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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
INTRODUCTION
The use of intravenous tissue plasminogen activator
(tPA) is now a standard therapy for acute ischemic
stroke (AIS) in selected patients. The approval of tPA in
treating stroke patients within three hours of onset was
based primarily on the National Institute of Neurological
Disorders and Stroke (NINDS) rt-PA Stroke Study
From the Department of Neurology, Chia-Yi Christian
Hospital, Chiayi, Taiwan.
Received June 23, 2008. Revised August 25, 2008.
Accepted September 22, 2008.
Reprint requests and correspondence to: Sheng-Feng Sung,
MD. Department of Neurology, Chia-Yi Christian Hospital,
No. 539, Chung-Shao Road, Chiayi 600, Taiwan.
E-mail: 02442@cych.org.tw
Intravenous Thrombolytic Therapy for Acute Ischemic Stroke:
The Experience of A Community Hospital
Yung-Chu Hsu, Sheng-Feng Sung, Cheung-Ter Ong, Chi-Shun Wu, and Yu-Hsiang Su
Abstract-
Background and Purpose: Tissue plasminogen activator (tPA) is a standard therapy for acute ischemic
stroke (AIS) but only limited data are noted in Taiwan. The purpose of this study was to assess the safe-
ty, feasibility, and efficacy of treatment in a community hospital setting.
Methods: We retrospectively reviewed the medical records of all patients who had received intravenous tPA
therapy from 1998 to 2007 in our hospital. We compared the characteristics, complications, and out-
comes in our patients with those of patients in the National Institute of Neurological Disorders and
Stroke (NINDS) trial.
Results: A total of 43 patients were reviewed with a mean age of 63 years and a male predominane (64%).
The median pretreatment National Institutes of Health Stroke Scale score was 18. In our patients, car-
dioembolism was the leading course of the strokes. The mean time from stroke onset to treatment was
134 minutes, and the mean door-to-computed tomography-time was 34 minutes while the mean door-
to-needle time was 93 minutes. Within 36 hours symptomatic intracerebral hemorrhage occurred in two
patients (4.7%). Four patients (9.3%) developed brain herniation with fatality. At follow-up, fourteen
patients (33%) had a favorable outcome on the modified Rankin Scale (0-1). Patient outcome was not
significantly different from that in the NINDS trial.
Conclusion: Although the number of patients with AIS receiving tPA in this study was small, thrombolytic
therapy can be performed safely and effectively by physicians in the community hospital setting.
Key Words: Ischemic stroke, Thrombolytic therapy, Tissue plasminogen activator
Acta Neurol Taiwan 2009;18:14-20
Original Articles
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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
Group trial(1). The tPA treatment for AIS patients was
shown to be beneficial despite a symptomatic intracere-
bral hemorrhage (ICH) rate of 6.4%. Several studies sup-
ported the safety of thrombolytic therapy in clinical
practice(2). Overall, the proportion of stroke patients who
actually received tPA therapy varied widely in different
community practices(3-6).
Stroke remains one of the major causes of death in
Taiwan. Unfortunately, there have been scarce data on
thrombolytic therapy for stroke in Taiwan(7,8). In one
study, Lien et al.(7) found that a high percentage of viola-
tions to the NINDS protocol led to high incidences of
symptomatic ICH and low chances of a favorable func-
tional outcome. Therefore, we presented our experience
with intravenous tPA for AIS by assessing the feasibility
of a 3-hour time window and comparing the safety data
and outcome with those described in the NINDS trial.
METHODS
Chia-Yi Christian Hospital (CYCH) serves an area
that includes Chiayi City, Chiayi County, southern
Yunlin County, and northern Tainan County with a popu-
lation of approximately 1,000,000 people. There are
seven other regional hospitals in this area. Around 600
patients are admitted each year with a diagnosis of AIS.
