| Article Access Statistics|
| Viewed||3400 |
| Printed||204 |
| Emailed||5 |
| PDF Downloaded||112 |
| Comments ||[Add] |
| Cited by others ||3 |
Click on image for details.
|Year : 2011 | Volume
| Issue : 2 | Page : 180-184
Low vs standard dose of recombinant tissue plasminogen activator in treating East Asian patients with acute ischemic stroke
Pornpatr A Dharmasaroja1, Junya Pattaraarchachai2
1 Department of Internal Medicine, Division of Neurology, Thammasat University, Thailand
2 Department of Community Medicine, Data Analysis and Management Unit, Thammasat University, Thailand
|Date of Submission||23-Nov-2010|
|Date of Decision||31-Dec-2010|
|Date of Acceptance||04-Jan-2011|
|Date of Web Publication||7-Apr-2011|
Pornpatr A Dharmasaroja
Division of Neurology, Faculty of Medicine, Thammasat University, Klong 1, Klong Luang, Pathumthani 12120
Source of Support: Faculty of Medicine, Thammasat University ,
Thailand, Conflict of Interest: None
Background : Intravenous recombinant tissue plasminogen activator (rtPA) has been approved to treat eligible patients with acute ischemic stroke within 4.5 hours of onset. The rationale for using a lower dose in Asian patients came from concerns about intracerebral hemorrhage because of the racial differences in blood coagulation-fibrinolysis factors. Aim : The aim of this systemic review was to compare the data from previous studies to address the efficacy and safety of using low-dose vs standard-dose rtPA in treating patients with acute ischemic stroke. Material and Methods : Previous studies were searched and analyzed. The confidence interval was calculated at 95%. Baseline characteristics and outcomes of the patients were compared between two doses of rtPA (0.6 vs 0.9 mg/kg), using Z test for two independent proportions. Results : Patients who received standard-dose rtPA had significantly higher favorable outcome at 3 months (33.1 vs 47.2%, P<0.0001), without significant difference in the rates of symptomatic intracerebral hemorrhage (3.5 vs 4.3%, P = 0.42) and mortality (13.1 vs 11.7%, P = 0.56). However, patients in the low-dose group were older and had more severe stroke. Conclusions : Patients receiving standard-dose rtPA seem to have higher rates of favorable outcome. However, there were significant differences in baseline characteristics between the two groups. A further, well-designed, randomized study in the same population is still needed to clarify the suspected benefit of the standard dose for East Asian patients.
Keywords: Asia, dose, intravenous thrombolysis, ischemic stroke, Thai
|How to cite this article:|
Dharmasaroja PA, Pattaraarchachai J. Low vs standard dose of recombinant tissue plasminogen activator in treating East Asian patients with acute ischemic stroke. Neurol India 2011;59:180-4
|How to cite this URL:|
Dharmasaroja PA, Pattaraarchachai J. Low vs standard dose of recombinant tissue plasminogen activator in treating East Asian patients with acute ischemic stroke. Neurol India [serial online] 2011 [cited 2019 Sep 23];59:180-4. Available from: http://www.neurologyindia.com/text.asp?2011/59/2/180/79132
| » Introduction|| |
Intravenous recombinant tissue plasminogen activator (rtPA) (0.9 mg/kg) has been approved by the US FDA since 1996 to treat eligible patients with acute ischemic stroke within 3 hours of onset, and the time window for treatment was expanded up to 4.5 hours in the 2009 recommendation from the American Heart Association/American Stroke Association. ,, The rationale for using a lower dose in Asian patients came from concerns about intracerebral hemorrhage because of the racial differences in blood coagulation-fibrinolysis factors.  In Japan, a low dose of rtPA (0.6 mg/kg) was approved to treat patients since 2005, and authors from the Japan Alteplase Clinical Trial concluded that the outcome after treatment and incidence of symptomatic intracerebral hemorrhage were comparable with published data for standard dose (0.9 mg/kg). , Low dose (0.72 ± 0.07 mg/kg) and standard dose (0.9 ± 0.02 mg/kg) of rtPA were also compared in Chinese patients and the data showed that symptomatic intracerebral hemorrhage and mortality were higher in the standard-dose group.  However, there was no prospective study comparing the efficacy and safety between low- and standard-dose rtPA in East Asian patients. The aim of this systemic review was to compare the data from previous studies to address the efficacy and safety of using low-dose vs standard-dose rtPA in treating patients with acute ischemic stroke.
