Consistent Reduction in MI with Cangrelor Deepak L Consistent Reduction in MI with Cangrelor Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart and Vascular Center Professor of Medicine, Harvard Medical School

Disclosures for Dr. Bhatt Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. This presentation discusses off-label and/or investigational uses of various drugs and devices.

Cangrelor Direct platelet P2Y12 receptor antagonist ATP analogue MW=800 Daltons Parenteral administration T1/2 = 3 to 6 minutes Offset = 60 minutes N H S C F 3 O P Cl 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.

CHAMPION PHOENIX Study Design OR Placebo3 oral (right before PCI or right after, per physician) CHAMPION PHOENIX N = 10,900 MITT SA/ NSTE-ACS/ STEMI Patients requiring PCI1 P2Y12 inhibitor naïve Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min) Clopidogrel 600 mg oral Rand PCI ~30’ Placebo2 bolus & infusion Placebo oral OR Clopidogrel3 (600 mg or 300 mg oral, per physician) 1 2 to 4 hours 1Randomization 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. 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 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-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI.

Death/ MI/ IDR/ Stent Thrombosis within 48 Hours cangrelor clopidogrel 5.9% 4.7% Event Rate (%) Log Rank P Value = 0.006 Patient at Risk Hours from Randomization Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213 Clopidogrel: 5470 5162 5159 5155 5152 5151 5147 Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

Stent Thrombosis within 48 Hours cangrelor clopidogrel 1.4% 0.8% Event Rate (%) Log Rank P Value = 0.01 Patient at Risk Hours from Randomization Cangrelor: 5472 5426 5421 5419 5418 5417 5416 5414 Clopidogrel: 5470 5392 5389 5388 5386 5385 5383 Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

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%) 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

IPST in CHAMPION PHOENIX 10,939 pts assessed by a blinded core lab Reduction of IPST with cangrelor P Int = 0.77 OR 0.76 [0.34,1.73] p=0.52 OR 0.75 [0.38,1.50] p=0.42 OR 0.65 [0.42,0.99] p=0.04 IPST (%) OR 0.50 [0.24,1.05] p=0.06 Généreux P et al. JACC 2013.

Effect of Cangrelor on Type 4a MI at 48 hrs Stratified by Peak CK-MB Peak CK-MB of Incident MI in CHAMPION-PHOENIX Cangrelor n=5470 Clopidogrel n=5469 OR (95% CI) 3.5% (194) 4.4% (239) 0.80 (0.66-0.98) ≥ 3x ULN 1.2% (106) 1.7% (129) 0.82 (0.63-1.06) ≥ 5x ULN 0.6% (37) 1.1% (62) 0.59 (0.39-0.89) ≥ 10x ULN 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 Hazard Ratio Cangrelor Better Cavender M, Bhatt, DL, Stone GW, et al and Harrington RA. Circulation 2016.

Results: Sensitivity analyses for composite endpoints Cangrelor (N=5472) Clopidogrel (N=5470) Odds Ratio (95% CI) Protocol-defined primary endpoint   4.7% (257/5470)   5.9% (322/5469) 0.79 (0.67, 0.93) Death/MI/IDR/ST Sensitivity Analyses Removal of IPST Death/MI/IDR/ARC-ST   4.2% (230/5470)   5.2% (286/5469) 0.80 (0.67, 0.95) Removal of IPST and MIs solely identified by CK-MB >3xULN but <10xULN Death/MI≥10xULN or Symptoms or ECG/IDR/ARC-ST   1.9% (106/5470)   2.9% (161/5469) 0.65 (0.51, 0.83) Removal of IPST and all MIs solely identified by biomarkers Death/MI with Symptom or ECG/IDR/ARC-ST    1.6% (86/5470)   2.4% (130/5469) 0.66 (0.50, 0.86) Favors Cangrelor Favors Clopidogrel Cavender M et al. Circulation 2016.

Effect of Cangrelor on MI at 48 hrs by SCAI Consensus Defintion Endpoints with SCAI Criteria for MI* Cangrelor (N=5472) Clopidogrel (N=5470 Odds Ratio (95% CI) P value CK-MB ≥10xULN or MI ≥5xULN + QWAVE or LBBB 1.0% (52/5470) 1.4% (79/5469)  0.65 (0.46, 0.93) 0.0176  Death/MI ≥10xULN or LBBB/IDR/ARC-ST (79/5470) 2.0% (112/5469) 0.70 (0.52, 0.94) 0.0159 *Moussa J, et al. J Am Coll Cardiol 2013;62:1563–70) Cavender M, Bhatt, DL, Stone GW, et al and Harrington RA. Circulation 2016.