We retrospectively reviewed the medical records of
all patients who were treated with intravenous tPA for
AIS at our hospital from 1998 to 2007. Stroke patients
who presented to our emergency room (ER) were
screened by an emergency doctor to determine eligibility
for thrombolytic therapy. All potentially eligible patients
were then examined by a neurologist. Treatment deci-
sions were made by the neurologist mainly based on the
NINDS protocol. After 2004, the tPA usage criteria of
The Bureau of National Health Insurance (BNHI) was
also taken into account. The pretreatment clinical severi-
ty was measured by the neurologist using the National
Institutes of Health Stroke Scale (NIHSS). Intravenous
tPA was administered at a dose of 0.9 mg/kg. After being
admitted to an intensive care unit, patients were surveyed
for the risk factors of strokes. We performed neuroimag-
ing studies 24 to 36 hours following thrombolysis for
each patient. Extracranial and intracranial circulation
was examined by means of color-coded duplex sonogra-
phy.
Using a standardized data extraction form, we
recorded patient demographics, risk factor profiles,
blood pressure, laboratory parameters, time of symptom
onset, time of arrival at the ER, time to computed tomog-
raphy (CT), time to tPA administration, and medications.
We also documented all complications related to the tPA
therapy. We classified stroke subtypes according to Trial
of Org 10172 in Acute Stroke Treatment criteria(9) and
the Oxfordshire Community Stroke Project(10). Functional
outcomes were obtained from the medical records three
months after stroke onset or at the last visit by using the
modified Rankin scale (mRS). A score of 0 or 1 on mRS
was considered to be a favorable outcome.
To compare our data with those from the NINDS
treatment cohort, χ2tests or Fisher’s exact tests were
used. Differences in continuous variables were compared
by use of the Student’s ttest.
RESULTS
For ty-three patients (27 men, 16 women) received
intravenous tPA for AIS from 1998 to 2007. These repre-
sented 0.8% of all ischemic stroke patients admitted to
CYCH. The ratio increased from 0.2% in 1998 to 1.6%
in 2007. The mean age was 63 years, which was younger
than that in the treatment group of the NINDS trial. The
median pretreatment NIHSS score was 18 (range from 6
to 32). As compared with the stroke risk factors in the
NINDS trial, more patients had atrial fibrillation (AF)
and fewer patients were on aspirin at the time of stroke
(Table 1). In contrast to the results of the NINDS trial
however, most of our patients (79%) suffered from car-
dioembolic strokes (Table 2). AF was seen in 27 patients
(63%), mechanical valve replacement in 2 (4.7%),
myocardial infarction within 4 weeks in 2 (4.7%), atrial
myxoma in 2 (4.7%), and sick sinus syndrome in 2
(4.7%).
Symptomatic ICH during the first 36 hours occurred
in 2 patients (4.7%), both of whom were male and non-
diabetic. The rate of symptomatic ICH did not differ sig-
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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
nificantly from that (6.4%) in the NINDS trial (P =
0.55). One of them, a 51-year-old man, had AF and took
aspirin regularly. He underwent craniectomy with
removal of the hematoma(11). He had moderate disability,
graded 3 on the mRS, at three months after a stroke. The
other patient was 74 years old and had signs of early
infarct on CT scan. He received conservative treatment
and his mRS remained at a level of 3 at three months fol-
lowing his stroke. One patient (2.3%) suffered from
asymptomatic ICH. Another two patients (4.7%) experi-
enced hemorrhages at other sites. Both of them had gum
bleeding and one had facial bruising.
Four patients were treated beyond the three-hour
time window (185, 190, 205, and 224 minutes respec-
tively). The pretreatment CT revealed hypodensity
involving more than 1/3 of the middle cerebral artery ter-
ritory in one patient. One patient had a favorable out-
come and none of them experienced symptomatic ICH.
Another 30-year-old man, with mechanical valve
replacement and AF, developed clinical symptoms and
signs of brain stem infarction. His pretreatment NIHSS
score was 32, which was against the tPA usage criteria of
BNHI. However, he had a full return to normal function
before discharge.
The mean time from stroke onset to treatment was
134 minutes (range: 30 to 224 min). The mean door-to-
CT time was 34 minutes and the mean door-to-needle
time was 93 minutes. There was no relationship between
the time from stroke onset to ER arrival and the door-to-
needle time. Although a neurologist was on call around
the clock for potential thrombolytic cases, he/she usually
stayed at the hospital only in weekdays during daytime
hours. Therefore, we tried to determine if the time inter-
vals to action were different depending on whether the
neurologist was at the hospital when he/she was paged.
