F4.最新突破性临床研究结果CLARITY&CCS2研究解读.ppt

强化抗血小板治疗新证据解读强化抗血小板治疗新证据解读每个临床研究均显示氯吡格雷每个临床研究均显示氯吡格雷75mg的显著优越性的显著优越性Each trial shows significant superiority of Clopidogrel 75mg Establishing long-term efficacy of Plavix in PCIEstablishing superior long-term efficacy and safety of Plavix compared with ASA in first large-scale trial in atherothromboisEstablishing Plavix on top of standard therapy*in largest-ever ACS(NSTEMI,UA)trialCAPRIE(n=19,185)CURE(n=12,562)CREDO(n=2,116)Establishing early efficacy of Plavix in acute STEMI CLARITY(n=3.500)Establishing mortality benefit of Plavix in acute STEMI COMITT/CCS-2(n=46000)CHARISMA(n15,000)Establishing long term efficacy of Plavix in patient at high risk of atherothrombotic eventsACTIVE(n15,000)Establishing efficacy of Plavix in patients with atrial fibrillation*Including ASA CLopidogrel as Adjunctive ReperfusIon TherapY Thrombolysis In Myocardial Infarction(TIMI)28氯吡格雷作为再灌注疗法的辅助治疗氯吡格雷作为再灌注疗法的辅助治疗心肌梗死的溶栓治疗（心肌梗死的溶栓治疗（TIMI）28CLopidogrel as Adjunctive ReperfusIon TherapY(CLARITY)TIMI 28 Trial Results目的目的:本试验旨在研究急性本试验旨在研究急性ST段抬高心梗患者在溶栓和段抬高心梗患者在溶栓和其他标准治疗的基础上加用氯吡格雷是否对血管其他标准治疗的基础上加用氯吡格雷是否对血管造影结果和临床预后产生益处造影结果和临床预后产生益处研究的组织和病例入组研究的组织和病例入组TIMI研究组研究组Eugene Braunwald,MD Brigham and Womens HospitalChristopher P.Cannon,MDHarvard Medical SchoolMarc S.Sabatine,MD,MPHAmy C.McCagg,MBA 入组国家入组国家Spain France Canada Belgium Russia Germany UK Israel 研究设计研究设计1*ASA=150325 mg(if no ASA within prior 24 hours)as loading dose.Patients received heparin if they received a fibrin specific thrombolyticAll patients received ASA 75162 mg/day plus other standard care给予研究药物直至行动脉造影给予研究药物直至行动脉造影(2 8 天天)或或 出院出院(至多至多 8 天天)n=1752n=1739溶栓溶栓,肝素和肝素和ASA*氯吡格雷氯吡格雷 300 mg 负荷剂量负荷剂量/75 mg每日一片每日一片安慰剂安慰剂随随机机双盲、随机、安慰剂对照研究双盲、随机、安慰剂对照研究 18-75岁，发病岁，发病12 小时的小时的ST抬高心梗患者抬高心梗患者临床随访直至第临床随访直至第30天天主要终点主要终点:血管造影发现动脉闭塞血管造影发现动脉闭塞(TIMI 血流分级血流分级 TFG 0/1级级),或动脉造影前发生死亡或动脉造影前发生死亡/心梗心梗Inclusion criteriaAge 18 75 yearsSTEMI within 12 hoursPlanned treatment with fibrinolyticMajor exclusion criteriaClopidogrel within 7 daysPlanned clopidogrel or GPIIb/IIIa before angiographyContraindications to thrombolysis(stroke,ICH,brain tumor)Cardiogenic shockIntention of angiography within 48 hoursCABG,creatinine 2.5 mg/dL,hepatic insufficiency,platelets 67 kg and 4000 U bolus UFH;67 kg and 5000 U bolus 1.1 mg/kg subcutaneous of enoxaparinInclusion/Exclusion Criteria1FOR INTERNAL USE ONLYPrimary endpoint:1.Composite of occluded infarct related artery(TFG 0/1)on pre-discharge angiogram,or death or MI before angiography1.Death or MI by hospital discharge(maximum 8 days)if no angiography performedSecondary endpoints:1.Angiographic(TFG 0/1)2.Clinical(death,recurrent MI or recurrent ischemia)3.Clinical events*at 30 days4.Safety