Mohamed Al-Khaled, MD,* Christine Matthis, MD, and J urgen Eggers, MD*

Predictors of In-hospital Mortality and the Risk of Symptomatic Intracerebral Hemorrhage after Thrombolytic Therapy with Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke Mohamed Al-Khaled, MD,* Christine Matthis, MD, and J urgen Eggers, MD* Recombinant tissue-plasminogen activator (rt-pa) therapy improves functional outcome in patients with acute ischemic stroke (AIS) but is associated with serious complications, including symptomatic intracerebral hemorrhage (sich). This study aimed to determine the independent predictors of in-hospital mortality (IHM) and the risk of sich after rt-pa therapy. A total of 1007 patients (mean age, 72 6 12 years; 52% women; mean National Institutes of Health Stroke Scale [NIHSS] score, 11.6 6 5.6) with AIS treated with rt-pawere enrolled in this study during a 42-month period beginning in November 2007. Univariate and multivariate regression analyses were performed to estimate the predictors of IHM. Eighty-three of the 1007 patients (8.2%) died during hospitalization (mean duration of hospitalization, 10 6 1.8 days). Logistic regression estimated the following independent predictors for IHM: age $80 years (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-3.0; P 5.031), aphasia (OR, 2.0; 95% CI, 1.1-3.4; P 5.017), altered consciousness (OR, 3.6; 95% CI, 2.0-6.2; P,.001), hypertension (OR, 4; 95% CI, 1.4-11.6; P 5 0.012), sich (OR, 5.9; 95% CI, 2.9-11.9; P, 0.001), and pneumonia during hospitalization (OR, 3.0; 95% CI, 1.8-5.0; P,.001). After rt-pa therapy, 58 patients (5.8%) sustained sich, 16 (28%) of whom died. Increased age (P 5.008), higher NIHSS score (P 5.011), and atrial fibrillation (P 5.025) were correlated with sich. The findings from this study may help clinicians estimate the prognosis and risk of sich in patients with AIS treated with rt-pa. Key Words: Stroke treatment prognosis outcome complication epidemiology. Ó 2014 by National Stroke Association Thrombolysis with intravenous (IV) recombinant tissue-plasminogen activator (rt-pa) is the only medically approved treatment for patients with acute ischemic stroke (AIS) that improves functional outcome after stroke and prevents disability caused by stroke. 1,2 Based From the *Department of Neurology; and Institute of Social Medicine, University of L ubeck, L ubeck, Germany. Received January 22, 2012; revision received February 22, 2012; accepted April 8, 2012. Address correspondence to Mohamed Al-Khaled, MD, Department of Neurology, University of L ubeck, Campus L ubeck, Ratzeburger Allee 160, 23538 L ubeck, Germany. E-mail: Mohamed.al-khaled@ neuro.uni-luebeck.de. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2012.04.004 on the findings of the European Cooperative Acute Stroke Study (ECASS) III, rt-pa therapy is effective when administered within 3-4.5 hours after symptom onset. 3 Two previous studies (ECASS I and ECASS II) failed to demonstrate the efficacy of administering IV rt-pa up to 6 hours after symptom onset. 4,5 However, patients who were treated with IV rt-pa had an higher rate of symptomatic intracerebral hemorrhage (sich) and greater mortality compared with patients with AIS in general, possibly related to the selection of more severely affected patients for IV rt-pa therapy. 6,7 The aims of the present population-based study were to estimate the short-term risk and predictors of early in-hospital mortality (IHM) after IV rt-pa therapy, and to determine the risk of sich in patients treated with IV rt-pa. Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 1 (January), 2014: pp 7-11 7

