冠心病抗血小板治療的出血風險控制

抗血小板治療的出血風險控制課件抗血小板治療的出血風險控制課件抗血小板治療藥物的演變氯吡格雷噻氯匹定阿司匹林1988年FDA批準用于臨床的抗血小板藥物單用療效有限，增加劑量會增加出血危險

第一個噻吩吡啶類

1991年FDA批準嚴重不良反應：中性粒細胞減少、血栓性血小板減少性紫癜1998年FDA批準療效、安全性被廣泛證實*普拉格雷*替格瑞洛抗血小板治療藥物的演變氯吡格雷噻氯匹定阿司匹林1988年當代抗血小板藥物治療的發(fā)展：缺血與出血風險的平衡抗血小板藥物單藥治療雙聯(lián)抗血小板藥物更強的血小板聚集抑制劑Reductionin

IschemicEventsIncreasein

MajorBleedsAdaptedfromGibson,AHA2007當代抗血小板藥物治療的發(fā)展：缺血與出血風險的平衡抗血小板藥物氯吡格雷+ASA雙聯(lián)治療12個月，顯著降低NSTE-ACS患者缺血風險達20%安全性：波立維?組與安慰劑組危及生命的大出血無顯著差異。YusufS,ZhaoF,MehtaSR,etal.NEnglJMed.2001;345(7):494-502.氯吡格雷+ASA雙聯(lián)治療12個月，顯著降低NSTE-ACS患NSTE-ACS患者應用氯吡格雷+ASA安全性良好TheCUREtrialinvestigators.NEngJMed.2001;345(7):494-502.CURE研究表明，與安慰劑+ASA相比，氯吡格雷+ASA導致危及生命出血或出血導致死亡的發(fā)生率無明顯增加NSTE-ACS患者應用氯吡格雷+ASA安全性良好TheCTRITON-TIMI38研究：普拉格雷的總體療效與安全性WiviottSD,BraunwaldE,McCabeCH,etal.NEnglJMed.2007;357:2001-15.事件率(％)CV死亡/MI/卒中CV死亡非致死性MI非致死性卒中(P<0.001)(P=0.31)(P<0.001)(P=0.93)RRR=19%RRR=24%療效：普拉格雷顯著降低15個月CV死亡/MI/卒中風險(主要缺血終點)達19%；獲益主要源于非致死性MI的降低。TIMI大出血危及生命出血非致命性出血致命性出血顱內出血出血率(％)(P=0.002)(P=0.03)(P=0.01)(P=0.23)(P=0.74)RRI=319%RRI=32%RRI=52%氯吡格雷普拉格雷出血：普拉格雷顯著增加非CABG相關TIMI大出血風險(主要安全終點)達32%；包括危及生命、致命性出血等。（非CABG相關出血）TRITON-TIMI38研究：普拉格雷的總體療效與安全性替格瑞洛顯著降低ACS患者

心血管事件發(fā)生危險達16%PLATO研究中替格瑞洛組平均用藥時間277天，替格瑞洛顯著降低CV死亡、MI或卒中復合終點發(fā)生危險16%Daysafterrandomisation060120180240300360121110987654321013累積發(fā)生率(%)9.811.7HR0.84(95%CI0.77–0.92),p=0.0003ClopidogrelTicagrelor替格瑞洛顯著降低ACS患者

心血管事件發(fā)生危險達16%PLA然而，代價是非CABG相關的

大出血風險明顯升高。。。70K-Mestimatedrate(%peryear)98654321Non-CABG

PLATOmajor

bleeding4.53.8p=0.032.82.2p=0.037.47.9NS5.35.8NSTicagrelorClopidogrelNon-CABG

TIMImajor

bleedingCABG

PLATOmajorbleedingCABG

TIMImajorbleedingWallentinLetal.NewEnglJMed.2009;361:DOI:10.1056/NEJMoa0904327.然而，代價是非CABG相關的

