替格瑞洛Champion-Phoenix-III期临床试验结果系列课件.ppt

1、CHAMPION PHOENIXDeepak L.Bhatt,MD,MPH,Gregg W.Stone,MD,Kenneth W.Mahaffey,MD,C.Michael Gibson,MS,MD,Ph.Gabriel Steg,MD,Christian Hamm,MD,Matthew Price,MD,Sergio Leonardi,MD,Dianne Gallup,MS,Meredith Todd,Simona Skerjanec,PharmD,Harvey D.White,DSc,and Robert A.Harrington,MD,on behalf of the CHAMPION

2、PHOENIX InvestigatorsDr.Bhatt Advisory Board:Medscape Cardiology;Board of Directors:Boston VA Research Institute,Society of Chest Pain Centers;Chair:American Heart Association Get With The Guidelines Science Subcommittee;Honoraria:American College of Cardiology(Editor,Clinical Trials,Cardiosource),D

3、uke Clinical Research Institute(clinical trial steering committees),Slack Publications(Chief Medical Editor,Cardiology Today Intervention),WebMD(CME steering committees);Other:Senior Associate Editor,Journal of Invasive Cardiology;Research Grants:Amarin,AstraZeneca,Bristol-Myers Squibb,Eisai,Ethicon

4、,Medtronic,Sanofi Aventis,The Medicines Company;Unfunded Research:FlowCo,PLx Pharma,Takeda.This presentation includes off-label and/or investigational uses of drugs,including clopidogrel and cangrelor.The CHAMPION PHOENIX trial was funded by The Medicines Company.DisclosuresAntiplatelet Therapy Anti

5、platelet therapy is a critical part of contemporary PCI.In the era of aspirin and unfractionated heparin,intravenous glycoprotein IIb/IIIa inhibition significantly reduced important periprocedural ischemic events,but significantly increased bleeding.ADP receptor antagonism with oral agents was also

6、shown to reduce ischemic events in PCI and especially ACS.However,available oral agents are limited by their relatively long duration of action and bioavailability,which might be a liability:if given prior to coronary angiography and urgent or emergent CABG is deemed necessary,in situations where ab

7、sorption may be problematic,such as with rapid times to PCI,in patients who are intubated,nauseated,with STEMI,or shock.Harrington RA,et al.PURSUIT.NEJM 1998Desai N and Bhatt DL.Periprocedural Antiplatelet Therapy.JACC Intervention 2010Cangrelor Cangrelor is an intravenous ADP receptor antagonist th

8、at is rapidly acting,potent,and reversible,with return of normal platelet function within an hour.Cangrelor was studied previously in two large Phase 3 PCI trials,CHAMPION PCI and CHAMPION PLATFORM.Neither study met its primary endpoint,but the secondary endpoint of stent thrombosis at 48 hours was

9、significantly reduced in CHAMPION PLATFORM and in a prespecified pooled analysis of the two trials.There was no excess in severe bleeding.The potential efficacy signal prompted us to launch the CHAMPION PHOENIX trial.Harrington RA,et al.CHAMPION PCI.NEJM 2009Bhatt DL,et al.CHAMPION PLATFORM.NEJM 200

10、9White HD,et al.Meta-Analysis of CHAMPION PCI and PLATFORM.AHJ 2012CHAMPION PHOENIX Executive CommitteeDeepak L.Bhatt,M.D.,M.P.H.(Co-Principal Investigator)VA Boston Healthcare System,Brigham and Womens Hospital,and Harvard Medical School Boston,MARobert A.Harrington,M.D.(Co-Principal Investigator)D

11、epartment of Medicine,Stanford University,Stanford,CAC.Michael Gibson,M.S.,M.D.Beth Israel Deaconess Medical Center,Division of Cardiology,Boston,MA Christian W.Hamm,M.D.Kerckhoff Heart and Thorax Center,Bad Nauheim,Germany Kenneth W.Mahaffey,M.D.Duke Clinical Research Institute,Durham,NCMatthew J.P

