1、Acute Coronary Syndromes:Management of UA/NSTEMIOverview of 2003 Updates to the ACC/AHA Guideline for UA/NSTEMI Assess likelihood of CAD Risk stratification Target therapy:more aggressive treatment in higher-risk patients Anti-ischemic,antithrombotic therapy Invasive vs conservative strategy Dischar
2、ge planning(risk factor modification and long-term medical therapy)ACC/AHA,American College of Cardiology/American Heart Association;UA,unstable angina;NSTEMI,nonST-segment elevation myocardial infarction.Braunwald E,et al.J Am Col.Cardiol.2000;36:970-1062.Acute Management of UA/NSTEMIAnti-Ischemic
3、TherapyOxygen,bed rest,ECG monitoringNitroglycerin-BlockersACE inhibitorsUA,unstable angina;NSTEMI,non-ST-segment elevation myocardial infarction;ECG,electrocardiogram;ACE,angiotensin-converting enzyme.Braunwald E,et al.J Am Coll Cardiol.2000;36:970-1062.Antithrombotic TherapyAntiplatelet therapyAnt
4、icoagulant therapyPossible ACSAspirinAspirin+IV Heparin+IV Platelet GP IIb/IIIa AntagonistDefinite ACS With Invasive Strategy(Catheterization/PCI)or High Risk(IIa)*ClopidogrelAspirin+SQ LMWH*orIV HeparinLikely/Definite ACSClopidogrel*Class IIa:enoxaparin preferred over UFH unless CABG planned within
5、 24 hours.ACC,American College of Cardiology;AHA,American Heart association;ACS,acute coronary syndrome;PCI,percutaneous coronary intervention;SQLMWH,subcutaneous low molecular-weight heparin;IV,intravenous.Braunwald E,et al.J Am Coll Cardiol.2000;36:970-1062.ACC/AHA Class I Recommendations for Anti
6、thrombotic Therapy*17.16.5*PlaceboASA05101520Patients(%)Unstable Angina 25.011.0*ASA01020303.31.9*ASA0123411.89.4*ASA051015Acute MIAspirin in Acute Coronary Syndromes*P.0001Death or MI*P=.003Reocclusion*P=.012MI*P.001DeathN=3973995134198587860085878600MI,myocardial infarction;ASA,acetylsalicylic aci
7、d;RISC,Research on InStability in Coronary artery disease.RISC Group.Lancet.1990;336:827-830.Roux S,et al.J Am Coll Cardiol.1992;19:671-677.ISIS-2.Lancet.1988;2:349-360.PlaceboPlaceboPlaceboAspirin in Acute Coronary Syndromes12.93.9*ASA05101511.93.3*ASA05101512.96.2*ASA0510152.21.3*ASA00.511.522.5UA
8、/NSTEMIPrimary PreventionStable Angina*P.0001MI*P=.0003MI*P=.008Death or MI*P=.012Death or MIN=1103411037155178279276118121MI,myocardial infarction;ASA,acetylsalicylic acid;RISC,Research on InStability in Coronary artery disease;ISIS-2,Second International Study of Infarct Survival.PHS.N Engl J Med.
