1. Name of the speaker: Germano DiSciascio I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest ACC 2008 – Disclosure Slide

2. ARMYDA (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study group Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional clopidogrel load in patients on chronic therapy - “ARMYDA-Reload” Principal Investigators: Giuseppe Patti, Vincenzo Pasceri, Giuseppe Colonna Investigators: Antonio Montinaro, Leonardo Lassandro Pepe, Antonio Tondo, Laura Gatto, Fabio Mangiacapra, Francesco Ciccirillo, Andrea D’Ambrosio, Annunziata Nusca, Giordano Dicuonzo, Gennaro Sardella, Bibi NGuyen Chairman: Germano Di Sciascio

3. Antiplatelet effects of a 600 mg load in pts with or without chronic clopidogrel Rx 0 20 40 60 80 100 ADP (5  mol/L)-induced aggregation, % 600 mg clopidogrel Before load After load No prior clopidogrel N=20 N=20 Chronic clopidogrel N=20 N=20 P<0.001 P<0.001 P<0.001 Kastrati et al. Circulation 2004

4. ARMYDA - Reload: BACKGROUND  In patients already receiving clopidogrel, concerns arise about bleeding (with reloading), and/or adequacy of antiplatelet effect (without additional loading) GOAL OF THE STUDY  To evaluate safety and effectiveness of a strategy of 600 mg clopidogrel reload in patients undergoing PCI while on chronic clopidogrel therapy, and to evaluate differences in outcome in patients with ACS vs stable angina

5. Stable angina N=269 568 Patients on chronic Clopidogrel therapy (>10 days) with Primary endpoint: - Death - MI - TVR 4-8hrs 30days Randomization Placebo ‡ N=283 Angiography Medical Rx (N=75) CABG (N=57) Clopidogrel 600 mg reload ‡ N= 285 NSTE-ACS N=167 - NSTE-ACS or Stable angina  CK-MB  Troponin-I  PRU Baseline blood sample PCI2 hrs8 and 24 hrs  PRU  CK-MB  Troponin-I  PRU ARMYDA-Reload: Study design PCI Reload N=130 PCI Placebo N=139 PCI Reload N=89 PCI Placebo N=78 ‡ On top of chronic therapy 219 Reload 217 Placebo PCI = 436

6. ARMYDA-Reload Study Endpoints Primary endpoint  30-day incidence of death, MI, TVR MI definition: Consensus statement of the Joint ESC/ACCF/AHA/WHF Task Force, as a post procedural increases of cardiac biomarkers (troponin or CK-MB) greater than 3 x 99 th percentile of the upper reference limit in patients with normal baseline levels of CK-MB, and as a subsequent elevation of more than three-fold in CK-MB from baseline value in patients with raised baseline levels of CK-MB Secondary endpoints Post-procedural increase of markers of myocardial injury above UNL (CK- MB, troponin I) Occurrence of any vascular/bleeding complications “Point of care” measurement of platelet reactivity (PRU) at different time points in the reload and placebo arms

7. Inclusion criteria Patients on chronic (> 10 days) therapy with clopidogrel (22% of PCI pts population in the recruiting centers) with stable angina or non-STE ACS undergoing PCI Exclusion criteria - Primary PCI - Platelet count <70x10 3 /ml - Pts with high risk of bleeding - Coronary by-pass surgery in the previous 3 months ARMYDA-Reload

8. ARMYDA-Reload Trial Clinical Characteristics Stable population: N=269 Age (yrs) Male gender (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) Reload N=130 Placebo N=139 P 66±10 90 (69) 39 (30) 92 (71) 104 (80) 26 (20) 40 (31) 66 (51) 14 (11) 45 (35) 53±7 130 (100) 127 (98) 67±11 94 (68) 41 (30) 98 (71) 105 (76) 28 (20) 43 (31) 61 (44) 10 (7) 44 (32) 54±8 139 (100) 130 (94) 0.44 0.88 0.97 0.93 0.46 0.90 0.92 0.31 0.42 0.70 0.28 - 0.17

9. ARMYDA-Reload Trial Clinical Characteristics ACS population: N=167 Age (yrs) Male gender (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Troponin +ve (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) Reload N=89 Placebo N=78 P 64±10 80 (90) 31 (35) 77 (87) 70 (79) 15 (17) 40 (45) 24 (27) 43 (48) 9 (10) 26 (29) 53±7 89 (100) 82 (92) 65±10 70 (90) 30 (39) 75 (96) 67 (86) 17 (22) 36 (46) 26 (33) 30 (39) 6 (8) 26 (33) 54±8 78 (100) 70 (90) 0.52 0.82 0.75 0.06 0.31 0.54 0.99 0.47 0.26 0.78 0.69 0.39 - 0.79

10. ARMYDA-Reload Trial Composite primary endpoint (30-day death, MI, TVR) Overall population N=436 % 9 7 P=0.70 600 mg Clopidogrel reloadPlacebo

11. ARMYDA-Reload Trial Composite primary endpoint (30-day death, MI, TVR) % 4 8 P=0.23 % 600 mg Clopidogrel reloadPlacebo Stable ACS P=0.035 18 7

12. ARMYDA-Reload Trial Individual components of primary endpoint 600 mg Clopidogrel reload Placebo 4 7 % 18 7 % Stable ACS 1

