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A Pilot Study of a New Thrombolytic Agent for Acute Ischemic Stroke in Taiwan Within A Five-Hour Window

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A Pilot Study of a New Thrombolytic Agent for Acute Ischemic Stroke in Taiwan Within A Five-Hour Window
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  A Pilot Study of a New Thrombolytic Agent for AcuteIschemic Stroke in Taiwan Within A Five-Hour Window Han-Hwa Hu, MD; Michael Mu-Huo Teng, MD; Li-Chi Hsu, MD; Wen-Jang Wong, MD;Lee-Min Wang, MD; Yun-On Luk, MD; Chang-Ming Chern, MD;Bing-Wen Soong, MD, PhD; Wen-Yung Sheng, MPH  Background and Purpose —This study was the first clinical trial in Taiwan of a new thrombolytic agent human tissueurokinase type plasminogen activator (HTUPA) in patients with acute ischemic stroke.  Methods —Patients were treated with a single bolus intravenous HTUPA under an open-label dose escalation design within5 hours after symptom onset. Safety outcomes were assessed by symptomatic and asymptomatic intracerebralhemorrhage (ICH) as well as other bleeding episodes. Preliminary efficacy was measured by National Institutes of Health Stroke Scale (NIHSS).  Results —Three doses of HTUPA (0.3 mg/kg, 0.35 mg/kg, and 0.4 mg/kg) were administered to 33 patients, with themajority of patients (n  29) receiving 0.3 mg/kg. Two cases of fatal ICH occurred: 1 in the patient who received 0.4mg/kg and the other in the 0.3 mg/kg group. Asymptomatic ICH occurred in 6 patients. Other treatment-related seriousadverse events were ecchymosis, hematuria, and upper gastrointestinal bleeding, which were completely recovered. Atday 90, in patients treated with 0.3 mg/kg within a 0- to 5-hour window, 34% reached NIHSS scores 0 to 1, whereasof those treated within 0 to 3 hours, 86% reached this score. Conclusion —Intravenous HTUPA, given at 0.3 mg/kg as a bolus injection within 5 hours after symptom onset, had anacceptable safety and efficacious profile in patients with acute ischemic stroke.  ( Stroke . 2006;37:918-919.)Key Words:  stroke, ischemic    thrombolytic therapy S troke is one of the leading causes of death worldwide 1–2 ;in Taiwan, it kills only after cancer and represents thesingle most common cause of permanent disability. 3 Standardtreatment in local hospitals has been mostly supportive,whereas tissue plasminogen activator (t-PA) was approved inTaiwan only in 2004. Reports on the use of thrombolytics forstroke patients in the Asian population have been lacking.Human tissue urokinase type plasminogen activator (HTUPA),produced locally, is a genetically engineered hybrid moleculeof urokinase and t-PA. 4 In canine coronary thrombolyticstudies, HTUPA induced prompt and sustained coronarythrombolysis at lower doses when compared with t-PA. 5–6 The present study was a pilot analysis of HTUPA in patientswith acute ischemic stroke. Methods This study was approved by the institutional review board andthe Department of Health, Taiwan. Written informed consent wasobtained from each participating patient. Patients of cerebral ische-mia confirmed by head computed tomography (CT) scans withNational Institutes of Health Stroke Scale (NIHSS)  9 and  20 andwho could receive the study medication within 5 hours after the onsetof symptoms were eligible to enroll (for brain stem stroke, patientswith NIHSS  20 could be included at the investigator’s discretion).Patients with any signs of intracranial hemorrhage or tumor wereexcluded. Other exclusion criteria followed guidelines from theAmerican Heart Association for the use of t-PA in ischemic strokepatients. 7 Head CT scan and neurological evaluation were performedimmediately before the administration of HTUPA and at 24 hoursand 90 days after treatment. Neurological evaluations with NIHSS,Barthel Index, modified Rankin Scale, and Glasgow Outcome Scalewere performed at baseline, 30 minutes (NIHSS only), 60 minutes(NIHSS only), 2 hours, 24 hours, 48 hours, 7 days, 30 days, and 90days after treatment. Results A total of 35 patients were enrolled into the study betweenJune 2001 and July 2004. Among them, 29 received 0.3mg/kg of HTUPA, 3 received 0.35 mg/kg, and 1 received 0.4mg/kg. Two patients were withdrawn from the study beforeadministration of HTUPA because of the use of endotrachealand nasopharyngeal tubes with traumatic bleeding.The mean age of the patients was 69.1  10.9 years; 60%were male. The median NIHSS score was 13 (range 9 to 38).Eighty-three percent of patients had a medical history of hypertension, 43% diabetes mellitus, and 29% hyperlipid-emia. Sixty-nine percent of patients had large-vessel athero- Received December 5, 2005; accepted December 12, 2005.From the Departments of Neurology (H.