Thrombolysis Outcomes among Obese and Overweight Stroke Patients: An Age- and National Institutes of Health Stroke Scale matched Comparison

Thrombolysis Outcomes among Obese and Overweight Stroke Patients: An Age- and National Institutes of Health Stroke Scale matched Comparison Raymond C. S. Seet, MRCP,* Yi Zhang, MD,* Eelco F. M. Wijdicks, MD, PhD,* and Alejandro A. Rabinstein, MD* Background: Whether obese and overweight stroke patients respond differently to intravenous thrombolysis is unclear. The purpose of this study is to determine the influence of obesity and risk components of metabolic syndrome to stroke recovery in patients undergoing intravenous thrombolysis. Methods: Outcomes after recombinant tissue plasminogen activator treatment were compared between obese (body mass index [BMI].30 kg/m 2 ), overweight (BMI 25-30 kg/m 2 ), and normal weight (BMI,25 kg/m 2 ) patients. The association between BMI, risk components of the metabolic syndrome, and dose of recombinant tissue plasminogen activator per kilogram of body weight to stroke outcomes were assessed in a multivariable model. Results: A total of 169 patients (mean age 75 years; baseline National Institutes of Health Stroke Scale score 11) were included. No differences in the frequency of symptomatic intracranial hemorrhage and poor functional recovery were observed among obese, overweight, and normal weight patients. A linear trend toward worse stroke recovery was observed in patients with a greater number of metabolic risk components (P for trend.043). By contrast, there were no significant associations between the number of risk components of metabolic syndrome with respect to symptomatic intracranial hemorrhage. Using stepwise regression analyses, age, baseline stroke severity, and the number of risk components of the metabolic syndrome accounted for 52% variation in functional recovery after intravenous thrombolysis. Conclusions: Acute stroke outcomes do not differ between obese and overweight patients undergoing intravenous thrombolysis. The number of metabolic risk components contributes more significantly to functional recovery following intravenous thrombolysis. Key Words: Ischemic stroke metabolic syndrome obesity recombinant tissue plasminogen activator. Ó 2014 by National Stroke Association The prevalence of obesity is rising rapidly in most developing and developed countries. In the United States, 1 in 3 adults has a body mass index (BMI).30 kg/m 2 and approximately 5% of the general population has a BMI.35 kg/m 2. 1 Excess weight is associated with a cluster of risk factors, such as atherogenic dyslipidemia, abnormal glucose tolerance, and hypertension, that characterize metabolic syndrome, a condition that is From the *Department of Neurology, Mayo Clinic, Rochester, Minnesota; and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Received February 25, 2012; revision received March 26, 2012; accepted April 8, 2012. Dr. Seet has received grants from the National Medical Research Council and National Research Foundation, Singapore. Dr. Wijdicks receives honoraria from Springer for his role as the Editor-in-Chief of Neurocritical Care and receives royalties from books published with Oxford University Press. Dr. Rabinstein serves as a Section Editor for Current Treatment Options in Neurology and Neurocritical Care and receives research support from CardioNet, Inc. Address correspondence to Raymond C. S. Seet, MRCP, Department of Neurology, Mayo Clinic, W8B, 200 First St SW, Rochester, MN 55905. E-mail: raymond_seet@nus.edu.sg. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2012.04.001 Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 1 (January), 2014: pp 1-6 1

