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

2. Dr. Germano Di 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:

6. Chang SM, et al. Cathet Cardiovasc Interv 2004
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. Primary combined end point: CK-MB, troponin-I, myoglobin, CRP
ARMYDA-ACS trial: Study design
580 pts excluded for:
statin therapy
emergency angiography
LVEF <30%
contraindications to statins
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
1st blood sample
(pre-PCI)
2nd and 3rd
blood samples
(8 and 24 hrs
post-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
Variable
Atorvastatin (n=86)
Placebo (n = 85) p
Male sex
68 (79)
67 (79)
0.88
Age (years)
64±11
67±10
0.06
Diabetes mellitus
25 (29)
28 (33)
0.70
Systemic hypertension
63 (73)
63 (74)
0.96
Hypercholesterolemia
27 (31)
Chronic Renal Failure
12 (14)
13 (15)
0.81
Current smokers
18 (21)
0.18
Previous coronary intervention
9 (10)
9 (11)
0.82
Previous by-pass surgery
2 (2)
3 (4)
0.99
Left ventricular ejection fraction (%)
557
548
0.38
Multivessel coronary artery disease
29 (34)
39 (46)
0.14
CLINICAL PATTERN:
NSTEMI
34 (40)
27 (32)
0.37
Mean time to angiography (hrs)
23±12
22±10
0.56
PHARMACOLOGICAL Rx:
Aspirin
86 (100)
85 (100) 1
Clopidogrel mg load
Beta-Blockers
26 (30)
23 (27)
0.77
Ace-Inhibitors
67 (78)
65 (76)
0.97
IIb/IIIa Inhibitors
0.50

11. ARMYDA-ACS: Procedural Features in the Atorvastatin and Placebo Groups
Variable
Atorvastatina (N=86)
Placebo (N=85) P
Vessel treated:
Left main -
1 (1)
0.97
Left anterior descending
51 (50)
54 (59)
0.94
Left circumflex
31 (30)
28 (25)
0.56
Right coronary artery
20 (19)
26 (24)
Saphenous vein graft
0.51
Lesion type B2/C
73 (85)
71 (84)
Multivessel intervention
17 (20)
25 (29)
0.20
Type of intervention:
Balloon only
0.48
Stent
85 (99)
84 (99)
Bifurcations with kissing balloon
8 (9)
0.81
No.of stents per patient
1.4±0.6
1.5±0.9
0.40
Stent diameter (mm)
3.1±0.4
3.1±0.3
0.90
Total stent lenght (mm)
16.7±5.7
16.9±5.5
0.82
Use of DES
55 (64)
47 (55)
0.32
Direct stenting
41 (48)
36 (42)
0.59
No. of pre-dilatation
2.1±1.4
2.2±1.7
0.68
Stent-deployment pressure (atm)
11.2±4.1
11.6±2.7
0.44
Duration of stent deployment (sec)
16±7
16±5 1

12. Composite primary end-point (30-day death, MI, TVR)
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=0.002
P=0.028
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 1 2 3 7 14 21 30
Days after PCI

17. ARMYDA-ACS: Odds Ratio for 30-day MACE1 2 3 4 5
NSTEMI
1.3 ( )
LVEF <40%
3.6 ( )
IIb/IIIa inhibitors
4.2 ( )
Beta-blockers
0.75 ( )
Ace-inhibitors
0.88 ( )
Atorvastatin
0.12 ( )

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. Possible mechanisms of the clinical benefit:
Improvement of endothelial function
* P<0.05
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
PLT CD40L expression (AU)
Prothrombin fragment F1+2 (nM)
P<0.01
43+15
45+12
46+15
2+1
2+1
P<0.05
2+1
32+6
Sanguigni V, et al. Circulation 2005

22. ARMYDA-CAMs RESULTS 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
Post-procedural 24-hour
% increase from baseline 60 42 45
E-selectin peak levels (ng/mL) 30 40 30 20 15
No Damage
Damage
No Damage
Damage
ICAM-1
E-selectin
VCAM-1
Atorvastatin
Placebo
Patti G et al. JACC 2006;48:1560

23. given a few hours before ischemia/reperfusion
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
Variable
Atorvastatin
(N=86)
Placebo
(N=85) P
Male sex
68 (79)
67 (79)
0.88
Age (years)
64±11
67±10
0.06
Diabetes mellitus
25 (29)
28 (33)
0.70
Systemic hypertension
63 (73)
63 (74)
0.96
Hypercholesterolemia
27 (31)
Chronic renal failure
Current smokers
12 (14)
13 (15)
18 (21)
0.81
0.18
Previous coronary intervention
9 (10)
9 (11)
0.82
Previous by-pass surgery
2 (2)
3 (4)
0.99
Left ventricular ejection fraction (%)
557
548
0.38
Multivessel coronary artery disease
29 (34)
39 (46)
0.14
CLINICAL PATTERN:
Unstable angina
52 (60)
58 (68)
0.37
NSTEMI
34 (40)
27 (32)
Mean time to angiography (hrs)
23±12
22±10
0.56
PHARMACOLOGICAL Rx:
Aspirin
86 (100)
85 (100) 1
Clopidogrel mg load
Beta-blockers
26 (30)
23 (27)
0.77
Ace-inhibitors
67 (78)
65 (76)
0.97
IIb-IIIa inhibitors
0.50

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
Variable
Atorvast
(N=86)
Placebo
(N=85) P
Vessel treated:
Left main -
1 (1)
0.97
Left anterior descending
51 (50)
54 (49)
0.94
Left circumflex
31 (30)
28 (25)
0.56
Right coronary artery
20 (19)
26 (24)
Saphenous vein grafts
0.51
Lesion type B2/C
73 (85)
71 (84)
Multivessel intervention
17 (20)
25 (29)
0.20
Type of intervention:
Balloon only
0.48
Stent
85 (99)
84 (99)
Bifurcations with kissing balloon
8 (9)
0.81
No. of stents per patient
1.40.6
1.50.9
0.40
Stent diameter (mm)
3.10.4
3.10.3
0.90
Total stent length (mm)
16.75.7
16.95.5
0.82
Use of DES
55 (64)
47 (55)
0.32
Direct stenting
41 (48)
36 (42)
0.59
No. of pre-dilatations
2.11.4
2.21.7
0.68
Stent deployment pressure (atm)
11.24.1
11.62.7
0.44
Duration of stent deployment (sec)
167
165 1

31. Post-PCI incidence of myocardial infarction
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
Placebo
Atorvastatin

33. ARMYDA-ACS trial 30 days PCI Patients with NSTE ACS and Indication to
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. Patti G, Di Sciascio G; JACC 2006:48:1560-6
ARMYDA-CAMs RESULTS
P=0.0001
100
P=0.0001 80
P=0.20 60
Post-procedural 24-hour
% increase from baseline 40 20
ICAM-1
E-selectin
VCAM-1
Atorvastatin
Placebo
Patti G, Di Sciascio G; JACC 2006:48:1560-6

35. Post-procedural CK-MB and Tn-I elevation above UNL
ARMYDA-ACS trial
Secondary endpoint:
Post-procedural CK-MB and Tn-I elevation above UNL
Data on the first 153 pts (Sept ’06)
P=0.025
P=0.040 56 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 40 50 40
P=0.001 30
P=0.006
CK-MB (%) 30
Troponin-I (%) 20 20 10 10
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
Atorvastatin
(N=86)
Placebo
(N=85) P
Death -
Myocardial infarction
4 (5%)
13 (15%)
0.04
Target vessel revascularization
1 (2%) 1
Total MACE
14(17%)
0.01

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

42. Thank You!
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