9、1989;321:129-35.Ridker PM,et al.AJC.1991;114:835-839.Cairns JA,et al.N Engl J Med.1985;313:1369-1375.Theroux P,et al.N Engl J Med.1988;319:1105-1111.PlaceboPlaceboPlaceboPlaceboPatients(%)Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients*Odds reduction.Treatment effect P.000
10、1.ASA,acetylsalicylic acid.Adapted with permission from BMJ Publishing Group.Antithrombotic Trialists Collaboration.BMJ.2002;324:71-86.0.51.01.52.0500-1500 mg34 19160-325 mg19 2675-150 mg12 32162 mg/d(n=2179)Primary end point16.418.6Death,MI,stroke6.26.1Death2.81.7MI2.02.1Stroke2.12.8Urgent hospital
11、 care9.510.6Urgent resuscitation7.310.0Internal bleeding2.43.3Any bleeding11.115.4Transfusion1.02.0Clopidogrel+ASA(N=6259)Placebo+ASA*(N=6303)CURE:Major Bleeding at 1 year by ASA Dose 200 mg(N=4110)3.7%4.9%P value for trend.0001.0009*P=.0001.P=.0009.Adapted from Peters RJG,et al.Circulation.2003;108
12、:1682-1687.ASA DoseRR:Death/MIASA Alone 68/655=10.4%Heparin+ASA 55/698=7.9%BBBBBBB0.1110Summary Relative Risk0.67(0.44-0.1.02)TherouxRISCCohen 1990ATACSHoldrightGurfinkelComparison of Heparin+ASA vs ASA AloneASA,acetylsalicylic acid;RISC,Research on InStability in Coronary artery disease;ATACS,Antit
13、hrombotic Therapy in Acute Company Syndromes;RR,relative risk;MI,myocardial infarction.Oler A,et al.JAMA.1996;276:811-815.(with permission)TIMI,Thrombosis in Myocardial Infarction;ESSENCE,Efficacy and Safety of Subcutaneous Enozapam in NonQ-Wave Coronary Events;UHF,unfractionated heparin;ENOX,enoxap
14、arin;MI,myocardial infarction;OR,odds ratio.Antman EM,et al.Circulation.1999;100:1602-1608.(with permission)TIMI IIB/ESSENCE Metanalysis:Enoxaparin vs Unfractionated Heparin8.6 7.1 0.82(0.69-0.97)18 .026.5 5.2 0.79(0.65-0.96)21 .025.3 4.1 0.77(0.62-0.95)23 .021.81.4 0.80(0.55-1.16)20 .24 0.512Day281
15、443UFH(%)ENOX(%)OR(95 CI)Favors ENOXFavors UFHPORDeath or MI%0123456789081624324048566472Patients(%)Hours from Randomization7.3%5.5%RRR 24%P=.026UFH(n=1957)ENOX(n=1953)UHF,unfractionated heparin;ENOX,enoxaparin;RRR,relative risk ratio.Antman EM.Circulation.1999;100:1593-1601.(with permission)TIMI II
16、B:Early Phase Death/MI/Urgent Revasc0123456789081624324048566472Patients(%)Hours from Randomization7.3%5.5%RRR 24%P=.026UFH(n=1957)ENOX(n=1953)4.6%1.8%0%2%4%6%UFHEnoxaparinP=.03Major Bleeds96 HoursINTERACT:Enoxaparin vs Unfractionated Heparin With GP IIb/IIIa InhibitorsGoodman SG,et al.Circulation.2
17、003;107:238-244.9%5%0%2%4%6%8%10%Death/MI30 DaysP=.031UFHEnoxaparinPercentA-Phase Study DesignUA/NSTEMIFinal A visit 30 days Randomize-24 hours Chest pain Min 0 hourMax 120 hourTirofiban+ASA Hour 0Aggressive or conservativecare per local practice20261961ENOX1mg/kg q12 hrUFHWeight-adjustedZZ Treat&Ev
18、aluate for Z-Phase2018195239871 endpoint 7 daysBlazing M.presented at ACC 2003.0102030024681012UFHEnoxaparinUFHENOXDays From RandomizationEvent Rates(%)Day 78.4%(169 events)9.4%(184 events)Blazing M.presented ACC 2003.Enox Test vs OutcomesMoliterno DJ,et al.JACC.2003;42:1132-1139.(with permission)De
19、ath/MI/Urg TVRBleeding302520151050200 250 300 350 400 450 500 550 600200 250 300 350 400 450 500 550 600Probability of MACE(%)Probability of Any Bleeding(%)302520151050ENOX Time(sec)ENOX Time(sec)Direct Thrombin Inhibitor Trialists CollaborationDirect Thrombin Inhibitor Trialists Collaborative Group
