1. Robert F. Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield, UK Stent thrombosis Future directions

2. Disclosures RF Storey has received research grant support and/or consultancy fees from AstraZeneca, Lilly, The Medicines Company, Merck Sharp & Dohme, Sanofi Aventis, and Bristol Myers Squibb

3. Platelet Activation Mechanisms Storey RF. Current Pharmaceutical Design 2006 Thrombin Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR1 PAR4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x AZD6140 CANGRELOR GPIIB/IIIA ANTAGONISTS x

4. Arachidonic acid-induced platelet aggregation in 190 IHD patients Compliance rather than aspirin resistance Schwartz et al. Am J Cardiol 2005

5. Storey RF et al. Platelets 2002; 13: 407-413 Variable response to clopidogrel with incomplete P2Y 12 receptor blockade Final response to 20 µM ADP before and after clopidogrel 300 mg followed by 75 mg daily for 4-7 days in patients undergoing PCI +/- 150 nM cangrelor added in vitro 0 20 40 60 80 100 BaselinePost Clopidogrel Post Clopidogrel + cangrelor Mean % Platelet Aggregation * * * P<0.05

6. Subacute stent thrombosis

7. Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCI Whole blood single platelet counting in response to ADP 10 uM Patient with subacute stent thrombosis Smith SMG et al. Platelets 2006; 17: 250-258

8. Prasugrel Novel thienopyridine (CS-747) in phase III development (PCI in ACS patients) Different pathways of metabolism to clopidogrel and higher potency probably related to more efficient production of active metabolite

9. Prasugrel 5-20 mg daily vs clopidogrel 75 mg daily in healthy volunteers – inhibition of ADP induced platelet aggregation at 10 days JA Jakubowski et al. ACC Annual Scientific Session 2005.

10. Clinical Target Vessel Thrombosis P= NS Target Vessel Revasc or Documented Total Occlusion RR=0.25 [0.1, 0.9] P = 0.03 Prasugrel LD/MDTreatment Group

11. Significant Non-CABG Bleeding 30 d (%) (TIMI Major + Minor) – Primary Endpoint P= NSP = 0.77 Prasugrel LD/MD Treatment Group

12. TRITON – TIMI 38 Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL CLOPIDOGREL 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Re-ischemia CV death, MI, UTVR Median duration of therapy - 12 months N= 13,000

13. AZD6140 Class: CPTP* (non-thienopyridine) Reversible platelet P2Y 12 receptor antagonist Orally active Rapid onset of action (2 h) with or without a loading dose Acts directly (no metabolic activation required) Plasma t ½ ~12 h *cyclo-pentyl-triazolo-pyrimidine

14. Comparison of clopidogrel 300 mg loading dose vs AZD6140 90-270 mg loading doses in ACS patients Inhibition of platelet aggregation induced by ADP 20  M

15. Suppression of residual platelet aggregation response by AZD6140 in clopidogrel-pretreated ACS patients Platelet aggregation induced by ADP 20  M

16. PLATO Double-blind ACS (STEMI or NSTEMI) ASA AZD6140 CLOPIDOGREL N= 16,000 Estimated number of countries: 40 Estimated number of sites: 1,000 Estimated trial size: 16,000 patients Patient recruitment to start late 2006

17. Cangrelor Stabilised ATP analogue Reversible platelet P2Y 12 receptor antagonist Intravenous use only Onset of action within minutes Acts directly (no metabolic activation required) Plasma t ½ < 9 minutes Phase 3 studies - CHAMPION

18. Higher incidence of late stent thrombosis seen with DES in BASKET-LATE study and in follow up studies of Taxus and Cypher stents Heparin coated stents – no convincing evidence of clinical benefit Stem cells – under investigation to assess whether they can be used to promote endothelialisation Need for new agents, either systemic or stent coated, that reduce neointima formation without impairing endothelialisation Stent coatings

19. CONCLUSIONS (1) True aspirin resistance is rare Compliance is important – patients should be advised of the reasons for antiplatelet therapy, intended duration of treatment and risks of poor compliance

20. CONCLUSIONS (2) Inadequate P2Y 12 receptor blockade by clopidogrel in some patients is probably a major risk factor for stent thrombosis and 3 new P2Y 12 antagonists are in phase 3 development to address this: Prasugrel (oral thienopyridine) AZD6140 (oral reversible antagonist) Cangrelor (short-acting iv antagonist)

21. CONCLUSIONS (3) DES appear to increase the risk of late stent thrombosis and further work is required to establish whether novel stent coatings or systemic agents can reduce subacute and late thrombosis risk