Paul Gurbel, Kevin Bliden, Tania Gesheff, Yvonne Kreutz, Udaya Tantry Sinai Center for Thrombosis...
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Transcript of Paul Gurbel, Kevin Bliden, Tania Gesheff, Yvonne Kreutz, Udaya Tantry Sinai Center for Thrombosis...
Paul Gurbel, Kevin Bliden, Tania Gesheff, Paul Gurbel, Kevin Bliden, Tania Gesheff, Yvonne Kreutz, Udaya TantryYvonne Kreutz, Udaya Tantry
Sinai Center for Thrombosis ResearchSinai Center for Thrombosis ResearchSinai Hospital of BaltimoreSinai Hospital of BaltimoreBaltimore, Maryland, U.S.A.Baltimore, Maryland, U.S.A.
A Mechanistic Link Between High Platelet Reactivity, Inflammation Marker Release and Myonecrosis in
Patients Undergoing Stenting: CLEAR PLATELETS Ib Study
Disclosures
Research Grants Honoraria - Schering - Schering - Millennium - Millennium - Astra Zeneca - Astra Zeneca - Bayer - Bayer
- NIH
- Haemoscope
- Medtronic
- Boston Scientific
This study was supported by Millennium and Schering
Background
• Thrombosis and inflammation influence the development of ischemic events following PCI.• Recent trials established the effectiveness of GPIIb/IIIa inhibitors with clopidogrel and aspirin in reducing thrombotic events following PCI.• However, controversy remains regarding the optimal antiplatelet strategy for elective stenting.• Response variability to clopidogrel has been demonstrated in patients undergoing elective stenting.1,2
1. Gurbel et al. J Am Coll Cardiol 2005;45:1392-6
2. Gurbel et al. Circulation. 2003;107: 2908-2913
Background
• In the CLEAR PLATELETS Study a loading dose of clopidogrel with a GPIIb/IIIa inhibitor (eptifibatide) produced:
- superior platelet inhibition - lower myocardial necrosis compared to 300 mg or 600 mg clopidogrel loading alone.1
• Potential anti-inflammatory effects of clopidogrel and GPIIb/IIIa inhibitors have been recently reported.2
• The comparative anti-inflammatory effects of clopidogrel ± GPIIb/IIIa blockade during stenting are unknown.1. Gurbel PA. et al Circulation 2005; 111:1153-9 2. Nannizzi-Alaimo L et al. Circulation 2003; 107:1123-1128
• The primary objective of the current investigation (CLEAR PLATELETS -1b): Compare the effects of the antiplatelet regimens employed in the CLEAR PLATELETS study on early inflammation and cardiac marker release
after PCI.
• The secondary objective:
Study relation between platelet inhibition and inflammation
Objectives
Study Design of CLEAR PLATELETS-1bStudy Design of CLEAR PLATELETS-1b
CLEAR PLATELETS
CLEAR PLATELETS 1b
N = 60 N = 60 N = 60
Study Design of CLEAR PLATELETS-1bStudy Design of CLEAR PLATELETS-1bStudy Design of CLEAR PLATELETS-1bStudy Design of CLEAR PLATELETS-1b
2 X 2 Factorial Elective Stent Study
Clopidogrel 300 mg in lab(n = 60)
Clopidogrel 600 mg in lab (n = 60)
- Eptifibatide(n = 30)
+ Eptifibatide(n = 30)
- Eptifibatide(n = 30)
+ Eptifibatide (n = 30)
Heparin per ESPIRIT dosing , Clopidogrel 75 mg qd, ASA 325 mg qd
Laboratory Measurements - Before and 18-24 hours Post-Stenting
Platelet Aggregation Light transmittance ( 5 and 20 M ADP) Platelet Activation Markers
ADP-stimulated: - active GPIIb/IIIa - P-selectin by flow cytometry
Inflammation Markers - C-reactive protein - Tumor necrosis factor -by ELISA
Necrosis Markers - Creatinine Kinase MB - Troponin I
- Myoglobin
Biomarker Profile by Luminex®
Results - Results - Patient DemographicsPatient Demographics
Clopidogrel(n=60)
Clopidogrel +Eptifibatide (n=60)
p-value
Age (years) 63+/-14 65+/-12 nsRace (Caucasian) (%) 70 70 nsGender (Male) (%) 63 70 nsBMI 29+/-5 30+/-6 ns
