Research Association of baseline dyslipidemia with stroke recurrence within five-years after ischemic stroke Emre Kumral1*, Dilek Evyapan1, Figen Gökçay1, Bedriye Karaman1, and Mehmet Orman2 Background and purpose The association between dyslipidemia (DL) and stroke recurrence is unclear, but may be influenced by different subtypes of stroke. This study aims to explore whether DL contributes to the recurrence of certain subtypes of ischemic stroke. Methods Data from the Ege Stroke Registry was examined, and five-years follow-up data for stroke recurrence was analyzed. Trial of Org 10172 in Acute Stroke Treatment criteria was used to classify the subtypes of all stroke. Recurrent stroke was defined as a new neurological deficit compatible to ischemic stroke or intracerebral hemorrhage. The association between DL and stroke recurrence in patients with different sroke subtypes was analyzed using univariable and multivariable logistic regression models. Survival curves were estimated with Kaplan–Meier methods, and survival analyses were undertaken using Cox proportional hazards models. Results Of the 9940 patients with ischemic stroke, 5838 (58·7%) had DL and 2202 (22·2%) experienced a stroke recurrence within five-years. The frequency of stroke recurrence of patients with DL was unsignificantly higher than those without at five-years of follow-up (18·0% vs. 17·0%; P = 0·21). After stratification by Trial of Org 10172 in Acute Stroke Treatment subtypes, multivariable analysis revealed a significant association between DL and stroke recurrence in all ischemic stroke at five-years (odds ratio, 1·2; 95% confidence interval, 1·02–1·42), and in the large-artery disease subtype (odds ratio, 1·46; 95% confidence interval, 1·12–1·91), but not in the other stroke subtypes (cardioembolic: odds ratio, 1·18; 95% confidence interval, 0·84–1·65; small-artery disease: odds ratio, 1·24; 95% confidence interval, 0·87–1·76; other subtype: odds ratio, 0·79; 95% confidence interval, 0·48–1·31). The probability of stroke recurrence increased in patients with large-artery
Correspondence: Emre Kumral*, Stroke Unit, Neurology Department, Ege University, School of Medicine, Bornova, Izmir 35100, Turkey. E-mail: [email protected] 1 Stroke Unit, Neurology Department, Ege University, School of Medicine, I˙zmir, Turkey 2 Biostatistic Department, Ege University, School of Medicine, I˙zmir, Turkey Received: 27 November 2013; Accepted: 20 May 2014 Conflict of interest: We have no actual or potential conflicts of interest for all authors involved in this paper. Ethical Committee Approval: Ege University Medical Ethical Committee has approved this study prior to beginning (1998), following the principles outlined in the Helsinki Declaration. Authors’ contribution: Principal author: Emre Kumral. Study concept or design: Emre Kumral. Acquisition of data: Bedriye Karaman, Dilek Evyapan, Figen Gökçay. Analysis or interpretation of data: Bedriye Karaman. Statistical analysis: Mehmet Orman. Study supervision or coordination: Emre Kumral. DOI: 10.1111/ijs.12341 © 2014 World Stroke Organization
disease and DL, compared with other subtypes of stroke [log rank test (Mantel–Cox) P < 0·013]. Conclusions Our results showed that DL is related to the recurrent strokes in patients with ischemic stroke within five-years after ischemic stroke, specifically to the large-artery disease subtype. Key words: cardioembolic stroke, large-artery disease, lipids, small-artery disease, stroke recurrence
Introduction Known as a major risk factor contributing to the causes of ischemic stroke (IS), dyslipidemia (DL) has not been well studied as a risk factor for subsequent strokes (1–8). Studies evaluating the relationship between DL with the recurrence of strokes have reported varied associations. Much of the discrepancy may be based on differences in methodology, population studied, and differences of end-points analyzed (9). Dyslipidemia, therefore, may not contribute to subsequent strokes of different subtypes equally. This is because IS is a heterogeneous disease with variable pathogenesis (10,11). Most previous studies examined DL as a potential risk factor for recurrent stroke among IS patients without distinguishing the initial IS subtypes (1–8). The objective of our study was to determine the association between DL and stroke recurrence in patients with different IS subtypes, as defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification (12). Patients and methods Our Ege Stroke Registry is a hospital-based registry that enrolls consecutive stroke patients within first week after stroke onset in our Aegean region. The objectives of the Ege Study were to determine the risk factors in patients presenting with a manifestation of cerebrovascular disease, and to study predictors for stroke recurrence in these high-risk patients in our Aegean region. The methods of case ascertainment and data gathering in the Ege Stroke Registry were described as published elsewhere (13). Initial stroke included IS, intracerebral hemorrhage, and subarachnoid hemorrhage. The enrollment of patients in the study started January 1998 and stopped in January 2009. Detailed baseline data were abstracted prospectively by using paper-based registry forms and stored in the computer environment. Patients or their authorized proxies were contacted every year after stroke onset between 1999 and 2013. The study was approved by the ethics committee of the Ege University Medical Center, and written informed consent was obtained from all participants. The current analysis included all consecutive patients in our Stroke Registry who had been diagnosed with acute IS according to the World Health Organization criteria (14), and with confirmation by brain computed tomography (CT) or magnetic resonance Vol ••, •• 2014, ••–••
