急性冠脉综合征抗栓治疗(版)课件

1、急性冠脉综合征抗栓治疗急性冠脉综合征抗栓治疗（优选）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IIaXa513 ATIII ATIII135 IIa ATIIILMWH510 ATIII Xa三种肝素类药物抗凝机制对比戊糖5 ATIII5 ATIII Xa510肝素IIaXa513 ATIII ATIII135低分子肝素和肝素抗凝区别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Anti-Xa activityAnti-IIa activity.5,00010,00015,00020,0002001000MWAcivity(U/mg)IIaXaIIaXa1 :

2、 1肝素1 : - LMWH低分子肝素和肝素抗凝区别肝素和低分子肝素抗Xa因子和抗IIa肝素结果总结10%5%015%250300350400450激活的凝血时间头 7-天事件发生率Abciximab + 肝素出血肝素出血Abciximab + 肝素death/MI/revasc.肝素death/MI/revasc.肝素结果总结10%5%015%250300350400450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 秒肝素最适 ACT 对有效性普通肝素存在的问题不确定的剂量反应性 - 血浆结合蛋白 - 同时使用

3、IV 硝酸甘油, DIC肝素抵抗有天然抑制剂 - (PF4)不能抑制结合于血栓的凝血酶 不规则病变引发凝血酶生成剂量过高，清除半衰期延长需要实验室监测普通肝素存在的问题不确定的剂量反应性由于肝素作用失败使患者处于血栓形成风险中由于肝素作用失败使患者处于血栓形成风险中肝素用于高危 PCI肝素作用钝化，当凝血酶和纤维蛋白结合循环中 PF-4 抑制肝素作用高剂量导致血小板聚集典型患者人群既往使用过肝素治疗既往存在血栓形成 (MI后)急性冠状动脉综合症 (使用肝素)肝素用于高危 PCI肝素作用钝化，当肝素在 ACS 中反应钝化Wilson et al 1995激活的凝血时间对 10,000 单位肝素发

4、生反应肝素在 ACS 中反应钝化Wilson et al 1995抗因子 Xa:IIa生物利用度监测 ACT 对PF4敏感 No High 1 No Yes Low =1 Yes 为什么在 PCI 中使用LMWH?LMWHATXaUFHATIIaHep抗因子 Xa:IIa生物利用度监测 ACT 对PF4敏感 N优点：使用方便、半衰期长更有效抑制 Xa减少凝血酶原 、减少反弹较少免疫反应 、减少HIT和GP IIb/IIIa抑制剂合用出血可能减少 只证明依诺肝素优于普通肝素具有成本效益缺点：难以检测(? necessary)用拮抗药不能完全逆转注射部位瘀斑可能更多的出血在特殊人群中潜在危险，如肾

5、功能不全的病人 、超重的病人直接成本增加为什么在 PCI 中使用LMWH?优点：缺点：为什么在 PCI 中使用LMWH?LMWH取代UFH ? !NSTE ACS STE ACSPCIVTE+ + +?+ STEEPLELMWH取代UFH ? !NSTE ACS +30天死亡或心梗非ST 段抬高急性心梗患者随机接受依诺肝素或普通肝素的疗效Petersen. JAMA 2004;292:8996TrialEnoxaparinUFHOR (95% CI)FavorsEnoxaparinFavorsUFHEvents, No./Total (%)0.21.02.0OR (95% CI)ESSENCE

6、0.76 (0.58-1.01)94/1607(5.8)118/1564(7.5)TIMI 11B0.88 (0.70-1.11)145/1953(7.4)163/1957(8.6)ACUTE II0.97 (0.51-1.83)25/315(7.9)17/210(8.1)INTERACT0.54 (0.30-0.96)19/380(5.0)33/366(9.0)A to Z0.94 (0.73-1.20)137/1852(7.4)139/1768(7.9)SYNERGY0.96 (0.86-1.07)696/4992(14.0)722/4982(14.5)OVERALL0.91 (0.83-

7、0.99)1116/11099(10.1)1192/10847(11.0)30天死亡或心梗非ST 段抬高急性心梗患者随机接受Peter安全性分析随机化7天后所有人群的严重出血情况Petersen. JAMA 2004;292:8996TrialEnoxaparinUFHOR (95% CI)FavorsEnoxaparinFavorsUFHEvents, No./Total (%)0.21.02.0OR (95% CI)ESSENCE0.90 (0.63-1.27)64/1578(4.1)69/1529(4.5)TIMI 11B1.52 (0.85-2.70)29/1938(1.5)19/19

