血小板GPIIbIIIa受體拮抗劑臨床應(yīng)用新視點(diǎn)

1血小板GPIIb/IIIa受體拮抗劑臨床應(yīng)用新視點(diǎn)2IIb/IIIa受體拮抗劑的作用機(jī)制3PharmacologicInterventioninThrombosisUFH=unfractionatedheparin.LMWH=low-molecular-weightheparinADP=adenosinediphosphate.TFPI=tissuefactorpathwayinhibitorSelwynA.AmJCardiol.2003;91:3H-11H.CoagulationcascadePlateletsLMWHThienopyridinesGPIIb/IIIainhibitorsThrombolyticsLMWHUFHLMWHUFHDirectthrombininhibitorsTissuefactorFactorXaProthrombinThrombinPlateletsA2vWFADPActivatedplateletsFibrinogencross-linkingPlateletaggregationAspirinFibrinogenFibrinFibrindegradationCollagenLeukocytesTFPIAnti-thrombinAnti-thrombinThromboxanePlasminThrombus45三類(lèi)

GPIIb/IIIa受體拮抗劑的化學(xué)結(jié)構(gòu)6三類(lèi)

GPIIb/IIIa受體拮抗劑的特點(diǎn)Abciximab(ReoPro)Tirofiban(Aggrastat)Eptifibatide(Integrilin)PharmaFabportionofchimericmonoclonalantibodySyntheticnon-peptideCyclicheptapeptideHalf-life30mins1.8hrs2.5hrsRenalAdj.NoYesYesDosage0.25mcg/kgbolusfollowedby0.125mcg/kg/mindrip(max10mcg/min)forupto12hours0.4mcg/kg/minfor30minutesfollowedby0.1mcg/kg/mindripfor48-96hours25mcg/kgfor3minutesfollowedby0.15mcg/kg/mindripforupto18hours180mcg/kgbolus(x2)followedby2.0mcg/kg/mindripfor12-18hours7IIb/IIIa受體拮抗劑的循證依據(jù)8GPIIb/IIIaInhibitorsCoronaryInterventionEPICRESTORECAPTUREEPILOGRAPPORTIMPACTIIEPISTENTESPRITCADILLACTARGET24,141PatientsUnstableAnginaNon-QWaveMIPURSUITPRISMPRISMPLUSPARAGONAPARAGONBGUSTO-IV31,056PatientsOralIIb/IIIaPCI-ACSEXCITEOPUS1stSYMPHONY2ndSYMPHONY33,340PatientsST-ElevationAcuteMIGUSTO-VASSENT-322,683PatientsCompletedearlyLargeRCTs9IIb/IIIa受體拮抗劑在PCI患者中的應(yīng)用10KongD,etal.AmJCardiol.2003;92:651-655.Placebo

BetterIIb/IIIa

BetterTrialControlTreatmentN0.1110RESTORE1.1%0.9%12,940EPILOG1.2%0.9%4891RAPPORT1.3%1.0%5374CAPTURE1.3%1.0%6639EPIC1.7%1.5%20991.3%IMPACT

I1.0%67891.2%IMPACT

II0.9%10,799ESPRIT1.0%0.8%17,403ISAR-21.1%0.8%17,804ADMIRAL1.2%0.8%18,104EPISTENT1.1%0.8%15,3391.3%CADILLAC

0.9%20,186OddsRatioand95%CI0.73(0.55,0.96)P=0.024Meta-analysisofSurvivalwithPlatelet

GPIIb/IIIaAntagonistsforPCI11Favors

ControlFavors

TreatmentYearCAPTURE1997RESTORE1998EPISTENT19991997CADILLAC-P2002ADMIRAL2001RAPPORT1998Petronio2002CADILLAC-S20020.010.1110100StudyERASER1999ISAR-22000EPICRiskRatioand95%CIRR

0.79Z=-2.272P=0.023EPILOG1999ESPRIT2002OverallTamburino2002N126521411603209910463004838910362254012792206415,651107Karvouni

E,etal.JAmColl

Cardiol.

