欣维宁盐酸替罗非班在急性冠脉综合症临床应用床应用

Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,欣维宁,（盐酸替罗非班）在急性冠脉综合征的临床应用,中日友好医院心内科 李宪伦,欣维宁,(,盐酸替罗非班,),血栓形成的病理生理过程,ACS,疾病简介,抗血栓药物作用机理,GPIIb/IIIa,临床应用,替罗非班临床应用,欣维宁临床应用,血栓形成过程中血小板的激活,Adhesion,1,Platelets,Lipid,core,Collagen,GP la/lla bind,von Willebrand,Factor/GP lb bind,Activation,2,Thrombin,ADP,5,HT,TXA,2,Aggregation,3,Fibrinogen,Activated,GP llb/llla,Handin RI.,Harrisons Principles of Internal Medicine,. Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339-345.,Schafer AI.,Am J Med,. 1996;101:199-209.,黏附,激活,聚集,血小板聚集在血栓形成中的作用,血小板聚集一方面可作为血栓形成的核,心，另一方面通过激活凝血系统使血栓形,成发生，因此,血小板聚集在血栓形成中发,挥着关键的作用。,抗血小板聚集是,ACS,的首要治疗措施之一。,欣维宁,(,盐酸替罗非班,),血栓形成的病理生理过程,ACS,疾病简介,抗血栓药物,GPIIb/IIIa,临床应用,替罗非班临床应用,欣维宁临床应用,ACS,是指由冠状动脉急性缺血所导致的一系列疾病，通常（但并非总是）由,CAD,所致,并,且可以增加心性死亡和,MI,的危险。这类病人起 病急，危险程度十分不均一。,对,ACS,进行早期诊断、及时危险分层和合理的临床干预，是减少不良心血管事件、改善预后的关键。,急性冠状动脉综合征,(Acute coronary syndrome ACS),ACS,的分型,1,ST,段抬高的,ACS,ST,断抬高的急性心肌梗死,(STEMI),2,ST,段不抬高的,ACS,ST,断不抬高的心肌梗死,(NSTEMI)-,cTn,不稳定性心绞痛,(UA),UA/NSTEMI,是病因和临床表现相似但严重程度不同的密切相关的情况，其主要区别在于缺血是否严重到有足够量的心肌损害，以至于能够检测到心肌损害的标记物：,TnI,，,TnT,或,CK-MB,。,胸部不适、胸痛,病史、体检和系列心电图,持续,ST,段抬高,急性冠状动脉综合征（,ACS,）,ST,段不抬高,TnT(TnI),升高,TnT(TnI),不升高,STEMI,NSTEMI,UAP,ACS,临床诊断,ACS,的特征和治疗原则,STEMI,闭塞性血栓，纤维蛋白成分为主,血管性闭塞，血流持续中断,“亡羊补牢”，有一定的不可挽救性,尽早、完全、持续开通梗死相关动脉,避免形成,Q,波,溶栓、直接,PTCA,NSTEMI/UA,非闭塞性血栓，血小板成分为主,血流减少，或者间歇中断；栓塞,可“防患未然”，具有可挽救性,稳定破裂的斑块，维持冠状动脉呈开通状态,避免形成,ST,段抬高的心肌梗死,抗栓,+,抗缺血,+PCI,不能溶栓,ST,抬高的,ACS,ST,不抬高的,ACS,ACS,的病理生理学,Fuster et al.,N Engl J Med.,1992;326:310-318.,Davies et al.,Circulation.,1990;82(Suppl II):II-38, II-46.,不稳定血栓,(UA/NQMI),脂肪池,巨噬细胞,内在的压力，张力,外部的剪切力,裂缝,大裂缝,小裂缝,闭合血栓,(QwMI),动脉粥样硬化斑块,斑块破裂,血栓,ACS,治疗策略,Medical Theapy,Risk Modification,CABG,PCI,Antithrombotic therapy,Other medical therapy,ADP antagonists,Nitrates,BBs,STATINS,ACE-I,OTHERS,Heparin,ASA,GPIIb/IIIas,非,ST,段抬高,ACS,的初始抗栓治疗方案,（,Circulation.,2003;107:2640.) 