1. Platelet Activation in ACS

2. Platelet Activation in Angina Pectoris1
800
700
600
500
400
300
200
100
0
30
25
20
15
10
5
0
750
700
650
600
550
500
450
400
350
300
250
Fibrinogen (mg/dl) CD62 (+) Platelets GP IIb/IIIa (MFI)
Unstable Angina Stable Angina
1
Chakhtoura, Watson, et al. Am J Cardiol. 2000;86:835-839.
p=0.028 p=0.026 p=0.04

3. Mean Platelet Volume in Stable and Unstable Angina
8
9
10
11
12
Syndrome: Noncardiac Stable Unstable Unstable
Angina Angina Angina + PTCA
Pizzulli L et al. Eur Heart J. 1998;19:80-84.

4. Thrombosis RIsk Progression (TRIP) Study
Relation Between Platelet Physiology and Inflammation and Disease ActivityRelation Between Platelet Physiology and Inflammation and Disease Activity
InflammationInflammation
CRP(ug/mL)
p=.006
p=0.2
0
5
10
15
20
25
AS SA UA
Interleukin-8(pg/mL)
0
4
8
12
16
AS SA UA
P<.001
p=.11
Platelet-Fibrin
60
63
66
69
72
AS SA UA
Clot-Strength(mm)
P=.002P=.002
P=.053P=.053
AS SA UA
0
1.5
3
4.5
6
Fibrinogen(mg/mL)
P=.15P=.15
P=.22P=.22
Prothrombotic StateProthrombotic StateReactive PlateletsReactive Platelets
0
14
28
42
56
AS SA UA
GPIIb/IIIa-
Unstimulated(MFI)
p=.051
P<.001
0
60
120
180
240
300
AS SA UA
GPIIb/IIIa-
ADP-Stimulated(MFI)
P=.14
P=.002
AS = Asymptomatic Patients, SA=AS = Asymptomatic Patients, SA= Stable Angina, UA=Stable Angina, UA= Unstable AnginaUnstable Angina
A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation,
hypercoagulability, and inflammation marks the development of symptomatic cardiovascular disease from
chronic stable disease
InflammationInflammation
?? ?? Prothrombotic StateProthrombotic State
(Hypercoagulability)(Hypercoagulability)
Unstable CoronaryUnstable Coronary
Artery DiseaseArtery Disease
ReactiveReactive
PlateletsPlatelets
Gurbel PA et al. J Am Coll Cardiol. 2007;49:196A.

5. Platelet Hyper-Reactivity in
Acute Coronary Syndromes
50
40
30
20
10
0
0.5 ADP 1.0 ADP 1.5 ADP 2.0 ADP
ACS Patients*
Controls
Agonist Concentration (uM)
*Despite ASA Treatment
Williams et al. Circulation. 2003;108:IV-378.
%Aggregation

6. 0
10
20
30
40
50
Spontaneous Platelet Activation in Acute
Coronary Syndromes: TIMI 12 Results
Normals Patients Baseline Day 7 Day 28
%PlateletsCD62
Controls TIMI 12 ACS
Ault KA et al. J Am Coll Cardiol. 1999;33:634-639.

7. Conclusion
• ACS is a “Platelet-Centric Disease”
Shear Stress, PCIShear Stress, PCI
Plaque RupturePlaque Rupture
Platelet
Platelet
ADPADP
TxATxA
22
Granule
Secretion
MembraneMembrane
PL’sPL’s
PlateletPlatelet
AggregationAggregation
Microaggregates
Myocardial Infarction
GPIIb/IIIaGPIIb/IIIa
ActivationActivation
XX
XX XX
Initial
Activation
Sustained Activation
P-selectinP-selectin
CD-40LCD-40L
PLT-WBCPLT-WBC
Aggregation/Aggregation/
MicroparticlesMicroparticles
Inflammation
CytokineCytokine
ReleaseRelease
GrowthGrowth
FactorFactor
ReleaseRelease
Restenosis
Stent
Thrombosis
ProcoagulantProcoagulant
StateState
Hypercoagulability
ThrombinThrombin
TFTF
AspirinAspirin
ClopidogrelClopidogrel
GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor
TFTF

