Antiplatelet Therapy in

General Overview

Antiplatelet Therapy in

General Overview

Prof. Lale Tokgözoğlu MD, FACC, FESCHacettepe University Faculty of Medicine

Department of Cardiology

Prof. Lale Tokgözoğlu MD, FACC, FESCHacettepe University Faculty of Medicine

Department of Cardiology

Cause of Death by Gender in Europe:

Cause of Death by Gender in Europe:

WHO 2008

Platelets are important in atherothrombosis

Platelets are important in atherothrombosis

After release from bone marrow, circulate for 7-10 days without interaction with vessel wall

If exposed to subendothelium, platelets activated

After release from bone marrow, circulate for 7-10 days without interaction with vessel wall

If exposed to subendothelium, platelets activated

Unstable plaques activate

platelets

Unstable plaques activate

plateletsPlaqueFissure or Rupture

PlateletAggregation

PlateletActivation

PlateletAdhesion

ThromboticOcclusion

Adhesion

Adhesion mediated by vWF, agonists like ADP, secreted granules and TXA2 cause aggregation, exposed GPIIbIIIa

receptors crosslink with fibrinogen to form platelet aggregates

Adhesion mediated by vWF, agonists like ADP, secreted granules and TXA2 cause aggregation, exposed GPIIbIIIa

receptors crosslink with fibrinogen to form platelet aggregates

Aggregation3

Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

1

Activation2

MONOCYTEMONOCYTE

MACROPHAGEMACROPHAGE

THROMBOCYTEAGGREGATIONTHROMBOCYTEAGGREGATION

FIBRINFIBRINTHROMBUSTHROMBUS

SMOOTH MUSCLE CELL SMOOTH MUSCLE CELL

ENDOTHELIUMENDOTHELIUM

THROMBOCYTEADHESIONTHROMBOCYTEADHESION

Platelet surface membrane receptors play important role

Platelet surface membrane receptors play important role

Platelets also important in stent thrombosis:Mechanism of AMI after stent implantation

Platelets also important in stent thrombosis:Mechanism of AMI after stent implantation

Relative frequency

48%

40%

12%

Atherothrombosis at newlocation (after 27 months)

Restenosis (after 19 months)

Stent thrombosis (after 9 months)

Alexopoulos D. Am Heart J 2010; 159: 439-445

Different mechanisms of antiplatelet drugs:Different mechanisms of antiplatelet drugs:1. COX-1 inhibitors

ASA, Omega 3

2. Phosphodiesterase inhibitorsDipyrdamole, Cilostazol

3. ADP-P2Y12 interaction blokersTiclopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor

4. GP IIb/IIIa blokers

5. Thrombin receptor antagonists

1. COX-1 inhibitorsASA, Omega 3

2. Phosphodiesterase inhibitorsDipyrdamole, Cilostazol

3. ADP-P2Y12 interaction blokersTiclopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor

4. GP IIb/IIIa blokers

5. Thrombin receptor antagonists

AAAA

TxA2TxA2

GPIIb/IIIa

Aggregation

Aspirin

PLATELETPLATELET

Clopidogrel

Prasugrel

Cangrelor Heparin, hirudin

Blocking different pathways for additional clinical benefit:

GP IIb/IIIa antagonists

Epinephrine Collagen

ADP

Epinephrine Collagen

ADP

ASAASA

Inactivates COX irreversibly blocking TXA2 formation (potent mediator of aggregation and vasoconstriction)

Effective 15-30 minutes after oral administration

Large dose over 10 gr eicosapentaenoic acid also blocks TXA2

Inactivates COX irreversibly blocking TXA2 formation (potent mediator of aggregation and vasoconstriction)

Effective 15-30 minutes after oral administration

Large dose over 10 gr eicosapentaenoic acid also blocks TXA2

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors

Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine

Clinical trials failed to show efficacy alone, enhances warfarin and ASA

MR form useful for stroke prevention Cilostazol may be useful in claudicatio

and has vasodilatory and antiplatelet effects

Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine

Clinical trials failed to show efficacy alone, enhances warfarin and ASA

MR form useful for stroke prevention Cilostazol may be useful in claudicatio

and has vasodilatory and antiplatelet effects

ThienopyridinesThienopyridines Bind to P2Y12

receptor inhibiting interaction with ADP that would result in activation and aggregation