Risk Factors (%)Smoking 45 38 nsFamily history of CAD 38 36 nsHypertension 60 73 nsHyperlipidemia 80 87 nsDiabetes 50 53 nsPrior Myocardial Infarction 25 35 nsPrior CABG 25 20Prior PTCA 35 55 0.03
Baseline Medications (%)Beta blockers 87 97 nsACE Inhibitors 62 75 nsCalcium blockers 20 27 nsLipid lowering agents
CYP3A4 metabolized 62 57 ns Non -CYP 3A4 metabolized 20 20 ns
ns
Results - Results - Procedural CharacteristicsProcedural Characteristics
Clopidogrel(n=60)
Clopidogrel +Eptifibatide
(n=60)
p-value
Length of procedure (min.) 60+/-21 60+/-22 nsEjection Fraction (%) 54+/-8 52+/-9 nsNumber of vessels treated 1.2+/-0.5 1.4+/-0.6 nsLesion MorphologyDenovo (%) 93 87 ns
Lesion Location (%)LAD 32 33 nsCX 23 28 nsRCA 40 32 nsSVG 5 7Stent Types (%)Drug eluting 70 67 nsBare metal 23 27 nsPTCA only 7 4 nsReference vessel diameter(mm)
3.1+/-0.5 3+/-0.4 ns
Total lesion length (mm) 20.2+/-12.0 21+/-13.0 nsPre-stenosis (%) 85+/-7 84+/-7 nsPost-stenosis (%) 3+/-1 4+/-2 ns
Relative Change in Platelet Aggregation, P-Selectin and Active GPIIb/IIIa Expression:
Four Treatment Groups
-120
-100
-80
-60
-40
-20
0
Rel
ativ
e C
han
ge
(%)
300 C 600 C 300 C+E 600 C+E
p=0.04 p=0.004 p=ns p<0.01
p=ns p=ns p=ns
p<0.001
LTA LTA Stimulated Stimulated
5 uM ADP 20 uM ADP GPIIb/IIIa P-selectin
Relative Change in Plasma TNF- and CRP: Four Treatment Groups
-50
-40
-30
-20
-10
0
10
20
30
40
50 TNF- CRP
Rel
ativ
e C
han
ge
(%)
300 C 600 C 300 C+E 600 C+E
p<0.001
p = ns
p = 0.009
p = ns
Myocardial Necrosis Markers:Clopidogrel vs. Clopidogrel + Eptifibatide
11
5
9
16
3
0
34
0
4
8
12
16
20
Nu
mb
er
of
Pa
tie
nts
Clopidogrel Clopidogrel + Eptifibatide
CKMB (>1-3xULN)
CKMB (>3xULN)
Tn - I (>ULN)
Myoglobin (>2xULN)
Clopidogrel Clopidogrel + Eptifibatide
-120
-100
-80
-60
-40
-20
0
20
40
60
Re
lati
ve
Ch
an
ge
(%
)
p<0.001
p<0.001
p<0.001p<0.001
p=0.095
p<0.001
LTA- LTA- Stimulated Stimulated TNF-Alpha CRP
5uM ADP 20uM ADP GPIIb/IIIa P-Selectin
Relative Change in Aggregation, P-Selectin, Active GPIIb/IIIa, TNF-, CRP:
Clopidogrel vs. Clopidogrel + Eptifibatide
Relation of Necrosis Marker Release to Plasma CRP and TNF-
0.0
1.5
3.0
4.5
6.0
7.5
Po
st-T
reat
men
t C
RP
(m
g/L
)
CK-MB (NL)
CK-MB (>3X ULN)
CK-MB(>1-3X ULN)
p=0.01 p=0.09
p=0.001
0
60
120
180
240
300
Po
st-T
reat
men
t T
NF
-Alp
ha
(n
g/m
L)
CK-MB (NL)
CK-MB(>1-3X ULN)
CK-MB (>3X ULN)
p<0.001
p<0.001
Absolute Change in Platelet Aggregation and (%) Patients Treated with Eptifibatide in CRP Quartiles
0
20
40
60
80
<2.1 2.2-3.6 3.7-4.6 >4.7
Ab
so
lute
Ch
an
ge
in
P
late
let
Ag
gre
ga
tio
n (
%) p=0.003
CRP (mg/L) Quartiles
0
20
40
60
80
< 2.1 2.2-3.6 3.7-4.6 >4.7
CRP (mg/L) Quartiles
Fre
qu
ency
of
Pat
ien
ts
Tre
ated
Wit
h E
pti
fib
atid
e (%
)
p=0.06
p=0.004
p<0.001
Clopidogrel
Clopidogrel + Eptifibatide
Biomarker Profile by MAP:Clopidogrel vs. Clopidogrel + Eptifibatide
-100 -50 0 50 100
MMP-9 <0.0001
vWF 0.001
Tissue Factor <0.0001
Fibrinogen 0.007
RANTES 0.006
MIP-Alpha 0.03
TNF-Alpha 0.003
CRP <0.0001
VCAM-1 0.03
CD40-L 0.001
Fatty Acid Binding Protein <0.0001
Myoglobin <0.0001
Relative Change (%)
Conclusions
• Clopidogrel + eptifibatide produces a distinctly different periprocedural
biomarker profile than clopidogrel alone in elective stenting:
significant inhibition of inflammation and myocardial necrosis
marker release.
• Inhibition of platelet aggregation and active GP IIb/IIIa expression but not
p-selectin expression was associated with inhibition of inflammation.
• The mechanistic and clinical implications of attenuated periprocedural
inflammation and myocardial necrosis with a strategy of GPIIb/IIIa
inhibition warrant further investigation.
Necrosis
GPIIb/IIIa Inhibition
Inflammation