Journal of the Neurological Sciences 340 (2014) 44–49

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Intravenous thrombolysis with rt-PA for acute ischemic stroke within 24 h of a transient ischemic attack Piotr Sobolewski a,⁎, Waldemar Brola b, Małgorzata Wiszniewska c, Wiktor Szczuchniak a, Małgorzata Fudala b, Mariusz Domagalski c, Monika Śledzińska-Dźwigał a a b c

Department of Neurology and Stroke Unit, Holy Spirit Specialist Hospital in Sandomierz, Sandomierz, Poland Department of Neurology and Stroke Unit, Saint Luke's Hospital in Końskie, Końskie, Poland Department of Neurology and Stroke Unit, Hospital in Piła, Piła, Poland

a r t i c l e

i n f o

Article history: Received 2 December 2013 Received in revised form 19 January 2014 Accepted 20 February 2014 Available online 26 February 2014 Keywords: Transient ischemic attack Acute ischemic stroke rt-PA iv-thrombolysis Safety Efficacy

a b s t r a c t Background: Intravenous thrombolysis (iv-thrombolysis) with the use of rt-PA in patients after recent transient ischemic attack (TIA) is an important clinical problem. The aim of the study was to assess the impact of TIA within 24 h preceding acute ischemic stroke (AIS) on the safety and efficacy of iv-thrombolysis. Methods: We retrospectively evaluated the clinical and demographic data of 400 patients with AIS who were consecutively treated with iv-thrombolysis from September 2006 to May 2011 in three stroke centers. Results: At three-month follow-up, 58.0% of patients were independent (modified Rankin scale; mRS 0–2), 17.8% had died, 17.0% suffered hemorrhagic transformation (HT) and 4.3% experienced symptomatic intracerebral hemorrhage (SICH). There were 29 patients (7.3%) who had a previous ipsilateral TIA within 24 h before established stroke. In the TIA subgroup, there was no significant higher percentage of favorable outcome (p = 0.07) and higher SICH rate (p = 0.15). Multivariate analysis showed the impact of prior TIA within 24 h before stroke onset in the presence of SICH (p = 0.01), no impact of TIA on unfavorable outcomes after three months (p = 0.25) and on the mortality rate within three months (p = 0.41). Conclusion: TIA within 24 h prior to ischemic stroke can portend severe intracerebral bleeding in patients qualified to iv-thrombolysis with the use of rt-PA. © 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction Transient ischemic attacks (TIAs) are brief episodes of neurological dysfunction resulting from cerebral ischemia not associated with permanent cerebral infarction. The traditional definition of TIA on the basis of a temporal criterion needs revision since almost one-third of patients with transitory symptoms within the 24 h threshold have had a new related infarction, as assessed by diffusion-weighted magnetic resonance imaging (DW-MRI) [1,2]. As endorsed by 2009 guidelines from the American Heart Association and American Stroke Association (AHA/ASA), transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction [3]. Precise estimates of the incidence and prevalence of TIAs are difficult to determine, mainly because of the varying criteria used in epidemiological studies to identify ⁎ Corresponding author at: Department of Neurology and Stroke Unit, Holy Spirit Specialist Hospital in Sandomierz, 13 Schinzla Str., 27-600 Sandomierz, Poland. Tel.: + 48 608510991, + 48 158330650; fax: + 48 158330593. E-mail address: [email protected] (P. Sobolewski).

TIA. TIAs have been shown to be a strong predictor of subsequent stroke and death [4]. The risk of stroke after a TIA has been estimated at 14.6% within three months of observation, and the risk of TIA/stroke/death is 25.2% [5]. The history of an established TIA within the previous three months is not a formal contraindication for intravenous thrombolysis. However, TIA could influence outcome after iv-thrombolysis, because some patients may have, invisible in the CT scans, ischemic lesions and intracerebral microbleeds. Only a few studies have assessed the impact of prior TIA on the longterm outcome and safety of iv-thrombolysis in patients with acute ischemic stroke. Limitations of these studies are: the relatively small groups of patients with a history of TIA and performing only computed tomography (CT) imagings as a rule [6,7]. This also applies to our study. We also had to base our analysis on data from an interview from patients or their guardians, and only in some cases were we able to observe a TIA in our stroke units. The objective of the present study was to assess the impact of TIA within 24 h preceding an acute ischemic stroke (AIS) on the safety and efficacy of intravenous thrombolytic therapy.