Prodrugs requiring transformation to active metabolites

Bind to P2Y12 receptor inhibiting interaction with ADP that would result in activation and aggregation

Prodrugs requiring transformation to active metabolites

Ticlopidine dramatically changed interventional cardiology by making stent implantation safe

Ticlopidine dramatically changed interventional cardiology by making stent implantation safe

0

2

4

6

8

10

12

14

Prim. Cardiac EP Abrupt vesselclosure

Prim. NoncardiacEP

Bleeding

Ticlo + ASA UFH + Warfarin + ASA

0

2

4

6

8

10

12

14

Prim. Cardiac EP Abrupt vesselclosure

Prim. NoncardiacEP

Bleeding

Ticlo + ASA UFH + Warfarin + ASA

Schomig, NEJM 1996

Ticlopidine replaced by clopidogrel: more effective, safer

Ticlopidine replaced by clopidogrel: more effective, safer

0

1

2

3

4

5

MACE Mortality

Ticlopidine

Clopidogrel

0

1

2

3

4

5

MACE Mortality

Ticlopidine

Clopidogrel

Bhatt, JACC 2002

Antiplatelet Resistance:Antiplatelet Resistance: Genetic polymorphism in platelet proteins

(CYP2C19 reduced function alleles have 30 % decrease in active clopidogrel)

Drug interaction (NSAID , drugs metabolized with Cytochrome P450 )

Environmental factors(Smoking, DM, HTN, HLP, ACS)

VARIABILITY IN RESPONSE NOT ALWAYS RESISTANCE:

Insufficent dosing, differences in assays and cutoffs, no gold standart

Genetic polymorphism in platelet proteins (CYP2C19 reduced function alleles have 30 % decrease in active clopidogrel)

Drug interaction (NSAID , drugs metabolized with Cytochrome P450 )

Environmental factors(Smoking, DM, HTN, HLP, ACS)

VARIABILITY IN RESPONSE NOT ALWAYS RESISTANCE:

Insufficent dosing, differences in assays and cutoffs, no gold standart

Is Aspirin Resistance Clinically Significant?

Is Aspirin Resistance Clinically Significant?

JACC 2003:41; 961JACC 2003:41; 961Circulation 2002, 105: 1650

326 stable CAD 5.2 % Aspirin resistance In HOPE study, @ 5 year follow up

MI, stroke, death rate 1.8 % increased in the group with 11- deoxythromboxane B2 level !

326 stable CAD 5.2 % Aspirin resistance In HOPE study, @ 5 year follow up

MI, stroke, death rate 1.8 % increased in the group with 11- deoxythromboxane B2 level !

ASA resistance vs. clopidogrel resistance vs. dual resistanceASA resistance vs. clopidogrel resistance vs. dual resistance

The prevalence of drug resistance: ASA 16%, CLOPI 15%, dual 9%The risk is 7x higher with dual resistence and 4.5x higher with multivessel PCI

Eshtehardi P, Am Heart J 2010; 159: 891-898

26%

37%

5

10

15

20

25

30

35

40

Periprocedur.MI Ischaemic events within 30 days

No resistance

ASA resistance

CLOPI resistance

Dual resistance

0

Per

cen

tag

eP

erce

nta

ge

Definition of Resistance Varies with Method Used: ASA Resistance Measured

by PFA-100 and Aggregometry

Definition of Resistance Varies with Method Used: ASA Resistance Measured

by PFA-100 and Aggregometry

23.8 %

5.5 %

70.7 % Aspirin Sensitive

RESISTANTRESISTANT

Partial responsePartial response

9.5 %

90.5 %Aspirin Resistant

Stable AP n= 325 patients

AggregometryResponse to ADP and AA

AggregometryResponse to ADP and AA

PFA-100PFA-100

Gum P. Am J Cardiol 2001;88:230-235

Routine assessment of platelet aggregation not recommended (II-B)

Routine assessment of platelet aggregation not recommended (II-B)

Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract 1100-1159.

