1. 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

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

3. Background Periprocedural bleeding (PCI) – Increased morbidity and mortality – Bleeding reduction strategies Access site – Femoral – Radial  Bleeding  Access site complications Valgimigli M, et al. Lancet. 2015 Jun 20;385(9986):2465-76

4. 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

5. 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. 2013 Jul 25;369(4):393-4

6. 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. 2013 Jul 25;369(4):393-4 CHAMPION PHOENIX

7. 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 MI3.84.70.80 (0.67,0.97)0.02 Q-wave MI0.20.30.61 (0.29,1.29)0.19 IDR0.50.70.74 (0.45,1.20)0.22 Death0.3 1.00 (0.52,1.92)>0.99 CV Death0.3 1.00 (0.52,1.92)>0.99 CHAMPION PHOENIX: Primary efficacy outcomes Bhatt DL et al. N Engl J Med. 2013 Jul 25;369(4):393-4

8. 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

9. 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

10. Results: Cangrelor vs. Clopidogrel Baseline characteristics FemoralRadial CangrelorClopidogrelP-valueCangrelorClopidogrelP-value Characteristic Demographic n = 4053n = 40110.51n = 1410n =14450.11 Age Median64 yr. 64.5 yr.64 yr. Interquartile range Female sex, (%)28.227.60.5329.326.40.09 Weight Median84 kg 0.8684 kg85 kg0.008 Medical history (%) Diabetes27.3 0.9929.130.30.46 Current smoker28.929.30.7025.928.30.15 Hypertension80.278.90.1779.980.70.59 Hyperlipidemia69.468.60.4970.0 0.61 Prior stroke or TIA5.24.50.154.34.20.89 Prior MI20.923.00.0317.518.00.73 Prior PTCA or PCI22.623.70.2525.126.50.38 CABG12.210.90.065.74.40.09 Heart failure10.211.10.209.7 0.99 PAD8.26.70.018.67.80.47

11. Results: Cangrelor vs. Clopidogrel Procedure characteristics FemoralRadial CangrelorClopidogrelP-valueCangrelorClopidogrelP-value Indication (%) 0.95 0.06 Stable angina56.5 56.3 63.062.6 NSTE ACS 27.1 25.923.6 STEMI16.416.7 11.113.8 Antithrombotic (%) Aspirin95.194.70.4792.5 92.70.86 Clopidogrel, 300 mg loading dose32.633.20.575.64.30.11 Clopidogrel, 600 mg loading dose67.466.80.5794.495.70.11 Low-molecular-weight heparin14.314.40.8710.612.10.23 Unfractionated heparin75.175.30.8586.5 86.00.70 Fondaparinux2.92.30.092.83.00.74 Bivalirudin23.323.40.8721.822.60.61 Glycoprotein IIb/IIIa inhibitor 2.74.30.00012.93.70.22

12. 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 10 1 0.1

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

14. 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 0.1 1 10

15. Results: Radial vs. Femoral Baseline characteristics FemoralRadialP-value Characteristic Demographic N=8064N=2855 Age-years Median64 0.28 Female sex, n (%)2251 (27.9)795 (27.8)0.94 Weight - kilograms Median84 0.004 Medical history (%) Diabetes27.329.70.01 Current smoker29.127.10.04 Hypertension79.680.30.38 Hyperlipidemia69.069.50.62 Prior stroke or TIA4.84.30.22 Prior MI21.917.7<0.0001 Prior PTCA or PCI23.125.80.004 CABG11.65.0<0.0001 Heart failure10.69.70.18 PAD7.58.20.19

16. Results: Radial vs. Femoral Procedure characteristics CharacteristicFemoralRadialP-value N=8064N=2855 Indication, n (%) Stable angina56.462.8<0.0001 NSTE ACS27.124.7 STEMI16.512.5 Antithrombotic, n (%) Aspirin94.992.6<0.0001 Clopidogrel, 300 mg loading dose 32.94.9<0.0001 Clopidogrel, 600 mg loading dose 67.195.1<0.0001 LMWH14.411.4<0.0001 Unfractionated heparin75.286.3<0.0001 Fondaparinux2.62.90.42 Bivalirudin23.422.20.19 Glycoprotein IIb/IIIa inhibitor 3.53.30.63

17. 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/ST5.45.10.95 (0.78,1.15)1.03 (0.81, 1.29)0.83 Death0.40.20.68 (0.30,1.56)0.98 (0.37, 2.58)0.96 MI4.14.51.08 (0.88,1.33)1.13 (0.88, 1.45)0.34 IDR0.6 1.06 (0.62,1.83)1.29 (0.67, 2.46)0.44 ST1.20.90.74 (0.48,1.16)0.93 (0.55, 1.56)0.78

18. 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 (0.12-1.01)0.05 TIMI - bleeding Major / minor18 (0.2)4 (0.1)0.63 (0.21,1.85)0.34 (0.07-1.54)0.16 ACUITY - bleeding Major / minor1173 (14.5)262 (9.2)0.60 (0.52,0.68)0.70 (0.59-0.83)<0.0001

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. BACK UP SLIDES

26. Results: Cangrelor vs. Clopidogrel (Femoral)

27. Results: Cangrelor vs. Clopidogrel (Radial)

28. 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 0.20.11.73 (0.51-5.93)0.1 1.02 (0.14-7.28)0.65 Moderate0.50.31.65 (0.81-3.39)0.1 2.05 (0.19-22.61)0.87 Severe / moderate 0.70.41.68 (0.90-3.11)0.30.21.37 (0.31-6.11)0.80 TIMI-bleeding Major 0.1 0.99 (0.20-4.91)0.1 1.02 (0.14-7.28)0.98 Minor0.20.12.97 (0.80-11.0)0.0 Major/minor0.30.11.98 (0.74-5.29)0.1 1.02 (0.14-7.28)0.55 ACUITY- bleeding Major5.23.11.69 (1.35-2.12)1.50.72.17 (1.02-4.62)0.54 Minor12.69.21.42 (1.23-1.64)9.96.51.57 (1.19-2.06)0.53 Major/minor17.012.01.50 (1.32-1.70)11.27.21.62 (1.25-2.11)0.59 Blood transfusion0.50.31.56 (0.80-3.05)0.20.11.54 (0.26-9.21)0.99

29. 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 (0.12-1.01)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 (0.07-1.54)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 (0.59-0.83)<0.0001