For those patients who presented to the ER, the onset-to-
needle time, onset-to-door time, and door-to-needle time
were similar. However, there was significant difference
in the door-to-CT time (P = 0.02). It took a longer time
for patients who arrived at our ER during daytime on
weekdays to finish the CT scan (Fig. 1).
Two patients in our series were inpatients at the time
of stroke onset. Both patients were admitted for other
Table 1. Patient characteristics in CYCH and comparison
with NINDS
Characteristic CYCH NINDS, Part II
(n = 43) (n = 168)
Age, mean (SD), year * 63 (13) 69 (12)
Male, % 64 57
NIHSS, median (range) 18 (6-32) 14 (2-37)
Blood pressure, mmHg
Systolic, mean (SD) 150 (29) 153 (22)
Diastolic, mean (SD) 86 (16) 85 (14)
Glucose, mean (SD), mg/dL 134 (55) 149 (66)
Stroke risk factors, %
Hypertension 77 67
Atrial fibrillation ** 63 20
Diabetes mellitus 21 20
Hyperlipidemia 56 --
Prior strokes 19 12
Smoking 28 27
Prior aspirin use * 19 40
*: P < 0.01; **: P < 0.0001; SD: standard deviation; CYCH:
Chia-Yi Christian Hospital; NINDS: National Institute of
Neurological Disorders and Stroke.
Table 2. Stroke subtypes and clinical stroke classifications of
ischemic strokes
Variable, % CYCH NINDS, Part II
(n = 43) (n = 168)
Stroke subtype
Small-vessel occlusive 0 14
Large-vessel occlusive 5 39
Cardioembolic 79 45
Undetermined/other 16 2
Clinical syndromes
TACI 61
PACI 30
POCI 9
LACI 0
TACI indicates total anterior circulation infarct; PACI: partial
anterior circulation infarct; POCI: posterior circulation infarct;
LACI: lacunar infarct; CYCH: Chia-Yi Christian Hospital;
NINDS: National Institute of Neurological Disorders and
Stroke.
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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
medical problems. It took 88 and 106 minutes from
stroke onset to CT, and 140 minutes from stroke onset to
treatment. Both CT and treatment were delayed for the
ward patients.
At the time of hospital discharge, 29 patients (67%)
experienced a 4-point or more improvement in the
NIHSS score. At the time of follow-up, 14 patients
(33%) had a favorable outcome on the mRS (Fig. 2),
which was not significantly different from the data of
NINDS treatment group at 3 months (P = 0.35). Four
patients (9.3%) died before discharge, which was lower
than the mortality rate (17%) at 3 months in the NINDS
trial but no statistical significance was noted (P = 0.22).
All of them died of herniation due to cerebral edema
without any hemorrhagic transformation (HT).
Figure 1.
For patients with acute ischemic stroke directly presenting to the ER, the time intervals were similar whether they arrived
during daytime or nightime on weekdays except for the door-to-CT time. (*P = 0.02).
Figure 2.
Functional outcome of CYCH patients at follow-up compared with patients in NINDS trial at three months.
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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
DISCUSSION
Controlled multicenter trials have proved the effica-
cy of IV tPA treatment in selected cases of AIS(1,12). The
feasibility of this therapeutic option in clinical practice
has been assessed in other community-based studies(3-6).
Our data showed some differences in comparison with
the results of other studies.
The most common etiology of strokes in our series
was cardioembolism, which was secondary to AF in
most patients. In contrast to the data of NINDS trial, the
patients with cardioembolic stroke considerably outnum-
bered the cases due to other etiologies (Table 2). The
most common clinical syndrome was total anterior circu-
lation infarct. There was no case of lacunar infarct in our
series. In the NINDS trial, patients with cardioembolic
stroke had less chance to achieve a favorable outcome
than those with lacunar infarct. The predominance of
cardioembolic stroke could explain the higher pretreat-
ment NIHSS scores and lower rate of favorable outcome
in our series. Strokes secondary to cardioembolism usu-
ally produce maximal deficit at onset and are prone to
causing decreased consciousness due to massive infarc-
tion such as total anterior circulation infarct(13). Patients
with severe neurologic deficits tended to present to the
ER early after symptom onset(14,15). As a result they were
more likely to arrive in time for thrombolytic therapy. On
the contrary, lacunar strokes typically produce mild
symptoms at onset which are probably neglected by
patients and family members in Taiwan. Consequently,
patients with lacunar strokes may have a longer delay
between symptom onset and arrival at the ER. We found
a similar distribution of etiologies in a Japanese study(16),
in which 77.7% of their patients suffered from cardioem-
bolic strokes. This implies that education of general pop-
ulation about stroke identification and immediate
response to strokes can result in a better outcome.
