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1、陈纪言广东省心血管病研究所,Adjunctive Medical Management in STE-ACSSTE-ACS的抗栓治疗进展,“Man lives with arterosclerosis,and dies of the complicating thrombosis”Dedichen J.Brit Med J 1956;11:1038-1039,Platelet Activation,Thrombus,Injury,Platelet Aggregation,Thrombin Generation,Thrombin Activity,Thrombus,Platelet Activa
2、tion,Injury,Platelet Aggregation,Thrombin Generation,Thrombin Activity,AspirinTiclopidineClopidogrel,IIb/IIIa blockers,HeparinLMW heparinPentasaccharideWarfarin,LMW heparinHeparinAntithrombins,STE-ACS的抗栓治疗新进展,STEMI的抗血小板治疗STEMI的抗凝治疗,ST段抬高型急性冠脉综合征的新进展,ST段抬高型急性冠脉综合征(STEMI),抗血小板药物低分子肝素,CLARITY：研究设计,设计：双
3、盲、安慰剂对照、随机化人群：3491例 STEMI 12 小时 18-75 岁治疗：氯吡格雷 300mg 负荷剂量75 mg/天+ASA vs 安慰剂+ASA主要终点:动脉闭塞（TIMI 0/1）、死亡、MI 次要终点:死亡、MI、再发缺血,主要终点降低 36%,氯吡格雷安慰剂风险比(n=1752)(n=1739)(95%CI)p 值主要复合终点（%）TFG 0/1、MI 或死亡15.021.70.64(0.530.76)0.001主要终点的各个构成(%)TFG 0/111.718.40.59(0.480.72)0.001 再发 MI2.53.60.70(0.471.04)0.08死亡2.62
4、.21.17(0.751.82)0.49,1.Sabatine MS et al.New Engl J Med 2005,30天的临床事件,*CV 死亡、MI 再发缺血导致急诊血管重建术的风险比,Time(days),临床终点的发生率(%),0,5,10,15,0,5,10,15,20,25,30,安慰剂,氯吡格雷,20%*p=0.026,Sabatine MS et al.New Engl J Med 2005;352:1179-1189,安全性,氯吡格雷安慰剂(n=1733)(n=1719)p 值主要出血性终点（%）TIMI 严重出血 23(1.3)19(1.1)0.64次要出血性终点（%
5、）TIMI 轻度出血17(1.0)9(0.5)0.17TIMI 严重出血或轻度出血 40(2.3)28(1.6)0.18 颅内出血8(0.5)12(0.7)0.3830 天的出血（%）TIMI 严重出血 33(1.930(1.7)0.80TIMI 轻度出血27(1.6)16(0.9)0.12TIMI 严重出血或轻度出血 59(3.4)46(2.7)0.24,Sabatine MS et al.New Engl J Med 2005;352:1179-1189,PCI-CLARITY：研究设计,氯吡格雷 300（LD）75 mg/天（预处理）（n=1572）,安慰剂（无预处理）（n=1739）,
6、住院PTCA(n=933),住院 PTCA(n=930),在CLARITY-TIMI 28试验中n=3491 名患者随机分组,冠状动脉造影,随访 30天的MACE,Sabatine M,Montalecot G.ESC 2005:Clinical Trial Update I,PCI 后的心血管死亡、MI 或脑卒中,0,10,20,30,0,2,4,6,8,PTCA后天数,氯吡格雷 3.6%,预处理,无预处理 6.2%,风险比 0,54,(IC 95%0.35-0.85),p=0.008,46%,CV 死亡、MI、脑卒中%,Sabatine M,Montalecot G.ESC 2005:Cl
7、inical Trial Update I,CV死亡、MI、脑卒中随机分组 30 天,风险比 0.59(IC 95%0.43-0.81),ARR:4.5%,NNT=23,0,2,4,6,8,10,12,氯吡格雷,预处理,无预处理,7.5%,12%,CV死亡、MI、脑卒中%,41%p=0.001,Sabatine M,Montalecot G.ESC 2005:Clinical Trial Update I,研究设计,设计：双盲、安慰剂 对照、随机化人群：46,000 例STEMI 24 小时 治疗：氯吡格雷 75 mg/d 安慰剂 主要终点：死亡死亡、MI、脑卒中安全性终点：非颅内的严重出血出
8、血性脑卒中,30 天的死亡率,死亡/MI/脑卒中,脑卒中,14%SE 9下降P0.1,NS,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.Chen ZM et al.ACC 2005.,PPCI,再灌注治疗,RescuePCI,Routineangiography-emergent/elective?,Watchfulwaiting?,ASA+Clopidogrel(300/75),ASA+Clopidogrel(300/75),Facilitation？,90 minCI to TLX,STEMI的抗血小板处理:小结,所有STEMI患者（无论随后是否治疗TLx或PPCI）都应首
9、先接受强化的抗血小板治疗氯吡格雷 300 mg+ASA 治疗,STE-ACS的抗栓治疗新进展,STEMI的抗血小板治疗STEMI的抗凝治疗,方案设计,STEMI 6 h适合溶栓治疗,研究者决定溶栓剂(TNK,tPA,rPA,SK),普通肝素推注 60U/kg滴注 12U/kg/h 持续 48 h,依诺肝素 75 y:无静脉推注皮下 0.75mg/kg q 12h（至出院或满8天）,双盲双模拟,Day 30主要有效性终点：死亡/再梗主要安全性终点：TIMI严重出血,阿斯匹林（ASA）,N=21,000,小结 1,所有STEMI患者（无论随后是否治疗TLx或PPCI）都应首先接受强化的抗血小板治疗
