Published online before print March 5, 2009, doi: 10.1161/STROKEAHA.108.532473
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(Stroke. 2009;40:1729.)
© 2009 American Heart Association, Inc.
Original Contributions |
Prior Statin Use, Intracranial Hemorrhage, and Outcome After Intra-Arterial Thrombolysis for Acute Ischemic Stroke
From the Departments of Neurology (N.M., K.N., A.G., U.F., O.F., H.P.M., M.A.) and Neuroradiology (C.B., L.R., G.S.), Inselspital, University Hospital Bern and University of Bern, Bern, Switzerland.
Correspondence to Marcel Arnold, MD, Department of Neurology, Inselspital, University Hospital Bern and University of Bern, Freiburgstrasse 4, CH-3010 Bern, Switzerland. E-mail marcel.arnold{at}insel.ch
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Abstract |
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Background and Purpose— There are only limited data on whether prior statin use and/or cholesterol levels are associated with intracranial hemorrhage (ICH) and outcome after intra-arterial thrombolysis. The purpose of this study was to evaluate the association of statin pretreatment and cholesterol levels with the overall frequency of ICH, the frequency of symptomatic ICH, and clinical outcome at 3 months.
Methods— We analyzed 311 consecutive patients (mean age, 63 years; 43% women) who received intra-arterial thrombolysis.
Results— Statin pretreatment was present in 18%. The frequency of any ICH was 20.6% and of symptomatic ICH 4.8%. Patients with any ICH were more often taking statins (30% versus 15%, P=0.005), more often had atrial fibrillation (45% versus 30%, P=0.016), had more severe strokes (mean National Institute of Health Stroke Scale score 16.5 versus 14.7, P=0.022), and less often good collaterals (16% versus 24%, P=0.001). Patients with symptomatic ICH were more often taking statins (40% versus 15%, P=0.009) and had less often good collaterals (0% versus 24%, P<0.001). Any ICH or symptomatic ICH were not associated with cholesterol levels. After multivariate analysis, the frequency of any ICH remained independently associated with previous statin use (OR, 3.1; 95% CI, 1.53 to 6.39; P=0.004), atrial fibrillation (OR, 2.5; CI, 1.35 to 4.75; P=0.004), National Institutes of Health Stroke Scale score (OR, 1.1; CI, 1.00 to 1.10; P=0.037), and worse collaterals (OR, 1.7; CI, 1.19 to 2.42; P=0.004). There was no association of outcome with prior statin use, total cholesterol level, or low-density lipoprotein cholesterol level.
Conclusion— Prior statin use, but not cholesterol levels on admission, is associated with a higher frequency of any ICH after intra-arterial thrombolysis without impact on outcome.
Key Words: cerebral ischemia • cholesterol • hemorrhage • statins • thrombolysis
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Introduction |
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Local intra-arterial thrombolysis (IAT) is a well-established therapeutic option for the treatment of acute ischemic stroke. The most devastating complication of IAT is symptomatic intracranial hemorrhage (sICH), which is related to an adverse outcome.1–3 High serum glucose level2,4,5 and high National Institute of Health Stroke Scale (NIHSS) score2,5 on admission, time to recanalization,2 poor collaterals,6 urokinase dose,6 early ischemic signs on cranial CT,6 and a high-risk cardioembolic source2 have previously been shown to be associated with sICH after IAT.
Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are potent cholesterol-lowering drugs. They are widely used and have been shown to prevent both first-ever and recurrent ischemic strokes.7–9 On the other hand, the influence of statins and low cholesterol (especially low-density lipoprotein [LDL] cholesterol) levels on the incidence of primary intracranial hemorrhage (ICH) is still under debate. In a large meta-analysis with more than 90 000 patients treated with statins for primary and secondary stroke prevention, the frequency of brain hemorrhage was not increased.7 However, in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial in which high-dose atorvastatin for secondary stroke prevention was analyzed, a significant increase of brain hemorrhages in the treatment group was observed, whereas total and LDL cholesterol levels did not affect the risk of hemorrhagic stroke.8
There are only limited data on whether prior statin use and/or low cholesterol levels influence the incidence of sICH after thrombolysis for acute ischemic stroke. In a recent study analyzing 104 thrombolyzed patients (25% intravenously, 75% intra-arterially), low LDL cholesterol levels but not prior statin use were associated with a significantly higher incidence of sICH in multivariate analysis.10
The present study aims to evaluate the influence of statin pretreatment and cholesterol levels on admission on the incidence of overall and sICH in patients with acute ischemic stroke receiving IAT and on clinical outcome after 3 months.