8. Primary Therapeutic Goal for ACS:
•Attenuate platelet activation and aggregation
•Prevent the development of occlusive thrombus
•Arrest procoagulant activity and inflammation
•Promote platelet disaggregation
•Facilitate perfusion
Treat the Platelet!Treat the Platelet!
Prevent Ischemic Events
• MPA=Maximum
Platelet Aggregation
• “Resistance” = < 10%
platelet aggregation
Adapted from: von BeckerathN, et al. Circulation 2005;112(19):2946-2950

9. Clinical Practice Guideline
Recommendations for
Antiplatelet Therapy in ACS

10. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines
Oral Antiplatelet TherapyOral Antiplatelet Therapy
Adapted from: King et al. Circulation. 2008;117:261-295.
PRIOR TO OR DURING A PCI, IT IS RECOMMENDED
• Patients ALREADY TAKING daily long-term aspirin therapy should take 75 mg to 325
mg of aspirin
• Patients NOT ALREADY TAKING daily long-term aspirin therapy should be given 300
mg to 325 mg of aspirin at least 2 hours, and preferably 24 hours, prior to the
procedure
• A loading dose of clopidogrel*, generally 600 mg, should be administered before or
when PCI is performed
• In patients undergoing a PCI within 12 to 24 hours of receiving fibrinolytic therapy,
clopidogrel 300 mg oral loading dose may be considered
* Higher oral loading doses of clopidogrel more rapidly inhibit platelet aggregation and achieve a higher absolute
level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of these higher oral loading
doses have not been rigorously established

11. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines
Oral Antiplatelet TherapyOral Antiplatelet Therapy
Adapted from: King et al. Circulation. 2008;117:261-295.
AT THE TIME OF THE PCI, IT IS REASONABLE TO GIVE
• In patients for where there is concern about risk of bleeding, a lower dose of 75 mg to 162 mg
of aspirin during the initial period after stent implantation
• If clopidogrel is given, supplementation with GP IIb/IIIa receptor antagonists can be beneficial
• For patients with an absolute contraindication to aspirin, a 300 mg to 600 mg loading dose of
clopidogrel (administered at least 6 hours prior PCI) and/or a GP IIb/IIIa antagonist

12. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines
Oral Antiplatelet TherapyOral Antiplatelet Therapy
Adapted from: King et al. Circulation. 2008;117:261-295.
THE FOLLOWING MIGHT BE CONSIDERED
• Continue clopidogrel therapy beyond 1 year following DES placement
REMEMBER TO CONSIDER CLOPIDOGREL RESISTANCE
• ? ticlopidine
• Think of replacing clopidogrel therapy with prasugrel

13. Recommended Dosing of Antiplatelet AgentsRecommended Dosing of Antiplatelet Agents
Drug Recommended Dose Dosing Adjustments
GP IIb/IIIa Inhibitors
Abciximab Bolus: 0.25 mg/kg (10-60 minutes before the start of
PCI) and infusion 0.125 µg/kg/min (to a maximum of 10
µg/min) for 12 hours
Eptifibatide Bolus: 180 µg/kg and
infusion 2 µg/kg per min
↓ infusion by 50% to 1 µg/kg per min
if CrCl < 50 mL per min or serum
creatinine = 2 mg–4 mg/dL
Tirofiban Bolus: 0.4 µg/kg and
infusion 0.1 µg/kg per min
↓ bolus and infusion by 50% to 0.05
µg/kg per min if CrCl < 30 mL/min
Aspirin Initial dose: 162-325 mg
Maintenance: 75 mg-162 mg/day
Clopidogrel Loading dose: 300mg/600mg;
Maintenance: 75mg per day
Ticlopidine 250 mg bid with food in combination with aspirin (75-
162 mg/day) for up to 30 days of therapy following stent
implantation
Adapted from: Alexander KP et al. JAMA. 2005;294:3108-3116.

