1、急性冠脉综合征抗栓治疗（优选）急性冠脉综合征抗栓治疗肝素肝素IIaXa513 ATIII ATIII135 IIa ATIIILMWH510 ATIII Xa三种肝素类药物抗凝机制对比三种肝素类药物抗凝机制对比戊糖5 ATIII5 ATIII Xa510低分子肝素和肝素抗凝区低分子肝素和肝素抗凝区别别肝素和低分子肝素抗肝素和低分子肝素抗XaXa因子和抗因子和抗IIaIIa因子活性随因子活性随着分子量的变化而改变着分子量的变化而改变.5,00010,00015,000 20,0002001000MWAcivity(U/mg)肝素结果总结肝素结果总结10%5%015%250300350400450
2、激活的凝血时间激活的凝血时间头头 7-天事件发生率天事件发生率Abciximab+肝素出血肝素出血肝素出血肝素出血Abciximab+肝素肝素death/MI/revasc.肝素肝素death/MI/revasc.肝素最适肝素最适 ACT 对有效性 单纯肝素 350+秒 和 GP2b3a 无关 对安全性 单纯肝素 300 秒 和 GP2b3a 225 秒普通肝素存在的问题普通肝素存在的问题 不确定的剂量反应性不确定的剂量反应性 肝素抵抗有天然抑制剂肝素抵抗有天然抑制剂 不能抑制结合于血栓的凝血酶不能抑制结合于血栓的凝血酶 剂量过高，清除半衰期延长剂量过高，清除半衰期延长 需要实验室监测需要实验
3、室监测由于肝素作用失败使患者处于由于肝素作用失败使患者处于血栓形成风险中血栓形成风险中肝素用于高危肝素用于高危 PCI 肝素作用钝化，当肝素作用钝化，当 凝血酶和纤维蛋白结合凝血酶和纤维蛋白结合 循环中循环中 PF-4 抑制肝素作用抑制肝素作用 高剂量导致血小板聚集高剂量导致血小板聚集 典型患者人群典型患者人群 既往使用过肝素治疗既往使用过肝素治疗 既往存在血栓形成既往存在血栓形成(MI后后)急性冠状动脉综合症急性冠状动脉综合症(使用肝素使用肝素)肝素在肝素在 ACS 中反应钝化中反应钝化Wilson et al 1995激活的凝血时间对激活的凝血时间对 10,000 单位肝素发生反应单位肝素
4、发生反应为什么在 PCI 中使用LMWH?使用方便、半衰期长使用方便、半衰期长更有效抑制更有效抑制 Xa减少凝血酶原减少凝血酶原、减少反弹、减少反弹较少免疫反应较少免疫反应、减少、减少HIT和和GP IIb/IIIa抑制剂合用出血抑制剂合用出血可能减少可能减少 只证明依诺肝素优于普通肝素只证明依诺肝素优于普通肝素具有成本效益具有成本效益难以检测难以检测(?necessary)用拮抗药不能完全逆转用拮抗药不能完全逆转注射部位瘀斑注射部位瘀斑可能更多的出血可能更多的出血在特殊人群中潜在危险，在特殊人群中潜在危险，如肾功能不全的病人如肾功能不全的病人、超重的病人超重的病人直接成本增加直接成本增加为什
5、么在为什么在 PCI PCI 中使用中使用LMWH?LMWH?Should LMWH Replace UFH in STEMI also?LMWH取代取代UFH?!NSTE ACS STE ACSPCIVTESTEEPLETo summarize与免疫相关药物副反应，产生针对血小板因子（PF）-4和肝素复合物的抗体，可视作医源性损害之一。High to Very High RiskOR(95%CI)在STEMI的病人中给予溶栓治疗，与UFH相比LMWH:Dyspepsia or GERD symptoms肝素和低分子肝素抗Xa因子和抗IIa因子活性随着分子量的变化而改变抗血小板聚集，应用凝血酶
6、直接抑制剂（DTI）和抗Xa制剂以降低血栓形成风险Fondaparinux:Enoxaparin is superior to UFH只证明依诺肝素优于普通肝素30天的心血管死亡或心肌梗死Hb是心血管不良事件的独立预测因子（Arant等）单纯肝素 350+秒The recommended ACT with no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s(HemoTec device)or 300 to 350 s(Hemochron device).Fondaparinux:OR(95%CI)在随后的PC
7、I中有效；Aged 60 years or moreSarnak MJ.No indication for Enoxaparin or UFHLMWH在在STST抬高的抬高的ACSACS中低分子肝素和中低分子肝素和普通肝素普通肝素n=1429n=1431Adjusted for type of lytic,infarct location,h/o HTN,cardiac medications,time to angiography,and propensity score for LMWH use.Sabatine et al.Circulation 2005 使动脉闭塞或死亡心肌梗死使动脉
8、闭塞或死亡心肌梗死肝素诱导的血小板减少症肝素诱导的血小板减少症Heparin-induced thrombocytopeniaMyth or reality?HITHIT定义定义 Heparin-Induced Thrombocytopenia 肝素诱导血小板减少症肝素诱导血小板减少症n多见于肝素治疗第多见于肝素治疗第5-14天，血小板计数相对值下降天，血小板计数相对值下降50或绝对值或绝对值降至降至50-80109/L，停药后，停药后4-14天恢复正常天恢复正常。n与免疫相关药物副反应，产生针对血小板因子（与免疫相关药物副反应，产生针对血小板因子（PF）-4和肝素复和肝素复合物的抗体，可视作
9、医源性损害之一。合物的抗体，可视作医源性损害之一。型型HIT型型HIT发生频率发生频率10-202-30发生时间发生时间1-3d（大剂量肝素）（大剂量肝素）5-14d（各剂量各途径（各剂量各途径）血小板计数血小板计数100-150109/L50-80109/L抗体存在抗体存在否否是是血栓形成血栓形成无无30-80%出血表现出血表现无无罕见罕见处理原则处理原则观察观察停肝素，选择其他抗凝停肝素，选择其他抗凝药物替代药物替代HITHIT临床分型临床分型HITHIT治疗治疗高度警惕，早诊早治高度警惕，早诊早治停用停用UFH和和LMWH，避免一切潜在肝素来源，避免一切潜在肝素来源抗血小板聚集，应用凝血
