急性心肌梗塞的溶栓治疗

CombinationLyticTherapyin

AcuteMyocardialInfarctionC.MichaelGibson,M.D.第一页，共四十页。PathophysiologyofCombinationTherapyinAMI*Gibsonetal.JAmCollCardiol.1995;25:582-589.Gibsonetal.Circulation.2001;103:2550-2554.CombinationTherapyThrombus%StenosisMinimumDiameterEpicardialFlowMyocardialBlushSTResolutionMyocardialFlowFacilitatesPCIReduces

Reinfarction*第二页，共四十页。RecentClinicalTrialsUnfractionatedheparinEnoxaparinUnfractionatedheparinEnoxaparinAbciximabAbciximabNoneNoneENTIREACC/AHAheparindoseLow-doseheparinEnoxaparinNoneAbciximabNoneASSENT-3Standard-doseheparinLow-doseheparinNoneAbciximab 50%TNK-tPA 50%TNK-tPA 100%TNK-tPA 100%TNK-tPA 100%TNK-tPA 50%TNK-tPA 100%TNK-tPA 100%r-PA 50%r-PAGUSTO-VAnticoagulantGPIIb/IIIaReceptorInhibitorLyticTrial第三页，共四十页。ClinicalTrials:OngoingLow-doseheparinLow-doseheparinLow-doseheparinEptifibatideEptifibatideEptifibatide 50%TNK-tPA 75%TNK-tPA 100%TNK-tPAINTEGRITILow-doseheparinLow-doseheparinLow-doseheparinTirofibanTirofibanTirofiban 50%TNK-tPA 75%TNK-tPA 100%TNK-tPAFASTERAnticoagulantGPIIb/IIIaReceptorInhibitorLyticTrial第四页，共四十页。54%32%GUSTO-I:A20%IncreaseinTIMIGrade3FlowisNeededtoYielda1%MortalityReductionTheGUSTOAngiographicInvestigators.NEnglJMed.1993;329:1615-1622.03050604020%TIMIGrade3Flowt-PASK10t-PA57.4%6.3%SK876第五页，共四十页。TIMIGrade3Flow–PooledDataFromDoseConfirmationPhasesofRecentTrials040801006020%PatientsWithTIMIGrade3FlowGUSTO-I90minT14t-PA90minT14r-PA90minSPEED60-90minINTRO-AMI60minPooled60-90min547370474056787354566429263879881329588810075321LyticaloneCombination第六页，共四十页。SPEED:ResultsofDose-ConfirmationPhaseTherewasa7.4%improvementintherateofTIMIGrade3flowIfa20%improvement

isrequiredtoimprovemortalityby1%,thena7.4%improvementwouldbepredictedtoimprovemortalityby0.3%TheSPEEDStudyGroup.Circulation.2000;101:2788-2794.04080100r-PA10+10Ur-PA5+5U+Abx6020Patency(%)TIMI-2TIMI-3n=109n=11521.654.947.528.7第七页，共四十页。GUSTO-V:StudyDesignTheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.ST,lyticeligible,<6h(n=16,588)ASANoAbciximab2x10Ubolus(30’)Full-doser-PAAbciximabLow-doseHeparin:60U/kgbolusfollowedby

7U/kg/hinfusion1ºendpoint:mortalityat30days2ºendpoint:clinicalandsafetyeventsat30days2x5Ubolus(30’)Half-doser-PAStandardHeparin:5000Ubolusfollowedby

800U/h(<80kg)or

1000U/h(80kg)infusion第八页，共四十页。PrimaryEndPoint:30-DayMortalityTheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.0%MortalityDays051015202530P=.43forsuperiorityNon-InferiorityRR0.95(95%CI,0.84-1.08)Std.Reteplase(n=8260)Abx+DoseReteplase(n=8328)4625.9%5.6%第九页，共四十页。GUSTO-V:NoninferiorityAnalysisAdaptedwithpermissionfromtheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.Non-InferiorityRR0.95