大出血風險明顯升高。。。70K一旦出血，無論大小，都很麻煩一旦出血，無論大小，都很麻煩小出血臨床常見，顯著降低患者治療依從性ACS患者(n=396)成功置入支架，接受ASA+普拉格雷≥1個月1個月內普拉格雷總停藥率6%*滋擾性出血63%內出血33.3%令人驚恐的出血3.7%1個月內總體出血發(fā)生率13.6%采用Roy’s出血分類及定義：令人驚恐的出血：顱內出血、危及生命出血或需輸血。內出血：血腫、鼻衄、口腔出血、陰道出血、黑便、眼睛出血、血尿及嘔血。滋擾性出血：容易瘀傷、小切口出血、瘀點及瘀斑。小出血=滋擾性或內出血因滋擾性出血或內出血停藥其他原因停藥15.3%4%P=0.03*79%為患者自發(fā)停藥小出血臨床常見，顯著降低患者治療依從性ACS患者(n=396出血后過早停用抗血小板治療是影響臨床結局的重要因素32.4%發(fā)生院內出血，其中近1/10出院后停用任何抗血小板藥物：出院后停用抗血小板藥物顯著增加6個月死亡/MI/卒中風險(14.3%vs用藥者7.8%，P<0.0001)N=26,451，入選自PURSUIT,PARAGONA&B，SYNERGYPCI亞組分析：過早停用抗血小板治療對院內PCI患者長期預后更具危險性雙聯(lián)抗血小板治療顯著減少死亡等主要臨床終點事件AmHeartJ.2010;160:1056-1064.e2.出血后過早停用抗血小板治療32.4%發(fā)生院內出血，其中近1/logrankp-valueforallfourcategories<0.0001dbleeding=0.02log-rankp-valueformildvs.moderatebleeding<0.0001log-rankp-valueformoderatevs.severe<0.001出血風險與臨床不良預后密切相關RaoSV,etal.AmJCardiol.2005按不同出血危險分層，30天的Kaplan－Meier生存分析GUSTOIIb,PARAGONA,PARAGONB,和PURSUIT等研究，N=26,452ACS患者,logrankp-valueforallfour大出血0-1天

2-7天

8-30天

>31天0.512481632HR(95%CI)死亡P值<0.001<0.0010.0010.12<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.0016.7(3.1-14.7)8.1(4.6-14.1)6.4(3.7-10.9)3.1(2.1-4.5)71517315.5(2.7-11.0)5.8(3.5-9.7)5.6(3.5-8.8)2.4(1.7-3.3)918244217.6(10.8-28.7)8.2(5.0-13.6)2.9(1.6-5.3)1.4(0.9-2.1)21191225MI0-1天

2-7天

8-30天

>31天輸血0-1天

2-7天

8-30天

>31天HR(95%CI)ACUITY研究中，對于ACS患者遠期死亡的作用再發(fā)MI：隨時間而減弱，30天已無顯著性大出血和輸血：存在持續(xù)影響，1年時仍具顯著性對ACS患者遠期結局的持續(xù)影響大出血/輸血的影響更甚于缺血EurHeartJ.2009;30:1457-1466.大出血0-1天0.51如何評估出血風險？如何評估出血風險？出血評估的有效工具出臺

——

CRUSADE出血評分CRUSADE出血評分計算器（可從/index.html

獲得）Circulation2009;119;1873-1882出血評估的有效工具出臺

——C缺血高危因素與出血高危因素大多一致HectorBueno,FranciscoFernandez-Aviles.Heart2012;98:162-168ACS缺血風險主要預測因素ACS出血風險主要預測因素老年患者和腎功能不全等特殊人群臨床治療尤其應重視出血與缺血平衡缺血高危因素與出血高危因素大多一致HectorBueno,抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilostazol,vorapaxar,cangrelor)調整DAPT持續(xù)時間？減少APT劑量？圍PCI過程中，何種策略減少出血風險？消化道出血，加用PPI？抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cil抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilostazol,vorapaxar,cangrelor)調整DAPT持續(xù)時間？減少APT劑量？圍PCI過程中，何種策略減少出血風險？抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilCilostazolvsAsaparinCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.CilostazolvsAsaparinCochraneCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.CVEVENTS整理課件21CochraneDatabaseSystRev.

20IschaemicstrokeCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.IschaemicstrokeCochraneDatabHaemorrhagicstrokeCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.HaemorrhagicstrokeCochraneDaMICochraneDatabaseSystRev.

2011Jan19;(1):CD008076.MICochraneDatabaseSystRev.

VasculardeathCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.VasculardeathCochraneDatabasExtracranialhaemorrhageCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.ExtracranialhaemorrhageCochraGIbleedingCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.GIbleedingCochraneDatabaseSCilostazol+ASAvsASAAmericanHeartJournalJune2008Cilostazol+ASAvsASAAmericanRevascularizatinRevascularizatinRestenosisRestenosis抗血小板治療的出血風險控制課件ConclusionforcilostazolNOstrongevidenceforCilostazolinCHDStrongerthanASA,maybeequivalenttoTICLIDDecreasebleedingNeedmoredatetosupportitsuseinCHDanti-platelettherapyConclusionforcilostazolNOstVorapaxarprotease-activated–receptor1antagonistTwolargescaleRCTresultspublishedVorapaxarprotease-activated–reOriginalArticle

Thrombin-ReceptorAntagonistVorapaxarinAcuteCoronarySyndromes(NSTEACS)PierluigiTricoci,

