Research Statin treatment in patients with acute ischemic stroke Mohamed Al-Khaled1*, Christine Matthis2, and Jürgen Eggers1 Background and purpose We aimed to investigate the association of statin treatment with outcomes in patients with acute ischemic stroke. Methods Over a 4.5-year period (starting November 2007), 12 781 patients (mean age, 72·8 ± 12·6 years; 48·6% women) with acute ischemic stroke from 15 hospitals in SchleswigHolstein, Germany, were enrolled in a population-based study and prospectively evaluated. The primary outcomes were the mortality during hospitalization and the disability (modified Rankin Scale score ≥2) at discharge from hospital. The secondary outcomes were the mortality and disability at three-months after discharge. Results A total of 7535 patients (59%) with acute ischemic stroke were treated with statins. During hospitalization (mean, nine-days), the in-hospital mortality rate (4·7%; 95% confidence interval, 4·3–5·1%) was lower in patients treated with statins than in those without statins (2·3% vs. 7·9%, respectively; P < 0·001). At three-months after discharge, the mortality rate (6·9%; 95% confidence interval, 6·4–7·5%) was lower in patients treated with statins than in those without statins (5·0% vs. 10·6%, respectively; P < 0·001). Adjusted logistic regression analysis showed that statin treatment was associated with reduced rates of in-hospital mortality (odds ratio, 0·39; 95% confidence interval, 0·31–0·48; P < 0·001) and three-month mortality (odds ratio, 0.47; 95% confidence interval, 0·34–0·63; P < 0·001). A comparison of the patient groups revealed that patients on statins were likely to have lower disability rates at discharge (59% vs. 67%, respectively; P < 0·001) and after three-months (33% vs. 42%, respectively; P < 0·001) in patients who had survived the stroke. Conclusion Statin treatment may improve the outcomes in patients with acute ischemic stroke. Further studies are necessary to confirm this finding. Key words: stroke, statin, mortality, disability, plaques, hypercholesterolemia
Introduction Stroke-related death and disability will rise as a consequence of an increase in stroke incidence. The occurrence of stroke has severe consequences for patients, their family members, and society. These consequences include the loss of patient independence, higher costs of care, and loss of individual productivity (1). The rates of stroke occurrence and stroke death depend on ethnicity, gender, and income status of countries (2,3). To date, recombiCorrespondence: Mohamed Al-Khaled*, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23538, Germany. E-mail: [email protected] 1 Department of Neurology, University of Lübeck, Lübeck, Germany 2 Institute of Social Medicine, University of Lübeck, Lübeck, Germany Received: 6 May 2013; Accepted: 16 December 2013; Published online 4 March 2014 Conflict of interest: None declared. Funding: The study (QugSS2) was funded by the Bundesministerium für Gesundheit und Soziale Sicherung (BMGS-AZ 217-43794-6/7). DOI: 10.1111/ijs.12256 © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
nant tissue-plasminogen activator is the only approved medical therapy for acute ischemic stroke (AIS) that improves patient outcomes (4). Other medical options for treating ischemic stroke are not available for clinical daily use. Clinical studies have shown that the administration of cholesterol-lowering 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevents stroke and cardiovascular events in individuals (5–7). Research has also suggested that pretreatment with statins may reduce in-hospital mortality in patients suffering from AIS (8). Other randomized studies investigating the impact of statins have revealed their beneficial effects on stroke and total mortality, most notably a decrease in cerebrovascular disease mortality (9). In addition, research has revealed that the administration of statin immediately after stroke (≤72 h) may improve stroke outcomes (10). Therefore, international guidelines recommend that patients suffering from AIS should be treated with statins for secondary prevention that may be due to pleiotropic effects and low-density lipoprotein-lowering effects (11). We decided to investigate the association between the statin treatment and the stroke outcomes in patients suffering from AIS.