Ag

gre

gat

ion

inh

ibit

ion

(%

)A

gg

reg

atio

n in

hib

itio

n (

%)

Clopidogrel, 600 mgClopidogrel, 600 mgClopidogrel, 300 mgClopidogrel, 300 mg

*P=0.01** P=0.02

‡ P=0.0008

* **‡

*

**

0

60

40

20

80

0 2 4 6

HoursHours

600 mg clopidogrel loading is faster and more effective !

600 mg clopidogrel loading is faster and more effective !

ARMYDA-IIARMYDA-II

Circulation 2005;111:2099Circulation 2005;111:2099

Doubling loading and maintenance dose of clopidogrel in ACS patients undergoing PCIDoubling loading and maintenance dose of clopidogrel in ACS patients undergoing PCI

CV death, MI or stroke

Days

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel standard

Clopidogrel double

HR 0.8595% CI: 0.74-0.99p=0.036

15% RRR

Cu

mu

lati

ve h

azar

dC

um

ula

tive

haz

ard

0.000.00

0.010.01

0.020.02

0.030.03

0.040.04

-20

0

20

40

60

80

100

Clopidogrel to Prasugrel Crossover Study: Less variability with prasugrel since it produces

higher concentrations of active metabolite

Clopidogrel to Prasugrel Crossover Study: Less variability with prasugrel since it produces

higher concentrations of active metabolite

IPA (20 µM ADP) 24 hours

Healthy volunteers Crossover study

Clopidogrel reply Prasugrel reply

Pla

tele

t ag

gre

gat

ion

in

hb

itio

n (

%)

Clopidogrel effective

Clopidogrel resistant

N=66

Brandt et al. J Am Coll Cardiol 2005;45(3 Suppl 1):87A – abstract 868-5

TRITON-TIMI 38: 13608 patients with ACS

TRITON-TIMI 38: 13608 patients with ACS

Key safety end point: non-CABG related TIMI Major Bleeding

& Planned PCI

ASA

ASA

Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

=

UA/NSTEMI (TIMI Risk Score ≥ 3)

STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days)

RD

ay 3

Day

30

Day

90

Prasugrel60 mg LD/ 10 mg MD

Clopidogrel300 mg LD/ 75 mg MD

Day

450

Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR

=

14.5 month actual median

12.0 month planned median

Double-blind treatment 6 - 15 months planned

follow-up

Wiviott SD et al. New Engl J Med 2007;357:2001-2015; Wiviott SD et al. Am Heart J 2006;152:627-635

TRITON TIMI-38:TRITON TIMI-38: Balance of efficacy and safety in patients Balance of efficacy and safety in patients

< 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804) < 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804)

0

2

4

6

8

10

12

14

16

0 30 90 180 270 360 450

En

dp

oin

t (%

)

HR 1.24(95% CI: 0.91-1.69)p=0.17, NNH 222

HR 0.74(95% CI: 0.66-0.84)p<0.001, NNT 37

Clopidogrel 11.0%

Prasugrel 8.3%

Clopidogrel 1.5%

Prasugrel 1.9%

Days

CV death, NF MI, or NF stroke

TIMI major bleeding

Wiviott SD et al. Circulation 2010;122:394-403

Prevention of bleeding just as important as prevention of ischemia:

Prevention of bleeding just as important as prevention of ischemia:

SafetySafety

EfficacyEfficacy

In Clopidogrel group ,30 % of subjects had reduced function allele for CYP, these had 3X more stent

thrombosis

In Clopidogrel group ,30 % of subjects had reduced function allele for CYP, these had 3X more stent

thrombosis

Genetic and Platelet Fx Tests are Complementary

Genetic and Platelet Fx Tests are Complementary

Genome

Transcriptome

Proteome

Phenotype

EnvironmentGenetics

Platelet function testing

Variable Response to ClopidogrelVariable Response to Clopidogrel

Test: Increase dose

Alternative treatment:Genetic,

platelet function

+ Personalise

- Complex

+ Easy

- Efficacy, safety ?