(95%CI,0.84-1.08)1.11ORand95%CI0.02.01.0Abciximab+

Half-doser-PAsuperiorFull-doser-PA

superiorUpperBoundaryof95%CIforNoninferiority第十页，共四十页。AComparisonoftheOutcomesWithr-PAMonotherapyinGUSTO-IIIvsGUSTO-VTrialsTheGUSTO-IIIInvestigators.NEnglJMed.1997;337:1118-1123.TheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.037851264GUSTOIIIGUSTOV7.4%5.9%10,1388,260DeathP<.00104050203010GUSTOIIIGUSTOV48%37%10,1388,260AnteriorMI0GUSTOIIIGUSTOV0.91%0.59%10,1388,260ICHP=.0150.1第十一页，共四十页。2.3GUSTO-V:CausesofReinfarction*Unblinded,unadjudicatedTheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.01342MyocardialInfarction(%)AnyQ-waveEnzymaticIschemicSTChange*2.7r-PAr-PA+AbxP<.0001第十二页，共四十页。Non-IntracranialBleedingThroughDischarge/Day7TheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.0%ofPatients15253020r-PAr-PA+Abx10SevereBleedingModerateBleedingMildBleedingAnyBleedingReceivingTransfusions3.511.420.013.724.64.05.7第十三页，共四十页。ICHbyAgeGroup*Significanttreatmentinteractionfortheage75dichotomy;P=.033.TheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.0132%ofPatients70yrs>70yrs75yrs>75yrs2.1r-PA(n=8260)r-PA+Abx(n=8328)0.3P=.66P=.53P=.27*P=.069*12/108824/114928/717937/717225/203031/213521/619324/6230第十四页，共四十页。****GUSTO-V:PCIWithin6Hours(Urgent)

andThroughDay7*P<.0001.TheGUSTO-VInvestigators.Lancet.2001;357:1905-1914.5.625.427.98.601525302010PCI(%)UrgentThroughDay75r-PAr-PA+Abx第十五页，共四十页。2.89.05.4GUSTO-V:EventRatesinThoseRequiringUrgentPCIHeartwireNews.September2,2001.GUSTO-V:Combinationhalf-dosefibrinolyticplusIIb/IIIablocker.AnAlternativeapproachtoMI?0410128MyocardialInfarction(%)r-PAr-PA+Abxn=1173DeathRepeatMIDeathPlusRepeatMI26第十六页，共四十页。GUSTO-V:ConclusionsComparedwithr-PAmonotherapy,combinationtherapywith

r-PAandabciximabresultedinAmortalityratethatwasnotinferiortor-PAmonotherapyFewernonfatalreinfarctions(primarilyareducedincidence

ofrecurrentSTelevation)AlowerrateofurgentrevascularizationMorenoncerebralbleedingcomplications,transfusions,

andthrombocytopeniaAhigherrateofICHinelderlypatientsovertheageof

75years第十七页，共四十页。ASSENT-3:RationaleforUseofEnoxaparinTNK-tPAplusenoxaparinFavorableeffectsofLMWHsinrecentsmall-scale

thrombolysistrialsHigherlatepatency: HART-2

ASSENT-Plus

AMI-SKLessreocclusion: HART-2Fewerreinfarctions: ASSENT-Plus

AMI-SK

Wilson,etal.ASSENT-3isthefirstlarge-scaletrialtotestLMWH第十八页，共四十页。ASSENT-3:StudyDesignST-SegmentElevationAMI(n=6095patients)150to325mgASA(daily)RandomizedFull-doseTNK-tPA