endpoints:5.Primary:TIMI major bleeding6.Secondary:TIMI minor bleeding,ICHStudy Endpoints1*CV death,MI,stroke or recurrent ischemia leading to urgent target vessel revascularizationFOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)TIMI Flow Grade Definitions1TIMI flow grade describes epicardial blood flow:Grade 0:complete occlusionGrade 1:penetration of obstruction with no distal perfusionGrade 2:perfusion of artery with delayed flowGrade 3:full perfusion with normal flowTFG 0OcclusionTFG 1PenetrationTFG 2Slow flowTFG 3Normal flowFOR INTERNAL USE ONLY1.Gibson CM et al.Circulation 2004:109:30963105.TIMI Myocardial Perfusion Grade Definitions1TIMI Myocardial Perfusion Grade(TMPG)or blush score describes blood flow in the microvasculature:Grade 0:no dye entersGrade 1:dye slowly enters but fails to exitGrade 2:delayed entry and exit of dyeGrade 3:normal entry and exit of dyeTMPG 3 TMPG 3 TMPG 2 TMPG 2 TMPG 1 TMPG 1 TMPG 0 TMPG 0 FOR INTERNAL USE ONLY1.Gibson CM et al.Circulation 2004:109:30963105.Relationship Between Angiographic Outcomes and Long-term Mortality11.Gibson CM et al.Circulation 2002;105:19091913.TFG 0/12-year mortality(%)14.5%TFG 2/3TMPG 0/1TMPG 2/36.4%4.8%9.1%HR:0.41(p=0.001)HR:0.51(p=0.038)TIMI flow gradeTIMI myocardial perfusion grade*Assessed on 90 minute angiogram in TIMI 10b trial;HR=hazard ratioFOR INTERNAL USE ONLYBaseline Characteristics1Clopidogrel PlaceboCharacteristic (n=1752)(n=1739)Age(years)57.757.2Male gender(%)79.980.7Hypertension(%)42.843.9Hyperlipidemia(%)32.233.0Current smoker(%)50.749.9Diabetes mellitus(%)16.516.4Prior MI(%)9.19.1Prior PCI(%)4.84.9Anterior MI(%)41.240.1FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Concomitant Medications1Clopidogrel PlaceboCharacteristic (n=1752)(n=1739)Fibrin-specific thrombolytic(%):Tenecteplase47.847.3Reteplase11.912.3Alteplase9.18.9Non-fibrin specific thrombolytic(%):Streptokinase30.931.2No thrombolytic given(%)0.20.3ASA(%)98.598.6Heparin(%):UFH 46.145.5LMWH30.129.1FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Patient Management1ClopidogrelPlaceboParameter(n=1752)(n=1739)Symptom onset to fibrinolytic(hours)2.72.6Fibrinolytic to study drug(minutes)1010Median doses of study medication44Angiography performed(%)9494Time to angiography(hours)8484Coronary revascularization(%):6363PCI 5757CABG66FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Other Cardiac Medications During Index Hospitalization1Clopidogrel PlaceboCharacteristic(%)(n=1752)(n=1739)Beta-blockers 88.789.6Statins 80.481.1ACE inhibitors/ARBs72.772.1After angiography*Clopidogrel 54.555.6Ticlopidine 3.52.9*Some patients received open-label ADP-receptor antagonists after angiography and primary endpoint ascertainmentFOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)主要终点主要终点:氯吡格雷改善冠脉再灌注氯吡格雷改善冠脉再灌注安慰剂安慰剂安慰剂安慰剂氯吡格雷氯吡格雷氯吡格雷氯吡格雷P=0.00000036P=0.00000036相对危险性相对危险性相对危险性相对危险性 0.640.64(95%CI 0.53-0.76)(95%CI 0.53-0.76)1.00.40.60.81.21.6氯吡格雷更佳氯吡格雷更佳氯吡格雷更佳氯吡格雷更佳安慰剂更佳安慰剂更佳安慰剂更佳安慰剂更佳n=1752n=173936%相对危险性降低相对危险性降低动动脉脉阻阻塞塞或或死死亡亡或或心心梗梗%Clopidogrel Reduced Primary Endpoint by 36%1Clopidogrel PlaceboOdds ratio(n=1752)(n=1739)(95%CI)p valuePrimary composite endpoint(%)TFG 0/1,MI or death15.021.70.64(0.53 0.76)0.001Individual components of primary endpoint(%)TFG 0/111.718.40.59(0.48 0.72)0.001 Recurrent MI2.53.60.70(0.47 1.04)0.08Death2.62.21.17(0.75 1.82)0.49FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Number ofOdds Event rates(%)CharacteristicpatientsreductionClopidogrelPlaceboOVERALL34913615.021.7Age65 years24664213.221.0 65 years10152219.023.1GenderMale27963514.520.8Female6853816.924.7Infarct locationAnterior14163315.020.7Non-anterior20653815.022.2FibrinolyticFibrin-specific23973114.720.1Non-fibrin specific10844415.724.9Predominant heparinLMWH14293111.415.7UFH14314217.827.1None6212617.121.91.00.40.60.81.21.6Clopidogrel betterPlacebo betterConsistent Results for Primary Endpoint Across Subgroups1FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Clopidogrel Improved Angiographic Outcomes1Clopidogrel PlaceboOdds ratio(n=1752)(n=1739)(95%CI)p valueAngiographic outcomes(%)TFG 3*67.860.81.36(1.18 1.57)0.001TMPG 355.851.21.21(1.05 1.40)0.008Thrombus43.050.80.73(0.64 0.84)0.001FOR INTERNAL USE ONLY*TFG=TIMI Flow GradeTPMG=TIMI Myocardial Perfusion Grade1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)氯吡格雷氯吡格雷 75mg 进一步降低进一步降低30天临床事件达天临床事件达20%*Odds Ratio(OR)in CV death,MI or recurrent ischemia leading to urgent revascularization 时间（天）时间（天）临床终点发生率临床终点发生率(%)(%)051015051015202530安慰剂安慰剂氯吡格雷氯吡格雷20%*p=0.03Consistent Benefit Across 30-Day Endpoints1OddsreductionClopidogrel PlaceboCV death34.44.5Recurrent MI314.15.9Recurrent ischemialeading to urgent243.54.5 revascularizationStroke460.91.7CV death or MI178.49.9CV death,MI or stroke189.110.9CV death,MI or recurrentischemia leading to urgent2011.614.1 revascularizationCV death,MI,stroke orrecurrent ischemia leading2112.315.0to urgent revascularizationPercentage ofpatients with eventEndpointOdds ratio(95%CI)1.00.40.60.81.2Clopidogrel betterPlacebo better1.6FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)Safety1ClopidogrelPlacebo(n=1733)(n=1719)p valuePrimary bleeding endpoint(%)TIMI major 23(1.3)19(1.1)0.64Secondary bleeding endpoints(%)TIMI minor 17(1.0)9(0.5)0.17TIMI major or minor 40(2.3)28(1.6)0.18 Intracranial hemorrhage8(0.5)12(0.7)0.38Bleeding through 30 days(%)TIMI major 33(1.9)30(1.7)0.80TIMI minor 27(1.6)16(0.9)0.12TIMI major or minor 