Bivalirudin With and Without Eptifibatide for Elective Stenting:

A Pharmacodynamic Study of Platelet Reactivity in Relation to the Occurrence of Periprocedural Myocardial Infarction

(The CLEAR PLATELETS-2 Study) (The CLEAR PLATELETS-2 Study)

Gurbel PA, Bliden KP, DiChiara J, Bassi A, Herzog WR, Gesheff TB, Tantry US

Sinai Center for Thrombosis Research, Sinai Hospital of BaltimoreBaltimore, Maryland, U.S.A..

Dr. Paul A. Gurbel has received research grants and honoraria from:

Haemoscope

Astra Zeneca

Schering Plough

Medtronic

Daiichi/Sankyo

Lilly

Sanofi-Aventis

Boston Scientific

Bayer

Portola

DisclosuresDisclosures

Background

The optimal antiplatelet and anticoagulant strategy for elective coronary

stenting remains controversial.

Elective stenting is commonly performed in the presence of only aspirin

and an anticoagulant, without clopidogrel pretreatment or GPIIb/IIIa

inhibition.

In the CLEAR PLATELETS Study the addition of the GPIIb/IIIa inhibitor,

eptifibatide to low or high loading dose clopidogrel + heparin administered

at the time of stenting (no pretreatment) produced:

- superior platelet inhibition and lower myocardial necrosis

than 300 mg or 600 mg clopidogrel + heparin.

High platelet reactivity was associated with peri-procedural myocardial

necrosis. (Threshold for MI ?) 1

The optimal antiplatelet and anticoagulant strategy for elective coronary

stenting remains controversial.

Elective stenting is commonly performed in the presence of only aspirin

and an anticoagulant, without clopidogrel pretreatment or GPIIb/IIIa

inhibition.

In the CLEAR PLATELETS Study the addition of the GPIIb/IIIa inhibitor,

eptifibatide to low or high loading dose clopidogrel + heparin administered

at the time of stenting (no pretreatment) produced:

- superior platelet inhibition and lower myocardial necrosis

than 300 mg or 600 mg clopidogrel + heparin.

High platelet reactivity was associated with peri-procedural myocardial

necrosis. (Threshold for MI ?) 1

1. Gurbel PA et al. Circulation. 2005;111:1153-91. Gurbel PA et al. Circulation. 2005;111:1153-9

High periprocedural platelet reactivity and high platelet-fibrin clot strength are risk

factors for short and long-term ischemic events. 1-3

It has been proposed that bivalirudin, a direct thrombin inhibitor, may be a superior

antithrombotic agent compared to heparin for stenting.4

There are no randomised data on platelet reactivity and clot characteristics in

elective stent patients treated with bivalirudin vs. bivalirudin + eptifibatide.

CLEAR PLATELETS-2 Objectives: Compare in elective stenting the effect of:

bivalirudin (B) + eptifibatide (E) vs. bivalirudin alone on:

1) platelet reactivity (aggregometry)

2) physical characteristics of clot (thrombelastography)

Relation of platelet reactivity to post-stent myonecrosis

High periprocedural platelet reactivity and high platelet-fibrin clot strength are risk

factors for short and long-term ischemic events. 1-3

It has been proposed that bivalirudin, a direct thrombin inhibitor, may be a superior

antithrombotic agent compared to heparin for stenting.4

There are no randomised data on platelet reactivity and clot characteristics in

elective stent patients treated with bivalirudin vs. bivalirudin + eptifibatide.

CLEAR PLATELETS-2 Objectives: Compare in elective stenting the effect of:

bivalirudin (B) + eptifibatide (E) vs. bivalirudin alone on:

1) platelet reactivity (aggregometry)

2) physical characteristics of clot (thrombelastography)

Relation of platelet reactivity to post-stent myonecrosis

1. Gurbel PA, et al. Circulation. 2005; 111:1153-9 2. Gurbel PA, et al. J Am Coll Cardiol. 2005; 46:1820-6 3. Bliden KP, et al. J Am Coll Cardiol. 2007; 49:657-66 4. Lincoff M, et al. JAMA . 2003; 289:853-631. Gurbel PA, et al. Circulation. 2005; 111:1153-9 2. Gurbel PA, et al. J Am Coll Cardiol. 2005; 46:1820-6 3. Bliden KP, et al. J Am Coll Cardiol. 2007; 49:657-66 4. Lincoff M, et al. JAMA . 2003; 289:853-63

BackgroundBackground

Methods

Clopidogrel 600 mg in lab [clopidogrel naïve (n=128)]On 75 mg clopidogrel maintenance, no load (n=72)

