The Effect of Cangrelor and Access Site on Ischemic and Bleeding Events – Insights from CHAMPION PHOENIX J. Antonio Gutierrez, MD, MHS, Robert A. Harrington, MD, James C. Blankenship, MD, Gregg W. Stone, MD, Ph. Gabriel Steg, MD, C. Michael Gibson, MS, MD, Christian W. Hamm, MD, Matthew J. Price, MD, Philippe Genereux, MD, Jayne Prats, PhD, Efthymios N. Deliargyris, MD, Kenneth W. Mahaffey, MD, Harvey D. White, DSc, Deepak L. Bhatt, MD, MPH, on Behalf of the CHAMPION PHOENIX Investigators

Disclosures Dr. Antonio Gutierrez is a consultant for Boehringer-Ingelheim The CHAMPION PHOENIX trial was sponsored by The Medicines Company

Background Periprocedural bleeding (PCI) – Increased morbidity and mortality – Bleeding reduction strategies Access site – Femoral – Radial  Bleeding  Access site complications Valgimigli M, et al. Lancet Jun 20;385(9986):

Objectives 1.Evaluate the efficacy and safety of cangrelor vs. clopidogrel according to PCI access site 2.Explore the effect of PCI access site (radial vs. femoral) on ischemic and bleeding events

Background Cangrelor – Potent intravenous adenosine diphosphate (ADP) receptor antagonist – Rapidly acting 2 minutes – Reversible Return of normal platelet function within 1 hour Bhatt DL et al. N Engl J Med Jul 25;369(4):393-4

Background 1 2 to 4 hours0 Cangrelor bolus & infusion (30ug/kg; 4ug/kg/min) Clopidogrel 600 mg oral SA/ NSTE-ACS/ STEMI Patients requiring PCI P2Y 12 inhibitor naïve OR Placebo oral (right before PCI or right after, per physician) Placebo bolus & infusion Placebo oral PCI ~30’ OR Clopidogrel (600 mg or 300 mg oral, per physician) Rand Bhatt DL et al. N Engl J Med Jul 25;369(4):393-4 CHAMPION PHOENIX

Background Cangrelor (N=5472) Clopidogrel (N=5470) OR (95% CI)P-value Death/MI/IDR/ST4.7% 5.9%0.78 (0.66, 0.93)0.005 Stent thrombosis0.8%1.4%0.62 (0.43,0.90)0.01 MI (0.67,0.97)0.02 Q-wave MI (0.29,1.29)0.19 IDR (0.45,1.20)0.22 Death (0.52,1.92)>0.99 CV Death (0.52,1.92)>0.99 CHAMPION PHOENIX: Primary efficacy outcomes Bhatt DL et al. N Engl J Med Jul 25;369(4):393-4

Methods Cangrelor vs. Clopidogrel (randomized) – Femoral & Radial subgroups Radial vs. Femoral (nonrandomized)* Primary composite – Death, MI, IDR, and Stent Thrombosis Bleeding – GUSTO, TIMI, and ACUITY; transfusion – GUSTO severe bleeding primary safety endpoint *Multivariable analysis

Results 11,145 patients randomized 10,492 – Received study treatment and PCI (mITT) – 8,064 (74%) femoral artery access – 2,855 (26%) radial artery access *mITT = modified intention to treat

Results: Cangrelor vs. Clopidogrel Baseline characteristics FemoralRadial CangrelorClopidogrelP-valueCangrelorClopidogrelP-value Characteristic Demographic n = 4053n = n = 1410n = Age Median64 yr yr.64 yr. Interquartile range Female sex, (%) Weight Median84 kg kg85 kg0.008 Medical history (%) Diabetes Current smoker Hypertension Hyperlipidemia Prior stroke or TIA Prior MI Prior PTCA or PCI CABG Heart failure PAD

Results: Cangrelor vs. Clopidogrel Procedure characteristics FemoralRadial CangrelorClopidogrelP-valueCangrelorClopidogrelP-value Indication (%) Stable angina NSTE ACS STEMI Antithrombotic (%) Aspirin Clopidogrel, 300 mg loading dose Clopidogrel, 600 mg loading dose Low-molecular-weight heparin Unfractionated heparin Fondaparinux Bivalirudin Glycoprotein IIb/IIIa inhibitor