20、.Lancet.2002;359:294-302.(with permission)11 RCTS36,000 PtsACS,PCI Death orMyocardialInfarctionDirect ThrombinInhibitorHeparin(N=18,736)(N=17,184)OR(95%Cl)End of treatment7 days30 daysEnd of treatment7 days3 daysDeathMyocardialInfarctionEnd of treatment7 days30 daysEnd of treatment7 days30 daysStrok
21、eMajor bleedingduring treatmentIntracranial bleeding during treatment815(4.3%)883(5.1%)947(5.0%)990(5.8%)1399(7.4%)1409(8.2%)355(1.9%)346(2.0%)422(2.2%)395(2.3%)685(3.6%)642(3.7%)522(2.8%)596(3.5%)601(3.2%)672(3.9%)876(4.7%)917(5.3%)62(0.33%)60(0.35%)72(0.38%)70(0.41%)120(0.64%)110(0.64%)360(1.90%)4
22、03(2.30%)21(0.11%)28(0.16%)0.01.02.0Direct ThrombinInhibitorHeparin Better0.85(0.77-0.94%)0.88(0.80-0.96%)0.91(0.84-0.99%)0.97(0.83-1.13%)1.00(0.87-1.16%)1.01(0.90-1.12%)0.80(0.71-0.90%)0.81(0.72-0.91%)0.87(0.79-0.95%)0.95(0.66-1.35%)0.94(0.68-1.31%)1.01(0.78-1.31%)0.75(0.65-0.87%)0.72(0.42-1.23%)Ea
23、rly invasive strategy+/-GP IIb/IIIa Catheterization within 8 hours of last subcutaneous doseUA/NSTEMIIdentified,LMWH-GP IIb/IIIa+GP IIb/IIIa Catheterization between 8-12 hours of last subcutaneous doseNo additionalUFH or LMWHAdditionalEnoxaparin0.3 mg/kg IV bolusSupplementwith UFH 50U/kg,aim forACT
24、200-250Supplementwith UFH 0.1 g/LCAPTUREPRISM14.810.27.59.105101520TnI 0.1 g/LP0.1P.0014.919.65.25.80510152025HeparinTirofibanHeparinAbciximab+HeparinDeath or MI at 30 days(%)GP IIb/IIIa Inhibition in TnI+Patients by Revascularization:PRISM StudyTnI,troponin I;PRISM,Platelet Receptor Inhibition for
25、Ischemic Syndrome Management study;MI,myocardial infarction.Heeschen C,et al.Lancet.1999;354:1757-1762.(with permission)Death/MI at 30 Days0.37(0.15-0.93)P=.020.30(0.10-0.84)P=.0041612840051015202530Event rate(%)Follow-up(days)No revascularizationRevascularizationHeparinHeparinTirofiban TirofibanGP
26、IIb/IIIa Inhibition in DiabeticsRoffi M,et al.Circulation.2001;104:2767-2771.(with permission)30-Day Mortality in Diabetic Patients2163687362167741211576458PURSUITPRISMPRISM-PLUSGUSTO IVPARAGON APARAGON BPooled6.1%4.2%6.7%7.8%6.2%4.8%6.2%5.1%1.8%3.6%5.0%4.6%4.9%4.6%P=.33P=.07P=.17P=.022P=.51P=.93P=.
27、007TrialNOdds Ratio&95%ClPlaceboIIb/IIIaBreslow-Day:P=.50IIb/IIIa BetterPlacebo BetterOR=0.7400.511.52Intravenous GP IIb/IIIa Antagonists in ACS:Death or MI(at 30 Days)in PCI/CABG 5 Days Cohort and in Medical Treatment Cohort17.310.514.310.102468101214161820InterventionMedical TreatmentDeath or MIPl
28、aceboIV GP IIb/IIIaP=.001P=NS(N=5847)(N=25,555)ACS,acute coronary syndrome;MI,myocardial infarction;PCI,percutaneous coronary intervention;CABG,coronary artery bypass graft;NS,not significant.Boersma E,et al.Lancet.2002;359:189-198.Interaction P.02GP Iib/IIIa Inhibitor NSTE ACS Trials Analysis Risk-
29、Adjusted Mortality at 30 DaysPeterson ED,et al.J Am Coll Cardiol.2003;42:45-53.Boersma E,et al.Lancet.2002;359:189-198.0.52.01.0NRMI1Boersma20.83-1.010.910.79-0.970.8895%CIOdds RatioOdds Ratio for Mortality at 30 DaysGP IIb/IIIa Inhibitor Favored(aspirin+heparin)Control Arm Favored(aspirin+heparin)M
