重组组织型纤溶酶原激活剂静脉溶栓治疗急性脑梗死的疗效观察
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摘要
背景与目的：脑梗死(Cerebral infarction, CI)是指因脑部血液循环障碍,缺血、缺氧所致的局限性脑组织的缺血性坏死或软化。目前脑梗死已成为危害我国中老年人身体健康和生命的主要疾病。及时有效的治疗与患者的预后密切相关。目前急性脑梗死公认的处理原则强调早期诊断、早期治疗、早期康复和早期预防再发。超早期的溶栓治疗一直被认为是最重要的恢复血流措施。急性脑梗死溶栓治疗的研究始于20世纪80年代,经过20多年多种药物多项大规模多中心、双盲、安慰剂对照临床试验,已经证实溶栓治疗应该做为急性脑梗死超早期治疗的首选方法,循证医学指南A级推荐缺血性脑卒中首选治疗措施为3h静脉应用重组组织型纤溶酶原激活剂(Recombinant tissue-type plasminogen activator,rt.PA)治疗。尽管已经有越来越多的医务人员和患者认识到超早期溶栓治疗的重要性,但由于各种原因,即使在美国亦仅有1.8-3.0%的缺血性卒中患者,64%的医院能进行溶栓治疗。而在我国能够得到溶栓治疗的患者则远不足1%。国内一些研究对rt-PA溶栓治疗及目前临床常用药物(丹参、肝素等)的疗效及安全性进行了对比,这些研究提不rt-PA静脉溶栓治疗急性脑梗死较以往常用药物治疗更安全有效。奥扎格雷钠(ozagrel)具有抗血小板聚集、抑制血栓形成和溶通血栓等功能,目前是治疗急性脑梗死的临床常用药物,其疗效及安全性获得肯定。但目前关于rt-PA静脉溶栓与静脉应用奥扎格雷钠治疗急性脑梗死的疗效及安全性对比研究,国内尚未见报道。为深入研究rt-PA静脉溶栓治疗急性脑梗死的有效性及安全性,并与国内临床常用药物奥扎格雷钠进行对比,为国内规范治疗急性缺血性卒中提供循证依据,本实验应用rt-PA静脉溶栓治疗急性脑梗死患者,与静脉应用奥扎格雷钠治疗的患者进行了对照研究。
方法：分析自2006年1月至2009年10月间在我院神经内科诊疗的符合溶栓标准的30例发病时间在3h内的急性脑梗死患者,rt-PA组与对照组各15例。rt-PA组3h时间窗内给予静脉重组组织型纤溶酶原激活剂,剂量为0.9mg／kg(最大剂量90mg),先静脉推注10%(1min),其余剂量连续静滴,60min滴完。溶栓后24h复查凝血系列及头颅CT,在排除出血后给予阿司匹林300mg／d,口服,共10 d,后改为阿司匹林100mg／d,口服。对照组3h内给予奥扎格雷钠氯化钠注射液80mg静滴,每日2次,共14d。改善脑细胞代谢及抗脑水肿的治疗二组相同。神经功能缺损评分及疗效判定采用国立卫生研究院卒中量表(NIHSS)评定溶前及溶后24h.7d.14d.21d的疗效；日常生活能力评定采用日常生活能力量表Barthel指数(BI)评定溶后14d及21 d的日常生活能力。以溶栓后14d内的继发性颅内出血率及死亡率来评价安全性。
结果：rt-PA组和对照组的性别比例、年龄、既往史、伴发病和初始神经功能评分均无统计学差异(P>0.05)；两组治疗后7d、14d、21 d时疗效比较表明,7d时两组疗效无明显差异,14d、21 d时rt-PA组较对照组疗效更好,差异显著(P<0.05)；日常生活能力14d时两组恢复率(BI≥95分)无显著性差异,21 d时日常生活能力恢复率rt-PA组26.6%,对照组无1例(P<0.05):rt-PA组与对照组均无1例症状性脑出血发生；rt-PA组与对照组死亡率分别为13.3％,6.6％(P>0.05):rt-PA组与对照组血管再闭塞率分别为6.66%,13.3%(P>0.05)。
结论：1、本研究表明rt-PA组和对照组治疗后各时间点NIHSS评分、BI指数等与治疗前比较均显著改善,但随着治疗时间延长,rt-PA组较对照组改善更显著。提示应用rt-PA静脉溶栓治疗急性脑梗死更可显著改善患者预后,降低致残率,提高生活质量。2、rt-PA组和对照组均无症状性脑出血发生,两组死亡率亦无显著性差异,提示两种药物治疗急性脑梗死均是安全的。3、对于符合溶栓指征的急性脑梗死患者推荐早期应用rt-PA静脉溶栓治疗,以取得最佳疗效。
Background and purpose:Cerebral infarction is limitations of brain tissue necrosis or softening which is induced by brain blood circulation disorder, ischemia and hypoxia. Currently infarction has become a health hazard for the elderly in our major diseases. Timely and effective treatment and the prognosis is closely related to. Currently accepted principles of acute cerebral infarction emphasis on early diagnosis, early treatment, early rehabilitation and early prevention of recurrence. Ultra-early thrombolytic therapy has been considered the most important measures to restore blood flow. Thrombolytic therapy of acute cerebral infarction began in the 20th century 80s, after more than 20 years of multi-drug number of large-scale multi-center,double-blind, placebo-controlled clinical trials have confirmed that thrombolytic therapy be used as early cerebral infarction Preferred method of treatment, evidence-based medicine guidelines recommend A-level choice for the treatment of ischemic stroke measures 3h