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Advances in AntiplateletTherapy in PCI and ACS
Stephan Windecker
Department of Cardiology
Swiss Cardiovascular Center and Clinical Trials Unit Bern
Bern University Hospital, Switzerland
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Targets for Platelet Inhibition
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Mode of Action of Antiplatelet DrugsSchömig A. N Engl J Med 2009;361:1108-1111
Limitations of Clopidogrel
1. Delayed onset of action
2. Large interindividual
variability in platelet
response
3. Irreversibility of inhibitory
action
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Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI
Hours
IPA
% (
20 µ
M A
DP
) Prasugrel 60 mg
***p<0.0001 Prasugrel vs. Clopidogrel
Clopidogrel 600 mg
*********
***
0.5 4 8 12 16 20 24
0
20
40
60
80
100
62
IPA=inhibition of platelet aggregation;
PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932
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Healthy Volunteer Crossover Study
-20
0
20
40
60
80
100
IPA
at
24 h
ou
rs (
%)
Response to
Prasugrel 60 mgResponse to
Clopidogrel 300 mg
Clopidogrel Responder
Clopidogrel Non-responder
Inte
rpati
en
t
Vari
ab
ilit
y
Inte
rpatie
nt
Varia
bility
From Brandt JT AHJ 153: 66e9,2007
N=66
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Ticagrelor and Inhibition of Platelet AggregationGurbel PA al. Circulation 2009
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Ticagrelor and Inhibition of Platelet Aggregation in Clopidogrel-Nonresponsive Patients
Gurbel PA et al. Circulation 2010;121:1188-99
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Clopidogrel vs Prasugrel and Ticagrelor
• Inhibition of Platelet Aggregation
– Prasugrel and ticagrelor show more rapid onset of
platelet inhibition than clopidogrel
– Prasugrel and ticagrelor afford greater inhibition of
platelet aggregation than clopidogrel
– Prasugrel and ticagrelor provide more predictable
inhibition of platelet aggregation than clopidogrel
• Offset of Inhibition of Platelet Aggregation
– Ticagrelor shows more rapid offset than
clopidogrel after discontinuation
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TRITON-TIMI 38
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0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)
P=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days
Pri
ma
ry E
nd
po
int
(%)
12.1
(781)
9.9
(643)
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)
Triton TIMI 38 – Prasugrel vs. ClopidogrelWiviott SD et al. N Engl J Med 2007;357:2001-15
Primary Endpoint: CV Death, MI, Stroke
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Risk Reduction (%)
Endpoint Absolute Relative P value
Primary: CV death/ Nonfatal
MI/ Nonfatal stroke
2.2 19 <0.001
CV Death 0.3 11 0.31
Nonfatal MI 2.3 24 <0.001
Urgent target vessel revascularization
1.2 34 <0.001
Stent thrombosis 1.3 52 <0.001
Recurrent MI followed by CV death
0.3 42 0.02
Triton TIMI 38 – Prasugrel vs. Clopidogrel
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PLATO
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Ticagrelor versus Clopidogrel in ACS Wallentin L al. N Engl J Med 2009;361:1045-57
p=0.0003
HR 0.84 (95% CI 0.77–0.92)
RRR = 16%, ARR = 1.87%, NNT = 54
9.8%
11.7%
Primary Endpoint: CV Death, MI or Stroke
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Ticagrelor versus Clopidogrel in ACSWallentin L al. N Engl J Med 2009;361:1045-57
4,54
5,8
1,5 1,1
5,95,1
6,9
1,3 1,1
0
4
8
12
All Cause Death CV Death MI Stroke Ischemic Stroke
Ticagrelor Clopidogrel
HR= 0.78
(0.69–0.89)
P<0.01
HR=0.79
(0.69–0.91)
P=0.001
HR=0.84
(0.75–0.95)
P=0.005
Individual Ischemic Endpoints
