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