ARMYDA-4 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study

Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional 600 mg 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

(%)

ARMYDA-2 RESULTSPrimary end-point30-day Death, MI, TVR

Circulation 2005;111:2099-2106

P=0.041

4%

12%

0

3

6

9

12

15

600 mg

300 mg

Antiplatet effects of a 600 mg load on chronic clopidogrel Rx Antiplatet effects of a 600 mg load on 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

PCI “reload” arm

N= 180

464 Patients on clopidogrel

therapy with Stable angina

or NSTE ACS

undergoing coronary angiography

Primary end point: Death, MI*, TVR

2nd and 3rd blood sample at 8 and 24 hours

30 days

Ran

dom

izat

ion

Angiography

Clopidogrel600 mg

re-loading ‡ N= 230

1st blood samplebefore PCI

- CK-MB, troponin-I, myoglobin, CRP

ARMYDA-4: Study designARMYDA-4: Study design

Placebo ‡N= 234

PCI - placebo arm

N= 180

4 -8 Hours pre-PCI

* MI = >3 times UNL CK-MB‡ On top of chronic therapy

Medical RxN= 62

CABGN= 42

N= 360

Inclusion criteria

- Pts on chronic therapy with clopidogrel (> 10 days) with stable angina or non-STE ACS undergoing PCI

Exclusion criteria

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

ARMYDA-4ARMYDA-4

STUDY ENDPOINTS

Primary endpoint

30-day incidence of death, MI, TVR

(MI definition: post-procedural increase of CK-MB >3 times above UNL in patients with normal baseline

levels of creatine kinase-MB)

Secondary endpoints

Any postprocedural increase of markers of myocardial injury above UNL (CK-MB, troponin I, myoglobin)

Mean peak values of CK-MB, troponin I and myoglobin after intervention Occurrence of any vascular/hemorragic complications “Point of care” evaluation of platelet reactivity at different time points in the

two arms

Age (yrs)Male sex (%) Diabetes mellitus (%)Hypertension (%)Hypercolesterolemia (%)Current smokers (%)

Previous MI (%)Previous PCI (%)Previous CABG (%)Clinical pattern (%) Non STE ACS Multivessel disease (%)

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

600 mgClopidogrel

reload N=180

Placebo

N=180

P

65±10140 (78) 56 (31)

136 (75)142 (79)36 (20)

54 (30)88 (49)16 (9)

67 (37)

78 (43)

55±7180 (100)171 (95)

65±10139 (77) 59 (33)

149 (83)142 (79)34 (19)

57 (31)77 (43)13 (7)

70 (39)

67 (37)

55±7180 (100)168 (93)

10.99 0.820.12

10.82

0.820.290.69

0.83

0.83

0.2811

ARMYDA-4Clinical Characteristics

N=360 pts

P

Vessel treated (%) Left main LAD LCx Right coronary SVG

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

Restenotic lesions (%)

Lesion type B2/C (%)

Multivessel intervention (%)

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

5 (2)82 (40) 46 (22) 70 (34)

5 (2)

18 (10)

13 (7)

123 (59)

28 (15)

18 (10) 162 (90)

76 (42)

4 (2)86 (40) 47 (22) 67 (31)

8 (3)

10 (5)

13 (7)

130 (61)

33 (18)

14 (8) 166 (92)

78 (43)

0.970.92 0.92 0.710.60

0.17

1

0.92

0.57

0.58 0.58

0.91

600 mgClopidogrel

reload N=180

Placebo

N=180

ARMYDA – 4 Trial Procedural features

0

3

6

9

12

Placebo

Reload

ARMYDA-4 TrialComposite primary end-point (30-day death, MI, TVR)

%

78

P=0.96

ARMYDA-4 TrialIndividual events at 30 days

600 mg Clopidogrel reloadPlacebo

0

2

4

6

8

10

Death MI TVR

7

8%

ARMYDA-4 Trial Secondary end points

Post-procedural elevation of markers of myocardial injury above UNL%

of

pat

ien

ts

600 mg Clopidogrel

re loadPlacebo

0

10

20

30

40

50

CK-MB Troponin-I

P=0.98

P=0.584546

2730

ARMYDA-4 Trial Secondary end points

Post-PCI peak levels of markers of myocardial injury (CK-MB and Troponin-I)

600 mg Clopidogrel

reloadPlacebo

Pea

k v

alu

e o

f C

K-M

B (

ng

/ml)

Pea

k v

alu

e o

f T

n-I

(n

g/m

l)

5.6±7.5 5.3±12

0.52±2.20.39±0.87

0

2

4

6

8

CK-MB

P=0.90

CK-MB

0

0,2

0,4

0,6

0,8

1 P=0.55

600 mg Clopidogrel

reloadPlacebo

Troponin-I

0.39±1.1

ARMYDA-4 Trial Secondary end points

Bleeding rates

0

2

4

6

Major bleeding Minor bleeding

600 mg Clopidogrelreload

Placebo

% 4 4

0 0

211±66

166±60

217±66

183±68177±71

153±65

208±68

173±69199±64

178±62174±65

146±63

Base Study PCI 2 hrs 6 hrs 24 hrs

Drug

100

120

140

160

180

200

220

240

Pla

tele

t re

acti

on u

nits

(P

RU

)ARMYDA-4: Platelet aggregometry*

P=0.2

* By Accumetrics

Placebo

Clopidogrel

600 mg

Placebo

Further load

Results of the ARMYDA-4 trial indicate that a pre-PCI 600 mg loading dose does not confer additional clinical benefit in patients already receiving chronic therapy with clopidogrel

Point of care aggregometry testing shows no significant differences in platelet reactivity in the 2 arms

No increased bleeding risk is observed in the “reload” approach

Patients on chronic clopidogrel therapy can safely undergo PCI without need of further reload

CONCLUSIONS

• Several studies have demonstrated beneficial clinical effects of a 600 mg clopidogrel loading dose in patients undergoing percutaneous coronary intervention (PCI).

• Laboratory evidence suggests that an additional pre-PCI 600 mg loading further decreases platelet aggregation in patients already on chronic treatment with clopidogrel. However, there are no clinical data on the safety and efficacy of this strategy.

BACKGROUND