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INCITE StudyINCITE Study
Co-PI: Frederick Welt, M.D. Co-PI: Daniel I. Simon, M.D.
Brigham and Women’s HospitalWest Roxbury VA Medical Center
Harvard Medical SchoolBoston, MA
INflammatory Cessation with abcIximab or InTEgrilin
INflammatory Cessation with abcIximab or InTEgrilin
INCITE
InflammationInflammationInflammationInflammation AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis
ThrombosisThrombosisThrombosisThrombosis
Thrombus
Quiescentplaque
Plateletsand thrombin
Plaque rupture
Acute Coronary Syndromes Evolving Understanding of Pathophysiology
CD40LCD40L
CD40L in Immunity:Isotype Switching
CD40L in Immunity:Isotype Switching
TMTMTNF HomologyTNF HomologyTNF HomologyTNF Homology
Helper T cellHelper T cellHelper T cellHelper T cell B cellB cellB cellB cell
CD40LCD40LCD40LCD40L
sCD40LsCD40LsCD40LsCD40LNNNN CCCC
CD40LCD40LCD40LCD40L CD40CD40CD40CD40
CD40L Distribution
300300
200200
100100
00
CD
40L
Uni
ts/m
L bl
ood
CD
40L
Uni
ts/m
L bl
ood BloodBlood
PlateletsPlatelets LymphocytesLymphocytesCD
40L
Uni
ts/1
x10
CD
40L
Uni
ts/1
x1066
cells
cel
ls
P=P=0.0160.016
CellsCells
PlateletsPlatelets LymphocytesLymphocytes
33
22
11
00
Henn et al., Blood, 2001, 98, 1047Lindmark et al. ATVB, 2000, 20, 2322Andre et al., Nature Med., 2002, 8, 247
CD40L in Vascular Disease• CD40L antibody inhibits atherosclerotic lesion
progression in LDLR -/- mice
• CD40L gene deletion inhibits lesion progression in Apo E-/-mice
• Soluble form detected in ACS and PCI
• Elevated plasma levels of sCD40L identify healthy women at risk for CV events.
• CD40L antibody inhibits atherosclerotic lesion progression in LDLR -/- mice
• CD40L gene deletion inhibits lesion progression in Apo E-/-mice
• Soluble form detected in ACS and PCI
• Elevated plasma levels of sCD40L identify healthy women at risk for CV events.
Nature 1998;391:591Nature 1998;391:591PNAS 2000;97:7458PNAS 2000;97:7458Nature Med 1999;5:1313Nature Med 1999;5:1313
Circulation 1999;100:614Circulation 1999;100:614Circulation 2001;104:2266Circulation 2001;104:2266
Platelet CD40L-Induced Inflammation
thrombinthrombin
CD40LCD40LCD40LCD40L
Cultured HUVECsCultured HUVECs
IL-8IL-8MCP-1MCP-1
ICAM
-1
ICAM
-1
VCAM-1
VCAM-1
TFTF
Modified from: Nature 1998;391:591
sCD40LsCD40L
(min
)
WT
CD40L-/-
CD40 -/
-0
10
20
30
40 *
CD40L-/-
+ rsCD40
L
Time to reach occlusion
sCD40L Promotes Thrombosis:sCD40L Promotes Thrombosis:Delayed Arterial Occlusion in CD40L-/- MiceDelayed Arterial Occlusion in CD40L-/- Mice
30 min after FeCl3
WT
CD40L-/-
* P < 0.0005† P < 0.02
Nature Med, 2002, v.8, 247-52
GP IIb-IIIa Antagonism:GP IIb-IIIa Antagonism: sCD40L Release and AggregationsCD40L Release and Aggregation
00 11 22 33 44 55
125125
100100
7575
5050
2525
00
Eptifibatide (Eptifibatide (M)M)
125125
100100
7575
5050
2525
00
00 0.20.2 0.40.4 0.60.6 0.80.8 11
Tirofiban (Tirofiban (M)M)Abciximab (Abciximab (M)M)
00 0.20.2 0.40.4 0.60.6 0.80.8 11
% s
CD
40L
Rel
ease
% s
CD
40L
Rel
ease
% a
gg
reg
atio
n%
ag
gre
gat
ion
Circulation, Supplement. 2001;104:II-318, 1533
sCD40LsCD40LsCD40LsCD40L
InflammationInflammation
ThrombosisThrombosis
Functions of Released sCD40LFunctions of Released sCD40L
sCD40LsCD40LsCD40LsCD40LGP IIb/IIIa
Abciximab: Anti-Inflammatory Action
AM Lincoff at al. Circ 2001;104:163
GP IIb-IIIa Inhibitors: Specificity/Selectivity
IIb/IIIa xxx xxx xxx
V3 xxx ?x
Mac-1 x
Abciximab Eptifibatide Tirofiban
Charo IF et al. Proc Natl Acad Sci. 1986;83:835Coller BS et al. Blood. 1991;77:75Altieri DC et al. J Immunol. 1988;141:2656Simon DI et al. Arterioscler Thromb Vasc Biol 1997;17:528Lele M et al. Circ 2001;104:582
INCITE: INCITE: HypothesisHypothesis
Our central hypothesis is that GP IIb-IIIa inhibitors will modulate peri-PCI inflammation by virtue of their effect on platelet-induced leukocyte activation.
Our central hypothesis is that GP IIb-IIIa inhibitors will modulate peri-PCI inflammation by virtue of their effect on platelet-induced leukocyte activation.