2003;41:26-32.IntravenousGPIIb/IIIaReceptorAntagonistsReduceMortalityafterPCI12ISAR-REACT600mgClopidogrelload≥2hoursbeforePCILow-riskPCI?30-DayIschemicandBleedingEvents?Europeanand1USCenterPlaceboAbciximabDesignPatientsExcluded:IDDMACSorrecentMIVeingraftsThromboticlesionsLVEF<30%13p=NSp=NSp=NSp=NSNEJM2004;350:232-80.3%3.8%4.0%0.6%0.3%3.7%4.0%0.9%0%5%10%DeathMIDeath/MIUrgRevacPlaceboAbciximabISAR-REACT

low-riskPCI--30daysoutcome14p=0.06p=0.03p=0.34p=0.64JAMA2006;295:1531-381.6%10.5%11.5%1.2%1.1%8.1%8.6%1.0%0%5%10%DeathMIDeath/MIUrgRevacPlaceboAbciximabISAR-REACT2

high-riskPCI--30daysoutcome15

InpatientsundergoingelectivePCItreatedwithUFHandnotpretreatedwithclopidogrel,itisreasonabletoadministeraGPIIb/IIIainhibitor(abciximab,double-boluseptifibatide,orhigh-bolusdosetirofiban).IntravenousAntiplateletTherapy:SIHDIIIaIIbIIIB2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention16InpatientsundergoingelectivePCIwithstentimplantationtreatedwithUFHandadequatelypretreatedwithclopidogrel,itmightbereasonabletoadministeraGPIIb/IIIainhibitor(abciximab,double-boluseptifibatide,orhigh-bolusdosetirofiban).IntravenousAntiplateletTherapy:SIHD(cont.)IIIaIIbIIIB2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention17IIb/IIIa受體拮抗劑在NSTE-ACS患者中的應(yīng)用18STEMIClinicalfindingEKGSerummarkersRiskassessmentNon-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,PriorAspirinExertionalpainTheSpectrumofACS19PRISM(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:

DeathorMIat30Days20BenefitofGPIIb/IIIaBlockadeinACSMeta-AnalysisofSixMajorTrials(31,402Patients)AllpatientswithACSPatientswithACS,undergoingPCIwithin5daysBoersmaEetal.Lancet2001.1AntiGPIIb/IIIabetterRelative30-DayRiskofDeathandMI21IIb/IIIaACSMeta-analysis30-DayDeathorMIBoersmaetal.Lancet2002;359:189-9815%9%6%3%012%18%Placebo(n=11,148)11.4%IIb/IIIa(n=15,876)10.7%NoPCIwithin120hours15%9%6%3%012%18%Placebo(n=1957)14.5%IIb/IIIa(n=2421)11.8%PCIwithin120hoursOR=0.95(0.87-1.02)OR=0.77(0.64-0.92)22IIb/IIIaACS

30-dayDeathorMI–EarlyPCI23IIb/IIIaACS

30-dayDeathorMI–NoEarlyPCI24ACUITY:

IschemicCompositeEndpointStoneGW.ACC2007presentation*Death,MI,unplannedrevascularizationforischemia2526EARLY-ACSstudy27ACC/AHA2012年UA/NSTEMI指南預(yù)行PCI的中、高危UA/NSTEMI患者，與阿司匹林聯(lián)合應(yīng)用GPⅡb/Ⅲ受體拮抗劑，開(kāi)始于術(shù)前(I/B)或術(shù)中(I/A)Bivalirudin作為術(shù)中抗凝時(shí)可不用GPⅡb/Ⅲa受體拮抗劑對(duì)于選擇保守策略的UA/NSTEMI患者，可應(yīng)用依替巴肽或替羅非班進(jìn)行抗栓治療(Ⅱb/B)預(yù)行PCI的高危UA/NSTEMI且非高出血風(fēng)險(xiǎn)患者，與雙聯(lián)抗血小板藥聯(lián)合上游應(yīng)用GPⅡb/Ⅲ受體拮抗劑(Ⅱb/B)阿昔單抗不應(yīng)當(dāng)應(yīng)用于不準(zhǔn)備行PCI的患者（Ⅲ/A）預(yù)行PCI的低危UA/NSTEMI患者或高出血風(fēng)險(xiǎn)患者，不推薦與雙聯(lián)抗血小板藥聯(lián)合上游應(yīng)用GPⅡb/Ⅲ受體拮抗劑(Ⅲ/B)28InUA/NSTEMIpatientswithhigh-riskfeatures(e.g.,elevatedtroponinlevel)nottreatedwithbivalirudinandnotadequatelypretreatedwithclopidogrel,itisusefulatthetimeofPCItoadministeraGPIIb/IIIainhibitor(abciximab,double-boluseptifibatide,orhigh-bolusdosetirofiban)inpatientstreatedwithUFH.IntravenousAntiplateletTherapy:UA/NSTEMI

