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PathophysiologyofCombinationTherapyinAMI*Gibsonetal.JAmCollCardiol.2019;25:582-589.Gibsonetal.Circulation.2019;103:2550-2554.CombinationTherapyThrombus%StenosisMinimumDiameterEpicardialFlowMyocardialBlushSTResolutionMyocardialFlowFacilitatesPCIReduces
Reinfarction*PathophysiologyofCombinationRecentClinicalTrialsUnfractionatedheparinEnoxaparinUnfractionatedheparinEnoxaparinAbciximabAbciximabNoneNoneENTIREACC/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/IIIaReceptorInhibitorLyticTrialRecentClinicalTrialsUnfractiClinicalTrials: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/IIIaReceptorInhibitorLyticTrialClinicalTrials:OngoingLow-do54%32%GUSTO-I:A20%IncreaseinTIMIGrade3FlowisNeededtoYielda1%MortalityReductionTheGUSTOAngiographicInvestigators.NEnglJMed.1993;329:1615-1622.03050604020%TIMIGrade3Flowt-PASK10t-PA57.4%6.3%SK87654%32%GUSTO-I:A20%IncreaseTIMIGrade3Flow–PooledDataFromDoseConfirmationPhasesofRecentTrials040801006020%PatientsWithTIMIGrade3FlowGUSTO-I90minT14t-PA90minT14r-PA90minSPEED60-90minINTRO-AMI60minPooled60-90min547370474056787354566429263879881329588810075321LyticaloneCombinationTIMIGrade3Flow–PooledDatSPEED: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=11521.654.947.528.7SPEED:ResultsofDose-ConfirmGUSTO-V:StudyDesignTheGUSTO-VInvestigators.Lancet.2019;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)infusionGUSTO-V:StudyDesignTheGUSTOPrimaryEndPoint:30-DayMortalityTheGUSTO-VInvestigators.Lancet.2019;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%PrimaryEndPoint:30-DayMortGUSTO-V:NoninferiorityAnalysisAdaptedwithpermissionfromtheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.Non-InferiorityRR0.95
(95%CI,0.84-1.08)1.11ORand95%CI0.02.01.0Abciximab+
Half-doser-PAsuperiorFull-doser-PA
superiorUpperBoundaryof95%CIforNoninferiorityGUSTO-V:NoninferiorityAnalysAComparisonoftheOutcomesWithr-PAMonotherapyinGUSTO-IIIvsGUSTO-VTrialsTheGUSTO-IIIInvestigators.NEnglJMed.2019;337:1118-1123.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.037851264GUSTOIIIGUSTOV7.4%5.9%10,1388,260DeathP<.00104050203010GUSTOIIIGUSTOV48%37%10,1388,260AnteriorMI0GUSTOIIIGUSTOV0.91%0.59%10,1388,260ICHP=.0150.1AComparisonoftheOutcomesW2.3GUSTO-V:CausesofReinfarction*Unblinded,unadjudicatedTheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.01342MyocardialInfarction(%)AnyQ-waveEnzymaticIschemicSTChange*2.7r-PAr-PA+AbxP<.00012.3GUSTO-V:CausesofNon-IntracranialBleedingThroughDischarge/Day7TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.0%ofPatients15253020r-PAr-PA+Abx10SevereBleedingModerateBleedingMildBleedingAnyBleedingReceivingTransfusions3.511.420.013.724.64.05.7Non-IntracranialBleedingThroICHbyAgeGroup*Significanttreatmentinteractionfortheage75dichotomy;P=.033.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.0132%ofPatients70yrs>70yrs75yrs>75yrs2.1r-PA(n=8260)r-PA+Abx(n=8328)0.3P=.66P=.53P=.27*P=.069*12/108824/114928/717937/717225/203031/213521/619324/6230ICHbyAgeGroup*Significantt****GUSTO-V:PCIWithin6Hours(Urgent)
andThroughDay7*P<.0001.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.5.625.427.98.601525302010PCI(%)UrgentThroughDay75r-PAr-PA+Abx****GUSTO-V:PCIWithin6Hour2.89.05.4GUSTO-V:EventRatesinThoseRequiringUrgentPCIHeartwireNews.September2,2019.GUSTO-V:Combinationhalf-dosefibrinolyticplusIIb/IIIablocker.AnAlternativeapproachtoMI?0410128MyocardialInfarction(%)r-PAr-PA+Abxn=1173DeathRepeatMIDeathPlusRepeatMI262.89.05.4GUSTO-V:EventRatesGUSTO-V:ConclusionsComparedwithr-PAmonotherapy,combinationtherapywith
