paul a. gurbel, m.d. sinai center for thrombosis research baltimore, maryland clopidogrel response...

Paul A. Gurbel, M.D.Sinai Center for Thrombosis Research

Baltimore, Maryland

Clopidogrel Response Variability and

Resistance

P2Y12: A Pivotal Platelet Receptor

Platelet

P2Y12

*Platelet*

Tissue Factor

Coagulation Cascade

Thrombin

WBC

Thrombin, Collagen, Tx A2

Am

plific

atio

n

Procoagulant Surface

Activatio

n

P-selectin CD-40L

ADP

Degranulation

Activation

AA Tx A2 Tx A2

Am

plific

atio

n

Degranulation

ADP

Aggregation

GPIIb/IIIaActivation

Inflammation

Laboratory Measurements of Clopidogrel ResponsivenessLaboratory Measurements of Clopidogrel Responsiveness

1. ADP-Induced Platelet Aggregation - LTA (PRP) - TEG (Whole Blood)

2. Flow Cytometry - ADP- induced P-selectin, PAC-1

P2Y12 Specific

1. P2Y12 Reactivity Ratio-

VASP Phosphorylation- Flow cytometry

2. VerifyNow-P2Y12 Assay Point-of-Care

ClopidogrelResponsiveness

(Gurbel et al. (Gurbel et al. Nat Clin Pract

Cardiovasc Med. 2006;3:387-95.)

P2Y12

GPIIb/IIIa Activation,GPIIb/IIIa Activation,Platelet AggregationPlatelet Aggregation

X

PLC

cAMP

VASP-P

Ca++

Mobilization

AD

P

AdenylylCyclase

Granule Secretion

ADP

GqG12

Shape Change

P2Y1

PI3-K

Rap-1bAkt

Rho Kinase

Gi

ADPRelease

ClopidogrelBisulfate

Intestinal Absorption

Hydrolysis

85%

Carboxyl Inactive Metabolite

15% CYP3A4,5,1A2Conversion

Active Thiol Metabolite

Definition of Clopidogrel Resistance

Antiplatelet Drug

Non-responsiveness/Resistance= Failure to Inhibit Target/

Persistent Activity of the Target

Clopidogrel

1. Absolute change in (ADP) aggregation 10%

Aggregation = Max. baseline aggregation - Max. post-drug aggregation..11

2. Relative platelet inhibition < 10% 2

3 . > 50% PRI (P2Y12 Reactivity- VASP-P assay)3

1. Gurbel et al. Circulation. 2003;107:2908-13., 2. Muller et al. Thromb Haemost. 2003;89:783, 3. Barragan et. al. Catheter Cardiovasc Interv. 2003;59:295;

Clopidogrel Resistance/Response Variability:Initial Observations

The Plavix Reduction Of New Thrombus Occurrence (PRONTO) Study

0

20

40

60

80

(%)

Inh

ibit

ion

300 mg Loading (3-24 hours prior to stenting)

Prior to Stent 2 hrs 5 hrs 12 hrs 2 day 5 day

Wide response variability

(Gurbel et al. J Am Coll Cardiol 37: 32 A, 2001; Eur Heart J, 2001; Am Heart J 2003;145:239-47)

Clopidogrel Resistance: Importance of Time and Dose

300 mg 300 mg vs 600 mg

1Gurbel PA et al. Circulation. 2003;107:2908-2913. 2Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.

1 263

31 31

15

28

8

53

3532

21

32

8

0

10

20

30

40

50

60

70

2 h 24 h 5 d 30 d 300 mg 600 mg

Pa

tie

nts

(%

)

5 uM ADP 20 uM ADP

Time Clopidogrel

Effect of Time Effect of Dose

A (5 M ADP-induced Aggregation) at 24 h

Patie

nts

(%) Resistance = 28% (300 mg)

Resistance = 8% (600 mg)

0

3

6

9

12

15

18

21

24

27

30

33

≤ −30(−30,−20]

(−20,−10](−10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

(60,70]> 70

300 mg clopidogrel

600 mg clopidogrel

Clopidogrel ResponseClopidogrel Response Variability (300 vs. 600 mg):Importance of Dose (n = 194)

(Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392)

2005 Dr. Paul Gurbel. All rights reserved. This presentation may not be copied or reproduced without permission.

Variability in Post-Treatment Aggregation5 M ADP

Cumulative Frequency Distribution:Cumulative Frequency Distribution: 24 Hours after a 300mg Clopidogrel Load24 Hours after a 300mg Clopidogrel Load

