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Progress in Oral Anti-Platelet Therapy
Rabih R. Azar, MD, MSc, FACC
Division of Cardiology
Hotel Dieu de France Hospital
1
Role of the Platelets in ThrombosisRole of the Platelets in ThrombosisRole of the Platelets in Thrombosis
UA/NQMI:Partially-occlusive thrombus (primarily
platelets)
Intra-plaque thrombus (platelet dominated)
Plaque core
ST MI:occlusive thrombus (platelets,
red blood cells, and fibrin)
Intra-plaque thrombus (platelet dominated)
Plaque core
SUDDEN DEATHAdapted from Davies MJ. Circulation.1990; 82 (supl II): 30-46.
Pathogenesis of UA and Acute MIPathogenesis of UA and Acute MI
GP IIb/IIIa Receptor Activation Pathway
ASPIRIN
ASPIRIN
HEPARINS
ASPIRIN
ASPIRIN
ASPIRIN
ASPIRIN
GP IIb/IIIa
GP IIb/IIIa
Thickness of lineindicates strengthof activator
5HT
PAF
Epi
Thrombin ADPTXA2
ASPIRIN Vasopressin
Collagen
Fibrinogen
PLATELET
PLATELET
CLOPIDOGREL
Thienopyridine Structures
Ticlopidine(1st generation)
N
SCl
N
SCl
Prasugrel(CS-747, LY640315)
S
N
F
O
OCH3
O
Clopidogrel(2nd generation)
OCH3
N
SCl
N
SCl
O
Meadows TA, et al. Circulation Research 2007;100:1261-1275; Sugidachi A, et al. J Thromb Haemost 2007;5:1545-1551
Ticlopidine (ticlid) and clopidogrel (plavix)
Ticlopidine Clopidogrel
twice / day once / day
Neutropenia No neutropenia
CBC monitoring No need for CBC monitoring
Skin reactions (rash) No skin reactions
Delayed onset of effect Rapid onset of effect
Role of Thienopyridines
¨ Inhibit platelet aggregation
¨ Improve cardiovascular outcome• Decrease the risk of MI
• Decrease the risk of stent thrombosis
• Decrease the risk of death
What is the Effect of Clopidogrel on Platelet
Aggregation?
Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.
Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment
% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)
97.597.5
92.592.5
87.587.5
82.582.5
77.577.5
72.572.5
67.567.5
62.562.5
57.557.5
52.552.5
47.547.5
42.542.5
37.537.5
32.532.5
27.527.5
22.522.5
17.517.5
12.512.5
7.57.5
2.52.5
2020
1515
1010
55
00
Nu
mb
erN
um
ber
of
of
Pat
ien
tsP
atie
nts
Bleeding riskBleeding risk Ischemic riskIschemic risk
Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days)
Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)
Why is the onset of action of clopidogrel late and why
is the response to clopidogrel variable?
Change the Agent?
Prasugrel
Sankyo Ann Report 51:1,1999
Pro-drug
Oxidation(Cytochrome P450)
HOOC* HS
N
O
F
Active Metabolite
N
S
O
FO
Sem Vasc Med 3:113, 2003
Hydrolysis(Esterases)
N
S
O
CH3
CO
FON
S
O
Cl
O CH3C
Clopidogrel
85% Inactive Metabolites
Esterases
N
S
O
Cl
O CH3C
ON
S
O
Cl
O CH3C
Active Metabolite
HOOC* HS
N
O
Cl
OCH3
Is There a Correlation Between Poor Platelet Inhibition and Adverse
Cardiovascular Outcome?
Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness
Clinical RelevanceFunctional ParameterN
Stent thrombosis↑shear-induced platelet aggregation49Ajzenberg et al.JACC 2005
Stent thrombosis↑P2Y12 reactivity ratio; ↑platelet
aggregation;
↑stimulated GPIIb/IIIa expression
120Gurbel et al.JACC 2005
Stent thrombosis↑P2Y12 reactivity ratio (VASP-levels)36Barragan et al. CCI 2003
Stent thrombosis↓inhibition of platelet aggregation105Mueller et al.
Thromb Haemost2003
Angiolillo DJ et al. Am J Cardiov Drugs. 2007.
