The Big Antiplatelet Debate: Why I Prefer Ticagrelor Over Prasugrel Paul A. Gurbel, M.D. Sinai Center for Thrombosis Research Associate Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland, U.S.A. 1 1

Paul A. Gurbel, MD Consulting: Eli Lilly and Company, Pozen, Inc., Accumetrics, Inc., Daiichi Sankyo, Novartis AG, Bayer Corporation, Sanofi-Aventis, Boehringer Ingelheim Vetmedica GmbH, Merck and Company, Inc. and Medtronic, Inc. Grant Support: Daiichi Sankyo, Eli Lilly and Company, CSL, Haemoscope Corporation, Harvard Clinical Research Institute, Duke Clinical Research Institute, Pozen, Inc., Accumetrics, Inc., Helena Laboratories, Verum Diagnostica GmbH and Portola Pharmaceuticals, Inc.

Disclosures Honoraria/Consulting Research Grants/Support Nanosphere Pozen AstraZeneca Daiichi Sankyo/Lilly Accumetrics Nanosphere Boehringer Merck Medtronic CSL t2 Biosystems Research Grants/Support Nanosphere Haemonetics Daiichi Sankyo/Lilly CSL Pharmaceuticals HCRI NIH Dr. Gurbel has patents in the field of platelet function testing 3

5 Reasons: 1) Mechanism (s) of Action

Do All P2Y12 Inhibitors Have the Same Basic Effect? - Molecular structure of clop and pras are ~same - Equipotent AM - No known significant off target effects - At same level of platelet reactivity: Thrombotic risk should be same Prasugrel-AM Clopidogrel-AM ADP binding site ADP - Ticagrelor is in different class (CPTP) - ? Important off target effects: - At same level of platelet reactivity: thrombotic risk ? less due to off target effect Off-target effect can’t be measured by PFT Ticagrelor binds reversibly and independently from ADP - inhibits conformational change van Giezen JJ et al. Thromb Res. 2009;124:565-71 5

Off-Target Effect: Inhibition of Adenosine Reuptake Inhibition Ticagrelor and Coronary Blood Flow Velocity (CBFV) pre-placebo post-placebo pre-ticagrelor post-ticagrelor p=0.008 Wittfeldt A et al. J Am Coll Cardiol 2013;61:723–7

Reason 2. Pharmacology ONSET/OFFSET Study Stable CAD pts Loading Hours 20 40 60 80 100 4 8 12 16 24 Clopidogrel 600 mg Ticagrelor 180mg IPA (%; 20 mM ADP, Final) .5 * Loading *, P<0.0001 ticagrelor vs clopidogrel; †, P<0.005 ticagrelor vs clopidogrel; ‡, P<0.05, ticagrelor vs clopidogrel Maintenance and Offset Gurbel PA et al. Circulation. 2009;120:2577-85 7

Pharmacokinetics of Ticagrelor Stable CAD pts After 180mg LD tmax ~2 hrs At Steady State After Multiple Ticagrelor 90mg bid dosing (4wks–ONSET; 2-4 wks RESPOND) tmax ~2 hrs Husted S and Gurbel PA et al. Clin Pharmacokinet. 2012;51:397-409. 8

Ticagrelor: Rapid Elimination of HPR Predose 0.5 hr 1 hr 2 hr 8 hr 24 hr ≥2 wks % of Patients with VASP-PRI >50% 20 40 60 80 100 p<0.0001 for all post-dose comparisons 76 74 82 65 94 96 5 97 8 4 2 47 11 Stable CAD pts Ticagrelor (180mg/90mg bid) Clopidogrel (600mg/75mg qd) Bliden KP, Gurbel P et al. Am Heart J . 2011;162:160-5. Pooled Analysis of ONSET-OFFSET and RESPOND Studies VASP-PRI (%) Prasugrel 301 ACS pts undergoing PCI VASP measured 6 hrs 60 mg prasugrel Bonello L et al. J AM Coll Cardiol . 2011;58:467–73 30-day MACE 25.2%

Ticagrelor: No Influence of CYP2C19 Genotype on PD 100 NSTEMI or STEMI + PCI (n =213) LoF Non-LoF GoF Prasugrel 75mg LD + 10mg qd 4 wks Non-GoF p=0.03 Cuisset T et al. J AM Coll Cardiol Intv 2012;5:1280-7 p-values between genotypes = NS LoF Non-LoF GoF Ticagrelor 180mgLD + 90mg BID 2-6 wks Stable CAD (n =92) EM Tantry US et al. Circ Cardiovasc Genet 2010;3;556-566 80 60 VASP-PRI 40 20

Reason 3. Reduced Ischemic Events and Mortality (Despite Clopidogrel PreRx)

Influence on Ischemic Outcomes: Prasugrel vs. Ticagrelor Wiviott SD et al. N Engl J Med. 2007;357:2001-15 5 10 15 30 60 90 180 270 360 450 Days after randomization Cumulative Incidence (%) 12.1 9.9 Prasugrel Clopidogrel HR=0.81 (95%CI,0.73-0.90,p<0.001 n=13,608 Wallentin L et al. N Engl J Med. 2009;36:1045-57 n=18,624 ~Parallel Curves Post-30D Diverging Curves Post-30d (despite clop pre-Rx) Early Separation (? due to no clop pre-Rx) No early Separation - In Non-Clopidogrel Pretreated Patient: ? Use Prasugrel Early then Switch to Clopidogrel 12 12

Is the mortality reduction the trump card for ticagrelor in ACS? Cardiovascular Death Is the mortality reduction the trump card for ticagrelor in ACS? 60 120 180 240 300 360 6 4 3 2 1 Clopidogrel Ticagrelor 4.0 5.1 HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5 Days after randomisation CV death (%) Wallentin L et al. N Engl J Med. 2009;36:1045-57 60 120 180 240 300 360 8 4 2 Clopidogrel Ticagrelor 3.4 4.3 6 Days after randomization Cumulative incidence (%) HR 0.82 (95% CI = 0.68–0.98), p=0.025 Invasive Cannon CP et al. Lancet. 2010;375:283-93

Reason 4: No Difference in Overall TIMI Major or CABG-Related Bleeding in PLATO vs. Clopidogrel

Life-threatening/ Fatal bleeding Non-CABG major bleeding 3 6 9 7.9 7.7 p=NS 2.8 2.2 p=0.03 5.3 5.8 Cumulative Incidence (%) Ticagrelor Clopidogrel vs. Wallentin L et al. N Engl J Med. 2009;361:1045-57

5. No Influence of Genotype on Clinical Outcomes 2 4 6 8 10 12 14 12.1 8.5 8.0 9.8 11.2 8.6 10.0 8.8 LoF Carriers LoF Non-carriers Primary Efficacy Outcome (%0 Clopidogrel Prasugrel Ticagrelor Pint = ? Pint = 0.46 Gurbel PA et al. Expert Rev Cardiovasc Ther. 2004;2:535-45 16

Why Do I Prefer Ticagrelor? 1) Potential Off Target Beneficial Effects 2) Pharmacologic Properties - faster offset - elimination of HPR - no influence of genetics 3) Clinical Outcomes - no influence of genetics - benefit on top of clopidogrel preRx - accruing benefit over time- KM curves continue to separate - mortality benefit - no difference in CABG –related bleeding vs clopidogrel