M.D.,Ph.D.,ZhenHuang,

M.S.,ClaesHeld,

M.D.,Ph.D.,DavidJ.Moliterno,

M.D.,PaulW.Armstrong,

M.D.,FransVandeWerf,

M.D.,HarveyD.White,

D.Sc.,PhilipE.Aylward,

M.D.,LarsWallentin,

M.D.,Ph.D.,EdmondChen,

M.D.,YuliyaLokhnygina,

Ph.D.,JinglanPei,

M.S.,SergioLeonardi,

M.D.,TyrusL.Rorick,

R.N.,AnnM.Kilian,

B.S.,LisaH.K.Jennings,

Ph.D.,GiuseppeAmbrosio,

M.D.,Ph.D.,ChristophBode,

M.D.,AngelCequier,

M.D.,JanH.Cornel,

M.D.,RafaelDiaz,

M.D.,AycanErkan,

M.D.,Ph.D.,KurtHuber,

M.D.,MichaelP.Hudson,

M.D.,LixinJiang,

M.D.,J.WouterJukema,

M.D.,Ph.D.,BasilS.Lewis,

M.D.,A.MichaelLincoff,

M.D.,GillesMontalescot,

M.D.,JoséCarlosNicolau,

M.D.,Ph.D.,HisaoOgawa,

M.D.,MatthiasPfisterer,

M.D.,JuanCarlosPrieto,

M.D.,WitoldRuzyllo,

M.D.,PeterR.Sinnaeve,

M.D.,Ph.D.,RobertF.Storey,

M.D.,D.M.,MarcoValgimigli,

M.D.,Ph.D.,DavidJ.Whellan,

M.D.,PetrWidimsky,

M.D.,Dr.Sc.,JohnStrony,

M.D.,RobertA.Harrington,

M.D.,KennethW.Mahaffey,

M.D.,fortheTRACERInvestigatorsNEnglJMedVolume366(1):20-33January5,2012OriginalArticle

Thrombin-RecStudyOverviewInthistrial,vorapaxar,aprotease-activated–receptor1antagonistthatinhibitsthrombin-inducedplateletactivation,wasnoteffectiveinreducingtheprimarycardiovascularefficacyendpoint,anditincreasedratesofbleeding,includingseriousbleedingandintracranialhemorrhage.StudyOverviewInthistrial,vStudyEndPoints.TricociPetal.NEnglJMed2012;366:20-33Theprimaryefficacyendpointwasacompositeofdeathfromcardiovascularcauses,myocardialinfarction,stroke,recurrentischemiawithrehospitalization,orurgentcoronaryrevascularization.

Theprespecifiedkeysecondaryendpointwasacompositeofdeathfromcardiovascularcauses,myocardialinfarction,orstroke.

StudyEndPoints.TricociPetEfficacyEndPoints.EfficacyEndPoints.RiskofBleeding.TricociPetal.NEnglJMed2012;366:20-33RiskofBleeding.TricociPetBleedingEndPointsintheAs-TreatedPopulation.TricociPetal.NEnglJMed2012;366:20-33BleedingEndPointsintheAs-ConclusionsInpatientswithacutecoronarysyndromes(NSTEACS),theadditionofvorapaxartostandardtherapy(ASA+Thienopyridine)didnotsignificantlyreducetheprimarycompositeendpointbutsignificantlyincreasedtheriskofmajorbleeding,includingintracranialhemorrhage.ConclusionsInpatientswithac抗血小板治療的出血風險控制課件background26449patientsover3yearspriorMI,strokeorperipheralvasculardiseaserandomizationtovorapaxarorplaceboinadditiontoASAorASA+Thienopyridinebackground26449patientsover2BaselineCharacteristics2BaselineCharacteristicsCharacterizationofActualThienopyridineUseFromRandomizationCharacterizationofActualThiCardiovasculardeath,MI,orstrokestratifiedbyplannedthienopyridineuseCardiovasculardeath,MI,orsEfficacyendpointsstratifiedbyplannedthienopyridineuseEfficacyendpointsstratifiedBleedingEndPointsStratifiedbyPlannedThienopyridineUse