P=0.74HR=1.17
(0.91–1.52)
P=0.22
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24,045 Patients
Major Bleeding: 3.9%
HR=1.64, 95% CI 1.2-2.3
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3.4
1.4
0.27 0.28
6.2
2.2
0.3 0.29
0
2
4
6
8
Minor Bleeding Major Bleeding Fatal Bleeding Intracranial
Hemorrhage
Single APT DAPT
(%)
Risk of Bleeding With DAPTSerebruany VL et al. Fund Clin Pharmacology 2008;22:315-21
56%
RR=1.56
(1.47-1.66)47%
RR=1.47
(1.36-1.60)
RR=1.10
(0.87-1.40)
RR=1.07
(0.85-1.35)
18 RCTs With 129,314 Patients Comparing
Single versus Dual Antiplatelet Therapy
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Risk of Bleeding With DAPT in Long- versus Short-term Studies
Bowry DK et al. Am J Card 2008;101:960-66
Long-term Studies
Short-term Studies
OR= 1.80 (1.40-2.30)
OR= 1.07 (0.86-1.34)
8 RCTs With 91,744 Patients Comparing
Single versus Dual Antiplatelet Therapy
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1,8
0,9 0,9
0,10,3
2,4
1,41,1
0,4 0,3
0
2
4
TIMI Major Bleeds
Life Threatening Nonfatal Fatal ICH
Bleeding Events Safety Cohort(N=13,457)
% E
ven
ts
ARD 0.6%
HR 1.32
P=0.03
NNH=167
Clopidogrel
Prasugrel
ARD 0.5%
HR 1.52
P=0.01
ARD 0.2%
P=0.23
ARD 0%
P=0.74
ARD 0.3%
P=0.002
ICH in Pts w
Prior Stroke/TIA
(N=518)
Clop 0 (0) %
Pras 6 (2.3) %
(P=0.02)
Triton TIMI 38 – Prasugrel vs. ClopidogrelWiviott SD et al. N Engl J Med 2007;357:2001-15
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3,2
1,8
13,4
2,4
0
5
10
15
CABG TIMI Major Bleeding Non-CABG TIMI Major Bleeding
Clopidogrel Prasugrel
HR= 4.73
(1.90–11.82)
P<0.001
HR= 1.32
(1.03–1.68)
P= 0.03
CABG and Non-CABG Related Bleeding
Triton TIMI 38 – Prasugrel vs. ClopidogrelWiviott SD et al. N Engl J Med 2007;357:2001-15
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Early and Late Risks of Prasugrel Over Clopidogrel in ACS Patients Undergoing PCI
Antman E et al. J Am Coll Cardiol 2008;51:2028-33
Major Bleeding
0-3 Days 3-450 Days
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Ticagrelor versus Clopidogrel in ACSWallentin L al. N Engl J Med 2009;361:1045-57
p=0.0003
HR 0.84 (95% CI 0.77–0.92)
RRR = 16%, ARR = 1.87%, NNT = 54
11.2%
11.6%
CABG and Non-CABG Related Bleeding
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Ticagrelor versus Clopidogrel in ACSWallentin L al. N Engl J Med 2009;361:1045-57
11,2
3,8
7,7
2,2
11,6
4,5
7,9
2,8
0
5
10
15
Plato Major Bleeding
Non-CABG PLATO major
TIMI Major Bleeding
Non-CABG TIMI major
Clopidogrel Ticagrelor
HR= 1.04
(0.95–1.13)
P= 0.43
HR= 1.19
(1.02–1.38)
P= 0.03
HR= 1.03
(0.93–1.15)
P= 0.57
HR= 1.25
(1.03–1.53)
P= 0.03
CABG and Non-CABG Related Bleeding
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Risk of Definite Stent ThrombosisCook, Windecker. Circulation 2009;119:657-9
Stable Angina UA/
NSTEMI
STEMI
Bare Metal
Stents
0-0.5% 1.4-1.6% 2.9%
Drug-Eluting
Stents
0.3-0.4% 1.2-1.9% 3.1%
Risk of Early Stent Thrombosis
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Platelet Reactivity and Risk of Early Stent Thrombosis
Sibbing D et al. J Am Coll Cardiol 2009;53:849-56
0.2 0.20.4
2.2
0.6
2.8
0
1
2
3
4
5
Definite ST Probable ST Definite/ Probable ST
Normal Responders (N=1285) Low Responders (N=323)
P<0.0001 P=0.13 P<0.0001
Multiple Electrode Platelet Aggregometry (Point-of-Care Analysis)
-1608 consecutive patients between 02/2007 and 04/2008
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Stent Thrombosis (ARC Definite + Probable)
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48
P <0.0001
Prasugrel
Clopidogrel2.4
(142)
NNT= 77
1.1
(68)
Days
En
dp
oin
t (%
)
Any Stent at Index PCI
N= 12,844
Triton TIMI 38 – Prasugrel vs. ClopidogrelWiviott SD et al. N Engl J Med 2007;357:2001-15