2 associated with decreased sensitivity or responsiveness of tissues to the metabolic actions of insulin. 2-4 A metaanalysis of 57 prospective studies observed a nonlinear association between obesity and mortality. 5 Among those with BMI.25, each 5 kg/m 2 increase in BMI is associated with a 40% increased risk of stroke mortality. Several studies, however, report no relationship between BMI and total stroke, 6,7 while others observe a U- or J-shaped association. 8,9 Accumulating data, however, suggest a survival benefit in stroke patients who are overweight and moderately obese. 10,11 In patients with first-ever stroke, an obesity paradox is observed among obese stroke patients; these patients have significantly better early and long-term survival rates compared to those with normal BMI. 11 In the acute setting, increased BMI is associated independently with better outcomes in patients with myocardial infarction, 12 heart failure, 13 renal dialysis, 14 percutaneous transluminal coronary angioplasty, 15 and coronary artery bypass surgery. 16 These findings, which imply protective effects of these risk factors with respect to survival, appear counterintuitive, given the overwhelming evidence that supports the detrimental implications of obesity on both individual and population health. 17 The influence of obesity has not been extensively studied in stroke patients undergoing intravenous thrombolysis. The confounding effects of age and stroke severity have not been considered a priori in the design of studies that investigated the effects of obesity on stroke outcomes. 6-10 It is not known, for example, whether the perceived favorable outcomes in obese stroke patients is explained by the younger age of these patients at the time of stroke onset and whether the preponderance for obese patients to develop lacunar infarction may erroneously lead to the conclusion that obese patients have better stroke outcomes. Similarly, older patients who appeared to have normal body weight may harbor a greater burden of chronic medical illnesses, which makes them more vulnerable to developing more severe strokes. To investigate the phenomenon of the obesity paradox, we performed a retrospective cohort study of acute stroke patients undergoing intravenous thrombolysis who were stratified according to the extent of obesity. The confounding effects of age and stroke severity are considered by matching these variables in patients who were obese, overweight, and normal weight. Methods Study Population Patients with acute ischemic stroke who received intravenous thrombolysis within 3 hours of symptom onset at St. Marys Hospital, Mayo Clinic, Rochester, MN between April 2006 and January 2011 were included in this study. Those who underwent primary or adjunctive endovascular treatments because of a contraindication to or after intravenous thrombolysis were excluded. All patients eligible for intravenous thrombolysis were treated using a standard protocol adopted from the American Heart Association/American Stroke Association guidelines. 18 Information on vascular risk factors, stroke severity, and baseline hemodynamic and laboratory indices were collected. Computed tomographic (CT) scans of the brain were performed before intravenous thrombolysis and repeated 24 hours later or whenever clinically indicated for patients with worsening stroke symptoms. Additional diagnostic tests, which included ultrasonology studies, magnetic resonance (MR) and CT angiography, and echocardiogram, were performed to identify potential mechanisms of cerebral infarction and, on the basis of the results, etiologic subgroups were determined using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Power calculations, performed based on data derived from a pilot study, 19 indicated that a minimum sample size of 50 subjects in each group, matched for age and baseline National Institutes of Health Stroke Scale (NIHSS) score, was required to reject the null hypothesis that there were no differences in outcomes in patients according to BMI, with a probability (power) of 0.80. The type I error probability to test this null hypothesis was 0.05 (a). BMI was derived by dividing weight in kilograms by squared height in meters. Patients were categorized as normal weight (BMI,25mg/kg 2 ), overweight (BMI 25-30 mg/kg 2 ), and obese (BMI.30mg/kg 2 ). Body weight was measured using a weighing bed. Stratified randomization was performed to ensure an equal (or nearly equal) distribution of age and stroke severity between study groups. The risks of thrombolysis were compared between overweight and obese stroke patients, with respect to those with normal weight who served as the reference group. The metabolic syndrome status of individuals was defined using modified criteria of the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI). 20 These included: elevated triglycerides (.1.7 mmol/l), reduced highdensity lipoprotein (HDL) cholesterol (,1.03 mmol/l in males and,1.3 mmol/l in females), fasting glucose ($110 mg/dl), and elevated blood pressure (.130 mm Hg systolic blood pressure or.85 mm Hg diastolic blood pressure or previously diagnosed as hypertensive and on treatment). A modification to the AHA/NHLBI criteria was performed by using BMI (.25 kg/m 2 ) instead of waist circumference. The criteria for blood pressure were computed by using the average outpatient blood pressure measurements within 6 months before stroke onset. Study Outcomes R.C.S. SEET ET AL. The presence and severity of intracerebral hemorrhage (ICH) was classified according to the criteria of the European Cooperative Acute Stroke Study. Symptomatic ICH

