Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) Yuesong Pan, MD*; Xueli Cai, MD*; Jing Jing, MD, PhD; Xia Meng, MD, PhD; Hao Li, PhD; Yongjun Wang, MD; Xingquan Zhao, MD, PhD; Liping Liu, MD, PhD; David Wang, DO; S. Claiborne Johnston, MD, PhD; Tiemin Wei, MD; Yilong Wang, MD, PhD; on behalf of the CHANCE Investigators Background and Purpose—We aimed to determine the association between stress hyperglycemia and risk of new stroke in patients with a minor ischemic stroke or transient ischemic attack. Downloaded from Methods—A subgroup of 3026 consecutive patients from 73 prespecified sites of the CHANCE trial (Clopidogrel in High- Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Stress hyperglycemia was measured by glucose/glycated albumin (GA) ratio. Glucose/GA ratio was calculated by fasting plasma glucose divided by GA and categorized into 4 even groups according to the quartiles. The primary outcome was a new stroke (ischemic or hemorrhagic) at 90 days. We assessed the association between glucose/GA ratio and risk of stroke by multivariable Cox http://stroke.ahajournals.org/ regression models adjusted for potential covariates. Results—Among 3026 patients included, a total of 299 (9.9%) new stroke occurred at 3 months. Compared with patients with the lowest quartile, patients with the highest quartile of glucose/GA ratio was associated with an increased risk of stroke at 3 months after adjusted for potential covariates (12.0% versus 9.2%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.06–2.01). Similar results were observed after further adjusted for fasting plasma glucose. We also observed that higher level of glucose/GA ratio was associated with an increased risk of stroke with a threshold of 0.29 using a Cox regression model with restricted cubic spline. Conclusions—Stress hyperglycemia, measured by glucose/GA ratio, was associated with an increased risk of stroke in by guest on October 23, 2017 patients with a minor ischemic stroke or transient ischemic attack. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00979589. (Stroke. 2017;48:3006-3011. DOI: 10.1161/STROKEAHA.117.019081.) Key Words: clopidogrel ◼ diabetes mellitus ◼ hyperglycemia ◼ risk ◼ stroke tress hyperglycemia is the relative transient increase ischemic attack (TIA). Furthermore, most previous studies Sin glucose secondary to neurohormonal derangements defined stress hyperglycemia according to fasting or random and the inflammatory that occur during a critical illness like glucose without considering the background glucose level, stroke.1,2 Previous study showed that acute stress hypergly- although they were analyzed by diabetic status.3,4 Previous cemia predicts increased risks of in-hospital mortality and study showed that relative hyperglycemia, defined as admis- poor functional recovery after ischemic stroke.3 However, sion glucose divided by estimated average glucose derived few study investigated the association of stress hyperglycemia from glycosylated hemoglobin (HbA1c), was a better predic- with the risk of new stroke after ischemic stroke or transient tive biomarker of critical illness than absolute hyperglycemia.2 Received August 13, 2017; final revision received September 4, 2017; accepted September 14, 2017. From the Department of Neurology, Beijing Tiantan Hospital (Y.P., J.J., X.M., H.L., Yongjun Wang, X.Z., L.L., Yilong Wang) and Department of Epidemiology and Health Statistics, School of Public Health (Y.P.), Capital Medical University, Beijing, China; China National Clinical Research Center for Neurological Diseases, Beijing (Y.P., J.J., X.M., H.L., Yongjun Wang, X.Z., L.L., Yilong Wang); Center of Stroke, Beijing Institute for Brain Disorders, China (Y.P., J.J., X.M., H.L., Yongjun Wang, X.Z., L.L., Yilong Wang); Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China (Y.P., J.J., X.M., H.L., Yongjun Wang, X.Z., L.L., Yilong Wang); Beijing Municipal Key Laboratory of Clinical Epidemiology, China (Y.P.); Department of Neurology (X.C.) and Department of Cardiology (T.W.), Lishui Hospital of Zhejiang University (the Central Hospital of Lishui), China; INI Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria (D.W.); and Dell Medical School, University of Texas at Austin (S.C.J.). *Drs Pan and Cai contributed equally. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 117.019081/-/DC1. Correspondence to Yilong Wang, MD, PhD, No. 6 Tiantanxili, Dongcheng District, Beijing 100050, China. E-mail [email protected] © 2017 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.117.019081 3006 Pan et al Stress Hyperglycemia and Prognosis of Stroke 3007 Glycated albumin (GA) is a well-validated measure of the by quartiles of glucose/GA ratio (Q1–Q4) for further comparisons. The mean glucose concentration over ≈2 to 4 weeks.5,6 GA can novel index of glucose/GA ratio quantifies the extent of acute elevation reflect the background glucose level before the event when in plasma glucose compared with the background plasma glucose levels. tested within 2 days after the onset of stroke or TIA. In addi- tion, GA is not affected by chronic kidney disease and ane- Outcome Assessment mia and can be more accurately reflecting the actual status of The primary outcome in the current analyses was a new stroke (isch- glycemic control compared with HbA1c.7,8 Therefore, it can emic or hemorrhagic) during the 90-day follow-up period, which was same as that in the trial.10 Secondary outcomes included a new be postulated that the ratio of fasting plasma glucose (FPG) composite vascular event (ischemic stroke, hemorrhagic stroke, myo- to GA could reflect the stress hyperglycemia considering the cardial infarction, or vascular death) and ischemic stroke alone. All background glucose level before the onset of event. reported events were verified by a central adjudication committee that In this study, we investigated the association of stress was blinded to the study group assignments. hyperglycemia, measured by glucose/GA ratio, and outcomes of patients with a minor ischemic stroke or TIA, using the data Statistical Analysis derived from the CHANCE trial (Clopidogrel in High-Risk Continuous variables were presented as median with interquartile and Patients With Acute Nondisabling Cerebrovascular Events). categorical variables as percentages. The baseline characteristics of the patients included in and excluded from the analysis were com- pared using Wilcoxon rank-sum test for continuous variables and χ2 Methods test for categorical variables. The baseline variables among different Downloaded from Study Participants quartiles of glucose/GA ratio were compared by Kruskal–Wallis test for continuous variables and χ2 test for categorical variables. The CHANCE trial is a randomized, double-blind, controlled trial con- We tested the statistical significance of group of glucose/GA ducted at 114 hospitals in China between October 2009 and July 2012. ratio×study group assignment in a multivariable Cox model to exam- Details on the rational, design, and major results of the CHANCE trial 9–11 ine the interaction effect of category of stress hyperglycemia by study have been published previously. In brief, 5170 patients with a minor group assignment. Adjusted hazard ratios and their 95% confidence ischemic stroke (National Institutes of Health Stroke Scale score of http://stroke.ahajournals.org/ intervals were calculated using multivariable Cox regression mod- 3) or high-risk TIA (ABCD2 score [age, blood pressure, clinical fea- ≤ els to assess the associations between quartiles of glucose/GA ratio tures, duration of TIA, and diabetes] of ≥4) within 24 hours after onset and prognosis of minor stroke or TIA. In the multivariable regression of the events were randomized to the group of clopidogrel plus aspirin analyses, 2 models were performed. In the first model, we adjusted (day 1: clopidogrel 300 mg and open-label aspirin 75–300 mg; days for all the potential covariates including history of diabetes melli- 2–21: clopidogrel 75 mg and aspirin 75 mg/d; and days 22–90: clopi- tus. In the second model, we further adjusted for FPG to assess the dogrel 75 mg/d) or aspirin alone (day 1: open-label aspirin 75–300 mg; and days 2–90: aspirin 75 mg/d) in the CHANCE trial. The pro- tocol of the CHANCE trial was approved by ethics committee at each Table 1. Baseline Characteristics of the Patients Included study center. Written informed consent was obtained from all partici- and Excluded by guest on October 23, 2017 pants or their representatives before being enrolled into the study. Data are available to researchers on request for purposes of reproducing Included Excluded P the results or replicating the procedure by directly contacting the cor- Characteristic (n=3026) (n=2144) Value responding author ([email protected]). Age (y), median (IQR) 62.2 (54.7–71.2) 62.3 (54.6–71.4) 0.77 Among 114 clinical sites included in the CHANCE trial, 73 (64%) sites with 3044 patients had prior experience collecting samples and Female, n (%) 1015 (33.5) 735 (34.3) 0.58 agreed to participate in the prespecified biomarker substudy. All patients recruited by these 73 sites participated this substudy,