ACC 2008 – 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

ACC 2008 – Disclosure Slide

ARMYDA (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study group

Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional clopidogrel load

in patients on chronic therapy - “ARMYDA-Reload”

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

Chairman: Germano Di Sciascio

Antiplatet effects of a 600 mg load in pts Antiplatet effects of a 600 mg load in pts with or without chronic clopidogrel Rx with or without chronic clopidogrel Rx

0

20

40

60

80

100

AD

P (

5 A

DP

(5 m

ol/L

)-in

du

ced

agg

rega

tion

, %m

ol/L

)-in

du

ced

agg

rega

tion

, %

600 mg clopidogrel600 mg clopidogrelBefore loadBefore load Before loadBefore loadAfter loadAfter load After loadAfter load

No prior clopidogrelNo prior clopidogrel N=20N=20

Chronic clopidogrelChronic clopidogrel N=20N=20

P<0.001P<0.001

P<0.001P<0.001

P<0.001P<0.001

Kastrati et al. Circulation 2004Kastrati et al. Circulation 2004

ARMYDA - Reload: BACKGROUND

The ARMYDA-2 trial confirmed improved PCI outcome with 600 mg clopidogrel loading vs a 300 mg dose in clopidogrel naïve patients

In patients already receiving clopidogrel, concerns about bleeding (with reloading), and/or adequacy of antiplatelet effect (without additional loading)

GOAL OF THE STUDY

To evaluate safety and effectiveness of a strategy of 600 mg clopidogrel reload in patients undergoing PCI while on chronic clopidogrel therapy, and to evaluate difference in outcome in patients with ACS vs stable angina

Stable angina N=269

568 Patients on

chronic Clopidogrel

therapy (>10 days)

with

Primary endpoint:- Death- MI- TVR

4 - 8 hrs 30 days

Ran

dom

izat

ion

Placebo ‡N=283

Angiography

Medical Rx (N=75)

CABG (N=57)

Clopidogrel600 mg reload ‡N= 285

NSTE-ACSN=167

- NSTE-ACS or Stable angina

CK-MB Troponin-I PRU

Baselineblood sample

PCI 2 hrs 8 and 24 hrs

PRU CK-MB Troponin-I PRU

PRU

ARMYDA-Reload: Study design

PCI ReloadN=130

PCI PlaceboN=139

PCI ReloadN=89

PCI PlaceboN=78

‡ On top of chronic therapy

219 Reload217 Placebo

PCI = 436

ARMYDA-ReloadSTUDY ENDPOINTS

Primary endpoint

30-day incidence of death, MI, TVR

MI definition: Consensus statement of the Joint ESC/ACCF/AHA/WHF Task Force, as a post procedural increases of cardiac biomarkers (troponin or CK-MB) greater than 3 x 99 th percentile of the upper reference limit in patients with normal baseline levels of CK-MB, and as a subsequent elevation of more than three-fold in CK-MB from baseline value in patients with raised baseline levels of CK-MB

Secondary endpoints

Post-procedural increase of markers of myocardial injury above UNL (CK-MB, troponin I)

Occurrence of any vascular/bleeding complications “Point of care” testing of platelet reactivity (PRU) at different time points in

the reload and placebo arms

Inclusion criteria

Patients on chronic (> 10 days) therapy with clopidogrel (22% of PCI pts population in the recruiting centers) with stable angina or non-STE ACS undergoing PCI

Exclusion criteria

- Primary PCI- Platelet count <70x103/ml- Pts with high risk of bleeding- Coronary by-pass surgery in the previous 3 months

ARMYDA-ReloadARMYDA-Reload

Age (yrs)Male gender (%) Diabetes mellitus (%)Hypertension (%)Hypercholesterolemia (%)Current smokers (%)

Previous MI (%)Previous PCI (%)Previous CABG (%) Multivessel disease (%)

LVEF (%)Aspirin (%)Statins (%)

600 mgClopidogrel

reload N=130

Placebo

N=139

P

ARMYDA-Reload TrialClinical Characteristics Stable population: N=269

66±1090 (69) 39 (30)92 (71)

104 (80)26 (20)

40 (31)66 (51)14 (11)

45 (35)

53±7130 (100)127 (98)