IIIaIIbIIIA2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention29InUA/NSTEMIpatientswithhigh-riskfeatures(e.g.,elevatedtroponinlevel)treatedwithUFHandadequatelypretreatedwithclopidogrel,itisreasonableatthetimeofPCItoadministeraGPIIb/IIIainhibitor(abciximab,double-boluseptifibatide,orhigh-bolusdosetirofiban).IntravenousAntiplateletTherapy:UA/NSTEMI(cont.)IIIaIIbIIIB2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention30IIb/IIIa受體拮抗劑在A(yíng)MI患者中的應(yīng)用31早期研究IIb/III受體拮抗劑對(duì)AMI直接PCI的作用32Relative

RiskofDeath+MI+TVRAbciximabvsControl00.511.530Days6MonthsRAPPORT,

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A(yíng)MI患者PCI中的應(yīng)用3333FINESSE:StudydesignEllisetal.NEngJMed.2008;358:2205-2217.TreatmentPre-PCItreatmentwith?-doselyticplusabciximab,pre-PCIabciximabalone,andabciximabattimeofPCIInclusionSuspectedacuteMI(STchangeor

LBBB)within6hofsymptomonsetExclusionLowrisk(<60yo,localizedinferiorinfarct)highriskforbleeding1°OUTCOMESDeath,VFafter48hours,shock,

CHFwithin90days3434Ellisetal.NEngJMed.2008;358:2205-221735FINESSE–90-DayEndpointsEllisS.ESC2007Vienna36FINESSE–90-DayBleedingEllisS.ESC2007Vienna37CARESS–Abciximabwith1/2DoseReteplaseDiMarioC.ESC2007Vienna3838OnTIME2:StudydesignAcutemyocardialinfarctiondiagnosedinambulanceorreferralcenterASA+600mgClopidogrelAngiogramTirofiban*PlaceboTransportationPCIcentreAngiogramTirofibanprovisionalTirofibancont’dPCIvan’tHofetal.Lancet2008;372:537-46.*Bolus25μg/kg&0.15μg/kg/mininfusion3939OnTIME2:endpointsPrimaryResidualSTsegmentdeviation(>3mm)1hourafterPCIKeyClinicalSecondaryCombinedoccurrenceofdeath,recurrentMI,urgentTVRorthromboticbailoutat30daysfollow-upSafety(majorbleeding)Deathat1yearfollow-up4040On-TIME2:Resultsvan’tHofetal.Lancet2008;372:537-46ResidualSTDeviationafterPCIp=0.003 3.6±4.6mm 4.8±6.3mm41On-TIME2:Results

Event-freeSurvivalsurvivalfreefromdeath,recurrentmyocardialinfarction,urgenttargetvesselrevascularisation,orblindedbail-outuseofstudydrug42On-TIME2:Resultsvan’tHofetal.Lancet2008;372:537-46.Event-freeSurvivalat30daysDeathat1yr.inprimaryPCIgroup:Tirofiban(2.4%)vs.Placebo(5.5%)(p=0.007,RR=0.44(0.24-0.81))ClinicaloutcomePlacebotirofibanP-valueDeath/recurrentMIorurgentTVR39/477(8.2%)33/473(7.0%)0.48543InpatientsundergoingprimaryPCItreatedwithUFH,itisreasonabletoadministeraGPIIb/IIIainhibitor(abciximab,double-boluseptifibatide,orhigh-bolusdosetirofiban),whetherornotpretreatedwithclopidogrel.ForGPIIb/IIIainhibitoradministrationinpatientsnotpretreatedwithclopidogrel.ForGPIIb/IIIainhibitoradministrationinpatientswhoarepretreatedwithclopidogrel.IntravenousAntiplateletTherapy:STEMIIIIaIIbIIIAIIIaIIbIII2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention4444

ItisreasonabletostarttreatmentwithglycoproteinIIb/IIIareceptorantagonistsatthetimeofprimaryPCI(withorwithoutstenting)inselectedpatientswithSTEMI: abciximab tirofibanandeptifibatideUseofGlycoproteinIIb/IIIaReceptorAntagonistsinSTEMIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIBIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIAModifiedRecommendation4545UseofGlycoproteinIIb/IIIaReceptorAntagonistsinSTEMIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIIIaIIaIIaIIbIIbIIbIIIIIIIIIBTheusefulnessofglycoproteinIIb/IIIareceptorantagonists(aspartofapreparatorypharmacologicstrategyforpatientswithSTEMIpriortoarrivalinthecardiaccatheterizationlaboratoryforangiographyandPCI)isuncertain.ModifiedRecommendation46BRAVE3:StudydesignMehillietal.Circ.2009;119:1933-1940TREATMENT: pre-PCItreatmentwithclopidogrel(600 mg),followedbyabciximabvs.placebo INCLUSION: suspectedacuteMI(STchangeor

