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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Acute Coronary Syndromes: Management of UA/NSTEMI,Acute Coronary Syndromes: Ma,Overview 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,Discharge 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.,Overview of 2003 Updates to th,Acute Management of UA/NSTEMI,Anti-Ischemic Therapy,Oxygen, bed rest, ECG monitoring,Nitroglycerin,-,Blockers,ACE inhibitors,UA, 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 Therapy,Antiplatelet therapy,Anticoagulant therapy,Acute Management of UA/NSTEMIA,Possible ACS,Aspirin,Aspirin,+,IV Heparin,+,IV Platelet GP IIb/IIIa,Antagonist,Definite ACS With Invasive Strategy (Catheterization/PCI),or High Risk (IIa)*,Clopidogrel,Aspirin,+,SQ LMWH*,or,IV Heparin,Likely/Definite ACS,Clopidogrel,*Class IIa: enoxaparin preferred over UFH unless CABG planned within 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 Antithrombotic Therapy*,Possible ACSAspirinAspirinDef,17.1,6.5*,Placebo,ASA,0,5,10,15,20,Patients (%),Unstable Angina,25.0,11.0*,ASA,0,10,20,30,3.3,1.9*,ASA,0,1,2,3,4,11.8,9.4*,ASA,0,5,10,15,Acute MI,Aspirin in Acute Coronary Syndromes,*,P,.0001,Death or MI,*,P,=.003,Reocclusion,*,P,=.012,MI,*,P,.001,Death,N=3973995134198587860085878600,MI, myocardial infarction; ASA, acetylsalicylic acid; 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.,Placebo,Placebo,Placebo,17.16.5*PlaceboASA05101520Pati,Aspirin in Acute Coronary Syndromes,12.9,3.9*,ASA,0,5,10,15,11.9,3.3*,ASA,0,5,10,15,12.9,6.2*,ASA,0,5,10,15,2.2,1.3*,ASA,0,0.5,1,1.5,2,2.5,UA/NSTEMI,Primary Prevention,Stable Angina,*,P,.0001MI,*,P,=.0003MI,*,P,=.008Death or MI,*,P,=.012Death or MI,N=1103411037155178279276118121,MI, 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.,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.,Placebo,Placebo,Placebo,Placebo,Patients (%),Aspirin in Acute Coronary Synd,Indirect Comparisons of ASA Doses on Vascular Events in High-Risk Patients,*Odds reduction.,Treatment effect,P,.0001.,ASA, acetylsalicylic acid.,Adapted with permission from,BMJ Publishing Group. Antithrombotic Trialists Collaboration,. BMJ.,2002;324:71-86.,0.5,1.0,1.5,2.0,500-1500 mg34 19,160-325 mg19 26,75-150 mg12 32,162 mg/d(n=2179),Primary end point16.418.6,Death, MI, stroke6.26.1,Death2.81.7,MI2.02.1,Stroke2.12.8,Urgent hospital care9.510.6,Urgent resuscitation7.310.0,Internal bleeding2.43.3,Any bleeding11.115.4,Transfusion1.02.0,BRAVO: Bleeding By ASA doseTo,Clopidogrel,+ 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;108:1682-1687.,ASA Dose,ClopidogrelPlaceboCURE: Major,RR:,Death/MI,ASA Alone 68/655=10.4%,Heparin + ASA 55/698=7.9%,B,B,B,B,B,B,B,0.1,1,10,Summary Relative Risk,0.67 (0.44-0.1.02),Theroux,RISC,Cohen 1990,ATACS,Holdright,Gurfinkel,Comparison of Heparin + ASA vs ASA Alone,ASA, acetylsalicylic acid; RISC, Research on InStability in Coronary artery disease; ATACS, Antithrombotic Therapy in Acute Company Syndromes; RR, relative risk; MI, myocardial infarction.,Oler A, et al,. JAMA.,1996;276:811-815. (with permission),RR: ASA Alone 68/655=10.4%Hepa,TIMI, Thrombosis in Myocardial Infarction; ESSENCE, Efficacy and Safety of Subcutaneous Enozapam in