ASA 325 mg

Bivalirudin (1mg/kg bolus; 2.5 mg/kg/hr)

+ Eptifibatide (n = 98)(180 g/kg bolus x 2, 2.0 g/kg/min infusion x 18h)

Elective coronary stenting, open label, randomised, 2 center study (n = 200)- Sinai Hospital of Baltimore

- University of Oklahoma Health Sciences Center - J Saucedo

Exclusion Criteria:

Blood Samples:Pre-PCI; 2 hrs, 6-8hrs and 18hrs post-PCI

- Eptifibatide (n = 102)

Bleeding diathesis , MI < 48hrs, CVA within 3 months, EF < 25%Platelets < 100,000/mm3, Hct < 30%, Cr > 2.0 mg/dlGPIIb/IIIa or anticoagulant use prior to the procedure

Bleeding diathesis , MI < 48hrs, CVA within 3 months, EF < 25%Platelets < 100,000/mm3, Hct < 30%, Cr > 2.0 mg/dlGPIIb/IIIa or anticoagulant use prior to the procedure

Methods: Laboratory Studies

Light Transmittance Aggregometry - (Chronolog)

- PPACK tubes (75 M)

- 5 and 20uM ADP, 15 and 25uM TRAP, 2ug/mL Collagen, 2mM AA

Flow Cytometry (FACScan, BD Biosciences)

- PPACK tubes (75 M)

- Non-stimulated and ADP-stimulated (1 M):

P-selectin expression (% positive cells), Activated GPIIb/IIIa (MFI)

Thrombelastography (Haemoscope)

- Maximum platelet - fibrin clot strength stimulated by kaolin (MA, mm)

- Time to initial platelet-fibrin clot formation (R, min.)

Triage Meter (Biosite)

- CKMB, Troponin-I, Myoglobin

Light Transmittance Aggregometry - (Chronolog)

- PPACK tubes (75 M)

- 5 and 20uM ADP, 15 and 25uM TRAP, 2ug/mL Collagen, 2mM AA

Flow Cytometry (FACScan, BD Biosciences)

- PPACK tubes (75 M)

- Non-stimulated and ADP-stimulated (1 M):

P-selectin expression (% positive cells), Activated GPIIb/IIIa (MFI)

Thrombelastography (Haemoscope)

- Maximum platelet - fibrin clot strength stimulated by kaolin (MA, mm)

- Time to initial platelet-fibrin clot formation (R, min.)

Triage Meter (Biosite)

- CKMB, Troponin-I, Myoglobin

Methods: Clinical Outcomes

• In-hospital and up to 12 month ischemic and bleeding events

• Definition of Ischemic Events:

- Death (secondary to cardiovascular cause)

- MI (symptoms and Tn I >ULN and/or CKMB > 3x ULN)

- Stroke

- Definite stent thrombosis (angiographically documented)

- Any unplanned coronary intervention

• Bleeding Events

– TIMI Major (intracranial, a fall in Hgb>5g/dL or a fall in Hct of >15%)1

– TIMI Minor (fall in Hgb of 3-5g/dL or a fall in Hct of 9-15%)1

• In-hospital and up to 12 month ischemic and bleeding events

• Definition of Ischemic Events:

- Death (secondary to cardiovascular cause)

- MI (symptoms and Tn I >ULN and/or CKMB > 3x ULN)

- Stroke

- Definite stent thrombosis (angiographically documented)

- Any unplanned coronary intervention

• Bleeding Events

– TIMI Major (intracranial, a fall in Hgb>5g/dL or a fall in Hct of >15%)1

– TIMI Minor (fall in Hgb of 3-5g/dL or a fall in Hct of 9-15%)1

1. Bovill EG, et al. Ann Intern Med. 1991;115:256-65.1. Bovill EG, et al. Ann Intern Med. 1991;115:256-65.

Results: Patient Demographics

600C+B (n=66)

75C+B (n=36)

600C+B+E (n=62)

75C+B+E (n=36)

Age (years) 6411 6411 6516 6014

Race (Cauc.%) 60 56 70 65

Gender (Male%) 59 40 66 74

BMI 326 317 316 3410

Risk Factors/Past Medical History (%)

Smoker 46 49 57 25

Non-smoker 52 46 42 48

Family history of CAD 34 40 39 39

Hypertension 84 76 82 68

Hyperlipidemia 73 78 80 77

Diabetes 39 43 34 48

Prior Myocardial Infarction 25 43 33 42

Prior CABG 16 32 34 19

Prior PTCA 33 59 34 54

Results: Patient Demographics

600C+B (n=66)

75C+B (n=36)

600C+B+E (n=62)

