Early Hospitalization of Patients with TIA: A Prospective, Population-based Study

Early Hospitalization of Patients with TIA: A Prospective, Population-based Study Mohamed Al-Khaled, MD, and J urgen Eggers, MD Background: The German Stroke Society (GSS) recommends early hospitalization of patients with transient ischemic attack (TIA) regardless of ABCD 2 score. This population-based study determined the rate of stroke during hospitalization and within 3 months after discharge, as well as the rates of mortality and readmission during the 3 months after discharge in patients with TIA. Methods: During a 36-month period (starting November 2007), 2200 consecutive patients (mean age, 70.6 6 12.8 years; 49% women) with TIA from 15 hospitals in the Federal State of Schleswig-Holstein (1 of the 16 states in Germany) were prospectively evaluated during hospitalization and a follow-up time of 3 months after discharge. The primary outcomes were stroke during hospitalization and 3 months after discharge, as well as readmission and mortality at 3 months. Odds ratios (ORs) were calculated by the adjusted logistic regression analysis. Results: Of 2200 patients (median time of admission, 6 hours from symptom onset), 24 patients (1.1%; 95% confidence interval [CI], 0.7%-1.5%) experienced a stroke during hospitalization (mean, 6 days), and of 1335 patients, 38 (2.8%; 95% CI, 2.1%-3.8%) experienced a stroke during the 3 months after discharge. Stroke during hospitalization was independently correlated with male sex (OR, 3.5) and acute brain infarction detected by brain imaging (OR, 2.6), whereas stroke within 3 months correlated with age greater than 65 years (OR, 3.0). The readmission rate (11.1%; 95% CI, 9.3%-12.7%) was increased in patients who had had previous stroke (OR, 1.7) but decreased in patients who were discharged with statin medication (OR, 0.6). The 3-month mortality (1.4%; 95% CI, 0.9%-1.9%) was independently correlated with unilateral weakness (OR, 2.6) and atrial fibrillation (AF) (OR, 2.6). Conclusions: These findings may help clinicians to estimate the TIA prognosis in patients who were hospitalized early with TIA. Key Words: Workup stroke mortality readmission statin epidemiology. Ó 2014 by National Stroke Association Transient ischemic attack (TIA) is an unstable condition that is associated with a high risk of stroke after the first event. The risk of stroke after TIA is 10% in the first 7 days after symptom onset, with half occurring in the first 48 From the Department of Neurology, University of L ubeck, L ubeck, Germany. Received July 9, 2012; revision received August 28, 2012; accepted October 1, 2012. Address correspondence to Mohamed Al-Khaled, MD, Department of Neurology, University of 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 http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2012.10.001 hours after symptoms begin. 1,2 The early risk of stroke can be predicted with the ABCD 2 score, 1,3,4 which includes age greater than 60 years, blood pressure greater than 140/90 mm Hg, clinical features, duration of symptoms, and history of diabetes. International guidelines vary regarding how to manage patients with TIA. According to the American Heart Association, 5,6 patients with TIA should be hospitalized if they have an ABCD 2 score greater than or equal to 3. By contrast, a study by Amarenco et al 7 showed that the risk of stroke at the 3-month follow-up in patients with an ABCD 2 score less than or equal to 3 could be similar to that of patients with an ABCD 2 scoregreaterthan3.thegermanstrokesociety (GSS) recommends early hospitalization, regardless of the ABCD 2 score, in patients with TIA so that they can undergo Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 1 (January), 2014: pp 99-105 99