30、ortality by Hospitals Use of Early GP IIb/IIIa Inhibitors(N=1189 Hospitals)Hospital Use of Early GP IIb/IIIa inhibitors in NRMI(%)In-Hospital Mortality(%)3014121086420NRMI,National Registry of Myocardial Infarction.Peterson ED,et al.J Am Coll Cardiol.2003;42:45-53.(with permission)In-Hospital Mortal
31、ity(%)Efficacy of Clopidogrel or Ticlopidine in Reducing Coronary Events After StentingCLASSICS,Clopidogrel Aspirin Stent Intervention Coopoerative Study.Bhatt DL,et al.J Am Coll Cardiol.2002;39:9-14.(with permission)30-Day Major Adverse Cardiac EventsOdds Ratio&95%CITiclopidine BetterClopidogrel Be
32、tterTrialClopid.(%)Ticl.(%)NOverall13,9552.03.90.1110TOPPSCLASSICS101610202.61.33.50.9Lenox HillCCF256523692.45.73.88.9Mller7003.11.7Wessex-3613.45.2N.Memorial13780.82.2S.Illinois8752.11.4Wash.Hosp.8442.00.5Mayo28270.61.6OR=.73,P=.003CURE,Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic
33、Events;MI,myocardial infarction;CV,cardiovascular;RRR,relative risk reduction.Plavix package insert;2002.Adapted with permission(2002)from the Massachusetts Medical Society.Yusuf S,et al.N Engl J Med.2001;345:494-502.0.000.020.040.060.080.100.120.14Cumulative Hazard RateClopidogrel+Aspirin369Placebo
34、+AspirinFollow-up(mo)P=.00009(N=12,562)01220%RRRCURE:Primary End Point MI/Stroke/CV DeathCURE:MI/Stroke/CV Death/Severe Ischemia Within 24 Hours of RandomizationCURE,Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events;MI,myocardial infarction;CV,cardiovascular;RRR,relative risk reduc
35、tion;RR,relative risk.Adapted from Yusuf S,et al.Circulation.2003;107:966-972.Hours After RandomizationCumulative Hazard Rates0.00.0050.0100.0150.0200.025024681012141618202224RR=0.67P=.003Placebo+AspirinClopidogrel+Aspirin33%RRRCURE,clopidogrel in Unstable Angina to Prevent Ischemic Events;TIMI,Thro
36、mbosis in Myocardial Infarction;CV,cardiovascular;MI,myocardial infarction;RRR,relative risk reduction;ARR,Absolute risk reduction.*In addition to other standard therapies.Budaj A,et al.Circulation.2002;106:1622-1626.(with permission)Primary Composite End Point(CV Death,MI,Stroke)0510152025304.19.81
37、5.95.711.420.7Low(0-2)Intermediate(3-4)High(5-7)Patients(%)TIMI Risk Stratification29%RRRP.04ARR1.61.64.8 15%RRRP.0327%RRRP.004Placebo+Aspirin*Clopidogrel+Aspirin*CURE:Benefit of Clopidogrel+Aspirin Across All TIMI Risk Score GroupsPCI-CURE:Study DesignCLOPIDOGREL+ASA*PCIPLACEBO+ASA*Open-label thien
38、opyridinePretreatmentOpen-label thienopyridinePretreatmentN=2658 patients undergoing PCIN=1345N=1313CUREPCI-CURERMehta SR,et al.Lancet.2001;358:527-533.30 days post-PCIEnd of follow-upup to 12 months after randomizationPCI CURE:Benefit of Pretreatment With Clopidogrel at 30 Days051015202530Follow-up
39、(days)0.00.020.040.060.0830%RRRP=.03N=2658Cumulative Hazard RateMehta SR,et al.Lancet.2001;358:527-533.(with permission)6.4%4.5%Clopidogrel+ASAPlacebo+ASACardiovascular Death,MI,or Urgent RevascularizationAdapted from Mehta SR,et al.Lancet.2001;358:527-533.(with permission)CV Death or MI From Random
40、ization to End of Follow-upPCI-CURE:Long-term Results0.150.100.050.00100200300400Follow-up(days)12.6%8.8%P=.002N=2658Clopidogrel+AspirinPlacebo+AspirinCumulative Hazard Rates31%Relative RiskReductionSteinhubl S,et al.JAMA.2002;288:2411-2420.Credo Study:Study Design Clopidogrel ArmPlacebo ArmPCI28 Da
