Intravenous Thrombolysis with Recombinant Tissue-type Plasminogen Activator for Acute Ischemic Stroke in Patients with Metabolic Syndrome Piotr Sobolewski, MD, PhD,* Waldemar Brola, MD, PhD,† Wiktor Szczuchniak, MD,* Ma1gorzata Fudala, MD, PhD,† and Grzegorz Kozera, MD, PhD‡
Background: The metabolic syndrome (MetS) is common in patients with acute ischemic stroke (IS); however, its impact on outcome after intravenous thrombolysis (iv-thrombolysis) remains unclear. Thus, we aimed at evaluating the relationship between MetS and functional long-term outcome, mortality, and the presence of hemorrhagic complications in patients with IS treated with iv-thrombolysis. Methods: We retrospectively evaluated the demographic and clinical data of 535 Caucasian patients with acute IS who were consecutively treated with iv-thrombolysis from September 2006 to June 2013 in 2 experienced stroke centers in Poland. A favorable functional long-term outcome was defined as a modified Rankin scale score less than or equal to 2 points on day 90, and hemorrhagic complications were assessed with European Cooperative Acute Stroke Study criteria. Results: MetS was recognized in 192 (35.9%) patients (44.8% men; mean age, 70.8 6 11.1 years), diabetes in 29.7%, dyslipidemia in 79.2%, and arterial hypertension in 75.5%. At 3 months, favorable outcome was found in 55.3% of patients, symptomatic intracerebral hemorrhage (SICH) in 18.3%, and 4.4 % of patients died. There was no difference regarding the presence of favorable outcome between patients with and without MetS (52.6% versus 56.9%, P 5 .34). The presence of SICH and 3-month mortality were more frequent in patients with MetS than without MetS (6.8% versus 2.9%, P 5 .03 and 23.4% versus 15.5%, P 5 .02, respectively); however, a multivariate analysis showed no impact of MetS on mortality or SICH. Conclusions: Results of our study provide no data to suggest that the effect of intravenous tissue-type plasminogen activator differs based on the presence or absence of MetS. Key Words: Metabolic syndrome—acute ischemic stroke—rt-PA— intravenous thrombolysis. Ó 2015 by National Stroke Association
From the *Department of Neurology and Stroke Unit of Holy Spirit Specialist Hospital in Sandomierz, Sandomierz; †Department of Neurology and Stroke Unit of Saint Luke’s Hospital in Ko nskie, Ko nskie; and ‡Department of Neurology, Medical University of Gda nsk, Gda nsk, Poland. Received October 4, 2014; revision received March 30, 2015; accepted April 1, 2015. P.S. contributed to the study design, patient selection, clinical work, data collection, analysis, interpretation, and writing of the manuscript. W.B. contributed to the study design, patient selection, clinical work, data collection, analysis, and interpretation. W.S. contributed to patient selection, clinical work, data collection, statistical analysis,
and interpretation. M.F. contributed to patient selection, clinical work, data collection, analysis, and interpretation; G.K. contributed to data analysis, interpretation, and the rewriting of the manuscript. No potential conflict of interests relevant to this article were reported. Address correspondence to Piotr Sobolewski, MD, PhD, Department of Neurology and Stroke Unit of Holy Spirit Specialist Hospital in Sandomierz, 13 Schinzla Str., 27-600 Sandomierz, Poland. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.001
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Introduction Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that is highly prevalent in the adult population of developed countries and significantly increases the risk of cardiovascular events and all-cause mortality.1-4 An increased risk of ischemic stroke (IS) associated with MetS mainly derives from its high potential to enhance the early development and further progress of atherosclerosis in brain-supplying arteries and to defect endogenous fibrinolysis.5-9 Consequently, MetS is more common in IS patients than in the general population and significantly predicts a poor outcome after IS.10-12 Numerous proatherothrombotic effects of MetS on endogenous fibrinolysis and the vascular endothelium may also contribute to a higher resistance to thrombolytic interventions in patients with IS. Patients with MetS show impaired response after thrombolytic therapy for acute myocardial infarction and a higher incidence of major adverse cardiac events after percutaneous coronary intervention.13,14 However, the impact of MetS on the safety and efficacy of cerebral systemic thrombolysis (intravenous [iv] thrombolysis) with tissue-type plasminogen activator (t-PA), which is the only proven medical therapy for IS, is not clear. Studies of iv-thrombolysis in patients with MetS have had inconsistent results, regarding both outcome and complication rates. Moreover, published analyses are based on a relatively limited number of subjects and inconsistent definitions of MetS.15-17 Therefore, we aimed at evaluating the relationship between MetS and functional long-term outcome, mortality, and the presence of hemorrhagic complications in a cohort of Caucasian patients with acute IS consecutively treated with iv-thrombolysis.
