ARMYDA-4 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study Germano Di Sciascio, MD, FACC, FESC Professor & Chairman of Cardiology Director, Department of Cardiovascular Sciences Institute Campus Biomedico University of Rome Rome, Italy  

TCT 2007 – Disclosure Slide 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

in patients on chronic therapy - “ARMYDA-Reload” 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 3

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

Antiplatet effects of a 600 mg load in pts with or without 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 Before load After load Before load After load 600 mg clopidogrel Kastrati et al. Circulation 2004

ARMYDA-4: Study design N= 360 N= 230 N= 180 N= 180 N= 234 Hours pre-PCI 30 days 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 or Angiography Randomization ü NSTE ACS PCI - placebo arm N= 180 ü undergoing Placebo ‡ N= 234 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

ARMYDA-4: 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) Peak values of CK-MB, troponin I and myoglobin after intervention Occurrence of any vascular/bleeding complications “Point of care” evaluation of platelet reactivity at different time points in the two arms

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

Clinical Characteristics ARMYDA-4 Clinical Characteristics N=360 pts 600 mg Clopidogrel reload N=180 Placebo N=180 P Age (yrs) Male sex (%) Diabetes mellitus (%) Hypertension (%) Hypercolesterolemia (%) Current smokers (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Clinical pattern (%) Non STE ACS Non STEMI Multivessel disease (%) LVEF (%) Aspirin (%) Statins (%) 65±10 140 (78) 56 (31) 136 (75) 142 (79) 36 (20) 54 (30) 88 (49) 16 (9) 67 (37) 22 (12) 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) 14 (8) 67 (37) 55±7 180 (100) 168 (93) 1 0.99 0.82 0.12 0.29 0.69 0.83 0.51 0.28

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 (%) IIb/IIIa inhibitors 5 (2) 82 (40) 46 (22) 70 (34) 18 (10) 13 (7) 123 (59) 28 (15) 162 (90) 76 (42) 20 (11) 4 (2) 86 (40) 47 (22) 67 (31) 8 (3) 10 (5) 13 (7) 130 (61) 33 (18) 14 (8) 166 (92) 78 (43) 0.97 0.92 0.71 0.60 0.17 1 0.57 0.58 0.91 0.45

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

Individual components of composite primary endpoint ARMYDA-4 Trial Individual components of composite primary endpoint % 8 7 600 mg Clopidogrel reload Placebo

Post-procedural elevation of markers of myocardial injury above UNL 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

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

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

ARMYDA-4: Platelet aggregometry* 240 211±66 217±66 220 Clopidogrel 600 mg 200 208±68 183±68 199±64 173±69 177±71 Placebo Reload 180 178±62 Platelet reaction units (PRU) 174±65 153±65 160 166±60 140 146±63 120 Placebo 100 Estimated Study PCI 2 hrs 6 hrs 24 hrs baseline ** Drug ** Using baseline TRAP channel * By VerifyNow TM

CONCLUSIONS The ARMYDA-4 trial indicates that a pre-PCI 600 mg loading 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

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.

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 Before load After load Before load After load 600 mg clopidogrel Kastrati et al. Circulation 2004