THROMBOLYSIS OUTCOMES AMONG OBESE AND OVERWEIGHT STROKE PATIENTS 3 was defined by hemorrhagic transformation that was associated with at least a 4-point increment in the NIHSS score. Functional recovery was determined 3 months after the onset of stroke using the modified Rankin scale (mrs). Poor outcome was considered in patients with a mrs score.2. The study protocol was reviewed and approved by the Mayo Clinic Institutional Review Board. Statistical Analysis Statistical analyses were performed using SPSS software (version 16.0; SPSS Inc, Chicago, IL). Data are presented as mean (standard deviation) or median (interquartile range) for continuous measures, and counts and percentages for categorical variables. Differences between BMI groups were compared using analysis of variance with Bonferroni adjustments and Chi-square and Fisher exact tests for categorical variables. A multivariate stepwise logistic regression model was fitted to determine the independent association of significant variables P,.05) with stroke outcomes. P,.05 was considered statistically significant. Results A total of 169 patients (50 normal weight, 65 overweight, and 54 obese) were included in this study. The mean (standard deviation) age of the study cohort was 75.2 (12.0) years, with median (interquartile range) baseline NIHSS score of 11 (range 5-13). The mean values of BMI within each category were 22.7 kg/m 2, 27.7 kg/m 2, and 33.9 kg/m 2, respectively. Seventy-nine percent of patients fulfilled the AHA/NHLBI criteria for metabolic syndrome. Those with higher BMI tended to have lower HDL levels and received less recombinant tissue plasminogen activator (rtpa) per kg body weight, but were comparable in terms of gender, risk factors, stroke characteristics, blood pressure, and laboratory parameters (Table 1). Poor functional recovery (mrs.2) was observed in 48% of patients with normal body weight, 46% of overweight patients, and 52% of obese patients, while symptomatic ICH was observed in 5% patients with normal body weight, 6% of overweight patients, and 5% of obese patients. There were no differences in the frequency of symptomatic ICH and poor functional recovery between patients in these different BMI categories, before and after adjusting for age, stroke severity, and stroke subtype (Table 2). There were no significant differences in the outcomes of stroke patients weighing.100 kg compared to those weighing,100 kg, despite the fact that the former received less rtpa per kilogram of body weight based on the approved 0.9 mg/kg dosage with a maximum dose of 90 mg. When individual components of the metabolic syndrome were compared with outcomes, stroke patients who fulfilled the AHA/NHLBI criteria for hypertension and hyperglycemia had a greater propensity of developing poor functional recovery (odds ratio [95% confidence intervals] 3.0 [1.5-7.5] and 1.8 [1.4-2.5], respectively). No significant differences were observed between triglycerides, HDL, and functional recovery. A linear trend toward worse functional outcomes after rtpa treatment was observed in patients with a greater number of risk components of the metabolic syndrome (P value for trend.043; Fig 1). By contrast, there were no significant associations between individual metabolic risk components or the number of metabolic risk components in relation to symptomatic ICH. Using stepwise regression analyses, a model with 3 explanatory variables (age, baseline stroke severity, and the number of metabolic risk components) was found to be statistically significant, accounting for 52% variation in poor functional stroke recovery after rtpa treatment (Table 3). Discussion We did not observe differences in stroke outcomes in patients undergoing