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.
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.
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
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
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” ???
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(20MADP)
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
Notas del editor
Percutaneous coronary intervention is inherently thrombogenic. Deep vessel wall injury induced by balloon dilatation and stent implantation triggers thrombosis resulting in thrombin generation, platelet activation and a profound, systemically detectable inflammatory response. These responses, namely thrombin generation, platelet activation and vascular inflammation lead to vessel thrombus formation, which in turn leads to vessel occlusion and downstream passage of clot, myocardial ischemia and infarction. In order to combat this response, several pharmacological agents have been developed to suppress these effect.
This slide places our findings in the context of prior studies of antiplatelet therapy in ACS. The introduction of single antiplatelet therapy with aspirin, as summarized in the APTC report, was associated with a 22% reduction in ischemic events. Moving to dual antiplatelet therapy with clopidogrel + aspirin in CURE produced a further 20% reduction in ischemic events. The higher IPA achieved with the combination of prasugrel and aspirin produced yet a further 19% reduction in ischemic events. Each of these advances in antiplatelet therapy was associated with a progressive increase in major bleeds as depicted in the red bars along the bottom. In each case, as with TRITON-TIMI 38, the absolute reduction in ischemic events was greater than the increase in major bleeds, resulting in net clinical benefit with increasingly potent oral antiplatelet regimens.
To answer this question, we are currently recruiting up to 850 sites for participation in a global phase 3 trial of prasugrel vs. clopidogrel in patients with acute coronary syndromes with planned PCI, called TRITON-TIMI 38. This trial will enroll 13,000 patients across the ACS spectrum. Patients will be randomized to either prasugrel or standard doses of clopidogrel. Patients will be followed on maintenance therapy for a median of 12 months. The primary endpoint will be the composite of cardiovascular death, MI and stroke. Important secondary endpoints include bleeding, recurrent ischemia and urgent target vessel revascularization. Thank you for your attention.