Letters to the Editor

Journal of Clinical Neuroscience 18 (2011) 160–161

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier .com/ locate/ jocn

Comment on ‘‘Efficacy and safety of different doses of intravenous tissueplasminogen activator in Chinese patients with ischemic stroke”

Dear Professor Kaye,

We read with interest the study by Zhou et al.1 regarding theefficacy and safety of different doses of intravenous tissue plasmin-ogen activator (IV-TPA) in Chinese patients with acute ischemicstroke (IS). The study raises some important issues specifically rel-evant to the Asian context.

Limited data are available regarding sytemic thrombolysis inAsian patients with acute IS, primarily due to the small proportionof patients who receive this definitive therapy.2 The problem is fur-ther compounded since acute IS accounts for about 3 milliondeaths annually in developing countries,3 often occurring in rela-tively younger patients.4 The data from systematic clinical trialsfrom Asia are available only for patients with acute IS from Japanand suggest that the clinical efficacy and safety of low-dose IV-TPA (0.6 mg/kg body weight) are comparable to thrombolysis withstandard-dose IV-TPA (0.9 mg/kg body weight) in a predominantlyWestern population.4,5 Results from the Japanese studies haveencouraged many Asian centers to adopt the low-dose or even var-iable-dose IV-TPA regimens.6–10 Some of the possible incentives oflow-dose TPA include the reduced treatment cost, anticipated low-er rates of symptomatic intracranial hemorrhage (SICH) and com-parable efficacy to the standard-dose.

It is difficult to compare various reports from Asia due to thewide differences in ethnicities, baseline stroke severity, outcomemeasures and TPA dose regimens.1,6–10 Interestingly, most of thestudies from Asia have reported considerably better functionaloutcomes with the standard-dose IV-TPA regimen, withoutincreasing the risk of SICH.7–9 In our own experience at a tertiarycentre in Singapore, the low-dose IV-TPA6 resulted in the func-tional outcomes that barely matched with the J-ACT4 and NINDS5

trials. Furthermore, we observed considerably higher rates of SICH.Interestingly, revision of the IV-TPA dose regimen (to the standarddose) resulted in significantly better functional outcomes (modi-fied Rankin scale, 0–1 in 59% of patients) with low (1.7%) rates ofSICH. Our multi-racial Singaporean population is comprised ofmany major Asian ethnicities and might be considered as a repre-sentative sample from Asia. Similar results have been reportedwith standard-dose IV-TPA in Thai7 and Indian9 patients. Zhouet al.1 have also observed a trend towards better clinical resultswith the standard-dose IV-TPA in Chinese patients. These resultsclearly suggest that the Japanese experience with low-doseIV-TPA cannot be applied directly to all Asian countries and thestandard dose could be safely used to obtain better clinicaloutcomes as compared to the Western population. These findingsassume immense significance since a comparative study between

the low- and standard-dose IV-TPA in acute IS has never been con-ducted (including in Japan). We agree with Zhou et al.1 that a ran-domized controlled clinical trial could settle the controversial issueof IV-TPA dose in China. However, it is not feasible to conduct sepa-rate clinical trials in every Asian country or major ethnicity. Alterna-tively, a properly designed larger multinational registry of all Asianpatients treated with IV-TPA could provide satisfactory answers tomost of the important and clinically relevant clinical questions.

In conclusion, we express our concern about the widely preva-lent practice of variable-dose regimes of IV-TPA across Asian coun-tries. Rapidly improving socioeconomic conditions and changinglifestyles are expected to increase the incidence of IS as well asthe proportion of patients treated with IV-TPA. Therefore, urgentefforts are warranted to establish the safer and effective dose ofuniform IV-TPA in Asia. Since a large randomized controlled trialdoes not appear feasible, we propose an Asia-wide ischemic strokethrombolysis registry to address the prevailing confusion aboutthe IV-TPA dose.

References

1. Zhou XY, Wang SS, Collins ML, et al. Efficacy and safety of different doses ofintravenous tissue plasminogen activator in Chinese patients with ischemicstroke. J Clin Neurosci 2010;17:988–92.

2. Poungvarin N. Stroke in the developing world. The Lancet 1998;352(Suppl. III):19–22.

3. Ueshima S, Matsuo O. The differences in thrombolytic effects of administratedrecombinant t-PA between Japanese and Caucasians. Thromb Haemost2002;87:544–6.

4. Yamaguchi T, Mori E, Minematsu K, et al. Japan Alteplase Clinical Trial (J-ACT)Group. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset:Japan Alteplase Clinical Trial (J-ACT). Stroke 2006;37:1810–5.

5. The National Institute of Neurological Disorders and Stroke rt-PA Stroke StudyGroup. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med1995;333:1581–7.

6. Sharma VK, Tsivgoulis G, Tan JH, et al. Feasibility and safety of intravenousthrombolysis in multiethnic Asian stroke patients in Singapore. J StrokeCerebrovasc Dis 2010 [Epub ahead of print]. PMID: 20554224.

7. Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic therapy inacute ischemic stroke in Asia: the first prospective evaluation. Clin NeurolNeurosurg 2006;108:549–52.

8. Salam KA, Ummer K, Pradeep Kumar VG, et al. Intravenous thrombolysis foracute ischemic stroke: the Malabar experience 2003 to 2008. J Clin Neurosci2009;16:1276–8.

9. Padma MV, Singh MB, Bhatia R, et al. Hyperacute thrombolysis with IV rtPA ofacute ischemic stroke: efficacy and safety profile of 54 patients at a tertiaryreferral center in a developing country. Neurol India 2007;55:46–9.

10. Chao AC, Hsu HY, Chung CP, et al. The Taiwan Thrombolytic Therapy for AcuteIschemic Stroke (TTT-AIS) Study Group. Outcomes of thrombolytic therapy foracute ischemic stroke in Chinese patients. The Taiwan Thrombolytic Therapyfor Acute Ischemic Stroke (TTT-AIS) Study. Stroke 2010;41:885–90.

Aftab AhmadVijay K. Sharma

Division of Neurology,National University Hospital, 5 Lower Kent Ridge Road,

Singapore 119074, SingaporeTel.: +65 67722516; fax: +65 68723566

E-mail address: drvijay@singnet.com.sg (V.K. Sharma)

Letters to the Editor / Journal of Clinical Neuroscience 18 (2011) 160–161 161

doi:10.1016/j.jocn.2010.07.104

Reply to ‘Comment on ‘‘Efficacy and safety of different doses of intravenous tissueplasminogen activator in Chinese patients with ischemic stroke”’

Dear Professor Kaye,We thank Doctors A. Ahmad and V. K. Sharma for their helpful

comments1 on our recent study on the different dosages of intra-venous tissue plasminogen activator (r-tPA) in Chinese patientswith acute ischemic stroke.2

We would like to emphasize that the patients in our studyare all Han Chinese. Therefore, this Han Chinese cohort providesa homogeneous ethnic group and substantially eliminates poten-tial bias on the effects of ethnicity that exists in other studies,even allowing for subgroup analyses.3,4 We note that the debateregarding appropriate r-tPA dosage in Chinese patients has gath-ered momentum since the publication of the Japan AlteplaseClinical Trial (J-ACT) study which administered a lower dosageof t-PA.5 This led to a proportion of clinicians in China toadminister lower dosage r-tPA on the assumption that there ex-ists similar thrombolytic response between a Han Chinese co-hort and the Japanese cohort. In contrast to the J-ACT study,our study suggests improved efficacy and safety of standarddosages of r-tPA on the Han Chinese cohort in favour of lowerdosage of r-tPA. This outcome is in accordance with the latestChinese Guidelines on Acute Ischemic Stroke which has recom-mended 0.9 mg/kg r-tPA for all patients in China, including HanChinese.6

We look forward with interest to the publication of Drs Ahmadand Sharma’s study on the ‘‘Feasibility and safety of intravenousthrombolysis in multiethnic Asian stroke patients in Singapore”.7

In addition, we agree that it would be impractical to conduct a ran-domised controlled study on different dosages of thrombolysis inAsian countries. It follows that the establishment of a thrombolysisregistry in Asia is a more realistic proposal.

References

1. Aftab Ahmad, Vijay K. Sharma. Comment on ‘‘Efficacy and safety of differentdoses of intravenous tissue plasminogen activator in Chinese patients withischemic stroke”. J Clin Neurosci 2011:18;160.

2. Zhou XY, Wang SS, Collins ML, et al. Efficacy and safety of different doses ofintravenous tissue plasminogen activator in Chinese patients with ischemicstroke. J Clin Neurosci 2010;17:988–92.

3. The National Institute of Neurological Disorders and Stroke rt-PA Stroke StudyGroup. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med1995;333:1581–7.

4. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA stroke trial. Stroke 1997;28:2119–25.

5. Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acuteischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT).Stroke 2006;37:1810–5.

6. Liu M, Zhang SM, Rao ML. 2010 Chinese guideline of acute ischemic stroke. J ChinNeurol 2010;43:146–60.

7. Sharma VK, Tsivgoulis G, Tan JH, et al. Feasibility and safety of intravenousthrombolysis in multiethnic Asian stroke patients in Singapore. J StrokeCerebrovasc Dis 2010, May 27 [Epub ahead of print].

Xiao-Yu ZhouDepartment of Neurology, The Branch of Shanghai Jiao Tong University,

Affiliated First People’s Hospital, Shanghai, China

Bernard YanDepartment of Neurology, Royal Melbourne Hospital, Grattan Street,

Parkville, Victoria 3050, Australia

Department of Neurology, The University of Melbourne,Parkville, Victoria, Australia

Tel.: +61 3 9349 2477; fax: +61 3 9342 8427E-mail address: bernard.yan@mh.org.au

doi:10.1016/j.jocn.2010.08.003