-H.H., L.-C.H., W.-J.W., Y.-O.L., C.M.C., B.-W.S., W.-Y.S.), Radiology (M.-H.T.), and the emergency room(L.-M.W.), Taipei Veterans General Hospital, Taiwan.Correspondence to Han-Hwa Hu, MD, Department of Neurology, Taipei Veterans General Hospital, 201 Shih-Pai Road, Sec 2 Taipei, Taiwan 11217.E-mail hhhu@vghtpe.gov.tw© 2006 American Heart Association, Inc. Stroke  is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000202591.18871.f7  918  by guest on June 22, 2015http://stroke.ahajournals.org/ Downloaded from   thrombotic stroke and 31% cardioembolic stroke. 8 The meantreatment window was 3.62  0.97 hours, and the mean doseof HTUPA was 20.4  3.8 mg.The incidence of intracerebral hemorrhage (ICH) within 24hours after HTUPA administration and its clinical outcomesare shown in the Table. At the lowest dose of 0.3 mg/kg, 1fatal symptomatic ICH (3%) and 5 asymptomatic ICH (17%)were observed. All these ICH incidences occurred in patientswho received treatment in the 3- to 5-hour window; nonewere in the 0- to 3-hour window. As the dose escalated to 0.4mg/kg, the first and only patient receiving this dose experi-enced a fatal ICH, thus enrollment at this dose was halted. Inthe patients (n  3) who received the next lower dose, 0.35mg/kg, asymptomatic ICH was observed in 1 patient in the3- to 5-hour treatment window. After 90 days, this patientshowed neurological improvement with NIHSS score changedfrom baseline score 13 to 5.Between 24 hours and 90 days, no additional ICH wasreported except 1 event of traumatic intracranial hemorrhagein a patient from falling at 1.5 months after administration.Two additional deaths occurred during this study period; 1was attributable to pneumonia and the other acute myocardialinfarction. Other non–central nervous system bleeding eventsin patients were: major bleeding (1 patient; upper gastroin-testinal bleeding); minor bleeding (12 patients; gum bleeding,ecchymosis, hematuria, and upper gastrointestinal bleeding);and insignificant bleeding (18 patients; ecchymosis and mildhematuria). At 24 hours after administration, preliminary effi-cacy analysis showed 45% (15 of 33) of all treated patientsand 48% (14 of 29) of the patients who received 0.3 mg/kghad major neurological improvement as defined by an im-provement of    4 points in NIHSS. At 90 days, in patientstreated at 0.3 mg/kg dosage, 34% reached NIHSS score 0 to1, among them, 86% treated within 0 to 3 hours reached thisscore, whereas in those treated within 3 to 5 hours, it was 18%. Discussion This study was the first clinical trial of a new thrombolyticagent in Taiwanese patients with acute ischemic stroke. Whenthe study began, there were 2 major concerns: 1 being thenewness of the test agent HTUPA and the other, the prepon-derance of intracranial vascular lesion in the Orientals overthe Occidental people. 9–11 Our study showed that the ICHincidences in Taiwanese patients treated with HTUPA at 0.3mg/kg with 1 intravenous bolus injection (Table) were withinthe limits of those reported for t-PA trials performed mostlyin Western countries. 12–13 However, interpretation of thisstudy is limited because of the small number of patients andthe lack of placebos. Further assessment of HTUPA wouldinclude using lower dosages, comparison with t-PA in Tai-wanese patients, as well as trials of HTUPA in patients of other ethnic srcins. References 1. American Heart Association.  Heart and Stroke Fact Statistics: 1999Statistical Supplement.  Dallas, Tex: American Heart Association; 1999.2. Murray CJL, Lopez AD, eds.  The Global Burden of Disease.  Vol 1.Boston, Mass: Harvard University Press; 1996.3. Hu HH, Sheng WY, Chu FL, Lan CF, Chiang BN. Incidence of stroke inTaiwan.  Stoke . 