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Methods |
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Patient Selection
We analyzed patients with acute ischemic stroke who underwent IAT in our stroke unit from January 2000 to April 2007. All data were collected prospectively. All procedures were in accordance with institutional guidelines. Some aspects of these patients have been reported previously.6,11,12
Patient Workup
We assessed medical history (history of coronary artery disease, atrial fibrillation, transient ischemic attack, or ischemic stroke), cardiovascular risk factors such as hypertension (defined by preadmission history and medical records), diabetes mellitus (preadmission history of diabetes, or fasting venous plasma glucose value 
7.0 mmol/L on at least 2 separate occasions and/or 11.1 mmol/L 2 hours after intake of 75 g of oral glucose and on one other occasion during the 2-hour test), current cigarette smoking, and current medication (statins, anticoagulants [vitamin K antagonists], or antiplatelet [acetylic salicylic acid or clopidogrel] drugs). Stroke severity on admission was graded by a neurologist using the NIHSS13 score. Nonfasting plasma triglyceride and cholesterol levels (total cholesterol and high-density lipoprotein [HDL] cholesterol) were measured immediately on admission. LDL cholesterol levels were calculated using the Friedewald formula.14 Missing data for total cholesterol, HDL cholesterol, and triglycerides were 1%, 6.7%, and 5.4%, respectively. LDL cholesterol was missing in 10.9%, 3.8% because of high triglyceride levels (>4.5 mmol/L), which are known to interfere with LDL cholesterol calculation.
Angiography and Thrombolysis
Inclusion criteria for IAT were: (1) clinical diagnosis of an acute stroke; (2) baseline NIHSS score of at least 4 points or isolated hemianopia or aphasia; (3) absence of hemorrhage on cranial CT or MRI; (4) cerebral digital subtraction angiography showing vessel occlusion correlating with the neurological deficit; (5) <6 hours from symptom onset to IAT, except in basilar artery occlusion where intervals up to 12 hours were permitted; (6) no individual clinical or laboratory findings contraindicating thrombolysis; (7) for patients aged >75 years, general condition before stroke not advising against it; and (8) informed consent from patient or family available. Time from symptom onset to thrombolysis and duration of thrombolysis, method of thrombolysis (intra-arterial fibrinolytic therapy with urokinase [Urokinase HS Medac, Wedel, Germany] with or without mechanical recanalization techniques, including clot retrieval, angioplasty or stenting), and urokinase dose were analyzed. The quality of collaterals was classified by an interventional neuroradiologist as reported previously.11,12 The degree of vessel recanalization was quantified according to the Thrombolysis in Myocardial Infarction classification15 and was dichotomized into poor (Thrombolysis in Myocardial Infarction 0 to 1) and good (Thrombolysis in Myocardial Infarction 2 to 3). According to our institutional guidelines, periprocedure medication was administered as follows: 250 to 500 mg of acetylic salicylic acid was given to all patients immediately after thrombolysis. We did not use either anticoagulation with heparin during the first 24 hours or the combination of acetylic salicylic acid with clopidogrel for the first 48 hours. Statin treatment of patients on statins before thrombolysis was continued. In patients with atherothrombotic stroke, statin treatment was started after 3 to 7 days.
Stroke Subtype Classification
Stroke subtype was classified according to the Trial of ORG 10172 in Acute Stroke Therapy criteria.16
Identification and Classification of Intracranial Hemorrhage
Cranial MRI or CT was performed routinely within 24 hours after thrombolysis or with any clinical deterioration. Overall frequency of ICH, defined as the appearance of any intracranial blood, was assessed. ICH was classified as "symptomatic" if a parenchymal hematoma Type 2 (according to the European–Australasian Acute Stroke Study criteria17) was accompanied by a 4-point increase in the NIHSS score or leading to death.18
Patient Follow-Up
Outcome was assessed using the modified Rankin Scale (mRS)19 3 months after IAT by clinical examination in 208 patients (66.9%). One hundred three patients (33.1%) who were not able to return for a follow-up visit were contacted by telephone by a neurologist or a trained nurse after a standardized questionnaire to determine their mRS score. A favorable outcome was defined as a mRS score 
2 and an unfavorable outcome as a mRS score 3. Additional analyses were performed with mRS score 1 defined as an excellent outcome and a mRS score 2 as a nonexcellent outcome.
