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替格瑞洛（倍林达）在抗血小板聚集中的作用Ticagrelorfortheroleofanti-plateletaggregation昌平区中医医院：张碎虎content概述临床效应替格瑞洛作用机制推荐使用替格瑞洛（倍林达）指南TicagrelorChangpingchinesesmedicinehospital噻吩吡啶类药物发展史Anti-plateletaggregation噻氯匹定法国Sanofi-aventis1979年氯吡格雷美国Sanofi-aventis1998年普拉格雷日本，美国DaiichiSankyo&EliLilly2009年普格瑞洛瑞典AstraZenecaAB2010年卜晓斐.现代药物与临床,27(1).血小板血栓形成过程Adhesion1Activation2ThrombinADP5HTPAFHandinRI.Harrison’sPrinciplesofInternalMedicine.Vol1.14thed.NY,NY:McGraw-Hill;1998:339-345.SchaferAI.AmJMed.1996;101:199-209.3FibrinogenActivatedGPllb/llla3Aggregation替格瑞洛P2Y12替格瑞洛（倍林达）作用机制替格瑞洛药物特点氯吡格雷：肝脏CYP450酶两步代谢（CYP2C19,CYP3A4等）•普拉格雷：肝脏CYP450一步代谢•替格瑞洛：2/3以原型化合物起效，1/3可经肝脏CYP3A4代谢，代谢产物仍有活性Yousuf,O.&Bhatt,D.L.Nat.Rev.Cardiol.advanceonlinepublication12July2011P2Y12受体抑制剂的药理特性比较ClarkMG,etal.Heart&Lung2015;44:141-149.FranchiF,etal.NatRevCardiol.2015;12:30-47.氯吡格雷普拉格雷替格瑞洛产品名波立维Effient倍林达P2Y12结合不可逆不可逆可逆推荐剂量(ACS)300-600mg负荷剂量，然后75mg/d60mg负荷量，后10mg/d(60kg的患者为5mg)180mg负荷剂量，然后90mg每日两次合用药阿司匹林的批准剂量75-325mg/d75-325mg/d325mg负荷剂量，然后75-100mg/d给药方式/频率口服/每日一次口服/每日一次口服/每日两次药理学特征前体药物；需要肝脏代谢前体药物需要肝脏代谢活性母体化合物；无需生物转化起效/失活时间2-8h/7-10天30min-4h/7-10天30min-4h/3-5天肝功能受损无，轻度至中度无，轻度至中度无，轻度药物基因组学CYP2C19弱代谢患者考虑其他治疗方案CYP2B6、2C9、2C19或3A5遗传变异无相关影响无需CYP2C19检测抗血小板效应延迟数小时至最大抗血小板效应起效更快且血小板聚集抑制程度大于氯吡格雷起效更快且血小板聚集抑制程度大于氯吡格雷手术最后一次给药后5天行手术最后一次给药后7天行手术最后一次给药后5天行手术替格瑞洛的临床作用PLATOHOUYI-STUDYSPEGASUS-TIMI54第一PPT模板网：～20087DESINEMulticenter(43country，893medicalcentral),double-blind,randomizedPURPOSEcomparedTicagrelor(180mgloadingdose,90mgtwicedailythereafter)andClopidogrel(300-to-600-mgloadingdose,75mgdailythereafter)forthepreventionofcardiovasculareventsPrimaryendpoint1.Efficacy:Compositeofdeathfromvascularcauses,MI,orstroke.2.Safety:AnymajorbleedingeventFollowed-UP12months1.1%ARRP=0.00121%RRRNNT=91HR95%CI0.790.69-0.91倍林达与氯吡格雷相比，显著降低心血管死亡率达21%倍林达®与氯吡格雷相比，总体主要出血发生率无显著差异*PLATO主要出血的定义:致命性或颅内出血、伴有心包填塞的心包内出血、由出血导致的低血容量休克或严重低血压需要升压药或手术、Hb下降(＞50g/L)、因出血而输血≥4u(全血或浓集红细胞[PRBC])；其他主要出血：显著的功能丧失(如眼内出血伴永久性失明)、Hb下降(30-50g/L)、因出血而输血2-3u(全血或PRBC)246810120121086420随机后时间(月)主要出血累积发生率(K-M%)倍林达®组(n=9,235)氯吡格雷组(n=9,186)两组均包含阿司匹林11.6%11.2%P=0.43HR=1.04(95%CI,0.95–1.13)WallentinL,etal.NEnglJMed2009;361:1045–1057.6.10%5.11%11.60%9.63%PEGASUS-TIMI54PATIENTS21162patientswithahistoryofspontaneousmyocardialinfarctionwithin1to3yearsTIMEOctober2010～April2013DESINEarandomized,double-blind,placebo-controlled,multinationalclinicaltrialPURPOSEevaluatetheefficacyandsafetyofticagrelorinadditiontoaspirin(75-150mg)forthepreventionofmajoradversecardiovasculareventsPrimaryendpointcardiovasculardeath,myocardialinfarction,orstrokeProgramASA+ticagrelor90mgtwicedailyvs.ASA+ticagrelor60mgtwicedailyvs.ASA+matchingplaceboFollowed-UPAtleast12monthsResult:Ticagrelor90mg,60mgvsplaceboReducedtherateoftheprimaryendpoint15%,16%BonacaMP.NEnglJMed.2015May7;372(19):1791-800.7.856.996.795.592.947.777.096.775.752.869.048.337.816.683.390.001.002.003.004.005.006.007.008.009.0010.00card-vasdea,MI,orstrokeDeafromCHD,MI,orstrokecar-vasdea,MIDeafromCHDorMIcard-vasdeaTicagredor90mgTicagredor60mgPlaceboEfficacyEndPointsas3yearKaplan-MeierEstimates(%)EfficacyEndPointsas3yearKaplan-MeierEstimates(%)TIMI主要出血TIMI轻微出血致死性出血或颅内出血颅内出血致死性出血P0.001P0.001P=NSP=NSP=NSHOUYIStudyHOUYIStudyPATIENTS57patientswithnon-STsegmentelevationmyocardialinfarction,STsegmentelevationmyocardialinfarctionandunstableanginaTIMEMay2013～March2014DESINEarandomized,open-label,60Chineseclinicalhospitalfrom5centralPURPOSEevaluatetheefficacyandsafetyofTicagrelorinadditiontoaspirin(75-150mg)forthepreventionofmajoradversecardiovasculareventsPrimaryendpointMeaninhibitionofplateletaggregation(IPA)at2hourafterfirstdoseProgramASA(100mgloading,100mg/d)+Ticagrelor(180mgloading,90mgtwicedailyvs.ASA(100mgloading,100mg/d)+Clopidogrel(600mgloading,75mg/d)Followed-UP6weeksPercentageofpatientswithaPRUvalueof＜240.PRU=P2Y12reactionunit替格瑞洛（倍林达）指南Ⅰ类推荐EuropeCanadaUnitedStatesChinese2012ESC心血管疾病预防指南32015ESCNSTE-ACS指南12012ESCSTEMI指南42014ESC/EACTS心肌血运重建指南2Europe1.RoffiM,etal.EuropeanHeartJournal.2015doi:10.1093/eurheartj/ehv3202.WindeckerS,etal.EurHeartJ.2014;35(37):2541-26193.PerkJ,etal.EuropeanHeartJournal.2012;33:1635–17014.StegG,etal.EuropeanHeartJournal.2012;33:2569–26192011AHA/ACCF二级预防指南42014ACC/AHANSTE-ACS指南12013ACCF/AHASTEMI指南22011ACCF/AHASCAIPCI指南52012ACCP抗栓指南3UnitedStates1.AmsterdamEA,etal.Circulation.2014;130:e344-e426.2.O'GaraPT,etal.Circulation.2013;127:e362-e4253.GuyattGH,etal.CHEST.2012;141:7S-47S4.SmithSCJr,etal.Circulation.2011;124(22):2458-24735.LevineGL,etal.JAmCollCardiol.2011;58:2550-2583；2011CCS门诊患者抗血小板治疗应用指南TheUseofAntiplateletTherapyintheOutpatientSetting:CanadianCardiovascularSocietyGuidelinesCanadaBellAD,etal.CanJCardiol.2011May-Jun;27SupplA:S1-S592012中国非ST段抬高ACS指南32015中国STEMI诊断和疗指南12012中国PCI指南2Chinese1.中华医学会心血管病学分会.中华心血管病杂志,2015;43(5):380-3932.中华医学会心血管病学分会介入心脏病学组.中华心血管病杂志.2012;40(4):271-2773.中华医学会心血管病分会中华心血管病杂志.2012;40(5):353-367summaryChangPingChinesemedicineh