intravenous recombinant tissue plasminogen activator for treatment. Despite a growing number of medical staff and patients recognize the importance of ultra-early thrombolytic therapy, but for various reasons, even in the United States has only 1.8 to 3.0% of ischemic stroke patients,64% of the hospitals in for thrombolytic therapy. And in China access to thrombolytic therapy is much less than 1% of patients. Some domestic research commonly used rt-PA thrombolytic therapy and current clinical drugs (Salvia, heparin, etc.) of the efficacy and safety were compared, these studies suggest that rt-PA thrombolytic therapy in acute cerebral infarction than in the past used drugs more safely and effectively. Sodium ozagrel with anti-platelet aggregation, inhibition of thrombosis and thrombus dissolution through functions, is currently the treatment of acute cerebral infarction commonly used drugs,its efficacy and safety was confirmed. But on the rt-PA intravenous thrombo-lytic therapy and intravenous therapy ozagrel acute cerebral infarction compared the efficacy and safety study is not yet reported. For further study of rt-PA thrombolytic therapy in acute cerebral infarction of the efficacy and safety, rt-PA thrombolytic therapy and intravenous drugs commonly used in domestic clinical intravenous treatment ozagrel compared. For the domestic standard treatment of acute ischemic stroke and to provide evidence,the experimental application of rt-PA thrombolytic therapy in acute cerebral infarction, and intravenous treatment of patients ozagrel a controlled study.
Method:Analysis from January 2006 to October 2009 in our hospital neurology clinic with the standard thrombolytic therapy in 30 patients with onset of acute cerebral infarction within 3h, rt-PA group was 15 cases and either was control group. rt-PA group 3h time window for intravenous recombinant tissue plasminogen activator with the dose of 0.9mg/kg (maximum dose 90mg), the first intravenous injection of 10%(1min), the remaining dose continuous intravenous infusion,60min drops End.24h after thrombolysis, coagulation review series and head CT, after the exclusion of bleeding, given aspirin 300mg/d, orally, a total of 10 d, later changed to aspirin 100mg/d,orally.3h after onset of acute cerebral infarction in the control group given 80mg ozagrel sodium chloride injection, iv 2 times a day, of 14d. Improving brain cell metabolism and anti-brain edema the same two groups. Neurological deficit score and efficacy determination by the National Institutes of Health Stroke Scale (NIHSS) assessed before and after solution dissolved 24h,7d,14d,21d; Barthel ADL index (BI) assess the activities of daily living of 14d and 21d after dissolving. To 14d after thrombolysis within the secondary intracranial hemorrhage and death rates to assess safety.