BleedingEndPointsStratifiedSafetyendpointstratifiedbyplannedthienopyridineuseSafetyendpointstratifiedbyNetClinicalOutcomeEndPointsStratifiedbyPlannedThienopyridineUseAmongPatientsWithaPreviousMIandNoHistoryofTIAorStrokeNetClinicalOutcomeEndPointapprovedbytheFDAandEMAforreducingischaemiceventsinpatientswithahistoryofMIthebenefitofvorapaxarinadditiontoaspirinandclopidogrelismodestandmustbecarefullyweighedagainsttheincreaseinbleedingeventsItsuseiscontraindicatedinpatientswithahistoryofcerebrovasculardisease.FDA&EMArecommendationapprovedbytheFDAandEMAfoCangrelorVol382December14,2013CVolIncludedstudies均聯(lián)合應用氯吡格雷+ASAIncludedstudies均聯(lián)合應用氯吡格雷+ASAEfficacyResultsEfficacyResultsVol382December14,2013Vol382DeceBleedingEventsVol382December14,2013BleedingEventswww.thelancet.cCangrelorreducedtheoddsofall-causedeath,myocardialinfarction,orischaemia-drivenrevascularisationnodifferenceintheprimarysafetyoutcome,inGUSTOmoderatebleedingincreasedGUSTOmildbleedingConclusionforCangrelorCangrelorreducedtheoddsof抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilostazol,vorapaxar,cangrelor)縮短DAPT持續(xù)時間？減少藥物劑量？圍PCI過程中，何種策略減少出血風險？合并常規(guī)抗凝藥物（房顫），如何處理？抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cil3months3months出血事件沒有差別！！！！！！出血事件沒有差別！！！！！！6monthsCirculationJanuary24,20126monthsCirculationJanuary241yearfollow-up，nodifferenceinbleeding1yearfollow-up，nodifference抗血小板治療的出血風險控制課件Stillnodifferenceinbleedingfor1yearStillnodifferenceinbleedin1month1monthDurationofDAPTfor1monthDurationofDAPTfor1monthConclusionforshorteningDAPTDurationLogicallyreasonableNodirectevidenceyetESC2015NSTEACSguidelineEvidence？？ConclusionforshorteningDAPTLoweringAPTdose？LoweringAPTdose？50mgvs75mgclopidogrel50mgvs75mgclopidogrel50mgvs75mgclopidogrelBecauseofsmallsamplesize,nodifferenceinbleeding50mgvs75mgclopidogrelBecausTicagrelor60mgbidVS90mgbidTicagrelor60mgbidVS90mgbiPEGASUSStudyPEGASUSStudy60mgvs90mg，略有減少？僅有3年的數(shù)據(jù)結果，更短時間是否有差異呢？60mgvs90mg，略有減少？僅有3年的數(shù)據(jù)結果，更短ConclusionforloweringdosesLowerdosesmaydecreasebleedingNeedmoredatatosupporttheefficacyandsafetyConclusionforloweringdosesL抗血小板治療時，如何減少出血風險？其它抗血小板藥物？調整DAPT持續(xù)時間？降低藥物劑量？圍PCI過程中，何種策略減少出血風險？(radialaccess,bivaludin，fondaparinux)抗血小板治療時，如何減少出血風險？其它抗血小板藥物？MATRIX

Co-primarycomposite

outcomesat30daysN=8404NSTE-ACS+STEMIRadialvs.femoralValgimigliMetal.Lancet.2015;385:2465-76All-causemortality,MI,strokeAll-causemortality,MI,stroke,orBARC3or5bleeding整理課件75MATRIX

Co-primarycomposite

ouRadialvsfemoralmeta-analysisNon-CABGmajorbleeedsDeath,MI,orstrokeDeathMIStrokePRR(95%CI)ValgimigliMetal.Lancet.2015;385:2465-76N>19000Radialvsfemoralmeta-analysiRadialapproach2015ESCNSTEACSGuidelineItisrecommendedthatcentrestreatingACSpatientsimplementatransitionfromtransfemoraltotransradialaccess.Proficiencyinthefemoralapproachshouldbemaintained(e.g.forIABPinsertionandstructuralaswellasperipheralprocedures)整理課件77Radialapproach2015ESCNSTEA比伐盧定的優(yōu)勢20個氨基酸的肽類藥物，凝血酶的直接抑制劑與凝血酶的結合過程可控可逆血濃度與APTT、PT和ACT正相關（r分別為0.77、0.73和0.8）不需要抗凝血酶Ⅲ（AT-Ⅲ）作為輔助因子，量效關系更吻合對血栓中和循環(huán)中的凝血酶的抑制作用幾乎相同不受激活血小板的影響不減少血小板比伐盧定的優(yōu)勢20個氨基酸的肽類藥物，凝血酶的直接抑制劑比伐盧定Vs肝素ACUITY試驗-JAMA2007REPLACE-2試驗-TCT2008ISAR-REACT-4試驗-AHA2011EUROMAX試驗-NEJM2013HORIZONSAMI試驗-NEJM2006，TCT2008比伐盧定Vs肝素ACUITY試驗-JAMA2007Diff=0.0%[-1.6,1.5]

RR=0.99[0.76,1.30]

Psup=0.95Diff=-3.3%[-5.0,-1.6]

RR=0.60[0.46,0.77]PNI≤0.0001Psup≤0.0001Diff=-2.9%[-4.9,-0.8]RR=0.76[0.63,0.92]

PNI≤0.0001Psup=0.0051endpoint1endpointMajor2endpointStoneGWetal.NEJM2008;358:2218-30HORIZONSAMI試驗3,602發(fā)病≤12小時的STEMI患者

3006例作支架分組治療，30天臨床結果Diff=0.0%[-1.6,1.5]Diff=HORIZONSAMI試驗3,602發(fā)病≤12小時的STEMI患者