Cumulative Frequency Distribution:Cumulative Frequency Distribution: DuringDuring 75 mg75 mg Clopidogrel MaintenanceClopidogrel Maintenance

-20 0 20 40 60 80 100

100

80

60

40

20

0

5 uM ADP Aggregation (%)

Relative frequency (%)

(Adapted from Bliden et al. J Am Coll Cardiol. 2007;49:657-66)

(Adapted from Gurbel et al.J Am Coll Cardiol. 2005;45:1392-6)

0 20 40 60 80 100

100

80

60

40

20

0

5uM ADP-Induced Platelet Aggregation (%)

Re

lati

ve

Fre

qu

en

cy

(%

)

5uM ADP-Induced Platelet Aggregation (%)

Re

lati

ve

Fre

qu

en

cy

(%

)

21%

32%

Clopidogrel Resistance: World ExperienceClopidogrel Resistance: World Experience

Investigators n Patients Clopidogrel Dose Resistance (mg Load)

1. Jaremo et al 18 PCI 300 28% (J Invest Med. 2002;252:233)

2. Gurbel et al 92 PCI 300 31-35% (Circulation 2003;107:2908)

3. Muller et al. 105 PCI 600 5-11% (Thromb Haemost. 2003;89:783)

4. Mobley et al 50 PCI 300 30% (Am J Cardiol. 2004;93:456)

5. Lepantalo et al. 50 PCI 300 40% (Eur Heart J. 2004;25-476)

6. Angiolillo et al. 48 PCI 300 44% (Thromb Res. 2005;115:101)

7. Matetzky et al. 60 PCI 300 25% (Circulation 2004;109:3171.)

8. Dzieweierz 31 PCI 300 23% (Kardiol Pol. 2005 ;62:108)

9. Gurbel et al. 192 PCI 300/600 8-32% (J Am Coll Cardiol. 2005;45:1392)

10. Lev Et al. 150 PCI 300 24% (J Am Coll Cardiol. 2006;47:27)

Total 616 5-44%Total 616 5-44%

A Common Misconception

Patients with low pre-treatment function and low Inhibition have

low post-treatment function and may be at Low Risk

(overestimation of risk based on low responsiveness)

Patients with high pre-treatment function and inhibition may still have high

post-treatment function and may be at High Risk

(underestimation of risk based on normal responsiveness)

Post-treatment platelet function is a better predictor of ischemic events than platelet inhibition (responsiveness)

Lack of Inhibition (Responsiveness) = High Risk

(Samara et al. Thromb Res. 2005;115:89-94)


CREST StudyCREST Study

Chronic Clopidogrel Therapy Undergoing PCI -

Pretreatment Platelet Function

PREPARE Post-Stenting StudyPREPARE Post-Stenting Study

Re

lati

ve

Fre

qu

en

cy

(%

)


p<0.02 for mean values between groups

Ischemic Events (n=38)

What Does High Post-Treatment Platelet Reactivity Mean Clinically? Emergence of a New Quantifiable and Modifiable Risk FactorEmergence of a New Quantifiable and Modifiable Risk Factor

0 20 40 60 80 100

100

80

60

40

20

0


Re

lati

ve

Fre

qu

en

cy

(%

)

No Ischemic Event (n=77)Ischemic Event (n=23)


Re

lati

ve

Fre

qu

en

cy

(%

)



Ischemic Events (n=38)

No Ischemic Event (n=154)No ST (n=100)

ST (n=20)


? T

hre

sho

ld f

or

ST

? T

hre

sho

ld f

or

Isch

emic

Eve

nt

? T

hre

sho

ld f

or

Isch

emic

Eve

nt

1 Year Follow-up

6 monthFollow-up

(Gurbel et al. J Am Coll Cardiol. 2005;46:1827-32) (Gurbel et al. J Am Coll Cardiol. 2005;46:1820-6)


Re

lati

ve

Fre

qu

en

cy

(%

)

(Bliden et al. J Am Coll Cardiol. 2007;49:657-66)

1. Barragan et al. P2Y12 reactivity ratio (VASP-P levels) Stent Thrombosis (Catheter Cardiovasc Interv. 2003;59::295)

2. Ajzenberg et al. Shear- Induced platelet aggregation Stent Thrombosis (J Am Coll Cardiol. 2005;45:1753)

3. Gurbel et al. P2Y12 reactivity ratio (CREST Study) ADP- induced aggregation Stent Thrombosis (J Am Coll Cardiol. 2005;46:1827) Stimulated GPIIb/IIIa expression