Materials and Methods We retrospectively evaluated the demographic and clinical data of 535 Caucasian patients with acute IS (52.7 % men; aged 41-92; mean age, 70.8 6 11.9) who were consecutively treated with iv-thrombolysis from September 2006 to June 2013 in 2 experienced stroke centers in Poland (the Department of Neurology and the Stroke Unit of the Holy Spirit Specialist Hospital in Sandomierz and the Department of Neurology and Stroke Unit of the Saint Lucas Hospital in Ko nskie). These study centers are recognized as stroke units according to the Polish national criteria, are equipped with the proper monitoring and diagnostic facilities, and provide a 24-hour stroke service 7 days a week.18
Protocol Participating stroke units performed diagnostic and treatment procedure protocols with respect to unified reg-
ular protocols of the management of acute IS and secondary prevention, according to international recommendations.19,20 A stroke physician examined all patients at the time of admission, and the severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS).21 Stroke onset was defined as the last occasion on which the patient was known to be without neurologic deficit. Examinations to evaluate the coagulation status in all patients were performed. Computed tomography scans were taken on admission to the hospital to establish the indication for treatment, between 22 and 36 hours and on the seventh day after iv-thrombolysis. Intravenous recombinant t-PA (rt-PA) was applied according to the recommendations for thrombolytic treatment. Since the publication of the European Cooperative Acute Stroke Study (ECASS-III) trial and data from the Safe Implementation of Thrombolysis in Stroke (SITS) registry, patients were treated within the 4.5-hour time window.22-24 To evaluate the etiology of stroke in patients, transcranial Doppler, carotid duplex ultrasonography, Holter electrocardiography, transthoracic echocardiography, and in case of some patients transesophagal echocardiography were performed. The 90-day stroke outcomes were measured using the modified Rankin scale (mRS).25 A favorable outcome was defined as an mRS score less than or equal to 2 points, whereas an unfavorable outcome was defined as an mRS score of 3-6 points. Hemorrhagic transformation and symptomatic intracerebral hemorrhage (SICH) rates were assessed according to the ECASS II criteria,26 by an experienced radiologist blinded to patients’ functional status and risk factor profile.
Metabolic Syndrome Definition We used the definition of MetS according to an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement, defining MetS as the presence of 3 or more of the following: (1) an elevated waist circumference of more than 102 cm for men and more than 88 cm for women; (2) elevated triglycerides greater than 150 mg/dL or on drug treatment for elevated triglycerides; (3) reduced HDL cholesterol of less than 40 mg/dL for men and less than 50 mg/dL for women or on drug treatment for reduced HDL cholesterol; (4) elevated blood pressure of 130 mm Hg or more of systolic blood pressure or 80 mm Hg or more of diastolic blood pressure or on antihypertensive drug treatment in patients with a history of hypertension; (5) elevated fasting blood glucose greater than or equal to 100 mg/dL or on drug treatment for elevated glucose.27 The ethics committee approved all data analyses ˛ tokrzyska Medical Chamber), (Ethics Committee of Swie and all patients treated with iv-thrombolysis were reported to the SITS registry.
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Results
Figure 1. A power chart calculated for MetS as a predictor for favorable outcome. Abbreviation: MetS, metabolic syndrome.
Statistical Analysis This study was based on a retrospective data analysis. Data gathering, and characteristic and univariate analysis were performed using Microsoft Excel 2010. Logistic regression analysis was performed with STATISTICA version 10 Stat Soft. Inc. Tulsa, OK 74104, USA. All continuous variables were tested for a normal distribution and equality of variances. Because of the non-normality of the variables, nonparametric Mann–Whitney U tests were used to perform the univariate analysis of the continuous variables. Categorical data were compared using chi-square tests, and P values less than .05 were considered statistically significant. The multivariate analysis was performed using multiple logistic regression models. Factors identified in the univariate analysis with a P value less than .05 were then examined using a multivariate model. The results of the logistic regression analysis were presented as odds ratios and corresponding 95% confidence intervals. The minimal power calculated for MetS as a predictor in a determined sample size was .867 regarding favorable outcome (Fig 1) and .936 regarding SICH (Fig 2).
Figure 2. A power chart calculated for MetS as a predictor for SICH. Abbreviations: MetS, metabolic syndrome; SICH, symptomatic intracerebral hemorrhage.
Among 535 patients with acute IS treated with iv-thrombolysis (median onset to treatment time, 162.6 minutes; range, 135.0-185.0 minutes; median NIHSS score on admission, 11; range, 8.0-16.0 points), 55.3% presented the favorable outcome after 3 months of follow-up (mRS score, 0-2), 18.3% died, and 4.4% experienced SICH. There were 192 (35.9%) patients with MetS (44.8% men, mean age, 70.8 6 11.1) in the studied group: 29.7% with diabetes, 79.2% with dyslipidemia, and 75.5% with arterial hypertension. Apart from the higher presence of MetS components, the subgroup of patients with MetS was characterized by a higher number of women, coronary heart disease, and old ischemic changes in a baseline computed tomography. Baseline median arterial blood pressure, systolic arterial blood pressure, and glucose level were also higher in patients with MetS. There were no other differences between both groups according to other demographic or vascular risk factors, laboratory and radiological findings, and etiological classification (Table 1). Both the univariate and multivariate analyses showed no difference between patients with and without MetS regarding the presence a favorable functional outcome after 3 months of follow-up. The presence of SICH and 3-month mortality were significantly higher in patients with MetS when compared with the group of patients without MetS; however, multivariate analysis showed no impact of MetS on the mortality or presence of SICH after systemic cerebral thrombolysis (Table 2).
