Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

Thrombolytic therapy in acute ischemic stroke in Asia: The first

prospective evaluation
Nijasri C. Suwanwela ∗ , Kammant Phanthumchinda, Yuttachai Likitjaroen
Neurological Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Bangkok 10330, Thailand

Received 30 May 2005; received in revised form 21 September 2005; accepted 27 September 2005

Abstract

Objective: Intravenous thrombolytic therapy has been widely recommended as a standard treatment for acute ischemic stroke in most clinical
practice guidelines. However, the experience in Asia is still limited. We report the first prospective case series of thrombolytic therapy in a
developing Asian country.
Patients and methods: Consecutive patients with acute ischemic stroke who presented within 3 h of onset were screened under stroke fast track
program. Those who were eligible were treated with intravenous recombinant tissue plasminogen activator (rt-PA). General and neurological
examinations together with the National Institute of Health stroke scale (NHISS) and modified Rankin scale (MRS) were recorded prior to
and after the treatment at 1 h, 24 h, on discharge and at 3 months. Hemorrhagic brain lesion and death within 3 months were also recorded.
Results: Thirty-four patients or 2.1% of patients with acute stroke received intravenous thrombolysis. The mean pretreatment NIHSS was
18.8 and the majority of patients had stroke in the middle cerebral artery territory. The mean door-to-needle time was 72.6 min (ranged
20–150 min). Major neurological improvement, defined as improving of the NIHSS >8 points or NIHSS of 0 points at 24 h, was observed in
17 patients (50%). Intracerebral hemorrhage was detected in four cases (11.8%), two of them were symptomatic (5.9%) and one was fatal.
Conclusion: Intravenous thrombolysis can be given in patients with acute stroke in our population. Our cases were more severe than other
studies. However, half of them experienced major neurological improvement. The risk of hemorrhagic brain lesion is not much higher than
previously reported.
© 2005 Elsevier B.V. All rights reserved.

Keywords: Thrombolysis; Intravenous thrombolysis; Ischemic stroke; Acute stroke; Developing country; Asia

1. Introduction complications especially intracerebral hemorrhage which is

Intravenous thrombolytic treatment has been used as a
standard therapy in acute ischemic stroke and is recom-
mended in various guidelines [1–6]. However, in Asia throm-
bolytic treatment has not been widely applied [7]. The major
obstacle behind is the limited short therapeutic window,
which requires awareness of the public and special setting
of emergency management. Limited knowledge and experi-
ence of the physicians have also made the treatment even
more sophisticated. Among those physicians who are knowl-
edgeable for the treatment, there is also fear of serious
known to be more common among the Asian [8]. This study
was performed at a university hospital in Thailand. A com-
prehensive stroke program which includes stroke fast track
for hyperacute stroke patients, multidisciplinary acute stroke
unit, neuroimaging and neurovascular ultrasound laboratory,
and homecare treatment has been established since the year
2000. Here we report our experience on thrombolytic therapy
under stroke fast track program in 34 patients. To our knowl-
edge, this is the first ever report of the thrombolytic treatment
outside the clinical trials in developing countries in Asia.

2. Methods
∗ Corresponding author. Tel.: +662 256 4655/669 799 8993;
fax: +66 2 256 4655. All acute ischemic strokes who presented at King Chu-
E-mail address: fmednsu@md2.md.chula.ac.th (N.C. Suwanwela). lalongkorn Memorial Hospital during 2001–2004 were

0303-8467/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.clineuro.2005.09.008