Study Results Clinical Relevance

Studies Linking Ex-Vivo Platelet Function to Clinical Events

4. Matzesky et al. ADP-Induced platelet aggregation Recurrent Cardiac (Circulation.2005;109:3171) Events (4th quartile)

5. Gurbel et al. Periprocedural platelet aggregation Myonecrosis and (CLEAR PLATELETS and CLEAR PLATELETS Ib) Inflammation Marker (Circulation. 2005;111:1153, J Am Coll Cardiol;2006 (in press) Release 7. Bliden et al. Platelet aggregation (pre-PCI) 1 yr Post -PCI Events (J Am Coll Cardiol. 2006; (in press) on chronic clopidogrel 8. Cuisset et al. Platelet aggregation 30-day Post-PCI events (J Thromb Haemost. 2006;3:542-9)

9. Lev et al. Clopidogrel/Aspirin resistant patients Post-PCI Myonecrosis (J Am Coll Cardiol. 2006;47:27)

10. Cuisset e al. Platelet aggregation 30-day Post-PCI events (J Am Coll Cardiol. 2006;48:1339-45) 600mg- less events

11. Hochholzer et al. Platelet aggregation (Upper quartile) 30 day MACE (J Am Coll Cardiol 2006:48:1742-50)

Variable Post-Treatment: P2Y12 Reactivity by VASP- P vs.

Reactivity ADP-Induced Platelet Aggregation

0.0

20.0

40.0

60.0

80.0

100.0

0.0 20.0 40.0 60.0 80.0 100.0

Post-Treatment Platelet Aggregation (20 uM ADP) (%)

P2

Y12

Re

ac

tiv

ity

Ra

tio

(%

)

R=0.703, p<0.001

0.0

20.0

40.0

60.0

80.0

100.0

20.0 40.0 60.0 80.0 100.0

Post-Treatment Platelet Aggregation (5uM ADP) (%)

P2

Y12

Re

ac

tiv

ity

Ra

tio

(%

)

R= 0.63, p<0.001

(n=40)

(Patients Loaded with 300 - 600 mg Clopidogrel)

(Gurbel PA et al. Thromb Res. 2007 Mar 30; [Epub ahead of print])

Mechanism of Clopidogrel Response Variability:Mechanism of Clopidogrel Response Variability:

ClopidogrelBisulfate

Intestinal Absorption

Inactive Carboxylic Acid Metabolite

CYP3A4

CYP3A5

CYP2C19

Active Thiol Metabolite

P2Y12 Receptor

Inhibition of Platelet Aggregation (Wide Response Variability)

Limited absorption capacity with ceiling effect at 600mg loading doseLimited absorption capacity with ceiling effect at 600mg loading dose

Hepatic P450Cytochromes

Drug-drug interaction with lipophilic statins,IVS10+12G>a polymorphism

Genetic polymorphisms

Genetic polymorphisms

Multistep Conversion

15%

Esterases

85%

~30%75mg/day for 30days

Post-PCI

~30%-40%75mg/day for 5-7days

volunteers

~30%-40%300 mg load

Post-PCI

~30%-50%600 mg load

Post-PCI

~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI2

(Gurbel PA et al. Thromb Res. 2006 (Epub), . Taubert et al. Clin Pharmacol. 2006, .von Beckerth et al. Eur Heart J. 2007 (epub))

P-glycoprotein(MDR1 3435T genotype)1

?

SmokingCYP1A2

Summary

Multiple studies have confirmed marked response variability to

clopidogrel therapy and a significant prevalence of resistance/non-

responsiveness.

Aggregometry remains the gold standard in detection.

VASP-P is the most specific available measurement of incomplete P2Y12

blockade.

A 600 mg loading dose is associated with less resistance, less

response variability, and lower post-treatment aggregation-

no conclusive data to support higher doses than 600 mg.

Current data suggest that high ex vivo platelet reactivity to

ADP/incomplete P2Y12 inhibition are risk factors for post-stenting

ischemic events including SAT.

Multiple studies have confirmed marked response variability to

clopidogrel therapy and a significant prevalence of resistance/non-

responsiveness.

Aggregometry remains the gold standard in detection.