r-PAandabciximabresultedinAmortalityratethatwasnotinferiortor-PAmonotherapyFewernonfatalreinfarctions(primarilyareducedincidence
ofrecurrentSTelevation)AlowerrateofurgentrevascularizationMorenoncerebralbleedingcomplications,transfusions,
andthrombocytopeniaAhigherrateofICHinelderlypatientsovertheageof
75yearsGUSTO-V:ConclusionsComparedwASSENT-3:RationaleforUseofEnoxaparinTNK-tPAplusenoxaparinFavorableeffectsofLMWHsinrecentsmall-scale
thrombolysistrialsHigherlatepatency: HART-2
ASSENT-Plus
AMI-SKLessreocclusion: HART-2Fewerreinfarctions: ASSENT-Plus
AMI-SK
Wilson,etal.ASSENT-3isthefirstlarge-scaletrialtotestLMWHASSENT-3:RationaleforUseofASSENT-3:StudyDesignST-SegmentElevationAMI(n=6095patients)150to325mgASA(daily)RandomizedFull-doseTNK-tPA
PlusEnoxaparin
Half-doseTNK-tPA
PlusAbciximab
PlusLow-doseHeparinFull-doseTNK-tPA
PlusWeight-
adjustedUFHTheASSENT-3Investigators.Lancet.2019;358:605-613.ASSENT-3:StudyDesignST-SegmeASSENT-3:PrimaryEndPointsPrimaryEfficacyEndPoint:Compositeof30-daymortalityor
in-hospitalreinfarctionorin-hospitalrefractoryischemia.PrimaryEfficacyPlusSafetyEndPoint:Compositeof30-daymortalityorin-hospitalreinfarctionorin-hospitalrefractoryischemiaplusin-hospitalintracranialhaemorrhageorin-hospitalmajorbleedingotherthanintracranial.ASSENT-3:PrimaryEndPointsPrASSENT-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*ASSENT-3:30-DayMortality,ReASSENT-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*ASSENT-3:30-DayMortality,ReKaplan-MeierCurvesUFHAbx*51015202530024681012141620180Enox*log-rankP=.0001*vsUFHDaystodeath,reinfarction,or
refractoryischemiaPrimaryEfficacyEndPointProbability(%)ReprintedwithpermissionfromtheASSENT-3Investigators.Lancet.2019;358:605-613.51015202530024681012141620180log-rankP=.0062*vsUFH+AbxDaystodeath,reinfarction,refractory
ischemia,ICH,ormajorbleedingPrimaryEfficacyPlus
SafetyEndPointProbability(%)UFHAbxEnox*Kaplan-MeierCurvesUFHAbx*510ASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatients>75YearsofAge*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabandagesuchthatpatientsovertheageof75hadpooreroutcomeswithabciximab(P=.001).%Riskof30-DayEfficacy
andSafetyEndPoint015253545TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH25.536.928.0P=.001*520304010ASSENT-3:PrimaryEfficacyandASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatientswithDiabetes*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabanddiabetes,suchthatdiabeticshadpooreroutcomeswithabciximabtherapy(P=.0007).%Riskof30-DayEfficacy
andSafetyEndPoint0152530TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.922.316.5P=.007*52010ASSENT-3:PrimaryEfficacyandASSENT-3:30-DayMortality04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.2562%Riskof30-DayMortalityASSENT-3:30-DayMortality0481ASSENT-3:30-DayDeathorMI%Riskof30-DayDeathorMI04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.019862ASSENT-3:30-DayDeathorMI%ASSENT-3:In-HospitalRecurrentMI%RiskofIn-Hospital
RecurrentMI0245TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.000931ASSENT-3:In-HospitalRecurrenASSENT-3:In-HospitalRefractoryIschemia%Riskof30-Day
RefractoryIschemia04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP<.000162ASSENT-3:In-HospitalRefractoASSENT-3:IncidenceofIn-HospitalThrombocytopeniaandNoncerebralBleedingComplications*While3-wayP-valueissignificant,EnoxvsUFHcomparisonP=NS Enox Abx UFH P-Value
(n=2040) (n=2019) (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 .0032ASSENT-3:IncidenceofIn-HospASSENT-3:In-HospitalStrokeRates*IncludinghemorrhagicconversionUnclassifiedHemorrhagicconversionIschemicstroke*IntracranialhemorrhageTotalstrokes70.070.400.640.940.881.491.62Abx
(n=2019)Enox
(n=2040)0.590.050.770.000.570.540.980.930.941.52P-ValueUFH
(n=2038)ASSENT-3:In-HospitalStrokeRPatientsUndergoingPCI:MortalityASSENT-3:In-HospitalPCIGUSTO-V:UrgentPCI057863Mortality(%)45.46.7TNK-tPA+
EnoxTNK-tPA+
AbxTNK-tPA+
UFHr-PA+
UFHr-PA+
AbxPatientsUndergoingPCI:MortaHowDoesActualWeightCompareto
EstimatedWeight?ReprintedwithpermissionfromCannonCP,etal.JAmCollCardiol.2019;37:323A.CorrelationBetweenEstimatedandActualPatientWeightinTIMI10B40.536.4188.5ActualPatientWeight(kg)EstimatedPatientWeight(kg)R2=0.93,P<.0001181HowDoesActualWeightCompareWeight-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.2019;37:323A.Weight-BasedDosingofThromboASSENT-3:StudyGroupConclusionsRegarding
TNK-tPA+AbciximabTherapy“Theresultsobtainedwithhalf-dosetenecteplaseplusabciximabareverysimilartothosewithhalf-dosereteplaseandabciximabseeninGUSTO-V.”“Inbothtrials,thesebenefitsareobtainedatthecostofahigherrate
ofmajorbleedingcomplicationsandbloodtransfusions.”“Nobenefitandperhapsevenharmwasobservedinpatientsabove
75yearsandindiabetics.”“Takentogethertheysuggestthatcautionshouldbeexercisedregardingtheuseofconjunctivetherapywithabciximabinelderlypatientswithanacutemyocardialinfarctiontreatedwithafibrinolyticagent.”TheASSENT-3Investigators.Lancet.2019;358:605-613.ASSENT-3:StudyGroupConclusiASSENT-3:StudyGroupConclusionsRegardingEnoxaparin“Inviewofthepresentdataandtheeaseofadministration,enoxaparinmightbeconsideredanattractivealternativeanticoagulanttreatmentwhengivenincombinationwithtenecteplase.”TheASSENT-3Investigators.Lancet.2019;358:605-613.ASSENT-3:StudyGroupConclusiENTIRETIMI-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.2019;22:15.Abstract145.UFH
40U/kgbolus
7U/kg/hinfusion
36hENTIRETIMI-23:StudyDesignSTOutstandingIssuesShouldenoxaparinreplaceUFHastheoptimalantithrombinagentforAMI?Willsimilarimprovementsinefficacyandsafetyoccurifenoxapariniscombinedwithalessfibrin-specificagentsuchasr-PA?Willphysiciansaccepttheuseofenoxaparininselectedpatients
withST-elevationMIwhomayrequirerescuePCI?WilltrialsofTNK-tPAplusthesmallmoleculeGPIIb/IIIareceptorinhibitorsproduceresultssimilartoASSENT-3?WhatistheoptimalstrategyforfacilitatedPCI?OutstandingIssuesShouldenoxaFutureTrials:PotentialDownstreamTargetsLargeembolii:FiltersSmallembolii(thrombii):Filters&GPIIb/IIIainhibitors,
p-selectininhibitorsVasoconstrictorrelease:GPIIb/IIIainhibitorsSpasm:Adenosine,Cachannelblockers,alphablockers,
avoidoversizingwithPCI,highpressureinflations,
serotonininhibitors,endothelininhibitorsEndothelial&Myocardialswelling:Myocardialcooling,
Cachannelblockers,DHEA,Na/Hpumpinhibitors,
anti-inflammatoryapproachesFutureTrials:PotentialDownsENDEND39急性心肌梗塞的溶栓治療課件40PathophysiologyofCombinationTherapyinAMI*Gibsonetal.JAmCollCardiol.2019;25:582-589.Gibsonetal.Circulation.2019;103:2550-2554.CombinationTherapyThrombus%StenosisMinimumDiameterEpicardialFlowMyocardialBlushSTResolutionMyocardialFlowFacilitatesPCIReduces
Reinfarction*PathophysiologyofCombinationRecentClinicalTrialsUnfractionatedheparinEnoxaparinUnfractionatedheparinEnoxaparinAbciximabAbciximabNoneNoneENTIREACC/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/IIIaReceptorInhibitorLyticTrialRecentClinicalTrialsUnfractiClinicalTrials: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/IIIaReceptorInhibitorLyticTrialClinicalTrials:OngoingLow-do54%32%GUSTO-I:A20%IncreaseinTIMIGrade3FlowisNeededtoYielda1%MortalityReductionTheGUSTOAngiographicInvestigators.NEnglJMed.1993;329:1615-1622.03050604020%TIMIGrade3Flowt-PASK10t-PA57.4%6.3%SK87654%32%GUSTO-I:A20%IncreaseTIMIGrade