Discussion Our observational study showed no association between the presence of MetS and the safety and efficacy of iv-thrombolysis in a population-based cohort of 535 Caucasian patients with acute IS. We could not detect any differences regarding stroke outcome, mortality, and presence of hemorrhagic complications between subjects with and without MetS. The effectiveness and safety of cerebral iv-thrombolysis in patients with MetS have not been clearly determined to date. Most studies have evaluated the association of individual vascular risk factors that are part of the definition of MetS with clinical outcomes after iv-thrombolysis. Only 2 studies have previously discussed the safety and efficacy of thrombolytic therapy in patients with a diagnosis of MetS; however, they were conducted on relatively small cohorts and used various definitions of MetS.15,16 Arenillas et al demonstrated that MetS was associated with a poor response to iv-thrombolysis in patients with acute middle cerebral artery (MCA) occlusions, as reflected by a higher resistance to clot dissolution. Resistance to iv-thrombolysis was defined as the absence of
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Table 1. The clinical characteristics of the subgroups of stroke patients treated with iv-thrombolysis with and without MetS
Variables
All patients
n (%) 535 Demographic data Age (y) mean, SD 70.8 6 11.9 Male gender, n (%) 282 (52.7) Risk factors, n (%) Baseline mRS 0-2 496 (92.7) Arterial hypertension 363 (67.9) Coronary heart disease 263 (49.2) History of heart infarct 79 (14.8) Atrial fibrillation 197 (36.8) Diabetes mellitus 95 (17.8) Dyslipidemia 360 (67.3) Smoking 111 (20.8) Prior stroke 87 (16.3) Prior TIA 42 (7.9) Antiplatelet therapy before stroke 307 (57.4) Anticoagulant therapy before stroke 67 (12.5) Onset to treatment time (min) median (IQR) 162.6 (135.0-185.0) NIHSS on admission (points) median (IQR) 11.0 (8.0-17.0) Arterial blood pressure on admission (mm Hg) median (IQR) MAP 108.0 (99.0-118.0) Systolic 154.0 (140.0-170.0) Diastolic 85.0 (80.0-95.0) Radiological findings in CT scans at baseline, n (%) Early ischemic changes 140 (26.2) Old ischemic changes 200 (37.4) Laboratory findings before thrombolysis, median (IQR) Glucose level [mmol/L] 6.5 (5.6-7.9) Cholesterol level [mmol/L] 4.9 (4.1-5.7) Hemoglobin level [g/dL] 14.0 (12.9-14.9) White blood cells [3109/L] 8.1 (6.8-9.7) Creatinine level [mmol/L] 86.6 (72.0-100.0) Glomerular filtration rate [mL/minute/1.73 m2]* 73.0 (58.0-87.0) Patients with renal insufficiency, n (%) 149 (27.9) aPTT, median (IQR) 28.1 (25.2-30.7) INR, median (IQR) 1.04 (1.0-1.2) Radiological findings in control CT scans, n (%) No ischemia 159 (30.1) Ischemic changes,1/3 MCA 137 (25.9) Ischemic changes .1/3 MCA 215 (40.6) COED 192 (36.3) Hemorrhagic transformationy 91 (17.2) Etiological classification, n (%) Large-vessel disease 240 (43.0) Cardioembolism 155 (29.0) Lacunar stroke 50 (9.3) Undetermined etiology 90 (16.8) mRS 0-2 at 3 months, n (%) 296 (55.3) SICH, ny 23 (4.4) Mortality, n (%) 98 (18.3)
Patients with MetS 192 (35.9) 70.8 6 11.1 86 (44.8)
Patients without MetS
P value
343 (64.1)
—
70.8 6 12.3 196 (57.14)
.96 .006
143 (91.1) 222 (93.7) .34 145 (75.5) 218 (63.6) .004 107 (55.7) 156 (45.5) .02 27 (14.1) 52 (15.2) .73 78 (40.6) 119 (34.7) .17 57 (29.7) 38 (11.1) ,.001 152 (79.2) 208 (60.65) ,.001 36 (18.8) 75 (21.9) .39 33 (17.2) 54 (15.7) .66 17 (8.9) 25 (7.3) .52 117 (60.9) 190 (55.4) .21 26 (13.5) 41 (12.0) .59 160.0 (135.0-180.0) 160.0 (135.0-190.0) .56 11.0 (8.0-16.0) 11.0 (8.0-17.0) .38 110.0 (100.0-120.0) 107.0 (97.0-117.0) .01 160.0 (144.5-170.0) 150.0 (134.0-170.0) ,.001 90.0 (80.0-96.0) 85.0 (80.0-95.0) .29 53 (27.6) 85 (44.3) 6.91 (6.2-8.6) 5.1 (4.1-5.8) 14.1 (13.0-15.2) 8.4 (7.00-9.5) 88.1 (73.9-104.2) 69.5 (56.0-86.0) 62 (32.3) 28.00 (25.1-30.5) 1.04 (.99-1.1)
87 (25.4) 115 (33.5) 6.2 (5.4-7.5) 4.9 (4.1-5.7) 13.9 (12.8-14.9) 8.0 (6.5-9.9) 86.3 (72.0-97.5) 74.0 (59.0-89.0) 87 (25.4) 28.2 (25.2-31.0) 1.0 (.99-1.2)
.57 .01 ,.001 .51 .08 .26 .37 .07 .09 .45 .82
55 (29.1) 54 (28.6) 75 (39.7) 72 (38.1) 35 (18.2)
104 (30.6) 83 (24.4) 140 (41.2) 120 (35.3) 56 (16.3)
.72 .30 .74 .52 .57
84 (43.8) 57 (29.7) 25 (13.02) 26 (13.5) 101 (52.6) 13 (6.8) 45 (23.4)
156 (45.5) 98 (28.6) 25 (7.3) 64 (18.7) 194 (56.9) 10 (2.9) 53 (15.5)
.70 .79 .03 .13 .34 .03 .02
Abbreviations: aPTT, activated partial thromboplastin time; COED, cerebral edema; CT, computed tomography; ECASS, European Cooperative Acute Stroke Study; INR, international normalized ratio; IQR, interquartile range (Q1-Q3); MAP, mean arterial pressure; MCA, middle cerebral artery; MDRD, modification diet for renal disease; MetS, metabolic syndrome; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SICH, symptomatic intracerebral hemorrhage; SD, standard deviation; TIA, transient ischemic attack. Significant P value are shown in bold italic. *According to the MDRD formula. yAccording to the ECASS II criteria.