http://dx.doi.org/10.1016/j.jns.2014.02.022 0022-510X/© 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

P. Sobolewski et al. / Journal of the Neurological Sciences 340 (2014) 44–49

2. Material and methods 2.1. Patient population We retrospectively evaluated the clinical and epidemiological data of 400 Caucasian patients with acute ischemic stroke who were consecutively treated with iv-thrombolysis from September 2006 to May 2011 in three experienced stroke centers in Poland (the Department of Neurology and the Stroke Unit of the Hospital in Sandomierz, the Department of Neurology and Stroke Unit of the Hospital in Końskie and the Department of Neurology and the Stroke Unit of the Hospital in Piła). These study centers are recognized as stroke units according to the Polish national criteria and are equipped with the proper monitoring and diagnostic facilities [8] and provided a 24-hour stroke service 7 days a week. 2.2. Protocol Participating stroke units share common, periodically updated protocols for the management of acute ischemic stroke and secondary prevention, according to international recommendations [9]. To collect the data a pre-specified database was used. All patients were examined at the time of admission by a stroke physician, and the severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) [10]. Stroke onset was defined as the last occasion on which the patient was known to be without neurological deficit. Exams to evaluate the coagulation status in all the patients were performed. CT scans were performed upon admission to hospital in order to establish the indication for treatment, between 22 and 36 h and on the seventh day after iv-thrombolysis. Intravenous 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 have been treated within the 4.5-hour time window [11–13]. In patients, to evaluate the etiology of stroke and to determine secondary prevention transcranial Doppler (TCD), carotid duplex ultrasonography, Holter electrocardiography (Holter ECG), transthoracic echocardiography (TTE) and in the case of some patients transesophageal echocardiography (TEE) was performed. The 90-day stroke outcomes were measured using the modified Rankin scale (mRS) [14]. A favorable outcome was defined as an mRS score ≤2 points, while an unfavorable outcome was defined as an mRS score of 3–6 points. The 90 day mRS was obtained by clinic or home visits. Hemorrhagic transformation (HT) and symptomatic intra-cerebral hemorrhage (SICH) rates were assessed according to the European Cooperative Acute Stroke Study (ECASS) II criteria. Radiographically, in ECASS II protocol HT was classified into hemorrhagic infarction (petechial infarction without space occupying effect) and parenchymal hematoma (hemorrhage with mass effect); clinically, SICH was defined as an intracranial hemorrhage if the patient had clinical deterioration causing an increase in the NIHSS score by 4 points, and if the hemorrhage was likely to be the cause of the clinical deterioration [15]. All included patients were specifically interviewed by a neurologist for symptoms of TIA suffered within 24 h prior to recruitment, or we observed incidents of TIA during hospitalization in our stroke units prior to thrombolytic therapy. When patients were not able to give the sought-after information, the relatives or medical records provided the data. TIA was defined on a clinical basis as a documented transient focal neurological deficit lasting b24 h. Due to the limited availability of MRI in routine practice, only patients with performed CT were included in this study. All patients had complete resolution of the neurologic symptoms of TIA before the acute ischemic stroke. Clinical symptoms, number of TIA events suffered, the time from TIA to definite symptom onset and duration of episodes were recorded. Only cases in which patients had a documented normal neurological examination after episode of TIA were included. Patients who qualified for thrombolytic

