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1、在非在非在非在非STST段抬高的急性冠状动脉综合征段抬高的急性冠状动脉综合征段抬高的急性冠状动脉综合征段抬高的急性冠状动脉综合征(NSTACS)(NSTACS)(NSTACS)中早期应用血小板糖蛋白中早期应用血小板糖蛋白中早期应用血小板糖蛋白中早期应用血小板糖蛋白中早期应用血小板糖蛋白中早期应用血小板糖蛋白IIbIIIaIIbIIIaIIbIIIa受体拮抗剂：受体拮抗剂：受体拮抗剂：受体拮抗剂：受体拮抗剂：受体拮抗剂：一项评估一项评估一项评估一项评估一项评估一项评估NSTACSNSTACSNSTACS治疗中早期应用依替巴肽治疗中早期应用依替巴肽治疗中早期应用依替巴肽治疗中早期应用依替巴肽治疗中
2、早期应用依替巴肽治疗中早期应用依替巴肽临床效果的随机、双盲、安慰剂对照试验临床效果的随机、双盲、安慰剂对照试验临床效果的随机、双盲、安慰剂对照试验临床效果的随机、双盲、安慰剂对照试验临床效果的随机、双盲、安慰剂对照试验临床效果的随机、双盲、安慰剂对照试验EarlyEarlyEarly Glycoprotein Glycoprotein IIb/IIIaIIb/IIIa Inhibition in Non-ST-segment Elevation Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomize
3、d, Double-blind, Placebo-Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded loaded EptifibatideEptifibatide in the Treatment of Patients with Non-ST- in
4、the Treatment of Patients with Non-ST-segment Elevation segment Elevation A AAcute cute C CCoronary oronary S SSyndromesyndromesEarlyEarly Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome: A Randomized, Elevation
5、Acute Coronary Syndrome: A Randomized, Double-blind, Placebo-Controlled Trial Evaluating the Double-blind, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-loaded Eptifibatide in the Clinical Benefits of Early Front-loaded Eptifibatide in the Treatment of Patients with Non-ST
6、-segment Elevation Treatment of Patients with Non-ST-segment Elevation A Acute cute C Coronary oronary S SyndromesyndromesDisclosuresDisclosuresllFunded by Millennium Pharmaceuticals and Schering Funded by Millennium Pharmaceuticals and Schering Plough Plough llIndividual disclosuresIndividual discl
7、osuresllArmstrongArmstrongllBraunwaldBraunwaldllCaliffCaliffllGibsonGibsonllGiuglianoGiuglianollHarringtonHarringtonllMontalescotMontalescotllNewbyNewbyllStronyStronyllVan de Van de WerfWerfStudy Structurefigure with the below Study Structurefigure with the below componentscomponentsllExec Exec Comm
8、CommllSteering CommitteeSteering CommitteellSponsorSponsorllCoordinating CentersDCRI, TIMI, CVCCoordinating CentersDCRI, TIMI, CVCllDSMBDSMBllSitesSitesllCECCECPrimary ObjectivePrimary ObjectiveTo demonstrate the superiority of a strategy of To demonstrate the superiority of a strategy of early, rou
9、tine eptifibatide begun shortly after early, routine eptifibatide begun shortly after presentation compared with a strategy of presentation compared with a strategy of delayed, provisional use of eptifibatide pre-PCI in delayed, provisional use of eptifibatide pre-PCI in reducing the composite of de
10、ath, MI, recurrent reducing the composite of death, MI, recurrent ischemia, and thrombotic bail-out within 96 hours ischemia, and thrombotic bail-out within 96 hours in patients with high-risk NSTE ACS managed in patients with high-risk NSTE ACS managed with an invasive strategywith an invasive stra
11、tegyStudy DesignStudy DesignHigh-risk NSTE ACSHigh-risk NSTE ACSn = 10,500 (n = 10,500 (95009500) )1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout2 Endpoint: 30-d Death/MIFade in safety endpoints at 120 hours (bleeding (GUSTO and TIMI scales), transfusions, stroke, non-hemorrhagic SAEsPl
12、acebo / provisional Placebo / provisional eptifibatide pre-PCIeptifibatide pre-PCIEarly, routine eptifibatide Early, routine eptifibatide (180/2/180)(180/2/180)Randomize within 12 hours of presentationRandomize within 12 hours of presentationInvasive strategyInvasive strategy: 12 to 96 hours after r
