Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

2. Dr. GermanoDi Sciascio ARMYDA-ACS: Atorvastatin Pretreatment Improves Outcome in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

3. ARMYDA-ACS (Atorvastatin for Reduction of MYocardial Damage during Angioplasty- Acute Coronary Syndromes ) trial Multicenter, randomized, double blind, prospective study evaluating effects on outcome of atorvastatin pre-treatment in patients with Acute Coronary Syndromes undergoing early PCI Chairman of the Study: Germano Di Sciascio Principal Investigators:Giuseppe Patti, Vincenzo Pasceri, Rino Sardella, Giuseppe Colonna Investigators: Antonio Montinaro, Marco Miglionico, Luigi Fischetti, Andrea D’Ambrosio, Annunziata Nusca, Giordano Dicuonzo, Bibi NGuyen, Laura Gatto, Fabio Mangiacapra

5. BACKGROUND • The original ARMYDA trial demostrated that 7-day pretreatment with atorvastatin (40 mg/day) confers 81% risk reduction of peri-procedural MI in patients with Stable Angina undergoing elective PCI Primary end point: Incidence of MI 18 P=0.025 MI (%) 5 Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004;110:674-678

6. BACKGROUND • Efficacy of statin pretreatment in patients with ACS undergoing early PCI has not characterized • An observational study on 119 pts has suggested that patients with ACS who were already receiving statins at the time of intervention have a lower incidence of peri-procedural myonecrosis; however, patients were treated with different types of statins, variable doses and unknown duration of previous treatment, and those findings have not been validated in a randomized trial. Chang SM, et al. Cathet Cardiovasc Interv 2004

7. ARMYDA-ACS trial • Inclusion criteria: • NSTE-ACS undergoing early angiography (<48 hrs) Exclusion criteria: • STEMI • ACS with high risk features warranting emergency angiography • Previous or current statin therapy • LVEF <30% • Contraindications to statins (liver or muscle disease) • Severe renal failure (creatininine >3 mg/dl)

8. ARMYDA-ACS trial: Study design 580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure 20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12) 30 days Atorvastatin 80 mg 12 hrs pre-angio; further 40 mg 2 hrs before N=96 771 pts with NSTE-ACS sent to early coronary angiography (<48 hours) Jan ’05 - Dec ‘06 Randomization (N=191) PCI atorvastatin N=86 Primary combined end point: 30-day death, MI, TVR Coronary angiography atorvast PCI placebo N=85 Placebo 12 hrs pre-angio; further dose 2 hrs before N=95 2nd and 3rd blood samples (8 and 24 hrs post-PCI) 1st blood sample (pre-PCI) CK-MB, troponin-I, myoglobin, CRP

9. ARMYDA-ACS trial: Study end points • Primary end point: • Incidence of major adverse cardiac events (MACE: death, MI, TVR) from the procedure up to 30 days • MI definition: • - If normal baseline levels of CK-MB: post-procedural increase of CK-MB >2 times above UNL, according to the consensus statement of the Joint ESC/ACC Committee for the Redefinition of Myocardial Infarction for clinical trials on coronary intervention. • - If elevated baseline levels of CK-MB: subsequent rise of >2 times in CK-MB from baseline value • Secondary end points: • Any post-procedural increase of markers of myocardial injury above UNL (CK-MB, troponin-I, myoglobin) • Post-PCI variations from baseline of CRP levels in the 2 arms

10. ARMYDA-ACS: Main Clinical Features in the Atorvastatin and Placebo Groups

11. ARMYDA-ACS:Procedural Features in the Atorvastatin and Placebo Groups

12. ARMYDA-ACS trial Composite primary end-point (30-day death, MI, TVR) % 17 P=0.01 5

13. ARMYDA-ACS Individual and Combined Outcome Measures of the Primary End Point at 30 days 14/85 (17%) % 13/85 (15%) P=0.01 P=0.04 4/86 (5%) 4/86 (5%) 1/85 (2%) Composite Primary End Point

14. ARMYDA-ACS: Secondary end point Cardiac markers elevations 1-3 times >3 times P=0.028 P=0.002 Creatine kinase-MB (%) Troponin-I (%)

15. ARMYDA-ACS: Secondary end point Post-PCI percent increase of CRP levels from baseline 147 P=0.01 % 63

16. ARMYDA-ACS: Actuarial Survival curves Atorvastatin Placebo 100 80 60 P=0.01 MACE-free survival (%) 40 20 0 1 2 3 7 14 21 30 Days after PCI

17. ARMYDA-ACS: Odds Ratio for 30-day MACE 1 2 0 3 4 5 NSTEMI 1.3 (0.36-4.8) LVEF <40% 3.6 (1.1-10.4) IIb/IIIa inhibitors 4.2 (2.1-12.2) Beta-blockers 0.75 (0.44-2.8) Ace-inhibitors 0.88 (0.59-3.9) Atorvastatin 0.12 (0.05-0.50)

18. ARMYDA-ACS: CONCLUSIONS • The ARMYDA-ACS trial indicates that even a short-term atorvastatin pretreatment prior to PCI may improve outcome in patients with Unstable Angina and NSTEMI. • This benefit is mostly driven by a reduction of peri-procedural MI (70% risk reduction) • Lipid-independent pleiotropic actions of atorvastatin may explain such effect • These findings may support the indication of “upstream” administration of high dose statins in patients with Acute Coronary Syndromes treated with early invasive strategy