In a meta-analysis of safety data from 15 open-label
studies(2), symptomatic ICH occurred at 36 hours in only
5.2% of patients, suggesting that tPA is potentially safe
in clinical practice. Protocol violation may predispose
patients to symptomatic ICH(17-19). Other factors which
can predict symptomatic ICH include stroke severity,
mass effect or hypodensity in head CT and old age(20,21).
Although we had four patients with time violations, one
with large hypodensity on CT, and one with severe initial
symptoms, no patients suffered from symptomatic ICH.
The rate of symptomatic ICH in our series was 4.7%,
which was comparable to that in the NINDS trial. Some
may have concern about the racial differences in throm-
bolytic effect and hemorrhagic complications by using
tPA(22,23). A dose of tPA at 0.6 mg/kg was used in Japan
(16). Nevertheless, our experience showed that a dose of
0.9 mg/kg was safe.
While HT is a natural consequence of cerebral
infarction and it happens in up to 71% of cardioembolic
strokes(13), in our study, HT only occurred in 7.0 % of our
patients despite the predominance of cardioembolic
strokes. The incidence of HT on CT after a cardioembol-
ic stroke increases with the time(24). Within 24 hours after
stroke onset, the percentage of HT could be as low as
5%(25). Since we performed the second neuroimaging
study between 24 and 36 hours after strokes, we proba-
bly underestimated the incidence of HT especially for
those patients who developed HT beyond 36 hours with-
out clinical deterioration. In addition, early spontaneous
recanalization in less than 6 hours after a cardioembolic
stroke was associated with no HT(26) while the majority
of tPA-indueced recanalizations occur during the first
hour after treatment(27). Based upon these observations,
we speculated that the overall rate of HT after cardioem-
bolic strokes might be reduced by successful treatement
with tPA.
The mean door-to-CT time (34 minutes) and the
mean door-to-needle time (93 minutes) were longer than
those recommended by the NINDS. They recommend
that from the time of arrival at the ER, a patient with AIS
should undergo CT examination within 25 minutes and
receive tPA within 60 minutes(28). At CYCH, patients
who arrived at the ER during nighttime hours were
inclined to receive CT scans sooner. This might be
because during the daytime, our CT services were preoc-
cupied by scheduled examinations. However, the advan-
tage of early CT examination at nighttime did not short-
en the time intervals from door to treatment. This was
probably due to delayed evaluation by the neurologists.
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Acta Neurologica Taiwanica Vol 18 No 1 March 2009
Physicians who are not neurologists tend not to give
patients thrombolytic treatment(5). Although the number
of in-hospital strokes was small, two patients who had an
in-hospital stroke had marked delays in CT examination.
This might be due to unfamiliarity of a thrombolytic
treatment in non-ER setting.
According to previous studies, predictors of good
outcome after thrombolysis include milder baseline
stroke severity, no history of diabetes mellitus, normal
pretreatment blood sugar, normal pretreatment blood
pressure, treatment within 90 minutes, and a normal CT
scan(29-32). The pretreatment NIHSS of our patients was
slightly higher than those in the NINDS trial, but our
mortality rate was lower although it did not reach statis-
tic significance. The overall outcome at three months
was comparable to that of the NINDS trial. This demon-
strates that intravenous tPA is an effective treatment in
our patients.
Despite academic acceptance of intravenous tPA
therapy for AIS, many neurologists have been unwilling
to use it in community practice settings(33). Although our
study has some flaws, including: a small number of
patients, retrospective design, and lack of a control
group, our data offer Taiwanese experience on tPA thera-
py. Furthermore the efficacy and safety results are con-
sistent with those of multicenter trials. In conclusion,
intravenous tPA can be a feasible, safe, and effective
treatment for AIS in the community hospital setting by
providing the protocol for physicians.
ACKNOWLEDGMENTS
The authors would like to thank Mr. Darren Wu for
help in the preparation of the manuscript.
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