75C+B+E (n=36)

Baseline Medications ( %)

Beta Blockers 53 66 58 76

ACE Inhibitors 48 51 31 79

Calcium Blockers 18 37 16 17

Lipid lowering agents 77 76 70 81

Laboratory Data

WBC’s (X 1000/mm3) 72 83 74 72

Platelets (X 1000/mm3) 23071 24560 21880 23665

Hemoglobin (g/dL) 13.41.8 12.82.6 13.81.6 13.31.8

Hematocrit (%) 41 4 395 415 405

Creatinine (g/dL) 1.20.4 0.90.3 1.10.2 1.00.3

Results: Procedural Characteristics

600C+B (n=66)

75C+B (n=36)

600C+B+E (n=62)

75C+B+E(n=36)

Length of procedure (min.) 4122 3915 4822 4519Ejection Fraction (%) 548 4810 527 5014Number of vessels treated 1.2.5 1.2.5 1.8.4 1.3.4De Novo % 95 80 85 86

Lesion Location (%)

LAD 30 39 42 34CX 41 21 19 17RCA 26 37 34 45SVG 3 3 5 4

Stent Types (%)

Drug eluting 69 78 76 64Bare metal 24 22 21 33PTCA 7 0 3 3Reference vessel diameter(mm)

3.1.5 2.8.3 2.9.4 2.8.8

Total lesion length (mm) 2419 2415 2612 2412Procedural success (%) 95 97 97 97

Results: Aggregation

0

20

40

60

80

100

Baseline 2 hrs 6-8 hrs 18 hrs

600 mg C+B 600 C+B +E75 mg C+B 75 mg C+B+E

++

+

* * *

5 M ADP-InducedAggregation (%)

5 M ADP-InducedAggregation (%)

20 M ADP-InducedAggregation (%)

20 M ADP-InducedAggregation (%)

+ p<0.05, 600 mg C+B vs. 75 mg C+B

* p<0.001, B+E vs. E

0

20

40

60

80

100

Baseline 2 hrs 6-8 hrs 18 hrs

++

+

* * *

600 mg C+B 600 C+B +E75 mg C+B 75 mg C+B+E

Results:Aggregation

25 uM TRAP-InducedAggregation (%)

25 uM TRAP-InducedAggregation (%)

2 ug/ml Collagen-InducedAggregation (%)

2 ug/ml Collagen-InducedAggregation (%)

0

20

40

60

80

100

Baseline 2 hrs 6-8 hrs 18 hrs

**

*

600 mg C+B 600 C+B + E 75 mg C+B 75 mg C+B+E

0

20

40

60

80

100

Baseline 2 hrs 6-8 hrs 18 hrs

++

* *

+

*

600 mg C+B 600 C+B + E75 mg C+B 75 mg C+B+E

+ p<0.05, 600 mg C+B vs. 75 mg C+B

* p<0.001, B+E vs. E

Results: Thrombelastography

50

55

60

65

70

75

Baseline 2 hr 6-8hr 18 hr

600mg C+B 600mg C+B+E

****

50

55

60

65

70

75

Baseline 2 hr 6-8hr 18 hr

75mg C+B 75mg C+B+E

(mm

)(m

m)

0

5

10

15

20

25

Baseline 2 hr 6-8 hr 18 hr

600mg C+B 600mg C+B+E

0

5

10

15

20

25

Baseline 2 hr 6-8 hr 18 hr

75mg C+B 75mg C+B+E

(min

)(m

in)

Platelet-Fibrin Clot StrengthPlatelet-Fibrin Clot Strength

Time to Initial Platelet-Fibrin Clot FormationTime to Initial Platelet-Fibrin Clot Formation

Clopidogrel NaïveClopidogrel Naïve Chronic ClopidogrelChronic Clopidogrel

Clopidogrel NaïveClopidogrel Naïve Chronic ClopidogrelChronic Clopidogrel

* p<0.05* p<0.05

ADP-Stimulated P-Selectin Expression

ADP-Stimulated GPIIb/IIIa Expression

Results- Flow Cytometry

*p<0.001*p<0.001

Clopidogrel Naive Chronic Clopidogrel

0

9

18

27

36

45

C+B C+B+E

Po

sit

ive

Ce

lls

(%

)