13、andomization: 12 to 96 hours after randomization2 of 3 high-risk criteria:2 of 3 high-risk criteria:1. Age 1. Age 60 years 60 years2. + CKMB or 2. + CKMB or TnTTnT/I/I3. ST 3. ST or transient ST or transient ST (Or age 50-59, Or age 50-59, h/oh/o CVD CVDand + CKMB or and + CKMB or TnTTnT/I/I)Key Exc
14、lusion CriteriaKey Exclusion CriteriallIncreased bleeding riskIncreased bleeding riskllactive bleeding or recent bleedactive bleeding or recent bleedllRecent surgery or traumaRecent surgery or traumallPrior ICH or recent ischemic strokePrior ICH or recent ischemic strokellSerious concomitant illness
15、 or pregnancySerious concomitant illness or pregnancyllESRD with dialysis ESRD with dialysis 30 days 30 daysllRecent or planned use of direct thrombin Recent or planned use of direct thrombin inhibitor, fXa inhibitor, inhibitor, fXa inhibitor, abciximab/tirofibanabciximab/tirofibanllamendment 1: biv
16、alirudin at PCIamendment 1: bivalirudin at PCIllamendment 2: acute fondaparinux or bivalirudinamendment 2: acute fondaparinux or bivalirudinBlinded Study Drug AdministrationBlinded Study Drug AdministrationllDouble bolus and infusion regimenDouble bolus and infusion regimenll180 180 ugug/Kg IV eptif
17、ibatide (or matching placebo) /Kg IV eptifibatide (or matching placebo) bolus as soon as possible after randomizationbolus as soon as possible after randomizationllImmediate initiation of 2 Immediate initiation of 2 ugug/Kg/min eptifibatide (or /Kg/min eptifibatide (or matching placebo) infusion (1
18、matching placebo) infusion (1 ugug/Kg/min if /Kg/min if CrClCrCl 50 cc/min)50 cc/min)llSecond 180 Second 180 ugug/Kg IV eptifibatide (or matching /Kg IV eptifibatide (or matching placebo) bolus 10 minutes after initial bolusplacebo) bolus 10 minutes after initial bolusllProvisional, blinded transiti
19、on to open label Provisional, blinded transition to open label eptifibatide at time of PCI using blinded bolus kiteptifibatide at time of PCI using blinded bolus kitllPCI active if transition before wire crossed lesionPCI active if transition before wire crossed lesionllPCI bailout if after wire cro
20、ssed the lesionPCI bailout if after wire crossed the lesionStatistical MethodsStatistical MethodsllPower = 85% to detect a 22.5% reduction in the primary Power = 85% to detect a 22.5% reduction in the primary quadruple composite assuming an event rate of 5.8% with quadruple composite assuming an eve
21、nt rate of 5.8% with placebo at alpha 0.048 after single interim efficacy analysisplacebo at alpha 0.048 after single interim efficacy analysisllPower = 85% for the key secondary efficacy endpoint of death Power = 85% for the key secondary efficacy endpoint of death or MI at 30 days (15% RRR, placeb
22、o rate 12.7%); also at alpha or MI at 30 days (15% RRR, placebo rate 12.7%); also at alpha 0.048, using step down testing procedure where formally tested 0.048, using step down testing procedure where formally tested only if primary endpoint significantonly if primary endpoint significantllPower aft
23、er sample size reduction to 9500 patientsPower after sample size reduction to 9500 patientsll98% for 96-hour primary composite endpoint98% for 96-hour primary composite endpointll81% for 30-day key secondary endpoint of death or MI81% for 30-day key secondary endpoint of death or MI llPrespecified s