Statistical Analysis
SPSS version 13.0 (SPSS Inc, Chicago, Ill) for Macintosh was used. Patients were grouped as follows: previous statin use versus no previous statin use. For differences in categorical variables, 
2 tests were performed. Continuous variables were compared with the Mann–Whitney test and Student t test. The following variables were analyzed: age, sex, hypertension, diabetes, current smoking, coronary artery disease, atrial fibrillation, previous transient ischemic attack, previous ischemic stroke, previous use of antiplatelets, previous use of anticoagulants, cholesterol levels, NIHSS score on admission, site of occlusion, time to and duration of thrombolysis, urokinase dose, use of mechanical recanalization techniques, quality of collaterals, degree of recanalization, stroke etiology, frequencies of any ICH and sICH, favorable outcome at 3 months, and death at 3 months. To determine an independent association between previous statin use and other variables, including any ICH, sICH, and outcome, logistic regression analysis by a forward stepwise method was performed including all variables with probability values 0.2 in univariate analysis.
To determine predictors of any ICH, we grouped the patients with any ICH and compared them with the group of patients without ICH. All previously mentioned variables were analyzed. To determine an independent association between any ICH and other variables, logistic regression analysis by a forward stepwise method was performed including all variables with probability values 0.2 in univariate analysis.
To determine predictors of sICH, the previously mentioned variables were compared between patients with sICH and those without ICH using univariate analysis. Due to the low number of patients with sICH, no multivariate analysis was performed. In all analyses, 2-sided probability values <0.05 were considered statistically significant.
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Results |
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We analyzed 311 patients (99.4% whites, 0.6% Asians). Mean age was 62.9 years (range, 17.5 to 87.2 years) and 56.6% were men. Fifty-five patients (17.7%) were treated with statins before their stroke. The statins used were: atorvastatin 36.4% (n=20, mean daily dose 23 mg), pravastatin 36.4% (n=20, mean daily dose 27 mg), simvastatin 21.8% (n=12, mean daily dose 30 mg), fluvastatin 1.8% (n=1, daily dose 80 mg), and unknown statin 3.6% (n=2). Table 1 summarizes data of patients with statin pretreatment and those without statin pretreatment. Patients receiving statins were older (67.3 versus 61.9 years, P=0.015), had more frequently a history of hypertension (92.6% versus 56.5%, P<0.001) and previous transient ischemic attacks (25.5% versus 8.6%, P<0.001), and more often had coronary artery disease (60.0% versus 36.7%, P=0.001). Antiplatelet agents (acetylic salicylic acid or clopidogrel) before stroke were present in 65.5% of patients on statin treatment (n=36) and in 16.0% of patients without prior statin treatment (n=41; P<0.001). Anticoagulation was present in 7.3% of patients on statin treatment (n=4) and in 6.3% of patients without previous statin treatment (n=16; P=0.779). No significant differences between statin-treated and untreated patients were found with regard to sex, diabetes, current smoking, atrial fibrillation, previous stroke, stroke severity on admission, stroke etiology, location of obstructed vessel, time to thrombolysis and duration of thrombolysis, use of mechanical recanalization techniques, urokinase dose, degree of recanalization, and collaterals.
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LDL and HDL cholesterol levels were significantly lower in the statin group (2.81 mmol/L versus 3.11mmol/L, P=0.02; and 1.29 mmol/L versus 1.41mmol/L, P=0.037, respectively), whereas triglyceride levels were significantly higher (2.30 mmol/L versus 1.64 mmol/L, P=0.001). Total cholesterol levels did not differ between the groups.
IAT with urokinase only was used in 77.2% and the combination of urokinase and mechanical recanalization in 22.8% of all patients. Mechanical recanalization techniques were used in 18.2% of patients on statin treatment (n=10) and in 23.8% (n=61) of patients not treated with statins.
Sixty-four patients (20.6%) had an ICH, of which 15 (4.8%) were symptomatic. In univariate analysis, the overall frequency of ICH was higher in patients with statin therapy before their stroke compared with those without (34.5% versus 17.6%, P=0.005) as was the frequency of sICH (10.9% versus 3.5%, P=0.02). Clinical outcome after 3 months did not differ significantly between the statin and nonstatin groups. There was no association between total cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels and the overall frequency of ICH or the frequency of sICH (probability values 0.42/0.75, 0.22/0.71, 0.13/0.17, and 0.96/0.79, respectively).