CangrelorClopidogrelOR (95% CI)P interaction Primary Endpoint Death/MI/IDR/ST Overall4.7%5.9%0.79 (0.67, 0.93) Femoral4.8%6.0%0.79 (0.65, 0.96)0.83 Radial4.4%5.7%0.76 (0.54, 1.06) Death Overall0.3% 1 (0.52, 1.92) Femoral0.3%0.4%0.92 (0.45, 1.92)0.64 Radial0.3%0.2%1.37 (0.31, 6.13) MI Overall3.8%4.7%0.8 (0.67, 0.97) Femoral3.7%4.5%0.81 (0.65, 1.01)0.70 Radial3.8%5.1%0.75 (0.52, 1.07) Ischemia Driven Revascularization Overall0.5%0.7%0.74 (0.45, 1.2) Femoral0.5%0.7%0.65 (0.36, 1.16)0.41 Radial0.6% 1.03 (0.41, 2.59) Stent Thrombosis Overall0.8%1.4%0.62 (0.43, 0.9) Femoral0.8%1.5%0.52 (0.34, 0.80)0.09 Radial0.9%0.8%1.11 (0.51, 2.45) Favors Cangrelor Favors Clopidogrel Results: Cangrelor vs. Clopidogrel

Results: Cangrelor vs. Clopidogrel Primary safety endpoint – GUSTO severe bleeding No significant increase – Transfusion No significant increase

CangrelorClopidogrelOR (95% CI) P interaction GUSTO-bleeding severe/moderate Overall0.6%0.3%1.63 (0.92, 2.90) Femoral0.7%0.4%1.68 (0.90, 3.11)0.80 Radial0.3%0.2%1.37 (0.31, 6.11) TIMI-bleeding major/minor Overall0.3%0.1%1.75 (0.73, 4.18) Femoral0.3%0.1%1.98 (0.74, 5.29)0.55 Radial0.1% 1.02 (0.14, 7.28) ACUITY-bleeding major/minor Overall15.5%10.9%1.50 (1.34, 1.68) Femoral17.0%12.0%1.50 (1.32, 1.70)0.59 Radial11.2%7.2%1.62 (1.25, 2.11) Favors Cangrelor Favors Clopidogrel Results: Cangrelor vs. Clopidogrel

Results: Radial vs. Femoral Baseline characteristics FemoralRadialP-value Characteristic Demographic N=8064N=2855 Age-years Median Female sex, n (%)2251 (27.9)795 (27.8)0.94 Weight - kilograms Median Medical history (%) Diabetes Current smoker Hypertension Hyperlipidemia Prior stroke or TIA Prior MI < Prior PTCA or PCI CABG < Heart failure PAD

Results: Radial vs. Femoral Procedure characteristics CharacteristicFemoralRadialP-value N=8064N=2855 Indication, n (%) Stable angina < NSTE ACS STEMI Antithrombotic, n (%) Aspirin < Clopidogrel, 300 mg loading dose < Clopidogrel, 600 mg loading dose < LMWH < Unfractionated heparin < Fondaparinux Bivalirudin Glycoprotein IIb/IIIa inhibitor

Results: Radial vs. Femoral Efficacy endpoints at 48 hours Endpoint (%)Femoral (%)Radial (%) OR (95% CI) Unadjusted OR (95% CI) Adjusted P-Value Death/MI/IDR/ST (0.78,1.15)1.03 (0.81, 1.29)0.83 Death (0.30,1.56)0.98 (0.37, 2.58)0.96 MI (0.88,1.33)1.13 (0.88, 1.45)0.34 IDR (0.62,1.83)1.29 (0.67, 2.46)0.44 ST (0.48,1.16)0.93 (0.55, 1.56)0.78

Results: Radial vs. Femoral Safety endpoints at 48 hours Femoral n/N (%) Radial n/N(%) OR (95% CI) Unadjusted OR (95% CI) Adjusted P-value N = 8064N = 2855 Endpoint n (%) GUSTO - bleeding Severe / moderate43 (0.5)7 (0.2)0.46 (0.21,1.02)0.35 ( )0.05 TIMI - bleeding Major / minor18 (0.2)4 (0.1)0.63 (0.21,1.85)0.34 ( )0.16 ACUITY - bleeding Major / minor1173 (14.5)262 (9.2)0.60 (0.52,0.68)0.70 ( )<0.0001