12、rice,M.D.Scripps Clinic and Scripps Translational Science Institute,La Jolla,CAPh.Gabriel Steg,M.D.INSERM U-698,Universit Paris-Diderot,and Hpital Bichat,Assistance-Publique-Hpitaux de Paris,Paris,France Gregg W.Stone,M.D.Columbia University Medical Center and the Cardiovascular Research Foundation,

13、New York,NY Harvey D.White,D.Sc.Auckland City Hospital,Auckland,New ZealandCHAMPION PHOENIX DSMBFrans Van de Werf,M.D.(Chair)Universitair Ziekenhuis Gasthuisberg,BelgiumDavid P.Faxon,M.D.Brigham&Womens Hospital,Dept.of Medicine,Boston,MA E.Magnus Ohman,M.D.Duke University Medical Center,Durham,NC Fr

14、eek W.A.Verheugt,M.D.Heartcenter University Medical Center,Amsterdam W.Douglas Weaver,M.D.Henry Ford Hospital,Detroit,MI Jan G.P.Tijssen,Ph.D.(Statistician)Department of Cardiology,Academic Medical Center-University of Amsterdam,The NetherlandsCHAMPION PHOENIX CECDuke Clinical Research InstituteREVI

15、EWERSPhase 1 Luciana Amaganijan BrazilMonique Anderson NC Akshay Bagai NCRobert W.Harrison NCPedro G.Melo de Barros E Silva BrazilPhase 2J.Matthew Brennan NCRenato D.Lopes NCChiara Melloni NCPierluigi Tricoci NCLEADERSHIPKenneth W.Mahaffey(Chair)Sergio Leonardi (co-Chair)Dianne Gallup (Lead Statisti

16、cian)Matthew D.Wilson (Project Leader)OPERATIONSStacey Mangum (Coordinator)Linda Dowd (Lead CDA)Dimitrios Stournaras (Lead CDS)Sachin Vyas (Lead CTA)CHAMPION PHOENIX Angiographic Core LabCardiovascular Research FoundationMaria AlfonsoAntoinette Allen Gerard CondittRosa DeJesusChampika DjurkovicSharw

17、at Jahan Greg KaluzaElena KonovalovaMitchell LustreKatharine LymberisDuval MichelSofia PapamitrouNicoletta PavloviciKhary PerrySaira PunjwaniConnie QiuRaquel SanchezElias SanidasShawnalee VassellDouey WrightReviewers and Data Entry StaffReviewers and Data Entry StaffLeadershipLeadershipPhilippe Gnre

18、ux (Director)Sorin BrenerLaura Lasalle12 Countries 153 SitesUSAPolandGermanyAustriaThailandRussiaGeorgiaBulgariaBrazilCzech RepublicUSAPolandGermanyNew ZealandAustriaItalyThailandRussiaGeorgiaBulgariaBrazilCHAMPION PHOENIX A Global TrialCHAMPION PHOENIX Study Design Randomized,double-blind,double-du

19、mmy,superiority Primary efficacy endpoint:Death/MI/IDR/ST at 48 hours Adjusted for 600 mg versus 300 mg clopidogrel use Modified Intent-to-Treat(MITT)analysis(patients actually got study drug and PCI)Key secondary endpoint:Stent Thrombosis at 48 hours Efficacy endpoints also examined at 30 days Prim

20、ary safety endpoint:GUSTO Severe Bleeding at 48 hoursHarrington RA,et al.CHAMPION PCI.NEJM 2009Bhatt DL,et al.CHAMPION PLATFORM.NEJM 2009White HD,et al.Meta-Analysis of CHAMPION PCI and PLATFORM.AHJ 2012CHAMPION PHOENIX Study Design12 to 4 hours0Cangrelor2 bolus&infusion(30ug/kg;4ug/kg/min)Clopidogr