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1.3
2.2
2.9
1.9
2.9
3.8
0
1
2
3
4
Definite Probable or Definite Definite, Probable or
Possible
Ticagrelor Clopidogrel
HR=0.67
(0.50–0.91)
P=0.009
HR=0.77
(0.62–0.95)
P=0.01
HR=0.75
(0.59–0.95)
P=0.02
Ticagrelor versus Clopidogrel in ACSWallentin L al. N Engl J Med 2009;361:1045-57
Stent Thrombosis
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Adjunctive therapy: primary PCI
• Aspirin:
A bolus of 150-325 mg (chewable) or 250-500 mg
i.v. followed by life long therapy. I B
• Clopidogrel:
Bolus (300 mg) or 600 mg. I C
• Heparin:
100 U/kg (60 U/kg with GP IIb/IIIa) I C
• Glycoprotein IIb/IIIa inhibitor
Abciximab (60 U/kg with GP IIb/IIIa) IIa A
Anti-trombotic therapy - ESC STEMI Guidelines 2008
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TRITON-TIMI 38: Study Design –Distribution of Patients in STEMI Cohort
ACS = acute coronary syndrome; LD = loading dose; MD = maintenance dose; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina
Double-blind, double-dummy, parallel, randomised controlled trial
All ACS/PCI patientsN = 13608
UA/NSTEMIn = 10074
Randomised patients with STEMI N = 3534
Prasugrel 60 mg LD/10 mg MDn = 1769
Clopidogrel 300 mg LD/75 mg MDn = 1765
2 patients did not receive study drug or undergo PCI
Primary PCI n = 2438
Secondary PCI n = 1094
Clopidogreln = 1235
Prasugreln = 1203
Clopidogreln = 530
Prasugreln = 564
Montalescot G et al. Lancet 2009;373(9665):723-731
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STEMI Cohort: Primary Endpoint(CV death, MI and Stroke at 15 Months)
Montalescot G et al. Lancet 2009;373:732–731
Time (days)
5
10
15
0
0 50 100 150 200 250 300 350 400 450
Pro
po
rtio
n o
f p
ati
en
ts (
%)
9.5
6.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=42
p=0.02
RRR=21%
p=0.002
RRR=32%
Clopidogrel
Prasugrel
Age-adjusted HR=0.81 (0.66–0.99)
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HR=0.58 (0.36–0.93) NNT=83
p=0.02
RRR=42%
0 100 200 300 400
0
1
2
3
Pro
po
rtio
n o
f p
ati
en
ts (
%)
Time (days)
2.4
1.2
2.8
1.6p=0.008
RRR=51%
Clopidogrel
Prasugrel
Age-adjusted HR=0.59 (0.37–0.96)
STEMI Cohort: Stent ThrombosisARC definite/probable
Montalescot G et al. Lancet 2009;373:732–731
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STEMI Cohort: TIMI Major Non-CABG BleedingMontalescot G et al. Lancet 2009;373:732–731
0.5
1.0
2.0
2.5
1.5
2.1
2.4
HR=1.11 (0.70–1.77) NNH=333Pro
po
rtio
n o
f p
ati
en
ts (
%)
Time (days)
p=0.65
0 100 200 300 400
0
Clopidogrel
Prasugrel
Age-adjusted HR=1.19 (0.75–1.89)
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• Potency
– More rapild onset of IPA
– More potent and reliable IPA
– Irreversible
• Benefit
– Lower rate of MI and ST
– Similar rate of overall or CV mortality
• Bleeding
– More CABG and non-CABG related
major bleeding
– caution in patients with unknown
coronary anatomy
– caution in patients at high risk of
bleeding
• STEMI
– Benefit without increased bleeding risk
• Potency
– More rapid onset and offset of IPA
– More potent and reliable IPA
– Reversible
• Benefit
– Lower rate of MI and ST
– Lower overall and CV mortality
• Bleeding
– More non-CABG related
– caution in patients at high risk of
bleeding
• STEMI
– Benefit without increased bleeding risk
• Compliance
– Dyspnea
– Twice daily intake
Clopidogrel vs Prasugrel Clopidogrel vs Ticagrelor
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Guideline RecommendationsAHA/ACC ESC
STEMI –
Thienopyridine
Loading
Clopidogrel 300-600 mg
Prasugrel 60 mg
Ticagrelor
I C
I B
I C/B
IB
STEMI -
Thienopyridine
Duration
> 12 months I B IIa C
UA/NSTEMI –
Thienopyridine
Loading
Clopidogrel 300-600 mg
Prasugrel
Ticagrelor
I C
II a
I C
IB
