Principal Investigators: Giuseppe Patti, Vincenzo Pasceri, Giuseppe Colonna

1. ARMYDA-4 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional 600 mg clopidogrel load in patients on chronic therapy - “ARMYDA-Reload” Chairman: Germano Di Sciascio 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

2. P=0.041 12% 4% ARMYDA-2 RESULTS Primary end-point 30-day Death, MI, TVR (%) Circulation 2005;111:2099-2106

3. Antiplatet effects of a 600 mg load on chronic clopidogrel Rx No prior clopidogrel N=20 Chronic clopidogrel N=20 P<0.001 100 P<0.001 80 P<0.001 ADP (5 mol/L)-induced aggregation, % 60 40 20 0 After load Before load After load Before load 600 mg clopidogrel Kastrati et al. Circulation 2004

4. ARMYDA-4: Study design 30 days 4 - 8 Hours pre-PCI Medical Rx N= 62 Clopidogrel 600 mg re-loading ‡ N= 230 N= 360 464 Patients on clopidogrel therapy with PCI “reload” arm N= 180 Primary end point: Death, MI*, TVR ü Stable angina Angiography or Randomization ü NSTE ACS PCI - placebo arm N= 180 Placebo ‡ N= 234 ü undergoing coronary angiography CABG N= 42 1st blood sample before PCI 2nd and 3rd blood sample at 8 and 24 hours - CK-MB, troponin-I, myoglobin, CRP ‡On top of chronic therapy * MI = >3 times UNL CK-MB

5. ARMYDA-4 Inclusion criteria - Pts on chronic therapy with clopidogrel (> 10 days) with stable angina or non-STE ACS undergoing PCIExclusion criteria- Primary PCI- Platelet count <70x103/ml- Pts at high risk of bleeding- Coronary by-pass grafting in the previous 3 months

6. 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 • Any postprocedural increase of markers of myocardial injury above UNL (CK-MB, troponin I, myoglobin) • Mean peak values of CK-MB, troponin I and myoglobin after intervention • Occurrence of any vascular/hemorragic complications • “Point of care” evaluation of platelet reactivity at different time points in the two arms

7. ARMYDA-4 Clinical Characteristics N=360 pts 600 mg Clopidogrel reload N=180 Placebo N=180 P 65±10 140 (78) 56 (31) 136 (75) 142 (79) 36 (20) 54 (30) 88 (49) 16 (9) 67 (37) 78 (43) 55±7 180 (100) 171 (95) 65±10 139 (77) 59 (33) 149 (83) 142 (79) 34 (19) 57 (31) 77 (43) 13 (7) 70 (39) 67 (37) 55±7 180 (100) 168 (93) 1 0.99 0.82 0.12 1 0.82 0.82 0.29 0.69 0.83 0.83 0.28 1 1 Age (yrs) Male sex (%) Diabetes mellitus (%) Hypertension (%) Hypercolesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Clinical pattern (%) Non STE ACS Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%)

8. ARMYDA – 4 Trial Procedural features 600 mg Clopidogrel reload N=180 Placebo N=180 P Vessel treated (%) Left main LAD LCx Right coronary SVG Chronic total occl. (>3 mo.)(%) Restenotic lesions (%) Lesion type B2/C (%) Multivessel intervention (%) Type of intervention (%) Balloon only Stent DES (%) 5 (2) 82 (40) 46 (22) 70 (34) 5 (2) 18 (10) 13 (7) 123 (59) 28 (15) 18 (10) 162 (90) 76 (42) 0.97 0.92 0.92 0.71 0.60 0.17 1 0.92 0.57 0.58 0.58 0.91 4 (2) 86 (40) 47 (22) 67 (31) 8 (3) 10 (5) 13 (7) 130 (61) 33 (18) 14 (8) 166 (92) 78 (43)

9. ARMYDA-4 Trial Composite primary end-point (30-day death, MI, TVR) P=0.96 % 8 7

10. ARMYDA-4 Trial Individual events at 30 days % 8 7 600 mg Clopidogrel reload Placebo

11. ARMYDA-4 Trial Secondary end points Post-procedural elevation of markers of myocardial injury above UNL P=0.98 46 45 P=0.58 30 27 % of patients 600 mg Clopidogrel re load Placebo

12. ARMYDA-4 Trial Secondary end points Post-PCI peak levels of markers of myocardial injury (CK-MB and Troponin-I) Troponin-I CK-MB P=0.90 P=0.55 5.6±7.5 5.3±12 0.52±2.2 0.39±0.87 0.39±1.1 Peak value of CK-MB (ng/ml) Peak value of Tn-I (ng/ml) 600 mg Clopidogrel reload 600 mg Clopidogrel reload Placebo Placebo

13. ARMYDA-4 Trial Secondary end points Bleeding rates % 4 4 0 0 600 mg Clopidogrel reload Placebo

14. ARMYDA-4: Platelet aggregometry* P=0.2 240 211±66 217±66 220 Clopidogrel 600 mg 200 208±68 183±68 199±64 177±71 173±69 180 Placebo 178±62 Further load Platelet reaction units (PRU) 174±65 153±65 160 166±60 140 146±63 Placebo 120 100 Base Study PCI 2 hrs 6 hrs 24 hrs Drug * By Accumetrics

15. CONCLUSIONS • Results of the ARMYDA-4 trial indicate that a pre-PCI 600 mg loading dose does not confer additional clinical benefit in patients already receiving chronic therapy with clopidogrel • Point of care aggregometry testing shows no significant differences in platelet reactivity in the 2 arms • No increased bleeding risk is observed in the “reload” approach • Patients on chronic clopidogrel therapy can safely undergo PCI without need of further reload

17. BACKGROUND • Several studies have demonstrated beneficial clinical effects of a 600 mg clopidogrel loading dose in patients undergoing percutaneous coronary intervention (PCI). • Laboratory evidence suggests that an additional pre-PCI 600 mg loading further decreases platelet aggregation in patients already on chronic treatment with clopidogrel. However, there are no clinical data on the safety and efficacy of this strategy.