血小板糖蛋白IIbIIIa受體拮抗劑在介入非介入患者中的應用

血小板糖蛋白IIb/IIIa受體拮抗劑在介入/非介入患者中的應用浙江大學醫(yī)學院附屬第二醫(yī)院心臟中心王建安基本原理分子結構適應癥和循證醫(yī)學結論血小板GPIIb/IIIa受體拮抗劑的作用機理

MechanismCompetitiveantagonistoftheGPreceptorontheplateletsurfaceforadhesiveproteinssuchasfibrinogen,VWFmaximallyinhibitthefinalcommonpathwayinvolvedinplateletaggregation

CollagenADP

ThromboxaneA2PlateletActivation

plateletaggregationThrombusformationGPIIb/IIIainhibitorAspirinCOXTiclopidinClopidogrel目前的GPIIb/IIIa受體拮抗劑依據化學結構的不同可分為三類1.單克隆抗體，Abciximab（阿昔單抗），最早應用于臨床的GPIIb/IIIa受體拮抗劑，是GPIIb/IIIa受體的單克隆抗體，通過占據受體的位置而阻斷血小板聚集反應。2.肽類抑制劑，Eptifibatide（埃替非巴肽），是一類含有GPIIb/IIIa受體識別序列的低分子多肽。3.非肽類抑制劑，靜脈的Tirofiban（替羅非班），是肽衍生物，其藥理性質與埃替非巴肽相似?？诜请念愐种苿?，Xemilofiban、Orbofiban、Rocifiban、Sibrafiban、Lefradafiban、但試驗結果均以失敗告終。三類

GPIIb/IIIa受體拮抗劑的化學結構STEMIClinicalfindingEKGSerummarkersRiskassessmentNon-cardiac

chestpainStable

anginaUANSTEMINegativePositiveST-Twave

changesSTelevationLow

probabilityMedium-highriskThrombolysis

PrimaryPCIAspirin+GPIIb/IIIainhibitorclopidogrel+heparin/LMWH+anti-ischemicRx

EarlyinvasiveRxDischargeNegativeDiagnostic

ruleoutMI/ACSpathwaySTEMINegativeAtypicalpainLowriskAspirin,heparin/low-molecular-weightheparin(LMWH)+clopidogrel

Anti-ischemicRx

EarlyconservativetherapyOngoingpainDM=diabetesmellitus.Cannon,Braunwald.HeartDisease.2001.Restpain,Post-MI,DM,PriorAspirinExertionalpainTheSpectrumofACSBenefitofGPIIb/IIIaBlockadeinACSMeta-AnalysisofSixMajorTrials(31,402Patients)AllpatientswithACSPatientswithACS,undergoingPCIwithin5daysBoersmaEetal.Lancet20020.50.60.71.1AntiGPIIb/IIIabetter0.80.91.0Relative30-DayRiskofDeathandMIPRISM(3232) 7.1% 5.8%?PRISM-PLUS(1915) 12.0% 8.7% 0.70 0.50-0.98

PURSUIT(10,948) 15.7% 14.2% 0.89 0.79-1.00

PARAGON-B(5225) 11.4% 10.6% 0.92 0.77-1.09

OddsRatioPlaceboIVGPIIb/IIIa95%CI*With/withoutheparin.?Withoutheparin.(l)=lowdose.(h)=high-dose.Adaptedfrom:BoersmaE,etal.Lancet.2002;359:189-198.PlaceboBetterGPIIb/IIIaBetterOddsRatio(95%CI)0.01.02.0Study(n)GPIIb/IIIaInhibitorsinUA/NSTEMI:

DeathorMIat30DaysFavorsControlFavorsTreatmentYearCAPTURE1997RESTORE1998EPISTENT19991997CADILLAC-P2002ADMIRAL2001RAPPORT1998Petronio2002CADILLAC-S20020.010.1110100StudyERASER1999ISAR-22000EPICRiskRatioand95%CIRR0.79Z=-2.272P=0.023EPILOG1999ESPRIT2002OverallTamburino2002N126521411603209910463004838910362254012792206415,651107KarvouniE,etal.JAmCollCardiol.2003;41:26-32.IntravenousGPIIb/IIIaReceptorAntagonistsReduceMortalityafterPCIKongD,etal.AmJCardiol.2003;92:651-655.PlaceboBetterIIb/IIIaBetterTrialControlTreatmentN0.1110RESTORE1.1%0.9%12,940EPILOG1.2%0.9%4891RAPPORT1.3%1.0%5374CAPTURE1.3%1.0%6639EPIC1.7%1.5%20991.3%IMPACTI1.0%67891.2%IMPACTII0.9%10,799ESPRIT1.0%0.8%17,403ISAR-21.1%0.8%17,804ADMIRAL1.2%0.8%18,104EPISTENT1.1%0.8%15,3391.3%CADILLAC0.9%20,186OddsRatioand95%CI0.73(0.55,0.96)P=0.024Meta-analysisofSurvivalwithPlatelet

GPIIb/IIIaAntagonistsforPCIACCP-7對NSTEACS治療建議：NSTEACS的中、高?；颊咴缙谥委?，在應用阿司匹林及肝素基礎上，加用Eptifibatide或Tirofiban（1A級）；同時應用氯吡格雷的中、高?；颊?，早期加用Eptifibatide或Tirofiban（2A級）。急性冠狀動脈綜合征（ACS）中的應用ACC/AHA2007年UA/NSTEMI指南

ESC2007年UA/NSTEMI指南

2007年ACC/AHA/SCAI關于UA/NSTEMI的PCI指南GPⅡb/Ⅲa受體拮抗劑在STEMI溶栓中的應用全劑量溶栓劑與GPⅡb/Ⅲa受體拮抗劑合用再灌注率提高，但出血風險明顯增加SPEED和GUSTO-ⅣPilot試驗顯示，Abciximab與半量t-PA合用，顯著提高梗死相關血管開通率，但出血風險仍高于溶栓組00.511.5Relative

RiskofDeath+MI+TVRAbciximabvsControl30Days6MonthsRAPPORT,

Breneretal.(PTCA)

Circulation1999ISAR-2

Neumannetal.

(Stent)

JAmCollCardiol2000ADMIRAL

Montalescotetal(Stent)

NEnglJMed,2001CADILLAC

Stoneetal.(Stent/PTCA) NEnglJMed,2002ACE

Antoniuccietal.(Stent) JAmCollCardiol2003PooledAbciximabforPCIinAMI00.511.5GPIIb/IIIa受體拮抗劑在AMI患者PCI中的應用ACC/AHA2007年關于

STEMI的PCI指南GPIIb/IIIa受體拮抗劑在PCI中的早期應用ELISAI、EVEREST、TIGER-PA、ON－TIME研究證明在PCI患者中，早期應用（急診室、監(jiān)護室或院前）GPIIb/IIIa受體拮抗劑（tirofiban）效果優(yōu)于晚期應用（導管室）ACC2008：ON-TIME-2：Ongoing-TirofibanInMyocardialInfarctionEvaluationAcutemyocardialinfarctiondiagnosedinambulanceorreferralcenterASA+600mgClopidogrelAngiogramTirofiban*PlaceboTransportationPCIcentreAngiogramTirofibanprovisionalTirofibancont’dN=9846/2006-11/2007PCI*Bolus:25μg/kg&0.15μg/kg/mininfusionResults:PrimaryEndpoint

ResidualSTdeviationat60minmean±SDPlaceboTirofibanp-valueReadableECG94.1%95.5%0.358ResidualST-deviation(mm)4.8±6.33.3±4.30.002>3mmST-deviation44.3%36.6%0.026normalECG30.2%37.3%0.031ResidualST>3mm(combined)PlacebobetterTirofibanbetterAllpatients(PCI)MalegenderFemalegenderDiabetesNodiabetesTIMIrisk>3TIMIrisk≤

3Age<medianvalueAge>medianvalue0.1110PrimaryEndpointSubgroupsEvent-fre