1. Reduction in Stent Thrombosis – better tablets or better stents? Dr James Cotton MD FRCP Heart and Lung Centre Wolverhampton

2. MY CONFLICTS OF INTEREST ARE Speaker Fees/Honoraria/Travel Support –Lilly/Daiichi Sankyo –Schering-Plough –The Medicines Company –Medtronic Research Support –J&J Cordis

3. % Stent Thrombosis ASA and Oral Anticoag ASA and Ticlopidine ASA and Clopidogrel New Generation DES Prasugrel Ticagrelor

4. Risk of Definite Stent Thrombosis Stable Angina UA/ NSTEMI STEMI Bare Metal Stents 0-0.5%1.4-1.6%2.9% Drug Eluting Stents 0.3-0.4%1.2-1.9%3.1% Cook, Windecker Circulation 2009

5. Angiographic DES Stent Thrombosis Bern - Rotterdam Cohort Study 3 2 1 0 Days after stent implantation Cumulative probabiity of stent thrombosis (%) thrombosis (%) Wenaweser et al. ESC, Barcelona Sept 2006 N = 8,146 Patients (SES=3875;PES=4271) Incidence = 1.3/100 pts year Cumulative Incidence 1.1% 1.2% 1.7% 2.3% 2.9% 2.9 % 2.9 % N = 152 Patients 020040060080010001200 Early 91 pts (60%) Late 61 pts (40%) Between 30 days to 3 years Slope = 0.6% / year

6. Better Drugs?

7. Discontinuation of thienopyridine therapy:Milan- Siegburg Cohort Study Airoldi F et al Circulation 2007 116:745-54

8. Stent Thrombosis and 2C19 polymorphisms Mega J et al JAMA 2010, 304(16) 1829-40

9. -20.0 0.0 20.0 40.0 60.0 80.0 100.0 Inhibition of Platelet Aggregation (%) Response to prasugrel Response to clopidogrel clopidogrel responder clopidogrel non-responder *Responder =  25% IPA at 4 and 24 h Clopidogrel (300 mg) vs. prasugrel (60 mg) Phase I – healthy subjects Brandt JT et al. Am Heart J 2007;153:66.e9-e16

10. Inhibition of Platelet Aggregation (%) Response to prasugrel Response to clopidogrel Clopidogrel (300 mg) vs. prasugrel (60 mg) Phase I – healthy subjects *Responder =  25% IPA at 4 and 24 h -20.0 Brandt JT et al. Am Heart J 2007;153:66.e9-e16

11. TRITON-TIMI 38: Stent thrombosis rates at end of study All Stents Bare-metal Stents 0 1 2 3 4 Stent Thrombosis* (%) Drug-eluting Stents 2.35 2.31 2.41 N=6,422n=2,878n=3,224 1.13 0.84 1.27 N=6,422 n=2,865n=3,237 clopidogrel prasugrel 52% RRR (1.2% ARR) 64% RRR (1.5% ARR) 48% RRR (1.1% ARR) P=0.0009P<0.0001 *Stent thrombosis defined as Academic Research Consortium definite plus probable ARC = Academic Research Consortium ARR = Absolute Risk Reduction HR = Hazard Ratio NNT = Number Needed to Treat PCI = Percutaneous Coronary Intervention RRR = Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363

12. P=NS Life Threatening P=NS P=0.002 IntracranialFatal Nonfatal P=0.01 (n=6,716) (n=6,741) End Point (%) Subsets of Life Threatening Bleeds n=85 n=56 0.9% 1.4% n=5 0.1% n=21 0.4% n=51 0.9% n=64 1.1% n=17 n=19 0.3% both + aspirin Wiviott SD et al. New Engl J Med 2007;357:2001-2015 TRITON-TIMI 38: Life Threatening Bleeds at 15 months (All ACS) NS = Not Significant

14. Will duration of DAPT be key? DAPT-2014 REAL –LATE - 2011 OPTIDUAL -2013

15. Better Stents?

16. New stent technologies

17. Comparative Endothelial Cell Coverage Rabbit Denudation Model (14 Days) EC Strut Coverage (%) (14 Days) p=0.05 Express vs. Liberte p=0.001 Express Element p=0.001 Express vs. Element ExpressLibertéElement Stent Strut Thickness (µm) Soucy. EuroPCR 2010

18. SPIRIT IV

19. The Abluminal Biodegradable Polymer DES PLA biodegradation and BA9™ elution Abluminal biodegradable coating absorbed after 6-9 months * 19 * I n vivo testing in porcine model demonstrates abluminal coating is absorbed after 6 to 9 months - Data on file at Biosensors Intl

20. Leaders Trial - Stent thrombosis

21. Other Bioabsorbable polymer studies COSTAR – II ISAR-TEST 3 ISAR TEST 4 NOBORI CORE NOBORI-I RESELUTION No reduction ST for DES BP Vs DES PP Salinas P Abs AHA 2010 6032

23. Genous- E-healing Registry n=4939 Acute Thrombosis 0.2% Subacute thrombosis 0.7% Late Thrombosis0.2% Silber S et al, Euro intervention In Press

24. Evolutions of Nevo Stent RES – 1 ( no coating) 200 patients NO ST ? Heparin coating may improve haemocompatability

26. Combo Bio-engineered Sirolimus Eluting Stent Granada, et al. CIRC Cardiovasc Interv, June 2010; 3

27. The Lancet Vol 373 March 14 2009

28. Absorb: histology and OCT

30. Further studies? Clinical trial aiming to demonstrate a reduction in ST from 0.4 to 0.2% 80% power 284,000 subjects!

31. ? Training

32. THANKYOU

33. ARC Definitions of ST Definite Stent Thrombosis –Angiographic or pathological conformation of partial or total thrombotic occlusion within the peri-stent region AND at least one of: –Acute ischaemic symptoms –Ischaemic ECG changes –Elevated biomarkers Probable Stent Thrombosis –Any unexplained death within 30 days of stent implantation –Any MI related to ischemia in the territory of the implanted stent without angiographic conformation of ST Possible Stent Thrombosis –Any unexplained death beyond 30 days