2003 American Heart Association, Inc.,）,欣维宁,(,盐酸替罗非班,),ACS,疾病简介,抗血栓药物作用机制,GPIIb/IIIa,临床应用,替罗非班临床应用,欣维宁临床应用,抗血栓药物,抗凝药,抗血小板药,溶栓药,环氧化酶抑制剂,如 阿司匹林,血小板,IIb/IIIa,受体拮抗剂,ADP,抑制剂,噻氯匹啶 氯吡格雷,单克隆抗体,abciximab,肽类,eptifibatide,非肽类衍生物,Tirofiban,lamifiban,抗血小板聚集药物的作用机制,White HD.,Am J Cardiol.,1997;80(4A):2B-10B.,GP IIb/IIIa Inhibitors,作用机理,Resting,platelet,Plaque,rupture and,platelet,adhesion,Platelet,activation,Prevention of platelet,aggregation,GP IIb/IIIa,expression,Fibrinogen,GP IIb/IIIa,inhibitor,vWF,vWF,vWF,Agonists,released,Vessel Wall,*GP IIb/IIIa inhibitor,与,Fibrinogen,竟争性抑制,GP IIb/IIIa,受体,*,血小板IIb/IIIa受体拮抗剂,作用机制：,血小板,IIb/IIIa,受体拮抗剂阻断或妨碍血小板,IIb/IIIa,受,体与纤维蛋白原等配体的特异性结合，有效的抑制,各种血小板激活剂诱导的血小板聚集，防止血栓形成，,从而达到抗血栓的目的。,快速,直接,可逆地,抑制血栓形成的关键和唯一通路,GP IIb/IIIa Inhibitors:,化学结构,Topol E, et al.,Lancet,. 1999;353:227-231.,Abciximab,Eptifibatide,Tirofiban,O,O,O,O,O,O,O,O,OH,HN,HN,S,S,N,H,N,H,N,N,H,H,N,NH,NH,H,2,N,H,2,N,HNSO,2,C,4,H,9,O,COOH,HN,Fab fragment of a chimeric monoclonal antibody,MW, 50,000 D,Nonpeptide tyrosine derivative,MW, 500 D,Cyclic heptapeptide,MW, 800 D,鼠源性单克隆抗体,合成非肽类,合成肽类,三种静脉,GPb/a,受体抑制剂的比较,Aciximab,Eptifibatide,Tirofiban,结构,鼠人,IgG,嵌合体,环肽,KGD,小分子非肽,RGD,分子量,(,道尔顿,),5000,800,500,GPb/a,选择性,差,较强,较强,化学计量法,1.5:1,100:1,100:1,血浆半衰期,10-15,分钟,1.5-2.5,小时,1.5-2.5,小时,受体抑制可逆性,差,(,输注血小板,),较强,(,停药,),较强,(,停药,),出血发生率,多,较少,较少,血小板无力症,相对较多,少,少,安全性,相对较差,相对较好,相对较好,价格,昂贵,相对较低,相对较低,适应症,(FDA),PCI,ACS;PCI,ACS;PCI,对血小板抑制的可逆性,%,血小板聚集率,100,80,60,40,20,0,0,6,12,18,24,30,36,依替巴肽,替罗非班,阿昔单抗,停用药物,小时,欣维宁,(,盐酸替罗非班,),ACS,疾病简介,抗血栓药物作用机理,GPIIb/IIIa,临床应用,替罗非班临床应用,欣维宁临床应用,GPIIb/IIIa,受体拮抗剂临床研究,GP IIb/IIIa,研究,:,汇总分析,1,IIb/IIIa,较好,安慰剂较好,N,17393,24311,1368,2311,12685,2901,所有,PCI,试验,所有,ACS,试验,ACS,肌钙蛋白,(+),ACS PCI,ACS,未行,PCI,ACS,肌钙蛋白,(-),0.668.5%5.6%,0.8912.8%11.4%,0.4216.3%6.9%,0.6614.4%9.6%,0.9314.3%13.3%,1.056.2%6.5%,RRR,安慰剂,IIb/IIIa,30,天死亡或,MI,Chew 36:2028,30-Day Mortality Among Nondiabetic Patients with ACS,Roffi M. et al.,Circulation,2001; 104:2767-71.,Trial,N,PURSUIT,7291,PRISM,2545,PRISM-PLUS,1208,GUSTO IV,6094,PARAGON A,1870,PARAGON B,4064,Pooled,23072,Placebo,IIb/IIIa,3.0%,3.0%,3.5%,2.4%,3.8%,3.6%,2.8%,3.5%,2.5%,3.3%,2.9%,2.4%,3.0%,3.0%,IIb/IIIa