10、酶直接抑制剂（抗血小板聚集，应用凝血酶直接抑制剂（DTIDTI）和抗）和抗XaXa制剂以制剂以降低血栓形成风险降低血栓形成风险不提倡输注血小板，避免早期使用华法林不提倡输注血小板，避免早期使用华法林对单纯血小板减少者，治疗至血小板计数恢复后对单纯血小板减少者，治疗至血小板计数恢复后2-4周；对血周；对血栓形成者则持续栓形成者则持续3-6月月THE MICHELANGELO OASIS 5 PROGRAMMichelAngelo:The Creation of Man(Fragment of the Sistine Chapel ceiling-Detail)(1511-12)In UA/NST
11、EMI(OASIS5)在在NSTE ACS病人中，病人中，Fondaparinux 和依诺肝素和依诺肝素对照研究对照研究Death/MI/RI/Major Bleeds:Day 30DaysCumulative Hazard0.00.020.040.060.080.100.12036912151821242730HR 0.83HR 0.8395%CI 0.7695%CI 0.76-0.900.90P0.00001P0.00001EnoxaparinFondaparinuxDeath,MI,revasc-血浆结合蛋白Enoxaparin is superior to UFH强调正确评价肾功能，患
12、者血肌酐水平不能反应肾功能，应该计算肌酐清除率。OR(95%CI)The recommended ACT with planned GP IIb/IIIa receptor antagonist treatment is 200 to 250 s.大出血治疗策略-中和抗栓药物Anti-IIa activity依诺肝素或普通肝素的疗效BivalirudinATIII与免疫相关药物副反应，产生针对血小板因子（PF）-4和肝素复合物的抗体，可视作医源性损害之一。不提倡输注血小板，避免早期使用华法林ATIIIEnoxaparin administered according to age,weight
13、,and creatinine clearance,given as an intravenous bolus,followed in 15 minutes by subcutaneous injection for the duration of the index hospitalization,up to 8 days or until revascularization;orThe recommended ACT with no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s(HemoTec devic
14、e)or 300 to 350 s(Hemochron device).appropriate dosage(according age,sex,and CrCl)依诺肝素或普通肝素的疗效Eur Heart J 2003;24:1815-23.Bivalirudin组死亡率有降低趋势。THE MICHELANGELO OASIS 5 PROGRAMMichelAngelo:The Creation of Man(Fragment of the Sistine Chapel ceiling-Detail)(1511-12)与依诺肝素相比，与依诺肝素相比，fondaparinux治疗治疗1000
15、NSTE ACS 病病人预防人预防:10 deaths or MI 4 strokes 25 major bleeds明显降低明显降低1个月和个月和6个月的死亡率个月的死亡率显著降低严重出血并发症显著降低严重出血并发症在在PCI 病人中并不比依诺肝素差病人中并不比依诺肝素差THE MICHELANGELO OASIS 5 PROGRAMMichelAngelo:The Creation of Man(Fragment of the Sistine Chapel ceiling-Detail)(1511-12)STEMI 病人在症状发作的病人在症状发作的12 h内内Fondaparinux和普和
16、普通肝素对照研究。通肝素对照研究。OASIS 6 ACC 2006Primary Efficacy OutcomePrimary Efficacy OutcomeDeath/MI at 30 Days Death/MI at 30 Days DaysCumulative Hazard0.00.020.040.060.080.100.12036912151821242730UFH/PlaceboFondaparinuxHR 0.86 95%CI 0.77-0.96P=0.008Death/Death/ReMIReMI in Stratum II at Study Endin Stratum II
17、 at Study EndPrimary PCI vs.no Primary PCIPrimary PCI vs.no Primary PCI0.0610.9510.69-1.481.013.23.21oPCI0.0090.43-0.880.614.06.5No 1oPCIReinfarction0.1130.7870.79-1.361.046.15.91oPCI0.0260.64-0.970.7911.915.1No 1oPCIDeath0.0370.6140.84-1.331.068.58.21oPCI(n =3772)0.0080.64-0.930.7714.919.0No 1o PCI
18、(n=2666)Death or ReinfarctionInteractnP95%CIHRFondaUFHNo.of Events(%)OASISOASIS-6 Conclusions:6 Conclusions:1.Fondaparinux significantly reduces mortality and re-MI in STEMI without increasing bleeding compared to placebo or UFH.2.Benefits emerge at 9 days and are sustained to 180 days.3.In primary