NonQ-Wave Coronary Events; UHF, unfractionated heparin; ENOX, enoxaparin; MI, myocardial infarction; OR, odds ratio.,Antman EM, et al.,Circulation.,1999;100:1602-1608. (with permission),TIMI,II,B/ESSENCE Metanalysis:Enoxaparin vs Unfractionated Heparin,8.6 7.1 0.82 (0.69-0.97) 18 .02,6.5 5.2 0.79 (0.65-0.96) 21 .02,5.3 4.1 0.77(0.62-0.95) 23 .02,1.81.4 0.80 (0.55-1.16) 20 .24,0.5,1,2,Day,2,8,14,43,UFH(%),ENOX,(%),OR,(95 CI),Favors ENOX,Favors UFH,P,OR,Death or MI,%,TIMI, Thrombosis in Myocardial,0,1,2,3,4,5,6,7,8,9,0,8,16,24,32,40,48,56,64,72,Patients (%),Hours from Randomization,7.3 %,5.5 %,RRR 24%,P,=.026,UFH (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,B: Early Phase Death/MI/Urgent Revasc,0,1,2,3,4,5,6,7,8,9,0,8,16,24,32,40,48,56,64,72,Patients (%),Hours from Randomization,7.3 %,5.5 %,RRR 24%,P,=.026,UFH (n=1957),ENOX (n=1953),0123456789081624324048566472,UFH,Enoxaparin,P,=.03,Major Bleeds96 Hours,INTERACT: Enoxaparin vs Unfractionated Heparin With GP IIb/IIIa Inhibitors,Goodman SG, et al.,Circulation.,2003;107:238-244.,Death/MI30 Days,P,=.031,UFH,Enoxaparin,Percent,UFHEnoxaparinP=.03Major Bleeds,A-Phase Study Design,UA/,NSTEMI,Final A visit 30 days,Randomize,- 24 hours,Chest pain,Min 0 hourMax 120 hour,Tirofiban,+ ASA,Hour 0,Aggressive or conservative,care per local practice,2026,1961,ENOX,1mg/kg q12 hr,UFH,Weight-adjusted,Z,Z,Treat & Evaluate,for Z-Phase,2018,1952,3987,1, endpoint,7 days,Blazing M. presented at ACC 2003.,A-Phase Study DesignUA/Final A,0,10,20,30,0,2,4,6,8,10,12,UFH,Enoxaparin,UFH,ENOX,Days From Randomization,Event Rates (%),Day 7,8.4% (169 events),9.4% (184 events),7- and 30-Day Primary Endpoint,Composite Death, MI and Refractory Ischemia,Blazing M. presented ACC 2003.,0102030024681012UFHEnoxaparinU,Enox Test vs Outcomes,Moliterno DJ, et al.,JACC.,2003;42:1132-1139. (with permission),Death/MI/Urg TVRBleeding,30,25,20,15,10,5,0,200,250,300,350,400,450,500,550,600,200,250,300,350,400,450,500,550,600,Probability of MACE (%),Probability of Any Bleeding (%),30,25,20,15,10,5,0,ENOX Time (sec),ENOX Time (sec),Enox Test vs OutcomesMoliterno,Direct Thrombin Inhibitor Trialists Collaboration,Direct Thrombin Inhibitor Trialists Collaborative Group.,Lancet.,2002;359:294-302. (with permission),11 RCTS,36,000 Pts,ACS, PCI,Death orMyocardialInfarction,Direct ThrombinInhibitorHeparin(N=18,736) (N=17,184),OR(95% Cl),End of treatment,7 days,30 days,End of treatment,7 days,3 days,Death,MyocardialInfarction,End of treatment,7 days,30 days,End of treatment,7 days,30 days,Stroke,Major bleedingduring treatmentIntracranial bleeding during treatment,815 (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%)403 (2.30%),21 (0.11%)28 (0.16%),0.0,1.0,2.0,Direct ThrombinInhibitor,Heparin Better,0.85(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%),Direct Thrombin Inhibitor Tria,Early invasive strategy,+/- GP IIb/IIIa,Catheterization within 8 hours of last subcutaneous dose,UA/NSTEMI,Identified, LMWH,- GP IIb/IIIa,+ GP IIb/IIIa,Catheterization between 8-12 hours of last subcutaneous dose,No,additional,UFH or,LMWH,Additional,Enoxaparin,0.3 mg/kg IV,bolus,Supplement,with UFH,50,U/kg, aim for,ACT 200-250,Supplement,with UFH,0.1 g/L,CAPTURE,PRISM,14.8,10.2,7.5,9.1,0,5,10,15,20,TnI,0.1 