| » Material and Methods|| |
We systematically searched for studies on thrombolytic treatment in East Asian patients with acute ischemic stroke using 'PubMed' and 'Medline.' The search terms, 'thrombolytic,' 'stroke,' and 'Asia,' were used. The initial search identified 55 articles. Of these, 46 articles were excluded because they did not meet the purpose of this review--they were not performed on East Asian patients, did not use intravenous thrombolysis as a treatment, or were not original studies. Finally, there were nine studies reviewed ,,,,,,,,,, [Table 1]. Studies that met the following criteria were included: (a) rates of symptomatic intracerebral hemorrhage, favorable outcome, and death at 3 months were reported; (b) baseline characteristics of the patients were presented; and (c) patients receiving intravenous rtPA were East Asian. A study in Chinese was excluded because this study was not a randomized study and patients in the low-dose group and standard-dose group received a wide range of doses from 0.55 to 0.84 mg/kg and 0.86 to 0.95 mg/kg, respectively.  A study that enrolled multiethnic patients and used a range of doses (0.5-0.9 mg/kg) in the low-dose group was also excluded.  Thus, there were six studies included in the statistical analysis.
|Table 1: Thrombolytic studies in East Asian patients with acute ischemic stroke |
Click here to view
Baseline characteristics and the outcomes of interest of the patients in each study were collected. The outcomes of interest were the rates of favorable outcome (modified Rankin Scale; mRS 0-1), death within 3 months, and symptomatic intracerebral hemorrhage. The severity of the stroke was evaluated by the National Institutes of Health Stroke Scale (NIHSS). Symptomatic intracerebral hemorrhage was defined by the European Cooperative Acute Stroke Study criteria, which is hemorrhage associated with worsening of ≥4 points on the NIHSS score.  The data were presented as a mean or a median for continuous variables and as percentage (number) for dichotomous variables. A 95% confidence interval on each variable was calculated. Baseline characteristics and outcomes of the patients were compared between two doses of rtPA (0.6 vs 0.9 mg/kg), using Z test for two independent proportions. Because the patients enrolled in the SAMURAI study were partially included in the Japan post-Marketing Alteplase Registration Study (J-MARS), and data from all Japanese trials were not significantly different from those in the J-MARS study [Figure 1], the outcomes of interest and baseline characteristics of the patients in the J-MARS study were chosen to be compared with data from the study by Dharmasaroja et al. [Table 2].
|Table 2: Baseline characteristics and the outcomes were compared between patients receiving low and standard dose of rtPA |
Click here to view
|Figure 1: Data from the thrombolytic studies in East Asian patients with acute ischemic stroke presented in proportion (95% confidence interval)|
Click here to view
| » Results|| |
As compared with patients receiving low-dose (0.6 mg/kg) rtPA, the patients with standard-dose rtPA (0.9 mg/kg) had significantly higher favorable outcome at 3 months (33.1 vs 47.2%, P<0.0001), without significant difference in the rates of symptomatic intracerebral hemorrhage (3.5 vs 4.3%, P = 0.42) and mortality (13.1 vs 11.7%, P = 0.56). However, several baseline characteristics and stroke subtypes were different between the two studies. Patients enrolled in the low-dose rtPA study were older, had more severe stroke and more common cardioembolic stroke subtype [Table 2].
| » Discussion|| |
Standard dose of rtPA was the dose used in the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study (NINDS),  based on the results from two previous open-label, dose-escalation studies. , A total of -74 patients were treated within 90 minutes of symptom onset over 7 dose tiers, ranging from 0.35 to 1.08 mg/kg.  The proportion of patients with major neurological improvement at 24 hours was higher in 0.85 mg/kg tier (55%) as compared with the 0.6 mg/kg tier (33%). There was no symptomatic intracerebral hemorrhage with doses of <0.95 mg/kg. With the lack of evidence for greater neurological improvement and the risk of serious hemorrhage at the higher dose, authors recommended further evaluation of an intermediate dose of 0.85 to 0.95 mg/kg. Twenty patients were treated with rtPA during 91 to 180 minutes after symptom onset over 3 dose tiers (0.6, 0.85, and 0.95 mg/kg).  Intracerebral hemorrhage was found in patients receiving ≥0.85 mg/kg of rtPA. The NINDS study chose to compare between 0.9 mg/kg of rtPA and placebo in treating the eligible patients with acute ischemic stroke within 180 minutes from the onset of symptoms. As compared with patients given placebo, although symptomatic intracerebral hemorrhage occurred more often in patients receiving rtPA, at least 30% of these patients were more likely to have minimal or no disability at 3 months. 