8 Methods Study Design This study is a part of the benchmarking project Quality of Treatment of Stroke in Schleswig-Holstein (QugSS2), which has been described previously. 8 The German federal state of Schleswig-Holstein has 2.8 million inhabitants. Of the 15 participating sites, 2 were university departments of neurology, 8 were departments of neurology at nonuniversity hospitals, and 5 were departments of internal medicine at nonuniversity hospitals. Ten of the hospitals had a stroke unit certified by the German Stroke Society. All patients provided written informed consent for inclusion in this study. Inclusion criteria included treatment of AIS with IV rtpa for up to 4.5 hours after symptom onset and main residence in the state of Schleswig-Holstein. Patients who received local thrombolytic therapy with rtpa were excluded. The documentation and data collection procedures followed a uniform study manual, in accordance with recommendations of the German Stroke Register Study Group. Baseline characterizations at admission sex, age, National Institutes of Health Stroke Scale (NIHSS) score, neurologic deficits at admission, vascular risk factors, history of stroke, and complications during hospitalization were documented and analyzed. sich was defined as any bleeding that was not detected on a previous computed tomography (CT) scan and was associated with a worsening NIHSS score of at least 4 points. All patients underwent a head CT scan before and 24 hours after IV rt-pa treatment as part of the clinical routine of administering thrombolytic therapy. Approval for the study was obtained from the local Ethics Committee of the University of L ubeck. Statistics Data analysis was done using SPSS PASW Statistics 18 (IBM, Armonk, NY). Correlations between categorical variables were identified using the c 2 test, and correlations between continuous variables were determined using the Student t test. The Wilcoxon test was used to compare modified Rankin Scale (mrs) scores at admission and at discharge. Logistic regression was performed to estimate odds ratios (ORs) for predictors of mortality. Baseline characteristics found to be significantly associated with mortality on univariate analysis, sich and pneumonia, were evaluated by logistic regression. A P value of,.05 was considered statistically significant. Results M. AL-KHALED ET AL. Between November 2007 and March 2011, a total of 1007 patients (mean age, 72 6 12 years; 52% women; mean NIHSS score, 11.6 6 5.6) with AIS received treatment with IV rt-pa. Eighty-three patients (8.2%) died during hospitalization (mean duration of hospitalization, 10 6 1.8 days). Table 1 presents the baseline characteristics Table 1. Baseline characteristics and risk factors Baseline characteristic/risk factor All (n 5 1007) IHM mortality (n 5 83) P value Age, years, mean (SD) 71.5 (12.2) 78.9 (8.4),.001 Age $80 years, n (%) 247 (25) 36 (44),.001 Female sex, n (%) 508 (51) 47 (57).22 NIHSS score, mean (SD); median (IQR) 11.6 (5.6); 11 (7-15) 16.4 (5.2); 17 (14-20),.001 mrs score, mean (SD); median (IQR) 4 (1.1); 4 (3-5) 4.5 (0.8); 5 (4-5).001 Paresis, n (%) 933 (94) 79 (98).15 Aphasia, n (%) 549 (56) 60 (74).001 Dysarthria, n (%) 672 (69) 61 (77).10 Dysphagia, n (%) 462 (49) 56 (71),.001 Altered unconsciousness, n (%) 136 (14) 29 (36),.001 Time to rt-pa, n (%),2 hours 367 (75) 24 (66) 2-3 hours 96 (20) 8 (22) 3-4.5 hours 25 (5) 4 (11).19 Admission on weekday, n (%) 717 (72) 56 (69) Admission on weekend, n (%) 285 (28) 26 (32).49 Hypertension, n (%) 795 (81) 77 (95) 0.001 Diabetes mellitus, n (%) 198 (20) 25 (31) 0.01 Hypercholesteremia, n (%) 477 (51) 30 (41) 0.06 Atrial fibrillation, n (%) 387 (40) 42 (54) 0.01 History of stroke, n (%) 197 (20) 15 (19) 0.79 Hospital stay, days, mean (SD) 10 (1.8) 3 (2.8),0.001 Abbreviations: IHM, in-hospital mortality; IQR, interquartile range; mrs, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; rt-pa, recombinant tissue-plasminogen activator; SD, standard deviation.