+ Efficacy- Cost ? Bleeding ?

Patients undergoing PCI with high platelet activity randomised to 75 mg C or 600 loading plus 150 mg C: GRAVITAS Study

End point High-dose clopidogrel (%)

Standard-dose clopidogrel (%)

HR (95% CI) p

Cardiovascular death/MI/stent thrombosis

2.3 2.3 1.01 (0.58-1.76) 0.98

Primary end point

Bleeding results Outcome High-dose

clopidogrel (%)Standard-dose clopidogrel (%)

p

GUSTO severe/moderate bleeding 1.4 2.3 0.10

Any GUSTO bleeding 12.0 10.2 0.18

Percentage of patients with persistently high platelet reactivity at 30 days Platelet reactivity units High-dose

clopidogrel (%)Standard-dose clopidogrel (%) p

>230 62 40 <0.001

AHA 2010

CangrelorCangrelor Potent inhibitor of ADP

induced aggregation ATP analogue that inhibits

P2Y12 by 100 % No renal/hepatic

metabolism to be activated İv,rapid action, platelets

back to normal in 60 minutes

Has additive effects to clopidogrel

Two short term trials discontinued for less than expected efficacy

Potent inhibitor of ADP induced aggregation

ATP analogue that inhibits P2Y12 by 100 %

No renal/hepatic metabolism to be activated

İv,rapid action, platelets back to normal in 60 minutes

Has additive effects to clopidogrel

Two short term trials discontinued for less than expected efficacy

TicagrelorTicagrelor

Stable, high affinity inhibitor of ADP induced aggregation

Oral agent acting directly on P2Y12 receptor without transformation

Rapid and greater action Reversibility 180 mg loading ,90 mg bid Higher doses cause dyspnea and

ventricular pause

Stable, high affinity inhibitor of ADP induced aggregation

Oral agent acting directly on P2Y12 receptor without transformation

Rapid and greater action Reversibility 180 mg loading ,90 mg bid Higher doses cause dyspnea and

ventricular pause

PLATO StudyPLATO Study . Lancet. 2002;359:189-198 . Lancet. 2002;359:189-198

NEJM 2009; 361:1045

Glycoprotein IIb/IIIa Inhibitors Block the Common Final Pathway to Platelet Aggregation

regardless of the stimulus for activation

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

Monoclonal Ab against IIb/IIIa: Abciximab

Peptide antagonist: Eptifibatid Nonpeptide antagonist: Tirofiban

Monoclonal Ab against IIb/IIIa: Abciximab

Peptide antagonist: Eptifibatid Nonpeptide antagonist: Tirofiban

GP IIb/IIIa Inhibitors in ACS:30 day death / MI (N=31,402) GP IIb/IIIa Inhibitors in ACS:30 day death / MI (N=31,402)

PRISMPRISM 7.1%7.1% 5.8%*5.8%* 0.800.80 0.60-1.060.60-1.06

PRISM-PLUSPRISM-PLUS 12.0%12.0% (*)(*) 8.7%8.7% 0.700.70 0.50-0.980.50-0.98((† )) 13.6%*13.6%* 1.171.17 0.80-1.700.80-1.70

PARAGON-APARAGON-A 11.7%11.7% (l)(l) 10.3%10.3% 0.870.87 0.58-1.290.58-1.29(h)(h) 12.3%12.3% 1.061.06 0.72-1.550.72-1.55

PURSUITPURSUIT 15.7%15.7% (l)(l) 13.4%13.4% 0.830.83 0.70-0.990.70-0.99(h)(h) 14.2%14.2% 0.890.89 0.79-1.000.79-1.00

PARAGON-BPARAGON-B 11.4%11.4% 10.6%10.6% 0.920.92 0.77-1.090.77-1.09

GUSTO-IVGUSTO-IV 8.0%8.0% (24h)(24h) 8.2%8.2% 1.021.02 0.83-1.240.83-1.24(48h)(48h) 9.1%9.1% 1.151.15 0.94-1.390.94-1.39

OverallOverall 11.8%11.8% 10.8%10.8%tt 0.910.91 0.85-0.980.85-0.98

Odds RatioPlacebo Gp IIb/IIIa 95% CI

Placebo iyiGp IIb/IIIa iyi

0 1.0 2.0

Study

P=.015

Boersma E, et al. Lancet. 2002;359:189-198.