24、ubgroupsPrespecified subgroupsllProper: Age, baseline troponin, hospital type, diabetes, early Proper: Age, baseline troponin, hospital type, diabetes, early clopidogrel, UFH vs enoxaparin, TIMI Risk Scoreclopidogrel, UFH vs enoxaparin, TIMI Risk ScorellPost-randomization (improper): By management s
25、trategy Post-randomization (improper): By management strategy (PCI, CABG, medical)(PCI, CABG, medical)EnrollmentEnrollmentllUse map of world with enrollment by country on the Use map of world with enrollment by country on the mapmapllRecognize top 20 (?30) enrollers worldwidecould Recognize top 20 (
26、?30) enrollers worldwidecould be a “build” on top of the mapbe a “build” on top of the mapStudy ConductStudy ConductPatients randomizedPatients randomized94929492Patients excluded for site conductPatients excluded for site conduct6464Patients without informed consentPatients without informed consent
27、2222Intent-to-treat populationIntent-to-treat population94069406Patients who received no study drugPatients who received no study drug7777As-treated safety populationAs-treated safety population93299329Lost to follow-upLost to follow-up1111Baseline CharacteristicsBaseline CharacteristicsERE (n=4722)
28、ERE (n=4722) DPE (n=4684)DPE (n=4684)Age (years)Age (years)67 (60, 75)67 (60, 75)68 (60, 75)68 (60, 75)Female (%)Female (%)32.032.031.231.2Region (%)Region (%) Most of World Most of World69.269.269.469.4 North America North America30.830.830.630.6Diabetes mellitus (%)Diabetes mellitus (%)30.130.130.
29、730.7Hypertension (%)Hypertension (%)70.570.571.971.9DyslipidemiaDyslipidemia (%) (%)57.957.957.857.8Prior MIPrior MI (%) (%)27.027.028.228.2Prior PCI (%)Prior PCI (%)24.324.325.025.0Prior CABG (%)Prior CABG (%)13.113.114.214.2Creatinine Clearance (cc/min)Creatinine Clearance (cc/min)75 (56, 96)75 (
30、56, 96)74 (56, 96)74 (56, 96)Troponin or CKMB positive (%)Troponin or CKMB positive (%) 85.985.987.087.0ST-segment shifts (%)ST-segment shifts (%)61.661.662.062.0Presentation to rand (hours)Presentation to rand (hours)5.4 (3.3, 8.8)5.4 (3.3, 8.8)5.7 (3.4,8.8)5.7 (3.4,8.8)In-hospital ManagementIn-hos
31、pital Management ERE (n=4722) DPE (n=4684)ERE (n=4722) DPE (n=4684)Cardiac CatheterizationCardiac Catheterization (%) (%)97.597.597.697.6 Randomization to Randomization to cathcath (hours) (hours) 21.4 (16.9, 34.2) 21.4 (16.7, 31.0) 21.4 (16.9, 34.2) 21.4 (16.7, 31.0)PCI PCI (%)(%)58.558.559.759.7 A
32、ctive provisional (%) Active provisional (%)24.924.926.826.8 Bailout (%) Bailout (%)11.311.312.012.0CABGCABG (%) (%)13.213.212.912.9Medically Treated onlyMedically Treated only (%) (%)30.330.331.431.4Use of Evidence-based Rx Use of Evidence-based Rx (%)(%) ASA ASA97.597.597.397.3 UFH or UFH or enoxa
33、parinenoxaparin94.394.394.294.2 Beta-blocker Beta-blocker87.787.787.787.7 StatinStatin86.486.486.986.9 ACEI / ARB ACEI / ARB78.478.478.578.5 Clopidogrel (intended early) Clopidogrel (intended early)74.874.875.275.2 Clopidogrel (any) Clopidogrel (any)90.490.490.690.696-Hour Primary Efficacy Results96
34、-Hour Primary Efficacy ResultsEREERE DPE DPEOROR P P (n=4722) (n=4722) (n=4684) (95% CI) (n=4684) (95% CI) Death, MI, RIUR, TBODeath, MI, RIUR, TBO9.39.3 10.0 10.00.920.92 0.23 0.23 (0.80-1.06) (0.80-1.06)DeathDeath0.80.8 0.9 0.9 0.96 0.96 0.87 0.87 (0.62-1.50) (0.62-1.50)Death / MIDeath / MI7.57.5