Stent ThrombosisStent Thrombosis
Clinical RelevanceFunctional ParameterN
Post-PCI ischemic events (30 days)
↑ platelet aggregation292Cuisset et al.JACC 2006
Post-PCI ischemic events (30 days)
Post-PCI ischemic events (3 months)
Post-PCI ischemic events (12 months)
↑ platelet aggregation (3rd & 4th quartiles)
↓ platelet inhibition
↑ platelet aggregation
802
379
100
Hocholzer et al.JACC 2006
Geisler et al.Eur Heart J 2006
Bliden et al.JACC 2007
Post PCI-myonecrosis↑ clopidogrel/aspirin-resistant patients120Lev et al.JACC 2006
Post-PCI ischemic events (30 days)
↑ platelet aggregation106Cuisset et al.J Thromb Haemost2006
Myonecrosis and inflammation marker release
↑ periprocedrual platelet aggregation 120Gurbel et al.Circulation 2005
Post-PCI ischemic events(6 months)
↑ periprocedrual platelet aggregation 192Gurbel et al.JACC 2005
Post-primary PCI ischemic events (6 months)
↑ platelet aggregation (4th quartile)60Matezky et al.Circulation 2004
Angiolillo DJ et al. Am J Cardiov Drugs. 2007.
PostPost-- Stent Ischemic Events and Stent Ischemic Events and PeriproceduralPeriprocedural InfarctionInfarction
Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness
Can We Improve the Outcome by Improving
Platelet Inhibition?
TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY
STENT THROMBOSIS
L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli.
Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCELaboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCEService de cardiologie, Hôpital d’aubagne, Aubagne; FRANCEService de cardiologie, Clinique clairval, Marseille; FRANCEService de cardiologie, Clinique Bouchard, Marseille; FRANCEService de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCELaboratoire de statistique, Faculté de la Timone, Marseille; FRANCEService de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE
Am J Cardiol 2009;103:5-10
DESIGN
Non-emergent PCI : ACS and Stable angina (n= 1122)
Loading dose (LD) -ASA 250mg -Clopidogrel 600mg
VASP ≥ 50%
Randomization(n=429)
CONTROL (n =215)
VASP-guided LD (n =214)
Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose -ASA 160 mg
-Clopidogrel 75 mg
1° endpoint: Definite stent thrombosis (ARC definition)
2° endpoints: MACE including CV death, MI and U-TVRTIMI major and minor bleeding at 30 days
Platelet reactivity monitoring
VASP after first LD 66 ± 11 67 ± 10
VASP after sensitization 37 ± 12†
17 patients (8%)
† p <0.01
Timing of early stent thrombosis
All early stent thrombosis occured during the first 7 days
Am J Cardiol 2009;103:5-10
How Can We Solve the Problem Caused by
Clopidogrel Resistance?
Is the answer by increasing the dose?
P < 0.05 vs. 300 mg LD
A Faster Onset of Action Was Seen with Higher Clopidogrel Loading Regimens
A Faster Onset of Action Was Seen with Higher A Faster Onset of Action Was Seen with Higher ClopidogrelClopidogrel Loading RegimensLoading Regimens
The ALBION trial
0
10
20
30
40
50
1 2 3 4 5 6
300 mg LD600 mg LD900 mg LD
Maximum Inhibition of Platelet Aggregation (5 µM ADP)
Time (h)
(%) Inhibition
Shortened time to reach the highest level of inhibition of the 300 mg LD
Montalescot G et al. J Am Coll Cardiol 2006;48:931-8
Change the Agent?
Prasugrel
Sankyo Ann Report 51:1,1999
Pro-drug
Oxidation(Cytochrome P450)
HOOC* HS
N
O
F
Active Metabolite
N
S
O
FO
Sem Vasc Med 3:113, 2003
Hydrolysis(Esterases)
N
S
O
CH3
CO
FON
S
O
Cl
O CH3C
Clopidogrel
85% Inactive Metabolites
Esterases
N
S
O
Cl
O CH3C
ON
S
O
Cl
O CH3C
Active Metabolite
HOOC* HS
N
O
Cl
OCH3
Inhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers)
-20.0
0.0
20.0
40.0
60.0
80.0
100.0
Inhi
bitio
n of
Pla
tele
t Ag
gre
gat
ion
(%)
Response to Prasugrel
Response to Clopidogrel
Clopidogrel ResponderClopidogrel Non-responder
*Responder = 25% IPA at 4 and 24 h
Inte
rpat
ient
Var
iabi
lity
Interpatient V
ariability
Brandt, Payne, Wiviott et al AHJ 2007
Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI
Hours
IPA
% (
20
µM
AD
P) 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
Inhibition of Platelet Aggregation in Healthy Volunteers