100 a TIA workup, preferably in a stroke unit. 8,9 The TIA workup included routine blood tests composed of complete blood count, chemistry panel, basic coagulation profile, and fasting lipid profile. Younger patients (,55 years) who had experienced TIA underwent extended coagulation screening tests (protein C and protein S levels, antithrombin III activity, and levels of factor V Leiden, von Willebrand factor, lupus anticoagulant, homocysteine, fibrinogen, D-dimer, plasminogen activator inhibitor-1, and anticardiolipin antibody) when no cause of TIA was identified. The TIA workup also incorporated brain imaging (cranial computed tomography [CCT] and/or magnetic resonance diffusion weighted imaging [MR- DWI]), duplex ultrasonography of the arteries in the brain and neck immediately after admission, monitoring in a stroke unit for at least 24 hours, long-term (24-hour monitoring) Holter electrocardiography (ECG), and transthoracic or transesophageal echocardiography. If the diagnostic evaluation revealed pathologic findings (eg, stenosis of the internal carotid artery, atrial fibrillation [AF]), patients remained in the hospital until sufficient therapy with a thromboendarterectomy/stent or oral anticoagulation (OAC) had been carried out. The aim of the present population-based study was to determine the rate of stroke during hospitalization and within 3 months after discharge, as well as the rates of readmission and mortality at the 3-month point in patients with TIA who were hospitalized within 48 hours of symptom onset. Methods Study Design The present population-based study included patients with TIA who underwent treatment at 15 hospitals in the Federal State of Schleswig-Holstein, Germany, as part of the benchmark project, Qualit atsgemeinschaft Schlaganfallversorgung in Schleswig-Holstein (QugSS2 [Quality of Stroke Treatment in Schleswig-Holstein]). This benchmark project has been described previously in the literature. 10,11 The federal state of Schleswig-Holstein is 1 of the 16 states in Germany and has 2.8 million inhabitants. During a 36-month period (starting November 2007), 2200 consecutive patients (mean age, 70.6 6 12.8 years; 49% women) with TIA from 15 hospitals were prospectively evaluated. All patients gave written informed consent for inclusion in this study. The study was approved by the local ethics committee at the University of L ubeck. In accordance with the definition put forth by the World Health Organization, a TIA was defined in this study as a sudden focal neurologic deficit with symptoms lasting less than 24 hours. 12 Patients were diagnosed with TIA by at least 1 vascular neurologist in the Department of Neurology and by 1 external neurologist in the Department of Internal Medicine at the hospitals included in this M. AL-KHALED AND J. EGGERS study. Patients who were admitted with neurologic symptoms were evaluated during their hospital stay. The diagnosis of TIA was made after admission and during hospital stay. According to the guidelines of the GSS, patients with TIA are generally hospitalized to provide a rapid evaluation of the origin of the TIA. The diagnostic procedures included routine blood tests (see earlier), CCT, ECG, monitoring in the stroke unit for at least 1 day, duplex ultrasonography of the arteries of the neck and brain, electroencephalography, long-term (24 hours) ECG, transthoracic or transesophageal echocardiography, and magnetic resonance imaging (MRI) including DWI. Secondary prevention strategies consisted of treatment with an antiplatelet drug immediately after admission; carotid revascularization using carotid endarterectomy or carotid angioplasty stenting for recently symptomatic stenosis of the internal carotid artery; treatment with oral anticoagulants for AF; medication with statins; optimization of the treatment of hypertension, diabetes, and hypercholesterolemia; advice about reducing vascular risk factors by activities such as physical exercise and practicing "Mediterranean alimentation"; and advisory information about