3006例作支架分組治療，1年隨訪結果1年凈臨床不良事件TCT2008HORIZONSAMI試驗3,602發(fā)病≤12HORIZONSAMI試驗3,602發(fā)病≤12小時的STEMI患者

3006例作支架分組治療，1年隨訪結果TCT2008HORIZONSAMI試驗3,602發(fā)病≤12HORIZONSAMI試驗3,602發(fā)病≤12小時的STEMI患者

3006例作支架分組治療，3年隨訪結果TheLancet,Volume377,Issue9784,2011,2193-2204MajorbleedingCardiacmortalityReinfarctionStentthrombosisHORIZONSAMI試驗3,602發(fā)病≤12AHA2013STEMIguidelineAHA2013STEMIguidelineBivalirudinseemstobeperfect!

HoweverBivalirudinseemstobeperfec

HEAT-PPCI

(UnfractionatedHeparinversusBivalirudininPrimaryPCI)研究---開放、單中心、隨機對照AdeelShahzad，ACC2014英國利物浦心胸醫(yī)院，14名介入醫(yī)生參加，歷時22個月1812例STEMI患者隨機分組比伐盧定組905例患者，751例(83%)造影后行介入治療；肝素組907例患者，740例(82%)行介入治療兩組GPIIb/IIIa抑制劑應用率相似，約13%30天臨床終點Lancet.2014Jul4.pii:S0140-6736(14)60924-7.HEAT-PPCI(UnfractionatedHepHEAT-PPCI30天臨床終點OutcomeBivalirudin(%)Heparin(%)RR(95%CI)pMACE2(1.1–2.1)0.01Definiteorprobablestentthrombosis1(1.6–9.5)0.001Majorbleeding3.53.1—NSHEAT-PPCI30天臨床終點Bivalirudin(對HEAT-PPCI的批評單中心入選速度（22個月近2000例患者）肝素用量（70U/kg)ACT偏低（H-236，B-270)入選患者低危再梗的判斷標準研究設計---知情簽署晚-倫理？橈動脈途徑比例高與出血低有關對HEAT-PPCI的批評單中心NAPLESIII研究830例高出血風險（危險積分≥10）擇期股動脈途徑PCI患者比伐盧定VsUFH主要終點：院內出血主要結果：按不同出血標準，兩組均無差異NAPLESIII研究830例高出血風險（危險積分≥10TCT2014

TCT2014BRIGHT研究StentThrombosisat30DaysEventBivalirudin(n=735),n(%)Heparin(n=729),n(%)Heparin+tirofiban,n(%)pAlldefinite/probablestentthrombosis4(0.6)6(0.9)5(0.7)0.77Acute(<24h)2(0.3)2(0.3)2(0.3)1.00Subacute(1–30d)2(0.3)4(0.6)3(0.4)0.66BRIGHT研究StentThrombosisat30AHA2014NSTE-ACSguidelineAHA2014NSTE-ACSguidelineRecommendationsforanticoagulationinNSTE-ACSRecommendationsClassLOEParenteralanticoagulationisrecommendedatthetimeofdiagnosisaccordingtobothischaemicandbleedingrisks.IBFondaparinux(2.5mgs.c.daily)isrecommendedashavingthemostfavourableefficacy–safetyprofileregardlessofthemanagementstrategy.IBBivalirudin(0.75mg/kgi.v.bolus,followedby1.75mg/kg/hourforupto4hoursaftertheprocedure)isrecommendedasalternativetoUFHplusGPIIb/IIIainhibitorsduringPCI.IAUFH70–100IU/kgi.v.(50–70IU/kgifconcomitantwithGPIIb/IIIainhibitors)isrecommendedinpatientsundergoingPCIwhodidnotreceiveanyanticoagulant.IBInpatientsonfondaparinux(2.5mgs.c.daily.)undergoingPCI,asinglei.v.bolusofUFH(70–85IU/kg,or50–60IU/kginthecaseofconcomitantuseofGPIIb/IIIainhibitors)isrecommendedduringtheprocedure.IBEnoxaparin(1mg/kgs.c.twicedaily)orUFHarerecommendedwhenfondaparinuxisnotavailable.IBCrossoverbetweenUFHandLMWHisnotrecommended.IIIBInNSTEMIpatientswithnopriorstroke/TIAandathighischaemicriskaswellaslowbleedingriskreceivingaspirinandclopidogrel,low-doserivaroxaban(2.5mgtwicedailyforapproximatelyoneyear)maybeconsideredafterdiscontinuationofparenteralanticoagulation.IIbBESC2015NSTE-ACSguideline整理課件93RecommendationsforanticoagulFondaparinux整理課件94Fondaparinux整理課件94ComparisonofFondaparinuxandEnoxaparininAcuteCoronarySyndromes（NSTEACS）TheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMedVolume354;14:1464-1476April6,2006ComparisonofFondaparinuxandCumulativeRisksofDeath,MyocardialInfarction,orRefractoryIschemia(PanelA)andofMajorBleeding(PanelB)throughDay9TheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMed2006;354:1464-1476CumulativeRisksofDeath,MyoMainEfficacyandSafetyOutcomesTheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMed2006;354:1464-1476MainEfficacyandSafetyOutcoCumulativeRisksofDeath(PanelA)andofDeath,MyocardialInfarction,orStroke(PanelB)throughDay180TheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMed2006;354:1464-1476CumulativeRisksofDeath(PanResultsofSubgroupAnalysesofEfficacy(theCompositeofDeath,MyocardialInfarction,orRefractoryIschemia)(PanelA)andSafety(MajorBleeding)(PanelB)atNineDaysTheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMed2006;354:1464-1476ResultsofSubgroupAnalysesoTreatments,Complications,andOutcomesamongPatientsUndergoingPercutaneousCoronaryIntervention(PCI)withintheFirstEightDaysafterRandomizationTheFifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigatorsNEnglJMed2006;354:1464-1476Treatments,Complications,andConclusionFondaparinuxissimilartoenoxaparininreducingtheriskofischemiceventsatninedays,butitsubstantiallyreducesmajorbleedingandimproveslongtermmortalityandmorbidityConclusionFondaparinuxissimiRecommendationsforanticoagulationinNSTE-ACSRecommendationsClassLOEParenteralanticoagulationisrecommendedatthetimeofdiagnosisaccordingtobothischaemicandbleedingrisks.IBFondaparinux