Baseline 18 hr

** **

0

9

18

27

36

45

C+B C+B+E

Baseline 18 hr

Me

an

Flu

ore

sc

en

ce

In

ten

sit

y

Clopidogrel Naive Chronic Clopidogrel

0

15

30

45

60

75

C+B C+B+E

Baseline 18 hr

***

0

15

30

45

60

75

C+B C+B+E

Baseline 18 hr

*p<0.001*p<0.001

Relation of Platelet Reactivity (5M ADP) to Myocardial Necrosis

Relation of Platelet Reactivity (5M ADP) to Myocardial Necrosis

100

90

80

70

60

50

40

30

20

10

0

CKMB

Mea

n P

ost

-Tre

atm

ent

Ag

gre

gat

ion

(%

)

NL >1-3 ULN >3X ULN

p<0.0001p<0.0001

p<0.0001p<0.0001

p=0.8p=0.8

Relation of Myonecrosis Marker Release to Treatment

0

5

10

15

20

(>1-3X ULN) (>3X ULN)

600C+B 75C+B 600C+B+E 75C+B+E

Pat

ien

t (%

)P

atie

nt

(%)

p=0.04p=0.04p=0.02p=0.02

631112Myoglobin (>2XULN), %

631712Troponin-I (>ULN), %

75C+B+E600C+B+E75C+B600C+BCardiac Marker

Relation of Platelet-Fibrin Clot Strength to Myocardial Necrosis

Relation of Platelet-Fibrin Clot Strength to Myocardial Necrosis

85

80

75

70

65

60

55

50

CKMB

Clo

t S

tren

gth

(m

m)

NL (>1-3X ULN) (>3X ULN)

p=0.04p=0.04

p=0.02p=0.02

p=NSp=NS

~ 25% greater ~ 25% greater clot strength clot strength ~ 25% greater ~ 25% greater clot strength clot strength

Relation of Platelet-Fibrin Clot Strength (G) to MA

0

10000

20000

30000

40000

50000

60000

0 10 20 30 40 50 60 70 80 90 100

MA (mm)

G (

dyn

/cm

^2)

Clot Strength Increases:

~ 1.8x Between MA 62- MA 74 (MI range)

~ 4.0x Between MA 50- MA 80 (total range)

Data on file from Haemoscope Corp.Data on file from Haemoscope Corp.Data on file from Haemoscope Corp.Data on file from Haemoscope Corp.

8160

14200

(0-30 days) (31-180 days)

C+B (n=102)

C+B+E (n=98)

C+B (n=95)

C+B+E (n=93)

Ischemic Events n(%)

Cardiac Death 0(0) 0(0) 1(1) 0(0)

Stent Thrombosis 1(1) 0(0) 1(1) 0(0)

Myocardial Infarction 10(10) 2(2) 1(1) 0(0)

Target Vessel Revascularization 1(1) 0(0) 3(3) 0(0)

Non-Target Vessel Revascularization 2(2) 1(1) 1(1) 1(1)

Total Patients with Events n(%) 11(11) 3(3) 5(5) 1(1)

Bleeding Events n(%)

Major Bleeding 0(0) 3(3) 1(1) 0(0)

Minor Bleeding 1(1) 3(3) 1(1) 0(0)

Results: Clinical Outcomes

Conclusions

1) Eptifibatide + bivalirudin = 1) superior platelet inhibition irrespective of agonist

2) lower platelet-fibrin clot strength

(most pronounced in clopidogrel naïve)

These 2 properties may explain lower periprocedural Ischemic events in patients

treated with eptifibatide + bivalirudin vs. bivalirudin.

2) CLEAR PLATELETS 2 further supports a link between high platelet reactivity and

the occurrence of post-stent infarction.

3) The addition of eptifibatide may reduce periprocedural MI in selected patients with

high platelet reactivity on bivalirudin + clopidogrel therapy

4) Selection of patients for adjunctive GPIIb/IIIa blockade may be facilitated in future

studies by individualized platelet function measurements-

? Target pt. with high on-clopidogrel treatment platelet reactivity

1) Eptifibatide + bivalirudin = 1) superior platelet inhibition irrespective of agonist

2) lower platelet-fibrin clot strength

(most pronounced in clopidogrel naïve)

These 2 properties may explain lower periprocedural Ischemic events in patients

treated with eptifibatide + bivalirudin vs. bivalirudin.

2) CLEAR PLATELETS 2 further supports a link between high platelet reactivity and

the occurrence of post-stent infarction.

3) The addition of eptifibatide may reduce periprocedural MI in selected patients with

high platelet reactivity on bivalirudin + clopidogrel therapy

4) Selection of patients for adjunctive GPIIb/IIIa blockade may be facilitated in future

studies by individualized platelet function measurements-

? Target pt. with high on-clopidogrel treatment platelet reactivity

• In elective stenting in clopidogrel naïve and chronic clopidogrel treated pts:• In elective stenting in clopidogrel naïve and chronic clopidogrel treated pts: