Letter to the editor

Intravenous thrombolysis is feasible and safe inmultiethnic Asian stroke patients in Singapore

V. K. Sharma�1, G. Tsivgoulis2, J. H. Tan1, B. K. C. Ong1, B. P. L. Chan1, and H. L. Teoh1

Intravenous tissue plasminogen activator (IV-TPA) is the only

approved therapeutic agent for acute ischaemic stroke (IS)

within 3 h of stroke-onset. Data regarding stroke thrombolysis

in Asia are scarce (1). Apart from logistic reasons, the

anticipated higher rate of TPA-related symptomatic intracra-

nial haemorrhage (SICH) among Asians remains a major

concern (2).

Stroke is the fourth leading cause of death and among the

top 10 causes of hospitalisation in Singapore (3). A compre-

hensive stroke programme was established at our tertiary-care

hospital in the year 2000 and has since developed an efficient

‘fast-track’ treatment approach for acute IS on a 24/7/365 basis.

We followed the inclusion and exclusion criteria of the

NINDS study for selecting candidates for thrombolysis (4).

Initially, owing to concerns of higher SICH in Asians (2), we

started a lower dose (0�9 mg/kg body weight, maximum dose

50 mg) of TPA (lower-dose group). During the first four years,

34 patients received thrombolytic therapy of which 32%

patients achieved good functional recovery at three months

(modified Rankin scale; mRS 0–1) with SICH in about 19%

patients. Influenced by a study from Thailand (1), based on

moderate rates of good outcomes and no SICH between 2004

and 2006 (14 patients), we revised our TPA dosing regimen.

From October 2006 onwards, all patients received the standard

dose of TPA at 0�9 mg/kg body weight with maximum of 90 mg

(standard-dose group).

Our stroke unit managed 4774 patients between January

2000 and June 2008. A total of 130 patients received IV-TPA

(Fig. 1). Their demographic characteristics, vascular risk

factors, stroke subtype, and baseline clinical parameters are

shown in Table 1. We analysed our patients according to the

dosages of IV-TPA (low dose vs. standard dose). The standard-

dose TPA-dose was safe as SICH occurred in only one out of 82

(1�2%) cases, compared with seven out of 48 (14�6%) patients

treated with the low-dose (P 5 0�004). None of the 12 patients

treated beyond the 3-hour therapeutic window (six in each

group) developed SICH. Patients treated with the standard-

dose IV-TPA experienced significantly greater improvements

(Table 1). Overall, standard-dose TPA was associated with a

significantly higher proportion of patients achieving func-

tional independence at 3 months (59 vs. 35% with low-dose

TPA; P 5 0�011). In a multivariate logistic regression model,

the following factors were independently associated with

functional independence at 3 months: lower admission NIHSS

scores (OR per 1 point increase 0�78; 95% CI 0�70–0�88), lower

pretreatment blood glucose values (OR per 1 mmoL/L increase

0�76; 95% CI 0�60–0�95), shorter time from symptom onset to

TPA treatment (OR per 1-min increase 0�97; 95% CI 0�94–1�0)

and the standard-dose TPA (OR 12�49; 95% CI 2�90–53�89).

One interesting observation in our population was the

higher incidence of SICH in the patients treated with low-

dose IV-TPA as compared with those who received the

standard dose. One possible explanation for this phenomenon

could have been our lack of experience during the initial years

of the ‘learning curve’. Although we did not monitor it, delayed

recanalisation induced by the lower dose of TPA could also

have contributed to the higher incidence of SICH (5, 6).

Fig. 1 Numbers and proportions of acute ischaemic stroke (IS) patients

treated with intravenous tissue plasminogen activator (IV-TPA) from January

2000 to June 2008. ‘Intervention’ in October 2006 included reorganisation

of the Acute Ischaemic Stroke Service and the revision of the IV-TPA dosage

regimen. Bottom row shows the rates (percentages) of symptomatic

intracranial haemorrhage (SICH) in TPA-treated patients from January 2000

to May 2008.

Correspondence: Vijay K. Sharma�, Division of Neurology, National

University Hospital, 5 Lower Kent Ridge Road, Singapore 119074,

Singapore. Tel: 165 67 722 517; Fax: 165 68 723 566;

e-mail: drvijay@singnet.com.sg1Department of Medicine, Division of Neurology, National University

Hospital, Singapore2Department of Neurology, Democritus University of Thrace, University

General Hospital, Alexandroupolis, Greece

& 2009 The Authors.320 & 2009 World Stroke Organization International Journal of Stroke Vol 4, October 2009, 320–321

Our experience supports initiatives among stroke physi-

cians in Asia to develop the organisation and expertise in

delivering a more aggressive therapy, including systemic

thrombolysis, for acute ischaemic stroke patients. Our data

from stroke patients of diverse ethnicities in Asia provide

strong support for the safety and feasibility of the standard-

dose IV-TPA therapy for acute ischaemic stroke in Asia.

References

1 Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic

therapy in acute ischemic stroke in Asia: the first prospective evaluation.

Clin Neurol Neurosurg 2006; 108:549–52.

2 Ueshima S, Matsuo O. The differences in thrombolytic effects of

administrated recombinant t-PA between Japanese and Caucasians.

Thromb Haemost 2002; 87:544–6.

3 Venketasubramanian N, Chen CL. Burden of stroke in Singapore. Int J

Stroke 2008; 3:51–4.

4 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.

5 Kimura K, Iguchi Y, Shibazaki K et al. Recanalization between 1 and 24

hours after t-PA therapy is a strong predictor of cerebral hemorrhage in

acute ischemic stroke patients. J Neurol Sci 2008; 270:48–52.

6 Saqqur M, Tsivgoulis GCLOTBUST Investigators: et al. Symptomatic

intracerebral hemorrhage and recanalization after IV rt-PA: a multi-

center study. Neurology 2008; 71:1304–12.

Table 1 Baseline characteristics and outcome measures in acute stroke patients treated with IV-TPA in the low-dose group (n 5 48) and standard-dose

group (n 5 82)

Variable Low-dose group Standard-dose group P

Age, years (mean7SD) 55712 62713 0�004

Male gender, % 54 62 0�369

Hypertension, % 71 87 0�028

Diabetes mellitus, % 35 33 0�772

Hypercholesterolaemia, % 50 82 o0�001

Smoking, % 33 24 0�217

Atrial fibrillation, % 15 40 0�002

Ischaemic heart disease, % 29 38 0�298

Median NIHSS-score, points (IQR) 12 (10) 15 (11) 0�048

Median onset-to-treatment time, min (IQR) 165 (30) 155 (47) 0�319

Total TPA dose in mg (mean7SD) 4674 72718 0�002

Pretreatment SBP, mmHg (mean7SD) 170726 158727 0�012

Pretreatment DBP, mmHg (mean7SD) 93714 85716 0�004

Pretreatment Blood Glucose, mmoL/L (mean7SD) 874 874 0�915

Ischaemic stroke subtype� o0�001

Large-artery atherosclerosis (%) 15 35

Cardioembolic stroke (%) 23 48

Lacunar infarction (%) 17 2

Infarct of an undetermined cause (%) 45 6

Infarct of other determined causes 0 9

Outcome measures

3-month functional independencew 35% 59% 0�011

3-month mortality 10% 13% 0�723

DNIHSS at dischargez, points (median, IQR) 4 (5) 7 (10) 0�001

DNIHSS at 3 monthsy, points (median, IQR) 6 (5) 9 (12) 0�001

�According to the TOAST criteria. wModified Rankin scale score of 0–1. zDNIHSS at discharge 5 NIHSSadmission�NIHSSdischarge.yDNIHSS at discharge 5

NIHSSadmission�NIHSS3months. DBP, diastolic blood pressure; IQR, interquartile range; IV-TPA, intravenous tissue plasminogen activator; SBP, systolic blood

pressure.

& 2009 The Authors.& 2009 World Stroke Organization International Journal of Stroke Vol 4, October 2009, 320–321 321

V. K. Sharma et al. Letter to the editor