VASP-P is the most specific available measurement of incomplete P2Y12

blockade.

A 600 mg loading dose is associated with less resistance, less

response variability, and lower post-treatment aggregation-

no conclusive data to support higher doses than 600 mg.

Current data suggest that high ex vivo platelet reactivity to

ADP/incomplete P2Y12 inhibition are risk factors for post-stenting

ischemic events including SAT.EMERGING CARDIOVASCULAR RISK FACTOR

Platelet ReceptorsPlatelet

ThrombinThrombin

ADPADP

EpinephrineEpinephrine

CollagenCollagen Anionicphospholipid

surfaces

GPGPIIb/IIIaIIb/IIIa

Platelet

Fibrinogen

GP Ia

P2Y1

GP VI

PAR-4

TBX ATBX A22 TBXA2-R

SerotoninSerotonin 5HT2A

P2Y12

PAR-1

GPGPIIb/IIIaIIb/IIIa

EPI-R

SCH 530348 (himbacine derivative) is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis.

Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).

TRA-Background

Study DesignStudy Design

Non-Urgent PCI or Cath possible PCI (All Receive Aspirin)

Randomization #1 — 3:1 SCH530348:Placebo (Single Loading Dose)

Sequential Groups: 1=10 mg; 2=20 mg; 3=40 mg, or Placebo

No PCI** No PCI**

Randomization #2 1:1:1Maintenance Therapy Once Daily for ~ 60 days

SCH 530348 Loading Dose SCH 530348Or Placebo Loading Dose Placebo

Safety: TIMI Major plus Minor BleedingEfficacy: Death/MACE

Safety: TIMI Major plus Minor Bleeding

* Primary Evaluable Cohort* Primary Evaluable Cohort **Secondary Evaluable Cohort**Secondary Evaluable Cohort

Cardiac Catheterization

Planned PCI (All Receive Clopidogrel and Antithrombin)

CABG

Quantify Postoperative Chest-Tube Drainage,

Transfusions, and Re-exploration

Medical Management

0.5 mgn~100

1 mgn~100

2.5 mgn~100

Placebon~100

SCH 530348

PlaceboPlacebo

SCH 530348SCH 530348

AllAll 10 mg10 mg 20 mg20 mg 40 mg40 mg

NumberNumber 151151 422422 129129 120120 173173

TIMI Major/MinorTIMI Major/Minor 5 (3.3%)5 (3.3%) 12 (2.8%)12 (2.8%) 2 (1.6%)2 (1.6%) 3 (2.5%)3 (2.5%) 7 (4.0%)7 (4.0%)

TIMI MajorTIMI Major 2 (1.3%)2 (1.3%) 3 (0.7%)3 (0.7%) 2 (1.6%)2 (1.6%) 00 1 (0.6%)1 (0.6%)

TIMI MinorTIMI Minor 3 (2.0%)3 (2.0%) 9 (2.1%)9 (2.1%) 00 3 (2.5%)3 (2.5%) 6 (3.4%)6 (3.4%)

Non-TIMI bleedingNon-TIMI bleeding 48 (32%)48 (32%) 170 (40%)170 (40%) 46 (36%)46 (36%) 51 (43%)51 (43%) 73 (42%)73 (42%)

PCI Cohort ResultsPCI Cohort Results

PlaceboPlacebo

(n=24)(n=24)

SCH 530348SCH 530348

AllAll

(n=51)(n=51)10 mg10 mg

(n = 10)(n = 10)20 mg20 mg

(n = 18)(n = 18)40 mg40 mg

(n=24)(n=24)

Any BleedAny Bleed 2424 5252 1010 1818 2424

TIMI Major/MinorTIMI Major/Minor 19 (79%)19 (79%) 48 (92%)48 (92%) 9 (90%)9 (90%) 17 (94%)17 (94%) 22 (92%)22 (92%)

Non-TIMINon-TIMI 8 (33%)8 (33%) 18 (35%)18 (35%) 3 (30%)3 (30%) 6 (33%)6 (33%) 9 (39%)9 (39%)

TransfusionTransfusion

PRBCPRBC 11 (46%)11 (46%) 32 (62%)32 (62%) 8 (80%)8 (80%) 9 (50%)9 (50%) 15 (63%)15 (63%)

>2 Units>2 Units 55 99 22 22 55

Chest Tube Chest Tube Drainage (ml)Drainage (ml) 996996 988988 13931393 10151015 870870