-High risk

- Diabetic

- ASA use on admission

PRISM-PLUS: Thrombus sizePRISM-PLUS: Thrombus size

0

10

20

30

40

50

Heparin(n=622)

Big

Tirofiban + Heparin(n=608)

Probable

Small

Medium

Probable

Small

Medium

Odds Ratio: 0.77

P=0.022

17.1%

24.1%

Big

Occlusion Occlusion

Circulation. 1999;100:1609-1615.

Cumulative (%)

ACUITY, timing GP IIb/IIIa at the time of PCI vs. upstream in everyone

ACUITY, timing GP IIb/IIIa at the time of PCI vs. upstream in everyone

Stone GW et al. JAMA 2007;297:591-602

Routine Upstream GP IIb/IIIa(N=4,605)

Deferred PCIGP IIb/IIIa(N=4,602)

98.3% 55.7%

6.2 6.2

0.6 4.6

11.7 11.7

7.1 7.9

6.1 4.9

Ischaemic EP

Net clinical benefit

Bleeding EP

Rand. to GP IIb/IIIa (h)

Rand. to angio/interv (h)

Overall exposure

DaysDays

6 months death/MI

15.5%15.5%

10.9%10.9%

8.4%8.4%7.2%7.2%

Chan A, et al. J Am Coll Cardiol. 2003;42:1188-1195.

TARGET: Benefit of triple antiplatelet therapy

TARGET: Benefit of triple antiplatelet therapy

Patients(%)

Patients(%)

No clopidogrel only tirofibanNo clopidogrel only abciximab

Clopidogrel and tirofibanClopidogrel and abciximab18

16

14

12

10

8

6

4

2

00 30 60 90 120 150 180

Relation between age, dosing and bleedingRelation between age, dosing and bleeding

Age

Ex

ces

s d

ose

%E

xce

ss

do

se %

Ex

ces

s d

ose

%E

xce

ss

do

se %

Ma

jor

ble

ed

ing

%M

ajo

r b

lee

din

g %

Ma

jor

ble

ed

ing

%M

ajo

r b

lee

din

g %

Eur Heart J Suppl 2007, 9 (Suppl A) A23-A31.Eur Heart J Suppl 2007, 9 (Suppl A) A23-A31.

Antithrombotic treatment options in myocardial revascularisation: STEMIAntithrombotic treatment options in myocardial revascularisation: STEMI

Antiplatelet therapy Classa Levelb

ASA I B

Clopidogrelc (with 600 mg loading dose as soon as possible) I C

Prasugreld I B

Ticagrelord I B

+ GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden)

Abciximab IIa A

Eptifibatide IIa B

Tirofiban IIb B

Upstream GPIIb–IIIa antagonists III B

Anticoagulation

Bivalirudin (monotherapy) I B

UFH I C

Fondaparinux III Ba: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

Eur Heart J 2010. On lineEur Heart J 2010. On line

Antithrombotic treatment options in myocardial revascularisation: NSTE-ACS

Antithrombotic treatment options in myocardial revascularisation: NSTE-ACS

Antiplatelet therapy Classa Levelb

ASA I C

Clopidogrelc (with 600 mg loading dose as soon as possible) I C

Clopidogrelc (for 9–12 months after PCI) I B

Prasugreld IIa B

Ticagrelord I B

+ GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden)

Abciximab (with DAPT) II B

Tirofiban, Eptifibatide IIa B

Upstream GPIIb–IIIa antagonists III B

a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs

Eur Heart J 2010. On lineEur Heart J 2010. On line

Antiplatelets for ischemic stroke or preventing systemic embolismAntiplatelets for ischemic stroke or preventing systemic embolism

Camm, ESC 2009

Warfarin vs placebo

Warfarin vs low dose Warfarin

Warfarin vs ASA

Warfarin vs ASA + clopidogrel

Warfarin better Other better

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

What is the ideal antiplatelet drug?