14. Clopidogrel Response
Variability

15. Clopidogrel Mechanism of Action
Papathanasiou et al. Hellenic J Cardiol. 2007;48:352.
• AC-adenyl cyclase;
• PKA-protein kinase A
• PLC - phospholipase
C;
• VASP - vasodilator
stimulated
phosphoprotein
A

16. Variable Response to Clopidogrel
• Platelet aggregation before and after Clopidogrel (%)
– “Resistance” = < 10% platelet aggregation
Adapted from: Gurbel PA et al. Circulation 2003; 107: 2908-2913

17. Clopidogrel Response Variability
GP IIb/IIIa receptorGP IIb/IIIa receptor
expressionexpression
Hepatic MetabolismHepatic Metabolism
Cytochrome P450 pathwayCytochrome P450 pathway
Poor compliance
Inadequate administration
Variable absorption
Drug-drug interactions
Genetic polymorphisms CYP enzymes
(CYP3A4/5, CYP2C19, CYP1A2)
Drug-drug interactions
Genetic polymorphisms P2Y12 receptor
Alternate pathways of platelet activation
- Release of circulating ADP
Higher baseline platelet reactivity
Genetic polymorphisms
O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.
Intestinal AbsorptionIntestinal Absorption
P2YP2Y1212 ReceptorReceptor
(irreversible inhibition)(irreversible inhibition)
Active MetaboliteActive Metabolite

18. ~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-PCI3
Inhibition of Platelet Aggregation (Wide Response Variability)1
Mechanism of Clopidogrel Response VariabilityMechanism of Clopidogrel Response Variability
Clopidogrel
Bisulfate
Intestinal
Absorption
Inactive Carboxylic Acid
Metabolite
CYP3A4
CYP3A5
CYP2C19
Active Thiol Metabolite
P2Y12 Receptor
Limited absorption capacity with ceiling effect at 600mg loading doseLimited absorption capacity with ceiling effect at 600mg loading dose
Hepatic P450
Cytochromes
lipophilic statins
Genetic polymorphisms
Genetic polymorphisms
Multistep Conversion
15%
Esterases
85%
1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9.
P-glycoprotein
(MDR1 3435T genotype)2
?
Smoking, proton pump inhibitorsCYP1A2
CYP2B6, 2C19

19. What is the Antiplatelet Effect of Clopidogrel?
(i) Delayed onset and unpredictability of pharmacodynamic response
(ii) A modest degree of mean platelet inhibition (30-50%)
(iii) Wide response variability with non-responsiveness or resistance that is associated with ischemic
events including stent thrombosis
Mechanism of Clopidogrel Response Variability and Nonresponsiveness
(i) CYP isoenzymes variable activity
- genetic polymorphisms or drug-drug interactions
- lipophilic statins, proton pump inhibitors, smoking
(ii) Variable intestinal absorption - ? genetic polymorphisms
Gurbel PA et al. J Am Coll Cadriol. 2008;51:261-263

20. The First Clopidogrel Resistance Study (300 mg)
A “Fingerprint” of Clopidogrel Response Variability
Gurbel PA et al. Circulation. 2003;107:2908-2913
2 Hours 24 Hours
5 Days 30 Days
Resistance = 31%
10
20
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance
Resistance
∆ Aggregation (%)
14
28
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 31%
∆ Aggregation (%)
Resistance
Patients(%)
11
22
≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
Resistance = 63%Resistance
Patients(%)
12
24
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60

21. P2Y12 – A Pivotal Platelet Receptor
Gurbel PA et al. Rev Cardiovasc Med. 2006;7:S20-S28
ShearShear
GPIIb/IIIa Activation
Platelet Aggregation
Inflammation
ADPADP
TxATxA22
MembraneMembrane
PhospholipidsPhospholipids
Granule
Secretion
Sustained
Activation
CollagenCollagen
ThrombinThrombin
P2Y12 Receptor
Activation ADPADP
Procoagulant
Surface
Coagulation
P-selectin
CD-40L Expression
Clopidogrel
Prasugrel
Tricagrelor
Cangrelor
PRT128
X
TxATxA22
Amplification
Amplification

22. Residual Platelet Aggregation Stratified by
CYP2C19*2 Genotype
0
20
40
60
Baseline Before PCI Pre-discharge
CYP2C19 *1/*1
CYP2C19 *1/*2
CYP2C19 *2/*2
Trenk D et al. J Am Coll Cardiol. 2008:51:1925-1934