3Flow–PooledDataFromDoseConfirmationPhasesofRecentTrials040801006020%PatientsWithTIMIGrade3FlowGUSTO-I90minT14t-PA90minT14r-PA90minSPEED60-90minINTRO-AMI60minPooled60-90min547370474056787354566429263879881329588810075321LyticaloneCombinationTIMIGrade3Flow–PooledDatSPEED: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=11521.654.947.528.7SPEED:ResultsofDose-ConfirmGUSTO-V:StudyDesignTheGUSTO-VInvestigators.Lancet.2019;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)infusionGUSTO-V:StudyDesignTheGUSTOPrimaryEndPoint:30-DayMortalityTheGUSTO-VInvestigators.Lancet.2019;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%PrimaryEndPoint:30-DayMortGUSTO-V:NoninferiorityAnalysisAdaptedwithpermissionfromtheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.Non-InferiorityRR0.95
(95%CI,0.84-1.08)1.11ORand95%CI0.02.01.0Abciximab+
Half-doser-PAsuperiorFull-doser-PA
superiorUpperBoundaryof95%CIforNoninferiorityGUSTO-V:NoninferiorityAnalysAComparisonoftheOutcomesWithr-PAMonotherapyinGUSTO-IIIvsGUSTO-VTrialsTheGUSTO-IIIInvestigators.NEnglJMed.2019;337:1118-1123.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.037851264GUSTOIIIGUSTOV7.4%5.9%10,1388,260DeathP<.00104050203010GUSTOIIIGUSTOV48%37%10,1388,260AnteriorMI0GUSTOIIIGUSTOV0.91%0.59%10,1388,260ICHP=.0150.1AComparisonoftheOutcomesW2.3GUSTO-V:CausesofReinfarction*Unblinded,unadjudicatedTheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.01342MyocardialInfarction(%)AnyQ-waveEnzymaticIschemicSTChange*2.7r-PAr-PA+AbxP<.00012.3GUSTO-V:CausesofNon-IntracranialBleedingThroughDischarge/Day7TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.0%ofPatients15253020r-PAr-PA+Abx10SevereBleedingModerateBleedingMildBleedingAnyBleedingReceivingTransfusions3.511.420.013.724.64.05.7Non-IntracranialBleedingThroICHbyAgeGroup*Significanttreatmentinteractionfortheage75dichotomy;P=.033.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.0132%ofPatients70yrs>70yrs75yrs>75yrs2.1r-PA(n=8260)r-PA+Abx(n=8328)0.3P=.66P=.53P=.27*P=.069*12/108824/114928/717937/717225/203031/213521/619324/6230ICHbyAgeGroup*Significantt****GUSTO-V:PCIWithin6Hours(Urgent)
andThroughDay7*P<.0001.TheGUSTO-VInvestigators.Lancet.2019;357:1905-1914.5.625.427.98.601525302010PCI(%)UrgentThroughDay75r-PAr-PA+Abx****GUSTO-V:PCIWithin6Hour2.89.05.4GUSTO-V:EventRatesinThoseRequiringUrgentPCIHeartwireNews.September2,2019.GUSTO-V:Combinationhalf-dosefibrinolyticplusIIb/IIIablocker.AnAlternativeapproachtoMI?0410128MyocardialInfarction(%)r-PAr-PA+Abxn=1173DeathRepeatMIDeathPlusRepeatMI262.89.05.4GUSTO-V:EventRatesGUSTO-V:ConclusionsComparedwithr-PAmonotherapy,combinationtherapywith
r-PAandabciximabresultedinAmortalityratethatwasnotinferiortor-PAmonotherapyFewernonfatalreinfarctions(primarilyareducedincidence
ofrecurrentSTelevation)AlowerrateofurgentrevascularizationMorenoncerebralbleedingcomplications,transfusions,
andthrombocytopeniaAhigherrateofICHinelderlypatientsovertheageof
75yearsGUSTO-V:ConclusionsComparedwASSENT-3:RationaleforUseofEnoxaparinTNK-tPAplusenoxaparinFavorableeffectsofLMWHsinrecentsmall-scale
thrombolysistrialsHigherlatepatency: HART-2
ASSENT-Plus
AMI-SKLessreocclusion: HART-2Fewerreinfarctions: ASSENT-Plus
AMI-SK
Wilson,etal.ASSENT-3isthefirstlarge-scaletrialtotestLMWHASSENT-3:RationaleforUseofASSENT-3:StudyDesignST-SegmentElevationAMI(n=6095patients)150to325mgASA(daily)RandomizedFull-doseTNK-tPA
PlusEnoxaparin
Half-doseTNK-tPA
PlusAbciximab
PlusLow-doseHeparinFull-doseTNK-tPA
PlusWeight-
adjustedUFHTheASSENT-3Investigators.Lancet.2019;358:605-613.ASSENT-3:StudyDesignST-SegmeASSENT-3:PrimaryEndPointsPrimaryEfficacyEndPoint:Compositeof30-daymortalityor