13. ARMYDA-Reload Secondary endpoints % of Pts with post-procedural elevation of markers of myocardial injury above UNL % of patients 600 mg Clopidogrel reload Placebo 25 % of patients 41 23 55 46 P=0.016 P=0.31 21 50 45 P=0.48 P=0.41 Stable ACS

14. ARMYDA-Reload Trial Secondary endpoints Bleeding rates in the overall population 600 mg Clopidogrel reload Placebo % 5 5 0 0

15. ARMYDA-Reload Trial Secondary endpoint Bleeding rates 600 mg Clopidogrel reloadPlacebo % 2 2 0 0 Stable ACS N=3 % 10 0 0 N=8 N=9 * P=0.03

16. ARMYDA-Reload: Platelet aggregometry* * By VerifyNow TM Placebo Reload 203±62 156±62 210±57 193±59 184±63 159±63 201±67 162±71 200±61 189±65 168±71 148±66 Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug 100 120 140 160 180 200 220 240 Platelet reaction units (PRU) P=0.12 Placebo Clopidogrel 600 mg ** Using baseline TRAP channel Stable ACS 218±62 171±61 227±85 180±79 172±83 126±61 215±69 176±71 205±55 192±63 186±61 132±51 Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug 100 120 140 160 180 200 220 240 Platelet reaction units (PRU) P=0.046 Placebo Clopidogrel 600 mg

17. Odds Ratios for 30-day MACE with Reload ARMYDA-Reload 0 12 ACS No ACS Diabetes mellitus 3 4 5 No diabetes MV intervention 0.36 (0.29-0.92) 1.2 (0.95-1.4) 0.75 (0.18-4.7) 0.90 (0.38-2.2) 1.2 (0.22-7.8) No MV intervention 0.80 (0.35-1.9)

18. EVENT CURVES 30-day MACE and Benefit with Reload ACS – Placebo Stable Angina - Reload ACS - Reload Stable Angina - Placebo ARMYDA-Reload 0 4 8 12 16 20 51015202530 Days Death/MI/Repeat revascularization (%) P=0.035 (ACS Placebo vs ACS Reload)

19.  The ARMYDA-Reload trial indicates that a significant proportion of patients undergoing PCI are on chronic clopidogrel therapy  Patients with stable angina who are already taking clopidogrel can safely undergo PCI without need of further reload  In patients with ACS, a 600 mg reloading strategy can significantly improve outcome (64% RR of MACE)  Serial point of care aggregometry studies show platelet reactivity curves consistent with clopidogrel status and clinical syndrome, and may correlate with outcome  No major bleeding, and no excess bleeding are observed in the reload approach vs placebo in either stable or ACS patients  Given the growing number of patients undergoing PCI while on clopidogrel, those results may influence practice patterns in interventional pharmacology CONCLUSIONS

21. ARMYDA-Reload Trial Individual events at 30 days 600 mg Clopidogrel reload Placebo 6.8 9 % 0.5

22. 30-day MACE and Benefit with Reload (600 mg Clopidogrel ) ACS Placebo Stable Angina Reload ACS Reload Stable Angina Placebo ARMYDA-RELOAD 0 4 8 12 16 20 51015202530 Days after randomization Death/MI/Repeat revascularization (%) P=0.035 (ACS Placebo vs ACS Reload)

23. P Vessels treated (%) Left main LAD LCx RCA SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) IIb/IIIa inhibitors (%) 600 mg Clopidogrel reload N=130 Placebo N=139 ARMYDA–Reload Trial Procedural features Stable population : N=269 4 (2) 63 (39) 38 (24) 54 (34) 2 (1) 18 (14) 70 (54) 30 (23) 15 (12) 115 (88) 70 (54) 7 (5) 4 (2) 78 (46) 37 (22) 50 (29) 2 (1) 12 (9) 71 (51) 31 (22) 11 (8) 128 (92) 65 (47) 6 (4) 0.79 0.28 0.77 0.47 0.66 0.25 0.74 0.99 0.42 0.30 0.90

24. P Vessels treated (%) Left main LAD LCx RCA SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) IIb/IIIa inhibitors (%) 600 mg Clopidogrel reload N=89 Placebo N=78 ARMYDA–Reload Trial Procedural features ACS population : N=167 2 (2) 41 (42) 20 (20) 29 (29) 7 (7) - 4 (5) 51 (57) 10 (11) 5 (6) 84 (94) 20 (22) 18 (20) 2 (2) 37 (42) 17 (19) 25 (28) 8 (9) - 3 (4) 50 (64) 11 (14) 5 (6) 73 (94) 20 (26) 16 (21) 0.69 0.90 0.99 0.98 0.83 0.86 0.46 0.75 0.91 0.77 0.88

25. 211±66 162±58 215±65 185±65 178±69 148±65 208±68 170±70 199±58 190±66 172±61 142±61 Estimated Study PCI 2 hrs 8 hrs 24 hrs baseline ** Drug 100 120 140 160 180 200 220 240 Platelet reaction units (PRU) ARMYDA-Reload: Platelet aggregometry* Overall population P=0.01 * By VerifyNow TM Placebo Clopidogrel 600 mg Placebo Reload ** Using baseline TRAP channel