Download Trial Overview - Clinical Trial Results

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)
ARMYDA-150 study
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: Study design
T-0
T-1
One month
T-2
One month
One month
Clopidogrel
75 mg/day
Clopidogrel
75 mg/day
Clopidogrel
150 mg/day
Clopidogrel
150 mg/day
N=25
N=50 patients
treated with
PCI
(600 mg
clopidogrel
load before
the
procedure)
Clopidogrel
75 mg/day
R
N=25
PRU= P2Y12 Reaction Units
FMD= Flow-mediated dilation
• PRU
• PRU
• PRU
NMD= Nitroglycerin-mediated dilation
• FMD, NMD
• FMD, NMD
• FMD, NMD
HS-CRP= High sensitivity C-reactive protein
• HS-CRP
• HS-CRP
• HS-CRP
ARMYDA-150
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
ARMYDA-150. Main characteristics in the two arms
150 then 75 mg/day
(N=25)
75 then 150 mg/day
(N=25)
P
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
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
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
Aspirin
25 (100)
25 (100)
-
Statins
25 (100)
25 (100)
-
-
-
-
Age (yrs)
Body mass index
Serum creatinine (mg/dl)
Medical Rx
Proton pump inhibitors
ARMYDA-150 results
Outcome measures: Platelet reactivity, Brachial artery reactivity, Inflammation
High dose
150 mg/day
Standard dose
75 mg/day
P
141±73
198±71
0.004
50±20
31±20
<0.0001
<0.0001
12
32
0.001
16.9±12.6
7.9±7.5
0.0001
16
58
0.0003
18.2±17.3
12.0±10.4
0.07
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
46
64
0.07
Platelet reactivity
PRU value
PRU inhibition from baseline (%)
Patients with PRU ≥240 (%)
Brachial artery reactivity
FDM (%)
Patients with FMD <7% (%)
NMD (%)
Inflammation
Patients with HS-CRP >3 mg/L (%)
Individual data of Platelet reactivity, Brachial artery reactivity, Inflammation
PRU
400
350
Platelet Reactivity
25
P=0.001
300
Brachial Artery Reactivity
FMD
(%) 30
250
200
150
240
20
15
P=0.0003
10
100
50
7%
5
150 mg
75 mg
HS-CRP
(mg/L) 40
75 mg
150 mg
Inflammation
35
30
25
20
P=0.07
15
10
5
3 mg/L
75 mg
150 mg
Difference in percentage of patients with PRU ≥240, FMD <7%
and HS-CRP >3 mg/L (150 mg/day vs 75 mg/day clopidogrel)
HS-CRP >3 mg/L
FMD <7%
PRU ≥240
-80%
-60%
-40%
-20%
0
Variations of PRU, FMD, NMD and HS-CRP at different time points
20
PRU
240
FMD (%)
300
*
180
*
120
60
*
16
12
*
8
* P=0.004
4
* P=0.0001
Cross-over
Cross-over
0
0
T-0
T-1
*
NMD (%)
16
*
12
8
4
* P=0.07
Cross-over
6
4
*
* P=0.016
Cross-over
0
T-1
T-2
*
8
2
0
T-0
T-1
10
HS-CRP (mg/L)
20
T-0
T-2
T-2
Patients initially randomized to 75 mg/day clopidogrel
T-0
T-1
T-2
Patients initially randomized to 150 mg/day clopidogrel
CONCLUSIONS
 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