19、PCI,there was no benefit with fondaparinux.4.The benefits are marked in those receiving no reperfusion therapy and those receiving thrombolytics(21%RRR at 30 days),with lower severe bleeding.5.Mortality is significantly reduced 3 important areas:1.Active site:fibrinogen binding2.Exosite I:major dock
20、ing site-interaction with fibrinogen and other receptors;fibrinogen recognition site3.Exosite II:interacts with heparinThrombinHirudin 医学上的水蛭病医学上的水蛭病古时候埃及人和希古时候埃及人和希腊人用于解除身体腊人用于解除身体上的上的“坏体液坏体液”在在1919世纪中期最盛世纪中期最盛行行Hirudo medicinalisBivalirudin 模拟天然模拟天然水蛭素水蛭素Gly-Pro-Arg-Pro(active site binding region)
21、(Gly)4C-terminal dodecapeptide(exosite 1-binding region)7天时发生事件患者%出血出血Death,MI,revascUnstable&MI后后n=241Unstable 用肝素用肝素n=1,006MI后后n=741没有危没有危险因素险因素n=2,806Heparin16.5%14.0%Heparin11.8%9.9%Bivalirudin3.3%5.8%Bivalirudin2.4%4.9%Bivalirudin3.8%6.1%Bivalirudin4.1%7.4%Heparin11.9%10.3%Bivalirudin 用于用于 PCI
22、的结果的结果 特定高危人群的初步结果特定高危人群的初步结果Heparin8.3%7.0%HeparinQuadruple Endpoint 30 Day Primary Endpoint Componentsp 0.001Fondaparinux:强调正确评价肾功能，患者血肌酐水平不能反应肾功能，应该计算肌酐清除率。2004;43:20092014.Eur Heart J 2003;24:1815-23.Bivalirudin在随后的PCI中有效；0g/L，心血管事件危险降低20Patients with STEMI undergoing reperfusion with fibrinolyt
23、ic therapy should receive anticoagulant therapy for a minimum of 48 hours,and preferably for the duration of the index hospitalization,up to 8 days or until revascularization if performed.Circulation 2005Abciximab+肝素Events,No.The recommended ACT with no planned GP IIb/IIIa receptor antagonist treatm
24、ent is 250 to 300 s(HemoTec device)or 300 to 350 s(Hemochron device).Death,MI,revascAbciximab+肝素High to Very High Risk累计事件发生率(%)Protamine sulfate has less impact on the neutralization of enoxaparin and has no effect on fondaparinux or bivalirudin.Enoxaparin administered according to age,weight,and c
25、reatinine clearance,given as an intravenous bolus,followed in 15 minutes by subcutaneous injection for the duration of the index hospitalization,up to 8 days or until revascularization;or发生消化道出血时，应积极处理局部出血灶（内镜下止血），尽量不停用抗血小板治疗。与依诺肝素相比，fondaparinux治疗1000 NSTE ACS 病人预防:REPLACE-2REPLACE-2 BivalirudinBiv
26、alirudin 能明显减少临床事件的发生率；能明显减少临床事件的发生率；明显降低住院期间的出血率；明显降低住院期间的出血率；两组间两组间MI、紧急血运重建等终点事件的发生率、紧急血运重建等终点事件的发生率相等；相等；BivalirudinBivalirudin组死亡率有降低趋势。组死亡率有降低趋势。结论结论在在PCI中，病人被随机分为中，病人被随机分为bivalirudin或肝素或肝素+GP IIb/IIIa抑制剂治疗：抑制剂治疗：Adjunctive Anticoagulant Therapy With FibrinolysisPatients with STEMI undergoing
27、reperfusion with fibrinolytic therapy should receive anticoagulant therapy for a minimum of 48 hours,and preferably for the duration of the index hospitalization,up to 8 days or until revascularization if performed.Recommended regimens include:a.UFH administered as a weight-adjusted intravenous bolu