After multivariate regression analysis, previous statin use remained independently associated with the overall frequency of ICH (OR, 2.7; 95% CI, 1.16 to 6.44; P=0.021), with a history of hypertension (OR, 6.9; CI, 1.95 to 24.20; P=0.003), and with previous use of antiplatelets (OR, 9.5; CI, 4.22 to 21.44; P<0.001; Tables 1 and 2
). Prior statin use, total cholesterol levels, and LDL cholesterol levels were not independently associated with the clinical outcome at 3 months (probability values 0.15, 0.912, and 0.744, respectively).
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Table 3 shows demographics, clinical and radiological data, and outcome of patients with any kind of ICH compared with those without ICH. Patients with an ICH were more often statin users (29.7% versus 14.6%, P=0.005) and had more often a history of atrial fibrillation (45.3% versus 29.6%, P=0.016). Their strokes were more severe with higher NIHSS scores on admission, and the collaterals were significantly worse. After multivariate analysis, the frequency of any ICH remained independently associated with previous statin use (OR, 3.1; CI, 1.53 to 6.39; P=0.004), atrial fibrillation (OR, 2.5; CI, 1.35 to 4.75; P=0.004), NIHSS score (OR, 1.1; CI, 1.00 to 1.10; P=0.037), and worse collaterals (OR, 1.7; CI, 1.19 to 2.42; P=0.004). Patients with an ICH had a significantly worse outcome with a lower frequency of a Rankin score 2 (28.3% versus 53.7%, P<0.001), a lower frequency of a Rankin score 1 (10.0% versus 32.1%, P<0.001), and a higher mortality (48.3% versus 15.4%, P<0.001).
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Table 4 summarizes demographics, clinical and radiological data, and outcome of patients with a sICH compared with those without ICH. Patients with a sICH were more often statin users (40.0% versus 14.6%, P=0.009). Their collaterals were significantly worse. There was a trend toward a higher frequency in smokers and antiplatelet users and toward higher NIHSS scores on admission. Patients with a sICH had a significantly worse outcome with a lower frequency of a Rankin score 2 (0% versus 53.7%, P<0.001), a lower frequency of a Rankin score 1 (0% versus 32.1%, P=0.009), and a higher mortality (80.0% versus 15.4%, P<0.001).
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Mortality rate in the statin group was 31.5% (n=17). Causes of death were: brain edema, 41.2% (n=7); sICH, 35.3% (n=6); pneumonia, 11.8% (n=2); recurrent stroke with brain edema, 5.9% (n=1); and unknown cause, 5.9% (n=1). Mortality rate of patients not pretreated with statins was 19.8% (n=50), which was not significantly different from the statin group (P=0.063). Causes of death were: brain edema, 46% (n=23); sICH, 12% (n=6); pneumonia, 16% (n=8); cardiac arrest, 4% (n=2); different causes, 6% (pulmonary embolism, n=1; malignancy, n=1; diabetic coma, n=1); and unknown cause, 16% (n=8).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we evaluated the influence of statin pretreatment and cholesterol levels on the incidence of ICH in patients receiving IAT with urokinase for acute ischemic stroke. The main finding is an independent association between statin pretreatment and the frequency of any ICH. However, statin pretreatment did not significantly influence the clinical outcome. Triglyceride and cholesterol levels on admission were not associated with bleeding. The fact that both hypertension and previous use of antiplatelets were independently associated with previous statin use might be partially explained by the fact that patients with cardiovascular risk factors are more likely to have cholesterol levels measured and are generally treated earlier and more aggressively.
Our findings are in contrast to previous reports. Bang et al analyzed 104 patients receiving intravenous or IAT with tissue-type plasminogen activator (tPA), including mechanical recanalization.10 In their study, lower LDL cholesterol levels on admission but not prior statin use were found to be independently associated with sICH. Clinical outcomes were not reported. Alvarez-Sabin et al analyzed 145 patients with middle cerebral artery infarctions who were treated with intravenous thrombolysis using tPA; prior statin treatment was an independent predictor of a favorable clinical outcome (mRS 2) after 3 months without an increased frequency of ICH20; cholesterol levels were not associated with ICH.21 The differences between those studies and our results cannot be fully explained. Apart from differences in patient selection, time to treatment, or treatment modalities (eg, additional mechanical recanalization), it is unknown whether and how different thrombolytic agents (urokinase versus tPA) and different ways of drug administration (systemically versus locally) may influence bleeding risk in patients with acute stroke on statins. Furthermore, the sample size of some studies was rather small.