(2.5mgs.c.daily)isrecommendedashavingthemostfavourableefficacy–safetyprofileregardlessofthemanagementstrategy.IBBivalirudin

(0.75mg/kgi.v.bolus,followedby1.75mg/kg/hourforupto4hoursaftertheprocedure)isrecommendedasalternativetoUFHplusGPIIb/IIIainhibitorsduringPCI.IAUFH70–100IU/kgi.v.(50–70IU/kgifconcomitantwithGPIIb/IIIainhibitors)isrecommendedinpatientsundergoingPCIwhodidnotreceiveanyanticoagulant.IBInpatientsonfondaparinux(2.5mgs.c.daily.)undergoingPCI,asinglei.v.bolusofUFH(70–85IU/kg,or50–60IU/kginthecaseofconcomitantuseofGPIIb/IIIainhibitors)isrecommendedduringtheprocedure.IBEnoxaparin(1mg/kgs.c.twicedaily)orUFHarerecommendedwhenfondaparinuxisnotavailable.IBCrossoverbetweenUFHandLMWHisnotrecommended.IIIBInNSTEMIpatientswithnopriorstroke/TIAandathighischaemicriskaswellaslowbleedingriskreceivingaspirinandclopidogrel,low-doserivaroxaban(2.5mgtwicedailyforapproximatelyoneyear)maybeconsideredafterdiscontinuationofparenteralanticoagulation.IIbBESC2015NSTE-ACSguideline整理課件102Recommendationsforanticoagul整理課件103整理課件103EffectsofFondaparinuxonMortalityandReinfarctioninPatientsWithAcuteST-SegmentElevationMyocardialInfarction:

TheOASIS-6RandomizedTrialEffectsofFondaparinuxonMorHoweverHowever2012ESCSTEMIGuideline2012ESCSTEMIGuidelineApproachduringperi-procedureBivaludindecreasesbleedingRadialaccessisprefferedFondaparinuxsuitableinNSTEACS，notSTEMI！！Approachduringperi-procedureBleedingriskevaluation！！！Radialaccess+bivaludinworks！！！！！MoredataneededfornewAPTtherapyShorteningDAPTdurationmayworks？？？Patient-centeredindividualizedstrategy！！！Take-homemessagesBleedingriskevaluation！！！Tak謝謝謝謝冠心病抗血小板治療的出血風險控制

抗血小板治療的出血風險控制課件抗血小板治療的出血風險控制課件抗血小板治療藥物的演變氯吡格雷噻氯匹定阿司匹林1988年FDA批準用于臨床的抗血小板藥物單用療效有限，增加劑量會增加出血危險

第一個噻吩吡啶類

1991年FDA批準嚴重不良反應：中性粒細胞減少、血栓性血小板減少性紫癜1998年FDA批準療效、安全性被廣泛證實*普拉格雷*替格瑞洛抗血小板治療藥物的演變氯吡格雷噻氯匹定阿司匹林1988年當代抗血小板藥物治療的發(fā)展：缺血與出血風險的平衡抗血小板藥物單藥治療雙聯(lián)抗血小板藥物更強的血小板聚集抑制劑Reductionin

