替格瑞洛的ChampionPhoenixIII期临床试验结果课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,CHAMPION PHOENIX,Deepak 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 PHOENIX Investigators,CHAMPION PHOENIX Deepak L. Bha,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; Honoraria:,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,Invasive 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 cangrelor.,The CHAMPION PHOENIX trial was funded by The Medicines Company.,Disclosures,Dr. Bhatt Advisory Board: Me,Antiplatelet Therapy,?,Antiplatelet 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 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 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 1998,Desai N and Bhatt DL. Periprocedural Antiplatelet Therapy. JACC Intervention 2010,Antiplatelet Therapy ?Antiplat,Cangrelor,?,Cangrelor is an intravenous ADP receptor antagonist that 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 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 2009,Bhatt DL, et al. CHAMPION PLATFORM. NEJM 2009,White HD, et al. Meta-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012,Cangrelor ?Cangrelor is an int,CHAMPION PHOENIX Executive Committee,Deepak L. Bhatt, M.D., M.P.H. (Co-Principal Investigator),VA Boston Healthcare System, Brigham and Womens Hospital, and,Harvard Medical School Boston, MA,Robert A. Harrington, M.D. (Co-Principal Investigator),Department of Medicine, Stanford University, Stanford, CA,C. 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, NC,Matthew J. Price, M.D.,Scripps Clinic and Scripps Translational Science Institute, La Jolla, CA,Ph. Gabriel Steg, M.D.,INSERM U-698, Universit,Paris-Diderot, and H?,pital Bichat, Assistance-Publique-,H?,pitaux de Paris, Paris, France,Gregg W. Stone, M.D.,Columbia University Medical Center and the Cardiovascular Research Foundation,New York, NY,Harvey D. White, D.Sc.,Auckland City Hospital, Auckland, New Zealand,CHAMPION PHOENIX Executive Com,CHAMPION PHOENIX DSMB,Frans Van de Werf, M.D. (Chair),Universitair Ziekenhuis Gasthuisberg, Belgium,David P,. Faxon, M.D.,Brigham & Womens Hospital, Dept. of Medicine, Boston, MA,E. Magnus Ohman, M.D,.,Duke University Medical 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,CHAMPION PHOENIX DSMB Frans Va,CHAMPION PHOENIX CEC,Duke Clinical Research Institute,REVIEWERS,Phase 1,Luciana Amaganijan,Brazil,Monique Anderson,NC,Akshay Bagai,NC,Robert W. Harrison,NC,Pedro G. Melo de Barros E Silva,Brazil,Phase 2,J. Matthew Brennan,NC,Renato D. Lopes,NC,Chiara Melloni,NC,Pierluigi Tricoci,NC,LEADERSHIP,Kenneth W. Mahaffey,(Chair),Sergio Leonardi,(co-Chair),Dianne Gallup,(Lead Statistician),Matthew D. Wilson,(Project Leader),OPERATIONS,Stacey Mangum,(Coordinator),Linda Dowd,(Lead CDA),Dimitrios Stournaras,(Lead CDS),Sachin Vyas,(Lead CTA),CHAMPION PHOENIX CEC Duke Clin,CHAMPION PHOENIX Angiographic Core Lab,Cardiovascular Research Foundation,Maria Alfonso,Antoinette Allen,Gerard Conditt,Rosa DeJesus,Champika Djurkovic,Sharwat Jahan,Greg Kaluza,Elena Konovalova,Mitchell Lustre,Katharine Lymberis,Duval Michel,Sofia Papamitrou,Nicoletta Pavlovici,Khary Perry,Saira Punjwani,Connie Qiu,Raquel Sanchez,Elias Sanidas,Shawnalee Vassell,Douey Wright,Reviewers and Data Entry Staff,Leadership,Philippe G,n,reux,(Director),Sorin Brener,Laura Lasalle,CHAMPION PHOENIX Angiographic,12 Countries 153 Sites,USA,Czech Republic,USA,Poland,Germany,New Zealand,Austria,Italy,Thailand,Russia,Georgia,Bulgaria,Brazil,CHAMPION PHOENIX,A Global Trial,12 Countries 153 Sites USA Cz,CHAMPION PHOENIX Study Design,?,Randomized, double-blind, double-dummy, 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,?,Primary safety endpoint: GUSTO Severe Bleeding at 48 hours,Harrington RA, et al. CHAMPION PCI. NEJM 2009,Bhatt DL, et al. CHAMPION PLATFORM. NEJM 