8、36(1.0)INTERACT0.47 (0.24-0.95)12/380(3.2)24/366(6.6)SYNERGY1.17 (0.99-1.39)276/4148(6.7)274/4775(5.7)OVERALL1.04 (0.89-1.30)381/8044(4.7)386/8606(4.5)安全性分析Petersen. JAMA 2004;292:8To summarizeVery Low risk Medium to High risk High to Very High Risk Use only ASANo indication for Enoxaparin or UFHESS

9、ENCE & TIMI 11BEnoxaparin is superior to UFHUA / NSTEMI patientsLater Invasive or Conservative ManagementVery Early Invasive ManagementSYNERGYEnoxaparin no better than UFHHigher bleeding with enoxaparinINTERACTEnoxaparin is superior to UFHA to ZEnoxaparin no better than UFHTo summarizeVery Low risk

10、Medi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 （Ara

11、nt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PCI中有效；Aged 60 years or moreSarnak MJ.No indication for Enoxaparin or UFHLMWH在ST抬高的ACS中低分子肝素和普通肝素应用对比与免疫相关药物副反

12、应，产生针对血小板因子（PF）-4和肝素复30天的心血管死亡或心肌梗死UFHLMWHP=0.030Adj Odds Ratio 0.68(95% CI 0.48-0.96)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 200530天的心血管死亡或心肌梗死UFHLMWHP=0.030Ad总结：在STEMI

13、的病人中给予溶栓治疗，与UFH相比LMWH : 使动脉闭塞或死亡心肌梗死降低 24% ； 使30天的心血管死亡或心肌梗死降低32% ； 在随后的PCI中有效； 并不增加TIMI 大出血、小出血或颅内出血。总结：在STEMI的病人中给予溶栓治疗，与UFH相比LMWH肝素诱导的血小板减少症Heparin-induced thrombocytopeniaMyth or reality?肝素诱导的血小板减少症Heparin-induced thHIT定义 Heparin-Induced Thrombocytopenia 肝素诱导血小板减少症多见于肝素治疗第5-14天，血小板计数相对值下降50或绝对值降

14、至50-80109/L，停药后4-14天恢复正常。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。HIT定义 Heparin-Induced Thro型HIT型HIT发生频率10-202-30发生时间1-3d（大剂量肝素）5-14d（各剂量各途径）血小板计数100-150109/L50-80109/L抗体存在否是血栓形成无30-80%出血表现无罕见处理原则观察停肝素，选择其他抗凝药物替代HIT临床分型型HIT型HIT发生频率10-202-30发生时间1HIT治疗高度警惕，早诊早治停用UFH和LMWH，避免一切潜在肝素来源抗血小板聚集，应用凝血酶直接

15、抑制剂（DTI）和抗Xa制剂以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；对血栓形成者则持续3-6月HIT治疗高度警惕，早诊早治急性冠脉综合征抗栓治疗(版)课件Fondaparinux:In UA/NSTEMI (OASIS5)在NSTE ACS病人中， Fondaparinux 和依诺肝素对照研究Fondaparinux:In UA/NSTEMI (OAS急性冠脉综合征抗栓治疗(版)课件Death, MI, revasc- 血浆结合蛋白Enoxaparin is superior to UFH强调正确评价肾功能，患者血肌酐水平不能反

16、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, and

17、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

18、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。与依诺肝素相比，fondaparinux治疗1000 NSTE ACS 病人预防: 10 deaths or MI 4 strokes 25 major bleeds明显降低1个月和6个月的死亡率显著降低严重出血并发症在PCI 病人中并不比依诺肝素差OASIS 5总结Death, MI, revasc与

19、依诺肝素相比，fondaFondaparinux:STEMI 病人在症状发作的12 h内Fondaparinux和普通肝素对照研究。OASIS 6ACC 2006Fondaparinux:STEMI 病人在症状发作的12 急性冠脉综合征抗栓治疗(版)课件急性冠脉综合征抗栓治疗(版)课件急性冠脉综合征抗栓治疗(版)课件 3 important areas:Active site: fibrinogen bindingExosite I: major docking site-interaction with fibrinogen and other receptors; fibrinogen r

20、ecognition site3. Exosite II: interacts with heparinThrombin 3 important areas:ThrombHirudin医学上的水蛭病古时候埃及人和希腊人用于解除身体上的“坏体液”在19世纪中期最盛行Hirudo medicinalisHirudin医学上的水蛭病Hirudo medicinalBivalirudin 模拟天然水蛭素Gly-Pro-Arg-Pro (active site binding region)(Gly)4C-terminal dodecapeptide(exosite 1-binding region)B

21、ivalirudin 模拟天然水蛭素Gly-Pro-Ar7天时发生事件患者% 出血Death, MI, revascUnstable& MI后n = 241Unstable 用肝素n = 1,006MI后n = 741没有危险因素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 PCI 的结果 特定高危人群的初步结果Heparin8.3%7.0%H