Three randomized double-blind trials of duteplase in patients with acute ischemic stroke within 6 hours of onset were conducted in Japanese patients. , On the basis of the angiographic recanalization rate, a dose of 20 mega-international units (MIU) of duteplase was found to be superior to placebo, and 20 MIU did not differ from 30 MIU in recanalization rate and clinical improvement. However, massive intracerebral hemorrhage occurred more often in patients receiving 30 MIU. ,, Twenty MIU of duteplase is equivalent to 0.33 MIU/kg or 0.6 mg/kg of rtPA.  A low dose of rtPA (0.6 mg/kg) was approved to treat patients in Japan since 2005.
Racial differences may influence patients' responses to thrombolytic therapy. Sane et al. studied patients with acute myocardial infarction and found that black patients had an apparent enhanced sensitivity to rtPA, which was manifested by increased thrombolytic efficacy, a more pronounced systemic fibrinogen breakdown, and increased transfusion.  Differences in thrombolytic effects of administrated rtPA between Japanese and Caucasians have been reported. The dose of rtPA administered in thrombolytic therapy for acute myocardial infarction in Japanese patients is lower than that of Caucasian patients (0.5-0.75 mg/kg vs 1-1.25 mg/kg) to yield the same patency rate (60-80%).  Plasma concentrations of fibrinogen and plasminogen activator inhibitor in Western Caucasians are higher than in Japanese. , With more reports about the difference of genetic polymorphism in coagulation factors due to race, , this might cause the different response to thrombolytic drugs.
Whether the low dose or standard dose of rtPA is appropriate for East Asian patients is still debated. There were two studies comparing between two doses in Asian patients. , The results from a study of Chinese patients favor the low dose, while another study in multiethnic Asian patients favors the standard dose. There is no prospective, randomized study directly comparing between doses in the same population. The patients with acute ischemic stroke in East Asian countries usually weigh less and have lower average income than those in developed countries. Each rtPA (alteplase) package usually contains two bottles of 50 mg. If the dosage of 0.6 or 0.7 mg/kg is used, the upper limits of weight for the use of a bottle (50 mg) are 83 or 71 kg, respectively. Thus, only a bottle of rtPA can be prescribed in most Asian patients, instead of two bottles in the standard dose. This will cut the cost by half. If treating with the low-dose rtPA (0.6 or 0.7 mg/kg) provides comparable efficacy and safety compared with the standard dose, perhaps more Asian patients will receive rtPA.
This systemic review showed that more favorable outcome was seen in patients with standard dose, without compromising safety outcomes. Although the comparison was made in quite the same population of interest (East Asian), there were still some significant differences in baseline characteristics which had been shown in previous studies that could affect the outcomes. Older age and more severe stroke in patients receiving the low dose may explain the less favorable outcomes.
This systemic review had some limitations. Because some reported data were presented in medians without available raw data, a complete hypothesis test could not be calculated. Only one study using 0.9 mg/kg of rtPA was compared with the low-dose group, because there were only few published studies using this dose in East Asian patients. In conclusion, patients receiving standard-dose rtPA seem to have a higher rate of favorable outcome. However, there were significant differences in baseline characteristics between the two dose groups. A further, well-designed, randomized study in the same population is still needed to clarify which dose should be recommended.
| » Acknowledgments|| |
Thanks to Dr. Sombat Muengtaweepongsa and Thammasat Stroke Team for helping in patient registration. This research was funded by Faculty of Medicine, Thammasat University , Thailand.