CLINEU-1460; No. of Pages 4

2 N.C. Suwanwela et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

screened for the eligibility for intravenous thrombolytic treat- Table 1

ment under the stroke fast track program. Those who received Baseline characteristics of our patients compared with the NINDS study
the treatment were prospectively studied. In this stroke fast Baseline characteristics Our study NINDS study
track program, the emergency room physicians and nursing Age (mean ± S.D.) 65.5 ± 12 68 ± 11
staff, radiologists, laboratory team and the neurology team Asian race (%) 100 0.01
were educated to be aware of the potential of thrombolytic Female (%) 62 42
Weight (kg) 65 ± 12 76 ± 16
treatment and the importance of the prompt reaction and man-
agement in patients who presented with hyperacute stroke. NIHSS score
Median (range) 20 (9–32) 14 (1–37)
When emergency room physician encountered a patient with
hyperacute stroke, s/he would activate the stroke fast track Stroke subtype
where essential blood tests and non-contrast CT scan were Cardioembolism 71 43
Large vessel occlusive 26 37
immediately performed. At the same time, an on-call neurol- Small vessel occlusive 3 16
ogist was notified and promptly saw the patient and the CT
Systolic blood pressure 149 ± 28 155 ± 22
scan result. Patients with evidence of intracranial hemorrhage
Diastolic blood pressure (mmHg) 85 ± 14 85 ± 13
were excluded. Ischemic stroke patients with CT evidence of Initial plasma glucose (mg/dL) 120 ± 49 149 ± 71
early cerebral edema or clear evidence of infarction more
than one-third of the middle cerebral artery territory were
also excluded. Patient and family discussion about the throm- window leaving 34 cases who received intravenous thrombol-
bolytic treatment would be done in the emergency room and ysis. This accounts for 2.1% of all acute stroke cases. Other
if there was no contraindication and all agreed, intravenous reasons for not giving thrombolysis included onset of more
recombinant tissue plasminogen activator (rt-PA) would be than 3 h or unclear onset in 21 cases, spontaneous improve-
given within 3 h of the stroke onset. For inclusion and exclu- ment of the symptoms before treatment or very mild deficit in
sion criteria, we adopted the criteria that were published in 24 cases, evidence of large infarct on CT scan contraindicated
the NINDS rt-PA trial [1]. The recommended dosage of rt-PA for thrombolysis in 20 cases, other medical contraindications
(Actilyse, Boehringer Ingelheim, Germany) was 0.9 mg/kg. such as high blood pressure in 5 cases, intracerebral hemor-
However, in some special circumstances such as in patients rhage in 58 cases, and non-stroke causes in 3 cases (1 had
who are older than 80 years, the dosage could be lowered to hypoglycemia and 2 had complicated migraine). Baseline
0.6 mg/kg [9]. Ten percent of the dosage was given as a bolus characteristics of our patients compared with those of the
dose and the remaining was infused intravenously within 1 h. NIINDS study are shown in Table 1.
General and neurological examinations together with the The location of ischemic stroke was mostly supratento-
National Institute of Health stroke scale (NIHSS) and mod- rial in the middle cerebral artery territory (94%). Only one
ified Rankin scale (MRS) were recorded prior to and after case had posterior circulation stroke and one had lacunar
the treatment. Types of stroke were defined by the criteria stroke. According to the stroke classification by Oxfordshire
used in TOAST study and the Oxfordshire Community Stroke Community Stroke Project, 50% of our patients had total
Project [10,11]. After thrombolysis, repeat measurements of anterior circulation stroke whereas partial anterior circula-
the NIHSS were done at 1 h, 24 h and on daily basis until the tion, posterior circulation and lacunar stroke accounted for
patient was discharged or dead. Major neurological improve- 44, 3, and 3%, respectively. Regarding the pathophysiology
ment was defined as improvement of NIHSS ≥8 points or of stroke, cardiogenic embolism was the most common cause
an NIHSS score of 0 at 24 h. Repeat CT scan of the brain and accounted for 70.6% of our cases. Atrial fibrillation was
was scheduled at 24 h after the initiation of the treatment. In found in most cases (64.7%).