LBBB) within24hofsymptomonsetEXCLUSION: highriskforbleeding,priorstroke,shock, trauma,thrombolytics,hypertension, relevanthematologicdeviations1°OUTCOMES: infarctsize,death,stroke,urgent revascularizationofaffectedartery47EffectsofAbciximabMehillietal.Circ.2009;119:1933-1940NosignificantdifferenceininfarctsizeormajorbleedingP=0.47P=0.4048

Routineprecatheterizationlaboratory(e.g.,ambulanceoremergencyroom)administrationofGPIIb/IIIainhibitorsaspartofanupstreamstrategyforpatientswithSTEMIundergoingPCIisnotbeneficial.IntravenousAntiplateletTherapy:STEMI(cont.)IIIaIIbIIIBNoBenefit2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention49冠脈內(nèi)注射IIb/IIIa受體拮抗劑50Meta-AnalysisI–AllACS+GpIIb/IIIa-Inh.Friedmanetal.AmJCardiol2011;108:1244-1251TIMI-3-FlowafterPCI0.56911.76FavorsIVrouteFavorsICrouteRiskratioDeibeleGuIversenDominguez-RodriguezWuThieleYangBellandiOverall

(I-squared=20.1%;p=0.27)1.07(0.89,1.28)8.661.03(0.97,1.10)34.901.10(0.98,1.24)17.431.29(0.95,1.76)3.271.22(1.01,1.48)7.960.98(0.86,1.12)14.251.27(0.98,1.64)4.601.15(0.96,1.37)8.921.08(1.02,1.15)100.00StudyRR(95%CI)WeightBleedingGuIversenDominguez-RodriguezWuThieleYangOverall

(I-squared=0.0%;p=0.562)Riskratio0.12218.22ReducedriskbyICrouteReducedriskbyIVroute1.11(0.68,1.81)35.690.69(0.41,1.17)38.010.67(0.12,3.65)3.690.76(0.31,1.91)11.820.80(0.22,2.87)6.512.17(0.63,7.51)4.050.92(0.68,1.24)100.00RR(95%CI)WeightStudy51Meta-AnalysisI–AllACS+GpIIb/IIIa-Inh.Friedmanetal.AmJCardiol2011;108:1244-1251Short-termMortalityGuIversenWuThieleYangBellandiOverall(I-squared=0.0%;p=0.772)StudyRR(95%CI)Weight0.69(0.22,2.16)28.340.20(0.04,0.93)37.420.49(0.05,5.27)8.050.67(0.11,3.68)11.970.19(0.01,3.71)10.331.05(0.07,15.70)3.900.45(0.23,0.90)100.000.09361107Riskratio52Meta-AnalysisII–STEMI+AbciximabNavareseetal.Platelets2011;1-8CICERO2010CRYSTALAMI2010Dominguez-Rodriguez2009EASY-MI2010Iversen2011Thiele2008500022271252553185777100932632325521707733.7%7.4%44.8%14.1%0.690.29(0.01;7.59)NotestimableNotestimable0.20(0.04;0.92)0.66(0.11;4.05)StudyorSubgroupIntracoronaryabciximabIntravenousabciximabOddsratioEventsTotalEventsTotalWeightM-H,Fixed95%Total(95%)Totalevents636610100.0%0.43(0.20;0.94)920Heterogeneity:Chi2=1.88,df=3(P=0.60);I2=0%Testforoveralleffect:Z=2.11(P=0.03)30-dayMortalityM-H,Fixed95%OddsratioFavorsICFavorsIV0.010.1110100FavorsICFavorsIVCICERO2010EASY-MI2010Iversen2011Thiele200830-dayMyocardialInfarction305027153185774082263521707727.5%55.5%17.0%StudyorSubgroupIntracoronaryabciximabIntravenousabciximabOddsratioEventsTotalEventsTotalWeightM-H,Fixed95%Total(95%)Totalevents636562100.0%0.54(0.23;1.28)814Heterogeneity:Chi2=0.58,df=2(P=0.75);I2=0%Testforoveralleffect:Z=1.39(P=0.17)M-H,Fixed95%Oddsratio0.010.11101000.72(0.16;3.27)Notestimable0.56(0.18;1.75)0.19(0.01;4.13)586CICERO2010EASY-MI2010Iversen2011Thiele200830-dayTargetVesselRevascularization90702715318577100162263521707727.5%55.5%17.0%StudyorSubgroupIntracoronaryabciximabIntravenousabciximabOddsratioEventsTotalEventsTotalWeightM-H,Fixed95%Total(95%)Totalevents636562100.0%0.53(0.29;0.99)1628Heterogeneity:Chi2=2.58,df=2(P=0.36);I2=2%Testforoveralleffect:Z=2.00(P=0.05)M-H,Fixed95%OddsratioFavorsICFavorsIV0.010.11101000.87(0.35;2.17)Notestimable0.38(0.15;0.94)0.19(0.01;4.13)58653Piccolo,Thieleetal.SubmittedIndividualPatient-basedMeta-AnalysisIII5randomizedtrials(n=1198);