Better,Placebo Better,30-Day Mortality Among Diabetic Patients with ACS,Roffi M. et al.,Circulation,2001; 104:2767-71.,Trial,N,PURSUIT,2163,PRISM,687,PRISM-PLUS,362,GUSTO IV,1677,PARAGON A,412,PARAGON B,1157,Pooled,5458,Placebo,IIb/IIIa,6.1%,5.1%,4.2%,1.8%,6.7%,3.6%,7.8%,5.0%,6.2%,4.6%,4.8%,4.9%,6.2%,4.6%,IIb/IIIa Better,Placebo Better,安慰剂更好,IIb/IIIa,拮抗剂,更好,0,1,2,7,项,GPIIb/IIIa,受体拮抗剂在,PCI,的临床研究,危险比,& 95% CI,试验名称,安慰剂,IIb/IIIa,N,EPIC,9.6%,6.6%,2,099,IMPACT-II,8.5%,7.0%,4,010,EPILOG,9.1%,4.0%,2,792,CAPTURE,9.0%,4.8%,1,265,6.3%,RESTORE,5.1%,2,141,10.2%,EPISTENT,5.2%,2,399,0.62 (0.55, 0.71),8.8%,汇总,5.6%,16,770,ESPRIT,2,064,10.2%,6.3%,30,天死亡,/MI,欣维宁,(,盐酸替罗非班,),ACS,疾病简介,抗血栓药物作用机理,GPIIb/IIIa,临床应用,替罗非班临床应用,欣维宁临床应用,The RESTORE Investigators.,Circulation.,1997; 96:1445-1453.,The PRISM-PLUS Study Investigators.,N Engl J Med,. 1998;338:1488-1497.,Tirofiban,在,ACS,中的临床试验,RESTORE,tirofiban,对高危冠脉介入病人预后和再狭,窄疗效的随机试验,PRISM-PLUS,tirofiban,对不稳定心肌缺血病人治疗研究,PRISM-PLUS,背景,非,ST,段抬高,ACS,的治疗措施主要是缓解缺血和阻,断冠脉内血栓形成过程,早期的临床试验表明，对,UA/NSTEMI,病人早期介,入干预结果未证实有效,原因可能与早期未使用支架和血小板,GPb/a,受,体拮抗剂有关,PRISM-PLUS,方法,一项随机、双盲、多中心研究,1570例12,h,内有静息心绞痛伴,ECG,或,CK-MB,变化并已接受,Asprin,治疗的,UA/NSTEMI,患者,研究复合终点事件为死亡、,MI、,或2天、,7,天内,的难治性缺血事件及30天、6月心脏事件,PRISM-PLUS,基线特征无统计学意义,Heparin,Tirofiban + Heparin,年龄 6312,6312,吸烟 70% 72%,高血压 56% 55%,糖尿病 24% 22%,UA 54% 55%,NSETMI 46% 45%,硝酸制剂 94% 95%,阻滞剂 81% 78%,钙拮抗剂 43% 49%,PRISM-PLUS,用药方法,n=1570,阿司匹林,325mg,随机,iv 30 min,m iv, 48h,肝素1,000u/h iv 48h,肝素5,000u iv,1000u/ h iv 48h,ACT2,倍,n=773,n=797,PCI,n=475,m iv, 1224h,肝素1,000u/h iv1224h,肝素5,0007500u iv,肝素,1000u/ h iv,1224h,ACT2,倍,PRISM-PLUS,RR=risk reduction.,The PRISM-PLUS Study Investigators.,N Engl J Med,. 1998;338:1488-1497.,RR=66%,P,2 Days,7 Days,RR=43%,P,RR=27%,P,30 Days,Patients (%),0,5,10,15,Heparin (n=797),Tirofiban + Heparin (n=773),MI,/,Death event,PRISM-PLUS,PTCA=percutanueous transluminal coronary angioplasty.,The PRISM-PLUS Study Investigators.,N Engl J Med,. 