28、s and infusion to obtain an activated partial thromboplastin time of 1.5 to 2.0 times control,for 48 hours or until revascularization;b.Enoxaparin administered according to age,weight,and creatinine clearance,given as an intravenous bolus,followed in 15 minutes by subcutaneous injection for the dura
29、tion of the index hospitalization,up to 8 days or until revascularization;or c.Fondaparinux administered with initial intravenous dose,followed in 24 hours by daily subcutaneous injections if the estimated creatinine clearance is greater than 30 mL/min,for the duration of the index hospitalization,u
30、p to 8 days or until revascularization.I IIa IIb IIII IIa IIb IIII IIa IIb IIII IIa IIb III2013 ACCF/AHA GuidelineAdjunctive Antithrombotic Therapy to Support Reperfusion With Primary PCIThe recommended ACT with planned GP IIb/IIIa receptor antagonist treatment is 200 to 250 s.The recommended ACT wi
31、th no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s(HemoTec device)or 300 to 350 s(Hemochron device).2013 ACCF/AHA Guideline出血对预后的影响5.15.13.03.05.35.37.07.018.618.616.116.115.315.322.822.80 010102020303040405050总体总体不稳定心绞痛不稳定心绞痛非非ST段抬高型段抬高型MIST段抬高型段抬高型MI患者患者院内死亡率院内死亡率 (%)(%)未大出血未大
32、出血大出血大出血*P P0.0010.001*Moscucci M et al.Eur Heart J 2003;24:1815-23.大出血患者院内死亡率大出血患者院内死亡率基于出血的30天死亡事件OASIS、OASIS-2及CURE研究(n=34 146)Eikelboom Circulation 2006;114:774-782;published online August 14 2006 风险风险 5倍倍 02468101214051015202530出血出血未出血未出血累计事件发生率累计事件发生率(%)3367633419331573299032879327693271047045
33、9440430420410408天天风险患者例数风险患者例数未出血未出血出血出血贫血对贫血对ACSACS预后预测价值预后预测价值Hb是心血管不良事件的独立预测因子（Arant等）-Hb每增加1.0g/L，心血管事件危险降低20 -有贫血的人群发生心血管事件的危险比无贫血的人群增加41 Arant CB.J Am Coll Cardiol.2004;43:20092014.Sarnak MJ.J Am Coll Cardiol.2002;40:2733.输血患者预后不良输血组输血组3030天的生存率：天的生存率：GUSTO IIbGUSTO IIb、PURSUITPURSUIT及及 PARAGO
34、N BPARAGON B研究研究 (n=24 000;10%(n=24 000;10%输血输血)-Rao SV,et.al.,JAMA 20040.90.920.940.960.98105101520253035时间（天）时间（天）生存率生存率未输血未输血输血输血冠心病出血、输血与预后的观点1.出血导致死亡和出血导致死亡和MI风险增加风险增加2.预防出血与预防缺血事件同等重要预防出血与预防缺血事件同等重要3.输血可能有潜在危害输血可能有潜在危害4.只有在发生致命性贫血只有在发生致命性贫血(红细胞压积低于红细胞压积低于 25%)时才应时才应输血输血 为什么在 PCI 中使用LMWH?贫血对ACS
35、预后预测价值Bivalirudin4 strokesPatients with STEMI undergoing reperfusion with fibrinolytic therapy should receive anticoagulant therapy for a minimum of 48 hours,and preferably for the duration of the index hospitalization,up to 8 days or until revascularization if performed.Medium to High riskAbciximab
36、+肝素OR(95%CI)古时候埃及人和希腊人用于解除身体上的“坏体液”4 strokesDyspepsia or GERD symptomsDyspepsia or GERD symptoms在随后的PCI中有效；Protamine sulfate has less impact on the neutralization of enoxaparin and has no effect on fondaparinux or bivalirudin.Active site:fibrinogen bindingHeparin-Induced ThrombocytopeniaBivalirudin出