59(3.4)46(2.7)0.24FOR INTERNAL USE ONLY1.Sabatine MS et al.New Engl J Med 2005;352(available at www.nejm.org)风险和获益风险和获益?75岁的岁的ST段抬高心肌梗死患者，接受段抬高心肌梗死患者，接受ASA和标准溶栓治疗，和标准溶栓治疗，氯吡格雷氯吡格雷 300mg负荷剂量随负荷剂量随后后75mg每天：每天：获益获益动脉造影时梗死相关动脉闭塞或死亡动脉造影时梗死相关动脉闭塞或死亡/心梗的发生率降低心梗的发生率降低了了36%(p 0.001)出院前血管造影或出院前（至多出院前血管造影或出院前（至多8天）天）30天时，心血管性死亡、心梗或缺血复发导致急诊血运天时，心血管性死亡、心梗或缺血复发导致急诊血运重建的发生率降低了重建的发生率降低了20%(p=0.03)主要终点是心血管发病率和死亡率的重要替代指标主要终点是心血管发病率和死亡率的重要替代指标风险风险TIMI严重出血和颅内出血无额外增多严重出血和颅内出血无额外增多结论结论“氯吡格雷带来了一种有效、简便、经济氯吡格雷带来了一种有效、简便、经济而安全的方法，改善梗阻相关动脉的通畅而安全的方法，改善梗阻相关动脉的通畅性，并减少缺血性并发症性，并减少缺血性并发症”M A R C H 9,2 0 0 5Sabatine MS,Cannon CP,Gibson CM,Lopez-Sendon JL,Montalescot G,Theroux P,Claeys MJ,Cools F,Hill KA,Skene AM,McCabe CH and Braunwald E代表代表 CLARITY-TIMI 28的研究者们的研究者们N Engl J Med 2005;352 www.nejm.org.ACC 2005 LBCT Slide Set available at www.timi.org.TPASK加用氯吡格雷加用氯吡格雷75mg 是提高中短期急性心梗患者预后里程碑式的进步是提高中短期急性心梗患者预后里程碑式的进步TIMI 1ASA+ClopidogrelASANEJM 1985;312:932APRICOTPlaceboASACirc 1993;87:152436%P0.00190 mins3 mos3.5 d47%P70(%)26.026.0Time from symptom onset to randomization(hrs)10.310.3Time from symptom onset 0.1,NS0.4 0.6 0.8 1.0 1.2 1.4 1.6FOR INTERNAL USE ONLY1.Chen ZM et al.ACC 2005.Effects of Clopidogrel on Non-Cerebral BleedingOdds ratio&95%CIClopi betterPlacebo better Clopidogrel PlaceboType(n=22,958)(n=22,891)Major Bleed*82(0.4%)73(0.3%)Other Bleed831(3.6%)721(3.1%)ALL896(3.9%)777(3.4%)16%SE 5IncreaseP=0.0040.4 0.6 0.8 1.0 1.2 1.4 1.6*Fatal or transfusedFOR INTERNAL USE ONLY1.Chen ZM et al.ACC 2005.Effects of Clopidogrel on Death,Re-MI or Stroke by Days of EventOdds ratio&95%CIClopi betterPlacebo better Clopidogrel PlaceboEvents by Day(n=22,958)(n=22,891)0463523 1486 527 2-3449451 4-7432463 8-28295347ALL2125(9.3%)2311(10.1%)FOR INTERNAL USE ONLY0.4 0.6 0.8 1.0 1.2 1.4 1.69%SE 3IncreaseP=0.0021.Chen ZM et al.ACC 2005.Consistent Effects of Clopidogrel on Death,Re-MI or Stroke by Age and GenderOdds ratio&95%CIClopi betterPlacebo better BaselineClopidogrel PlaceboFeatures(n=22,958)(n=22,891)Gender Male1276(7.7%)1416(8.6%)Female849(13.3%)895(14.0%)Age 60487(5.1%)513(5.4%)60-69747(10.2%)835(11.2%)70+891(14.9%)963(16.2%)ALL2125(9.3%)2311(10.1%)9%SE 3ReductionP=0.0020.40.60.81.01.21.41.6FOR INTERNAL USE ONLY1.Chen ZM et al.ACC 2005.Effects of Clopidogrel on Death,Re-MI,or Stroke by Time Delay and Fibrinolytic UseOdds ratio&95%CIClopi betterPlacebo better BaselineClopidogrel PlaceboFeatures(n=22,958)(n=22,891)Time Delay(hrs)0-6776(9.3%)904(10.9%)7-12672(9.7%)735(10.7%)13-24666(8.8%)666(8.7%)Lytic Given Yes1005(8.8%)1123(9.9%)No1120(9.7%)1188(10.3%)ALL2125(9.3%)2311(10.1%)9%SE 3ReductionP=0.0020.40.60.81.01.21.41.6FOR INTERNAL USE ONLY1.Chen ZM et al.ACC 2005.Clopidogrel(75 mg daily)on a background of standard