1
Research imaging (MRI). At least two senior neurologists from our stroke unit reviewed the clinical features and diagnostic test results, and then gave the subtype classifications. Vascular risk factors and lipid profiles Systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean arterial pressure, obesity, physical activity, current cigarette smoking, uric acid were recorded. A venous blood sample was collected after an overnight fast of eight-hours. Serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein (a) (Lp [a]), glucose, creatinine, and HbA1c levels in hemolysates were measured with commercial chemistry kits (Modular, Roche, Boehringer-Mannheim, Germany). Obesity was presumed if the waist circumference in men were ≥102·0 cm and in women ≥88·0 cm, and the body mass index (BMI) was ≥30 kg/m2. Hyperhomocysteinemia was considered if homocystein was >140 μg/dL in female and 7·2 mg/dL in men or >6·6 mg/dL in women. Hypertension (HT) was presumed when SBP was ≥140 mmHg or DBP was ≥90 mmHg on repeated measurements during the hospitalization or taking antihypertensive drugs. Diabetes mellitus was specified as fasting serum glucose ≥125 mg/dL, nonfasting serum glucose ≥200 mg/dL, or use of oral blood sugar-lowering drugs or insulin. Coronary heart disease (CHD) was registered in patients with history of myocardial infarction or angina pectoris. In our center, patients with DL were treated by a statin (atorvastatin, simvastatin, or rosuvastatin) to reach a ≥50% decrease in LDL-C from baseline. An LDL-C reduction ≥50% was used as an indicator of accurate statin use. Stroke subtypes Subtype classification of IS was based on patient’s clinical features combined with the results of one or more diagnostic tests, including brain imaging (CT and MRI), electrocardiogram (ECG), echocardiography (transesophageal or transthoracic), imaging of extracranial and intracranial arteries (carotid duplex, transcranial Doppler, CT angiography, magnetic resonance angiography, or digital subtraction angiography), and laboratory assessments for a prothrombotic state as defined by the TOAST classification (12). Large-artery disease (LAD) was presumed in patients having a stenosis of extracranial carotid artery or intracranial large arteries more than 50% with a stroke in the territory of stenosed artery. Clinical findings included cerebral cortical impairment (e.g., aphasia, neglect, apraxia, anopia, motor and/or sensory involvement) or brain stem or cerebellar dysfunction. Infarct areas were >1·5 cm in diameter on CT or MRI. Cardiac embolism (CE) included mainly nonvalvular atrial fibrillation, left ventricular akinetic segment, intracardiac thrombus or tumor, mitral stenosis, and other less common sources. Small-artery disease (SAD)
2
Vol ••, •• 2014, ••–••
E. Kumral et al. was defined in patients with infarcts of
Correspondence: Emre Kumral*, Stroke Unit, Neurology Department, Ege University, School of Medicine, Bornova, Izmir 35100, Turkey. E-mail: [email protected] 1 Stroke Unit, Neurology Department, Ege University, School of Medicine, I˙zmir, Turkey 2 Biostatistic Department, Ege University, School of Medicine, I˙zmir, Turkey Received: 27 November 2013; Accepted: 20 May 2014 Conflict of interest: We have no actual or potential conflicts of interest for all authors involved in this paper. Ethical Committee Approval: Ege University Medical Ethical Committee has approved this study prior to beginning (1998), following the principles outlined in the Helsinki Declaration. Authors’ contribution: Principal author: Emre Kumral. Study concept or design: Emre Kumral. Acquisition of data: Bedriye Karaman, Dilek Evyapan, Figen Gökçay. Analysis or interpretation of data: Bedriye Karaman. Statistical analysis: Mehmet Orman. Study supervision or coordination: Emre Kumral. DOI: 10.1111/ijs.12341 © 2014 World Stroke Organization
disease and DL, compared with other subtypes of stroke [log rank test (Mantel–Cox) P < 0·013]. Conclusions Our results showed that DL is related to the recurrent strokes in patients with ischemic stroke within five-years after ischemic stroke, specifically to the large-artery disease subtype. Key words: cardioembolic stroke, large-artery disease, lipids, small-artery disease, stroke recurrence