UA/NSTEMI -
Thienopyridine
Duration
DES > 12 months
BMS > 1 month,
ideally 12 months
I B
I B
I B
I B
Elective PCI –
Thienopyridine
Loading
Clopidogrel 300-600 mg I C I C
Elective PCI -
Thienopyridine
Duration
DES > 12 months
BMS > 1 month,
ideally 12 months
I B
I B
I C
I A
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2,64,6 4,3 3,7
5,1
12,3 12
0
5
10
15
Incidence of Bleeding in Relation to Antithrombotic Therapy
Sørensen R et al. Lancet 2009;374:1967-74
40 812 patients with MI between 2005-2008
Ye
arl
yin
cid
en
ce
(%)
Single
Therapy
Dual
Therapy
Triple
Therapy
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Risk of Bleeding and Mortality After Acute MIin Relation to Antithrombotic Therapy
Sørensen R et al. Lancet 2009;374:1967-74
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Management of Antithrombotic Therapy in AfibPatients With ACS and/or Undergoing PCIESC WG Thrombosis Consensus Document: Lip G et al. Eur Heart J 2010;31:1311-18
Hemorrhagic
Risk
Clinical Setting Stent Type Recommendation
Low or
intermediate
Elective BMS 1 month: ASA, Clop, OAC
Lifelong: OAC alone
Elective DES 3 months: ASA, Clop, OAC
3-12 months: Clop, OAC
Lifelong: OAC alone
ACS BMS/DES 6 months: ASA, Clop, OAC
6-12 months: Clop, ASA or Clop
Lifelong: OAC alone
High Elective BMS 2-4 weeks: ASA, Clop, OAC
Lifelong: OAC alone
ACS BMS 4 weeks: ASA, Clop, OAC
1-12 months: Clop, ASA or Clop
Lifelong: OAC alone
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Concurrent DAPT Studies Timeline to Final Data Collection
DAPT Study, n = 20,165
REAL-LATE, n = 2,000
ZEST-LATE,
n = 2,000
OPTIDUAL, n = 1,966
ISAR-SAFE, n = 6,000
ITALIC, n = 3,200
ADAPT-DES, n = 11,000
PARIS, n = 5,011
2010 2011 2012 2013 2014
OPTIMIZE, n = 3,120
‘Second Gen.’ DES (Colombo), n = 4,000
RCT > 12 m
RCT < 12m
Registries
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Triton TIMI 38 – Prasugrel vs. Clopidogrel by Diabetes Status: Primary End Point
Wiviott SD et al. Circulation 2008;118:1626-36
Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
Pri
mary
En
d P
oin
t (%
)
0
2
4
6
8
10
12
14
16
18
No Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
0
2
4
6
8
10
12
14
16
18HR 0.70 (0.58-0.85), P<0.001 HR 0.86 (0.76-0.98), P = 0.02
Clopidogrel 17.0
Prasugrel 12.2
Clopidogrel 10.6
Prasugrel 9.2
P interaction = 0.09
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Triton TIMI 38 – Prasugrel vs. Clopidogrel Wiviott SD et al. Circulation 2008;118:1626-36
Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
TIM
I M
ajo
r B
lee
din
g (
%)
0
1
2
3
4
5
No Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
0
1
2
3
4
5
HR 1.06 (0.66-1.69), P = 0.81 HR 1.43 (1.07-1.91), P = 0.02
Clopidogrel 2.6
Prasugrel 2.5
Clopidogrel 2.4
Prasugrel 1.6
Pinteraction = 0.29
Non-CABG TIMI Major Bleeding
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0
1
2
3
4
5
IDDM IDDM IDDM Diabetes Diabetes Diabetes Diabetes
Kuchulakanti
Circ 2006
Urban
Circ 2006
Iakovou
JAMA 2005
Daemen
Lancet 2007
Machecourt
JACC 2007
OR=2.0
(0.8-4.9)
OR=2.8
(1.7-4.3)
HR=3.7
(1.7-7.9)
HR=2.0
(1.1-3.8)
OR=2.7
(1.4-5.2)
Od
ds
/Ha
za
rd R
ati
o
Diabetes as Predictor of Stent Thrombosis
Iijima
Am J Card 2007
HR=2.2
(1.1-4.3)
HR=1.75
(1.0-3.0)
De la Torre
JACC 2008
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Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
Ste
nt
Th
rom
bo
sis
(%
)
0
1
2
3
4
5
No Diabetes Mellitus
Days
0 50 100 150 200 250 300 350 400 450
0
1
2
3
4
5HR 0.52 (0.33-0.84), P = 0.007 HR 0.45 (0.31-0.65), P<0.001
Clopidogrel 3.6
Prasugrel 2.0
Clopidogrel 2.0
Prasugrel 0.9
Pinteraction = 0.63
Triton TIMI 38 – Prasugrel vs. Clopidogrel Wiviott SD et al. Circulation 2008;118:1626-36
Stent Thrombosis