Re-explorationRe-exploration 33 22 11 00 11

CABG Cohort BleedingCABG Cohort Bleeding

60-Day Death or MACE60-Day Death or MACE

8%8%

00

4%4%

All TRAAll TRAn=422n=422

PCI Cohort

2%2%

6%6%

10%10%

PlaceboPlacebon=151n=151

8.6%8.6%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

8.5%8.5%

5.0%5.0%4.6%4.6%

SCH 530348SCH 530348

5.9%5.9%p = 0.26

p = 0.98

p = 0.25p = 0.15

p- value relative to placebo

80%80%

00

40%40%

Platelet Aggregation Substudy

20%20%

60%60%

100%100%


10 mg10 mgn=15n=15

20 mg20 mgn=18n=18

40 mg40 mgn=33n=33

2929

SCH 530348SCH 530348

00 00 00 00 00 00

5353

6868

8282

9696

46465454

66

4343

2121

30 minutes30 minutes




Subjects with >80% IPA to 15 Subjects with >80% IPA to 15 M TRAPM TRAP

Conclusions

PlaceboPlacebo

SCH 530348SCH 530348

AllAll 10 mg10 mg 20 mg20 mg 40 mg40 mg

NumberNumber 151151 422422 129129 120120 173173

TIMI Major/MinorTIMI Major/Minor 5 (3.3%)5 (3.3%) 12 (2.8%)12 (2.8%) 2 (1.6%)2 (1.6%) 3 (2.5%)3 (2.5%) 7 (4.0%)7 (4.0%)

TIMI MajorTIMI Major 2 (1.3%)2 (1.3%) 3 (0.7%)3 (0.7%) 2 (1.6%)2 (1.6%) 00 1 (0.6%)1 (0.6%)

TIMI MinorTIMI Minor 3 (2.0%)3 (2.0%) 9 (2.1%)9 (2.1%) 00 3 (2.5%)3 (2.5%) 6 (3.4%)6 (3.4%)

Non-TIMI bleedingNon-TIMI bleeding 48 (32%)48 (32%) 170 (40%)170 (40%) 46 (36%)46 (36%) 51 (43%)51 (43%) 73 (42%)73 (42%)

PCI Cohort ResultsPCI Cohort Results


SCH 530348SCH 530348

AllAlln=422n=422

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

OverallOverall 48 (32%)48 (32%) 170 (40%)170 (40%) 46 (36%)46 (36%) 51 (43%)51 (43%) 73 (42%)73 (42%)

Vascular PunctureVascular Puncture 20 (13%)20 (13%) 64 (15%)64 (15%) 16 (12%)16 (12%) 22 (18%)22 (18%) 26 (15%)26 (15%)

Arterial AccessArterial Access 19 (13%)19 (13%) 58 (14%)58 (14%) 14 (11%)14 (11%) 20 (17%)20 (17%) 24 (14%)24 (14%)

Contusion/BruiseContusion/Bruise 17 (11%)17 (11%) 64 (15%)64 (15%) 13 (10%)13 (10%) 20 (17%)20 (17%) 31 (18%)31 (18%)

Incidental CutsIncidental Cuts 10 (7%)10 (7%) 39 (9%)39 (9%) 5 (4%)5 (4%) 16 (13%)16 (13%) 18 (10%)18 (10%)

EpistaxisEpistaxis 12 (8%)12 (8%) 23 (5%)23 (5%) 8 (6%)8 (6%) 6 (5%)6 (5%) 9 (5%)9 (5%)

GIGI 2 (1%)2 (1%) 8 (2%)8 (2%) 2 (2%)2 (2%) 1 (1%)1 (1%) 5 (3%)5 (3%)

Gingival Gingival 2 (1%)2 (1%) 5 (1%)5 (1%) 2 (2%)2 (2%) 1 (1%)1 (1%) 2 (1%)2 (1%)

GenitourinaryGenitourinary 1 (1%)1 (1%) 13 (3%)13 (3%) 4 (3%)4 (3%) 6 (5%)6 (5%) 3 (2%)3 (2%)

Discontinue for AEDiscontinue for AE 2 (1.3%)2 (1.3%) 6 (1.4%)6 (1.4%) 1 (0.8%)1 (0.8%) 1 (0.8%)1 (0.8%) 4 (2.3%)4 (2.3%)