MORTALITY AND RISK OF SYMPTOMATIC ICH AFTER THROMBOLYTIC THERAPY 9 and risk factors found to correlate significantly with IHM on univariate analysis. The following independent predictors for IHM were estimated using logistic regression analysis: age $80 years (OR, 1.8; 95% CI, 1.1-3.0; P 5.031), aphasia (OR, 2.0; 95% CI, 1.1-3.4; P 5.017), altered consciousness (OR, 3.6; 95% CI, 2.0-6.2; P,.001), hypertension (OR, 4; 95% CI, 1.4-11.6; P 5.012), sich (OR, 5.9; 95% CI, 2.9-11.9; P,.001), and pneumonia during hospitalization (OR, 3.0; 95% CI, 1.8-5.0; P,.001) (Table 2). Neither the time between symptom onset and start of thrombolytic therapy variable nor the time of hospital admission variable (ie, weekend [28%] vs weekday [72%] admission) was correlated with IHM. After IV rt-pa treatment, 58 of the 1007 patients with AIS sustained sich (5.8%), 16 of whom died (27%). The patients with sich were significantly older than those without sich (78.8 years vs 70.9 years; P 5.008) and had a significantly higher mean NIHSS score at admission (13.5 vs 11.5; P 5.011). Atrial fibrillation was the sole baseline variable that was significantly more common in the patients with sich (55% vs 39%; P 5.025); no other baseline characteristics were associated with sich as a complication after IV rt-pa treatment. The data showed no significant increase in risk of sich in patients aged $80 years (Table 3). Complications after thrombolytic therapy with IV rt-pa and during hospitalization are summarized in Table 4. Patients who survived AIS had a significantly lower mean mrs score at discharge compared with that at admission (2.68 vs 3.98; P,.001). Discussion Data from Germany on the incidence of IHM and the risk of sich in population-based studies are sparse. We estimated the incidence of IHM and identified the independent predictors of early mortality in patients with AIS after thrombolytic therapy with IV rt-pa. The risk of IHM in our study cohort was 8.2%, lower than the previously reported 10%-11% risk of early mortality after rt-pa treatment. 1,9 Older age and greater severity of neurologic deficits at admission as measured by the NIHSS were significantly correlated with IHM. Logistic regression analysis revealed that patient age $80 years Table 2. Predictors of IHM in patients treated with IV rt-pa Predictor OR 95% CI P value Age $80 years 1.8 1.1-3.0.031 Aphasia 2.0 1.1-3.4.017 Altered consciousness 3.6 2.0-6.2,.001 Hypertension 4.0 1.4-11.6.012 sich 5.9 2.9-11.9,.001 Pneumonia 3.0 1.8-5.0,.001 Abbreviations: IHM, in-hospital mortality; IV, intravenous; OR, odds ratio; rt-pta, recombinant tissue-plasminogen activator; sich, symptomatic intracerebral hemhorrage. and the presence of neurologic deficits, such as aphasia and altered consciousness at admission, reflect the severity of stroke and are independent predictors of IHM. These findings are in agreement with those of a study by Heuschmann et al, 9 in which older age and altered consciousness were identified as independent predictors for hospital death in 1658 patients treated with rt-pa. The frequency of hypertension as a comorbid condition was 81% in our patient cohort overall, but 95% in the patients who died after receiving thrombolytic therapy with IV rt-pa. Our data also identify hypertension as an independent predictor of IHM, increasing the risk of death during hospitalization by approximately 4-fold. Hypertension generally promotes arteriosclerosis, possibly explaining the higher rate of IHM in patients with a known history of hypertension. The most feared complication after IV rt-pa therapy is sich, and after stroke is pneumonia suffered during hospitalization. The rate of sich in our study with 4.8% is lower than the rate (6%-7%) reported in previous studies. 9,10 On logistic regression analysis, the OR for death during hospitalization was approximately 6-fold higher in the patients with sich compared with those without sich. A previous study by Weimar et al 11 identified age and NIHSS score as independent predictors of outcome in ischemic stroke. In the present study, older age and higher NIHSS score were significantly correlated with sich. However, despite the significant correlation between older age and sich, no correlation was found between age $80 years and sich. Similarly, in a systematic review of 2244 patients, Engelter et al 12 found no difference in the likelihood of sich between patients aged.80 years and those aged,80 years. 