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therapy had symptoms for at least 30 min without a significant improvement before treatment. In patients who were admitted to the hospital due to TIA antiplatelet or anticoagulant therapy was implemented or continued according to the indications. All patients treated with iv-thrombolysis in our stroke units were reported to the SITS registry. The ethics committee approved all data analyses (Ethics Committee of Świętokrzyska Medical Chamber). Each patient, or in case of his/her inability, two physicians, signed the standardized consent form in respect of the Ethical Principles for Medical Research involving human subjects approved in Helsinki in 1964 by World Medical Association. 2.3. Statistical analysis This study was based on a retrospective data analysis. Data gathering and characteristics and univariate analysis were performed using Microsoft Excel 2010. Logistic regression was performed with STATISTICA v. 9.1. All continuous variables were tested for a normal distribution and equality of variances. Because of the non-normality of the variables, non-parametric Mann–Whitney U tests were used to perform the univariate analysis of the continuous variables. Categorical data were compared using chi square tests. p values b0.05 were considered statistically significant. The multivariate analysis was performed using multiple logistic regression. Factors identified on univariate analysis with a p value b0.1 were then examined using a multivariate model. In the analysis, age and sex were also included. The results of the logistic regression models were presented as odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). 3. Results In the analyzed group, there were 400 patients with acute ischemic stroke treated with iv-thrombolysis (54.5% male; aged 41–92; mean age 69.6 ± 11.8). Median onset to treatment time was 160 min (range 135–180 min). After three months of follow-up, 58.0% of patients were independent (mRS 0–2), 17.8% had died, 17.0% had suffered HT and 4.3% had experienced SICH according to the ECASS II definition. Baseline characteristics, onset to treatment time, stroke severity, the distributions of risk factors, previous treatments, laboratory findings, and radiological findings in CT scans at baseline and functional outcomes after the months in TIA and non-TIA patients are shown in Table 1. There were 29 patients (7.3%) who had a previous ipsilateral TIA within 24 h before established stroke. Most of the patients (n = 22; 75.9%) had a single episode of TIA, while seven patients (24.1%) had more than one episode. The time interval between the first TIA episode and the time of stroke onset ranged from 60 to 1320 min with a median duration of 369 min (range 160–720). The median duration of TIA was 45 min (range 4–300). All patients had ipsilateral TIA compared to the stroke signs. The groups of patients with prior TIA within 24 h before stroke onset and without TIA did not differ according to the presence of most vascular risk factors, onset to treatment time, laboratory and radiological findings at baseline. Coronary heart disease and the use of pre-stroke antiplatelet drugs were more frequent in the group of patients without prior TIA. Median arterial pressure (MAP), diastolic and systolic blood pressure at the time of admission were higher in group of patients with prior TIA. The NIHSS score at the time of admission was lower in patients with prior TIA (p = 0.04). 41% of patients with history of TIA prior to iv-thrombolysis were treated with antiplatelet agents and 24% — with anticoagulants (all patients had INR b1.7). In the TIA subgroup, there was no significant higher percentage of favorable outcome (p = 0.07) and higher SICH rate according to the ECASS definition (p = 0.15) (Table 1). Multivariate analysis showed the impact of prior TIA within 24 h before stroke onset in the presence of SICH (p = 0.01), no impact of

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Table 1 The clinical characteristics of the subgroups of thrombolytic patients without and with history of TIA within 24 h before stroke onset.

n (%) Demographic data Mean age (±SD) Male gender, n (%) Risk factors, n (%) Hypertension Coronary heart disease Atrial fibrillation Diabetes mellitus Dyslipidemia Smoking Pre-stroke antiplatelets Pre-stroke anticoagulants OCSP classification, n (%) TACI (Total Anterior Circulation Infarct) PACI (Partial Anterior Circulation Infarct) LACI (Lacunar Infarct) POCI (Posterior Circulation Infarct) Etiological classification, n (%) Large vessel disease Cardioembolism Lacunar stroke Undetermined etiology Stroke severity, median NIHSS (pts.) (IQR) Onset to treatment time (min) (IQR) Median arterial blood pressure before thrombolysis (mm Hg) (IQR) MAP Diastolic Systolic Laboratory findings before thrombolysis Median INR (IQR) Median glucose level, mmol/l (IQR) Median creatinine level, μmol/l (IQR) Radiological findings in CT scans at baseline, n (%) Old ischemic changes Early ischemic changes mRS 0–2 at three months, n (%) Hemorrhagic transformation (HT)a, n (%) SICHa, n (%) Mortality, n (%)

No prior TIA

Prior TIA within 24 h

p value

371 (92.8)

29 (7.2)

–

69.7 ± 11.9 202 (54.5)

67.7 ± 10.2 16 (55.2)

0.26 0.55

244 (65.8) 190 (51.2) 132 (35.6) 55 (14.8) 255 (68.7) 79 (21.3) 224 (60.4) 45 (12.1)

20 (69.0) 9 (31.0) 7 (24.1) 8 (27.6) 24 (82.8) 9 (31.0) 12 (41.4) 7 (24.1)

0.73 0.04 0.21 0.12 0.11 0.22 0.045 0.06

116(31.3) 183(49.3) 68(18.3) 4(1.1)

10(34.5) 10(34.5) 7(24.1) 2(6.9)

0.72 0.12 0.44 0.09

132 (35.6) 125(33.7) 43(11.6) 72(19.4) 11.0 (8.0–16.0) 160(135.0–180.0)

14 (48.3) 9(24.1) 5(17.2) 3(10.3) 8.0 (6.0–14.0) 160.0 (135.0–190.0)

0.17 0.29 0.55 0.23 0.04 0.93

108.0 (99.7–117.7) 85.0 (80.0–95.0) 155.0 (140.0–170.0)

113.3 (104.7–123.7) 90.0 (85.0–100.0) 165.0 (150.0–175.0)

0.02 0.01 0.04

1,05 (1.0–1.1) 6.4 (5.6–7.6) 88.4 (73.4–101.7)

1.03 (1.0–1.1) 6.2 (5.6–8.4) 86.1 (69.8–97.0)

0.36 0.77 0.68

132 (36.1) 89 (24.0) 211 (56.9) 63 (17.0) 13 (3.5) 67 (18.1)

12 (41.4) 10 (34.5) 21 (72.5) 5 (17.2) 4 (13.8) 4 (13.8)

0.57 0.21 0.07 0.63 0.15 0.56

mRS — modified Rankin scale, MAP — median arterial pressure, NIHSS — National Institutes of Health Stroke Scale, ECASS — European Cooperative Acute Stroke Study, SICH — symptomatic intracerebral hemorrhage, SD — standard deviation, IQR — interquartile range (Q1–Q3), CT — computed tomography, OCSP — Oxford Community Stroke Project, and pts. — points. a According to the ECASS II criteria.

TIA on unfavorable outcomes after three months (p = 0.25) and on the mortality rate within three months (p = 0.41). In the multivariate regression, lower NIHSS scores were associated with good outcomes (p b 0.0001) and higher NIHSS scores were associated with SICH (p = 0.02) and mortality (p b 0.0001). The analysis did not show the impact of prior to stroke treatment with antiplatelet agents or anticoagulants on the incidence of SICH in the TIA subgroup (Fig. 1). 4. Discussion Our analyses showed the impact of prior TIA within 24 h before stroke onset in the presence of SICH, no impact of TIA on unfavorable outcomes after three months and on the mortality rate within three months in a population-based cohort of 400 Caucasian patients with AIS. The reported prevalence of prior TIA in patients presenting with AIS ranges from 7% to 40% [3,16,17]. The effectiveness and safety of systemic cerebral thrombolysis in patients with previous TIA have not been clearly determined to date. Some studies have previously brought up the safety and efficacy of thrombolytic therapy in such patients. We

did not find any study that assessed the impact of TIA within 24 h before stroke on the efficacy of intravenous thrombolytic therapy. de Leciñana et al. conducted an observational study from a prospective registry of all AIS patients treated between 2003 and 2009 in Spain. There were 60 patients (6.8%) who had a previous ipsilateral TIA within one month prior to the current stroke; 71.6% of the patients had a single episode of TIA before an established stroke, while 28.4% had two or more than two episodes. 65% of TIA episodes occurred during the preceding 24 h [6]. Patients with previous TIA in our sample were older but fewer were severely affected at onset than those reported in the series in the observational study by de Leciñana et al. We also included patients N80 years of age in our series. Both in the group of patients from Spain as well as in our group, there were no statistically significant differences between the subgroups of patients with a history of TIA and without TIA regarding long-term outcomes and mortality. The most feared complication in acute ischemic stroke is symptomatic HT [18]. Blood–brain barrier (BBB) breakdown resulting from ischemia before reperfusion therapy is hypothesized to contribute to HT in AIS patients [19]. Following an acute ischemic stroke the integrity of the BBB may be compromised by the ischemic insult to the vascular

Fig. 1. Multivariate logistic regression analysis. Odds ratio (OR) and 95% CI for (a) independence, (b) mortality, and (c) symptomatic intracranial hemorrhage (SICH) associated with previous ipsilateral TIA.