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Table 2. Multivariate logistic regression models showing factors associated with 90 days unfavorable outcome, mortality, and SICH Unfavorable outcome mRS 3-5
Mortality
SICH
Variables
OR
95% CI
OR
95% CI
OR
95% CI
Male gender Coronary heart disease Systolic blood pressure Old ischemic changes in CT scans at baseline Glucose level [mmol/L] Lacunar stroke Metabolic syndrome
.66 .95 1.02 2.00 .98 .15 .84
.42-1.01 .62-1.46 1.01-1.03 1.28-3.11 .91-1.07 .06-.38 .53-1.33
.44 1.38 1.02 1.87 1.04 .27 1.40
.26-.76 .80-2.37 .99-1.02 1.09-3.21 .95-1.14 .08-.93 .81-2.44
.40 .32 1.01 1.70 .96 .40 1.61
.14-1.08 .12-.86 .99-1.03 .66-4.39 .81-1.14 .05-3.14 .62-4.17
Abbreviations: CI, confidence interval; CT, computed tomography; mRS–modified Rankin scale; OR, odds ratio; SICH, symptomatic intracerebral hemorrhage. Significant odds ratios (ORs) are shown in bold italic.
complete MCA recanalization 24 hours after tissue-type plasminogen activator infusion by transcranial Doppler criteria. Additionally authors indicated that MetS was associated with a higher resistance to intravenous rt-PA for acute MCA IS in women than in men.15,16 We realize that we cannot fully contrast our results with previously published findings because of incoherence of study protocols and sample sizes. We are also aware of some limitations of our study. This is a two-center observational report study with a retrospective analysis of data that were gathered in a prospective fashion. The other limitation is the lack of specific data to measure insulin resistance. We also realize that the lack of association between MetS and an unfavorable outcome revealed in a retrospective study does not definitively confirm that patients with MetS may be effectively and safely treated with iv-thrombolysis. However, we believe that our negative results will bring the benefit to the qualification for cerebral thrombolysis and support its widespread use. We also believe that, despite these limitations, our findings provide additional data for assessment of the safety and efficacy of iv-thrombolysis in patients with MetS and bring further insight into the role of MetS in acute stroke therapy.
Conclusion
3.
4.
5.
6.
7.
8.
9.
Results of our study provide no data to suggest that the effect of intravenous t-PA differs based on the presence or absence of MetS. 10.
References 1. Ford GS, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among US adults. Diabetes Care 2004;27:2444-2449. 2. Balkau B, Vernay M, Mhamdi L, et al, D.E.S.I.R. Study Group. The incidence and persistence of the NCEP (National Cholesterol Education Program) meta-
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bolic syndrome. The French D.E.S.I.R. study. Diabetes Metab 2003;29:526-532. Wyrzykowski B, Zdrojewski T, Sygnowska E, et al. Epidemiology of metabolic syndrome in Poland. The results of ‘‘WOBASZ’’ study. Kardiol Pol 2005; 63(Suppl 4):1-4. Wassink AM, van der Graaf Y, Olijhoek JK, et al, SMART Study Group. Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J 2008;29:213-223. Olijhoek JK, van der Graaf Y, Banga JD, et al, the SMART Study Group. The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J 2004; 25:342-348. Bonora E, Kiechl S, Willeit J, et al, Bruneck Study. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck study. Diabetes Care 2003;26:1251-1257. Balletshofer BM, Rittig K, Stock J, et al. Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intimamedia thickness. Atherosclerosis 2003;171:303-309. Maruyama K, Uchiyama S, Iwata M. Metabolic syndrome and its components as risk factors for first-ever acute ischemic noncardioembolic stroke. J Stroke Cerebrovasc Dis 2009;18:173-177. Anand SS, Yi Q, Gerstein H, et al, Study of Health Assessment and Risk in Ethnic Groups. Study of Health Assessment and Risk Evaluation in Aboriginal Peoples Investigators. Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease. Circulation 2003;108:420-425. Oh MY, Ko SB, Lee SH, et al. Association between metabolic syndrome and functional outcome in patients with acute ischaemic stroke. Eur J Neurol 2014; 21:177-179. Koren-Morag N, Goldbourt U, Tanne D. Relation between the metabolic syndrome and ischemic stroke or transient ischemic attack: a prospective cohort study in patients with atherosclerotic cardiovascular disease. Stroke 2005;36:1366-1371.