37、血导致死亡和MI风险增加OR(95%CI)J Am Coll Cardiol.出血风险评估出血风险评估推荐两个常用出血危险评估系统：推荐两个常用出血危险评估系统：GRACE出血评分系统和出血评分系统和CRUSADE出血评分系统来评估患者的出血风险。出血评分系统来评估患者的出血风险。严重出血独立危险因素包括高龄、女性、出血病史、严重出血独立危险因素包括高龄、女性、出血病史、PCI、肾功能、肾功能不全病史及使用不全病史及使用GPb/a受体拮抗剂。受体拮抗剂。强调正确评价肾功能，患者血肌酐水平不能反应肾功能，应该计强调正确评价肾功能，患者血肌酐水平不能反应肾功能，应该计算肌酐清除率。算肌酐清除率。预
38、防出血原则Prevention of bleeding encompasses the choice of：n safer drugsnappropriate dosage(according age,sex,and CrCl)n reduced duration of antithrombotic treatmentSafer drugs Consistent UFH/Enoxaparin Bivalirudin Fondaparimux Antiplatelet drugsUFH can be inhibited by an equimolar concentration of prota
39、mine sulfate.Protamine sulfate has less impact on the neutralization of enoxaparin and has no effect on fondaparinux or bivalirudin.Bivalirudin has a very short half-life,with the result that it may not be necessary to neutralize it.In the case of fondaparinux,recombinant factor VIIa has been recomm
40、ended,but is associated with an increased risk of thrombotic complications.301There is no known antidote to irreversible antiplatelet agents such as aspirin,clopidogrel,or prasugrel.Therefore,their action can be neutralized only by transfusion of fresh platelets.This is largely the same for ticagrel
41、or shortly(3 days)after withdrawal of the drug.小出血治疗原则小出血治疗原则消化道出血治疗消化道出血治疗YesPPIBhatt DL,Scheiman J,Abraham NS,et al.Circulation 2008.Need for antiplatelet therapyAssess GI risk factorsTest for H pylori;treat if infectedHistory of ulcer complication History of ulcer disease(nonbleeding)Dual antipla
42、telet therapyConcomitant anticoagulantMore than one risk factor:Aged 60 years or moreCorticosteroid useDyspepsia or GERD symptomsBivalirudin组死亡率有降低趋势。2013 ACCF/AHA Guideline7天时发生事件患者%Medium to High riskHigh to Very High RiskNeed for antiplatelet therapy明显降低住院期间的出血率；ATIIIOR(95%CI)不提倡输注血小板，避免早期使用华法林JA
43、MA 2004;292:8996Hb是心血管不良事件的独立预测因子（Arant等）Eur Heart J 2003;24:1815-23.难以检测(?necessary)大出血治疗策略输血原则不能抑制结合于血栓的凝血酶2002;40:2733.OR(95%CI)权衡利弊选择 BMSAdjunctive Antithrombotic Therapy to Support Reperfusion With Primary PCIHb是心血管不良事件的独立预测因子（Arant等）肝素和低分子肝素抗Xa因子和抗IIa因子活性随着分子量的变化而改变High to Very High RiskBivali
44、rudin推荐两个常用出血危险评估系统：GRACE出血评分系统和CRUSADE出血评分系统来评估患者的出血风险。ATIII单纯肝素 350+秒Eikelboom Circulation 2006;114:774-782;published online August 14 2006Death,MI,revasc在STEMI的病人中给予溶栓治疗，与UFH相比LMWH:为什么在 PCI 中使用LMWH?既往存在血栓形成(MI后)OR(95%CI)Myth or reality?safer drugsBivalirudinAnti-IIa activity大出血治疗策略输血原则为什么在 PCI 中使
45、用LMWH?在随后的PCI中有效；发生消化道出血时，应积极处理局部出血灶（内镜下止血），尽发生消化道出血时，应积极处理局部出血灶（内镜下止血），尽量不停用抗血小板治疗。量不停用抗血小板治疗。权衡利弊选择权衡利弊选择 BMS BMS 给药间隔时间：给药间隔时间：PPIPPI间隔间隔1212小时可能对氯吡格雷的影响较小小时可能对氯吡格雷的影响较小Antiplatelet and/or anticoagulation agents should not be reintroduced until strict control of the haemorrhage has been obtained for at least 24 h