67±1194 (68) 41 (30)98 (71)

105 (76)28 (20)

43 (31)61 (44)10 (7)

44 (32)

54±8139 (100)130 (94)

0.440.88 0.970.930.460.90

0.920.310.42

0.70

0.28-

0.17

Age (yrs)Male gender (%) Diabetes mellitus (%)Hypertension (%)Hypercholesterolemia (%)Current smokers (%)

Troponin +ve (%)

Previous MI (%)Previous PCI (%)Previous CABG (%) Multivessel disease (%)

LVEF (%)Aspirin (%)Statins (%)

600 mgClopidogrel

reload N=89

Placebo

N=78

P

ARMYDA-Reload TrialClinical Characteristics ACS population: N=167

64±1080 (90) 31 (35)77 (87)70 (79)15 (17)

40 (45)

24 (27)43 (48)9 (10)

26 (29)

53±789 (100)82 (92)

65±1070 (90) 30 (39)75 (96)67 (86)17 (22)

36 (46)

26 (33)30 (39)

6 (8)

26 (33)

54±878 (100)70 (90)

0.520.82 0.750.060.310.54

0.99

0.470.260.78

0.69

0.39-

0.79

0

3

6

9

12

Placebo

Reload

ARMYDA-Reload TrialComposite primary endpoint (30-day death, MI, TVR)

Overall population N=436

% 9

7

P=0.70

0

5

10

15

20

ARMYDA-Reload TrialComposite primary endpoint (30-day death, MI, TVR)

%

4

8

P=0.23

0

5

10

15

20

%

600 mg Clopidogrel reloadPlacebo

Stable ACS

P=0.03518

7

ARMYDA-Reload TrialIndividual components of primary endpoint

600 mg Clopidogrel reloadPlacebo

0

5

10

15

20

Death MI TVR

4

7

%

0

5

10

15

20

Death MI TVR

18

7

%

Stable ACS

1

ARMYDA-Reload Secondary endpoints

Post-procedural elevation of markers of myocardial injury above UNL

% o

f p

atie

nts

600 mg Clopidogrel reloadPlacebo

0

10

20

30

40

50

60

CK-MB Troponin-I

25

% o

f p

atie

nts

0

10

20

30

40

50

60

CK-MB Troponin-I

41

23

55

46

P=0.016

P=0.31

21

50

45

P=0.48

P=0.41

Stable ACS

ARMYDA-Reload Trial Secondary endpoints

Bleeding rates in the overall population

0

2

4

6

Major bleeding Minor bleeding

600 mg Clopidogrel reloadPlacebo

%

5 5

0 0

ARMYDA-Reload Trial Secondary endpoint

Bleeding rates

0

2

4

6

Major bleeding Minor bleeding*

600 mg Clopidogrel reloadPlacebo

%

2 2

0 0

0

3

6

9

12

Major bleeding Minor bleeding*

%10 10

0 0

Stable ACS

N=3 N=3 N=8 N=9

* P=0.03

ARMYDA-Reload: Platelet aggregometry*

* By VerifyNow TM

Placebo Reload

203±62

156±62

210±57

193±59184±63

159±63

201±67

162±71

200±61

189±65

168±71

148±66

Estimated Study PCI 2 hrs 8 hrs 24 hrs

baseline ** Drug

100

120

140

160

180

200

220

240

Pla

tele

t re

acti

on u

nit

s (P

RU

) P=0.12

Placebo

Clopidogrel

600 mg

** Using baseline TRAP channel

Stable ACS

218±62

171±61

227±85

180±79

172±83

126±61

215±69

176±71205±55

192±63

186±61

132±51

Estimated Study PCI 2 hrs 8 hrs 24 hrs

baseline ** Drug

100

120

140

160

180

200

220

240

Pla

tele

t re

acti

on u

nit

s (P

RU

) P=0.046

Placebo

Clopidogrel

600 mg

0 1 2

Odds Ratios for 30-day MACE

ACS

No ACS

Diabetes mellitus

3 4 5

No diabetes

MV intervention

0.36 (0.29-0.92)

1.2 (0.95-1.4)

0.75 (0.18-4.7)

0.90 (0.38-2.2)

1.2 (0.22-7.8)