Result:rt-PA group and the control group the sex ratio, age, past history, with the incidence and initial neurological function scores were not statistically different (P>0.05); After treatment,7d,14d,21d showed that 7d after treatment was no significant difference,14d,21d after treatment the rt-PA group to better effect than the control group, significant difference (P<0.05); 14d recovery rate of the two groups of daily living (BI>95 points) was no significant difference,21 d ADL recovery rate of 26.6% of rt-PA group, control group 1 cases (P<0.05); rt-PA group and the control group there was no one case of symptomatic intracranial hemorrhage; rt-PA group and the control group mortality was 13.3%,6.6%(P>0.05); rt-PA group and the control group of vascular re-occlusion rate was 6.66%,13.3%(P>0.05).
Conclusion:1.This study shows that rt-PA group and the control group at each time point after treatment, NIHSS score, BI index before treatment were significantly improved, but with the treatment time, rt-PA group than in the control group improved more significantly. It showed that rt-PA intravenous thrombolytic therapy can significantly improve prognosis and reduce disability, improve quality of life.2.rt-PA group and the control group had no symptoms of cerebral hemorrhage, the two groups no significant differences in mortality, suggesting the two drugs are the treatment of acute cerebral infarction is safe.3.Meet the indications for thrombolytic therapy of acute cerebral infarction recommend early application of rt-PA thrombolytic therapy in order to achieve the best effect.
方法：分析自2006年1月至2009年10月间在我院神经内科诊疗的符合溶栓标准的30例发病时间在3h内的急性脑梗死患者,rt-PA组与对照组各15例。rt-PA组3h时间窗内给予静脉重组组织型纤溶酶原激活剂,剂量为0.9mg／kg(最大剂量90mg),先静脉推注10%(1min),其余剂量连续静滴,60min滴完。溶栓后24h复查凝血系列及头颅CT,在排除出血后给予阿司匹林300mg／d,口服,共10 d,后改为阿司匹林100mg／d,口服。对照组3h内给予奥扎格雷钠氯化钠注射液80mg静滴,每日2次,共14d。改善脑细胞代谢及抗脑水肿的治疗二组相同。神经功能缺损评分及疗效判定采用国立卫生研究院卒中量表(NIHSS)评定溶前及溶后24h.7d.14d.21d的疗效；日常生活能力评定采用日常生活能力量表Barthel指数(BI)评定溶后14d及21 d的日常生活能力。以溶栓后14d内的继发性颅内出血率及死亡率来评价安全性。
结果：rt-PA组和对照组的性别比例、年龄、既往史、伴发病和初始神经功能评分均无统计学差异(P>0.05)；两组治疗后7d、14d、21 d时疗效比较表明,7d时两组疗效无明显差异,14d、21 d时rt-PA组较对照组疗效更好,差异显著(P<0.05)；日常生活能力14d时两组恢复率(BI≥95分)无显著性差异,21 d时日常生活能力恢复率rt-PA组26.6%,对照组无1例(P<0.05):rt-PA组与对照组均无1例症状性脑出血发生；rt-PA组与对照组死亡率分别为13.3％,6.6％(P>0.05):rt-PA组与对照组血管再闭塞率分别为6.66%,13.3%(P>0.05)。
结论：1、本研究表明rt-PA组和对照组治疗后各时间点NIHSS评分、BI指数等与治疗前比较均显著改善,但随着治疗时间延长,rt-PA组较对照组改善更显著。提示应用rt-PA静脉溶栓治疗急性脑梗死更可显著改善患者预后,降低致残率,提高生活质量。2、rt-PA组和对照组均无症状性脑出血发生,两组死亡率亦无显著性差异,提示两种药物治疗急性脑梗死均是安全的。3、对于符合溶栓指征的急性脑梗死患者推荐早期应用rt-PA静脉溶栓治疗,以取得最佳疗效。
Background and purpose:Cerebral infarction is limitations of brain tissue necrosis or softening which is induced by brain blood circulation disorder, ischemia and hypoxia. Currently infarction has become a health hazard for the elderly in our major diseases. Timely and effective treatment and the prognosis is closely related to. Currently accepted principles of acute cerebral infarction emphasis on early diagnosis, early treatment, early rehabilitation and early prevention of recurrence. Ultra-early thrombolytic therapy has been considered the most important measures to restore blood flow. Thrombolytic therapy of acute cerebral infarction began in the 20th century 80s, after more than 20 years of multi-drug number of large-scale multi-center,double-blind, placebo-controlled clinical trials have confirmed that thrombolytic therapy be used as early cerebral infarction Preferred method of treatment, evidence-based medicine guidelines recommend A-level choice for the treatment of ischemic stroke measures 3h intravenous recombinant tissue plasminogen