12 In the present study, the patients with sich were significantly older than those without sich; however, when age was dichotomized (with patients divided into those aged $80 years and those aged,80 years), the risk of sich was not significantly greater in the older age group. Moreover, we found that the occurrence of sich was associated with the presence of atrial fibrillation and was significantly associated with higher IHM. These findings are in accordance with previous studies reporting poor outcomes in patients with stroke and atrial fibrillation. 13,14 Other comorbidities, including diabetes mellitus, hypercholesterinemia, hypertension, previous stroke, and neurologic deficits (eg, paresis, aphasia, dysarthria, dysphagia, altered consciousness) were not correlated with sich in the present study. In accordance with previous studies, 15,16 we found no association between the presence of diabetes mellitus alone or in combination with a previous stroke and the occurrence of sich after thrombolytic therapy with IV rt-pa. Pneumonia is the most common complication during hospitalization and carries the highest attributable risk of death in patients with stroke. 17 In our cohort, 35 of

10 M. AL-KHALED ET AL. Table 3. Baseline characteristics in patients with and without sich Baseline characteristic/risk factor All (n 5 1007) SICH (n 5 58) P value Age, years, mean (SD) 71.5 (12.2) 75.6 (9).008 Age $80 years, n (%) 247 (25) 18 (31).25 Female sex, n (%) 508 (51) 29 (50).88 NIHSS score, median (IQR) 11 (7-15) 17 (10-18).011 Paresis, n (%) 933 (94) 54 (95).78 Aphasia, n (%) 549 (56) 32 (55).93 Dysarthria, n (%) 672 (69) 42 (73).54 Dysphagia, n (%) 462 (49) 28 (52).63 Altered conscious, n (%) 136 (14) 8 (14).93 Time to rt-pa, n (%),2 hours 367 (75) 21 (75) 2-3 hours 96 (20) 6 (21) 3-4.5 hours 25 (5) 1 (4).91 Hypertension, n (%) 795 (81) 48 (89).12 Diabetes mellitus, n (%) 198 (20) 14 (26).29 Hypercholesteremia, n (%) 477 (51) 20 (40).08 Atrial fibrillation, n (%) 387 (39) 29 (55).025 History of stroke, n (%) 197 (20) 8 (14).25 Abbreviations: IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; rt-pa, recombinant tissue-plasminogen activator; SD, standard deviation; SICH, symptomatic intracerebral hemhorrage. the 83 patients who died had pneumonia (42%). Logistic regression analysis revealed that pneumonia was associated with a 3-fold increased risk for IHM. Other complications, including symptomatic edema and cardiovascular disease, were also associated with increased risk of death after IV rt-pa treatment. Despite the risk of sich after IV rt-pa treatment and pneumonia as a complication of hospitalization, we found that overall, our patients with AIS benefited from IV rt-pa treatment. As assessed in this observational study, the patients who survived AIS had a significantly lower mrs score at discharge compared with that at admission (mean score, 2.68 vs 3.98; P,.001). This finding requires further investigation in a randomized trial including patients not treated with IV rt-pa. The present study has several strengths, including its investigation of the interval between symptom onset and IV rt-pa administration, its population-based design, its large patient cohort, and data acquisition from 15 hospitals that follow a uniform protocol in the standardized treatment of stroke (based on recommendations of the German Society for Neurology). A limitation of this study is its failure to include long-term outcomes after hospital discharge. Further investigation is needed to determine whether long-term mortality differs from early IHM. In conclusion, we have identified the following independent predictors for IHM after thrombolytic therapy: age $80 years, aphasia, altered level of consciousness, hypertension as a vascular risk factor, sich, and pneumonia. These findings may provide prognostic information about patients receiving IV rt-pa and help clinicians focus attention on patients with these predictors. Acknowledgment: This article is dedicated in memory of a colleague, Dr Nahel Othman, who was killed for his Table 4. Complications during hospitalization after rt-pa treatment Complication All (n 5 1007) IHM (n 5 83) P value sich, n (%) 58 (5.8) 16 (19),.001 Pneumonia, n (%) 183 (18) 35 (42),.001 Stroke recurrence, n (%) 30 (3) 3 (4).70 Early seizure, n (%) 16 (2) 3 (4).10 Symptomatic edema, n (%) 40 (4) 21 (25),.001 Confusion, n (%) 34 (3) 1 (1).20 Fall during hospital stay, n (%) 16 (2) 0.20 Cardiovascular complications, n (%) 35 (4) 20 (24),.001 Other complications, n (%) 139 (14) 32 (39),.001 Abbreviations: IHM, in-hospital mortality; rt-pa, recombinant tissue-plasminogen activator; sich, symptomatic intracerebral hemhorrage.

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