10、氯吡格雷 300 mg+ASA 治疗,小结 2,与UFH相比较，对接受溶栓治疗的STEMI病人使用LMWH可获得更低的缺血发生率更高的运期再灌注率但更高的出血并发症戊聚多糖的效果优于LMWH，尤其是没有接收PCI的病人更低的死亡发生率更低的再梗死发生率不增加出血,Thank you for your attention!,Fox KAA et al for the Randomized Intervention Trial of unstable Angina(RITA)investigators.Lancet 2002;360:74351,Interventional versus cons
11、ervative treatment for patients with unstable angina or non-ST-elevation myocardial infarction:the British Heart Foundation RITA 3 randomised trial,RITA 3,Objective,To test the hypothesis that routine intervention(early angiography with myocardial revascularization,as clinically indicated)is better
12、than conservative management in moderate-risk UA/NSTEMI patients,Inclusion Criteria,Suspected cardiac chest pain at rest and documented coronary artery disease,with at least one of the following:ECG evidence of myocardial ischaemiaPathological Q waves suggesting previous myocardial infarctionCoronar
13、y artery disease previously proven by arteriogram,Exclusion Criteria,Probable evolving MINew pathological Q wavesCK or CK-MB enzyme concentrations twice upper limit of normalMI within previous month PCI in the preceding yearCABG,CK,creatine kinase;CK-MB,creatine kinase myocardial band isoenzyme;PCI,
14、percutaneous coronary intervention;CABG,coronary artery bypass graft,UA/NSTEMI patients,Conservative,Early intervention,Medical treatment,PCI/CABG,Medical treatment,Angiography/PCI/CABG,Medical treatment,Angiography,UA,unstable angina;NSTEMI,non-ST-segment elevation myocardial infarction;PCI,percuta
15、neous coronary intervention;CABG,coronary artery bypass graft,Study Design,UA/NSTEMI patients(n=1810),Conservative(n=915),Early intervention(n=895),Enoxaparin+aspirin(n=1810),PCI/CABG,Medical treatment,Angiography/PCI/CABG,Assessed for primary endpoints,Medical treatment,+ischaemia,Angiography(72h),
16、Randomization,TIMI 11B-ESSENCE Meta-analysis:Benefits of Enoxaparin in PCI,OR,odds ratio,4.98,13.11,Death/MIat 1 year,6.26,11.97,Death/MIat 1 year,UFH(n=493),Enoxaparin(n=431),In-hospital,On-treatment,Primary Endpoints,Death/non-fatal MI/refractory angina at 4 monthsDeath/non-fatal MI at 1 year,Seco
17、ndary Endpoints,Angina scoresQuality-of-life scoresHealth-economic evaluations,Benefit of Intervention,7.6,8.3,9.6,14.5,0,5,10,15,Patients(%),Conservative(n=915),Death/MIat 1 year,Death/MI/RAat 4 months,P=0.001 RR 0.66 0.510.85,P=NS,RR,risk ratio,Intervention(n=895),Benefit of Intervention Cumulativ
18、e risk of death,MI or refractory angina reduced at 1 year,Patients(%),Time from randomization(months),0,4,12,0,2,4,6,8,10,12,14,16,18,20,At 4 monthsP=0.001,Conservative,Intervention,P=0.003,Prevalence of Angina Over Time,0,20,40,60,80,Grade 3/4,Grade 2,Grade 1,Intervention(n=895),Baseline,Conservati
19、ve(n=915),Intervention(n=856),Conservative(n=873),Intervention(n=799),Conservative(n=814),4 months,1 year,Proportion of patients(%),Reduction in angina Grades 24,P0.0001,P=0.0006,InterventionReduced incidence of refractory angina,6.5,11.6,4.4,9.3,0,2,4,6,8,10,12,Patients(%),Refractory anginaat 1 yea