23. Clopidogrel Non-Responsiveness
Correlation With CYP3A4 Enzyme Activity
0
20
40
60
80
100
Aggregation(%)
80  980  9
37  2037  20
5.0
4.0
3.0
2.0
1.0
0
1.9  0.71.9  0.7
2.7  1.02.7  1.0
Platelet aggregation CYP3A4**
4 hours post clopidogrel* activity
*450 mg PO (P=0.0002); **P=0.15
Nonresponders (25%)Nonresponders (25%)
14
CO2exhaled/h(%)
Lau WC et al. J Am Coll Cardiol. 2003;41:225A
Responders (75%)Responders (75%)

24. Clopidogrel Metabolism and Effect
P2Y12
GPIIb/IIIa ActivationGPIIb/IIIa Activation
Platelet AggregationPlatelet Aggregation
X
PLC
cAMP
VASP-P
Ca++
Mobilization
ADP
Adenylyl
Cyclase
Granule
Secretion
ADP
Gq
G12
Shape
Change
P2Y1
PI3-K
Rap-1b
Akt
Rho
Kinase
Gi
ADP Release
Clopidogrel
Prasugrel
Intestinal
Absorption
CYP P450
Conversion
Active Thiol
Metabolite
Irreversible Binding
Gurbel PA et al.Gurbel PA et al. Nat Clin Pract Cardiovasc Med. 2006;3:387-395

25. DES Thrombosis and Residual Platelet ReactivityPercentofpatientsfreefrom
definiteorprobableST(%)
Responders
Nonresponders*
*Residual platelet aggregation (10 µM ADP) ≥70%
Buonamici P et al. J Am Coll Cardiol. 2007;49:2312-2317
Time (Days)
98 198 1
91  391  3
Log rank P<0.001

26. Overcoming Limitations of
Clopidogrel Therapy

27. The New Drugs
Strategies to Overcome the Limitations of Clopidogrel Therapy
P2Y12 Inhibitors
Cangrelor ATP Analogue Parenteral Direct, Reversible Phase 3
Prasugrel Thienopyridine Oral Prodrug, Irreversible Phase 3
AZD 6140 Cyclopentyltriazolo- Oral Direct, Reversible Phase 3
pyrimidine (CPTP)
PRT060128 ? Parenteral/ Direct, Reversible Phase 2
Oral
PAR-1 Inhibitors
SCH530348 Himbacine Oral Direct Phase 2
Derivative
Soluble GP VI, P2Y1 Inhibitors, GPIb Inhibitors

28. Inhibition of ADP-Induced Aggregation
The Old and the New Drugs
MaintenanceDoses
Clopidogrel Prasugrel AZD6140
LoadingDoses
16%
29%
0
7
14
21
28
35
300 mg 600 mg
AbsoluteInhibition(%)
20uMADP
Gurbel et al.
J Am Coll Cardiol. 2005;45:1392
Jakubowski et al.
J Cardiovasc Pharmacol. 2007;49:167
36%
60%
0
15
30
45
60
75
300 mg
Clopidogrel
60 mg
Prasugrel
RelativeInhibition
20uMADP(%)
17%
52%
0
15
30
45
60
300 mg
Clopidogrel
180 mg
AZD6140
RelativeInhibition
20uMADP(%)
Storey et al.
J Am Coll Cardiol. 2006;47:204A
Von Beckerath et al.
Eur Heart J. 2007
Jakubowski et al.
J Cardiovasc Pharmacol. 2007;49:167
Storey et al.
J Am Coll Cardiol. 2006;47:204A
45%
65%
0
15
30
45
60
75
75 mg 150 mg
Post-TreatmentAggregation
5uMADP(%)
38%
65%
0
15
30
45
60
75
75 mg
Clopidogrel
15 mg
Prasugrel
RelativeInhibition
20uMADP(%)
25%
52%
0
15
30
45
60
75 mg
Clopidogrel
180 mg bid
AZD6140
RelativeInhibition
20uMADP(%)

29. Emerging
Treatment Options
Prasugrel

30. Evolution of Antiplatelet Therapy in ACS
0
1 08
Placebo APTC CURE TRITON-TIMI 38
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher
IPA
ASA
ASA + Clopidogrel
ASA +
Prasugrel- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction
in
Ischemic
Events
Increase
in
Major
Bleeds

31. Prasugrel
More Effective Platelet Inhibition
Prasugrel vs Clopidogrel1
• More potent
• More rapid in onset
• More consistent inhibition
of platelet aggregation
(IPA)
• Less frequent poor IPA
response
• More efficient generation of
its active metabolite
1. Wiviott SD et al. Am Heart J. 2006;152:627-635.
2. Payne CD et al. Am J Cardiol. 2006;98:S8.
Time Post-dose (Day/Hour)
IPA in healthy subjects2
-1 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
1/.25 1/.5 1/1 1/2 1/4 1/6 2/0 3/0 4/0 5/0 6/0 7/0 8/0 9/0
Pras 60/10
Clop 600/75
Clop 300/75
InhibitionofPlateletAggregation(%)

32. ******
***
*** ***
Comparative Platelet-Inhibition by Prasugrel and Clopidogrel
in Aspirin-Treated Patients with Coronary Artery Disease
0
20
40
60
80
100
Wallentin L et al. Eur Heart J. 2008;29:21-30.
MPA*(%)
h 0 0.5 1 2 4 24 + 4 Predose
Day Day
14+3 29+3*20 µM ADP max platelet agg ***p<0.001
Day 1
Loading dose Maintenance doses
/ /
Clopidogrel
Prasugrel
*** ***

33. Prasugrel Is Effective for
Clopidogrel Non-Responders
* Responder 25% IPA at 4 and 24 hours
-20-20
00
2020
4040
6060
8080
100100
IPAat24hours(%)IPAat24hours(%)
Response toResponse to
Prasugrel 60 mg
Response toResponse to
Clopidogrel 300 mg
Clopidogrel ResponderClopidogrel Responder
Clopidogrel Non-responderClopidogrel Non-responder
InterpatientInterpatient
VariabilityVariability
InterpatientInterpatient
VariabilityVariability
Brandt JT. Am Heart J. 2007;153: 66e9.

34. “Resistance” to Clopidogrel is a
Pharmacokinetic Problem
Husted S et al. Eur Heart J. 2006;27:1038.
Brandt et al. J Am Coll Cardiol. 2005;45:87A.Brandt et al. J Am Coll Cardiol. 2005;45:87A.
Disperse StudyDisperse Study
(n=39 stable ASCVD)(n=39 stable ASCVD)
Healthy Volunteer Crossover StudyHealthy Volunteer Crossover Study
60 mg60 mg300 mg
Uniform response:
“Polygenetic and environmental
influence” ???

35. PRASUGRELPRASUGREL
60 mg LD/ 10 mg MD60 mg LD/ 10 mg MD
CLOPIDOGRELCLOPIDOGREL
300 mg LD/ 75 mg MD300 mg LD/ 75 mg MD
TRITON-TIMI 38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
11oo
endpoint:endpoint: CV death, MI, strokeCV death, MI, stroke
22oo
endpoints:endpoints: CV death, MI, stroke, rehosp-rec ischCV death, MI, stroke, rehosp-rec isch
CV death, MI, UTVRCV death, MI, UTVR
Median duration of therapy - 12 monthsMedian duration of therapy - 12 months
N=13,600
Wiviott SD et al. Am Heart J. 2006;152:627-635.
UTVR: urgent target vessel revascularization;
NSTEMI: non-ST segment elevation MI

36. TRITON TIMI-38
Balance of Efficacy and Safety
Days
35
events
HR 0.81
(0.73-0.90)
P = .0004
HR 1.32
(1.03-1.68)
P = .03
138
events
NNT = 46
NNH = 167
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
EndPoint(%)
12.1
9.9
1.8
2.4
0
5
10
15
0 30 60 90 180 270 360 450
CV Death/MI/Stroke
TIMI Major
Non-CABG Bleeds
Clopidogrel
Prasugrel
Prasugrel
Clopidogrel
HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm

37. TRITON-TIMI-38
Primary Endpoint- CV Death, MI, StrokePrimary Endpoint- CV Death, MI, StrokePrimaryEndpoint(%)
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
p=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days
12.1 %
9.9 %
~ 10% Recurrent
Ischemic Events
- What is the Reason
for Treatment Failure?
- Ceiling effect of P2Y12
blocker?
- Selected patients with
high platelet reactivity?
- Other unblocked
pathways?
e.g. Thrombin - PAR-1?
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
Bleeding Events = Prasugrel (1.4%) vs. Clopidogrel (0.9%), p=0.01