Limitations Potential benefit of cangrelor might be attenuated with prolonged clopidogrel, prasugrel, or ticagrelor pretreatment Bleeding endpoints were not adjudicated Treatment by access site was not randomized CHAMPION PHOENIX was not powered to test the interaction between treatment and PCI access site

Conclusions Intravenous ADP receptor blockade with cangrelor – Reduces composite of death, MI, IDR, or stent thrombosis at 48 hours – Regardless of PCI access site Femoral: 21% odds reduction Radial: 24% odds reduction

Conclusions Cangrelor compared with clopidogrel – No significant increase at 48 hours GUSTO or TIMI defined bleeding Blood transfusions Regardless of access site – ACUITY bleeding (more sensitive) Increased rates of bleeding – Regardless of access site

Conclusions Radial vs. Femoral – Radial approach for PCI 30 to 66% reduction in bleeding – Depending on bleeding definition Improved bleeding profile was not associated with reduction in primary efficacy endpoint at 48 hours

Conclusions CHAMPION PHOENIX – Cangrelor Intravenous ADP receptor inhibition Reduces ischemic events No significant increase in GUSTO severe bleeding or blood transfusion – Radial artery access for PCI Reduces bleeding complications

Manuscript in press - European Heart Journal Thank you The Effect of Cangrelor and Access Site on Ischemic and Bleeding Events – Insights from CHAMPION PHOENIX J. Antonio Gutierrez, MD, MHS, Robert A. Harrington, MD, James C. Blankenship, MD, Gregg W. Stone, MD, Ph. Gabriel Steg, MD, C. Michael Gibson, MS, MD, Christian W. Hamm, MD, Matthew J. Price, MD, Philippe Genereux, MD, Jayne Prats, PhD, Efthymios N. Deliargyris, MD, Kenneth W. Mahaffey, MD, Harvey D. White, DSc, Deepak L. Bhatt, MD, MPH, on Behalf of the CHAMPION PHOENIX Investigators

BACK UP SLIDES

Results: Cangrelor vs. Clopidogrel (Femoral)

Results: Cangrelor vs. Clopidogrel (Radial)

Results: Cangrelor vs. Clopidogrel Safety end points at 48 hours after randomization FemoralRadial Endpoint Cangrelor (%) Clopidogrel (%) OR (95% CI) Cangrelor (%) Clopidogrel (%) OR (95% CI) P interaction GUSTO-bleeding Severe or Life threatening ( ) ( )0.65 Moderate ( ) ( )0.87 Severe / moderate ( ) ( )0.80 TIMI-bleeding Major ( ) ( )0.98 Minor ( )0.0 Major/minor ( ) ( )0.55 ACUITY- bleeding Major ( ) ( )0.54 Minor ( ) ( )0.53 Major/minor ( ) ( )0.59 Blood transfusion ( ) ( )0.99

Results: Femoral vs. Radial Safety endpoints at 48 hours Femoral n/N (%) Radial n/N(%) OR (95% CI) Unadjusted OR (95% CI) Adjusted P-value N = 8064N = 2855 Endpoint n (%) GUSTO - bleeding Severe or Life threatening 11 (0.1)4 (0.1)1.03 (0.33,3.23) Moderate32 (0.4)3 (0.1)0.26 (0.08,0.86) Severe / moderate43 (0.5)7 (0.2)0.46 (0.21,1.02)0.35 ( )0.05 TIMI - bleeding Major6 (0.1)4 (0.1)1.89 (0.53,6.67) Minor12 (0.1)0 (0.0)- Major / minor18 (0.2)4 (0.1)0.63 (0.21,1.85)0.34 ( )0.16 ACUITY - bleeding Major334 (4.1)31 (1.1)0.25 (0.18,0.37) Minor879 (10.9)233 (8.2)0.72 (0.63,0.85) Major / minor1173 (14.5)262 (9.2)0.60 (0.52,0.68)0.70 ( )<0.0001