35、8.3 8.30.89 0.89 0.13 0.13 (0.77-1.04) (0.77-1.04)Death / MI / RIURDeath / MI / RIUR8.48.4 9.4 9.40.890.89 0.11 0.11 (0.77-1.03 (0.77-1.03) )Kaplan-Meier Curves for Primary EndpointKaplan-Meier Curves for Primary EndpointDeath, MI, RIUR or TBO (%)Death, MI, RIUR or TBO (%)005510101515Time Since Rand
36、omization (Hours)Time Since Randomization (Hours)004488121216162020242428283232363640404444484852525656606064646868727276768080848488889292969610.0%10.0%9.3%9.3%Delayed provisional Delayed provisional eptifibatideeptifibatide4684468446946925.9 (18.7, 48.4)25.9 (18.7, 48.4)Early routineEarly routinee
37、ptifibatideeptifibatide4722472243943931.1 (18.8, 62.2)31.1 (18.8, 62.2)P = 0.23P = 0.23(stratified for intended early (stratified for intended early clopidogrel use)clopidogrel use)NN# Events# EventsHours to EventHours to EventDelayed provisional eptifibatideDelayed provisional eptifibatideEarly rou
38、tine eptifibatideEarly routine eptifibatide30-Day Secondary Efficacy Results30-Day Secondary Efficacy ResultsEREERE DPE DPEOROR P P (n=4722) (n=4722) (n=4684) (95% CI) (n=4684) (95% CI) Death or MIDeath or MI11.211.2 12.3 12.3 0.890.89 0.079 0.079 (0.79-1.01) (0.79-1.01)DeathDeath2.82.8 2.6 2.61.101
39、.10 0.46 0.46 (0.86-1.41) (0.86-1.41)Death, MI, RIURDeath, MI, RIUR12.512.5 13.8 13.80.890.89 0.065 0.065 (0.79-1.01) (0.79-1.01)Kaplan-Meier Curves for 30-day Death or MIKaplan-Meier Curves for 30-day Death or MIDeath or MI (%)Death or MI (%)005510101515Time Since Randomization (Days)Time Since Ran
40、domization (Days)0011223344556677889910101111121213131414151516161717181819192020212122222323242425252626272728282929303012.4%12.4%11.2%11.2%P = 0.079P = 0.079(stratified for intended early (stratified for intended early clopidogrel use)clopidogrel use)Delayed provisional Delayed provisional eptifib
41、atideeptifibatide468446845785782.1 (1.0, 5.8)2.1 (1.0, 5.8)Early routineEarly routineeptifibatideeptifibatide472247225285282.7 (1.0, 4.9)2.7 (1.0, 4.9)NN# Events# EventsDays to EventDays to EventDelayed provisional eptifibatideDelayed provisional eptifibatideEarly routine eptifibatideEarly routine e
42、ptifibatide96-hour Primary Efficacy Results96-hour Primary Efficacy ResultsBy By PrespecifiedPrespecified Subgroups Subgroups0.700.700.800.800.500.500.600.600.900.901.001.002.002.00Baseline CharacteristicBaseline CharacteristicOdds Ratio for UpstreamOdds Ratio for UpstreamEptifibatide (95% CI)Eptifi
43、batide (95% CI)Early Routine Early Routine Eptifibatide, %Eptifibatide, %Delayed Delayed Provisional Provisional Eptifibatide, %Eptifibatide, %OverallOverallMenMenWomenWomenAge 75 yrAge 75 yr75 yrTroponin positiveTroponin positiveTroponin negativeTroponin negativeDiabetesDiabetesNo DiabetesNo Diabet
44、esRandomized Randomized 4 hoursRandomized 4 hoursHigh TIMI Risk Score (5High TIMI Risk Score (5-7)7)Intermediate TIMI Risk Score (3Intermediate TIMI Risk Score (3-4)4)Low TIMI Risk Score (0Low TIMI Risk Score (0-2)2)Unfractionated heparin onlyUnfractionated heparin onlyLow molecular weight heparin o
45、nlyLow molecular weight heparin onlyPrimary Care HospitalPrimary Care HospitalTertiary Care HospitalTertiary Care Hospital9.39.310.010.09.19.19.89.89.79.710.410.48.68.69.59.511.411.411.411.49.59.510.610.67.77.76.86.88.98.910.610.69.59.59.89.88.98.910.510.59.59.59.89.810.410.410.810.89.49.410.110.16.