PlusEnoxaparin

Half-doseTNK-tPA

PlusAbciximab

PlusLow-doseHeparinFull-doseTNK-tPA

PlusWeight-

adjustedUFHTheASSENT-3Investigators.Lancet.2001;358:605-613.第十九页，共四十页。ASSENT-3:PrimaryEndPointsPrimaryEfficacyEndPoint:Compositeof30-daymortalityor

in-hospitalreinfarctionorin-hospitalrefractoryischemia.PrimaryEfficacyPlusSafetyEndPoint:Compositeof30-daymortalityorin-hospitalreinfarctionorin-hospitalrefractoryischemiaplusin-hospitalintracranialhaemorrhageorin-hospitalmajorbleedingotherthanintracranial.第二十页，共四十页。ASSENT-3:30-DayMortality,RecurrentMI,

RefractoryIschemia05101520%Riskof30-DayD/MI/RefIschTNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH*P-valuesaretheBonferroniP-valuesaftercorrectingformultiplecomparisons.TheuncorrectedP-valueswereP=.0002fortheenoxvsUFHcomparison,andP<.0001fortheabxvsUFHcomparison.11.411.115.43-wayP=.0001P=.0002*P=.0009*第二十一页，共四十页。ASSENT-3:30-DayMortality,RecurrentMI,

RefractoryIschemia,MajorBleedingandICH%Riskof30-DayD/MI/

RefIsch/MajBleed/ICH*P-valuesaretheBonferroniP-valuesaftercorrectingformultiplecomparisons.TheuncorrectedP-valueswereP=.0037fortheenoxvsUFHcomparison,andP=.0142fortheabxvsUFHcomparison.05101520TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.814.217.03-wayP=.0062P=.0057*P=.0146*第二十二页，共四十页。Kaplan-MeierCurvesUFHAbx*51015202530024681012141620180Enox*log-rankP=.0001*vsUFHDaystodeath,reinfarction,or

refractoryischemiaPrimaryEfficacyEndPointProbability(%)ReprintedwithpermissionfromtheASSENT-3Investigators.Lancet.2001;358:605-613.51015202530024681012141620180log-rankP=.0062*vsUFH+AbxDaystodeath,reinfarction,refractory

ischemia,ICH,ormajorbleedingPrimaryEfficacyPlus

SafetyEndPointProbability(%)UFHAbxEnox*第二十三页，共四十页。ASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatients>75YearsofAge*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabandagesuchthatpatientsovertheageof75hadpooreroutcomeswithabciximab(P=.001).%Riskof30-DayEfficacy

andSafetyEndPoint015253545TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH25.536.928.0P=.001*520304010第二十四页，共四十页。ASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatientswithDiabetes*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabanddiabetes,suchthatdiabeticshadpooreroutcomeswithabciximabtherapy(P=.0007).%Riskof30-DayEfficacy

andSafetyEndPoint0152530TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.922.316.5P=.007*52010第二十五页，共四十页。ASSENT-3:30-DayMortality04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.2562%Riskof30-DayMortality第二十六页，共四十页。ASSENT-3:30-DayDeathorMI%Riskof30-DayDeathorMI04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.019862第二十七页，共四十页。ASSENT-3:In-HospitalRecurrentMI%RiskofIn-Hospital

RecurrentMI0245TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.000931第二十八页，共四十页。ASSENT-3:In-HospitalRefractoryIschemia%Riskof30-Day

RefractoryIschemia04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP<.000162第二十九页，共四十页。ASSENT-3:IncidenceofIn-HospitalThrombocytopeniaandNoncerebralBleedingComplications*While3-wayP-valueissignificant,EnoxvsUFHcomparisonP=NS Enox Abx UFH P-Value

(n=2040) (n=2017) (n=2038) 3-wayAnythrombocytopenia 1.2 3.2 1.3 <.0001Thrombocytopenia <.0001