PCI Cohort Non-TIMI BleedingPCI Cohort Non-TIMI Bleeding

PlaceboPlacebon= 151n= 151

SCH 530348SCH 530348

AllAlln=422n=422

10 mg10 mgn= 129n= 129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

Death/MACE/StrokeDeath/MACE/Stroke 13 (8.6%)13 (8.6%) 26 (6.2%)26 (6.2%) 12 (9.3%)12 (9.3%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)

Death/MACE*Death/MACE* 13 (8.6%)13 (8.6%) 25 (5.9%)25 (5.9%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)

Death/MIDeath/MI 11 (7.3%)11 (7.3%) 19 (4.5%)19 (4.5%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 7 (4.0%)7 (4.0%)

DeathDeath 00 2 (0.5%)2 (0.5%) 1 (0.8%)1 (0.8%) 00 1 (0.6%)1 (0.6%)

MACEMACE 13 (8.6%)13 (8.6%) 24 (5.7%)24 (5.7%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 7 (4.0%)7 (4.0%)

MIMI 11 (7.3%)11 (7.3%) 18 (4.3%)18 (4.3%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 6 (3.5%)6 (3.5%)

Recurrent ischemiaRecurrent ischemia 1 (0.7%)1 (0.7%) 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00

RevascularizationRevascularization 1 (0.7%)1 (0.7%) 6 (1.4%)6 (1.4%) 3 (2.3%)3 (2.3%) 1 (0.8%)1 (0.8%) 2 (1.2%)2 (1.2%)

StrokeStroke 00 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint

PCI Cohort MACE ResultsPCI Cohort MACE Results


SCH 530348SCH 530348

AllAlln=422n=422

10 mg10 mgn= 129n= 129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173



Death/MIDeath/MI 11 (7.3%)11 (7.3%) 19 (4.5%)19 (4.5%) 7 7

(5.4%)(5.4%)5 (4.2%)5 (4.2%) 7 (4.0%)7 (4.0%)

DeathDeath 00 2 (0.5%)2 (0.5%) 1 (0.8%)1 (0.8%) 00 1 (0.6%)1 (0.6%)

MACEMACE 13 (8.6%)13 (8.6%) 24 (5.7%)24 (5.7%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 7 (4.0%)7 (4.0%)

MIMI 11 (7.3%)11 (7.3%) 18 (4.3%)18 (4.3%) 7 7

(5.4%)(5.4%)5 (4.2%)5 (4.2%) 6 (3.5%)6 (3.5%)

Recurrent ischemiaRecurrent ischemia 1 (0.7%)1 (0.7%) 1 (0.2%)1 (0.2%) 1 1

(0.8%)(0.8%)00 00

RevascularizationRevascularization 1 (0.7%)1 (0.7%) 6 (1.4%)6 (1.4%) 3 3

(2.3%)(2.3%)1 (0.8%)1 (0.8%) 2 (1.2%)2 (1.2%)

StrokeStroke 00 1 (0.2%)1 (0.2%) 1 1

(0.8%)(0.8%)00 00

MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint


TIMI Major/Minor BleedingTIMI Major/Minor Bleeding

4%4%

00

2%2%


2.8%2.8%

PCI Cohort

1%1%

3%3%

5%5%


3.3%3.3%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

1.6%1.6%

2.5%2.5%

4.0%4.0%

SCH 530348SCH 530348

p = 0.77

p = 0.35

p = 0.70

p = 0.73


TIMI BleedingTIMI Bleeding

4%4%

00

2%2%


PCI Cohort

1%1%

3%3%

5%5%


10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

2.12.1

SCH 530348SCH 530348

TIMI MinorTIMI Minor

TIMI MajorTIMI Major

2.02.0

0.70.7

00

1.61.6

2.52.5

00

3.43.4

0.60.6

1.31.3

p = ns for pairwise comparisons


SCH 530348SCH 530348

AllAlln=422n=422

10 mg10 mgn= 129n= 129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173



Death/MIDeath/MI 11 (7.3%)11 (7.3%) 19 (4.5%)19 (4.5%) 7 7

(5.4%)(5.4%)5 (4.2%)5 (4.2%) 7 (4.0%)7 (4.0%)

DeathDeath 00 2 (0.5%)2 (0.5%) 1 (0.8%)1 (0.8%) 00 1 (0.6%)1 (0.6%)

MACEMACE 13 (8.6%)13 (8.6%) 24 (5.7%)24 (5.7%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 7 (4.0%)7 (4.0%)