case of neurological worsening, CT scan would be performed Among patients who received thrombolytic therapy, the
soon after the detection of deterioration. Intracerebral hemor- average arrival time after stroke onset was 65.2 min (ranged
rhage was diagnosed by CT scan. Symptomatic hemorrhage 0–158 min) and the mean door-to-needle time was 72.6 min
was defined as hemorrhagic lesion on CT scan with clinical (ranged 20–150 min). The mean onset to treatment time was
worsening of NIHSS more than 4 points. Final evaluation 137.7 min (ranged 45–180 min). The treatment was started
of the NIHSS and MRS was performed at 3 months. Death within 3 h after stroke onset in all cases. In 32 cases, rt-PA was
within 3 months was also recorded. given as the standard protocol (0.9 mg/kg). In two patients
who were aged 86 and 87 years old, 0.6 mg/kg of rt-PA was
administered.
3. Results After thrombolysis, marked improvement of the mean
NIHSS was observed. The mean NIHSS reduced from 18.8
During the study period, there were 1624 acute stroke pretreatment to 11.3 at 24 h and the median NIHSS at 24 h
patients presented to the hospital. Stroke fast track program was 9.5. Neurological improvement (reduction of NIHSS of
was activated in 168 patients. There were 37 patients eligible 4 points or greater) was found in 24 cases. Major neurological
for the treatment. However, 3 of them encountered a delayed improvement, defined as improving of the NIHSS >8 points
process of laboratory tests and CT scan exceeding the 3-h or NIHSS of 0 points at 24 h, was found in 17 patients (50%).
 N.C. Suwanwela et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx
Table 2
Complications after thrombolytic treatment
Complications Cases (%)
Hemorrhagic brain lesion 4 (11.8)
Symptomatic 2 (5.9)
Death 2 (5.9)
Intracerebral hemorrhage 1 to the high rate of spontaneous hemorrhagic transformation
Massive infarction 1 and malignant brain edema [15].
There were nine cases who NIHSS did not improve for more
than 2 points after treatment. The mean NIHSS at 3 months
was 6.9. Regarding the treatment complications, intracere-
bral hemorrhage was found in 4 cases (11.8%). Two patients
died during acute phase of treatment. The complications are
shown in Table 2.
4. Discussion
We report our experience on rt-PA treatment in acute
ischemic stroke. According to our knowledge, this is the first
report of prospective case series in Asia. In Thailand, the cost
of thrombolytic treatment of all patients is paid either by the
government under the National program for universal cover-
age or private insurance. Therefore, the treatment is available
for all eligible patients in this study. Although the use of intra-
venous thrombolysis has been known to be effective in acute
stroke patients for almost a decade, we only treated seven
cases with intravenous thrombolysis during 4 years before
the establishment of stroke fast track protocol. The number
of treated patients increased to 34 after the program. This
accounted only for 2.1% of our acute stroke patients and the
rate was still much lower than those reported in developed
countries [12,13].
In this study, we treated 34 out of 37 eligible patients
presented within 3 h of onset. This suggests that with well-
organized in-hospital process, more than 90% of patients
who presented in time can be treated successfully. Hence,
our major obstacle for getting more patients is the delayed
in hospitalization. Since the ambulance system in Thailand
is still not well organized, we had only cases who presented
to the emergency room by themselves. We strongly believe
that public health initiatives and education are essential to
increase the number of patients eligible for treatment in the
future.
Among patients who were treated with thrombolytic
agent, the NIHSS prior to treatment in this study was much
higher than the NINDS studies. Moreover, most of our
patients clinically had large stroke in the MCA territory
which usually has severe focal deficits. In this study, 94%
of the cases had ischemic stroke in the middle cerebral artery
territory and 50% of them had total anterior circulation infarc-
tion. Regarding the cause of stroke, cardiogenic embolism
accounts for 71% of the cases. This may reflect the sudden
onset and the severity of the symptoms of cardiac emboli.
3