21、el 600 mg oralCHAMPION PHOENIXN=10,900 MITTSA/NSTE-ACS/STEMI Patients requiring PCI1P2Y12 inhibitor nave OR Placebo3 oral(right before PCI or right after,per physician)Placebo2 bolus&infusion Placebo oralPCI 30 OR Clopidogrel3(600 mg or 300 mg oral,per physician)1Randomization occurred once suitabil

22、ity for PCI was confirmed either by angiography or STEMI diagnosis.Double blind study medication was administered as soon as possible following randomization.2Study drug Infusion(cangrelor or matching placebo)was continued for 2-4 hours at the discretion of the treating physician.At the end of the i

23、nfusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy.3Clopidogrel loading dose(or matching placebo)was administered as directed by the investigator.At the time of patient randomization,a clopidogrel loading dose of 600 m

24、g or 300 mg was specified by the investigator.MITT=modified intent-to-treat;NSTE-ACS=non-ST-elevation acute coronary syndrome;PCI=percutaneous coronary intervention;SA=stable angina;STEMI=ST-elevation MI.RandDemographics,MITT Cangrelor(N=5472)Clopidogrel(N=5470)Age,years6464Female28%27%Diabetes mell

25、itus28%28%Patient Type Stable angina57%55%NSTE-ACS25%26%STEMI18%19%Loading Dose 300 mg clopidogrel26%26%600 mg clopidogrel74%74%Region United States37%37%Other countries63%63%Primary Efficacy Outcomes at 48 Hours,MITT Cangrelor(N=5472)Clopidogrel(N=5470)OR(95%CI)P-valuePrimary Analysis Adjusted1 Dea

26、th/MI/IDR/ST 257/5470(4.7%)322/5469(5.9%)0.78 (0.66,0.93)0.0051.The logistic model was adjusted for baseline status and clopidogrel dose.P value of 0.006 shown on the KM curve is log rank p value.Secondary Efficacy Outcomes at 48 Hours,MITTStent thrombosis(keysecondary endpoint)46/5470(0.8%)74/5469(

27、1.4%)0.62(0.43,0.90)0.01MI207/5470(3.8)255/5469(4.7)0.80(0.67,0.97)0.02 Q-wave MI 11/5470(0.2)18/5469(0.3)0.61(0.29,1.29)0.19IDR28/5470(0.5)38/5469(0.7)0.74(0.45,1.20)0.22Death18/5470(0.3)18/5469(0.3)1.00(0.52,1.92)0.99 CV Death18/5470(0.3)18/5469(0.3)1.00(0.52,1.92)0.99Bhatt DL,Stone GW,Mahaffey KW

28、,et al.Harrington RA.NEJM 2013 at www.nejm.orgDeath/MI/IDR/Stent Thrombosis within 48 HoursPatient at RiskHours from RandomizationCangrelor:547252335229522552235221522052175213Clopidogrel:547051625159515551525151515151475147cangrelorclopidogrel5.9%4.7%Log Rank P Value=0.006Event Rate(%)Bhatt DL,Ston

29、e GW,Mahaffey KW,et al.Harrington RA.NEJM 2013 at www.nejm.orgcangrelorclopidogrelLog Rank P Value=0.01Patient at RiskHours from RandomizationCangrelor:547254265421541954195418541754165414Clopidogrel:5470539253895388538653855385538353831.4%0.8%Event Rate(%)Stent Thrombosis within 48 HoursBhatt DL,St

30、one GW,Mahaffey KW,et al.Harrington RA.NEJM 2013 at www.nejm.orgEfficacy Outcomes at 30 Days,MITT Cangrelor(N=5472)Clopidogrel(N=5470)OR(95%CI)P ValueDeath/MI/IDR/ST(primary endpoint,adjusted)326/5462(6.0%)380/5457(7.0%)0.85(0.73,0.99)0.03Stent thrombosis 71/5462(1.3%)104/5457(1.9%)0.68(0.50,0.92)0.