MIMI 11 (7.3%)11 (7.3%) 18 (4.3%)18 (4.3%) 7 7

(5.4%)(5.4%)5 (4.2%)5 (4.2%) 6 (3.5%)6 (3.5%)

Recurrent ischemiaRecurrent ischemia 1 (0.7%)1 (0.7%) 1 (0.2%)1 (0.2%) 1 1

(0.8%)(0.8%)00 00

RevascularizationRevascularization 1 (0.7%)1 (0.7%) 6 (1.4%)6 (1.4%) 3 3

(2.3%)(2.3%)1 (0.8%)1 (0.8%) 2 (1.2%)2 (1.2%)

StrokeStroke 00 1 (0.2%)1 (0.2%) 1 1

(0.8%)(0.8%)00 00

MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint


60-Day Death or MI60-Day Death or MI

8%8%

00

4%4%


4.5%4.5%

PCI Cohort

2%2%

6%6%

10%10%


7.3%7.3%

10 mg10 mgn=129n=129

20 mg20 mgn=120n=120

40 mg40 mgn=173n=173

5.4%5.4%

4.2%4.2%4.0%4.0%

SCH 530348SCH 530348

p = 0.19p = 0.53

p = 0.28p = 0.20


PCI Cohort

Myocardial InfarctionMyocardial Infarction

8%8%

00

4%4%

2%2%

6%6%

10%10%

PlaceboPlacebo 40mg40mg20mg20mg10mg10mg

11 7722 33 44 55 6600

DaysDays

p = 0.52

p = 0.28

p = 0.12

TRA was not associated with an increase inTIMI major, minor, or non-TIMI bleeding

Using 15 M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved

≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained ≥ 80% IPA

at 30 and 60 days in all subjects

While not statistically significant, SCH 530348 was associated with: Death/MACE: 32% overall; 46% with 40 mg

MI: 41% overall; 52% with 40 mg

Conclusions

Clopidogrel Resistance:Maximum Aggregation vs. Final Aggregation

PCI Patients, n = 100

Ab

so

lute

Ch

an

ge

in

0

10

20

30

40

50

60

Total Patients Non- Responders Responders

Ag

gre

ga

tio

n (

%)

Maximum Aggregation Final Aggregation

5 M ADP-Induced Platelet Aggregation

0

10

20

30

40

50

Total Patients Non-Responders Responders

Ag

gre

ga

tio

n (

%)

Maximum Aggregation Final Aggregation

Maximum Final Aggregation AggregationAggregation (5uM ADP) Resistance 23% p=NS 17% Correlation R = 0.84, p<0.001Aggregation (20 uM ADP) Resistance 30% p=NS 27% Correlation R = 0.9, p<0.001

p = 0.006

p = ns

p = 0.003 p = 0.02

p = ns

p = 0.001

Ab

so

lute

Ch

an

ge

in

20 M ADP-Induced Platelet Aggregation

(Gurbel PA et al. Thromb Res. 2007 Mar 30; [Epub ahead of print])

The First Clopidogrel Resistance Study (300 mg):The First Clopidogrel Resistance Study (300 mg):Importance of Time of Post-treatment Measurement Importance of Time of Post-treatment Measurement

2 Hours 24 Hours

5 Days 30 Days

(Gurbel et al. Circulation. 2003;107: 2908-2913)

Sinai Center for Thrombosis Research Experience

Aggregation (%)

% o

f P

atie

nts

12

24

<= -30(-30,-20]

(-20,-10](-10,0]

(0,10]

(10,20]

(20,30](30,40]

(40,50](50,60]

>60

Resistance = 63% Resistance

0

Resistance = 31%

Aggregation (%)

% o

f P

atie

nts

10

20

<= -30

(-30,-20]

(-20,-10]

(-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Resistance

0

Aggregation (%)

% o

f P

atie

nts

11

22

<= -10(-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Resistance = 31% Resistance

0

Resistance = 15%

Aggregation (%)

% o

f P

atie

nts

14

28

<= -30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

>60

Resistance

0


n= 92

Gurbel et al. AHA 2007

-5

μM

AD

P-I

nd

uc

ed

Ag

gre

ga

tio

n (

%) 70

60

50

40

30

20

10

0Without Events With Events

(n=250) (n=82)

20

μM

AD

P-I

nd

uc

ed

Ag

gre

ga

tio

n (

%) 90

60

50

40

30

20

10

0Without Events With Events

(n=250) (n=82)

80

70

Relation of Platelet Reactivity to Long-Term Ischemic Events in PCI Patients (n=352)

? Overtreated ? Bleeding Risk

MAThrombin = measure of maximum thrombin-induced platelet-fibrin clot strength;

MAFibrin = contribution of fibrin to clot strength; MAADP or AA = represents clot strength after adenosine

diphosphate (ADP) or arachidonic acid (AA) stimulation.