41、ysPlacebo+aspirin(325 mg)Pretreatment3-24 h before PCIClopidogrel 300 mg+aspirin(325 mg)Clopidogrel 75 mg QD+aspirin 325 mg QDClopidogrel 75 mg QD+aspirin 325 mg QD12 MonthsPlacebo QD+aspirin(81-325 mg)QDClopidogrel 75 mg QD+aspirin(81-325 mg)QDRObjective:To assess the benefit of 1 year vs 1 month o
42、f clopidogrel plus aspirin in patients undergoing PCIEffect of Timing of Loading Dose:28-Day EndpointDeath,MI,UTVR0.40.60.81.01.2Hazard ratio(95%CI)3 to 6 hrs7.97.0893 6 to 24 hr5.89.4 851 RRR-13.4P=NSRRR 38.6P=.05RRR 18.5P=.23Overall CREDO ResultsN PT-Clopidogrel*No-PT*Events(%)No-PTBetterPT-Clopid
43、ogrelBetterPT,pretreatment;UTVR,urgent target vessel revascularization.*Plus ASA and other standard therapies.Steinhubl S,et al.JAMA.2002;288:2411-2420.CREDO:Benefits of Clopidogrel Plus Aspirin to 1 Year Following PCI CV Death,MI or Stroke*Plus ASA and other standard therapies.Steinhubl S,et al.JAM
44、A.2002;288:2411-2420.(with permission)Combined Endpoint Occurrence(%)Months From Randomization27%RRRP=.02Placebo*Clopidogrel*0510158.5%11.5%036912CURE:Bleeding ResultsCURE,Clopidogrel in Unstable Angina to Prevent Ischemic Events;*Other standard therapies were used as appropriate.Life-threatening an
45、d other major bleeding.Plavix package insert 2003.Event Clopidogrel+Aspirin*(n=6259)(%)Placebo+Aspirin*(n=6303)(%)P ValueMajor bleeding3.7 2.7.001Life-threateningbleeding 2.21.8.13Minor bleeding5.12.4.001Placebo+ASA(%)Clopidogrel+ASA(%)From PCI to 30 daysMajor1.41.6Life threatening0.70.7 Minor0.70.9
46、 From PCI to end of follow-upMajor2.52.7 Life threatening1.31.2 Minor2.13.5P=NS,P=0.03Adapted from Mehta SR,et al.Lancet.2001;358:527-533.PCI-CURE:Bleeding OutcomesMajor/Life-Threatening Bleeds Within 7 Days of CABG SurgeryPlaceboClopidRRPStopped 5 days prior to CABGN=454N=456Pts with Maj/LT Bld TIM
47、I Major5.3%2.4%4.4%1.8%0.830.72.53NSCURE investigators.N Engl J Med.2001;Fox KM.Presented at ESC 2002.CURE:Outcomes by CABG in Initial Hospitalization(CV death/MI/StrokePlaceboClopidogrelN(%)N(%)RRCICABG During Initial Hospitalization:No.of Patients528485 CV death/MI/stroke16.713.20.780.57-1.08No CA
48、BG:No.of Patients57755774 CV death/MI/stroke11.08.90.800.71-0.89CURE investigators.N Engl J Med.2001;Fox KM.Presented at ESC 2002.Early Clopidogrel Timing in ACS PCI-CURE and CREDO:Need to start clopidogrel early(6 h)to get post-PCI benefit 50%-60%of patients get PCI,8%-20%get CABG(half of whom are
49、5 d postcatheterization anyway)Tradeoff per 1000 UA/NSTEMI patient Rx:Early Rx prevents additional 10 major cardiac events vs creating 1.5 TIMI minor bleed post-CABGACS,acute coronary syndrome;PCI,percutaneous coronary intervention;CURE,Clopidogrel in Unstable Angina to Prevent Recurrent Events;CRED
50、O,Clopidogrel for Reduction of Events During Observation;CABG,coronary artery bypass graft;UA,unstable angina;NSTEMI,nonST-segment myocardial infarction;TIMI Thrombosis in Myocardial Infarction.Boersma E,et al.Lancet.2002;359:189-198.PRONTO Study:Effect of Co-Administration of Various Statins With C