46、86.88.08.09.19.111.011.09.99.99.99.99.09.09.79.79.49.410.110.1Early Eptifibatide BetterEarly Eptifibatide BetterDelayed Provisional Eptifibatide BetterDelayed Provisional Eptifibatide BetterUpfront clopidogrel intendedUpfront clopidogrel intendedNo upfront clopidogrel intendedNo upfront clopidogrel
47、intended8.88.89.59.510.810.811.511.5North AmericaNorth AmericaWestern EuropeWestern EuropeEastern EuropeEastern Europe10.310.310.610.67.37.38.68.611.211.211.211.2Middle East, Africa and AsiaMiddle East, Africa and Asia10.910.911.511.530-day Death or MI 30-day Death or MI By By PrespecifiedPrespecifi
48、ed Subgroups Subgroups0.700.700.800.800.500.500.600.600.900.901.001.002.002.00OverallOverall11.211.212.312.3MenMen11.411.412.012.0WomenWomen10.710.713.013.0Age 75 yrAge 75 yr75 yr14.014.014.614.6Troponin positiveTroponin positive11.611.613.013.0Troponin negativeTroponin negative8.18.18.48.4DiabetesD
49、iabetes11.711.713.813.8No DiabetesNo Diabetes10.910.911.711.7Randomized Randomized 4 hoursRandomized 4 hours11.211.212.112.1High TIMI Risk Score (5High TIMI Risk Score (5-7)7)13.213.213.313.3Intermediate TIMI Risk Score (3Intermediate TIMI Risk Score (3 -4)10.910.912.812.8Low TIMI Risk Score (0Low T
50、IMI Risk Score (0-2)2)8.18.19.19.1Unfractionated heparin onlyUnfractionated heparin only11.311.313.013.0Low molecular weight heparin onlyLow molecular weight heparin only11.311.312.812.8Primary Care HospitalPrimary Care Hospital10.710.712.312.3Tertiary Care HospitalTertiary Care Hospital11.311.312.4
51、12.4Upfront clopidogrel intendedUpfront clopidogrel intended10.310.312.012.0No upfront clopidogrel intendedNo upfront clopidogrel intended13.713.713.413.4Baseline CharacteristicBaseline CharacteristicOdds Ratio for UpstreamOdds Ratio for UpstreamEptifibatide (95% CI)Eptifibatide (95% CI)Early Routin
52、e Early Routine Eptifibatide, %Eptifibatide, %Delayed Delayed Provisional Provisional Eptifibatide, %Eptifibatide, %Early Eptifibatide BetterEarly Eptifibatide BetterDelayed Provisional Eptifibatide BetterDelayed Provisional Eptifibatide BetterNorth AmericaNorth AmericaWestern EuropeWestern EuropeEa
53、stern EuropeEastern Europe13.213.214.514.510.210.28.88.814.514.515.215.2Middle East, Africa and AsiaMiddle East, Africa and Asia11.011.011.611.6Safety Results Safety Results (through 120 hours)(through 120 hours)ERE ERE DPE DPE OR(95%CI) OR(95%CI) PP (n=4686) (n=4686)(n=4643)(n=4643)Bleeding (overal
54、l)Bleeding (overall)TIMI MajorTIMI Major 2.6 2.61.8 1.42 (1.07-1.89)1.8 1.42 (1.07-1.89)0.0150.015TIMI major or minorTIMI major or minor 5.8 5.83.4 1.75 (1.43-2.14)3.4 1.75 (1.43-2.14)0.0010.001GUSTO SevereGUSTO Severe 0.8 0.80.9 0.99 (0.64-1.55)0.9 0.99 (0.64-1.55)0.970.97GUSTO Moderate or SevereGU
55、STO Moderate or Severe 7.6 7.65.1 1.52 (1.28-1.80)5.1 1.52 (1.28-1.80)0.0010.001PRBC transfusionPRBC transfusion 8.6 8.66.7 1.31 (1.12-1.53)6.7 1.31 (1.12-1.53)0.0010.001Bleeding (CABG)Bleeding (CABG) Re-operation for bleedingRe-operation for bleeding 6.0 6.08.4 0.70 (0.39-1.27)8.4 0.70 (0.39-1.27)0