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1792 12. Li W, Ma D, Liu M, et al. Association between metabolic syndrome and risk of stroke: a meta-analysis of cohort studies. Cerebrovasc Dis 2008;25:539-547. 13. Yasar AS, Bilen E, Bilge M, et al. Impact of metabolic syndrome on coronary patency after thrombolytic therapy for acute myocardial infarction. Coron Artery Dis 2009; 20:387-391. 14. Uchida Y, Ichimiya S, Ishii H, et al. Impact of metabolic syndrome on various aspects of microcirculation and major adverse cardiac events in patients with ST-segment elevation myocardial infarction. Circ J 2012;76:1972-1979. 15. Arenillas JF, Ispierto L, Mill an M, et al. Metabolic syndrome and resistance to IV thrombolysis in middle cerebral artery ischemic stroke. Neurology 2008;71:190-195. 16. Arenillas JF, Sandoval P, Perez de la Ossa N, et al. The metabolic syndrome is associated with a higher resistance to intravenous thrombolysis for acute ischemic stroke in women than in men. Stroke 2009;40:344-349. 17. Calleja AI, Garcia-Bermejo P, Cortijo E, et al. Insulin resistance is associated with a poor response to intravenous thrombolysis in acute ischemic stroke. Diabetes Care 2011;34:2413-2417. 18. Cz1onkowska A, Sarzynska-D1ugosz I, Niewada M, et al. Eligibility of stroke units in Poland for administration of intravenous thrombolysis. Eur J Neurol 2006;13:220-224. 19. Adams HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. The American Academy of Neurology affirms the value of this
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guideline as an educational tool for neurologists. Circulation 2007;115:e478-e534. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25: 457-507. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220-2226. Hacke W, Kaste M, Bluhmki E, et al, for the ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischaemic stroke. N Engl J Med 2008;359: 1317-1329. Wahlgren N, Ahmed N, D avalos A, et al, for the SITS investigators. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008;372:1303-1309. Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009;40:2945-2948. Bonita R, Beaglehole R. Recovery of motor function after stroke. Stroke 1988;19:1497-1500. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998; 352:1245-1251. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement American Heart Association. Circulation 2005;112:2735-2752.
Background: The metabolic syndrome (MetS) is common in patients with acute ischemic stroke (IS); however, its impact on outcome after intravenous thrombolysis (iv-thrombolysis) remains unclear. Thus, we aimed at evaluating the relationship between MetS and functional long-term outcome, mortality, and the presence of hemorrhagic complications in patients with IS treated with iv-thrombolysis. Methods: We retrospectively evaluated the demographic and clinical data of 535 Caucasian patients with acute IS who were consecutively treated with iv-thrombolysis from September 2006 to June 2013 in 2 experienced stroke centers in Poland. A favorable functional long-term outcome was defined as a modified Rankin scale score less than or equal to 2 points on day 90, and hemorrhagic complications were assessed with European Cooperative Acute Stroke Study criteria. Results: MetS was recognized in 192 (35.9%) patients (44.8% men; mean age, 70.8 6 11.1 years), diabetes in 29.7%, dyslipidemia in 79.2%, and arterial hypertension in 75.5%. At 3 months, favorable outcome was found in 55.3% of patients, symptomatic intracerebral hemorrhage (SICH) in 18.3%, and 4.4 % of patients died. There was no difference regarding the presence of favorable outcome between patients with and without MetS (52.6% versus 56.9%, P 5 .34). The presence of SICH and 3-month mortality were more frequent in patients with MetS than without MetS (6.8% versus 2.9%, P 5 .03 and 23.4% versus 15.5%, P 5 .02, respectively); however, a multivariate analysis showed no impact of MetS on mortality or SICH. Conclusions: Results of our study provide no data to suggest that the effect of intravenous tissue-type plasminogen activator differs based on the presence or absence of MetS. Key Words: Metabolic syndrome—acute ischemic stroke—rt-PA— intravenous thrombolysis. Ó 2015 by National Stroke Association
From the *Department of Neurology and Stroke Unit of Holy Spirit Specialist Hospital in Sandomierz, Sandomierz; †Department of Neurology and Stroke Unit of Saint Luke’s Hospital in Ko nskie, Ko nskie; and ‡Department of Neurology, Medical University of Gda nsk, Gda nsk, Poland. Received October 4, 2014; revision received March 30, 2015; accepted April 1, 2015. P.S. contributed to the study design, patient selection, clinical work, data collection, analysis, interpretation, and writing of the manuscript. W.B. contributed to the study design, patient selection, clinical work, data collection, analysis, and interpretation. W.S. contributed to patient selection, clinical work, data collection, statistical analysis,
and interpretation. M.F. contributed to patient selection, clinical work, data collection, analysis, and interpretation; G.K. contributed to data analysis, interpretation, and the rewriting of the manuscript. No potential conflict of interests relevant to this article were reported. Address correspondence to Piotr Sobolewski, MD, PhD, Department of Neurology and Stroke Unit of Holy Spirit Specialist Hospital in Sandomierz, 13 Schinzla Str., 27-600 Sandomierz, Poland. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.001
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 8 (August), 2015: pp 1787-1792
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Introduction Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that is highly prevalent in the adult population of developed countries and significantly increases the risk of cardiovascular events and all-cause mortality.1-4 An increased risk of ischemic stroke (IS) associated with MetS mainly derives from its high potential to enhance the early development and further progress of atherosclerosis in brain-supplying arteries and to defect endogenous fibrinolysis.5-9 Consequently, MetS is more common in IS patients than in the general population and significantly predicts a poor outcome after IS.10-12 Numerous proatherothrombotic effects of MetS on endogenous fibrinolysis and the vascular endothelium may also contribute to a higher resistance to thrombolytic interventions in patients with IS. Patients with MetS show impaired response after thrombolytic therapy for acute myocardial infarction and a higher incidence of major adverse cardiac events after percutaneous coronary intervention.13,14 However, the impact of MetS on the safety and efficacy of cerebral systemic thrombolysis (intravenous [iv] thrombolysis) with tissue-type plasminogen activator (t-PA), which is the only proven medical therapy for IS, is not clear. Studies of iv-thrombolysis in patients with MetS have had inconsistent results, regarding both outcome and complication rates. Moreover, published analyses are based on a relatively limited number of subjects and inconsistent definitions of MetS.15-17 Therefore, we aimed at evaluating the relationship between MetS and functional long-term outcome, mortality, and the presence of hemorrhagic complications in a cohort of Caucasian patients with acute IS consecutively treated with iv-thrombolysis.