cerebrovascular diseases. The inclusion criteria for patients with TIA were admission to a hospital within the first 48 hours of symptom onset and main place of residence in Schleswig-Holstein. The exclusion criteria were admission to a hospital after 48 hours after symptom onset and age younger than 18 years. Patients who were admitted with TIA symptoms but diagnosed with a possible epileptic seizure, migraine, or functional disorders during hospitalization and after diagnostic procedures were not entered in the stroke registry. The decision to admit patients with neurologic symptoms was made by a neurologist in the Department of Neurology and by an internist in the Department of Internal Medicine. The follow-up time was 3 months. A follow-up questionnaire concerning medical information was mailed to patients 3 months after their discharge from the hospital. The questionnaire was created to evaluate the stroke after TIA, readmission after discharge, and mortality at 3 months. In case of lack of information or clarity, a telephone interview with patients and/or caregivers was performed to obtain reliable information about the medical status of the patient. When patients were unavailable, 3-month mortality was evaluated online by a request to the registration office. Baseline characteristics age, sex, TIA symptoms, time to admission, medical history, cause of TIA, diagnostic and therapeutic procedures, and secondary prevention strategies were recorded (Table 1). The primary outcomes were the rate of stroke during hospitalization and the rates of stroke, mortality, and readmission 3 months after discharge from the hospital. In accordance with the definition put forth by the World Health Organization, stroke was defined as a focal or global

EARLY HOSPITALIZATION OF TIA PATIENTS 101 Table 1. Baseline characteristics of patients with stroke during hospitalization versus those without Stroke during hospitalization Characteristic No, n 5 2176 (%) Yes, n 5 24 (%) P value Age (y), mean (SD) 70.5 (13) 70.8 (11).9 Male sex 1095 (50) 18 (78).008 ABCD 2 score 0-1 57 (3) 1 (4) 2-3 771 (36) 6 (25) 4-5 937 (44) 12 (50) 6-7 387 (18) 5 (21).72 Symptom onset to admission,3 h 845 (40) 13 (54) 3-6 h 609 (28) 4 (16) 6-24 h 304 (14) 3 (13) 24-48 h 315 (15) 4 (16).27 Admission time Workday 1694 (78) 20 (83) Weekend 482 (22) 4 (17).5 NIHSS score at admission 0 1135 (54) 13 (57).8 $1 956 (46) 10 (44) Symptoms of TIA Unilateral motor weakness 552 (26) 9 (38).18 Aphasia 319 (15) 5 (23).34 Dysarthria 321 (15) 5 (21).41 Medical history Previous stroke 525 (24) 8 (33).31 Hypertension 1719 (80) 22 (92).14 Diabetes mellitus 389 (18) 6 (25).38 Hypercholesterolemia 1177 (56) 18 (75).56 Atrial fibrillation 379 (18) 2 (8).23 AT before TIA 830 (39) 12 (50).25 TIA cause (TOAST) Large artery atherosclerosis 435 (20) 9 (38).3 Cardioembolism 413 (19) 5 (19) Small artery occlusion 489 (23) 1 (6) Other determined cause 65 (3) 1 (6) Undetermined cause 605 (28) 7 (45) Extracranial duplex ultrasonography 2082 (97) 23 (96).8 Intracranial duplex ultrasonography 1995 (92) 23 (96).4 Brain imaging (CCT) 2072 (94) 22 (92).6 Brain imaging, (MR-DWI) 1209 (57) 15 (63).6 Acute infarction in brain imaging (CCT/MRI) 330 (15) 9 (38).003 Treatment with rt-pa 7 (3) 0 (0).7 OAC 411 (19) 5 (21).8 CEA/stenting 61 (3) 4 (17),.001 AT within 48 hours of onset 1825 (85) 23 (96).12 Antihypertensive agents 1688 (78) 21 (88).26 Antidiabetes drugs 315 (15) 5 (21).39 Statins 1331 (62) 19 (79).08 Mean hospital stay (SD) (d) 6 (3) 9 (3),.001 Abbreviations: AT, antiplatelet therapy; CCT, cranial computed tomography; CEA, carotid endarterectomy; MR-DWI, magnetic resonance diffusion weighted imaging; NIHSS, National Institutes of Health Stroke Scale; OAC, oral anticoagulant; rt-pa, recombinant tissue plasminogen activator; SD, standard deviation; TIA, transient ischemic attack; TOAST, the Trial of Org 10172 in Acute Stroke Treatment.