2009,White HD, et al. Meta-Analysis of CHAMPION PCI and PLATFORM. AHJ 2012,CHAMPION PHOENIX Study Design,CHAMPION PHOENIX Study Design,1,2 to 4 hours,0,Cangrelor,2,bolus & infusion,(30ug/kg; 4ug/kg/min),Clopidogrel,600 mg oral,CHAMPION PHOENIX,N = 10,900 MITT,SA/ NSTE-ACS/ STEMI,Patients requiring PCI,1,P2Y,12,inhibitor na?,ve,OR,Placebo,3,oral (right before PCI or right after, per physician),Placebo,2,bolus & infusion,Placebo oral,PCI 30,OR,Clopidogrel,3,(600 mg or 300 mg oral, per physician),1,Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis.,Double blind study medication was administered as soon as possible following randomization.,2,Study 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 maintenance clopidogrel therapy.,3,Clopidogrel 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-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina;,STEMI=ST-elevation MI.,Rand,CHAMPION PHOENIX Study Design,Demographics, MITT,Cangrelor,(N= 5472),Clopidogrel,(N= 5470),Age, years,64,64,Female,28%,27%,Diabetes mellitus,28%,28%,Patient Type,Stable angina,57%,55%,NSTE-ACS,25%,26%,STEMI,18%,19%,Loading Dose,300 mg clopidogrel,26%,26%,600 mg clopidogrel,74%,74%,Region,United States,37%,37%,Other countries,63%,63%,Demographics, MITT Cangrelor,Primary Efficacy Outcomes at 48 Hours, MITT,Cangrelor,(N=5472),Clopidogrel,(N=5470),OR (95% CI),P-value,Primary Analysis Adjusted,1,Death/MI/IDR/ST,257/5470,(4.7%),322/5469,(5.9%),0.78 (0.66,0.93),0.005,1.,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, MITT,Stent thrombosis (key,secondary endpoint),46/5470,(0.8%),74/5469,(1.4%),0.62,(0.43,0.90),0.01,MI,207/5470 (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),0.19,IDR,28/5470 (0.5),38/5469 ( 0.7),0.74 (0.45,1.20),0.22,Death,18/5470 (0.3),18/5469 (0.3),1.00 (0.52,1.92),0.99,CV Death,18/5470 (0.3),18/5469 (0.3),1.00 (0.52,1.92),0.99,Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org,Primary Efficacy Outcomes at 4,替格瑞洛的ChampionPhoenixIII期临床试验结果课件,替格瑞洛的ChampionPhoenixIII期临床试验结果课件,Efficacy Outcomes at 30 Days, MITT,Cangrelor,(N=5472),Clopidogrel,(N=5470),OR (95% CI),P,Value,Death/MI/IDR/ST,(primary endpoint,adjusted),326/5462,(6.0%),380/5457,(7.0%),0.85 (0.73,0.99),0.03,Stent thrombosis,71/5462 (1.3%),104/5457,(1.9%),0.68 (0.50,0.92),0.01,MI,225/5462,(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),0.18,IDR,56/5462 (1.0%),66/5457 (1.2%),0.85 (0.59,1.21),0.36,Death,60/5462 (1.1%),55/5457 (1.0%),1.09 (0.76,1.58),0.64,CV Death,48/5462 (0.9%),46/5457 (0.8%),1.04 (0.69,1.57),0.84,Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org,Efficacy Outcomes at 30 Days,OR 95% CI,P Int,Overall,0.79 (0.67,0.93),Age,75,0.71 (0.50,1.02),0.55,Age =60,0.79 (0.66,0.94),0.89,Weight 100 mg,0.70 (0.52,0.94),Clopidogrel Load before PCI Start,0.80 (0.64,0.98),0.99,Clopidogrel Load after PCI Start,0.79 (0.59,1.06),Cangrelor infusion 129 minutes,0.85 (0.68,1.07),0.31,Cangrelor infusion 129 minutes,0.72 (0.56,0.92),Subgroups: Death/MI/IDR/ST at 48 Hours,(continued),5.0,1.0,0.2,Cangrelor Better,Clopidogrel Better,OR 95% CI P Int Prior TIA/,Non-CABG Bleeding at 48 Hours, Safety,Bleeding Scale,Cangrelor,(N=5529),Clopidogrel,(N=5527),OR (95% CI),P Value,GUSTO Severe,9 (0.16%),6 (0.11%),1.50 (0.53,4.22),0.44,GUSTO Moderate,22 (0.4%),13 (0.2%),1.69 (0.85,3.37),0.13,GUSTO Severe +,Moderate,31 (0.6%),19 (0.3%),1.63 (0.92,2.90),0.09,TIMI Major,5 (0.1%),5 (0.1%),1.00 (0.29,3.45),0.999,TIMI Minor,9 (0.2%),3 (0.1%),3.00 (0.81,11.10),0.08,TIMI Major + Minor,14 (0.3%),8 (0.1%),1.75 (0.73,4.18),0.2,Any Blood Transfusion,25 (0.5%),16 (0.3%),1.56 (0.83,2.93),0.16,ACUITY Major,235 (4.3%),139 (2.5%),1.72 (1.39,2.13),0.001,ACUITY w/out hematoma,42 (0.8%),26 (0.5%),1.62 (0.99,2.64),0.05,Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org,Non-CABG Bleeding at 48 Hours,OR 95% CI,P