Ethical Standards
This clinical study followed the Declaration of Helsinki and was approved by the Medical Ethics Committee of Chang Gung Memorial Hospital (CGMH), Taipei, Taiwan (IRB 201800689B0). As this was an observational study without active intervention, and all subjects were diagnosed, treated and followed as clinical routines, the Medical Ethics Committee of CGMH, Taipei, Taiwan had approved that the requirement for the written informed consent was waived.
Study population
All study patients with acute first-ever IS and high-grade CAS were recruited from the Stroke Unit of the Department of Neurology in Keelung CGMH from January 1, 2007, to April 30, 2012. The diagnosis of acute IS was made in accordance with the World Health Organization criteria, and was confirmed by brain magnetic resonance imaging or computed tomography (CT) scan [8]. For evaluate the severity of CAS, carotid duplex ultrasound was done within 7 days after stroke onset. If the result of ultrasound revealed ≧70% stenosis at carotid artery, brain magnetic resonance angiography was arranged for confirm the CAS and evaluate the location and volume of the infarction. We only recruited patients with high-grade CAS with the degree of stenosis ranged from 70% to 100%, and the acute stroke symptoms can be correlated with the vascular territory of the carotid artery with CAS. The exclusion criteria were: (1) the location of infarction cannot be correlated with the vascular territory of high-grade CAS; (2) patients received revascularization treatments; (3) patients with previous IS, cerebral hemorrhage, or stroke of uncertain causes; (4) patients with severe medical diseases such as hepatic or renal failure, or malignancy.
The renal function of the recruited patients with acute IS and high-grade CAS was assessed using the Modification of Diet in Renal Disease Study equation for eGFR: eGFR (mL/min/1.73 m2) = 186 × (serum creatinine [mg/dL])-1.154 × (Age [years])-0.203 × (0.742 if female) [9]. All recruited patients were stratified by eGFR into the following three groups for statistical analysis: (1) eGFR≺45 mL/min/1.73 m2; (2) eGFR 45-59 mL/min/1.73 m2; (3) eGFR≧60 mL/min/1.73 m2.
Clinical assessments
Comorbidities and vascular risk factors such as hypertension, diabetes mellitus (DM), hyperlipidemia, smoking, atrial fibrillation (AF), valvular heart disease, peripheral arterial diseases, and coronary artery disease (CAD) were identified after an in-depth review of the medical records. Hypertension was diagnosed as systolic blood pressure >160 mmHg and/or diastolic blood pressure > 95 mmHg on two different occasions, with the second measurement taken more than 5 days after the stroke, or known hypertension diagnosed by a clinician [10]. DM was identified in patients with fasting plasma glucose ≧ 7.0 mmol/L, a 2-hour value in the oral glucose tolerance test or a random plasma glucose concentration ≧ 11.1 mmol/L, in the presence of symptoms, or patients with previously treated DM. AF was identified by ECG and/or 24 hour ECG monitoring. Cigarette smoking was identified as a current smoker or a smoker with cessation less than 5 years ago. Laboratory assessments, such as complete blood cell count, biochemistry studies, lipid level, glycohemoglobin, coagulation testing, 12-lead electrocardiography, and transthoracic echocardiography, were done within 1 week after acute stroke onset. The clinical IS subtypes of the Oxfordshire Community Stroke Project classification [11], and the scores of National Institutes of Health Stroke scale, Modified Rankin scale [12], and Barthel index were recorded.
Follow-up
The timings of follow up were at the first and the third month after initial assessment of the acute ischemic stroke, and then every 3 months. All recruited patients were followed up for 5 years after the acute ischemic stroke. The primary end point was 5-year mortality, and every cause of death was reviewed. New major medical problems, such as death, recurrent IS, cerebral hemorrhage, cancer, head injury, and reason of re-hospitalization, were recorded.
Statistical analysis
Continuous variables were expressed as median (interquartile range) since they were not normally distributed. Categorical variables were expressed as a number (percentage) [13].
The clinical characteristics of the patients with different eGFR groups were analyzed using descriptive statistics. The Kruskal-Wallis or chi-square test was used for assessing the group differences [13]. To identify factors associated with the eGFR, the investigation utilized simple linear regression (SLR) analysis for demographic, biochemical and other variables. All significant variables (p < 0.05) assessed by SLR entered into the backward stepwise procedures [14]. The Kaplan-Meier survival analysis was used to estimate the cumulative overall survival for patients with different eGFR levels, and the log-rank test was used for assessing the group differences [15]. The Cox proportional hazards model was used to determine the significance of each variable in predicting the 5-year mortality. A univariate Cox model was used initially to measure the hazard ratio of all previously identified variables for mortality. Then, a backward, stepwise multivariate Cox regression model was used to identify the risk factors for the 5-year mortality [15]. All statistical analyses were done with IBM SPSS statistics 19 for Windows.