Methods Study population The Quality Association for Acute Stroke Treatment in SchleswigHolstein (QugSS2) is an ongoing population-based cohort study on stroke in Schleswig-Holstein, a German state with 2·8 million inhabitants. The QugSS2 study, which began in 2007, includes all hospitals involved in treating patients with cerebrovascular diseases. The 15 sites involved in the present study included two university departments of neurology, eight departments of neurology at nonuniversity hospitals, and five departments of internal medicine at nonuniversity hospitals. Approval for the study was obtained from the local ethics committee of the University of Lübeck. The inclusion in the stroke registry is part of the quality assessment program for stroke treatment in Schleswig-Holstein. The entry in the stroke registry is obligatory. A written consent form was required for the inclusion in the three-month follow-up questionnaire. The primary outcomes were in-hospital mortality and disability [defined here as a modified Rankin Scale (mRS) score ≥2] at discharge from hospitals. The secondary outcomes were the mortality and disability at three-months after discharge. During hospitalization, the occurrence of a recurrent stroke and symptomatic intracerebral hemorrhage were included in the secondary outcomes. The symptomatic intracerebral hemorrhage was defined as bleeding that was detected by computed tomography scan that was not seen on initial investigation and was associated with clinical worsening [National Institutes of Health Stroke Scale (NIHSS) ≥ 4 points]. Vol 9, July 2014, 597–601
597
Research The three-month mortality did not include the in-hospital mortality, and mRS equal to 6 (death) was not included in the disability at discharge and at three-months later. Hypercholesterolemia (HCH) was diagnosed when the value of the fasting cholesterol was greater than 200 mg/dl at the time of the acute stroke in patients who were newly diagnosed with HCH. In addition, prior records and historical data about the presence of HCH were taken into during the diagnostic evaluation of HCH. The statin treatment was performed during the hospitalization after admission in patients with AIS who were not treated with statin before. In accordance to the protocol of QugSS2, the statin treatment should be performed after the value of fasting cholesterol was measured, ideally within 24 h of admission in stroke patients with newly diagnosed HCH. Statin treatment was also initiated as a secondary prophylaxis in stroke patients with evidence of stenosis of brain-supplying arteries and in patients with microangiopatic stroke. Furthermore, statin treatment was administrated for plaque stabilization in patients with AIS when plaques were seen in the carotid bifurcation using the duplex sonography. The treating physician or neurologist determined the indication for statin treatment. Data acquisition From November 2007 through March 2012, all patients suffering from AIS who are over the age of 18 years and reside in SchleswigHolstein (one of the 16 States in Germany) are entered into the stroke registry (QugSS2). The inclusion criteria for patients in the present population-based study were a diagnosis of AIS (characterized in accordance with the definition put forth by the World Health Organization), main residence in Schleswig-Holstein, and admission to hospital. The exclusion criteria for patients were age under 18 years and a diagnosis of intracerebral hemorrhage, transient ischemic attack, or subarachnoid hemorrhage. The follow-up evaluation was three-months after discharge. Patients were questioned by letter and/or telephone interview. When patients did not respond to the letter and could not be contacted, we evaluated the mortality at three-months after discharge by making an online request to the registration office of the German federal state of Schleswig-Holstein. If patients changed their address during the follow-up period of threemonths after discharge, were no longer residing in the state of Schleswig-Holstein, and could not be contacted by telephone, they were considered lost to follow-up. Statistical analysis Data were analyzed with Statistical Product and Service Solutions software (version 20; IBM SPSS Statistics, Armonk, NY, USA). Data were described with mean and standard deviation (SD) values for continuous variables, absolute numbers and percentages for categorical variables, and median and interquartile range (IQR) values for ordinal variables. A chi-square test to determine the correlation between categorical variables, a t-test to compare continuous variables, and a Mann–Whitney U-test to compare ordinal variables were performed. Adjusted logistic regression analysis was carried out to estimate the odds ratio (OR). All variables of clinical parameters that were associated with out-
598
Vol 9, July 2014, 597–601
M. Al-Khaled et al. comes (mortality and disability) with P less than 0·1 were entered into the logistic regression model (Tables 2 and 3). A P value of less than 0.05 was considered significant.