intravenous thrombolysis on the basis of BMI. Instead, patients with a greater number of metabolic risk components had a greater risk of poor functional recovery. Data from the current study do not support the concept of the obesity paradox in stroke patients treated with thrombolysis, and suggest that the perceived paradox reported in the literature may be explained (in part) by differences in age and stroke severity among overweight and obese patients. Our findings are in contrast to those in studies of acute cardiac and renal patients, 12-16 which found improved outcomes among overweight or obese patients. One proposed explanation for this finding has been that obese patients have greater metabolic reserves to meet the demands of acute critical illnesses. Even if such benefits truly exist in stroke patients, it is likely that their effects are mitigated by the burden of excessive weight in patients undergoing poststroke rehabilitation, which is often necessary in patients with strokes severe enough to warrant thrombolysis. Based on our results, being overweight or obese has no or minimal overall impact on acute stroke outcomes for patients receiving intravenous rtpa. Consistent with data from the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), 21 there were no significant differences in the outcomes of stroke patients weighing.100 kg compared to those weighing,100 kg, despite the fact that the former received less rtpa per kilogram of body weight based on the approved 0.9 mg/kg dosage with a maximum dose of 90 mg. An alternative explanation to the lack of differences may relate to the fact that not all obese patients have the same burden of metabolic diseases. In a cross-sectional sample of 5440 participants of the National Health and Nutrition Examination Surveys (NHANES), nearly one-third of obese individuals were classified to have a metabolically benign profile. Pooled data from the

4 Table 1. Patient characteristics according to body mass index Body mass index R.C.S. SEET ET AL. Normal,,25.0 kg/m 2 (n 5 50) Overweight, 25.0-29.9 kg/m 2 (n 5 65) Obese, $30.0 kg/m 2 (n 5 54) P value Age, y 75.5 (12.9) 75.0 (11.2) 75.3 (12.4).978 Baseline NIHSS score, median (IQR) 12.6 (9-14) 12.3 (8-14) 12.2 (9-14).700 Body mass index, kg/m 2 22.7 (1.8) 27.7 (1.4) 33.9 (3.6),.001 Men (%) 25 (49%) 35 (54%) 27 (50%).857 Medical history (%) Hypertension 34 (67%) 49 (75%) 46 (85%).110 Diabetes mellitus 5 (10%) 7 (11%) 12 (22%).144 Hyperlipidemia 23 (46%) 38 (59%) 28 (52%).463 Coronary artery disease 23 (46%) 23 (35%) 20 (37%).528 Atrial fibrillation 16 (31%) 17 (26%) 16 (30%).857 Previous stroke/tia 12 (23%) 10 (15%) 7 (13%).411 Current smoking 9 (18%) 6 (9%) 3 (6%).326 Lipid profile Total cholesterol, mg/ml 165 (40) 172 (45) 169 (39).753 Triglycerides, mg/ml 129 (117) 111 (58) 153 (151).157 Low-density lipoprotein, mg/ml 91 (30) 104 (38) 98 (34).230 High-density lipoprotein, mg/ml 51 (15) 46 (13) 43 (9).007 Number of metabolic components 2.38 (0.91) 3.58 (0.81) 3.85 (0.86),.001 Metabolic syndrome ($3 metabolic 22 (44%) 59 (91%) 52 (96%),.001 components) Stroke characteristics Onset-to-treatment time, min 132 (28) 152 (60) 139 (43).170 Stroke subtype (%).462 Cardioembolic 23 (46%) 34 (52%) 30 (56%) Large artery occlusion 7 (13%) 8 (12%) 11 (20%) Lacunar 8 (15%) 5 (8%) 5 (9%) Undetermined 13 (26%) 18 (28%) 8 (15%) tpa dosage Total dose, mg 58.5 (13.9) 71.1 (11.3) 78.9 (12.1),.001 Total dose/body weight, mg/kg 0.90 (0.09) 0.88 (0.07) 0.85 (0.09),.001 Blood pressure, mm Hg* Systolic 156 (22) 151 (25) 156 (26).511 Diastolic 78 (17) 81 (15) 80 (22).727 Baseline laboratory parameters Hemoglobin, g/l 13.0 (1.7) 13.2 (1.7) 13.3 (1.7).823 Hematocrit, % 38.2 (4.9) 38.7 (4.7) 38.9 (4.8).779 Leukocytes, per ml 9.7 (6.7) 9.4 (5.8) 8.9 (2.8).780 Platelet count, 3 10 3 /ml 227 (68) 219 (104) 210 (42).570 Glucose, mg/dl 114 (31) 122 (34) 126 (50).409 Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; tpa, tissue plasminogen activator. Data are described as mean 6 standard deviation unless otherwise specified. *Average blood pressure measurements obtained from outpatient medical records 6 months before stroke onset. Atherosclerosis Risk in Communities and Cardiovascular Health Studies suggest that this distinction is important because obese individuals with a benign metabolic profile have cardiovascular risks that are intermediate between healthy normal-weight individuals and at-risk obese individuals. 