22、eparin7天时发生事件患者% 出血Death, MI, revascQuadruple Endpoint 30 Day Primary Endpoint Componentsp 0.001LincoffQuadruple Endpoint 30 Day PrimFondaparinux: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 repe

23、rfusion 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.Circulation 2005Abciximab + 肝素Events, No.The recommended ACT with no planned GP IIb/III

24、a receptor antagonist treatment 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 admin

25、istered according to age, weight, 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; 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

26、 ACS 病人预防:REPLACE-2Bivalirudin 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；两组间MI、紧急血运重建等终点事件的发生率相等；Bivalirudin组死亡率有降低趋势。结论在PCI中，病人被随机分为bivalirudin或肝素+ GP IIb/IIIa抑制剂治疗：Fondaparinux:REPLACE-2结论在PCI中，Adjunctive Anticoagulant Therapy With FibrinolysisPatients with STEMI undergoing reperfusion with fibrinolytic therapy

27、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:UFH administered as a weight-adjusted intravenous bolus and infusion to obtain an activated

28、 partial thromboplastin time of 1.5 to 2.0 times control, for 48 hours or until revascularization;Enoxaparin administered according to age, weight, and creatinine clearance, given as an intravenous bolus, followed in 15 minutes by subcutaneous injection for the duration of the index hospitalization,

29、 up to 8 days or until revascularization; or 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, up to 8 days or until revascular

30、ization. IIIaIIbIIIAIIIaIIbIIIAIIIaIIbIIIIIIaIIbIIIB2013 ACCF/AHA GuidelineAdjunctive Anticoagulant TheraAdjunctive 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 with no pla

31、nned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s (HemoTec device) or 300 to 350 s (Hemochron device).2013 ACCF/AHA GuidelineAdjunctive Antithrombotic Ther出血对预后的影响出血对预后的影响5.13.05.37.018.616.115.322.801020304050总体不稳定心绞痛非ST段抬高型MIST段抬高型MI患者院内死亡率 (%)未大出血大出血*P0.001*Moscucci M et al.Eur Heart

32、 J 2003;24:1815-23. 大出血患者院内死亡率5.13.05.37.018.616.115.322.801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 5倍 02468101214051015202530出血未出血累计事件发生率( % )33676334193315732990328793276932710470459440430420410408天风险患者例数未出血出血基于出血的

33、30天死亡事件OASIS 、 OASIS-2及C贫血对ACS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. 贫血对ACS预后预测价值Hb是心血管不良事件的独立预测因子 输血患者预后不良输血患者预后不良输血组30天的生存率：GUSTO IIb、 PURSUIT及 PARAGON B研究 (

34、n=24 000; 10% 输血)- Rao SV, et. al., JAMA 20040.90.920.940.960.98105101520253035时间（天）生存率未输血输血输血组30天的生存率：GUSTO IIb、 PURSUIT及冠心病出血、输血与预后的观点出血导致死亡和MI风险增加预防出血与预防缺血事件同等重要输血可能有潜在危害只有在发生致命性贫血(红细胞压积低于 25%)时才应输血 冠心病出血、输血与预后的观点出血导致死亡和MI风险增加为什么在 PCI 中使用LMWH?贫血对ACS预后预测价值Bivalirudin4 strokesPatients with STEMI un

35、dergoing 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 + 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 strok

36、esDyspepsia 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出血导致死亡和MI风险增加OR (95% CI)J Am Coll Cardiol.

37、出血风险评估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。 严重出血独立危险因素包括高龄、女性、出血病史、PCI、肾功能不全病史及使用GPb/a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，应该计算肌酐清除率。为什么在 PCI 中使用LMWH?出血风险评估推荐两个常用出预防出血原则Prevention of bleeding encompasses the choice of： safer drugsappropriate dosage (according age, sex, and CrCl) reduced dura

38、tion of antithrombotic treatment预防出血原则Prevention of bleeding eSafer drugsConsistent UFH/EnoxaparinBivalirudinFondaparimuxAntiplatelet drugsSafer drugsConsistent UFH/Enox急性冠脉综合征抗栓治疗(版)课件大出血治疗策略-中和抗凝药物大出血治疗策略-中和抗凝药物大出血治疗策略-中和抗栓药物UFH can be inhibited by an equimolar concentration of protamine sulfate.

39、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 recommended, bu

40、t 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 ticagrelor shortly (3 days) after withdrawal of the drug.大出血治疗策略-中和抗栓药物UFH can be inhi大出血治疗策略输血原则大出血治疗策略输血原则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Algorithm to Assess GI Risk With Antiplatelet TherapyYesYesNoPPIYesYesBhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.Need for antiplatelet therapyA