Results A total of 12 781 patients (mean age, 72·8 ± 12·6 years; 48·6% women; median NIHSS score, 4 [IQR: 2–9]) were diagnosed with AIS and entered into the stroke registry for the German federal state of Schleswig-Holstein. All patients were investigated over a period of 4·5 years (starting November 2007 through March 2012) in a population-based study. The frequencies of brain imaging investigations were 95% by cranial computed tomography scan and 53·4% by magnetic resonance imaging. Medical treatment with statin drugs was administered to 7535 patients (59%) before hospital admission and/or early after stroke during hospitalization. A comparison between patients treated with statins and those not treated with statins is shown in Table 1. Of 12 781 patients, 596 [4·7%; 95% confidence interval (CI), 4·2–5·1%] died during a mean hospital stay of nine-days (SD, 5·5) Table 1 Baseline characteristics and comparison between patients with statins vs. without statins Statin treatment
Baseline characteristics Age, mean (SD) Female sex Median NIHSS score (IQR) Hypertension Diabetes mellitus Hypercholesterolemia Previous stroke Atrial fibrillation AT before stroke Stroke etiology (TOAST) Large-artery atherosclerosis Cardioembolism Small-artery occlusion (lacunar) Other determined etiology Undetermined etiology Therapy with rt-PA OAC CEA/ Stenting Antihypertensive drugs Antidiabetic drugs Mortality (case fatality) during hospitalization Disability at discharge Secondary hemorrhagic stroke Ischemic stroke recurrence Mean duration of hospitalization (SD)
No (n = 5012)
Yes (n = 7535)
73·2 (14) 2635 (53) 5 (2–12) 3797 (77) 1006 (21) 673 (14) 1249 (25) 1874 (38) 1813 (37)
72·6 (11) 3451 (46) 4 (2–7) 6601 (89) 2152 (29) 5965 (82) 2300 (31) 1959 (27) 3424 (47)
749 (15) 2191 (44) 780 (16) 175 (4) 1077 (22) 512 (10) 1678 (34) 141 (3·2) 3605 (72) 811 (16) 394 (7·9)
1952 (26) 2291 (31) 1753 (23) 187 (3) 1305 (17) 675 (9) 1910 (26) 295 (4·5) 6641 (88) 1985 (27) 175 (2.3)
0·014
Introduction Stroke-related death and disability will rise as a consequence of an increase in stroke incidence. The occurrence of stroke has severe consequences for patients, their family members, and society. These consequences include the loss of patient independence, higher costs of care, and loss of individual productivity (1). The rates of stroke occurrence and stroke death depend on ethnicity, gender, and income status of countries (2,3). To date, recombiCorrespondence: Mohamed Al-Khaled*, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, Lübeck, 23538, Germany. E-mail: [email protected] 1 Department of Neurology, University of Lübeck, Lübeck, Germany 2 Institute of Social Medicine, University of Lübeck, Lübeck, Germany Received: 6 May 2013; Accepted: 16 December 2013; Published online 4 March 2014 Conflict of interest: None declared. Funding: The study (QugSS2) was funded by the Bundesministerium für Gesundheit und Soziale Sicherung (BMGS-AZ 217-43794-6/7). DOI: 10.1111/ijs.12256 © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
nant tissue-plasminogen activator is the only approved medical therapy for acute ischemic stroke (AIS) that improves patient outcomes (4). Other medical options for treating ischemic stroke are not available for clinical daily use. Clinical studies have shown that the administration of cholesterol-lowering 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevents stroke and cardiovascular events in individuals (5–7). Research has also suggested that pretreatment with statins may reduce in-hospital mortality in patients suffering from AIS (8). Other randomized studies investigating the impact of statins have revealed their beneficial effects on stroke and total mortality, most notably a decrease in cerebrovascular disease mortality (9). In addition, research has revealed that the administration of statin immediately after stroke (≤72 h) may improve stroke outcomes (10). Therefore, international guidelines recommend that patients suffering from AIS should be treated with statins for secondary prevention that may be due to pleiotropic effects and low-density lipoprotein-lowering effects (11). We decided to investigate the association between the statin treatment and the stroke outcomes in patients suffering from AIS.
Methods Study population The Quality Association for Acute Stroke Treatment in SchleswigHolstein (QugSS2) is an ongoing population-based cohort study on stroke in Schleswig-Holstein, a German state with 2·8 million inhabitants. The QugSS2 study, which began in 2007, includes all hospitals involved in treating patients with cerebrovascular diseases. The 15 sites involved in the present study included two university departments of neurology, eight departments of neurology at nonuniversity hospitals, and five departments of internal medicine at nonuniversity hospitals. Approval for the study was obtained from the local ethics committee of the University of Lübeck. The inclusion in the stroke registry is part of the quality assessment program for stroke treatment in Schleswig-Holstein. The entry in the stroke registry is obligatory. A written consent form was required for the inclusion in the three-month follow-up questionnaire. The primary outcomes were in-hospital mortality and disability [defined here as a modified Rankin Scale (mRS) score ≥2] at discharge from hospitals. The secondary outcomes were the mortality and disability at three-months after discharge. During hospitalization, the occurrence of a recurrent stroke and symptomatic intracerebral hemorrhage were included in the secondary outcomes. The symptomatic intracerebral hemorrhage was defined as bleeding that was detected by computed tomography scan that was not seen on initial investigation and was associated with clinical worsening [National Institutes of Health Stroke Scale (NIHSS) ≥ 4 points]. Vol 9, July 2014, 597–601