INCITE
INCITE: INCITE: Study DesignStudy DesignElective PCI
ASA, heparin (50-70 U/kg)Elective PCI
ASA, heparin (50-70 U/kg)
RPFA baseline and 10 min post-bolus
ELISA: sCD40L, RANTES, IL-6, sICAM-1
Timepoints: Baseline, 30 min, 2 hrs, 24 hrs
RPFA baseline and 10 min post-bolus
ELISA: sCD40L, RANTES, IL-6, sICAM-1
Timepoints: Baseline, 30 min, 2 hrs, 24 hrs
NoGP IIb-IIIa
(n=15)
NoGP IIb-IIIa
(n=15)
Abciximab0.25 mg/kg
0.1 g/kg/min(n=15)
Abciximab0.25 mg/kg
0.1 g/kg/min(n=15)
Eptifibatide180/180 g/kg2 g/kg/min
(n=15)
Eptifibatide180/180 g/kg2 g/kg/min
(n=15)
INCITE
Exclusion Criteria-Patients already on GP IIb/IIIa inhibitor-Patients with clear indications for GP IIb/IIIa:
-Acute ST elevation MI or non q-wave MI with CPK elevation
-Pain at rest with EKG changes < 24 hours-Visible Thrombus-Pain refractory to heparin
-Lesions located in vascular grafts or at sites of prior intervention
-Bleeding disorder-Thrombocytopenia (plts< 100)-History of GI bleeding-History of stroke or intracranial bleed-Uncontrolled hypertension (SBP > 200 mm Hg, DBP> 100 mm
Hg)-Condition requiring oral anticoagulation-History of allergy or contraindication for aspirin or heparin
None Abciximab Eptifibatide p-value
n 15 15 15
Age 70.3±11.4 64.3±9.7 61.6±10.8 NS
Diabetes Mellitus, % 20.0 46.7 26.7 NS
Hypertension, % 66.7 80.0 73.3 NS
Elevated Cholesterol, % 66.7 93.3 80.0 NS
Current Smoker, % 26.7 40.0 40.0 NS
Prior MI, % 26.7 53.3 53.3 NS
Prior PCI, % 26.7 53.3 20.0 NS
Prior CABG, % 33.3 46.7 46.7 NS
Unstable Angina, % 20.0 6.7 20.0 NS
WBC 6.6±1.8 7.1±1.9 7.3±2.0 NS
Platelet 223±80 227±61 246±67 NS
Hematocrit 37.1±3.3 37.4±4.1 41.1±3.6 NS
Creatinine 1.1±0.3 1.0±0.2 1.0±0.2 NS
Baseline Characteristics
Procedural Characteristics
None Abciximab Eptifibatide p-value
n 15 15 15
Activated Clotting Time 267±49 287±68 317±55 NS
Platelet Inhibition, % (RPFA)
N/A 93±4 98±3 P<0.01
Multivessel PCI, % 26.7 33.3 40.0 NS
INCITE
Plasma sCD40L Post-PCI
30 min 2 hour 24 hour
ANOVA P=0.018P<0.03 None vs Eptifibatide
-0.1
-0.05
0
0.05
0.1
Del
ta P
lasm
a C
once
ntra
tion
(ng/
ml) None
EptifibatideAbciximab
Plasma RANTES Post-PCI(Pro-inflammatory Platelet derived chemokine)
INCITE
30 min 2 hour 24 hour
ANOVA P=0.006P<0.005 None vs Eptifibatide
-150
-100
-50
0
50
100
De
lta P
lasm
a C
on
cen
tra
tion
(n
g/m
l) None
Eptifibatide
Abciximab
INCITE
Plasma sICAM-1 Post-PCI
30 min 2 hour 24 hour
ANOVA P=0.23
-100
-50
0
50
100
Del
ta P
lasm
a C
once
ntra
tion
(ng/
ml) None
Eptifibatide
Abciximab
INCITE
Plasma IL-6 Post-PCI
30 min 2 hour 24 hourANOVA P=0.1
0
1
2
3
4
5
6
Del
ta P
lasm
a C
once
ntra
tion
(ng/
ml) None
Eptifibatide
Abciximab
SummarySummary
INCITE
GP IIb/IIIa inhibition lowers levels of sCD40L and RANTES post stenting, possibly conferring anti-inflammatory as well as anti-thrombotic effects.
GP IIb/IIIa inhibition lowers levels of sCD40L and RANTES post stenting, possibly conferring anti-inflammatory as well as anti-thrombotic effects.
ConclusionConclusion
INCITE
These findings may have significant implications for long term benefits associated with GP IIb/IIIa inhibitor use.
The findings of this pilot study need to be examined in a larger clinical trial that confirms these findings and correlates reduction in inflammation with improved clinical outcome.
These findings may have significant implications for long term benefits associated with GP IIb/IIIa inhibitor use.
The findings of this pilot study need to be examined in a larger clinical trial that confirms these findings and correlates reduction in inflammation with improved clinical outcome.
Procedural Characteristics
None Abciximab Eptifibatide p-value
n 15 15 15
Activated Clotting Time 267±49 287±68 317±55 NS
Platelet Inhibition, % (RPFA)
N/A 93±4 98±3 P<0.01
Multivessel PCI, % 26.7 33.3 40.0 NS
Platelet aggregation inhibition with abciximab, eptifibatide, and tirofibanPlatelet aggregation inhibition with
abciximab, eptifibatide, and tirofiban
RIAR Study (Keriakes. Am J Cardiol 1999)
tirofiban 0.4/0.1 (n=9)
0
20
40
60
80
100
120
0
20
40
60
80
100
120
0
20
40
60
80
100
120
eptifibatide 180/2 (n=10)
abciximab 0.25/0.125 (n=10)
0.7 2 6 12 24 0.7 2 6 18 240.7 2 6 18 24
Time from bolus (h)
CRP
-20
0
20
40
60
80
Delta
Pla
sm
a C
oncentr
ation (
ng/m
l) None
Integrilin
Reopro
INCITE
Prelim
inar
y Res
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