56、.24 0.24 Chest tube output (mL/24 H) 720Chest tube output (mL/24 H) 720770770-0.410.41Thrombocytopenia (nadir 100K) 3.3Thrombocytopenia (nadir 100K) 3.32.82.8StrokeStroke 0.6 0.60.8 0.79 (0.48-1.30)0.8 0.79 (0.48-1.30)0.360.36llAmong high-risk NSTE ACS patients, a strategy of Among high-risk NSTE AC
57、S patients, a strategy of early, routine eptifibatide compared with delayed early, routine eptifibatide compared with delayed provisional eptifibatide at PCI provisional eptifibatide at PCI lldid not significantly reduce the primary composite did not significantly reduce the primary composite of D/M
58、I/RIUR/TBO at 96h (9.3% vs. 10.0%, OR of D/MI/RIUR/TBO at 96h (9.3% vs. 10.0%, OR 0.92; 0.80-1.06; p = 0.234)0.92; 0.80-1.06; p = 0.234)llresulted in a trend toward reduction in death or MI resulted in a trend toward reduction in death or MI at 30 days (11.2% vs. 12.3%; OR 0.89; 0.79-1.03; at 30 day
59、s (11.2% vs. 12.3%; OR 0.89; 0.79-1.03; p = 0.079), but no difference in 30-day mortality p = 0.079), but no difference in 30-day mortality ( (x.xx.x% vs. % vs. y.yy.y%; OR 0.xx; 0.yy-0.zz; p = 0.aa)%; OR 0.xx; 0.yy-0.zz; p = 0.aa)llresulted in significantly higher rates of non-life-resulted in sign
60、ificantly higher rates of non-life-threatening bleeding and transfusionsthreatening bleeding and transfusionsConclusionsConclusionsllThe results of EARLY ACS do not support a The results of EARLY ACS do not support a strategy of early, routine eptifibatide use among strategy of early, routine eptifi
61、batide use among NSTE ACS patients managed with an invasive NSTE ACS patients managed with an invasive strategystrategyllIt may be reasonable to consider early It may be reasonable to consider early eptifibatide use in selected high-risk subsets of eptifibatide use in selected high-risk subsets of A
62、CS patients with low risk of bleeding who are ACS patients with low risk of bleeding who are scheduled to undergo PCIscheduled to undergo PCIllIn selected high-risk NSTE ACS patients who In selected high-risk NSTE ACS patients who are also at increased bleeding risk, a delayed are also at increased
63、bleeding risk, a delayed provisional eptifibatide strategy pre-PCI would provisional eptifibatide strategy pre-PCI would be reasonablebe reasonableImplicationsImplicationsBack-up slidesBack-up slidesPrimary and Key Secondary Efficacy ResultsPrimary and Key Secondary Efficacy ResultsBy Clopidogrel St
64、rata at RandomizationBy Clopidogrel Strata at RandomizationERE ERE DPE DPE OR (95% CI)OR (95% CI)96-hr Death, MI, RIUR, TBO96-hr Death, MI, RIUR, TBOClopidogrel intendedClopidogrel intended8.88.89.59.50.92 (0.78-1.08)0.92 (0.78-1.08)No Clopidogrel intendedNo Clopidogrel intended10.810.811.511.50.93 (0.72-1.20)0.93 (0.72-1.20)30-day Death / MI30-day Death / MIClopidogrel intendedClopidogrel intended10.310.312.012.00.85 (0.73-0.91)0.85 (0.73-0.91)No Clopidogrel intendedNo Clopidogrel intended13.713.713.413.41.03 (0.81-1.31)1.03 (0.81-1.31)
