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. Harringt

2、on, MD, on behalf of the CHAMPION PHOENIX Investigators替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Dr. 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; Honor

3、aria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke 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 I

4、nvasive Cardiology; Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, 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 cangrel

5、or.The CHAMPION PHOENIX trial was funded by The Medicines Company. Disclosures替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Antiplatelet TherapyAntiplatelet therapy is a critical part of contemporary PCI. In the era of aspirin and unfractionated heparin, intravenous glycoprotein IIb/IIIa inhibition significantly

6、reduced important periprocedural ischemic events, but significantly increased bleeding.ADP receptor antagonism with oral agents was also shown to reduce ischemic events in PCI and especially ACS. However, available oral agents are limited by their relatively long duration of action and bioavailabili

7、ty, which might be a liability: if given prior to coronary angiography and urgent or emergent CABG is deemed necessary,in situations where absorption 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

8、 1998Desai N and Bhatt DL. Periprocedural Antiplatelet Therapy. JACC Intervention 2010替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CangrelorCangrelor is an intravenous ADP receptor antagonist that is rapidly acting, potent, and reversible, with return of normal platelet function within an hour. Cangrelor was stu

9、died 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 significantly reduced in CHAMPION PLATFORM and in a prespecified pooled analysis of the two trials. There was no

10、 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 2009White HD, et al. Meta-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀C

11、HAMPION 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)Department of Medicine, Stanford University, Stanford, CAC.

12、 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. Price, M.D.Scripps Clinic and Scripps Tr

13、anslational 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, New York, NY Harvey D. Whi

14、te, D.Sc.Auckland City Hospital, Auckland, New Zealand替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION 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 Med

15、ical Center, Durham, NC Freek 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 Netherlands替格瑞洛的ChampionPhoen

16、ixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION PHOENIX CECDuke Clinical Research InstituteREVIEWERSPhase 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 NCLEADERSHIPKenne

17、th W. Mahaffey (Chair)Sergio Leonardi (co-Chair)Dianne Gallup (Lead Statistician)Matthew D. Wilson (Project Leader)OPERATIONSStacey Mangum (Coordinator)Linda Dowd (Lead CDA)Dimitrios Stournaras (Lead CDS)Sachin Vyas (Lead CTA)替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION PHOENIX Angiographic Core LabCard

18、iovascular Research FoundationMaria AlfonsoAntoinette Allen Gerard CondittRosa DeJesusChampika DjurkovicSharwat Jahan Greg KaluzaElena KonovalovaMitchell LustreKatharine LymberisDuval MichelSofia PapamitrouNicoletta PavloviciKhary PerrySaira PunjwaniConnie QiuRaquel SanchezElias SanidasShawnalee Vas

19、sellDouey WrightReviewers and Data Entry StaffLeadershipPhilippe Gnreux (Director) Sorin BrenerLaura Lasalle替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀12 Countries 153 SitesUSAPolandGermanyAustriaThailandRussiaGeorgiaBulgariaBrazilCzech RepublicUSAPolandGermanyNew ZealandAustriaItalyThailandRussiaGeorgiaBulgar

20、iaBrazilCHAMPION PHOENIX A Global Trial替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION PHOENIX Study DesignRandomized, double-blind, double-dummy, superiorityPrimary efficacy endpoint: Death/MI/IDR/ST at 48 hoursAdjusted for 600 mg versus 300 mg clopidogrel useModified Intent-to-Treat (MITT) analysis (pati

21、ents actually got study drug and PCI)Key secondary endpoint: Stent Thrombosis at 48 hoursEfficacy endpoints also examined at 30 daysPrimary 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. Met

22、a-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION PHOENIX Study Design12 to 4 hours0Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min) Clopidogrel 600 mg oralCHAMPION PHOENIXN = 10,900 MITTSA/ NSTE-ACS/ STEMI Patients requiring PCI1P2Y12 inhibitor nave OR Place

23、bo3 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 suitability for PCI was confirmed either by angiography or STEMI diagnosis. Double blind study medication was adm

24、inistered 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 infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to

25、 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 mg or 300 mg was specified by the investigator.MITT=modified intent-to-treat; NSTE-ACS=non-ST-ele

26、vation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI.Rand替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Demographics, MITTCangrelor(N= 5472)Clopidogrel(N= 5470)Age, years6464Female28%27%Diabetes mellitus28%28%Patient TypeStable angina57%55%NSTE-ACS25%26%ST

27、EMI18%19%Loading Dose300 mg clopidogrel26%26%600 mg clopidogrel74%74%Region United States37%37% Other countries63%63%替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Primary Efficacy Outcomes at 48 Hours, MITTCangrelor(N=5472)Clopidogrel(N=5470)OR (95% CI)P-valuePrimary Analysis Adjusted1Death/MI/IDR/ST 257/5470 (4.