activator for treatment. Despite a growing number of medical staff and patients recognize the importance of ultra-early thrombolytic therapy, but for various reasons, even in the United States has only 1.8 to 3.0% of ischemic stroke patients,64% of the hospitals in for thrombolytic therapy. And in China access to thrombolytic therapy is much less than 1% of patients. Some domestic research commonly used rt-PA thrombolytic therapy and current clinical drugs (Salvia, heparin, etc.) of the efficacy and safety were compared, these studies suggest that rt-PA thrombolytic therapy in acute cerebral infarction than in the past used drugs more safely and effectively. Sodium ozagrel with anti-platelet aggregation, inhibition of thrombosis and thrombus dissolution through functions, is currently the treatment of acute cerebral infarction commonly used drugs,its efficacy and safety was confirmed. But on the rt-PA intravenous thrombo-lytic therapy and intravenous therapy ozagrel acute cerebral infarction compared the efficacy and safety study is not yet reported. For further study of rt-PA thrombolytic therapy in acute cerebral infarction of the efficacy and safety, rt-PA thrombolytic therapy and intravenous drugs commonly used in domestic clinical intravenous treatment ozagrel compared. For the domestic standard treatment of acute ischemic stroke and to provide evidence,the experimental application of rt-PA thrombolytic therapy in acute cerebral infarction, and intravenous treatment of patients ozagrel a controlled study.
Method:Analysis from January 2006 to October 2009 in our hospital neurology clinic with the standard thrombolytic therapy in 30 patients with onset of acute cerebral infarction within 3h, rt-PA group was 15 cases and either was control group. rt-PA group 3h time window for intravenous recombinant tissue plasminogen activator with the dose of 0.9mg/kg (maximum dose 90mg), the first intravenous injection of 10%(1min), the remaining dose continuous intravenous infusion,60min drops End.24h after thrombolysis, coagulation review series and head CT, after the exclusion of bleeding, given aspirin 300mg/d, orally, a total of 10 d, later changed to aspirin 100mg/d,orally.3h after onset of acute cerebral infarction in the control group given 80mg ozagrel sodium chloride injection, iv 2 times a day, of 14d. Improving brain cell metabolism and anti-brain edema the same two groups. Neurological deficit score and efficacy determination by the National Institutes of Health Stroke Scale (NIHSS) assessed before and after solution dissolved 24h,7d,14d,21d; Barthel ADL index (BI) assess the activities of daily living of 14d and 21d after dissolving. To 14d after thrombolysis within the secondary intracranial hemorrhage and death rates to assess safety.
Result:rt-PA group and the control group the sex ratio, age, past history, with the incidence and initial neurological function scores were not statistically different (P>0.05); After treatment,7d,14d,21d showed that 7d after treatment was no significant difference,14d,21d after treatment the rt-PA group to better effect than the control group, significant difference (P<0.05); 14d recovery rate of the two groups of daily living (BI>95 points) was no significant difference,21 d ADL recovery rate of 26.6% of rt-PA group, control group 1 cases (P<0.05); rt-PA group and the control group there was no one case of symptomatic intracranial hemorrhage; rt-PA group and the control group mortality was 13.3%,6.6%(P>0.05); rt-PA group and the control group of vascular re-occlusion rate was 6.66%,13.3%(P>0.05).
