High Versus Standard Clopidogrel Maintenance Dose After

Percutaneous Coronary Intervention: Effects on Platelet

Inhibition, Endothelial Function and Inflammation. Results of

the ARMYDA-150 mg (Antiplatelet Therapy for Reduction of

MYocardial Damage During Angioplasty) Randomized Study

Giuseppe Patti, MD, FACC

Department of Cardiovascular Sciences,Campus Bio-Medico University of Rome

GOAL OF THE STUDY

To investigate whether a 150 mg/day clopidogrel maintenance dose exerts, in addition

to a stronger antiplatelet effect, a more intense anti-inflammatory action and is

associated with improvement of endothelial function vs the conventional regimen (75

mg/day) in patients receiving percutaneous coronary intervention (PCI)

Inclusion criteria:

Consecutive patients (N=50) with non ST-segment elevation acute coronary syndrome or

chronic stable angina undergoing PCI

Exclusion criteria:

• Primary PCI for STEMI

• Active bleeding or bleeding diathesis

• Gastro-intestinal bleeding <6 months

• Cerebro-vascular accident <3 months

• Indication to oral anticoagulant therapy

• History of malignancy

• Severe liver disease or chronic renal failure with serum creatinine >2 mg/dL

• Platelet count <70x109/L

ARMYDA-150 studyARMYDA-150 study

One month

N=50 patients treated with

PCI

(600 mg clopidogrel load before

the procedure)

R

N=25

Clopidogrel75 mg/day

T-1 T-2T-0

• PRU

• FMD, NMD

• HS-CRP

ARMYDA-150: Study design ARMYDA-150: Study design

N=25

Clopidogrel 75 mg/day

Clopidogrel 150 mg/day

Clopidogrel 75 mg/day

Clopidogrel 150 mg/day

• PRU

• FMD, NMD

• HS-CRP

• PRU

• FMD, NMD

• HS-CRP

PRU= P2Y12 Reaction Units

FMD= Flow-mediated dilation

NMD= Nitroglycerin-mediated dilation

HS-CRP= High sensitivity C-reactive protein

One month One month

ARMYDA-150 ARMYDA-150 End-points evaluated in the two clopidogrel doses:End-points evaluated in the two clopidogrel doses:

Platelet reactivity expressed by P2Y12 Reaction Units (PRU) with the point-of-care VerifyNow assay: Absolute PRU values Percent inhibition of PRU values from estimated baseline (measured by the TRAP-channel) Percentage of patients with absolute PRU values ≥240

Brachial artery reactivity:

Percent Flow-mediated dilation (FMD) values Incidence of patients with FMD <7% Percent Nitroglycerin-mediated dilation (NMD) values

Inflammation:

Absolute High-sensitivity C-reactive protein (HS-CRP) values Variations of HS-CRP levels across study time points  

150 then 75 mg/day(N=25)

75 then 150 mg/day(N=25)

P

Age (yrs) 60.8±7.3 65.6±10.9 0.07

Male gender 21 (84) 21 (84) 1

Diabetes mellitus 11 (44) 9 (36) 0.77

Systemic hypertension 23 (92) 22 (88) 1

Hypercolesterolemia 21 (84) 21 (84) 1

Body mass index 30.3±4.6 28.8±4.2 0.23

Previous myocardial infarction 12 (48) 8 (32) 0.39

Previous PCI 12 (48) 13 (52) 1

NSTEMI/Unstable angina 10 (40) 8 (32) 0.77

Left ventricular ejection fraction (%) 57±5.4 55.5±5.6 0.34

Serum creatinine (mg/dl) 0.83±0.19 0.9±0.29 0.32

Multivessel coronary disease 11 (44) 12 (48) 0.77

Multivessel PCI 4 (16) 6 (24) 0.72

Use of DES 16 (64) 16 (64) 1

Medical Rx

Aspirin 25 (100) 25 (100) -

Statins 25 (100) 25 (100) -

Proton pump inhibitors - - -

ARMYDA-150. Main characteristics in the two arms

ARMYDA-150 results

Outcome measures: Platelet reactivity, Brachial artery reactivity, Inflammation

High dose150 mg/day

Standard dose75 mg/day

P

Platelet reactivity

PRU value 141±73 198±71 0.004

PRU inhibition from baseline (%) 50±20 31±20 <0.0001

<0.0001

Patients with PRU ≥240 (%) 12 32 0.001

Brachial artery reactivity

FDM (%) 16.9±12.6 7.9±7.5 0.0001

Patients with FMD <7% (%) 16 58 0.0003

NMD (%) 18.2±17.3 12.0±10.4 0.07

Inflammation

HS-CRP (mg/L) 3.6±3.0 7.0±8.6 0.016

Delta HS-CRP (mg/L) -3.3±7.0 -0.2±5.1 0.007

Patients with HS-CRP >3 mg/L (%) 46 64 0.07

Individual data of Platelet reactivity, Brachial artery reactivity, Inflammation

Platelet Reactivity Brachial Artery Reactivity FMD (%)

PRU

240

75 mg 150 mg

400

300

200

100

150

250

350

50

75 mg 150 mg

7%5

10

15

20

25

30

75 mg 150 mg

HS-CRP (mg/L)

3 mg/L5

10

15

20

25

30

35

40

Inflammation

P=0.001

P=0.0003

P=0.07

HS-CRP >3 mg/L

FMD <7%

PRU ≥240

-80% -60% -40% -20% 0

Difference in percentage of patients with PRU ≥240, FMD <7% and HS-CRP >3 mg/L (150 mg/day vs 75 mg/day clopidogrel)

0

60

120

180

240

300

T-0 T-1 T-2

PR

U

75 mg

75 mg

150 mg

150 mg

Cross-over

*

*

* P=0.004

Variations of PRU, FMD, NMD and HS-CRP at different time points

0

4

8

12

16

20

T-0 T-1 T-2

FM

D (

%)

75 mg

75 mg

150 m

g

150 mg

Cross-over

*

*

* P=0.0001

T-0 T-1 T-2

0

2

4

6

8

10

T-0 T-1 T-2

NM

D (

%)

0

4

8

12

16

20

75 mg

75 mg150 mg

150 mg

Cross-over

75 mg

75 mg

150 mg

150 mg

Cross-over

HS

-CR

P (

mg/

L)

* P=0.07

*

**

*

* P=0.016

Patients initially randomized to 75 mg/day clopidogrel Patients initially randomized to 150 mg/day clopidogrel

In patients receiving PCI, high clopidogrel maintenance dose (150 mg/day)

compared with the standard regimen (75 mg/day) is associated with stronger

platelet inhibition and reduction of low-responders

Use of the higher maintenance dose improved endothelial function (evaluated by

brachial artery reactivity) and reduced inflammation (evaluated by HS-CRP

levels)

In addition to more intense antiplatelet action, “pleiotropic effects” may further

explain mechanisms of the clinical benefit observed in recent trials with the 150

mg vs the 75 mg daily dose of clopidogrel

CONCLUSIONS