Intravenous thrombolysis with rt pa for acute ischemic stroke within 24 hrs of a ait

1. 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
Department of Neurology and Stroke Unit, Holy Spirit Specialist Hospital in Sandomierz, Sandomierz, Poland
b
Department of Neurology and Stroke Unit, Saint Luke's Hospital in Końskie, Końskie, Poland
c
Department of Neurology and Stroke Unit, Hospital in Piła, Piła, Poland
a b s t r a c ta 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
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 symptom-
atic 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.
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 be-
cause of the varying criteria used in epidemiological studies to identify
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 intra-
cerebral microbleeds.
Only a few studies have assessed the impact of prior TIA on the long-
term 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.
Journal of the Neurological Sciences 340 (2014) 44–49
⁎ 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: piotrsobolewski@poczta.onet.pl (P. Sobolewski).
http://dx.doi.org/10.1016/j.jns.2014.02.022
0022-510X © 2014 The Authors. Published by Elsevier B.V.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences
journal homepage: www.elsevier.com/locate/jns
Open access under CC BY-NC-ND license.
Open access under CC BY-NC-ND license.

2. 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 consec-
utively 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 moni-
toring 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 per-
formed. 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 hem-
orrhage (SICH) rates were assessed according to the European Coopera-
tive Acute Stroke Study (ECASS) II criteria. Radiographically, in ECASS II
protocol HT was classified into hemorrhagic infarction (petechial in-
farction without space occupying effect) and parenchymal hematoma
(hemorrhage with mass effect); clinically, SICH was defined as an intra-
cranial 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 includ-
ed 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
therapy had symptoms for at least 30 min without a significant im-
provement before treatment. In patients who were admitted to the hos-
pital 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 re-
spect 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 gath-
ering 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 per-
form the univariate analysis of the continuous variables. Categorical
data were compared using chi square tests. p values b0.05 were consid-
ered statistically significant. The multivariate analysis was performed
using multiple logistic regression. Factors identified on univariate anal-
ysis 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 out-
comes 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 vascu-
lar 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
45P. Sobolewski et al. / Journal of the Neurological Sciences 340 (2014) 44–49

3. 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 out-
comes (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 prospec-
tive 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 pre-
ceding 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 obser-
vational 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 regard-
ing long-term outcomes and mortality.
The most feared complication in acute ischemic stroke is symptom-
atic HT [18]. Blood–brain barrier (BBB) breakdown resulting from ische-
mia 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
Table 1
The clinical characteristics of the subgroups of thrombolytic patients without and with history of TIA within 24 h before stroke onset.
No prior TIA Prior TIA within 24 h p value
n (%) 371 (92.8) 29 (7.2) –
Demographic data
Mean age (±SD) 69.7 ± 11.9 67.7 ± 10.2 0.26
Male gender, n (%) 202 (54.5) 16 (55.2) 0.55
Risk factors, n (%)
Hypertension 244 (65.8) 20 (69.0) 0.73
Coronary heart disease 190 (51.2) 9 (31.0) 0.04
Atrial fibrillation 132 (35.6) 7 (24.1) 0.21
Diabetes mellitus 55 (14.8) 8 (27.6) 0.12
Dyslipidemia 255 (68.7) 24 (82.8) 0.11
Smoking 79 (21.3) 9 (31.0) 0.22
Pre-stroke antiplatelets 224 (60.4) 12 (41.4) 0.045
Pre-stroke anticoagulants 45 (12.1) 7 (24.1) 0.06
OCSP classification, n (%)
TACI (Total Anterior Circulation Infarct) 116(31.3) 10(34.5) 0.72
PACI (Partial Anterior Circulation Infarct) 183(49.3) 10(34.5) 0.12
LACI (Lacunar Infarct) 68(18.3) 7(24.1) 0.44
POCI (Posterior Circulation Infarct) 4(1.1) 2(6.9) 0.09
Etiological classification, n (%)
Large vessel disease 132 (35.6) 14 (48.3) 0.17
Cardioembolism 125(33.7) 9(24.1) 0.29
Lacunar stroke 43(11.6) 5(17.2) 0.55
Undetermined etiology 72(19.4) 3(10.3) 0.23
Stroke severity, median NIHSS (pts.) (IQR) 11.0 (8.0–16.0) 8.0 (6.0–14.0) 0.04
Onset to treatment time (min) (IQR) 160(135.0–180.0) 160.0 (135.0–190.0) 0.93
Median arterial blood pressure before thrombolysis (mm Hg) (IQR)
MAP 108.0 (99.7–117.7) 113.3 (104.7–123.7) 0.02
Diastolic 85.0 (80.0–95.0) 90.0 (85.0–100.0) 0.01
Systolic 155.0 (140.0–170.0) 165.0 (150.0–175.0) 0.04
Laboratory findings before thrombolysis
Median INR (IQR) 1,05 (1.0–1.1) 1.03 (1.0–1.1) 0.36
Median glucose level, mmol/l (IQR) 6.4 (5.6–7.6) 6.2 (5.6–8.4) 0.77
Median creatinine level, μmol/l (IQR) 88.4 (73.4–101.7) 86.1 (69.8–97.0) 0.68
Radiological findings in CT scans at baseline, n (%)
Old ischemic changes 132 (36.1) 12 (41.4) 0.57
Early ischemic changes 89 (24.0) 10 (34.5) 0.21
mRS 0–2 at three months, n (%) 211 (56.9) 21 (72.5) 0.07
Hemorrhagic transformation (HT)a
, n (%) 63 (17.0) 5 (17.2) 0.63
SICHa
, n (%) 13 (3.5) 4 (13.8) 0.15
Mortality, n (%) 67 (18.1) 4 (13.8) 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.
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.
46 P. Sobolewski et al. / Journal of the Neurological Sciences 340 (2014) 44–49

4. 47P. Sobolewski et al. / Journal of the Neurological Sciences 340 (2014) 44–49

5. 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 inci-
dence 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 inci-
dence 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 ret-
rospective nature of our data may be considered as a limitation of our
study, which has, therefore, inferior value than prospective and ran-
domized trial. Also, the small number of patients with TIA before stroke
and performing only CT imagings as a rule could be considered a limita-
tion 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 dem-
onstrated 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 approxi-
mately 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 throm-
bolytic 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]. There-
fore, 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 con-
trolled 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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