31、01MI225/5462(4.1%)272/5457(5.0%)0.82(0.68,0.98)0.03 Q-wave MI 14/5462(0.3%)22/5457(0.4%)0.63(0.32,1.24)0.18IDR56/5462(1.0%)66/5457(1.2%)0.85(0.59,1.21)0.36Death60/5462(1.1%)55/5457(1.0%)1.09(0.76,1.58)0.64 CV Death48/5462(0.9%)46/5457(0.8%)1.04(0.69,1.57)0.84Bhatt DL,Stone GW,Mahaffey KW,et al.Harri

32、ngton RA.NEJM 2013 at www.nejm.orgOR 95%CIP IntOverall 0.79(0.67,0.93)Age 750.71(0.50,1.02)0.55Age=600.79(0.66,0.94)0.89Weight 100 mg0.70(0.52,0.94)Clopidogrel Load before PCI Start0.80(0.64,0.98)0.99Clopidogrel Load after PCI Start0.79(0.59,1.06)Cangrelor infusion 129 minutes0.85(0.68,1.07)0.31Cang

33、relor infusion 129 minutes0.72(0.56,0.92)Subgroups:Death/MI/IDR/ST at 48 Hours(continued)5.01.00.2Cangrelor BetterClopidogrel BetterNon-CABG Bleeding at 48 Hours,SafetyBleeding ScaleCangrelor(N=5529)Clopidogrel(N=5527)OR(95%CI)P ValueGUSTO Severe9(0.16%)6(0.11%)1.50(0.53,4.22)0.44GUSTO Moderate22(0.

34、4%)13(0.2%)1.69(0.85,3.37)0.13GUSTO Severe+Moderate31(0.6%)19(0.3%)1.63(0.92,2.90)0.09TIMI Major5(0.1%)5(0.1%)1.00(0.29,3.45)0.999TIMI Minor9(0.2%)3(0.1%)3.00(0.81,11.10)0.08TIMI Major+Minor14(0.3%)8(0.1%)1.75(0.73,4.18)0.2Any Blood Transfusion25(0.5%)16(0.3%)1.56(0.83,2.93)0.16ACUITY Major235(4.3%)

35、139(2.5%)1.72(1.39,2.13)0.001ACUITY w/out hematoma42(0.8%)26(0.5%)1.62(0.99,2.64)0.05Bhatt DL,Stone GW,Mahaffey KW,et al.Harrington RA.NEJM 2013 at www.nejm.orgOR 95%CIP IntOverall1.63(0.92,2.90)Age 751.07(0.45,2.53)0.21Age=601.52(0.80,2.86)0.71Weight 100 mg1.49(0.74,3.03)Clopidogrel Load before PCI

36、 Start1.24(0.58,2.66)0.25Clopidogrel Load after PCI Start2.53(0.98,6.54)Cangrelor infusion 129 minutes1.71(0.81,3.59)0.85Cangrelor infusion 129 minutes1.52(0.62,3.73)Summary of Treatment Emergent Adverse Events Adverse EventCangrelor(N=5529)Clopidogrel(N=5527)P ValuePatients with at least one AE20.2

37、%19.1%0.13Patients with at least one AE causing study drug discontinuation0.5%0.4%0.21Transient dyspnea1.2%0.3%0.001Bhatt DL,Stone GW,Mahaffey KW,et al.Harrington RA.NEJM 2013 at www.nejm.orgLimitations A loading dose of 600 mg has become more common than 300 mg However,in the three quarters of pati

38、ents who received 600 mg,the benefit of cangrelor remained statistically significant and was not attenuated.It is possible the benefits we saw here would have been attenuated with a longer duration of pretreatment.Of note,the clopidogrel pretreatment was given“on the table”as is consistent with many

39、 practices around the world and in particular in the United States.Importantly,prospective randomized clinical trials,namely CREDO and PRAGUE-8,did not find a significant benefit for clopidogrel pretreatment.The benefits seen here may also have been attenuated had prasugrel or ticagrelor been used i

40、n the control arm.However,to date,the largest trial of prasugrel pretreatment,ACCOAST,was terminated by the DSMB for lack of efficacy and excess bleeding.Thus,oral pretreatment,while biologically appealing and intuitive,remains unproven in prospective randomized clinical trials.ConclusionsIn CHAMPIO