CHAMPION Trials Study Designs Randomised, Double Blind, Controlled Trials of patients undergoing PCI CHAMPION PHOENIX n=10,942 mITT SA / NSTE-ACS / STEMI P2Y12 naïve Placebo or clopidogrel before or after PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral OR Clopidogrel 600 mg or 300 mg oral CHAMPION PCI n=8,667 mITT SA / NSTE-ACS / STEMI Placebo or clopidogrel before PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral CHAMPION PLATFORM n=5,301 mITT SA / NSTE-ACS P2Y12 naïve Placebo or clopidogrel after PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral 1 2 hours Harrington RA, et al. NEJM 2009 Bhatt DL, et al. NEJM 2009 Bhatt DL, et al. NEJM 2013 PCI ~30’

Summary of Clinical Efficacy: Pooled Analysis Death / MI / IDR / ST OR (95% CI) p value p for interaction PLATFORM 0.72 (0.53, 0.97) 0.0330 PCI 0.90 (0.72, 1.14) 0.3859 PHOENIX 0.79 (0.67, 0.93) 0.0055 Pooled 0.81 (0.71, 0.91) 0.0007 0.4537 ST 0.31 (0.11, 0.85) 0.0157 0.73 (0.33, 1.59) 0.4242 0.62 (0.43, 0.90) 0.0101 0.59 (0.43, 0.80) 0.0008 0.3716 Death / MI / IDR 0.80 (0.67, 0.95) 0.0115 0.81 (0.71, 0.92) 0.0014 0.4681 Death / QMI / IDR    PLATFORM 0.55 (0.33, 0.93) 0.0224    PCI 0.66 (0.42, 1.05) 0.0779    PHOENIX 0.76 (0.53, 1.11) 0.1558    Pooled 0.68 (0.52, 0.87) 0.0022 0.6093 Cangrelor better Comparator better Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013.

Cangrelor Mehta SR. Lancet 2013.

Alexopolous D, Bhatt DL, Hamm CW, Steg PG, Stone GW Alexopolous D, Bhatt DL, Hamm CW, Steg PG, Stone GW. Am Heart J 2015;170:3-12

CHAMPION PHOENIX Overall and STEMI outcomes, 48 h Primary Endpoint Cangrelor Clopidogrel OR Overall mITT (N=10,942) 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66-0.93) STEMI (n=1,991) 27/961 (2.8%) 38/1030 (3.7%) 0.75 (0.46-1.25) Stent Thrombosis Overall mITT (N=10,942) 46/5470 (0.8%) 74/5469 (1.4%) 0.62 (0.43-0.90) STEMI (n=1,991) 12/961 (1.2%) 20/1030 (1.9%) 0.64 (0.31-1.31) GUSTO sev/mod bleeding Overall safety (N=11,056) 31/5529 (0.6%) 19/5527 (0.3%) 1.63 (0.92-2.90) STEMI (n=2,070) 12/1000 (1.2%) 7/1070 (0.7%) 1.84 (0.72-4.70) Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013;68:1303-13 and online appendix.

Pooled CHAMPION Trials Overall and STEMI outcomes, 48 h Primary Endpoint Cangrelor Clopidogrel OR Overall mITT* (N=24,910) 473/12,459 (3.8%) 579/12,422 (4.7%) 0·81 (0.71-0.91) STEMI† (n=2884) 41/1407 (2.9%) 51/1477 (3.5%) 0·84 (0.55-1.27) Stent Thrombosis Overall mITT* (N=24,881) 62/12,459 (0.5%) 105/12,422 (0.8%) 0·59 (0.43-0.80) STEMI (n=2,884) 16/1407 (1.1%) 24/1477 (1.6%) 0.70 (0.37-1.32) GUSTO sev/mod bleeding Overall safety* (N=25,107) 103 (0.8%) 79 (0.6%) 1·30 (0.97-1.75) STEMI (n=3008) 17/1463 (1.2%) 15/1545 (1.0%) 1.20 (0.60-2.41) * Overall population includes CHAMPION PHOENIX, PCI, and PLATFORM; †STEMI population from PHOENIX and PCI * Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013; 82:1981–92.

Oral Pretreatment in STEMI Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.

Oral Pretreatment in STEMI Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.

Summary There was a consistent risk reduction with cangrelor irrespective of the exact composite outcome examined. Specifically for MI, even when all biomarker defined MI were excluded, the treatment effect of cangrelor remained significant. Compared with clopidogrel, cangrelor reduces important ischemic events, even using the most restrictive definitions of MI and ST.

Conclusions In CHAMPION PHOENIX, cangrelor during PCI: Significantly reduced the primary endpoint (death/MI/IDR/ST) Significantly reduced the secondary endpoint (ST) Significantly reduced IPST as assessed by a blinded core lab Consistently reduced important ischemic events, irrespective of the MI definitions used and including “hard” events Cangrelor is superior to clopidogrel across the full spectrum of PCI in reducing important clinical events

Thank You! Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular Center Professor of Medicine, Harvard Medical School 1 (857) 307-1992 dlbhattmd@post.harvard.edu www.brighamandwomens.org/heart