in-hospitalreinfarctionorin-hospitalrefractoryischemia.PrimaryEfficacyPlusSafetyEndPoint:Compositeof30-daymortalityorin-hospitalreinfarctionorin-hospitalrefractoryischemiaplusin-hospitalintracranialhaemorrhageorin-hospitalmajorbleedingotherthanintracranial.ASSENT-3:PrimaryEndPointsPrASSENT-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*ASSENT-3:30-DayMortality,ReASSENT-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*ASSENT-3:30-DayMortality,ReKaplan-MeierCurvesUFHAbx*51015202530024681012141620180Enox*log-rankP=.0001*vsUFHDaystodeath,reinfarction,or
refractoryischemiaPrimaryEfficacyEndPointProbability(%)ReprintedwithpermissionfromtheASSENT-3Investigators.Lancet.2019;358:605-613.51015202530024681012141620180log-rankP=.0062*vsUFH+AbxDaystodeath,reinfarction,refractory
ischemia,ICH,ormajorbleedingPrimaryEfficacyPlus
SafetyEndPointProbability(%)UFHAbxEnox*Kaplan-MeierCurvesUFHAbx*510ASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatients>75YearsofAge*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabandagesuchthatpatientsovertheageof75hadpooreroutcomeswithabciximab(P=.001).%Riskof30-DayEfficacy
andSafetyEndPoint015253545TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH25.536.928.0P=.001*520304010ASSENT-3:PrimaryEfficacyandASSENT-3:PrimaryEfficacyandSafetyEndPointofDeath,ReinfarctionorRefractoryIschemia,ICHorMajorBleedinginPatientswithDiabetes*Therewasastatisticallysignificantinteractionbetweentreatmentwithabciximabanddiabetes,suchthatdiabeticshadpooreroutcomeswithabciximabtherapy(P=.0007).%Riskof30-DayEfficacy
andSafetyEndPoint0152530TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.922.316.5P=.007*52010ASSENT-3:PrimaryEfficacyandASSENT-3:30-DayMortality04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.2562%Riskof30-DayMortalityASSENT-3:30-DayMortality0481ASSENT-3:30-DayDeathorMI%Riskof30-DayDeathorMI04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.019862ASSENT-3:30-DayDeathorMI%ASSENT-3:In-HospitalRecurrentMI%RiskofIn-Hospital
RecurrentMI0245TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP=.000931ASSENT-3:In-HospitalRecurrenASSENT-3:In-HospitalRefractoryIschemia%Riskof30-Day
RefractoryIschemia04810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3-wayP<.000162ASSENT-3:In-HospitalRefractoASSENT-3:IncidenceofIn-HospitalThrombocytopeniaandNoncerebralBleedingComplications*While3-wayP-valueissignificant,EnoxvsUFHcomparisonP=NS Enox Abx UFH P-Value
(n=2040) (n=2019) (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 .0032ASSENT-3:IncidenceofIn-HospASSENT-3:In-HospitalStrokeRates*IncludinghemorrhagicconversionUnclassifiedHemorrhagicconversionIschemicstroke*IntracranialhemorrhageTotalstrokes70.070.400.640.940.881.491.62Abx
(n=2019)Enox
(n=2040)0.590.050.770.000.570.540.980.930.941.52P-ValueUFH
(n=2038)ASSENT-3:In-HospitalStrokeRPatientsUndergoingPCI:MortalityASSENT-3:In-HospitalPCIGUSTO-V:UrgentPCI057863Mortality(%)45.46.7TNK-tPA+
EnoxTNK-tPA+
AbxTNK-tPA+
UFHr-PA+
UFHr-PA+
AbxPatientsUndergoingPCI:MortaHowDoesActualWeightCompareto
EstimatedWeight?ReprintedwithpermissionfromCannonCP,etal.JAmCollCardiol.2019;37:323A.CorrelationBetweenEstimatedandActualPatientWeightinTIMI10B40.536.4188.5ActualPatientWeight(kg)EstimatedPatientWeight(kg)R2=0.93,P<.0001181HowDoesActualWeightCompareWeight-BasedDosingofThrombolysis:HowWellDoWeEstimateWeight?HowOftenWouldThisTranslateIntoErrorsWithAdministrationofThrombolyticDrugsandAdverseOutcomes?Errorsinestimatingweightareuncommon,especially
thos
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