597
Research The three-month mortality did not include the in-hospital mortality, and mRS equal to 6 (death) was not included in the disability at discharge and at three-months later. Hypercholesterolemia (HCH) was diagnosed when the value of the fasting cholesterol was greater than 200 mg/dl at the time of the acute stroke in patients who were newly diagnosed with HCH. In addition, prior records and historical data about the presence of HCH were taken into during the diagnostic evaluation of HCH. The statin treatment was performed during the hospitalization after admission in patients with AIS who were not treated with statin before. In accordance to the protocol of QugSS2, the statin treatment should be performed after the value of fasting cholesterol was measured, ideally within 24 h of admission in stroke patients with newly diagnosed HCH. Statin treatment was also initiated as a secondary prophylaxis in stroke patients with evidence of stenosis of brain-supplying arteries and in patients with microangiopatic stroke. Furthermore, statin treatment was administrated for plaque stabilization in patients with AIS when plaques were seen in the carotid bifurcation using the duplex sonography. The treating physician or neurologist determined the indication for statin treatment. Data acquisition From November 2007 through March 2012, all patients suffering from AIS who are over the age of 18 years and reside in SchleswigHolstein (one of the 16 States in Germany) are entered into the stroke registry (QugSS2). The inclusion criteria for patients in the present population-based study were a diagnosis of AIS (characterized in accordance with the definition put forth by the World Health Organization), main residence in Schleswig-Holstein, and admission to hospital. The exclusion criteria for patients were age under 18 years and a diagnosis of intracerebral hemorrhage, transient ischemic attack, or subarachnoid hemorrhage. The follow-up evaluation was three-months after discharge. Patients were questioned by letter and/or telephone interview. When patients did not respond to the letter and could not be contacted, we evaluated the mortality at three-months after discharge by making an online request to the registration office of the German federal state of Schleswig-Holstein. If patients changed their address during the follow-up period of threemonths after discharge, were no longer residing in the state of Schleswig-Holstein, and could not be contacted by telephone, they were considered lost to follow-up. Statistical analysis Data were analyzed with Statistical Product and Service Solutions software (version 20; IBM SPSS Statistics, Armonk, NY, USA). Data were described with mean and standard deviation (SD) values for continuous variables, absolute numbers and percentages for categorical variables, and median and interquartile range (IQR) values for ordinal variables. A chi-square test to determine the correlation between categorical variables, a t-test to compare continuous variables, and a Mann–Whitney U-test to compare ordinal variables were performed. Adjusted logistic regression analysis was carried out to estimate the odds ratio (OR). All variables of clinical parameters that were associated with out-
598
Vol 9, July 2014, 597–601
M. Al-Khaled et al. comes (mortality and disability) with P less than 0·1 were entered into the logistic regression model (Tables 2 and 3). A P value of less than 0.05 was considered significant.
Results A total of 12 781 patients (mean age, 72·8 ± 12·6 years; 48·6% women; median NIHSS score, 4 [IQR: 2–9]) were diagnosed with AIS and entered into the stroke registry for the German federal state of Schleswig-Holstein. All patients were investigated over a period of 4·5 years (starting November 2007 through March 2012) in a population-based study. The frequencies of brain imaging investigations were 95% by cranial computed tomography scan and 53·4% by magnetic resonance imaging. Medical treatment with statin drugs was administered to 7535 patients (59%) before hospital admission and/or early after stroke during hospitalization. A comparison between patients treated with statins and those not treated with statins is shown in Table 1. Of 12 781 patients, 596 [4·7%; 95% confidence interval (CI), 4·2–5·1%] died during a mean hospital stay of nine-days (SD, 5·5) Table 1 Baseline characteristics and comparison between patients with statins vs. without statins Statin treatment
Baseline characteristics Age, mean (SD) Female sex Median NIHSS score (IQR) Hypertension Diabetes mellitus Hypercholesterolemia Previous stroke Atrial fibrillation AT before stroke Stroke etiology (TOAST) Large-artery atherosclerosis Cardioembolism Small-artery occlusion (lacunar) Other determined etiology Undetermined etiology Therapy with rt-PA OAC CEA/ Stenting Antihypertensive drugs Antidiabetic drugs Mortality (case fatality) during hospitalization Disability at discharge Secondary hemorrhagic stroke Ischemic stroke recurrence Mean duration of hospitalization (SD)
No (n = 5012)
Yes (n = 7535)
73·2 (14) 2635 (53) 5 (2–12) 3797 (77) 1006 (21) 673 (14) 1249 (25) 1874 (38) 1813 (37)
72·6 (11) 3451 (46) 4 (2–7) 6601 (89) 2152 (29) 5965 (82) 2300 (31) 1959 (27) 3424 (47)
749 (15) 2191 (44) 780 (16) 175 (4) 1077 (22) 512 (10) 1678 (34) 141 (3·2) 3605 (72) 811 (16) 394 (7·9)
1952 (26) 2291 (31) 1753 (23) 187 (3) 1305 (17) 675 (9) 1910 (26) 295 (4·5) 6641 (88) 1985 (27) 175 (2.3)
0·014