Materials and Methods We retrospectively evaluated the demographic and clinical data of 535 Caucasian patients with acute IS (52.7 % men; aged 41-92; mean age, 70.8 6 11.9) who were consecutively treated with iv-thrombolysis from September 2006 to June 2013 in 2 experienced stroke centers in Poland (the Department of Neurology and the Stroke Unit of the Holy Spirit Specialist Hospital in Sandomierz and the Department of Neurology and Stroke Unit of the Saint Lucas Hospital in Ko nskie). These study centers are recognized as stroke units according to the Polish national criteria, are equipped with the proper monitoring and diagnostic facilities, and provide a 24-hour stroke service 7 days a week.18
Protocol Participating stroke units performed diagnostic and treatment procedure protocols with respect to unified reg-
ular protocols of the management of acute IS and secondary prevention, according to international recommendations.19,20 A stroke physician examined all patients at the time of admission, and the severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS).21 Stroke onset was defined as the last occasion on which the patient was known to be without neurologic deficit. Examinations to evaluate the coagulation status in all patients were performed. Computed tomography scans were taken on admission to the hospital to establish the indication for treatment, between 22 and 36 hours and on the seventh day after iv-thrombolysis. Intravenous recombinant t-PA (rt-PA) was applied according to the recommendations for thrombolytic treatment. Since the publication of the European Cooperative Acute Stroke Study (ECASS-III) trial and data from the Safe Implementation of Thrombolysis in Stroke (SITS) registry, patients were treated within the 4.5-hour time window.22-24 To evaluate the etiology of stroke in patients, transcranial Doppler, carotid duplex ultrasonography, Holter electrocardiography, transthoracic echocardiography, and in case of some patients transesophagal echocardiography were performed. The 90-day stroke outcomes were measured using the modified Rankin scale (mRS).25 A favorable outcome was defined as an mRS score less than or equal to 2 points, whereas an unfavorable outcome was defined as an mRS score of 3-6 points. Hemorrhagic transformation and symptomatic intracerebral hemorrhage (SICH) rates were assessed according to the ECASS II criteria,26 by an experienced radiologist blinded to patients’ functional status and risk factor profile.
Metabolic Syndrome Definition We used the definition of MetS according to an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement, defining MetS as the presence of 3 or more of the following: (1) an elevated waist circumference of more than 102 cm for men and more than 88 cm for women; (2) elevated triglycerides greater than 150 mg/dL or on drug treatment for elevated triglycerides; (3) reduced HDL cholesterol of less than 40 mg/dL for men and less than 50 mg/dL for women or on drug treatment for reduced HDL cholesterol; (4) elevated blood pressure of 130 mm Hg or more of systolic blood pressure or 80 mm Hg or more of diastolic blood pressure or on antihypertensive drug treatment in patients with a history of hypertension; (5) elevated fasting blood glucose greater than or equal to 100 mg/dL or on drug treatment for elevated glucose.27 The ethics committee approved all data analyses ˛ tokrzyska Medical Chamber), (Ethics Committee of Swie and all patients treated with iv-thrombolysis were reported to the SITS registry.
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Results
Figure 1. A power chart calculated for MetS as a predictor for favorable outcome. Abbreviation: MetS, metabolic syndrome.
Statistical Analysis This study was based on a retrospective data analysis. Data gathering, and characteristic and univariate analysis were performed using Microsoft Excel 2010. Logistic regression analysis was performed with STATISTICA version 10 Stat Soft. Inc. Tulsa, OK 74104, USA. All continuous variables were tested for a normal distribution and equality of variances. Because of the non-normality of the variables, nonparametric Mann–Whitney U tests were used to perform the univariate analysis of the continuous variables. Categorical data were compared using chi-square tests, and P values less than .05 were considered statistically significant. The multivariate analysis was performed using multiple logistic regression models. Factors identified in the univariate analysis with a P value less than .05 were then examined using a multivariate model. The results of the logistic regression analysis were presented as odds ratios and corresponding 95% confidence intervals. The minimal power calculated for MetS as a predictor in a determined sample size was .867 regarding favorable outcome (Fig 1) and .936 regarding SICH (Fig 2).