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endothelium, multiple signaling molecules and mediators have been identified with respect to how rt-PA treatment may lead from BBB breakdown to HT. Even a relatively short period of ischemia will result in markedly increased vascular permeability [20–22]. Some studies showed, that the risk of bleeding complications increased in patients with more protracted symptoms duration and DWI lesion volume [2,3,23,24], but there have not been any prospective studies of this problem. We found a SICH rate of 13.8% (according to the ECASS definition) in patients with TIA preceding acute ischemic stroke who were treated with thrombolysis. The SICH rate was higher and the mortality rate was similar to that reported in previous clinical trials of thrombolysis for acute ischemic stroke [11,15,25] and a thrombolytic therapy registry [26,27]. The impact of prior TIA within 24 h before stroke onset in the presence of SICH was confirmed in multivariate analysis. Increased incidence of intracerebral bleeding complication in our study sample can be explained in two ways. First of all, our patients with a history of TIA were older (mean age 68) than in similar studies (63) [6,7]. Older age has been shown to be an important risk factor for SICH in some studies [15,28–31]. In addition, in these patients we found significantly higher diastolic and systolic blood pressure, which also could increase the incidence of SICH [32]. McKinney et al. analyzed 23 patients with acute ischemic stroke who received thrombolytic therapy within seven days of a documented TIA and monitored the incidence of SICH. However, the group of patients was not homogeneous. The authors also included in the analysis patients treated with intra-arterial thrombolysis (IA-thrombolysis) and combination therapy: thrombolysis and mechanical thrombectomy. They found a SICH rate (according to the NINDS definition) of 8.6% of patients with TIA preceding AIS who were treated with thrombolysis. In patients who received IA-thrombolysis or mechanical therapy, there were higher rates of SICH than in patients treated with iv-thrombolysis alone [7]. Although data collection was done in a prospective fashion, the retrospective nature of our data may be considered as a limitation of our study, which has, therefore, inferior value than prospective and randomized trial. Also, the small number of patients with TIA before stroke and performing only CT imagings as a rule could be considered a limitation of our study. Imaging studies have challenged the simplistic assumption that because clinical TIA symptoms are resolved, significant ischemic tissue injury does not occur. Several studies have shown that many patients meeting the clinical criteria for TIA demonstrate neuroanatomically relevant infarcts on neuroimaging, which contributed to a change in the definition of TIA. MRI has the potential to improve the accuracy of TIA diagnosis. The pooled analysis of 808 patients from 10 centers demonstrated that restricted diffusion lesions were present in 33% [33]. The combination of early DW-MR and perfusion-weighted MRI (PW-MR) can document the presence of a cerebral ischemic lesion in approximately half of all patients who present with a suspected hemispheric transient ischemic attack (TIA). This refers mostly to patients with neurological dysfunction that lasted more than 15 min. Hence, some concerns might exist regarding the risk of bleeding as a result of thrombolytic therapy in these patients [34]. The risk of secondary SICH may be increased after thrombolytic therapy in AIS patients who have cerebral microbleeds on T2*-weighted magnetic resonance imaging [35]. Therefore, MRI is becoming the standard in diagnosis of patients with TIA and in making decision on the thrombolytic therapy in these patients. In conclusion, our data suggest that iv-thrombolysis with the use of rt-PA in patients with AIS after recent TIA does not appear to have major influence on long-term outcomes. In patients with TIA within 24 h prior to a stroke, severe intracerebral bleeding may occur more frequently. However, our pre-stroke TIA group of patients had significantly lower baseline stroke severity and the frequency of pre-stroke anticoagulation was higher in the prior TIA group. We believe that our findings provide certain values to the assessment of the safety and efficacy of treatment

with rt-PA in this group of patients. In the future, a prospective controlled study with the use of DW-MR would determine this important clinical problem.

Disclosure of conflicts of interest The authors declare that they have no conflicts of interest.

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