Conclusion:1.This study shows that rt-PA group and the control group at each time point after treatment, NIHSS score, BI index before treatment were significantly improved, but with the treatment time, rt-PA group than in the control group improved more significantly. It showed that rt-PA intravenous thrombolytic therapy can significantly improve prognosis and reduce disability, improve quality of life.2.rt-PA group and the control group had no symptoms of cerebral hemorrhage, the two groups no significant differences in mortality, suggesting the two drugs are the treatment of acute cerebral infarction is safe.3.Meet the indications for thrombolytic therapy of acute cerebral infarction recommend early application of rt-PA thrombolytic therapy in order to achieve the best effect.
引文
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34. Roberts HC, Dillon WP, Furlan AJ,et al. Computed tomographic findings in patients undergoing intra-arterial thrombolysis for acute ischemic stroke due to middle cerebral artery occlusion:results from the PROACT Ⅱ trial. Stroke,2002 Jun;33(6):1557-1565.
35. Kohnert U, Horsch B, Ficher S. A variant of tissue plasminogen activator(t-PA) comprised of the kringle 2 and the protease domain shows a significant difference in the in vitrorate of plasmin formation as compared to the recombinant human t-PA from transformed Chinese bamster ovary cells. Hbrinolysis,1993,4:365-372.
36. Llevadot J, Giugliano RP, Antman EM. Bolus fibrinolytic therapy in acute myo-cardial infarction. JAMA,2001 Jul 25;286(4):442-449.
37. Menon V, Harringto RA, Hochman JS, Cannon CP, Goodman SD, Wilcox RG, Schunemann HJ, Ohman EM. Thrombolysis and adjunctive therapy in acute myocardial infarction:the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest,2004 Sep;126(3 Suppl):549S-575S.
38. Ellis SG, Tendera M, de Belder MA,et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med,2008 May 22; 358(21):2205-2217.
39. Khatri IA, Rana A, Kulsoom A. Intraarterial thrombolysis with reteplase in acute ischaemic stroke in a Pakistani center. J Pak Med Assoc,2008 Jul;58(7):408-11.
40.颜伟,马卫华.颈动脉注射瑞替普酶治疗急性脑梗死疗效观察.中国实用医药,2009,4(5).
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42. Van de Werf F, Barron HV, Armstrong PW, et al. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents:a comparison of TNK-tPA and rt-PA. Eur Heart J,2001 Dec;22(24):2253-2261.
43. Armstrong PW, Chang WC, Wallentin L,et al. ASSENT-3 and ASSENT-3 PLUS Investigators. Efficacy and safety of unfractionated heparin versus enoxaparin:a pooled analysis of ASSENT-3 and ASSENT-3 PLUS data. CMAJ,2006 May 9; 174(10):1421-1426.
44. Molina CA, Rubiera M, Santamarina E, et al. TNK induces faster MCA recanali-zation and leads to better short-and long-term clinical outcome than native tPA. The TNK-TPA Reperfusion Stroke Study. Stroke,2008,39:563.
45. Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, Levi CR. Acute ischemic stroke:imaging-guided tenecteplase treatment in an extended time window. Neurology,2009 Mar 10;72(10):915-921.
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47. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2):a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol,2009 Feb;8(2):141-150.
48. Furlan AJ, Eyding D, Albers GW, et al; DEDAS Investigators. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS):evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke,2006 May;37(5):1227-1231.
49. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-Ⅱ trial. Stroke,2008 Oct;39(10):2749-2755.
50. Paciaroni M, Agnelli G, Caso V, Corea F, Ageno W, Alberti A, Lanari A, Micheli S, Bertolani L, Venti M, Palmerini F, Billeci AM, Comi G, Previdi P, Silvestrelli G. Acute hyperglycemia and early hemorrhagic transformation in ischemic stroke.Cerebrovasc Dis,2009;28(2):119-123.
51. Ozdemir O, Beletsky V, Chan R, Hachinski V. Thrombolysis in patients with mar-ked clinical fluctuations in neurologic status due to cerebral ischemia. Arch Neurol,2008 Aug;65(8):1041-1043.