IschemicEventsIncreasein

MajorBleedsAdaptedfromGibson,AHA2007當代抗血小板藥物治療的發(fā)展：缺血與出血風險的平衡抗血小板藥物氯吡格雷+ASA雙聯(lián)治療12個月，顯著降低NSTE-ACS患者缺血風險達20%安全性：波立維?組與安慰劑組危及生命的大出血無顯著差異。YusufS,ZhaoF,MehtaSR,etal.NEnglJMed.2001;345(7):494-502.氯吡格雷+ASA雙聯(lián)治療12個月，顯著降低NSTE-ACS患NSTE-ACS患者應用氯吡格雷+ASA安全性良好TheCUREtrialinvestigators.NEngJMed.2001;345(7):494-502.CURE研究表明，與安慰劑+ASA相比，氯吡格雷+ASA導致危及生命出血或出血導致死亡的發(fā)生率無明顯增加NSTE-ACS患者應用氯吡格雷+ASA安全性良好TheCTRITON-TIMI38研究：普拉格雷的總體療效與安全性WiviottSD,BraunwaldE,McCabeCH,etal.NEnglJMed.2007;357:2001-15.事件率(％)CV死亡/MI/卒中CV死亡非致死性MI非致死性卒中(P<0.001)(P=0.31)(P<0.001)(P=0.93)RRR=19%RRR=24%療效：普拉格雷顯著降低15個月CV死亡/MI/卒中風險(主要缺血終點)達19%；獲益主要源于非致死性MI的降低。TIMI大出血危及生命出血非致命性出血致命性出血顱內出血出血率(％)(P=0.002)(P=0.03)(P=0.01)(P=0.23)(P=0.74)RRI=319%RRI=32%RRI=52%氯吡格雷普拉格雷出血：普拉格雷顯著增加非CABG相關TIMI大出血風險(主要安全終點)達32%；包括危及生命、致命性出血等。（非CABG相關出血）TRITON-TIMI38研究：普拉格雷的總體療效與安全性替格瑞洛顯著降低ACS患者

心血管事件發(fā)生危險達16%PLATO研究中替格瑞洛組平均用藥時間277天，替格瑞洛顯著降低CV死亡、MI或卒中復合終點發(fā)生危險16%Daysafterrandomisation060120180240300360121110987654321013累積發(fā)生率(%)9.811.7HR0.84(95%CI0.77–0.92),p=0.0003ClopidogrelTicagrelor替格瑞洛顯著降低ACS患者

心血管事件發(fā)生危險達16%PLA然而，代價是非CABG相關的

大出血風險明顯升高。。。70K-Mestimatedrate(%peryear)98654321Non-CABG

PLATOmajor

bleeding4.53.8p=0.032.82.2p=0.037.47.9NS5.35.8NSTicagrelorClopidogrelNon-CABG

TIMImajor

bleedingCABG

PLATOmajorbleedingCABG

TIMImajorbleedingWallentinLetal.NewEnglJMed.2009;361:DOI:10.1056/NEJMoa0904327.然而，代價是非CABG相關的

大出血風險明顯升高。。。70K一旦出血，無論大小，都很麻煩一旦出血，無論大小，都很麻煩小出血臨床常見，顯著降低患者治療依從性ACS患者(n=396)成功置入支架，接受ASA+普拉格雷≥1個月1個月內普拉格雷總停藥率6%*滋擾性出血63%內出血33.3%令人驚恐的出血3.7%1個月內總體出血發(fā)生率13.6%采用Roy’s出血分類及定義：令人驚恐的出血：顱內出血、危及生命出血或需輸血。內出血：血腫、鼻衄、口腔出血、陰道出血、黑便、眼睛出血、血尿及嘔血。滋擾性出血：容易瘀傷、小切口出血、瘀點及瘀斑。小出血=滋擾性或內出血因滋擾性出血或內出血停藥其他原因停藥15.3%4%P=0.03*79%為患者自發(fā)停藥小出血臨床常見，顯著降低患者治療依從性ACS患者(n=396出血后過早停用抗血小板治療是影響臨床結局的重要因素32.4%發(fā)生院內出血，其中近1/10出院后停用任何抗血小板藥物：出院后停用抗血小板藥物顯著增加6個月死亡/MI/卒中風險(14.3%vs用藥者7.8%，P<0.0001)N=26,451，入選自PURSUIT,PARAGONA&B，SYNERGYPCI亞組分析：過早停用抗血小板治療對院內PCI患者長期預后更具危險性雙聯(lián)抗血小板治療顯著減少死亡等主要臨床終點事件AmHeartJ.2010;160:1056-1064.e2.出血后過早停用抗血小板治療32.4%發(fā)生院內出血，其中近1/logrankp-valueforallfourcategories<0.0001dbleeding=0.02log-rankp-valueformildvs.moderatebleeding<0.0001log-rankp-valueformoderatevs.severe<0.001出血風險與臨床不良預后密切相關RaoSV,etal.AmJCardiol.2005按不同出血危險分層，30天的Kaplan－Meier生存分析GUSTOIIb,PARAGONA,PARAGONB,和PURSUIT等研究，N=26,452ACS患者,logrankp-valueforallfour大出血0-1天