Introduction Known as a major risk factor contributing to the causes of ischemic stroke (IS), dyslipidemia (DL) has not been well studied as a risk factor for subsequent strokes (1–8). Studies evaluating the relationship between DL with the recurrence of strokes have reported varied associations. Much of the discrepancy may be based on differences in methodology, population studied, and differences of end-points analyzed (9). Dyslipidemia, therefore, may not contribute to subsequent strokes of different subtypes equally. This is because IS is a heterogeneous disease with variable pathogenesis (10,11). Most previous studies examined DL as a potential risk factor for recurrent stroke among IS patients without distinguishing the initial IS subtypes (1–8). The objective of our study was to determine the association between DL and stroke recurrence in patients with different IS subtypes, as defined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification (12). Patients and methods Our Ege Stroke Registry is a hospital-based registry that enrolls consecutive stroke patients within first week after stroke onset in our Aegean region. The objectives of the Ege Study were to determine the risk factors in patients presenting with a manifestation of cerebrovascular disease, and to study predictors for stroke recurrence in these high-risk patients in our Aegean region. The methods of case ascertainment and data gathering in the Ege Stroke Registry were described as published elsewhere (13). Initial stroke included IS, intracerebral hemorrhage, and subarachnoid hemorrhage. The enrollment of patients in the study started January 1998 and stopped in January 2009. Detailed baseline data were abstracted prospectively by using paper-based registry forms and stored in the computer environment. Patients or their authorized proxies were contacted every year after stroke onset between 1999 and 2013. The study was approved by the ethics committee of the Ege University Medical Center, and written informed consent was obtained from all participants. The current analysis included all consecutive patients in our Stroke Registry who had been diagnosed with acute IS according to the World Health Organization criteria (14), and with confirmation by brain computed tomography (CT) or magnetic resonance Vol ••, •• 2014, ••–••
1
Research imaging (MRI). At least two senior neurologists from our stroke unit reviewed the clinical features and diagnostic test results, and then gave the subtype classifications. Vascular risk factors and lipid profiles Systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean arterial pressure, obesity, physical activity, current cigarette smoking, uric acid were recorded. A venous blood sample was collected after an overnight fast of eight-hours. Serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A (ApoA), apolipoprotein B (ApoB), lipoprotein (a) (Lp [a]), glucose, creatinine, and HbA1c levels in hemolysates were measured with commercial chemistry kits (Modular, Roche, Boehringer-Mannheim, Germany). Obesity was presumed if the waist circumference in men were ≥102·0 cm and in women ≥88·0 cm, and the body mass index (BMI) was ≥30 kg/m2. Hyperhomocysteinemia was considered if homocystein was >140 μg/dL in female and 7·2 mg/dL in men or >6·6 mg/dL in women. Hypertension (HT) was presumed when SBP was ≥140 mmHg or DBP was ≥90 mmHg on repeated measurements during the hospitalization or taking antihypertensive drugs. Diabetes mellitus was specified as fasting serum glucose ≥125 mg/dL, nonfasting serum glucose ≥200 mg/dL, or use of oral blood sugar-lowering drugs or insulin. Coronary heart disease (CHD) was registered in patients with history of myocardial infarction or angina pectoris. In our center, patients with DL were treated by a statin (atorvastatin, simvastatin, or rosuvastatin) to reach a ≥50% decrease in LDL-C from baseline. An LDL-C reduction ≥50% was used as an indicator of accurate statin use. Stroke subtypes Subtype classification of IS was based on patient’s clinical features combined with the results of one or more diagnostic tests, including brain imaging (CT and MRI), electrocardiogram (ECG), echocardiography (transesophageal or transthoracic), imaging of extracranial and intracranial arteries (carotid duplex, transcranial Doppler, CT angiography, magnetic resonance angiography, or digital subtraction angiography), and laboratory assessments for a prothrombotic state as defined by the TOAST classification (12). Large-artery disease (LAD) was presumed in patients having a stenosis of extracranial carotid artery or intracranial large arteries more than 50% with a stroke in the territory of stenosed artery. Clinical findings included cerebral cortical impairment (e.g., aphasia, neglect, apraxia, anopia, motor and/or sensory involvement) or brain stem or cerebellar dysfunction. Infarct areas were >1·5 cm in diameter on CT or MRI. Cardiac embolism (CE) included mainly nonvalvular atrial fibrillation, left ventricular akinetic segment, intracardiac thrombus or tumor, mitral stenosis, and other less common sources. Small-artery disease (SAD)
2
Vol ••, •• 2014, ••–••
E. Kumral et al. was defined in patients with infarcts of
