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

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

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 MI (%) Primary end point: Incidence of MI Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004;110: P=0.025

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

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)

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

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 ARMYDA-ACS trial: Study end points

ARMYDA-ACS: Main Clinical Features in the Atorvastatin and Placebo Groups VariableAtorvastatin (n=86)Placebo (n = 85)p Male sex68 (79)67 (79)0.88 Age (years)64±1167± Diabetes mellitus 25 (29)28 (33)0.70 Systemic hypertension 63 (73)63 (74) 0.96 Hypercholesterolemia 27 (31)28 (33) 0.96 Chronic Renal Failure12 (14)13 (15)0.81 Current smokers 27 (31)18 (21) 0.18 Previous coronary intervention9 (10)9 (11)0.82 Previous by-pass surgery2 (2)3 (4)0.99 Left ventricular ejection fraction (%) 55  754  Multivessel coronary artery disease29 (34)39 (46)0.14 CLINICAL PATTERN: NSTEMI34 (40)27 (32)0.37 Mean time to angiography (hrs) 23±12 22± PHARMACOLOGICAL Rx: Aspirin86 (100)85 (100)1 Clopidogrel mg load86 (100)85 (100)1 Beta-Blockers26 (30)23 (27)0.77 Ace-Inhibitors67 (78)65 (76)0.97 IIb/IIIa Inhibitors23 (27)18 (21)0.50

VariableAtorvastatina (N=86)Placebo (N=85)P Vessel treated: Left main-1 (1)0.97 Left anterior descending 51 (50)54 (59)0.94 Left circumflex31 (30)28 (25)0.56 Right coronary artery20 (19)26 (24)0.56 Saphenous vein graft1 (1) 0.51 Lesion type B2/C73 (85)71 (84)0.97 Multivessel intervention17 (20)25 (29)0.20 Type of intervention: Balloon only1 (1) 0.48 Stent85 (99)84 (99)0.48 Bifurcations with kissing balloon 8 (9) 0.81 No.of stents per patient1.4±0.61.5± Stent diameter (mm)3.1±0.43.1± Total stent lenght (mm)16.7± ± Use of DES55 (64)47 (55)0.32 Direct stenting41 (48)36 (42)0.59 No. of pre-dilatation2.1±1.42.2± Stent-deployment pressure (atm) 11.2± ± Duration of stent deployment (sec) 16±716±51 ARMYDA-ACS: Procedural Features in the Atorvastatin and Placebo Groups

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

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

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

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

Atorvastatin Placebo Days after PCI MACE-free survival (%) P=0.01 ARMYDA-ACS: Actuarial Survival curves

0 12 ARMYDA-ACS: Odds Ratio for 30-day MACE NSTEMI LVEF <40% IIb/IIIa inhibitors 345 Beta-blockers Ace-inhibitors 1.3 ( ) 3.6 ( ) 4.2 ( ) 0.75 ( ) 0.88 ( ) Atorvastatin 0.12 ( )

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

Possible mechanisms of the clinical benefit: Improvement of endothelial function Wassmann S, et al. Circ Res 2003 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 * P<0.05

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

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

ARMYDA-CAMs RESULTS ICAM-1E-selectinVCAM-1 Atorvastatin Placebo Post-procedural 24-hour % increase from baseline P= P= Patti G et al. JACC 2006;48: P=0.55 P=0.33 P= No Damage DamageNo Damage Damage E-selectin peak levels (ng/mL) Possible mechanisms of the clinical benefit: Attenuation of endothelial activation

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

ARMYDA-ACS: Main Clinical Features in the Atorvastatin and Placebo Groups Variable Atorvastatin (N=86) Placebo (N=85) P Male sex68 (79)67 (79)0.88 Age (years)64±1167± Diabetes mellitus25 (29)28 (33)0.70 Systemic hypertension63 (73)63 (74)0.96 Hypercholesterolemia27 (31)28 (33)0.96 Chronic renal failure Current smokers 12 (14) 27 (31) 13 (15) 18 (21) Previous coronary intervention9 (10)9 (11)0.82 Previous by-pass surgery2 (2)3 (4)0.99 Left ventricular ejection fraction (%) 55  754  Multivessel coronary artery disease29 (34)39 (46)0.14 CLINICAL PATTERN: Unstable angina52 (60)58 (68)0.37 NSTEMI34 (40)27 (32)0.37 Mean time to angiography (hrs)23±1222± PHARMACOLOGICAL Rx: Aspirin86 (100)85 (100)1 Clopidogrel mg load 86 (100)85 (100)1 Beta-blockers26 (30)23 (27)0.77 Ace-inhibitors67 (78)65 (76)0.97 IIb-IIIa inhibitors23 (27)18 (21)0.50

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

ARMYDA-ACS: Procedural Features in the Atorvastatin and Placebo Groups VariableAtorvast (N=86) Placebo (N=85) P Vessel treated: Left main-1 (1)0.97 Left anterior descending51 (50)54 (49)0.94 Left circumflex31 (30)28 (25)0.56 Right coronary artery20 (19)26 (24)0.56 Saphenous vein grafts1 (1) 0.51 Lesion type B2/C73 (85) 71 (84)0.97 Multivessel intervention17 (20)25 (29)0.20 Type of intervention: Balloon only1 (1) 0.48 Stent85 (99)84 (99)0.48 Bifurcations with kissing balloon8 (9) 0.81 No. of stents per patient 1.4   Stent diameter (mm) 3.1   Total stent length (mm) 16.7   Use of DES55 (64)47 (55)0.32 Direct stenting41 (48)36 (42)0.59 No. of pre-dilatations 2.1   Stent deployment pressure (atm) 11.2   Duration of stent deployment (sec)16  716  51

RESULTS PlaceboAtorvastatin CK-MB (%) Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL) P=0.025 Primary end point 18 5

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

ARMYDA-CAMs RESULTS ICAM-1E-selectinVCAM-1 Atorvastatin Placebo Post-procedural 24-hour % increase from baseline P= P=0.20 Patti G, Di Sciascio G; JACC 2006:48:1560-6

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

Improving outcome after PCI by reducing peri-procedural MI The ARMYDA trials 18% 6% 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 Pts with CSA or ACS Pts with ACS

PlaceboAtorvastatin CK-MB (%) P= PlaceboAtorvastatin Troponin-I (%) P=0.001 > 1 time2-5 times>5 times UNL ARMYDA trial - Secondary end point: Incidence of any post-PCI increase of CK-MB and Troponin-I above UNL Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004

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

Individual and Combined Outcome Measures of the Primary End Point at 30 days in the Atorvastatin and Placebo Groups Atorvastatin (N=86) Placebo (N=85) P Death-- Myocardial infarction4 (5%)13 (15%)0.04 Target vessel revascularization-1 (2%)1 Total MACE4 (5%)14(17%)0.01

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 Randomized, placebo-controlled, double blind, prospective trial, evaluating whether pretreatment with atorvastatin load influences outcome in patients with acute coronary syndromes undergoing early PCI ARMYDA-ACS (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Acute Coronary Syndromes) trial

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