Figure 2. A power chart calculated for MetS as a predictor for SICH. Abbreviations: MetS, metabolic syndrome; SICH, symptomatic intracerebral hemorrhage.
Among 535 patients with acute IS treated with iv-thrombolysis (median onset to treatment time, 162.6 minutes; range, 135.0-185.0 minutes; median NIHSS score on admission, 11; range, 8.0-16.0 points), 55.3% presented the favorable outcome after 3 months of follow-up (mRS score, 0-2), 18.3% died, and 4.4% experienced SICH. There were 192 (35.9%) patients with MetS (44.8% men, mean age, 70.8 6 11.1) in the studied group: 29.7% with diabetes, 79.2% with dyslipidemia, and 75.5% with arterial hypertension. Apart from the higher presence of MetS components, the subgroup of patients with MetS was characterized by a higher number of women, coronary heart disease, and old ischemic changes in a baseline computed tomography. Baseline median arterial blood pressure, systolic arterial blood pressure, and glucose level were also higher in patients with MetS. There were no other differences between both groups according to other demographic or vascular risk factors, laboratory and radiological findings, and etiological classification (Table 1). Both the univariate and multivariate analyses showed no difference between patients with and without MetS regarding the presence a favorable functional outcome after 3 months of follow-up. The presence of SICH and 3-month mortality were significantly higher in patients with MetS when compared with the group of patients without MetS; however, multivariate analysis showed no impact of MetS on the mortality or presence of SICH after systemic cerebral thrombolysis (Table 2).
Discussion Our observational study showed no association between the presence of MetS and the safety and efficacy of iv-thrombolysis in a population-based cohort of 535 Caucasian patients with acute IS. We could not detect any differences regarding stroke outcome, mortality, and presence of hemorrhagic complications between subjects with and without MetS. The effectiveness and safety of cerebral iv-thrombolysis in patients with MetS have not been clearly determined to date. Most studies have evaluated the association of individual vascular risk factors that are part of the definition of MetS with clinical outcomes after iv-thrombolysis. Only 2 studies have previously discussed the safety and efficacy of thrombolytic therapy in patients with a diagnosis of MetS; however, they were conducted on relatively small cohorts and used various definitions of MetS.15,16 Arenillas et al demonstrated that MetS was associated with a poor response to iv-thrombolysis in patients with acute middle cerebral artery (MCA) occlusions, as reflected by a higher resistance to clot dissolution. Resistance to iv-thrombolysis was defined as the absence of
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Table 1. The clinical characteristics of the subgroups of stroke patients treated with iv-thrombolysis with and without MetS
Variables
All patients
n (%) 535 Demographic data Age (y) mean, SD 70.8 6 11.9 Male gender, n (%) 282 (52.7) Risk factors, n (%) Baseline mRS 0-2 496 (92.7) Arterial hypertension 363 (67.9) Coronary heart disease 263 (49.2) History of heart infarct 79 (14.8) Atrial fibrillation 197 (36.8) Diabetes mellitus 95 (17.8) Dyslipidemia 360 (67.3) Smoking 111 (20.8) Prior stroke 87 (16.3) Prior TIA 42 (7.9) Antiplatelet therapy before stroke 307 (57.4) Anticoagulant therapy before stroke 67 (12.5) Onset to treatment time (min) median (IQR) 162.6 (135.0-185.0) NIHSS on admission (points) median (IQR) 11.0 (8.0-17.0) Arterial blood pressure on admission (mm Hg) median (IQR) MAP 108.0 (99.0-118.0) Systolic 154.0 (140.0-170.0) Diastolic 85.0 (80.0-95.0) Radiological findings in CT scans at baseline, n (%) Early ischemic changes 140 (26.2) Old ischemic changes 200 (37.4) Laboratory findings before thrombolysis, median (IQR) Glucose level [mmol/L] 6.5 (5.6-7.9) Cholesterol level [mmol/L] 4.9 (4.1-5.7) Hemoglobin level [g/dL] 14.0 (12.9-14.9) White blood cells [3109/L] 8.1 (6.8-9.7) Creatinine level [mmol/L] 86.6 (72.0-100.0) Glomerular filtration rate [mL/minute/1.73 m2]* 73.0 (58.0-87.0) Patients with renal insufficiency, n (%) 149 (27.9) aPTT, median (IQR) 28.1 (25.2-30.7) INR, median (IQR) 1.04 (1.0-1.2) Radiological findings in control CT scans, n (%) No ischemia 159 (30.1) Ischemic changes,1/3 MCA 137 (25.9) Ischemic changes .1/3 MCA 215 (40.6) COED 192 (36.3) Hemorrhagic transformationy 91 (17.2) Etiological classification, n (%) Large-vessel disease 240 (43.0) Cardioembolism 155 (29.0) Lacunar stroke 50 (9.3) Undetermined etiology 90 (16.8) mRS 0-2 at 3 months, n (%) 296 (55.3) SICH, ny 23 (4.4) Mortality, n (%) 98 (18.3)