22 The results from the current study emphasize the importance of considering components of the metabolic syndrome (especially hypertension and hyperglycemia), rather than obesity alone, as important modifiable risk factors within the community that could ultimately influence stroke outcomes. In previous studies, women with features of metabolic syndrome and demonstrable arterial occlusion were found to be more resistant to the beneficial effects of intravenous thrombolysis. 23,24 The reasons for the proportional increase in adverse stroke outcomes in patients with a greater number of metabolic risk components and the resistance of these patients to

THROMBOLYSIS OUTCOMES AMONG OBESE AND OVERWEIGHT STROKE PATIENTS 5 Table 2. Odds ratios of stroke outcomes according to body mass index Unadjusted OR (95% CI) P value Adjusted OR* (95% CI) P value Adjusted ORy (95% CI) P value Symptomatic intracerebral hemorrhage Normal body mass index (reference) 1.00 1.00 1.00 Overweight 0.92 (0.09-2.00).423 0.94 (0.52-5.12).892 0.93 (0.60-3.23).782 Obese 1.09 (0.29-4.17).896 0.82 (0.63-4.94).801 0.90 (0.62-2.94).838 Poor functional recovery Normal body mass index (reference) 1.00 1.00 1.00 Overweight 0.90 (0.41-2.00).800 1.12 (0.54-6.21).666 1.05 (0.63-5.12).712 Obese 1.13 (0.50-2.59).766 1.08 (0.45-4.21).812 1.04 (0.70-3.89).823 Abbreviations: CI, confidence interval; OR, odds ratio. *Adjusted for age and baseline National Institutes of Health Stroke Scale score. yadjusted for age, baseline National Institutes of Health Stroke Scale score, and stroke subtype. thrombolysis treatment are not known. One potential reason is that the constitution and response of these clots to thrombolysis may differ in patients with different degrees of the metabolic syndrome. Our study has several limitations. First, we considered BMIasasurrogateofobesity,asusedinpreviousstudies. 5-16 Accumulating data, however, suggest that measures of central obesity, principally waist circumference and waist hip ratio, are more closely associated with morbidity and mortality. Therefore, it is not known whether our results would change if different methods to determine obesity, such as CT detection of visceral obesity, were used. Second, despite a sufficiently large sample size to detect differences between patients within the risk categories of obesity, the number of patients included in this study did not allow us to perform exploratory analyses to investigate the differences in stroke outcomes in obese and overweight patients stratified according to their metabolic status. Third, we did not measure waist circumference as a component of metabolic syndrome, but used BMI instead. Fourth, because a majority of patients included in this analysis had moderately severe stroke (median NIHSS score of 12), these findings may not be generalized to other stroke patients who present with either milder or very severe neurologic deficits. Lastly, when comparing our results with previous studies of obesity and metabolic syndrome in stroke patients, it is important to bear in mind that we only included patients treated with intravenous thrombolysis. This study highlights the importance of considering age, stroke severity, and risk components of the metabolic syndrome when evaluating the effects of obesity on the outcomes of rtpa-treated stroke patients. Recognition of metabolic syndrome may identify a subgroup of patients with lower probability of achieving favorable functional outcome, in whom more aggressive treatment approaches may, perhaps, be warranted. Table 3. Predictors of poor stroke recovery after intravenous recombinant tissue plasminogen activator treatment Regression model B weights P value Adjusted R 2.519 P value,.001 Explanatory variables Age 0.048.019 Baseline stroke severity 0.332,.001 No. of metabolic risk components 0.523.021 Figure 1. Comparison between the number of risk components of the metabolic syndrome and the proportion of patients with poor functional recovery after treatment with intravenous recombinant tissue plasminogen activator. Variables not included in the equation include the dose of recombinant tissue plasminogen activator per kilogram of body weight and body mass index.

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