No MV intervention 0.80 (0.35-1.9)

ARMYDA-Reload

EVENT CURVES

30-day MACE and Benefit with Reload

ACS Placebo

Stable Angina Reload

ACS Reload

Stable Angina Placebo

ARMYDA-Reload

0

4

8

12

16

20

5 10 15 20 25 30

Days after randomization

Dea

th/M

I/R

epea

t re

vasc

ular

izat

ion

(%)

P=0.035 (ACS Placebo vs ACS Reload)

The ARMYDA-Reload trial indicates that a significant proportion of patients undergoing PCI are on chronic clopidogrel therapy

Patients with stable angina who are already taking clopidogrel can safely undergo PCI without need of further reload

In patients with ACS, a 600 mg reloading strategy can significantly improve outcome (64% RR of MACE)

Serial point of care aggregometry studies show platelet reactivity curves consistent with clopidogrel status and clinical syndrome, and may correlate with outcome

No major bleeding, and no increased bleeding risk are observed in the “reload” approach vs placebo in either stable or ACS patients

Given the growing number of patients undergoing PCI while on clopidogrel, those results may influence practice patterns in interventional pharmacology

CONCLUSIONS

ARMYDA-Reload TrialIndividual events at 30 days

600 mg Clopidogrel reloadPlacebo

0

2

4

6

8

10

Death MI TVR

6.8

9

%

0.5

30-day MACE and Benefit with Reload (600 mg Clopidogrel)

ACS Placebo

Stable Angina Reload

ACS Reload

Stable Angina Placebo

ARMYDA-RELOAD

0

4

8

12

16

20

5 10 15 20 25 30

Days after randomization

Dea

th/M

I/R

epea

t re

vasc

ular

izat

ion

(%)

P=0.035 (ACS Placebo vs ACS Reload)

P

Vessels treated (%) Left main LAD LCx RCA SVG

Chronic total occl. (>3 mo.)(%)

Restenotic lesions (%)

Lesion type B2/C (%)

Multivessel intervention (%)

Type of intervention (%) Balloon only Stent DES (%)

IIb/IIIa inhibitors (%)

600 mgClopidogrel

reload N=130

Placebo

N=139

ARMYDA–Reload Trial Procedural features

Stable population : N=269

4 (2)63 (39) 38 (24) 54 (34)

2 (1)

18 (14)

18 (14)

70 (54)

30 (23)

15 (12) 115 (88)

70 (54)

7 (5)

4 (2)78 (46) 37 (22) 50 (29)2 (1)

12 (9)

12 (9)

71 (51)

31 (22)

11 (8) 128 (92)

65 (47)

6 (4)

0.790.28 0.77 0.470.66

0.25

0.25

0.74

0.99

0.42 0.42

0.30

0.90

P

Vessels treated (%) Left main LAD LCx RCA SVG

Chronic total occl. (>3 mo.)(%)

Restenotic lesions (%)

Lesion type B2/C (%)

Multivessel intervention (%)

Type of intervention (%) Balloon only Stent DES (%)

IIb/IIIa inhibitors (%)

600 mgClopidogrel

reload N=89

Placebo

N=78

ARMYDA–Reload Trial Procedural features

ACS population : N=167

2 (2)41 (42) 20 (20) 29 (29)

7 (7)

-

4 (5)

51 (57)

10 (11)

5 (6) 84 (94)

20 (22)

18 (20)

2 (2)37 (42) 17 (19) 25 (28)8 (9)

-

3 (4)

50 (64)

11 (14)

5 (6) 73 (94)

20 (26)

16 (21)

0.690.90 0.99 0.980.83

0.86

0.46

0.75

0.91 0.91

0.77

0.88

211±66

162±58

215±65

185±65

178±69

148±65

208±68

170±70199±58

190±66

172±61

142±61

Estimated Study PCI 2 hrs 8 hrs 24 hrs

baseline ** Drug

100

120

140

160

180

200

220

240

Pla

tele

t re

acti

on u

nits

(P

RU

)ARMYDA-Reload: Platelet aggregometry* Overall population

P=0.01

* By VerifyNow TM

Placebo

Clopidogrel

600 mg

Placebo

Reload

** Using baseline TRAP channel