Moreover, the cardioembolic nature might influence the out-
come since patients with cardiogenic embolism are more
likely to have migration of embolus resulting in sponta-
neous improvement [14]. On the other hand, the prognosis
of patients with large hemispheric stroke in the MCA terri-
tory is relatively poor despite any conventional treatment due
In this study, we were able to administer thrombolytic
agent within 3 h in all cases. Our mean door-to-needle time
was comparable to other studies performed in developed
countries [11,16–18]. In two extreme elderly patients, only
0.6 mg/kg of rt-PA were administered. This is mainly due to
attending physician preference since older patients were more
likely to develop bleeding complications. The rt-PA dosage
of 0.6 mg/kg was also used in a study of thrombolysis from
Japan [9]. Despite the severe symptoms and possible large
area of ischemia at presentation, 50% of our patients had
major neurological improvement. A recent study using the
data from the NINDS trial found that the major neurological
improvement was noted in 32.5% of the cases [19].
It is generally believed that risk of intracerebral hemor-
rhage is higher among the Asian than the Caucasian. This
is mainly based on the incidence of hypertensive cerebral
hemorrhage. However, the risk of hemorrhagic transforma-
tion in patients with ischemic stroke among the Asian is
not well documented. In general, the occurrence of hem-
orrhagic complications after ischemic stroke is associated
with large infarcts especially proximal MCA occlusion due
to cardioembolic stroke as in our study population [20–23].
In this study, however, the overall rate of intracerebral hem-
orrhage was 11.8% and the symptomatic hemorrhage was
found in 5.9%. Although it is little higher than the rate of
hemorrhage in the NINDS study (6.7%), we believed that it
is mainly due to the severity of our patients. In this study, more
than 50% of the cases had the pretreatment NIHSS score of
more than 20. It was shown in the NINDS study that hem-
orrhages were likely to occur in patients with very severe
strokes (NIHSS scores > 20). However, these patients with
severe stroke would probably have died or been left disabled
without thrombolytic treatment [24,25].
In conclusion, our experience on the rt-PA treatment in
Asian stroke patients showed that it is feasible to set up a spe-
cial stroke fast track program in order to identify hyperacute
stroke patients. With this program we were able to effec-
tively treat 2.1% of our cases with intravenous thrombolytic
therapy. Although we treated more severe patients, the rate of
major improvement was as high as those previously reported.
More importantly, the rate of symptomatic and asymptomatic
intracerebral hemorrhages were only little higher than other
studies. Therefore, we recommend that thrombolytic treat-
ment in acute ischemic stroke in our selected Asian popula-
tion is at least as useful and not more harmful when compare
to the Caucasian. We are aware that we have limited number
of cases in this series and further studies in Asia are needed
to confirm our findings.
4 N.C. Suwanwela et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx
References
[1] The National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group. Tissue plasminogen activator for acute ischemic
stroke. N Engl J Med 1995;333:1581–7.
[2] Hacke W, Kaste M, Fieschi C, Toni D, Lesaffire E, von Kum-
mer R, et al. Intravenous thrombolysis with recombinant tissue
plasminogen activator for acue hemispheric stroke: the European
Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017–
25.
[3] Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier
D, et al. Randomised double-blind placebo-controlled trial of throm-
bolytic therapy with intravenous alteplase in acute oischemic stroke
(ECASS II). Lancet 1998;352:1245–51.
[4] Klijn CJM, Hankey G. Management of acute ischemic stroke: new
guidelines from the American Stroke Association and European
Stroke Initiative. Lancet Neurol 2003;2:698–701.
[5] Adams Jr HP, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Gold-
stein LB, et al., Stroke Council of the American Stroke Association.
Guidelines for the early management of patients with ischemic
stroke. A scientific statement from the Stroke Council of the Amer-
ican stroke Association. Stroke 2003;34:1056–83.