individualpatient-basedmeta-analysis

ICAbciximabn=611IVAbciximabn=587Death+ReinfarctionIVAbciximab587572568552559555

ICAbciximab6116035975955945940061218243002468HR0.54(95%CI0.30;0.95);p=0.03DaysafterRandomizationProbabilityofdeath

orreinfarction(%)Patientsatrisk:ICAbciximabIVAbciximab54Piccolo,Thieleetal.SubmittedIndividualPatient-basedMeta-AnalysisIII5randomizedtrials(n=1198);

individualpatient-basedmeta-analysis

ICAbciximabn=611IVAbciximabn=587MortalityIVAbciximab587577574572570567

ICAbciximab6116066036026026020061218243002468HR0.43(95%CI0.20;0.94);p=0.03DaysafterRandomizationProbabilityofdeath(%)Patientsatrisk:ICAbciximabIVAbciximab55InpatientsundergoingprimaryPCIwithabciximab,itmaybereasonabletoadministerintracoronaryabciximab.IntravenousAntiplateletTherapy:STEMI(cont.)IIIaIIbIIIB2011ACCF/AHA/SCAIGuidelineforPercutaneousCoronaryIntervention56不同IIb/IIIa受體拮抗劑的比較5757

UseofGlycoproteinIIb/IIIaReceptorAntagonistsinSTEMIGrumetal.SmallMoleculeGPIIb/IIIaInhibitorsprimaryPCI.CircCardiovasIntervent.2009;2:230-2236.StudyNameYearStatisticsp-valueDead/TotalSMGPIAbciximabValgimigli20050.667(0.11-4.09)0.6612/873/88EVA-AMI20071.017(0.36-2.86)0.9748/2267/201MULTISTRATEGY20080.438(0.13-1.44)0.1734/3729/372FATA20081.367(0.43-4.35)0.5967/3515/3410.843(0.46-1.55)0.58125FavorsSMGPIFavors AbciximabORand95%CIof30-dayMortality58High-DoseBolusTirofibanvs.AbciximabPooledAnalysisof5Studies

Abciximab

Tirofiban

Study 0.25mg/kgbolus

25μg/kgbolus 0.125μg/kg/mininfusion 0.15μg/kg/mininfusionBolognese 31 30Danzi 280 274Gunasekara 110 109TENACITY 194 189Valgimigli 88 87TotalSubjects: 703 689DawsonCBetal.AHA20065930-DayAdverseOutcomesTirofibanBetterAbciximabBetterDeath 0.401MI 0.827TVR 0.500Composite 0.45802.0Endpoint OddsRatio&95%CI P-Value1.06.53High-DoseBolusTirofibanvs.AbciximabN=1,392DawsonCBetal.AHA200660不同IIb/IIIa受體拮抗劑的比較既往由于缺乏相關(guān)循證依據(jù)以及應(yīng)用劑量的關(guān)系，認(rèn)為阿昔單抗優(yōu)于小分子IIb/IIIa受體拮抗劑，尤其在A(yíng)MI患者目前認(rèn)為三者之間臨床效果差別不大，阿昔單抗應(yīng)用于STEMI證據(jù)級(jí)別更強(qiáng)，而小分子IIb/IIIa受體拮抗劑用于non-STEMIACS證據(jù)級(jí)別更強(qiáng)阿昔單抗延長(zhǎng)應(yīng)用于A(yíng)CS保守治療策略時(shí)部分激活αIIbβ3受體，反而激活了血小板(GUSTOIV)61GPⅡb/Ⅲa受體拮抗劑在STEMI溶栓中的應(yīng)用GPⅡb/Ⅲa受體拮抗劑合用全劑量或半劑量溶栓劑再灌注率、梗死相關(guān)血管開(kāi)通率提高，但出血風(fēng)險(xiǎn)明顯增加，臨床凈效益不肯定，歐美指南均未給出推薦意見(jiàn)622010ESC:A