19. * P<0.05 Possible mechanisms of the clinical benefit: Improvement of endothelial function N=27 pts with stable angina randomized to placebo or pravastatin (single dose of 40 mg). At 24 hrs, significant attenuation of acetylcholine-mediated vasoconstriction Wassmann S, et al. Circ Res 2003

20. Possible mechanisms of the clinical benefit: Vasodilation of coronary microvessels Coronary flow velocity reserve (hyperemic/basal peak diastolic velocity) N=32 pts without CAD randomized to placebo or atorvastatin (single dose of 40 mg) transthoracic doppler evaluation of LAD (baseline and 1 hr) P<0.01 Hinoi T, et al. Am J Cardiol 2005

21. Possible mechanisms of the clinical benefit: Antithrombotic effects N=30 hypercholesterolemic pts randomized to diet or atorvastatin (10 mg/d) for 3 days Prothrombin fragment F1+2 (nM) PLT CD40L expression (AU) P<0.01 45+12 46+15 43+15 P<0.05 2+1 2+1 2+1 32+6 1.4+0.4 Sanguigni V, et al. Circulation 2005

22. Possible mechanisms of the clinical benefit: Attenuation of endothelial activation ARMYDA-CAMs RESULTS P=0.0008 P=0.0001 78 100 P=0.33 75 P=0.0001 80 P=0.55 59 60 P=0.20 60 Post-procedural 24-hour % increase from baseline 42 45 E-selectin peak levels (ng/mL) 30 40 30 20 15 0 0 No Damage Damage No Damage Damage ICAM-1 E-selectin VCAM-1 Atorvastatin Placebo Patti G et al. JACC 2006;48:1560

23. UNRESOLVED ISSUES • ARMYDA-ACS results cannot be directly extrapolated to - pts with ST-segment elevation myocardial infarction - pts with ACS undergoing emergency revascularization - pts with ACS treated medically or receiving bypass surgery • It is unclear whether patients on chronic statin treatment may have a clinical benefit similar to that observed with acute administration. Indeed, in a rat model of ischemia/reperfusion, the acute protective effect of atorvastatin on myocardial injury wanes with a longer treatment, but this effect can be recaptured by a “reloading” given immediately before ischemia/reperfusion Supplementary dose given a few hours before ischemia/reperfusion Mensah K et al – JACC 2005

28. ARMYDA-ACS: Main Clinical Features in the Atorvastatin and Placebo Groups

29. Possible mechanisms of the clinical benefit: Direct myocardial protection Ischemia/reperfusion on isolated perfused mouse hearts Effect prevented by an inhibitor of PI3K Bell RM, et al. JACC 2003

30. ARMYDA-ACS: Procedural Features in the Atorvastatin and Placebo Groups

31. Primary end point RESULTS Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL) 30 P=0.025 18 20 CK-MB (%) 10 5 0 Placebo Atorvastatin

33. ARMYDA-ACS trial 30 days Atorvastatin 80 mg the day before and 40 mg 4 to 6 hrs before PCI N=76 • Patients with • NSTE ACS • and • Indication to • PCI, • “Statin-naive” Atorvastatin group Primary endpoint: 30-day occurrence of death, MI*, TVR Randomization PCI Placebo group Placebo the day before and 4 to 6 hrs before PCI N=77 1° blood sample (before PCI) 2° and 3° blood samples (8 and 24 hrs after PCI) • MI= CK-MB >2 times UNL or • >2 times the baseline value (if increased) CK-MB, troponin I, myoglobin, CRP

34. ARMYDA-CAMs RESULTS P=0.0001 100 P=0.0001 80 P=0.20 60 Post-procedural 24-hour % increase from baseline 40 20 0 ICAM-1 E-selectin VCAM-1 Atorvastatin Placebo Patti G, Di Sciascio G; JACC 2006:48:1560-6

35. ARMYDA-ACS trial Secondary endpoint: Post-procedural CK-MB and Tn-I elevation above UNL Data on the first 153 pts (Sept ’06) 56 P=0.025 P=0.040 49 % 38 30 CK-Mb Tn-I

36. Improving outcome after PCI by reducing peri-procedural MI The ARMYDA trials 18% 6% 5% 5% ARMYDA-1 No statin No 600 mg clop. ARMYDA-1 Atorvastatin No 600 mg clop. ARMYDA-2 Statin 600 mg clop. ARMYDA-ACS Atorvastatin 600 mg clop. Pts with CSA or ACS Pts with CSA Pts with ACS

37. ARMYDA trial - Secondary end point: Incidence of any post-PCI increase of CK-MB and Troponin-I above UNL 50 40 P=0.001 40 P=0.006 30 30 CK-MB (%) Troponin-I (%) 20 20 10 10 0 0 Atorvastatin Placebo Atorvastatin Placebo > 1 time 2-5 times >5 times UNL Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004

38. Final results of the ARMYDA-ACS (Atorvastatin for Reduction of MYocardial Damage during Angioplasty- Acute Coronary Syndromes) trial

39. Individual and Combined Outcome Measures of the Primary End Point at 30 days in the Atorvastatin and Placebo Groups

40. ARMYDA-ACS (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Acute Coronary Syndromes) trial Randomized, placebo-controlled, double blind, prospective trial, evaluating whether pretreatment with atorvastatin load influences outcome in patients with acute coronary syndromes undergoing early PCI Chairman:Germano Di Sciascio Principal investigator: Giuseppe Patti Investigators: Vincenzo Pasceri,Giuseppe Colonna,Gennaro Sardella, Marco Miglionico, Dionigi Fischetti, Andrea D’Ambrosio, Bibi Nguyen, Antonio Montinaro, Annunziata Nusca

41. Question & Answer

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