102 disturbance of brain function, which is rapidly developed and lasts more than 24 hours with no appearance of nonvascular causes. 13 The stroke during hospitalization was diagnosed clinically and by brain imaging. Patients who showed stroke-related symptoms underwent emergency CCT and received stroke management and stroke care. Statistical Analysis We analyzed the data using the Statistical Product and Service Solutions (SPSS) software program, version, 20 (SPSS, IBM Corp, Armonk, NY). The data were described with mean and standard deviation values for continuous variables and with absolute numbers and percentages for categorical variables. We performed a chi-square test to determine the correlation between categorical variables, a t test to determine the correlation between continuous variables, and a Mann-Whitney test to determine the correlation between ordinal variables. Adjusted logistic regression was carried out to estimate the odds ratios (ORs). All variables with a P value less than.10 were entered into the logistic regression model. A P value less than.05 was considered significant. Results A total of 2200 patients (mean age, 70.6 6 12.8 years; 49% women) met the inclusion criteria. Approximately two thirds of patients were admitted within 6 hours of symptom onset. Among 54% of patients, the TIA symptoms were resolved before admission (National Institutes of Health Stroke Scale score 5 0). All patients received the required diagnostic and therapeutic management as well as the implementation of secondary preventive procedures during their hospital stay, which lasted for a mean of 6 days. During hospitalization, 24 patients (1.1%; 95% confidence interval [CI], 0.7%-1.5%) experienced a stroke. Table 1 shows a comparison between patients who experienced stroke during hospitalization and those who did not. Using the adjusted logistic regression analysis, male sex (OR, 3.5; 95% CI, 1.3-9.7; P 5.012) and acute brain infarction detected by brain imaging (OR, 2.8; 95% CI, 1.2-6.8; P 5.017) were identified as factors associated with stroke during hospitalization. Of the 2200 patients included in this study, 1335 patients (61%) responded to the follow-up questionnaire. As shown in Table 2, among the 1335 patients who responded to the follow-up questionnaire, 38 patients (2.8%; 95% CI, 2.1%-3.8%) experienced stroke, and 148 patients (11.1%; 95% CI, 9.3%-12.7%) were readmitted to the hospital for reasons other than stroke during the 3 months after discharge. Using adjusted logistic regression analysis, age greater than 65 years (OR, 3.0; 95% CI, 1.1-8.6; P 5.04) was independently correlated with stroke during the 3 months after discharge. The adjusted logistic regression analysis revealed an increased rate of readmission in patients with a previous stroke (OR, 1.6; 95% CI, 1.1-2.5; P 5.023) and a reduced rate of readmission in patients who were discharged with statins (OR,.5; 95% CI,.4-.8; P 5.004). The rate of mortality at 3 months after discharge was obtained for 2125 patients (Table 2); of these, 30 patients (1.4%; 95% CI,.9%-1.9%) died. According to the adjusted logistic regression analysis, unilateral motor weakness (OR, 2.6; 95% CI, 1.2-5.5; P 5.009) and AF (OR, 2.6; 95% CI, 1.2-5.6; P 5.011) were independently identified as associated with mortality at 3 months after discharge from the hospital. The ABCD 2 score did not show a correlation with the stroke risk during hospitalization or with follow-up outcomes at 3 months, including rates of stroke, mortality, and readmission (Fig 1). Discussion M. AL-KHALED AND J. EGGERS In the present study, all patients were admitted to the hospital within a median time of 6 hours from symptom onset and were evaluated and treated during the hospital stay. According to the guidelines of the GSS, patients with TIA are generally hospitalized to provide a rapid evaluation of the origin of the TIA. The rate of stroke during hospitalization was 1.1% in our population. This result was markedly lower than in other studies, which reported a stroke risk ranging from 5% to 10% (depending on the study design and population) in the first week after TIA. 4 The low rate of stroke in our population may be explained by the early admission, rapid evaluation, and early implementation of secondary prevention strategies immediately after admission. The risk of stroke in the present study was comparable to that of a study in which a 4% risk of stroke was found in patients who were admitted to hospital within a median time of 3 days. 14 Another study reported a risk of stroke of 1.5% at 7 days after the first event in patients with TIA who were admitted to hospital and evaluated during hospitalization. 