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

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 600 mg 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

Antiplatet effects of a 600 mg load in pts with or without chronic clopidogrel Rx 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

ARMYDA - Reload: BACKGROUND  The ARMYDA-2 trial confirmed improved PCI outcome in patients pretreated (mean 6 hrs) with 600 mg clopidogrel loading, vs a 300 mg dose  In patients already receiving clopidogrel, concerns 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 on chronic clopidogrel therapy, and to evaluate difference in outcome in patients with ACS vs stable angina

Stable angina N= 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  Creatine kinase-MB  Troponin-I  PRU 1 st blood sample Baseline 2 nd, 3 rd and 4 th blood samples At the time of PCI 2 hrs after PCI 8 and 24 hrs after PCI  PRU  Creatine kinase-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

STUDY ENDPOINTS Primary endpoint  30-day incidence of death, MI, TVR (MI definition: post-procedural increase of CK-MB >3 times above UNL in patients with normal baseline levels of creatine kinase-MB) Secondary endpoints Post-procedural increase of markers of myocardial injury above UNL (CK- MB, troponin I, myoglobin) Occurrence of any vascular/bleeding complications “Point of care” evaluation of platelet reactivity at different time points in the two arms

Inclusion criteria Pts on chronic therapy with clopidogrel (> 10 days) with stable angina or non-STE ACS undergoing PCI (22% of PCI patient population in the recruiting centers) 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

Age (yrs) Male sex (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) 600 mg Clopidogrel reload N=130 Placebo N=139 P ARMYDA-RELOAD Trial Clinical Characteristics Stable population N=269 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)

Age (yrs) Male sex (%) Diabetes mellitus (%) Hypertension (%) Hypercholesterolemia (%) Current smokers (%) Troponin +ve (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) 600 mg Clopidogrel reload N=89 Placebo N=78 P ARMYDA-RELOAD Trial Clinical Characteristics ACS population N=167 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)

P Vessel 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)

P Vessel 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)

ARMYDA-RELOAD Trial Composite primary endpoint (30-day death, MI, TVR) Overall population N=436 % 9 7 P=0.70

ARMYDA-RELOAD Trial Composite primary endpoint (30-day death, MI, TVR) % 4 8 P=0.23 % 600 mg Clopidogrel reloadPlacebo Stable ACS P=

ARMYDA-RELOAD Trial Individual events at 30 days 600 mg Clopidogrel reload Placebo % 0.5

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

0 12 Odds Ratios for 30-day MACE ACS No ACS Diabetes mellitus No diabetes MV intervention 0.36 ( ) 1.2 ( ) 0.75 ( ) 0.90 ( ) 1.2 ( ) No MV intervention 0.80 ( ) ARMYDA-RELOAD

Secondary endpoint Any post-procedural elevation of markers of myocardial injury above UNL % of patients 600 mg Clopidogrel reload Placebo 25 % of patients P=0.016 P= P=0.48 P=0.41 Stable ACS

ARMYDA-RELOAD Trial Secondary endpoint : Bleeding rates in the overall population 600 mg Clopidogrel reload Placebo %

ARMYDA-RELOAD Trial Secondary endpoint : Bleeding rates 600 mg Clopidogrel reload Placebo % % Stable ACS N=3 N=8 N=9

EVENT CURVES 30-day MACE and Benefit with Reload ACS Placebo Stable Angina Reload ACS Reload Stable Angina Placebo ARMYDA-RELOAD Days after randomization Death/MI/Repeat revascularization (%) P=0.035 (ACS Placebo vs ACS Reload)

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 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

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 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 Platelet reaction units (PRU) P=0.046 Placebo Clopidogrel 600 mg

 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 reload strategy can significantly improve outcome  Point of care aggregometry testing shows differences in platelet reactivity consistent with clopidogrel status and clinical syndrome  No major bleeding, and no increased bleeding risk are observed in the “reload” approach in either stable or ACS patients  Given the growing number of patients on clopidogrel undergoing PCI, those results may influence practice patterns in interventional pharmacology CONCLUSIONS