| » References|| |
|1.||Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the stroke council of the American Stroke Association. Stroke 2003;34:1056-83. |
|2.||Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr; American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: A science advisory from the American Heart Association/ American Stroke Association. Stroke 2009;40:2945-8. |
|3.||Hankey GJ. Thrombolysis for acute ischemic stroke. J Clin Neurosci 2001;8:103-5. |
|4.||Ueshima S, Matsuo O. The differences in thrombolytic effects of administrated recombinant t-PA between Japanese and Caucasians. Thromb Haemost 2002;87:544-6. |
|5.||Toyoda K, Koga M, Naganuma M, Shiokawa Y, Nakagawara J, Furui E, et al. Routine use of intravenous low-dose recombinant tissue plasminogen activator in Japanese patients; General outcomes and prognostic factors from the SAMURAI register. Stroke 2009;40:3591-5. |
|6.||Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, et al. 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. |
|7.||Chao AC, Hsu HY, Chung CP, Liu CH, Chen CH, Teng MM, et al. Outcomes of thrombolytic therapy for acute ischemic stroke in Chinese patients; The Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study. Stroke 2010;41:885-90. |
|8.||Dharmasaroja PA, Dharmasaroja P, Muengtaweepongsa S. Outcomes of Thai patients with acute ischemic stroke after intravenous thrombolysis. J Neurol Sci 2011;300:74-7. |
|9.||Sharma VK, Tsivgoulis G, Tan JH, Wong LY, Ong BK, Chan BP, et al. Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore. J Stroke Cerebrovasc Dis 2010;19:424-30. |
|10.||Hacke W, Kaste M, Fiesche C, von Kummer R, Davalos A, Meier D, et al. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-51. |
|11.||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. |
|12.||Yoneda Y, Yamamoto S, Hara Y, Ohta K, Matsushita M, Yamamoto D, et al. Post-licensed 1-year experience of systemic thrombolysis with tissue plasminogen activator for ischemic stroke in a Japanese neuro-unit. Clin Neurol Neurosurg 2007;109:567-70. |
|13.||Walgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): An observational study. Lancet 2007;369:275-82. |
|14.||Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Sasaki M, Hirano T, et al. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion. Japan Alteplase Clinical Trial II (J-ACT II). Stroke 2010;41:461-5. |
|15.||Nakawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori E, et al. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice. The Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke 2010;41:1984-9. |
|16.||Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7. |
|17.||Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, et al. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23:632-40. |
|18.||Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, et al. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke 1992;23:641-5. |
|19.||Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 1992;42:976-82. |
|20.||Yamaguchi T, Kikuchi H, Hayakawa H, Japanese thrombolysis study group. Clinical efficacy and safety of intravenous tissue plasminogen activator in acute embolic stroke: A randomized, double-blind, dose-comparison study of duteplase. In: Yamaguchi T, Mori E, Minematsu K, del Zoppo GJ, editors. Thrombolytic therapy in acute ischemic stroke III. Tokyo: Springer-Verlag; 1995. p. 223-9. |
|21.||Sane DC, Stump DC, Topol EJ, Sigmon KN, Clair WK, Kereiakes DJ, et al. Racial differences in responses to thrombolytic therapy with recombinant tissue-type plasminogen activator. Increase fibrin(ogen)olysis in blacks. The thrombolysis and angioplasty in myocardial infarction study group. Circulation 1991;83:170-5. |
|22.||Iso H, Folsom AR, Sato S, Wu KK, Shimamoto T, Koike K, et al. Plasma fibrinogen and its correlates in Japanese and US population samples. Arterioscler Thromb 1993;13:783-90. |
|23.||Iso H, Folsom AR, Koike KA, Sato S, Wu KK, Shimamoto T, et al. Antigens of tissue plasminogen activator and plasminogen activator inhibitor 1: Correlates in nonsmoking Japanese and Caucasian Men and Women. Thromb Haemost 1993;70:475-80. |
|24.||Kangsadalampai S, Board PG. The Val34Leu polymorphism in A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity. Blood 1998;92:2766-70. |
|25.||Murata M. Genetic polymorphisms associated with thrombotic disorders in the Japanese population. Fibrinolysis Proteolysis 2000;14:155-64. |
[Table 1], [Table 2]
|This article has been cited by|
||Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
| ||Ji-Wei Cheng,Xiao-Jing Zhang,Li-Shan Cheng,Guo-Yi Li,Li-Jun Zhang,Kang-Xiang Ji,Qing Zhao,Yu Bai |
| ||Journal of Stroke and Cerebrovascular Diseases. 2018; 27(2): 381 |
|[Pubmed] | [DOI]|
||The Chinese Stroke Association scientific statement: intravenous thrombolysis in acute ischaemic stroke
| ||Qiang Dong,Yi Dong,Liping Liu,Anding Xu,Yusheng Zhang,Huaguang Zheng,Yongjun Wang |
| ||Stroke and Vascular Neurology. 2017; 2(3): 147 |
|[Pubmed] | [DOI]|
||Consensus Statement on the Use of Intravenous Recombinant Tissue Plasminogen Activator to Treat Acute Ischemic Stroke by the Chinese Stroke Therapy Expert Panel
| ||An-Ding Xu,Yong-Jun Wang,David Z Wang |
| ||CNS Neuroscience & Therapeutics. 2013; 19(8): 543 |
|[Pubmed] | [DOI]|