Platelet aggregation in response to ADP or AA is calculated with computerized software on the basis of the formula:

% Inhibition = [1- (MAADP or AA− MAfibrin)/(MAthrombin − MAfibrin)] × 100

Thrombelastograph Platelet Mapping Analysis Parameters

Gurbel et al. J Am Coll Cardiol. 2005;46:1820-6

PRE 24 h POST

Agg = 43 and 37%

Agg = 5 and -13%

Responder 300mg

Non-Responder 900mg

Aggregation Curves of Clopidogrel Responders and Non-Responders

% A

gg

reg

ati

on

% A

gg

reg

ati

on

% A

gg

reg

ati

on

% A

gg

reg

ati

on

5 uM ADP5 uM ADP

5 uM ADP 5 uM ADP

Relation of Platelet Aggregation Measured by Light Transmittance Relation of Platelet Aggregation Measured by Light Transmittance Aggregometry and Thrombelastography Platelet Mapping AssayAggregometry and Thrombelastography Platelet Mapping Assay

0 20 40 60 80 100

0

20

40

60

80

100

R=0.821, p<0.001

Thrombelastography (MAADP) (%)

LT

A (

5 M

AD

P)

(%)

(Bliden KP et al. Presented World Congress of Cardiology, Barcelona. 2006)

P2Y12 Reactivity Measured by VASP-P Indicator of Receptor Inhibition by Clopidogrel

Biocytex Assay

1. Stimulate Platelets with PGE1

Maximum VASP Phosphorylation:

MFI PGE1

2. Stimulate with PGE1 + ADP

MFI PGE1 + ADP

Reactivity Ratio = 100 x MFI(PGE1) - MFI(PGE1+ADP)

MFI(PGE1) (Gurbel PA et al. J Am Coll Cardiol. 2005:46:1827-32)

If P2Y12 Receptors are unblocked, VASP

Phosphorylation Levels Fall after ADP

Stimulation

Clopidogrel Response Variability and Impact of P2Y1 on Maximum ADP-Induced Aggregation

(Aliel et al. J Thromb Haemost. 2005;3:85-92)

In vitro Effect of ARC-C69931MX on Platelet Aggregation Induced by 5 uM ADP

Clopidogrel Response Variability As Measured by VASP-Phosphorylation

P2Y1

Contribution

Response Variability

Pla

tele

t R

ea

cti

vit

y I

nd

ex

(%

)

Li g

ht

Tra

nsm

iss i

on

(%

)P

l ate

l et

Ag

gre

ga t

ion

(%

)

VerifyNow-P2Y12 Assay

(van Werkum J.W. et al. Journal Thromb Haemost. 2006; 4:2516-8)

Relation of VerifyNow P2Y12 Assay and Aggregometry Assay

• Assay is based on the ability of activated platelets to bind to fibrinogen.• Adenosine diphosphate and prostaglandin E1 are added to activate platelets.• Light transmittance increases as activated platelets bind and aggregate fibrinogen-coated beads.• The instrument measures this change in optical signal and reports results in P2Y12 reaction units (PRU).

Simple and reproducible point-of-care methods to study ex vivo platelet reactivity and its relation to adverse events: What are the critical receptors/pathways that drive events?

Ongoing: On Horizon: Oral reversible P2Y12 antagonists (AZD6140) Blockade of: Parenteral P2Y12 antagonists (cangrelor) P2Y1 Potent irreversible P2Y12 antagonists (prasugrel) GPIb, Increased clopidogrel maintenance dose GPIV Thrombin receptor antagonists

Personalized Therapy:

Defining the patient’s propensity for thrombosis and adjust antiplatelet therapy to

achieve a target response:

• ? Reduced stent thrombosis

• ? Reduced post-discharge ischemic events

• ? Reduced In-hospital ischemic events post-PCI

The Future

paul a. gurbel, m.d. sinai center for thrombosis research baltimore, maryland clopidogrel response...

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