1992;23:1237–1241.4. Lee SG, Kalyan N, Wilhelm J, Hum WT, Rappaport R, Cheng SM, DheerS, Urbano C, Hartzell RW, Ronchetti-Blume M, et al. Construction andexpression of hybrid plasminogen activators prepared from tissue-typeplasminogen activator and urokinase-type plasminogen activator genes.  J Biol Chem . 1988;263:2917–2924.5. Fu KP, Lee S, Hetzel N, Fenichel R, Hum HW, Speth J, Kalyan N, HungPP. Clearance of a novel recombinant tissue plasminogen activator inrabbits.  Thromb Res . 1988;50:679–685.6. Weinheimer CJ, James HL, Kalyan NK, Wilhelm J, Lee SG, Hung PP,Sobel BE, Bergmann SR. Induction of sustained patency after clot-selective coronary thrombolysis with Hybrid-B, a Genetically Engineeredplasminogen activator with a prolonged biological half-life.  Circulation .1991;83:1429–1436.7. Adams HP, Brott TG, Furlan AJ, et al. Guidelines for thrombolytictherapy for acute stroke.  Stroke . 1996;27:1711–1718.8. Albanese MA, Clarke WR, Adams HP Jr, Woolson RF. Ensuring reli-ability of outcome measures in multicenter clinical trials of treatments foracute ischemic stroke. The program developed for the Trial of Org 10172in Acute Stroke Treatment (TOAST).  Stroke . 1994;25:1746–1751.9. Feldmann E, Daneault N, Kwan E, Ho KJ, Pessin MS, Langenberg P,Caplan LR. Chinese-white differences in the distribution of occlusivecerebrovascular disease.  Neurology . 1990;40:1541–1545.10. Tanaka H, Hayashi M, Date C, Imai K, Asada M, Shoji H, Okazaki K,Yamamoto H, Yoshikawa K, Shimada T, et al. Epidemiologic studies of stroke in Shibata, a Japanese provincial city: preliminary report on risk factors for cerebral infarction.  Stroke . 1985;16:773–780.11. Gross CR, Kase CS, Mohr JP, Cunningham SC, Baker WE. Stroke insouth Alabama: incidence and diagnostic features—a population-basedstudy.  Stroke . 1984;15:249–255.12. Tissue plasminogen activator for acute ischemic stroke. The NationalInstitute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  N Engl J Med.  1995;333:1581–1587.13. Albers GW, Clark WM, Madden KP, Hamilton SA. ATLANTIS trial:results for patients treated within 3 hours of stroke onset. AlteplaseThrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. Stroke . 2002;33:493–496. Incidence of ICH Within 24 Hours After HTUPA Administrationand Its Clinical Outcomes Outcomes Dosage of HTUPA 0.3 mg/kg(n  29)0.35 mg/kg(n  3)0.4 mg/kg(n  1) Asymptomatic ICH, n (%) 5 (17) 1 (33) 0Symptomatic ICH, n (%) 1 (3) 0 1 (100)Person who had symptomaticICH died at day 31       Person who had symptomaticICH died at day 10        1NIHSS at baseline median(range)19 (12–20) 13 (11–16) 15 (15)NIHSS at day 90 median(range)15 (5–22) 5 (4–12) 38 (38) Hu et al Study of a New Thrombolytic Agent For Acute Stroke  919  by guest on June 22, 2015http://stroke.ahajournals.org/ Downloaded from   Luk, Chang-Ming Chern, Bing-Wen Soong and Wen-Yung ShengHan-Hwa Hu, Michael Mu-Huo Teng, Li-Chi Hsu, Wen-Jang Wong, Lee-Min Wang, Yun-On A Five-Hour WindowA Pilot Study of a New Thrombolytic Agent for Acute Ischemic Stroke in Taiwan Within Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2006 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Stroke doi: 10.1161/01.STR.0000202591.18871.f72006;37:918-919; srcinally published online January 19, 2006; Stroke. http://stroke.ahajournals.org/content/37/3/918 World Wide Web at: The online version of this article, along with updated information and services, is located on the  http://stroke.ahajournals.org//subscriptions/ is online at: Stroke Information about subscribing to Subscriptions:  http://www.lww.com/reprints Information about reprints can be found online at: Reprints:  document. Permissions and Rights Question and Answer process is available in theRequest Permissions in the middle column of the Web page under Services. Further information about thisOnce the online version of the published article for which permission is being requested is located, click can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Stroke in Requests for permissions to reproduce figures, tables, or portions of articles srcinally published Permissions:  by guest on June 22, 2015http://stroke.ahajournals.org/ Downloaded from 
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