What is the ideal antiplatelet drug?

Effective platelet inhibition without bleeding Uniformly effective in all patients (no resistance) Simple dosage No side effects No drug interactions Reasonable price

FOR NOW: Beware of drug interactions and bleeding Keep ASA dose low in combination Calculate GPI dose meticulously

Effective platelet inhibition without bleeding Uniformly effective in all patients (no resistance) Simple dosage No side effects No drug interactions Reasonable price

FOR NOW: Beware of drug interactions and bleeding Keep ASA dose low in combination Calculate GPI dose meticulously

New Horizons in Antiplatelet Therapy:

New Horizons in Antiplatelet Therapy:

- TRA thrombin receptor antagonists

- Antagonists to A1 domain on vWF: ARC1779

- Collagen induced platelet aggregation blockers : CTRP-1

- TRA thrombin receptor antagonists

- Antagonists to A1 domain on vWF: ARC1779

- Collagen induced platelet aggregation blockers : CTRP-1

TRITON-TIMI 38: Therapeutic considerations for

subgroups

TRITON-TIMI 38: Therapeutic considerations for

subgroups

Majority of patients:Significant benefit with prasugrel 10 mg (MD)

Age ≥75 years or weight <60 kg:Prasugrel 10 mg equivalent to clopidogrel(Prasugrel 5 mg under investigation)

Prior stroke/TIA:Prasugrel is

contraindicated

80%

4%

16%

PRAGUE-8 (with 600 mg load): Patients undergoing elective PCIPRAGUE-8 (with 600 mg load):

Patients undergoing elective PCI

Widimsky P et al. Eur Heart J 2008;29:1495-1503

Pre-treatment Clop 600 mg(n=155)

No Pre-treatmentClop 600 mg(n=143)

0

20

D/MI/CVA/UTVR Troponin >3XULN Major + MinorBleeding

p=NS

p=NS

p=0.0068.4

2.8

11.9

1.3

10

15

5

7.1

0.7

Per

cen

tag

e p

atie

nts

Activated platelets express CD 40L triggering inflammation and thrombosis

Activated platelets express CD 40L triggering inflammation and thrombosis

ISAR-CHOICEISAR-CHOICE

Circulation 2005;112:2946Circulation 2005;112:2946

30th DAY DEATH / MI WITH GPI%

Par

ient

s

10.9

1.8

9

4.8

10.1

3.6

14.1

3.9

10.2

5.9

16.7

11.6

0

2

6

10

14

18

EPIC CAPTURE EPILOG EPISTENT PRISM-PLUS PURSUIT

Placebo GP IIb-IIIa Inhibitor

Klopidogrel Prasugrel

300/75 40/7.5 60/10 60/15

JUMBO - TIMI 26 (Phase II)PCI + Stent (n= 904)

ASA 325 + % 70 GP2b/3a

JUMBO - TIMI 26 (Phase II)PCI + Stent (n= 904)

ASA 325 + % 70 GP2b/3a

Clopidogrel Prasugrel

300/75 40/7.5 60/10 60/15

Circulation 2005;111:3366Circulation 2005;111:3366

1,2

1,7

0

1

2

Major, minor bleeding

1,2

1,7

0

1

2

Major, minor bleeding

9,4

7,2

0

5

10

MACE

9,4

7,2

0

5

10

MACE

%%%%

Variable Clopidogrel Response Variable Clopidogrel Response At 5 Days

UA Patients* (n = 32)

At 5 DaysUA Patients* (n = 32)

Responders47%

Low responders32%

Nonresponders22%

*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily.Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.