<20,000cells/µL 0.1 0.5 0.2

20,000to50,000cells/µL 0.2 0.6 0.2

50,000to<100,000cells/µL 0.9 2.0 1.0Bleedingepisodes

Total 25.6* 39.7 21.1 <.0001

Major 3.0* 4.3 2.2 .0005

Minor 22.6* 35.4 18.8 <.0001Bloodtransfusion 3.4* 4.2 2.3 .0032第三十页，共四十页。ASSENT-3:In-HospitalStrokeRates*IncludinghemorrhagicconversionUnclassifiedHemorrhagicconversionIschemicstroke*IntracranialhemorrhageTotalstrokes70.070.400.640.940.881.491.62Abx

(n=2017)Enox

(n=2040)0.590.050.770.000.570.540.980.930.941.52P-ValueUFH

(n=2038)第三十一页，共四十页。PatientsUndergoingPCI:MortalityASSENT-3:In-HospitalPCIGUSTO-V:UrgentPCI057863Mortality(%)45.46.7TNK-tPA+

EnoxTNK-tPA+

AbxTNK-tPA+

UFHr-PA+

UFHr-PA+

Abx第三十二页，共四十页。HowDoesActualWeightCompareto

EstimatedWeight?ReprintedwithpermissionfromCannonCP,etal.JAmCollCardiol.2001;37:323A.CorrelationBetweenEstimatedandActualPatientWeightinTIMI10B40.536.4188.5ActualPatientWeight(kg)EstimatedPatientWeight(kg)R2=0.93,P<.0001181第三十三页，共四十页。Weight-BasedDosingofThrombolysis:HowWellDoWeEstimateWeight?HowOftenWouldThisTranslateIntoErrorsWithAdministrationofThrombolyticDrugsandAdverseOutcomes?Errorsinestimatingweightareuncommon,especially

thosethatwouldleadtoadosechange(1.3%or49/3730

forTNK-tPAand4.5%or13/290fort-PA).Noadverseoutcomeswereseenamongpatientswho

receivedanincorrectdose,suggestingabroadsafety

profileforthenewsingle-bolusagentTNK-tPA.CannonCP,etal.JAmCollCardiol.2001;37:323A.第三十四页，共四十页。ASSENT-3:StudyGroupConclusionsRegarding

TNK-tPA+AbciximabTherapy“Theresultsobtainedwithhalf-dosetenecteplaseplusabciximabareverysimilartothosewithhalf-dosereteplaseandabciximabseeninGUSTO-V.”“Inbothtrials,thesebenefitsareobtainedatthecostofahigherrate

ofmajorbleedingcomplicationsandbloodtransfusions.”“Nobenefitandperhapsevenharmwasobservedinpatientsabove

75yearsandindiabetics.”“Takentogethertheysuggestthatcautionshouldbeexercisedregardingtheuseofconjunctivetherapywithabciximabinelderlypatientswithanacutemyocardialinfarctiontreatedwithafibrinolyticagent.”TheASSENT-3Investigators.Lancet.2001;358:605-613.第三十五页，共四十页。ASSENT-3:StudyGroupConclusionsRegardingEnoxaparin“Inviewofthepresentdataandtheeaseofadministration,enoxaparinmightbeconsideredanattractivealternativeanticoagulanttreatmentwhengivenincombinationwithtenecteplase.”TheASSENT-3Investigators.Lancet.2001;358:605-613.第三十六页，共四十页。ENTIRETIMI-23:StudyDesignSTMI<6h(n=461)UFH

60U/kgbolus

12U/kg/hinfusion

36h

ENOX

varyingdoses

+/-IVbolus

IndexHosp(8d)ASAENOX

varyingdoses

+/-IVbolus

IndexHosp(8d)Combination

Reperfusion:Half-doseTNK-tPA+Abx

(0.27mg/kg)Standard

Reperfusion:Full-doseTNK-tPA

(0.53mg/kg)AntmanE,etal.EurHeartJ.2001;22:15.Abstract145.UFH

40U/kgbolus

7U/kg/hinfusion

36h第三十七页，共四十页。OutstandingIssuesShouldenoxaparinreplaceUFHastheoptimalantithrombinagentforAMI?Willsimilarimprovementsin