Int,Overall,1.63 (0.92,2.90),Age,75,1.07 (0.45,2.53),0.21,Age =60,1.52 (0.80,2.86),0.71,Weight 100 mg,1.49 (0.74,3.03),Clopidogrel Load before PCI Start,1.24 (0.58,2.66),0.25,Clopidogrel Load after PCI Start,2.53 (0.98,6.54),Cangrelor infusion 129 minutes,1.71(0.81,3.59),0.85,Cangrelor infusion 129 minutes,1.52(0.62,3.73),Subgroups: GUSTO Severe/Modera,Summary of Treatment Emergent,Adverse Events,Adverse Event,Cangrelor,(N=5529),Clopidogrel,(N=5527),P Value,Patients with at least one AE,20.2%,19.1%,0.13,Patients with at least one AE,causing study drug discontinuation,0.5%,0.4%,0.21,Transient dyspnea,1.2%,0.3%,0.001,Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org,Summary of Treatment Emergent,Limitations,?,A loading dose of 600 mg has become more common than 300 mg,?,However, in the three quarters of 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 with 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 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.,Limitations ?A loading dose of,Conclusions,?,In 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 secondary 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,NSTEMI, and STEMI.,Conclusions ?In CHAMPION PHOEN,For Full Details, Please Go to www.NEJM.org,Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at www.nejm.org,For Full Details, Please Go to,THANK YOU!,THANK YOU!,BACKUP SLIDES,BACKUP SLIDES,Cangrelor,?,Direct platelet P2Y,12,receptor antagonist,?,ATP analogue MW=800 Daltons,?,Parenteral administration,?,T1/2 = 3 to 6 minutes,?,Offset = 60 minutes,N,N,N,N,N,H,S,C,F,3,O,H,O,H,O,O,P,O,O,P,P,O,O,O,Cl,Cl,O,O,O,S,4Na,+,Angiolillo DJ, Schneider DJ, Bhatt 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.,Cangrelor ?Direct platelet P2Y,CHAMPION PCI,|,PLATFORM,?,PCI,|,all comers PCI,|,58% ACS,| on,clopidogrel allowed,|,clopidogrel,600mg administered at the,start,of PCI in the control arm,?,PLATFORM,|,all comers PCI,|,65% ACS,|,clopidogrel,na?,ve,|,clopidogrel,600mg administered at the,end,of PCI in the control arm,1,2 hours,0,PCI 25,Cangrelor 30,?,g/kg then 4,?,g/kg/min,Cangrelor 30,?,g/kg then 4,?,g/kg/min,Clopidogrel,600 mg oral,Clopidogrel,600 mg oral,CHAMPION PCI,N = 9000,SA/UA/ACS/STEMI,On clopidogrel allowed,CHAMPION PLATFORM,N = 6400,SA/UA/ACS,No clopidogrel allowed,Harrington RA, et al. NEJM 2009,Bhatt DL, et al. NEJM 2009,CHAMPION PCI | PLATFORM ?PCI |,48-Hour Events,PLATFORM,OR 95% CI,P value,Death/MI/IDR,0.87 (0.71,1.07),0.17,Death/Q-MI/IDR,0.55 (0.33,0.93),0.02,Death/Q-MI/ST,0.38 (0.20,0.72),0.003,PCI,Death/MI/IDR,1.05 (0.89,1.24),0.57,Death/Q-MI/IDR,0.66 (0.42,1.05),0.08,Death/Q-MI/ST,0.74 (0.43,1.27),0.27,POOLED,Death/MI/IDR,0.97 (0.86,1.11),0.68,Death/Q-MI/IDR,0.61 (0.43,0.86),0.005,Death/Q-MI/ST,0.55 (0.36,0.83),0.004,Cangrelor Better,5.0,2.0,1.0,0.2,0.5,Comparator Better,Summary of Clinical Efficacy,1. 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. AHJ 2012.,48-Hour Events PLATFORM OR 95,CHAMPION PHOENIX,Lessons from CHAMPION PCI | PLATFORM,Trial Design,Implementation,Patient population,All comers PCI,Inclusion of patients with normal cardiac markers,at baseline,|,est. 65% trial population,P2Y,12,inhibitor na?,ve,Patients not pre-treated with P2Y,12,inhibitor,within 7 days prior to angiogram,Endpoint definitions,MI definition,1,UDMI,|,Central lab to assure consistency of,CKMB mass assay globally,|,angiographic core,lab to consistently assess evidence of ischemia,Stent thrombosis,definition,2,ARC Definition includes,occurrence associated,with IDR,|,Death,|,MI,|,also intra-procedural stent,thrombosis measured by angiographic core lab,3,1. 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.,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;6:36,43.,CHAMPION PHOENIX Lessons from,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. Universa