A Look into the Future of Antiplatelet Therapy

1. A Look into the Future of Antiplatelet Therapy Robert A. Harrington MD, FACC, FAHA, FSCAI Richard Sean Stack MD Distinguished Professor Director, Duke Clinical Research Institute Duke University Medical Center

2. Relationships Relevant to this Presentation • Research grants/contracts to DCRI • NHLBI, ACC, AHA, sanofi-aventis, Lilly, Daiichi-Sankyo, GSK, TMC, BMS, Astra Zeneca, J&J, BI, Portola, Novartis, Merck, Regado • Consulting • Sanofi-aventis, Astra Zeneca, BMS, Novartis, Merck, Portola, Regado, Eiasi • Full listing of all relationships with industry • http://www.dcri.duke.edu/research/coi.jsp

3. Antiplatelet Therapy: Lessons Learned • Platelets matter • Enormous body of high-quality evidence • Multiple drugs with different MOA effective, including in various combinations • Thromboxane, GP IIb/IIIa and P2Y12 all validated targets • More intense ADP blockade better than less • Most of the effect is on MI reduction but mortality reductions possible (COMMIT; PLATO) • Balance of efficacy and safety challenging, especially with combinations of antithrombotics (plts and coag) • Personalized approach attractive but elusive

4. Global Cardiovascular Disease Burden 1990:25% of all deaths were from CVD. 2020:40% of all deaths will be from CVD. In developing countries, MI and CVD deaths occur 10–20 years earlier. • CVD deaths < 70 y.o. in developing countries: 50% • CVD deaths < 70 y.o. in Western countries: 20% —Reddy KS. NEJM 2004

8. Co-morbidities among Patients with CAD:Baseline Characteristics –STEMI and NSTEMI ACTION Registry-GWTG DATA: July 1, 2009 – June 30, 2010

11. Properties of Elinogrel • The only reversible and competitive P2Y12 receptor antagonist • Direct-acting: no metabolic activation required • Available for intravenous and oral administration, enabling acute and chronic use • Immediate and near maximal platelet inhibition achieved with IV • Duration of action • Half-life: 12 hours • No major CYP metabolism – low potential for drug-drug interactions (including PPIs) • Balanced clearance: 50% renal; 50% hepatic (10% metabolized to pharmacologically inactive metabolite)

13. Pharmacodynamic Effect of Elinogrel vs. Clopidogrel PD Sub-study C (N=17) E100 (N=12) E150 (N=17) 5 uM ADP - Peak Peri-PCI pre-2nd oraldose pre-3rd oral dose or discharge * * Extent of platelet aggregation (%) * clopidogrel 120mg IV + 150mg oral 120mg IV + 100mg oral TIME AFTER DOSING (hrs) 74% of pts represented above were on maintenance clopidogrel * p<0.025 for both elinogrel vs. clopidogrel comparisons Median, quartiles 13

14. S H N N + 4Na N O O O C F O N 3 N S O P P P O O O O O Cl Cl H O O H Cangrelor Direct platelet P2Y12 receptor antagonist • ATP analogue MW=800 Daltons • Parenteral administration • Rapid inhibition (> 90%) at 4 mg/kg/min after a weight-based bolus • Full recovery of platelet function in <60 minutes • t1/2 - 3- 5 minutes • Putative metabolism by endothelial-associated ectonucleotidases/CD 39 Meadows TA, Bhatt DLCirc Res 2007;100:1261-75; Akers J Clin Pharmacol. 2010;50:27-35; Steinhubl Thromb Res. 2008;121:527-34.

16. Summary of clinical efficacy (includes post hoc analyses) 0.2 0.5 1.0 2.0 5.0 Cangrelor Better Comparator Better

17. CHAMPION PHOENIX Cangrelor

18. Trial Design Usual Care: Thienopyridine Discontinuation 5-7 Days Prior to CABG 100 CABG 75 Thieno Therapy 50 Platelet Inhibition (%) Treat per Standard Care 25 (CABG planned) 0 -1 0 1 2 3 4 5-7 180 210 240 Cangrelor Infusion 100 Demonstrate that cangrelor maintains inhibition. CABG 75 Cangrelor Infusion: 0.75 µg/kg/min 50 Platelet Inhibition (%) Treat per Standard Care 25 (CABG planned) 0 -1 0 1 2 3 4 5-7 180 210 240 Thru Hospital Discharge Elapsed Days • Randomization to usual care or cangrelor Thieno Therapy

21. Vorapaxar Metabolism • Vorapaxar undergoes oxidative metabolism in the liver by the CYP3A4 enzymes • 90% is excreted in the bile as the inactive metabolite • Steady-state exposure tovorapaxar - is increased upon co-administration with potent CYP3A4 inhibitors (e.g. ketoconazole) - is decreased upon co-administration with potent CYP3A4 inducers (e.g. rifampin)

23. TRA•CER and TRA•2P TIMI-50 Tricocci et al. Am Heart J. 2009:158:327-334 Morrow et al. Am Heart J. 2009:158:325-341

28. Jan 2011

30. Objectives: to evaluate • long-term effectiveness and safety • short- and long-term MI treatment • patterns and adherence • antiplatelet medication switching • economic cost implications • use of platelet function testing Prospective, observational study of antiplatelet treatment among AMI patients treated with PCI ENROLLMENT before MI discharge Clopidogrel Ticlopidine Prasugrel FOLLOW-UP interviews– conducted by the DCRI Months Index AMI Hospitalization 1 3 15 6 12 (majority of in-hospital data entered via NCDR) www.translate-acs.org

31. The Future of Antiplatelet Therapy • Thrombosis key mechanism in large variety of cardiovascular diseases • Multiple choices now available for antiplatelet therapies across multiple thrombotic diseases • Challenges with increasing patient complexity along with understanding nuances of various combinations and interface with care strategies • Research needed to aid clinical decision making as well as to better understand combination therapies • Personalized approach choices based on genetics and phenotypes of response is the future but work remains