52. Jovanovic DR, Beslac-Bumbasirevic Lj, Budimkic M, Pekmezovic T, Zivkovic M, Kostic VS; SETIS Investigation Group. Do women benefit more from systemic thrombolysis in acute ischemic stroke? A Serbian experience with thrombolysis in ischemic stroke (SETIS) study. Clin Neurol Neurosurg,2009 Nov;111(9): 729-732.
53. Tang J, Li YJ, Li Q, Mu J, Yang DY, Xie P. Endogenous tissue plasminogen activator increases hemorrhagic transformation induced by heparin after ischemia reperfusion in rat brains. Neurol Res,2009 Mar 23.
54. Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS, Chong JY. Symptomatic Intracerebral Hemorrhage Among Eligible Warfarin-Treated Pati-ents Receiving Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke. Arch Neurol,2010 Mar 8;67(5).
55. Tsivgoulis G,Frey JL,Flaster M,Sharma VK,Lao AY,Hoover SL,Liu W,Stamboulis E,Alexandrov AW, Malkoff MD, Alexandrov AV.Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke, 2009 Nov; 40(11):3631-3634.
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16. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, et al. Intravenous thrombolysis with recom-binant tissue plasminogen activator for acute hemispheric stroke.The European Cooperative Acute Stroke Study(ECASS). JAMA,1995 Oct 4;274 (13):1017 1025.
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21. Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke,2005 Oct; 36(10):2311-2320.
22. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med,2008 Sep 25;359(13):1317-1329.
23. Wahlgren N, Ahmed N, Davalos A, Hacke W, Millan M, Muir K, Roine RO, Toni D, Lees KR; SITS investigators. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR):an observational study. Lancet,2008 Oct 11; 372 (9646):1303-1309.
24. Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke:a metaanalysis. Stroke,2009 Jul;40(7):2438-2441.
25. Li YH, Li MH, Zhao ZG, et al. Comparison of MRI-based thrombolysis for patients with middle cerebral artery occlusion
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28. Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Waller JL, Fagan SC. Minocycline and tissue-type plasminogen activator for stroke:assessment of interaction potential. Stroke,2009 Sep;40(9):3028-3033.
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31. Kobayashi A, Wardlaw JM, Lindley RI, Lewis SC, Sandercock PA, Czlonkowska A; IST-3 Collaborative Group. Oxfordshire community stroke project clinical stroke syndrome and appearances of tissue and vascular lesions on pretreatment ct in hyperacute ischemic stroke among the first 510 patients in the Third International Stroke Trial (IST-3). Stroke,2009 Mar;40(3):743-748.
32. Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase Ⅱ randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke,1998 Jan;29(1):4-11.
33. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study:a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA,1999 Dec 1;282(21):2003-2011.
34. Roberts HC, Dillon WP, Furlan AJ,et al. Computed tomographic findings in patients undergoing intra-arterial thrombolysis for acute ischemic stroke due to middle cerebral artery occlusion:results from the PROACT Ⅱ trial. Stroke,2002 Jun;33(6):1557-1565.
35. Kohnert U, Horsch B, Ficher S. A variant of tissue plasminogen activator(t-PA) comprised of the kringle 2 and the protease domain shows a significant difference in the in vitrorate of plasmin formation as compared to the recombinant human t-PA from transformed Chinese bamster ovary cells. Hbrinolysis,1993,4:365-372.
36. Llevadot J, Giugliano RP, Antman EM. Bolus fibrinolytic therapy in acute myo-cardial infarction. JAMA,2001 Jul 25;286(4):442-449.
37. Menon V, Harringto RA, Hochman JS, Cannon CP, Goodman SD, Wilcox RG, Schunemann HJ, Ohman EM. Thrombolysis and adjunctive therapy in acute myocardial infarction:the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest,2004 Sep;126(3 Suppl):549S-575S.
38. Ellis SG, Tendera M, de Belder MA,et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med,2008 May 22; 358(21):2205-2217.
39. Khatri IA, Rana A, Kulsoom A. Intraarterial thrombolysis with reteplase in acute ischaemic stroke in a Pakistani center. J Pak Med Assoc,2008 Jul;58(7):408-11.