[6] European Stroke Initiative Executive Committee and Writing Com-
mittee. The European Stroke Initiative recommendation for stroke
management update. Cerebrovasc Dis 2003;16:311–8.
[7] Yamaguchi T, Japanese Thrombolysis Study Group. Intravenous tis-
sue plasminogen activator in acute carotid artery territory stroke: a
placebo controlled, double blind trial. In: del Zoppe GJ, Mori E,
Hacke W, editors. Thrombolytic Therapy in Acure Ishcmic Strije II.
New York, NY: Springer Verlag; 1993. p. 59–65.
[8] The Asian Acute Stroke Advisory Panel. Stroke epidemiological
data of nine Asian countries. Asian Acute Stroke Advisory Panel
(AASAP). J Med Assoc Thai 2000 Jan;83(1):1–7.
[9] Minematsu K, Yamaguchi T, Hashi K, Shinohara Y, Saito I, Mori
E, et al. Results of clinical trial of intravenous rt-PA (Alteplase) for
acute ischemic stroke: Japan Alteplase Clinical Trial (J-ACT). In:
Presented at 5th World Stroke Congress. 2004 (abstract).
[10] Bamford J, Sandercock P, Dennis M, Warlow C, Jones L, McPher-
son K, et al. A prospective study of acute cerebrovascular disease
in the community: the Oxfordshire Community Stroke Project. 1.
Methodology, demography and incident cases of first-ever stroke. J
Neurol Neurosurg Psychiatry 1988;51:1373–80.
[11] Adams Jr HP, Bendixen BH, Kappelle LJ, Biller J, Love BB,
Gordon DL, et al. Classification of subtype of acute ischemic
stroke. Definitions for use in a multicenter clinical trial. TOAST.
Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:
35–41.
[12] Kapral MK, Laupacis A, Phillips SJ, Silver FL, Hill MD, Fang J, et
al., for the investigators of the registry of the Canadian Stroke Net-
work. Stroke care delivery in institutions participating in the registry
of the Canadian stroke network. Stroke 2004;35:1756–62.
[13] Grotta JC, Burgin WS, El-Mitwalli A, Long M, Campbell M, Mor-
genstern LB, et al. Intravenous tissue-type plasminogen activator
therapy for ischemic stroke: Houston experience 1996 to 2000. Arch
Neurol 2001;58(12):2009–13.
[14] Minematsu K, Yamaguchi T, Omae T. Spectacular shrinking deficit:
rapid recovery from a major hemispheric syndrome by migration of
an embolus. Neurology 1992;42(1):157–62.
[15] Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kum-
mer R. Malignant middle cerebral artery territory infarction: clinical
course and prognostic signs. Arch Neurol 1996;53(4):309–15.
[16] Szoeke CE, Parsons MW, Butcher KS, Baird TA, Mitchell PJ, Fox
SE, et al. Acute stroke thrombolysis with intravenous tissue plas-
minogen activator in an Australian tertiary hospital. Med J Aust
2003;178(7):324–8.
[17] Merino JG, Silver B, Wong E, Foell B, Demaerschalk B, Tamayo
A, et al. Southwestern Ontario Stroke Program. Extending tissue
plasminogen activator use to community and rural stroke patients.
Stroke 2002;33(1):141–6.
[18] Koennecke HC, Nohr R, Leistner S, Marx P. Intravenous tPA for
ischemic stroke team performance over time, safety, and efficacy in
a single-center, 2-year experience. Stroke 2001;32(5):1074–8.
[19] Brown DL, Johnston KC, Wagner DP, Haley EC. Predicting major
neurological improvement with intravenous recombinant tissue plas-
minogen activator treatment of stroke. Stroke 2004;35:147–50.
[20] Rimdusid P, Wardlow J, Lindley RI, Sandercock P, on behalf of the
International Stroke Tiral Collaboration Group. Hemorrhagic infarc-
tion in acute ischemic stroke patients: International Stroke Trial Pilot
Study. Cerebrovasc Dis 1995;5:264.
[21] Pessin MS, Teal PA, Caplan LR. Hemorrhagic transformation: guilt
by association? Am J Neuroradiol 1992;12:1123–6.
[22] Caplan LR, Mohr JP, Kistler JP, Koroshetz WJ. Should thrombolytic
therapy be the first-line treatment for acute ischemic stroke? N Engl
J Med 1997;337:1309–13.
[23] Schneweis S, Grond M, Neveling M, Schmulling S, Rudolf J, Heiss
WD. Intravenous thrombolysis in proximal middle cerebral artery
occlusion. Cerebrovasc Dis 2001;11(3):212–5.
[24] Grotta J. t-PA—the best current option for most patients. N Engl J
Med 1997;337:1309–13.
[25] Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S,
Grond M, et al. Markers of increased risk of intracerebral hem-
orrhage after intravenous recombinant tissue plasminogen activator
therapy for acute ischemic stroke in clinical practice, the multicenter
rt-PA acute stroke survey. Circulation 2002;105:1679–85.