15 Even though there was no difference in the ABCD 2 scores between men and women in the present study, male sex was identified as a factor associated with stroke after TIA. Acute brain infarction detected by brain imaging (CCT and/or MR-DWI) was also found to be independently associated with stroke during hospitalization after TIA in the present study. This finding is in agreement with previous studies 16-18 that investigated the prognostic value of acute brain infarction for stroke risk after TIA. Researchers have thus proposed the incorporation of acute brain infarction in the ABCD 2 system. The rate of stroke at the 3-month follow-up was 2.8% in our population, which was lower than the stroke risk of 9.8% that was predicted by the ABCD 2 score 4 (median ABCD 2 score, 4 points) for our population. An age greater than 65 years was independently determined to correlate with the risk of a stroke occurring in the first 90 days after

Characteristics Table 2. Characteristics of the 3-month follow-up: stroke risk, readmission, and mortality 3-month stroke risk (n 5 1335) 3-month readmission (n 5 1335) 3-month mortality (n 5 2125) No, n 5 1297 (%) Yes, n 5 38 (%) P value No, n 5 1187 (%) Yes, n 5 148 (%) P value No, n 5 2095 (%) Yes, n 5 30 (%) P value Age (y), mean (SD) 70.4 (12) 74.1 (8.6).06 70.4 (12) 71.1 (12).56 70.4 (13) 84.8 (8),.001 Male sex 692 (53) 20 (53).9 548 (46) 74 (50).33 1062 (51) 11 (37).12 ABCD 2 score 0-1 34 (2.7) 1 (3) 34 (3) 1 (1) 55 (3) 1 (3) 2-3 470 (37) 16 (42) 434 (37) 52 (36) 746 (36) 9 (30) 4-5 549 (43) 13 (34) 498 (43) 64 (44) 899 (43) 11 (37) 6-7 226 (18) 8 (21).75 205 (18) 29 (20).4 371 (18) 9 (30).38 TIA symptoms Unilateral weakness 308 (24) 7 (18).43 274 (23) 41 (28).2 527 (25) 15 (50).002 Aphasia 177 (14) 9 (24).08 163 (14) 23 (16).51 311 (15) 7 (23).2 Dysarthria 170 (13) 4 (11).62 148 (13) 26 (18).08 305 (15) 7 (23).18 Medical history Previous stroke 253 (20) 12 (33).044 223 (19) 42 (29).006 498 (24) 12 (40).043 Hypertension 1019 (79) 30 (81).77 930 (79) 119 (81).58 1654 (80) 29 (97).021 Diabetes mellitus 209 (16) 9 (24).19 188 (16) 30 (21).16 373 (18) 8 (27).22 Hypercholesterolemia 705 (56) 22 (60).65 656 (57) 71 (49).09 1135 (56) 18 (60).63 Atrial fibrillation 212 (17) 6 (16).96 185 (16) 33 (22).039 353 (17) 13 (43),.001 AT before TIA 453 (35) 17 (45).22 409 (35) 61 (42).09 797 (39) 16 (53).09 AT,48 h after TIA 1098 (86) 30 (79).25 1000 (85) 128 (87).54 1764 (85) 24 (83).76 AT at discharge 1068 (83) 30 (79).46 976 (83) 122 (83).91 1744 (84) 25 (86).76 Acute brain infarction 214 (17) 8 (21).4 190 (16) 32 (22).08 328 (16) 3 (10).3 by CCT/MR-DWI OAC 264 (21) 7 (18).74 238 (20) 33 (22).54 397 (19) 4 (14).46 CEA /stenting 45 (4) 0.23 40 (4) 5 (3).98 64 (3) 1 (3).92 Abbreviations: AT, antiplatelet therapy; CCT, cranial computed tomography; CEA, carotid endarterectomy; MR-DWI, magnetic resonance diffusion weighted imaging; OAC, oral anticoagulant; SD, standard deviation; TIA, transient ischemic stroke. EARLY HOSPITALIZATION OF TIA PATIENTS 103

104 Figure 1. Stroke risk during hospitalization, and stroke risk, mortality, and readmission 3 months after discharge in association with ABCD 2 score. Values are recorded in percentages. discharge from the hospital. The risk of stroke during hospitalization and at the 3-month follow-up was lower than expected. These results may be attributed to the urgent management of TIA, comprehensive evaluation, and early hospitalization of patients with TIA in our study. Similarly, Calvet et al 15 found that patients with TIA who were admitted to the hospital had a stroke risk of 2.9% at the 3-month follow-up. The rate of readmission to the hospital after discharge was increased in patients who experienced a stroke before TIA and decreased in patients who were discharged with statins (OR, 0.5). Previous research has reported that treatment with statins has a neuroprotective effect in patients with cerebrovascular disease. 