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March 24-27, 2007
New Orleans, LA
 Dr. Germano Di Sciascio

ARMYDA-ACS: Atorvastatin Pretreatment

Improves Outcome in Patients With Acute
Coronary Syndromes Undergoing
Percutaneous Coronary Intervention
 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
 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

20 18
P=0.025
15

Atorvastatin
10
Placebo
5
5

Pasceri V, Patti G, Di Sciascio G, et al. Circulation 2004;110:674-678

 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)
 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
Randomization (N=191)

771 pts with PCI

2 hrs before Primary
atorvastatin
NSTE-ACS N=96 combined
N=86
sent to atorvast end point:
Coronary
early coronary angiography 30-day
angiography PCI death, MI,
(<48 hours) Placebo placebo TVR
12 hrs pre-angio; N=85
Jan ’05 - Dec ‘06
further
dose 2 hrs
before
N=95
1st blood sample 2nd and 3rd
blood samples
(pre-PCI)
(8 and 24 hrs
post-PCI)

CK-MB, troponin-I, myoglobin, CRP

 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
 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) 28 (33) 0.96

Chronic Renal Failure 12 (14) 13 (15) 0.81
Current smokers 27 (31) 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 - 600 mg load 86 (100) 85 (100) 1
Beta-Blockers 26 (30) 23 (27) 0.77
Ace-Inhibitors 67 (78) 65 (76) 0.97
IIb/IIIa Inhibitors 23 (27) 18 (21) 0.50
 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 51 (50) 54 (59) 0.94
descending
Left circumflex 31 (30) 28 (25) 0.56
Right coronary artery 20 (19) 26 (24) 0.56
Saphenous vein graft 1 (1) 1 (1) 0.51
Lesion type B2/C 73 (85) 71 (84) 0.97
Multivessel intervention 17 (20) 25 (29) 0.20
Type of intervention:
Balloon only 1 (1) 1 (1) 0.48
Stent 85 (99) 84 (99) 0.48
Bifurcations with kissing 8 (9) 8 (9) 0.81
balloon
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 11.2±4.1 11.6±2.7 0.44
(atm)
Duration of stent deployment 16±7 16±5 1
(sec)
 ARMYDA-ACS trial
Composite primary end-point (30-day death, MI, TVR)

% 20 17

15 P=0.01

Atorvastatin
10
Placebo
5
5

0
 ARMYDA-ACS
Individual and Combined Outcome Measures
of the Primary End Point at 30 days

21
14/85
% 18 13/85 (17%)
(15%)
15 P=0.01
P=0.04
12
9
4/86 4/86
6 (5%) (5%)
1/85
3 (2%)

0
Death MI TVR MACE
Composite
Primary End Point
Atorvastatin Placebo
 ARMYDA-ACS: Secondary end point
Cardiac markers elevations

1-3 times >3 times

40 60
P=0.002 P=0.028
50
30
40

20 30

20
10
10

0 0
Atorvastatin Placebo Atorvastatin Placebo
 ARMYDA-ACS: Secondary end point
Post-PCI percent increase of CRP levels from baseline

147
160
P=0.01
% 120

63 Atorvastatin
80
Placebo

40

0
 ARMYDA-ACS: Actuarial Survival curves

Atorvastatin Placebo
100
MACE-free survival (%)

80

60
P=0.01

40

20

0
1 2 3 7 14 21 30
Days after PCI
0 1 2 3 4 5

1.3 (0.36-4.8)

3.6 (1.1-10.4)

4.2 (2.1-12.2)

0.75 (0.44-2.8)

0.88 (0.59-3.9)

0.12 (0.05-0.50)
 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

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

Wassmann S, et al. Circ Res 2003

 Possible mechanisms of the clinical benefit:
Vasodilation of coronary microvessels

Coronary flow velocity reserve

(hyperemic/basal peak diastolic velocity)

N=32 pts without CAD 4

P<0.01
randomized to placebo
or 3
atorvastatin (single dose of 40 mg)
transthoracic doppler 2 Before

evaluation of LAD (baseline and 1 hr) After

1

0
Placebo Atorvastatin

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

PLT CD40L expression (AU) Prothrombin fragment F1+2 (nM)

P<0.01
50 43+15 45+12 46+15 3

40 2+1 2+1 P<0.05

2+1
32+6
2
30 1.4+0.4
Before Before
20 After After
1
10

0 0
Placebo Atorvastatin Placebo Atorvastatin

Sanguigni V, et al. Circulation 2005

 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
P=0.55
80 59 60
P=0.20
60 42 45
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
 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
Atorvastatin Placebo P
Variable (N=86) (N=85)
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) 28 (33) 0.96

Chronic renal failure 12 (14) 13 (15) 0.81

Current smokers 27 (31) 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:

Unstable angina 52 (60) 58 (68) 0.37

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 - 600 mg load 86 (100) 85 (100) 1
Beta-blockers 26 (30) 23 (27) 0.77
Ace-inhibitors 67 (78) 65 (76) 0.97
IIb-IIIa inhibitors 23 (27) 18 (21) 0.50
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

ARMYDA-ACS: Procedural Features in the Atorvastatin and Placebo Groups
Variable Atorvast Placebo P
(N=86) (N=85)
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) 0.56
Saphenous vein grafts 1 (1) 1 (1) 0.51

Lesion type B2/C 73 (85) 71 (84) 0.97

Multivessel intervention 17 (20) 25 (29) 0.20

Type of intervention:
Balloon only 1 (1) 1 (1) 0.48
Stent 85 (99) 84 (99) 0.48
Bifurcations with kissing balloon 8 (9) 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
 Primary end point
RESULTS
Post-PCI incidence of myocardial infarction
(CK-MB> 2 times UNL)

30
P=0.025

18
20

10
5

0
Placebo Atorvastatin
 ARMYDA-ACS trial

30 days
Atorvastatin 80 mg
the day before and
40 mg 4 to 6 hrs
before PCI
N=76 Atorvastatin
Patients with group Primary
Randomization

endpoint:
- NSTE ACS
and PCI 30-day
- Indication to occurrence
PCI, of death, MI*,
Placebo TVR
“Statin-naive”
Placebo group
the day before and
4 to 6 hrs
before PCI
N=77

1° blood 2° and 3°
sample blood
samples
(before PCI)
(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
 ARMYDA-CAMs RESULTS

P=0.0001
100

P=0.0001
80

P=0.20
60

40

20

0
ICAM-1 E-selectin VCAM-1

Atorvastatin Placebo

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)

60 P=0.025 P=0.040 56
49

% 50
38
40
30
Atorvastatin
30
Placebo
20

10

0
CK-Mb Tn-I
 Improving outcome after PCI by reducing peri-procedural MI
The ARMYDA trials

18%

6% 5% 5%

ARMYDA-1 ARMYDA-1 ARMYDA-2 ARMYDA-ACS

No statin Atorvastatin Statin Atorvastatin
No 600 mg clop. No 600 mg clop. 600 mg clop. 600 mg clop.

Pts with
Pts with CSA Pts with ACS
CSA or ACS
 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
30
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

 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 Placebo P
(N=86) (N=85)

Death - -
Myocardial infarction 4 (5%) 13 (15%) 0.04
Target vessel revascularization - 1 (2%) 1
Total MACE 4 (5%) 14(17%) 0.01
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
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