28、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 (1.4%)0.62 (0.43,

29、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

30、 KW, et al. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Death/ MI/ IDR/ Stent Thrombosis within 48 HoursPatient at RiskHours from RandomizationCangrelor:547252335229522552235221522052175213Clopidogrel:547051625159515551525151515151475147cangrelorclopidogrel5.9%4.7%Log Rank P Value =

31、0.006Event Rate (%)Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀cangrelorclopidogrelLog Rank P Value = 0.01Patient at RiskHours from RandomizationCangrelor:547254265421541954195418541754165414Clopidogrel:5470539253895388538653855385538353831.4%0

32、.8%Event Rate (%)Stent Thrombosis within 48 HoursBhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Efficacy Outcomes at 30 Days, MITTCangrelor(N=5472)Clopidogrel(N=5470)OR (95% CI)P ValueDeath/MI/IDR/ST (primary endpoint, adjusted)326/5462 (6.0%)380/

33、5457 (7.0%)0.85 (0.73,0.99)0.03Stent thrombosis71/5462 (1.3%)104/5457 (1.9%)0.68 (0.50,0.92)0.01MI225/5462 (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 (0.7

34、6,1.58)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. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀OR 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

35、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)0.31Cangrelor infusion 129 minutes0.72 (0.56,0.92)Subgroups: Death/MI/IDR/ST at 48 Hours (continued)5.01.00.2Cangrelor BetterClopidogrel Better替格瑞洛的ChampionPhoenixII

36、I期臨床試驗結(jié)果優(yōu)秀Non-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 (0.4%)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 (

37、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%)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)0.0

38、5Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀OR 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 Start1.24 (0.58,2.66)0.25Clopidogrel Load after PCI

39、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)替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Summary of Treatment Emergent Adverse EventsAdverse EventCangrelor(N=5529)Clopidogrel(N=5527)P ValuePatients with at least one AE20.2%19.1%0.13Patients w

40、ith 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 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀LimitationsA loading dose of 600 mg has become more common than 300 mgHowever, in the three quarters of

41、patients 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 w

42、ith many 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

43、been used in 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.替格

44、瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀ConclusionsIn CHAMPION 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 second

45、ary endpoint of stent thrombosis was also significantly reduced, 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, NSTE

46、MI, and STEMI.替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀For Full Details, Please Go to www.NEJM.orgBhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at 替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀THANK YOU!替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀BACKUP SLIDES替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CangrelorDirect platelet

47、 P2Y12 receptor antagonist ATP analogue MW=800 DaltonsParenteral administrationT1/2 = 3 to 6 minutesOffset = 60 minutesNNNNNHSCF3OHOHOOPOOPPOOOClClOOOS4Na+Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangr

48、elor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀CHAMPION PCI | PLATFORMPCI | all comers PCI | 58% ACS | on clopidogrel allowed | clopidogrel 600mg administered at the start of PCI

49、 in the control armPLATFORM | all comers PCI | 65% ACS | clopidogrel nave | clopidogrel 600mg administered at the end of PCI in the control arm 12 hours0PCI 25Cangrelor 30g/kg then 4g/kg/minCangrelor 30g/kg then 4g/kg/minClopidogrel600 mg oralClopidogrel600 mg oral CHAMPION PCIN = 9000SA/UA/ACS/STEM

50、IOn clopidogrel allowedCHAMPION PLATFORMN = 6400SA/UA/ACSNo clopidogrel allowedHarrington RA, et al. NEJM 2009Bhatt DL, et al. NEJM 2009替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀48-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/ST0.38 (0.20,0.72

51、)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 Efficacy1. Bha

52、tt 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

53、 al. AHJ 2012.替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀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

54、 inhibitor within 7 days prior to angiogramEndpoint 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 |

55、 Death | MI | also intra-procedural stent thrombosis measured by angiographic core lab 31. Thygesen K, Alpert JS, and White HD, on behalf of the Joint ESC/ACCF/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J. 2007;28:2525-2538.

56、 2. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-2351.3. Brener SJ, Cristea E, Kirtane AJ, et al. Intra-Procedural Stent Thrombosis. J Am Coll Cardiol Intv 2013;6:3643.替格瑞洛的ChampionPhoenixIII期臨床試

57、驗結(jié)果優(yōu)秀Universal Definition of MI Thygesen K, Alpert JS, and White HD, on behalf of the Joint ESC/ACCF/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J. 2007;28:2525-2538.Better discrimination of MI with consideration of multiple

58、criteria CKMB elevations | ischemic symptoms | angiographic evidence | ECG changesDiagnosis of MI from various perspectives Type 1 | spontaneous MI related to ischemia Type 2 | MI secondary to ischemia | change in O2 demand/supply Type 3 | sudden unexpected cardiac death Type 4 | associated with cor

59、onary angioplasty | stents Type 4a | MI associated with PCI Type 4b | MI associated with Stent Thrombosis Type 5 | MI associated with CABG替格瑞洛的ChampionPhoenixIII期臨床試驗結(jié)果優(yōu)秀Definition of STAngiographic Evidence:ARC ST (Academic Research Consortium)1Acute (24 hours and 30 days) Definite from probable st

60、ent thrombosisAdjudicated by the CECIPST (Intra-procedural stent thrombosis)New or worsening thrombus related to the stent or Abrupt closure due tothrombosis1. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007