g/L,P,0.1,P,.001,4.9,19.6,5.2,5.8,0,5,10,15,20,25,Heparin,Tirofiban,Heparin,Abciximab + Heparin,Death or MI at 30 days (%),Benefit of IIb/IIIa inhibitors,GP IIb/IIIa Inhibition in TnI + Patients by Revascularization: PRISM Study,TnI, troponin I; PRISM, Platelet Receptor Inhibition for Ischemic Syndrome Management study; MI, myocardial infarction. Heeschen C, et al.,Lancet.,1999;354:1757-1762. (with permission),Death/MI at 30 Days,0.37 (0.15-0.93),P,=.02,0.30 (0.10-0.84),P,=.004,16,12,8,4,0,0,5,10,15,20,25,30,Event rate (%),Follow-up (days),No revascularization,Revascularization,Heparin,Heparin,Tirofiban,Tirofiban,GP IIb/IIIa Inhibition in TnI,GP IIb/IIIa Inhibition in Diabetics,Roffi M, et al.,Circulation,. 2001;104:2767-2771. (with permission),30-Day Mortality in Diabetic Patients,2163,687,362,1677,412,1157,6458,PURSUIT,PRISM,PRISM-PLUS,GUSTO IV,PARAGON A,PARAGON B,Pooled,6.1%,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,=.33,P,=.07,P,=.17,P,=.022,P,=.51,P,=.93,P,=.007,TrialNOdds Ratio & 95% ClPlaceboIIb/IIIa,Breslow-Day:,P,=.50IIb/IIIa BetterPlacebo Better,OR=0.74,00.511.52,GP IIb/IIIa Inhibition in Diab,Intravenous GP IIb/IIIa Antagonists in ACS: Death or MI (at 30 Days) in PCI/CABG 5 Days Cohort and in Medical Treatment Cohort,17.3,10.5,14.3,10.1,0,2,4,6,8,10,12,14,16,18,20,Intervention,Medical Treatment,Death or MI,Placebo,IV GP IIb/IIIa,P,=.001,P,=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,.02,Intravenous GP IIb/IIIa Antago,GP Iib/IIIa Inhibitor NSTE ACS Trials Analysis Risk-Adjusted Mortality at 30 Days,Peterson ED, et al.,J Am Coll Cardiol.,2003;42:45-53.Boersma E, et al.,Lancet.,2002;359:189-198.,0.5,2.0,1.0,NRMI,1,Boersma,2,0.83-1.01,0.91,0.79-0.97,0.88,95% CI,Odds Ratio,Odds Ratio for Mortality at 30 Days,GP IIb/IIIa Inhibitor Favored (aspirin,+,heparin),Control Arm Favored (aspirin,+,heparin),GP Iib/IIIa Inhibitor NSTE ACS,Mortality 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 (%),30,14,12,10,8,6,4,2,0,NRMI, National Registry of Myocardial Infarction.,Peterson ED, et al.,J Am Coll Cardiol.,2003;42:45-53. (with permission),In-Hospital Mortality (%),Mortality by Hospitals Use of,Efficacy of Clopidogrel or Ticlopidine in Reducing Coronary Events After Stenting,CLASSICS, 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 Events,Odds Ratio & 95% CI,Ticlopidine Better,Clopidogrel Better,Trial,Clopid. (%),Ticl. (%),N,Overall,13,955,2.0,3.9,0.1,1,10,TOPPS,CLASSICS,1016,1020,2.6,1.3,3.5,0.9,Lenox Hill,CCF,2565,2369,2.4,5.7,3.8,8.9,M,ller,700,3.1,1.7,Wessex,-361,3.4,5.2,N. Memorial,1378,0.8,2.2,S. Illinois,875,2.1,1.4,Wash. Hosp.,844,2.0,0.5,Mayo,2827,0.6,1.6,OR=.73,P,=.003,Efficacy of Clopidogrel or Tic,CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic 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.,0.00,0.02,0.04,0.06,0.08,0.10,0.12,0.14,Cumulative Hazard Rate,Clopidogrel + Aspirin,3,6,9,Placebo + Aspirin,Follow-up (mo),P,=.00009,(N=12,562),0,12,20%,RRR,CURE: Primary End Point MI/Stroke/CV Death,CURE, Clopidogrel in Unstable,CURE: MI/Stroke/CV Death/Severe Ischemia Within 24 Hours of Randomization,CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events; MI, myocardial infarction; CV, cardiovascular; RRR, relative