19,20 However, treatment with statins did not correlate with the other primary outcomes of our study. We also found that AF was independently correlated with mortality at the 3-month follow-up. In our population, patients with AF had higher rates of readmission and mortality at the 3-month followup; these findings are in agreement with those of other studies in which poor outcomes were found in patients with AF after the development of cerebrovascular disease. 21,22 Unilateral motor weakness, a known symptom of TIA, was also independently identified as a factor associated with 3-month mortality, which was lower than that (2.6%) reported in a previous study among patients with TIA who presented to emergency departments. 23 One of the most striking findings of the present study was the lack of association between the ABCD 2 score and the risk of stroke during hospitalization and at 90 days after discharge. These results are in agreement with those of the study by Amarenco et al, 7 which demonstrated that patients with an ABCD 2 score greater than 3 have the same risk of stroke at the 3-month follow-up as do patients with an ABCD 2 score less than or equal to 3. A mean hospitalization period of 6 days in our population might seem long, but this period includes cardiac monitoring for at least 24 hours in a stroke unit (in adherence to the guidelines of the GSS and all diagnostic evaluation procedures, including routine blood tests (see earlier), brain imaging (CCT and/or MR-DWI), duplex ultrasonography of arteries in the brain and neck, long-term Holter ECG, and transesophageal or transthoracic echocardiography. In addition, if the diagnostic evaluation revealed pathologic findings (eg, stenosis of the internal carotid artery, cardioembolism), patients stayed at the hospital until sufficient treatment was carried out. The following types of treatments were administered to a proportion of patients in our population: antihypertensive agents (78%), statins (62%), OAC (19%), antidiabetes drugs (15%), and surgical intervention and stenting for the internal carotid artery (3%). These procedures may have extended the hospital stay; however the mean hospital stay in the present study was shorter than in other populations in Germany (7.7 days). 24 We acknowledge that the urgent management of TIA in an outpatient setting or in a TIA clinic may have the same benefit, a finding that has been previously shown in the EXPRESS study (Existing Preventive Strategies for Stroke) 25 and the SOS-TIA study. 26 An outpatient setting has considerable advantages compared with hospitalization, namely, low health care cost and patient preference. Unfortunately, TIA clinics or outpatient settings specializing in the urgent evaluation of TIA do not exist in Germany. Our study has several limitations. First, approximately 40% of patients did not respond to the questionnaire. Second, the study protocol did not provide data about the findings of the CCT angiography and the cranial MRI angiography; therefore the frequency of intracranial stenosis was not recorded. Finally, the questionnaire used in the present study was not validated. Despite these limitations, this population-based study showed that the rate of stroke in patients with TIA during hospitalization and the rates of stroke, mortality, and readmission 3 months after discharge from the hospital were lower than the risk predicted by the ABCD 2 score. The low rates of stroke and mortality may be attributed to the benefits of early hospitalization and the rapid management of patients with TIA in our study. These findings may help clinicians to estimate the prognosis after a TIA in patients who were hospitalized early. References M. AL-KHALED AND J. EGGERS 1. Lovett JK, Dennis MS, Sandercock PA, et al. Very early risk of stroke after a first transient ischemic attack. Stroke 2003;34:138-140. 2. Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. 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