1998;338:1488-1497.,2,4,14,21,28,7,0.12,0.08,0.04,0.00,Heparin only,RR=44%,475 Patients Undergoing PTCA,0.030,0.025,0.020,0.015,0.010,0.005,0.000,6,30,0,12,18,24,36,42,48,Heparin only,Tirofiban + Heparin,RR=66%,All 1570 Patients Evaluated,Hours,Days,+,20 hours,Probability,of Death or MI,Tirofiban + Heparin,PRISM-PLUS:,0,10,20,30,40,50,Heparin,(n=622),Large,Tirofiban + Heparin,(n=608),Possible,Small,Moderate,Possible,Small,Moderate,Overall,P,17.1%,24.1%,Large,Recent Occlusion,Recent Occlusion,Zhao X-Q, et al.,Circulation,. 1999;100:1609-1615.,血栓病变,(%),TIMI=Thrombolysis in Myocardial Infarction.,Zhao X-Q, et al.,Circulation.,1999;100:1609-1615.,0,5,10,15,20,25,Minimal,Perfusion,(TIMI 1),Tirofiban + Heparin,(n=570),Heparin,(n=580),Total,Occlusion,(TIMI 0),Partial,Perfusion,(TIMI 2),Total,Occlusion,(TIMI 0),Partial,Perfusion,(TIMI 2),Overall,Odds Ratio:,P,18.1%,25.5%,PRISM-PLUS: TIMI Flow,TIMI 3,达81.9%,TIMI Flow,(%),PRISM-PLUS：,出血发生率,PRISM-PLUS Study Investigators.,N Engl J Med.,1998;338:1488-1497.,n=773,n=797,P,*主要出血的定义：血红蛋白下降、需输血,2u,、需外科纠正出血、颅内出血、腹膜后出血、任何复合出血情况,*,Tirofiban in Patients with Diabetes,PRISM-PLUS Investigators.,N Engl J Med,. 1998;338:1488-1497.,Throux P, et al.,Circulation,. 2000;102:2466-2472.,Heparin,Tirofiban,+ Heparin,RR=30%,RR=22%,Heparin,RR=46%,RR=72%,Tirofiban,+ Heparin,Day,Day,All Patients (n=1570),Diabetic Patients (n=362),P,P,P,2,6,10,14,18,0,7,30,60,90,120,150,180,2,6,10,14,18,0,30,60,90,120,150,180,P,PRISM-PLUS: Death/MI at 6 Months*,*,Y-axes represent percentage of patients that experienced death/MI at 6 months.,PRISM-PLUS: Death/MI in Diabetes,Heparin,(n=193),Tirofiban + Heparin,(n=169),Patients,(%),9.3%,0.0%,P,15.5%,4.7%,P,19.2%,11.2%,P,Day 7,Day 30,Day 180,5,0,15,10,20,1.2%,3.1%,48 hours,P,100%,87%,70%,42%,Throux P, et al.,Circulation,. 