risk reduction; RR, relative risk.,Adapted from,Yusuf S, et al.,Circulation.,2003;107:966-972.,Hours After Randomization,Cumulative Hazard Rates,0.0,0.005,0.010,0.015,0.020,0.025,0,2,4,6,8,10,12,14,16,18,20,22,24,RR=0.67,P,=.003,Placebo,+ Aspirin,Clopidogrel,+ Aspirin,33%,RRR,CURE: MI/Stroke/CV Death/Sever,CURE, clopidogrel in Unstable Angina to Prevent Ischemic Events; TIMI, Thrombosis 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),0,5,10,15,20,25,30,4.1,9.8,15.9,5.7,11.4,20.7,Low (0-2),Intermediate (3-4),High (5-7),Patients (%),TIMI Risk Stratification,29% RRR,P,.04,ARR1.61.64.8,15% RRR,P,.03,27% RRR,P,.004,Placebo + Aspirin*,Clopidogrel + Aspirin*,CURE: Benefit of Clopidogrel + Aspirin Across All TIMI Risk Score Groups,CURE, clopidogrel in Unstable,PCI-CURE: Study Design,CLOPIDOGREL,+ ASA*,PCI,PLACEBO,+ ASA*,Open-label thienopyridine,Pretreatment,Open-label thienopyridine,Pretreatment,N=2658 patients undergoing PCI,N=1345,N=1313,CURE,PCI-CURE,R,Mehta SR, et al.,Lancet.,2001;358:527-533.,30 days post-PCI,End of follow-up,up to 12 months after randomization,PCI-CURE: Study DesignCLOPIDOG,PCI CURE: Benefit of Pretreatment With Clopidogrel at 30 Days,0,5,10,15,20,25,30,Follow-up (days),0.0,0.02,0.04,0.06,0.08,30% RRR,P,=.03,N=2658,Cumulative Hazard Rate,Mehta SR, et al.,Lancet.,2001;358:527-533. (with permission),6.4%,4.5%,Clopidogrel+ ASA,Placebo + ASA,Cardiovascular Death, MI, or Urgent Revascularization,PCI CURE: Benefit of Pretreat,Adapted from,Mehta SR, et al.,Lancet.,2001;358:527-533. (with permission),CV Death or MI From Randomization to End of Follow-up,PCI-CURE: Long-term Results,0.15,0.10,0.05,0.0,0,100,200,300,400,Follow-up (days),12.6%,8.8%,P,=.002N=2658,Clopidogrel,+ Aspirin,Placebo,+ Aspirin,Cumulative Hazard Rates,31%,Relative RiskReduction,Adapted from Mehta SR, et al.,Steinhubl S, et al.,JAMA,. 2002;288:2411-2420.,Credo Study: Study Design,Clopidogrel Arm,Placebo,Arm,PCI,28 Days,Placebo + aspirin (325 mg),Pretreatment,3-24 h before PCI,Clopidogrel 300 mg+ aspirin (325 mg),Clopidogrel 75 mg QD+ aspirin 325 mg QD,Clopidogrel 75 mg QD+ aspirin 325 mg QD,12 Months,Placebo QD+ aspirin (81-325 mg) QD,Clopidogrel 75 mg QD+ aspirin (81-325 mg) QD,R,Objective: To assess the benefit of 1 year vs 1 month of clopidogrel plus aspirin in patients undergoing PCI,Steinhubl S, et al. JAMA. 2002,Effect of Timing of Loading Dose:28-Day EndpointDeath, MI, UTVR,0.4,0.6,0.8,1.0,1.2,Hazard ratio (95% CI),3 to 6 hrs7.97.0893,6 to 24 hr5.89.4 851,RRR -13.4,P,=NS,RRR 38.6,P,=.05,RRR 18.5,P,=.23,Overall CREDO Results,N,PT-Clopidogrel*,No-PT*,Events (%),No-PT,Better,PT-Clopidogrel,Better,PT, pretreatment; UTVR,urgent target vessel revascularization.,*Plus ASA and other standard therapies.,Steinhubl S, et al.,JAMA,. 2002;288:2411-2420.,Effect of Timing of Loading Do,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.,JAMA,. 2002;288:2411-2420,.,(with permission),Combined Endpoint Occurrence (%),Months From Randomization,27% RRR,P,=.02,Placebo*,Clopidogrel*,0,5,10,15,8.5%,11.5%,0,3,6,9,12,CREDO: Benefits of Clopidogrel,CURE: Bleeding Results,CURE,Clopidogrel in Unstable Angina to Prevent Ischemic Events;,*Other standa
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