2-7天

8-30天

>31天0.512481632HR(95%CI)死亡P值<0.001<0.0010.0010.12<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.0016.7(3.1-14.7)8.1(4.6-14.1)6.4(3.7-10.9)3.1(2.1-4.5)71517315.5(2.7-11.0)5.8(3.5-9.7)5.6(3.5-8.8)2.4(1.7-3.3)918244217.6(10.8-28.7)8.2(5.0-13.6)2.9(1.6-5.3)1.4(0.9-2.1)21191225MI0-1天

2-7天

8-30天

>31天輸血0-1天

2-7天

8-30天

>31天HR(95%CI)ACUITY研究中，對于ACS患者遠期死亡的作用再發(fā)MI：隨時間而減弱，30天已無顯著性大出血和輸血：存在持續(xù)影響，1年時仍具顯著性對ACS患者遠期結局的持續(xù)影響大出血/輸血的影響更甚于缺血EurHeartJ.2009;30:1457-1466.大出血0-1天0.51如何評估出血風險？如何評估出血風險？出血評估的有效工具出臺

——

CRUSADE出血評分CRUSADE出血評分計算器（可從/index.html

獲得）Circulation2009;119;1873-1882出血評估的有效工具出臺

——C缺血高危因素與出血高危因素大多一致HectorBueno,FranciscoFernandez-Aviles.Heart2012;98:162-168ACS缺血風險主要預測因素ACS出血風險主要預測因素老年患者和腎功能不全等特殊人群臨床治療尤其應重視出血與缺血平衡缺血高危因素與出血高危因素大多一致HectorBueno,抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilostazol,vorapaxar,cangrelor)調整DAPT持續(xù)時間？減少APT劑量？圍PCI過程中，何種策略減少出血風險？消化道出血，加用PPI？抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cil抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilostazol,vorapaxar,cangrelor)調整DAPT持續(xù)時間？減少APT劑量？圍PCI過程中，何種策略減少出血風險？抗血小板治療時，如何減少出血風險？其它抗血小板藥物？(cilCilostazolvsAsaparinCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.CilostazolvsAsaparinCochraneCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.CVEVENTS整理課件130CochraneDatabaseSystRev.

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2011Jan19;(1):CD008076.VasculardeathCochraneDatabasExtracranialhaemorrhageCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.ExtracranialhaemorrhageCochraGIbleedingCochraneDatabaseSystRev.

2011Jan19;(1):CD008076.GIbleedingCochraneDatabaseSCilostazol+ASAvsASAAmericanHeartJournalJune2008Cilostazol+ASAvsASAAmericanRevascularizatinRevascularizatinRestenosisRestenosis抗血小板治療的出血風險控制課件ConclusionforcilostazolNOstrongevidenceforCilostazolinCHDStrongerthanASA,maybeequivalenttoTICLIDDecreasebleedingNeedmoredatetosupportitsuseinCHDanti-platelettherapyConclusionforcilostazolNOstVorapaxarprotease-activated–receptor1antagonistTwolargescaleRCTresultspublishedVorapaxarprotease-activated–reOriginalArticle

Thrombin-ReceptorAntagonistVorapaxarinAcuteCoronarySyndromes(NSTEACS)PierluigiTricoci,

M.D.,Ph.D.,ZhenHuang,

M.S.,ClaesHeld,

M.D.,Ph.D.,DavidJ.Moliterno,

M.D.,PaulW.Armstrong,

M.D.,FransVandeWerf,

M.D.,HarveyD.White,

D.Sc.,PhilipE.Aylward,

M.D.,LarsWallentin,

M.D.,Ph.D.,EdmondChen,

M.D.,YuliyaLokhnygina,

Ph.D.,JinglanPei,

M.S.,SergioLeonardi,

M.D.,TyrusL.Rorick,

R.N.,AnnM.Kilian,

B.S.,LisaH.K.Jennings,

Ph.D.,GiuseppeAmbrosio,

M.D.,Ph.D.,ChristophBode,

M.D.,AngelCequier,

M.D.,JanH.Cornel,

M.D.,RafaelDiaz,

M.D.,AycanErkan,

M.D.,Ph.D.,KurtHuber,

M.D.,MichaelP.Hudson,

M.D.,LixinJiang,

M.D.,J.WouterJukema,

M.D.,Ph.D.,BasilS.Lewis,

M.D.,A.MichaelLincoff,

M.D.,GillesMontalescot,

M.D.,JoséCarlosNicolau,

M.D.,Ph.D.,HisaoOgawa,

M.D.,MatthiasPf