20、r,Refractory anginaat 4 months,P0.0001 RR 0.470.320.68,P=0.0002RR 0.56 0.410.76,RR,risk ratio,Conservative(n=915),Intervention(n=895),Summarized Comparison of 3 Trials,Base Main population therapyto benefitRITA 3EnoxaparinModerate-risk patientsTACTICS-TIMI 18TirofibanHigh-risk patientsFRISC IIDaltep
21、arinHigh-risk patients,Summary,Intervention significantly reduced the incidence of the combined endpoint of death,non-fatal MI or refractory angina in UA/NSTEMI patients:the principal effect was on refractory anginaSignificant and clinically meaningful reductions were found in severe angina and in t
22、he requirement for anti-angina therapiesThe planned 5-year follow-up needs to be completed to provide conclusive evidence of the effect of intervention on prognosis(death and MI)Hazards of intervention are more than offset by subsequent reduction in non-procedure-related MI,Conclusion,For moderate-r
23、isk UA/NSTEMI patients,an intervention strategy is preferable to a strategy of ischaemia-provoked revascularization,8 days血管再通率,比较 STRes90/180,临床事件Day 30,ENOX,ENOX,ENOX,Placebo,Placebo,Placebo,17,58,14,70,T 3,T 2,88,72,11,25,16,36,D,MI,RA,7.0,6.7,7.4,2.4,5.9,9.1,P=0.03,13.4,21.0,AMI-SK ENOX 对照于 Plac
24、ebo 联用 SK 治疗 STEMI(N=496),P=0.001,EHJ 2002;23:1282,HART IIENOX 对照于 UFH 联用 tPA 治疗STEMI(N=400),UFHb 5000Inf 15,ENOXb 30sc 1.0,90 min血管再通率,再阻塞 1 wkTIMI 3级血流 0,1,27,48,28,53,9,3,81,75,TFG 3,TFG 2,UFHb 5000Inf 15,ENOXb 30sc 1.0,Circulation 104:648,2001,ENOX 对照于 UFH 联用 TNK 治疗 STEMI,%Pts,52%,50%,2.4%,1.9%,
25、15.9%,4.4%,2.5,1.9,3.7,12.2,P=0.005,TIMI 3级血流 60 min,TIMI 严重出血,死亡/再梗 Day 30,Angio Eval Pts,All Treated Pts,P=NS,P=NS,160,82,ENOX,UFH,160,82,ENOX,UFH,20,15,10,5,141,73,ENOX,UFH,100,80,60,40,20,Circulation 2002;105:1642,N=,ASSENT 3 主要联合终点的组成,P(3 way):0.25 0.0009 0.0001,Lancet 358:605,2001,N=6095,ASSEN
26、T 3安全性,P(3 way):0.98 0.0005 0.0001,Lancet 358:605,2001,ASSENT PLUS：研究设计,随机分组,rt-PA法安明 120IU/kg s.c.4-7天,rt-PA普通肝素 i.v.48小时,观察30 天:死亡/心梗/血运重建,冠脉造影（4-7天）：TIMI 血流,ST 抬高心梗患者,L.Wallentin et al.European Heart Journal(2003)24,897-908,ASSENT PLUS：法安明疗效显著优于普通肝素,TIMI 2-3血流（）,P=0.006,70,75,80,85,90,法安明（n=202）,
27、普通肝素（n=176）,86.6%,75.5%,L.Wallentin et al.European Heart Journal(2003)24,897-908,ASSENT PLUS：法安明显著降低临床事件,0,1,2,3,4,5,6,7,8,9,2.3%,3.8%,1.4%,5.4%,3.6%,8.1%,7天时临床事件（）,法安明,普通肝素,死亡,再梗,死亡/再梗,P=0.36,P=0.02,P=0.046,L.Wallentin et al.European Heart Journal(2003)24,897-908,ASSENT PLUS：法安明不增加出血风险,0,2,4,6,8,10
28、,12,14,16,18,17.9%,16.7%,3.6%,5.2%,15.2%,13.3%,出血事件（）,法安明（n=224）,普通肝素（n=210）,所有出血,严重出血,轻度出血,L.Wallentin et al.European Heart Journal(2003)24,897-908,Rt-PA 进行溶栓治疗，法安明作为 辅助抗凝血酶制剂，疗效优于普通肝素,ASSENT PLUS：结论,L.Wallentin et al.European Heart Journal(2003)24,897-908,ASSENT 3 Plus 主要结果,3+,UFH(N=821),Enox(N=818),P=0.08,P=0.05,P=0.01,%,%,有效性(D/MI/Rec Isch),P=0.03,安全性,Oral Presentation AHA 2002,