therapy including ASA was beneficial for a wide range of acute STEMI patientsClopidogrel reduced the risk of in-hospital death by 7%(p=0.03)Clopidogrel reduced the risk of death,non-fatal MI,or non-fatal stroke by 9%(p=0.002)No significant increase in the risk of major(fatal or transfused)bleedingFor every million MI treated in hospital for about 2-3 weeks,clopidogrel could save 5000 lives and prevent another 5000 major vascular eventsConclusionsFOR INTERNAL USE ONLY1.Chen ZM et al.ACC 2005.Complementary Results of CLARITY and COMMIT for Patients with STEMI1.Significant improvement in coronary perfusion and clinical outcomes versus standard care(CLARITY)2.Significant reduction in mortality for patients receiving clopidogrel versus standard care alone(COMMIT)3.No significant increase in major bleeding or ICH(COMMIT and CLARITY)FOR INTERNAL USE ONLY过去十年内证实过去十年内证实未能降低未能降低ST段抬高心梗患者死亡率的药物段抬高心梗患者死亡率的药物FOR INTERNAL USE ONLYDouble-bolus t-PATNKrPAnPAGP IIb/IIIa inhibition+lyticOral GP IIb/IIIa inhibitionBivalirudinHirudinPexulizamabMagnesiumAdnosinePSGLGIKetc.氯吡格雷氯吡格雷75mg：迄今为止，在超过迄今为止，在超过92,000患者中的获益患者中的获益急性心梗急性心梗非非ST段抬高段抬高ACSD/MI/CVAup to 1 yrD/MI/CVAup to 1 yrCREDOPCIMI后后20%27%9%D/MI/CVAup to 3 yrsBlocked artery 36%CVD/MI/UR:20%事件的高事件的高危因素危因素Mortality“Claim”波立维循证医学证据有力推进指南的发展波立维循证医学证据有力推进指南的发展PCIPCI患者患者1.BraunwaldEetal.JAmCollCardiol2002;40:13661374.BertrandMEetal.EurHeartJ2002;23;1809-1840.Antmanetal.2004.ACC/AHAPracticeGuidelines.ACC-www.acc.org,AHA-www.americanheart.org.The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy:Evidence-Based Guidelines.CHEST 2004;40(3):suppl.指南指南人群特征人群特征方法方法疗程疗程2002 ACC/AHA非非STST段抬高段抬高急性冠脉综合症急性冠脉综合症波立维波立维+阿司匹林阿司匹林1-91-9个月个月2002 ESC非非STST段抬高段抬高急性冠脉综合症急性冠脉综合症波立维波立维 +阿司匹林阿司匹林9-129-12个月个月2004 ACC/AHASTST段抬高心梗段抬高心梗波立维波立维 +阿司匹林阿司匹林1212个月个月裸支架裸支架裸支架裸支架裸支架裸支架+药药物涂层支物涂层支架架支架类型支架类型 2004 ACCPPCIPCI波立维波立维 +阿司匹林阿司匹林1212个月个月裸支架裸支架+药药物涂层支物涂层支架架波立维循证医学证据有力推进指南的发展波立维循证医学证据有力推进指南的发展未行未行PCIPCI的急性冠脉综合征的急性冠脉综合征指南指南发表时间发表时间适应人群适应人群推荐内容推荐内容ACC/AHA2002年3月NSTEACS无论是否行PCI，都应尽早在阿司匹林的基础上加用波立维（氯吡格雷）至少1个月并维持到9个月ESC2002年11月NSTEACS无论是否行PCI，都应尽早在阿司匹林的基础上加用波立维（氯吡格雷）9-12个月ACC/AHA2004年7月ST段抬高心梗如ASA过敏，氯吡格雷可替代ASA用于AMI二级预防ACCP72004年9月ST段抬高心梗对阿司匹林过敏或不耐受者，氯吡格雷首剂300mg随后每日75mg，无限期服用ST段抬高心梗施行溶栓术对阿司匹林过敏或不耐受者，氯吡格雷首剂300mg随后每日75mg，作为阿司匹林替代治疗NSTEACS无论是否行PCI，都应尽早在阿司匹林的基础上加用波立维（氯吡格雷）9到12个月1.BraunwaldEetal.JAmCollCardiol2002;40:13661374.2.BertrandMEetal.EurHeartJ2002;23;1809-1840.3.Antmanetal.2004.ACC/AHAPracticeGuidelines.ACC-www.acc.org,AHA-www.americanheart.org4.Antman et al.JACC Vol.44,No.3,2004.Management of Patients With STEMI:Executive Summary August 4,2004:671719遵从指南，治疗成功率大大提高遵从指南，治疗成功率大大提高(n=45,987 美国403家医院)住住院院死死亡亡率率（）医院总体依从率医院总体依从率75%HoekstraJWetal.AceaEmergMed.2002Nov;9(11):1146-55