41、N PHOENIX,intravenous ADP receptor antagonism with cangrelor significantly(p=0.005)reduced the composite of death,myocardial infarction,ischemia-driven revascularization,or stent thrombosis at 48 hours,with a 22%odds reduction.The key secondary endpoint of stent thrombosis was also significantly red

42、uced,with a 38%odds reduction.The benefit was sustained through 30 days.There was no excess in severe bleeding or transfusions.Intravenous cangrelor may be an attractive option across the full spectrum of PCI,including stable angina,NSTEMI,and STEMI.For Full Details,Please Go to www.NEJM.orgBhatt DL

43、,Stone GW,Mahaffey KW,et al.Harrington RA.NEJM 2013 at www.nejm.orgTHANK YOU!BACKUP SLIDESCangrelor Direct platelet P2Y12 receptor antagonist ATP analogue MW=800 Daltons Parenteral administration T1/2=3 to 6 minutes Offset=60 minutesNNNNNHSCF3OHOHOOPOOPPOOOClClOOOS4Na+Angiolillo DJ,Schneider DJ,Bhat

44、t DL,et al.Pharmacodynamic effects of cangrelor and clopidogrel:the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition(CHAMPION)trials.J Thromb Thrombolysis 2012;34:44-55.CHAMPION PCI|PLATFORM PCI|all comers PCI|58%ACS|on clopid

45、ogrel allowed|clopidogrel 600mg administered at the start of PCI in the control arm PLATFORM|all comers PCI|65%ACS|clopidogrel nave|clopidogrel 600mg administered at the end of PCI in the control arm 12 hours0PCI 25Cangrelor 30 g/kg then 4 g/kg/minCangrelor 30 g/kg then 4 g/kg/minClopidogrel600 mg o

46、ralClopidogrel600 mg oral CHAMPION PCIN=9000SA/UA/ACS/STEMIOn clopidogrel allowedCHAMPION PLATFORMN=6400SA/UA/ACSNo clopidogrel allowedHarrington RA,et al.NEJM 2009Bhatt DL,et al.NEJM 200948-Hour EventsPLATFORMOR 95%CIP valueDeath/MI/IDR0.87(0.71,1.07)0.17Death/Q-MI/IDR0.55(0.33,0.93)0.02Death/Q-MI/

47、ST0.38(0.20,0.72)0.003PCI Death/MI/IDR1.05(0.89,1.24)0.57 Death/Q-MI/IDR0.66(0.42,1.05)0.08Death/Q-MI/ST0.74(0.43,1.27)0.27POOLED Death/MI/IDR0.97(0.86,1.11)0.68Death/Q-MI/IDR0.61(0.43,0.86)0.005Death/Q-MI/ST0.55(0.36,0.83)0.004Cangrelor Better5.02.01.00.20.5Comparator BetterSummary of Clinical Effi

48、cacy1.Bhatt DL,Lincoff AM,Gibson CM,et al.Intravenous platelet blockade with cangrelor during PCI.N Engl J Med 2009;361:2330-41.2.Harrington RA,Stone GW,McNulty S,et al.Platelet inhibition with cangrelor in patients undergoing PCI.N Engl J Med 2009;361:2318-29.3.White HD,Chew DP,Dauerman HL,et al.AH

49、J 2012.CHAMPION PHOENIXLessons from CHAMPION PCI|PLATFORMTrial DesignImplementationPatient populationAll comers PCIInclusion of patients with normal cardiac markers at baseline|est.65%trial populationP2Y12 inhibitor navePatients not pre-treated with P2Y12 inhibitor within 7 days prior to angiogramEn

50、dpoint definitionsMI definition 1UDMI|Central lab to assure consistency of CKMB mass assay globally|angiographic core lab to consistently assess evidence of ischemiaStent thrombosis definition 2 ARC Definition includes occurrence associated with IDR|Death|MI|also intra-procedural stent thrombosis me