40.颜伟,马卫华.颈动脉注射瑞替普酶治疗急性脑梗死疗效观察.中国实用医药,2009,4(5).
41. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecte-plase compared with front-loaded alteplase in acute myocardial infarction:the ASSENT-2 double-blind randomised trial. Lancet,1999 Aug 28;354(9180):716-722.
42. Van de Werf F, Barron HV, Armstrong PW, et al. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents:a comparison of TNK-tPA and rt-PA. Eur Heart J,2001 Dec;22(24):2253-2261.
43. Armstrong PW, Chang WC, Wallentin L,et al. ASSENT-3 and ASSENT-3 PLUS Investigators. Efficacy and safety of unfractionated heparin versus enoxaparin:a pooled analysis of ASSENT-3 and ASSENT-3 PLUS data. CMAJ,2006 May 9; 174(10):1421-1426.
44. Molina CA, Rubiera M, Santamarina E, et al. TNK induces faster MCA recanali-zation and leads to better short-and long-term clinical outcome than native tPA. The TNK-TPA Reperfusion Stroke Study. Stroke,2008,39:563.
45. Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, Levi CR. Acute ischemic stroke:imaging-guided tenecteplase treatment in an extended time window. Neurology,2009 Mar 10;72(10):915-921.
46. Werner Hacke, MD; Greg Albers, MD; Yasir Al-Rawi, MD;et al. The Desmote-plase in Acute Ischemic Stroke Trial (DIAS) A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase. Stroke,2005 Jan;36(1):66-73.
47. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2):a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol,2009 Feb;8(2):141-150.
48. Furlan AJ, Eyding D, Albers GW, et al; DEDAS Investigators. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS):evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke,2006 May;37(5):1227-1231.
49. Yong M, Kaste M. Dynamic of hyperglycemia as a predictor of stroke outcome in the ECASS-Ⅱ trial. Stroke,2008 Oct;39(10):2749-2755.
50. Paciaroni M, Agnelli G, Caso V, Corea F, Ageno W, Alberti A, Lanari A, Micheli S, Bertolani L, Venti M, Palmerini F, Billeci AM, Comi G, Previdi P, Silvestrelli G. Acute hyperglycemia and early hemorrhagic transformation in ischemic stroke.Cerebrovasc Dis,2009;28(2):119-123.
51. Ozdemir O, Beletsky V, Chan R, Hachinski V. Thrombolysis in patients with mar-ked clinical fluctuations in neurologic status due to cerebral ischemia. Arch Neurol,2008 Aug;65(8):1041-1043.
52. Jovanovic DR, Beslac-Bumbasirevic Lj, Budimkic M, Pekmezovic T, Zivkovic M, Kostic VS; SETIS Investigation Group. Do women benefit more from systemic thrombolysis in acute ischemic stroke? A Serbian experience with thrombolysis in ischemic stroke (SETIS) study. Clin Neurol Neurosurg,2009 Nov;111(9): 729-732.
53. Tang J, Li YJ, Li Q, Mu J, Yang DY, Xie P. Endogenous tissue plasminogen activator increases hemorrhagic transformation induced by heparin after ischemia reperfusion in rat brains. Neurol Res,2009 Mar 23.
54. Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS, Chong JY. Symptomatic Intracerebral Hemorrhage Among Eligible Warfarin-Treated Pati-ents Receiving Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke. Arch Neurol,2010 Mar 8;67(5).
55. Tsivgoulis G,Frey JL,Flaster M,Sharma VK,Lao AY,Hoover SL,Liu W,Stamboulis E,Alexandrov AW, Malkoff MD, Alexandrov AV.Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke, 2009 Nov; 40(11):3631-3634.
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 Dec 14;333(24):1581-1587.
2. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH,et al.Intravenous thrombolysis with recombi-nant tissue plasminogen activator for acute hemispheric stroke.The European Cooperative Acute Stroke Study(ECASS). JAMA,1995 Oct 4;274(13):1017-1025.
3. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS Ⅱ).Second European-Australasian Acute Stroke Study Investigators. Lancet,1998 Oct 17;352(9136):1245-1251.
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