2000;102:2466-2472.,PRISM-PLUS：,结论,静脉应用,Tirofiban,期间可明显降低死亡或心肌梗死,联合终点，达66%（,p0.05）,7天和30天心脏事件分别下降43%和27% （,p0.05）,在最初48小时用药后进行冠脉造影和血管重建,治疗可降低心脏事件的风险44% （,p0.05）,对糖尿病的近远期预后（7、30天和6月）均有明显,改善,与肝素合用出血副作用未见明显增加,一项随机、双盲、安慰剂对照、多中心研究,入选对象：,n=2141,，发病,72h,内接受,PTCA,或定,向斑块旋切术治疗的,UA/AMI,者,研究终点：各种原因的死亡、,MI,、,PCI,或复发性,心肌缺血需再行,PCI,或,CABG,者,由独立盲终点委员评价第,2,天、第,7,天、,30,天内的,终点事件,RESTORE,RESTORE,排除标准,24,小时内接受溶栓治疗或有溶栓禁忌症,有血小板功能异常或血小板减少史,有中风或其它颅内出血病变史,拟择期性,PCI,术者,RESTORE,基线特征,Tirofiban,组 安慰剂组,平均年龄,60Y 60Y,男性 ,70%,70%,糖尿病,20% 20%,高血压病,54% 56%,高胆固醇血症,50% 49%,吸烟,64% 67%,MI,史,35% 34%,PCI,史,21% 20%,CABG,史,6% 8%,UA 67% 68%,AMI 33% 32%,RESTORE,背景,心脏介入治疗时不可避免会造成血管内膜的损伤,可,导致急性或亚急性血栓形成的心脏事件或需再次的,PCI,及,CABG,已有临床试验显示, PCI,围手术期联合应用肝素和阿,司匹林后仍有,4%12.8%,发生血栓闭塞性事件,T,irofiban,是人工合成的小分子非肽类,GPb/a,受,体拮抗剂可阻断血小板聚集的最后通路,RESTORE,用药方法,n=2141,阿司匹林,325mg,肝素,10000u iv,介入导丝通过冠,脉病变,随机分组,tirofiban 10ug/kg iv 3 min,-1.,min,-1, 36h,安慰剂,10ug/kg iv 3 min,0.15ug.kg-1.min-1 36h,ACT 300400S,n=1071,n=1070,RESTORE,：,联合终点,The RESTORE Investigators.,Circulation.,1997; 96:1445-1453,.,Figure 1.,联合终点,:,tirofiban,组,第,2,天,下降,38%(p,0.05),第,7,天下降,27%(p,0.05),第,30,天下降,16%,RESTORE：,需再次,PCI/CABG,The RESTORE Investigators.,Circulation.,1997; 96:1445-1453,.,Figure 2.,联合终点中需再次,PCI,或需紧急,CAGB,者：,30,天内安慰剂组为,10 .5%,tirofiban,组,8%,相对下降,24%(p=0.52),RESTORE:30,天,MI,发生率,The RESTORE Investigators.,Circulation.,1997; 96:1445-1453,.,Figure 3. 30,天发生,MI,的比例,:,安慰剂组,5.7%,tirofiban,组,4.2% ,下降,26%(p,0.113),即使是在,PCI,早期发生了,MI,但停用,tirofiban,后未见任何反弹迹象,RESTORE-,出血发生率,The RESTORE Investigators.,Circulation.,1997; 96:1445-1453,.,Placebo,(n=1070), n (%),Tirofiban,(n=1071), n (%),P,大出血,40 (3.7),57 (5.3),.096,血红蛋白下降,5 g/dL,19 (1.8),25 (2.3),输血,2 U,24 (2.2),38 (3.5),出血需要外科治疗,3 (0.3),2 (0.2),颅内出血,3 (0.3),1 (0.1),腹膜后出血,3 (0.3),6 (0.6),大出血,(TIMI,标准,),22 (2.1),26 (2.4),.662,血小板减少,90 000/mm,3,10 (0.9),12 (1.1),血小板减少,200S,（,1C,）,UFH ACT,值,250,300S,（,1C,）,按体重调节,UFH 60,100IU/kg,（,2C,）,PCI,后常规静脉肝素,（证据,1A,）,是 否,PCI,抗栓治疗,UA/NSTEMI,病人,LMWH,治疗,距最后一次,注射,12 h,PCI,根据,LMWH,时间,（证据,1C,）,Seventh ACCP Conference on antithrombotic and thrombolytic therapy,2C,证据,: very weak recommendation,other alternative may be equally reasonable. From observational study,