Patients with MetS 192 (35.9) 70.8 6 11.1 86 (44.8)
Patients without MetS
P value
343 (64.1)
—
70.8 6 12.3 196 (57.14)
.96 .006
143 (91.1) 222 (93.7) .34 145 (75.5) 218 (63.6) .004 107 (55.7) 156 (45.5) .02 27 (14.1) 52 (15.2) .73 78 (40.6) 119 (34.7) .17 57 (29.7) 38 (11.1) ,.001 152 (79.2) 208 (60.65) ,.001 36 (18.8) 75 (21.9) .39 33 (17.2) 54 (15.7) .66 17 (8.9) 25 (7.3) .52 117 (60.9) 190 (55.4) .21 26 (13.5) 41 (12.0) .59 160.0 (135.0-180.0) 160.0 (135.0-190.0) .56 11.0 (8.0-16.0) 11.0 (8.0-17.0) .38 110.0 (100.0-120.0) 107.0 (97.0-117.0) .01 160.0 (144.5-170.0) 150.0 (134.0-170.0) ,.001 90.0 (80.0-96.0) 85.0 (80.0-95.0) .29 53 (27.6) 85 (44.3) 6.91 (6.2-8.6) 5.1 (4.1-5.8) 14.1 (13.0-15.2) 8.4 (7.00-9.5) 88.1 (73.9-104.2) 69.5 (56.0-86.0) 62 (32.3) 28.00 (25.1-30.5) 1.04 (.99-1.1)
87 (25.4) 115 (33.5) 6.2 (5.4-7.5) 4.9 (4.1-5.7) 13.9 (12.8-14.9) 8.0 (6.5-9.9) 86.3 (72.0-97.5) 74.0 (59.0-89.0) 87 (25.4) 28.2 (25.2-31.0) 1.0 (.99-1.2)
.57 .01 ,.001 .51 .08 .26 .37 .07 .09 .45 .82
55 (29.1) 54 (28.6) 75 (39.7) 72 (38.1) 35 (18.2)
104 (30.6) 83 (24.4) 140 (41.2) 120 (35.3) 56 (16.3)
.72 .30 .74 .52 .57
84 (43.8) 57 (29.7) 25 (13.02) 26 (13.5) 101 (52.6) 13 (6.8) 45 (23.4)
156 (45.5) 98 (28.6) 25 (7.3) 64 (18.7) 194 (56.9) 10 (2.9) 53 (15.5)
.70 .79 .03 .13 .34 .03 .02
Abbreviations: aPTT, activated partial thromboplastin time; COED, cerebral edema; CT, computed tomography; ECASS, European Cooperative Acute Stroke Study; INR, international normalized ratio; IQR, interquartile range (Q1-Q3); MAP, mean arterial pressure; MCA, middle cerebral artery; MDRD, modification diet for renal disease; MetS, metabolic syndrome; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; SICH, symptomatic intracerebral hemorrhage; SD, standard deviation; TIA, transient ischemic attack. Significant P value are shown in bold italic. *According to the MDRD formula. yAccording to the ECASS II criteria.
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Table 2. Multivariate logistic regression models showing factors associated with 90 days unfavorable outcome, mortality, and SICH Unfavorable outcome mRS 3-5
Mortality
SICH
Variables
OR
95% CI
OR
95% CI
OR
95% CI
Male gender Coronary heart disease Systolic blood pressure Old ischemic changes in CT scans at baseline Glucose level [mmol/L] Lacunar stroke Metabolic syndrome
.66 .95 1.02 2.00 .98 .15 .84
.42-1.01 .62-1.46 1.01-1.03 1.28-3.11 .91-1.07 .06-.38 .53-1.33
.44 1.38 1.02 1.87 1.04 .27 1.40
.26-.76 .80-2.37 .99-1.02 1.09-3.21 .95-1.14 .08-.93 .81-2.44
.40 .32 1.01 1.70 .96 .40 1.61
.14-1.08 .12-.86 .99-1.03 .66-4.39 .81-1.14 .05-3.14 .62-4.17
Abbreviations: CI, confidence interval; CT, computed tomography; mRS–modified Rankin scale; OR, odds ratio; SICH, symptomatic intracerebral hemorrhage. Significant odds ratios (ORs) are shown in bold italic.
complete MCA recanalization 24 hours after tissue-type plasminogen activator infusion by transcranial Doppler criteria. Additionally authors indicated that MetS was associated with a higher resistance to intravenous rt-PA for acute MCA IS in women than in men.15,16 We realize that we cannot fully contrast our results with previously published findings because of incoherence of study protocols and sample sizes. We are also aware of some limitations of our study. This is a two-center observational report study with a retrospective analysis of data that were gathered in a prospective fashion. The other limitation is the lack of specific data to measure insulin resistance. We also realize that the lack of association between MetS and an unfavorable outcome revealed in a retrospective study does not definitively confirm that patients with MetS may be effectively and safely treated with iv-thrombolysis. However, we believe that our negative results will bring the benefit to the qualification for cerebral thrombolysis and support its widespread use. We also believe that, despite these limitations, our findings provide additional data for assessment of the safety and efficacy of iv-thrombolysis in patients with MetS and bring further insight into the role of MetS in acute stroke therapy.
Conclusion
3.
4.
5.
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7.
8.
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Results of our study provide no data to suggest that the effect of intravenous t-PA differs based on the presence or absence of MetS. 10.
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