher mortality risk than those without (adjusted hazard ratio, 1.68; 95% confidence interval, 1.12–2.53; P=0.01), stroke recurrence (adjusted hazard ratio, 1.57, 95% confidence interval, 1.12–2.19; P=0.008), and poor outcome (adjusted odds ratio, 1.42; 95% confidence interval, 1.03–1.95; P=0.03) but not dependence after adjustment for potential confounders. Higher HOMA-IR quartile categories were associated with a higher risk of 1-year death, stroke recurrence, and poor outcome (P for trend =0.005, 0.005, and 0.001, respectively). Conclusions— Insulin resistance was associated with an increased risk of death, stroke recurrence, and poor outcome but not dependence in nondiabetic patients with acute ischemic stroke.

Post–Glucose Load Measures of Insulin Resistance and Prognosis of Nondiabetic Patients With Ischemic Stroke

Background Insulin resistance is associated with an increased risk of cardiovascular events in the general population. This study aimed to estimate the association between post–glucose load measures of insulin resistance and prognosis of nondiabetic patients with ischemic stroke. Methods and Results Data were derived from the ACROSS‐China (Abnormal Glucose Regulation in Patients with Acute Stroke across China) registry. Patients with ischemic stroke without a history of diabetes mellitus were included. Two post–glucose load measures of insulin sensitivity, the insulin sensitivity indices ISI(composite) and the ISI 0,120, were calculated. Outcomes included stroke recurrence, all‐cause death, and poor functional outcome at 12 months. Among 1203 patients, 63.3% were male with an average age of 62.1 years. At 12 months, 168 (14.4%) patients had recurrent stroke, 111 (9.2%) had died, and 288 (24.4%) had poor outcome. After adjustment for potential covariates, the first quartile of the ISI(composite) was associated with increased 12‐month stroke recurrence (adjusted hazard ratio 2.02, 95% CI 1.28–3.18, P=0.003), death (adjusted hazard ratio 2.78, 95% CI 1.59–4.86, P<0.001), and poor outcome (adjusted odds ratio 2.67, 95% CI 1.69–4.21, P<0.001) compared with the fourth quartile. Similar results were observed for the ISI 0,120 but with a larger magnitude of association. Using a multivariable regression model with restricted cubic spline, we found an L‐shaped association between the insulin sensitivity indices and the risk of each end point. Conclusions In this large‐scale registry, post–glucose load measures of insulin resistance with the ISI(composite) and the ISI 0,120 were associated with 12‐month poor outcomes of nondiabetic patients with ischemic stroke.

Impact of Glycemic Control on Efficacy of Clopidogrel in Transient Ischemic Attack or Minor Stroke Patients With CYP2C19 Genetic Variants

Background and Purpose— Dysglycemia may influence the predictive value of CYP2C19 loss-of-function allele for clinical efficacy of antiplatelet drug, but the role of glycated albumin (GA) remains unclear in patients with stroke on antiplatelet drugs. Methods— The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) included 2933 patients who had GA levels and CYP2C19 genotyping. Cox proportional hazards model was used to assess the interaction between CYP2C19 loss-of-function allele (*2, *3) carrier status and the effect of antiplatelet therapy based on their GA levels. Results— There was significant interaction between carrier status and antiplatelet therapy regimen on the risk of recurrent stroke (P=0.03) in patients with GA levels of ⩽15.5%, but not in those with GA levels of >15.5% (P=0.48). Only in noncarriers with low GA levels, dual-antiplatelet therapy reduced stroke recurrence (3.5%) compared with those on aspirin alone (14.7%; hazard ratio, 0.23; 95% confidence interval, 0.10–0.49; P<0.001). Similar effects were observed when examined the combined vascular event or ischemic stroke. No significant difference in bleeding was found among groups. Conclusions— In patients with minor stroke or high-risk transient ischemic attack, clopidogrel–aspirin when compared with aspirin alone reduced stroke recurrence only in noncarriers of CYP2C19 loss-of-function allele and normal GA levels. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589.

The max-intracerebral hemorrhage score predicts long-term outcome of intracerebral hemorrhage

Little is known about the performance of the maximally treated intracerebral hemorrhage (max‐ICH) score in predicting unfavorable long‐term functional outcome and death in patients with intracerebral hemorrhage (ICH) in China. We aimed to validate the performance of the max‐ICH score and compared it with other recognized scores.

Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Background We aimed to determine the risk conferred by metabolic syndrome (METS) and diabetes mellitus (DM) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High‐risk patients with Acute Non‐disabling Cerebrovascular Events) trial. Methods and Results In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society (CDS) and International Diabetes Foundation (IDF) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS, 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow‐up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89–3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98–3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke (P=0.82 for interaction in the fully adjusted model of CDS) was observed. Using the METS (IDF) criteria demonstrated similar results. Conclusions Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack.

Totaled Health Risks in Vascular Events Score Predicts Clinical Outcome and Symptomatic Intracranial Hemorrhage in Chinese Patients After Thrombolysis

Background and Purpose— The performance of the Totaled Health Risks in Vascular Events (THRIVE) score in predicting clinical outcomes in Chinese patients with acute ischemic stroke post intravenous thrombolysis is unknown. Methods— Data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) study was used to compare the THRIVE score with other scores used to predict clinical outcomes and symptomatic intracranial hemorrhage after intravenous thrombolysis. Results— Among the 1128 patients with acute ischemic stroke who were included in this study, areas under the curve of the THRIVE score for symptomatic intracranial hemorrhage, 3-month poor functional outcomes, and death rate were 0.69, 0.71, and 0.78, respectively. The increased THRIVE score was related to the higher risk of developing symptomatic intracranial hemorrhage, poor functional outcomes, or death in patients with acute ischemic stroke at 3 months after thrombolysis. Conclusions— The THRIVE score predicted reliably the risks of developing symptomatic intracranial hemorrhage, poor functional outcome, or death after intravenous thrombolysis therapy in Chinese patients with acute ischemic stroke.

Teaching NeuroImages: Isolated vertigo and imbalance due to deep border zone cerebellar infarct

An 81-year-old man with hypertension and diabetes suddenly developed persistent vertigo and imbalance at rest. Examination did not find any positive signs except direction-changing nystagmus on day 7. MRI displayed acute deep infarcts at the boundary zone between medial and lateral …