38. TRITON TIMI-38
Bleeding Events*
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
ARD 0.5%
HR 1.52
P = .01
PercentageofEvents
ARD 0.6%
HR 1.32
P = .03
NNH = 167
Clopidogrel
Prasugrel
ARD 0.2%
P = .23
ARD 0%
P = .74
ARD 0.3%
P = .002
1.8
0.9 0.9
0.1
0.3
2.4
1.4
1.1
0.4 0.3
0
2
4
TIMI Major
Bleeds
Life-threatening Nonfatal Fatal ICH
ICH in Patients with
Prior Stroke/TIA
(N = 518)
Clop 0 (0)%Clop 0 (0)%
Pras 6 (2.3)%
(P = .02)
*N = 13,457
TIA = transient ischemic attack; ICH = intracranial hemorrhage; ARD = absolute risk difference

39. TRITON TIMI-38 Net Clinical Benefit
Bleeding Risk Subgroups
Overall
≥60 kg
<60 kg
<75
No
Yes
0.5 1 2
Prior
Stroke / TIA
Age
Weight
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysis
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
≥75

40. TRITON TIMI-38: Stent Thrombosis
(ARC Definite + Probable)
Days
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48
P < .0001
Prasugrel
Clopidogrel 2.4
(142)
74 events
NNT = 77
1.1
(68)
EndPoint(%)
Any Stent at Index PCI
N = 12,844
ARC = Academic Research Consortium; PCI = percutaneous coronary intervention
Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.

41. 0.0
0.5
1.0
1.5
2.0
2.5
Stent Thrombosis* in Triton TIMI-38
DES
Number at risk Days
Prasugrel 2865 2782 2762 2746 2524 2474 2205 2123 1846 1334
Clopidogrel 2878 2760 2737 2726 2508 2472 2225 2140 1887 1367
Wiviott SD et al. Lancet. 2008;371:1353-1363.
Clopidogrel 0.84 vs. 2.31% HR 0.36 (0.22-0.58), p<0.0001
Prasugrel
1 year 0.74 vs. 2.05%
HR 0.35 (0.21 – 0.58), p<0.0001
%ofparticipants
0 50 100 150 200 250 300 350 400 450
* ARC definite or probable

42. 0.0
0.5
1.0
1.5
2.0
2.5
Stent Thrombosis* in Triton TIMI-38
BMS
Number at risk Days
Prasugrel 3237 3123 3086 3065 2757 2692 2419 2338 2008 1614
Clopidogrel 3224 3065 3035 3014 2722 2675 2368 2294 1997 1600
Clopidogrel 1.27 vs. 2.41% HR 0.52 (0.35-0.77), p=0.0009
Prasugrel
1 year 1.22 vs. 2.27%
HR 0.53 (0.36 – 0.79), p=0.0014
%ofparticipants
0 50 100 150 200 250 300 350 400 450
Wiviott SD et al. Lancet. 2008;371:1353-1363.

43. PRINCIPLE-TIMI 44
Prasugrel versus High Dose Clopidogrel
Adapted from Wiviott et al. Circulation. 2007;116:2923.
60 Prasugrel 10 Prasugrel / Day
600 Clopidogrel 50 Clopidogrel / Day
%IPA(20MADP)
p<0.0001 p<0.0001
0
10
20
30
40
50
60
70
80
90
100
6 Hours Post Load 14 Days Chronic Rx
Prasugrel
Clopidogrel
74.8 ± 13.0
31.8 ± 21.1
61.3 ± 17.8
46.1 ± 21.3

44. Summary
• Stent Thrombosis – rare complication of PCI with high mortality.
• Study data indicate that prasugrel is a drug with more rapid,
consistent, and greater inhibition of platelet aggregation
– superior to standard dose clopidogrel to prevent ischaemic events
– major reductions (~50%) in ST across a broad array of clinical
procedural characteristics
• Intensive antiplatelet therapy with PRASUGREL in stented
patients as compared to CLOPIDOGREL:
– Brings Substantial reduction in ST, regardless of stent type or ST
definition - Early and Late
• Effective in a broad range of clinical / procedural characteristics
– Fewer ischemic events, more major bleeding