Previous studies have shown that the benefit of statin treatment in ischemic stroke prevention exceeds what could be expected from cholesterol-lowering alone.22 Additional to and independent of their lipid-lowering ability, statins have pleiotropic effects.23,24 Several studies have shown antithrombotic activity.25–30 An increased local fibrinolytic activity has been shown in rats for different statins in different tissues by increase of both tPA and urokinase and a decrease of plasminogen activator inhibitor-1 activities.31–33 Different studies showed an increased activity of the fibrinolytic system also in humans as measured by tPA and plasminogen activator inhibitor-1 levels in the peripheral blood34–36 and cultured mesothelial cells.37,38 In patients with coronary artery disease receiving statins, an increase in susceptibility of blood clots to fibrinolytics has been shown under ex vivo conditions.39 Given the fact that cholesterol levels were not associated with ICH in our study, it might be possible that the pleiotropic effects of statins could be involved in the pathogenesis of bleeding after IAT in patients with prethrombolysis statin treatment.
Nevertheless, the benefit of statin treatment for primary and secondary ischemic stroke prevention has been proven in different studies,7–9,40 and several studies have shown that patients pretreated with statins have a favorable short-term41–43 and long-term44,45 outcome after ischemic stroke without thrombolytic treatment. In our study, statin pretreatment was not associated with an unfavorable clinical outcome after 3 months. The lack of a significant association between statin pretreatment and a poorer clinical outcome may be explained by the small sample size of symptomatic ICH. Furthermore, some beneficial pleiotropic effects of statin pretreatment such as antiinflammatory effects may play a role. Therefore, we believe that statin pretreatment should not influence patient selection for thrombolytic therapy. In addition, recent publications have shown that statin treatment discontinuation in the early phase of acute ischemic stroke may lead to an adverse outcome.46,47 Thus, we recommend not to withdraw statin treatment after thrombolysis.
Besides previous statin use, several other factors could be identified as being independently associated with the appearance of any ICH; atrial fibrillation, higher baseline NIHSS score, or bad collaterals are known risk factors for ICH.2,6 The fact that mechanical recanalization techniques were independently associated with any ICH might be explained by patient selection because mechanical recanalization techniques were mainly used in patients without successful recanalization after administration of intra-arterial urokinase.
Matrix-metalloproteinases (MMP), especially MMP-9, may be involved in the pathogenesis of ICH. Both tPA and urokinase can activate MMP-9 in vitro.48 It has been shown that MMP-9 baseline levels predict the appearance of ICH after tPA treatment,49 and that tPA can activate MMP-9.50 Simvastatin reduces tPA-induced upregulation of MMP-9 expression in rat cortical astrocytes in vitro.51 From one possible pathophysiological point of view, this finding stands in contrast to our findings and emphasizes the need for further research in that field.
The main limitations of the present study are its observational character, the nonblinded follow-up, and the small sample size of sICH. Furthermore, other potential risk factors for ICH such as blood glucose level, blood pressure, platelet count, or early signs of ischemia in brain imaging have not prospectively and systematically been analyzed. In addition, the increased risk of ICH in patients with statin pretreatment may be the result of those patients being sicker and therefore more prone to bleeding compared with patients without statin pretreatment. Another limitation and a potential source of discrepancy with other reports might be the fact that lipid panels were analyzed in a nonfasting state, yet cholesterol and triglyceride levels have been shown to remain stable within the first 48 hours after cerebrovascular events.52,53 At last, compliance with statin treatment could not directly be controlled but was based on information given by the patients or their proxies. Nevertheless, to our knowledge, this is the largest study analyzing the association of statin pretreatment and ICH after IAT for acute ischemic stroke.
In conclusion, statin use before the ischemic stroke, but not cholesterol levels on admission, are associated with a higher frequency of any ICH after IAT with urokinase for acute ischemic stroke. Further research is needed to confirm these results and to elucidate potential pathomechanisms of this association.
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Acknowledgments |
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We thank Pietro Ballinari, PhD, for statistical advice, Fred Buerki, MS, for his help with data acquisition, and Andros Tofield, MD, for his help with the manuscript.
Disclosures
H.P.M. has received research and educational grants and consulting and speaker’s honoraria from AGA Medical, AstraZeneca, Bayer Schering, Biogen Idec, Merck-Serono, GlaxoSmithKline, Pfizer, Merck Sharp & Dohme-Chibret, Sanofi-Aventis, Servier, Bristol Myers Squibb, Janssen-Cilag, and Novartis. M.A. has received speaker’s honoraria from AstraZeneca, Bayer Schering, and Sanofi-Aventis and a research grant from AstraZeneca.
Received July 23, 2008; revision received October 1, 2008; accepted October 24, 2008.
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