• Data are expressed as mean ± SEM. Arrows (↓) indicate day of dose administration
Payne CD et al. J Cardiovasc Pharmacol 2007;50(5):555-562
IPA
% (
20
M
AD
P)
Loading Dose Maintenance Doses
Time
-10
0
10
20
30
40
50
60
70
80
90
100
2 3 4 5 6 7 8 90.25 0.5 1 2 4 6
‡
*
* * * * * * * * * * *†
†
‡ ‡‡
*
Pre-doseIPA
Day 1, Hours Days
Clopidogrel 600 mg/75 mg
Clopidogrel 300 mg/75 mg
Prasugrel 60 mg/10 mg
IPA=Inhibition of platelet aggregation; ADP=Adenosine diphosphate
* p<0.001 Prasugrel vs Clopidogrel† p<0.05 Clopidogrel 600 mg vs 300 mg‡ p<0.001 Clopidogrel 600 mg vs 300 mg
TRial to Assess Improvement in Therapeutic Outcomes by
Optimizing Platelet InhibitioN with Prasugrel
TRITON-TIMI 38
Study funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company
ACS=Acute Coronary Syndrome; CV=Cardiovascular; IPA=Inhibition of Platelet Aggregation; MI=Myocardial Infarction; PCI=Percutaneous Coronary Intervention
1.Wiviott SD et al. New Engl J Med 2007;357:2001-20152. Wiviott SD et al. Am Heart J 2006;152:627-635
TRITON-TIMI 38: Study Objective and Hypothesis
¨ To test the hypothesis that an antiplatelet agent that results in higher and less variable IPA reduces ischemic events1
¨ To evaluate the safety of a regimen that produces higher IPA1
¨ To determine in ACS subjects with planned PCI whether:2
• Prasugrel is superior to clopidogrel in reducing occurrence of CV death, nonfatal MI, or nonfatal stroke
• Prasugrel has a similar safety profile to clopidogrel
TRITON-TIMI 38: Study Design and Primary Efficacy End Points
& Planned PCI
ASA
ASA
ASA=Acetylsalicylic Acid; CABG=Coronary Artery Bypass Graft surgery; LD=Loading Dose; MD=Maintenance Dose; MI=Myocardial Infarction; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; R=Randomization; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; UTVR=Urgent Target Vessel Revascularization
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
Key safety end point: non-CABG related TIMI Major Bleeding
Wiviott SD et al. New Engl J Med 2007;357:2001-2015Wiviott SD et al. Am Heart J 2006;152:627-635
TIMI Category
Intracranial hemorrhage
Clinically Overt (including imaging)
Hgb drop (g/dL)
Major X X ≥5
Minor X 3 to <5
Minimal X <3
TRITON-TIMI 38: TIMI Bleeding Definitions
Wiviott SD et al. Am Heart J 2006;152:627-635Hgb=Hemoglobin; PRBC=Packed Red Blood Cells; TIMI=Thrombolysis In Myocardial Infarction
Life Threatening: Any TIMI major bleeding event meeting any of the following criteria:
• Fatal
•Leads to hypotension requiring I.V. inotropic agents
• Requires surgical intervention for ongoing bleeding
• Necessitates transfusion of ≥ 4 units of blood (whole or PRBC) over 48 hour time period
• Any symptomatic intracranial bleed
ACS=Acute Coronary Syndrome; NSTEMI=Non–ST-Elevation Myocardial Infarction; CI=Percutaneous Coronary Intervention; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; NSAID=Non-steroidal Anti-Inflammatory Drug
Wiviott SD et al. Am Heart J 2006;152:627-635
TRITON-TIMI 38: Key Enrollment Criteria
Inclusion Criteria
¨ Moderate-high risk ACS patients with planned PCI:
• UA/NSTEMI (TIMI Risk Score ≥3) within 72 hours of symptom onset
• STEMI: Primary PCI (within 12 hours)
• STEMI: Primary PCI not planned (>12 hours to ≤14 days)
Exclusion Criteria
¨ Any thienopyridine within 5 days of randomization
¨ Daily treatment with NSAID or Cox-2 inhibitor
¨ Fibrin-specific fibrinolytic therapy <24 hours
¨ Increased bleeding risk
¨ History of hemorrhagic stroke; or ischemic stroke ≤3 months
TRITON-TIMI 38: Baseline Characteristics
Clopidogrel (n=6,795)
Prasugrel (n=6,813)
UA/NSTEMI (%)1 74 74
STEMI (%)1 26 26
Median age (years)1
≥75 years (%)6113
6113
Median weight (kg)2
<60 kg (%)835.3
844.6
Female (%)1 27* 25
NSTEMI=Non–ST-Elevation Myocardial Infarction; STEMI=ST-Elevation Myocardial Infarction; UA=Unstable Angina
1. Wiviott SD et al. New Engl J Med 2007;357:2001-20152. Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL
* P=0.02
TRITON-TIMI 38: Study Drug and Pharmacotherapies
Clopidogrel(n=6,795)
%
Prasugrel(n=6,813)
%
Timing of study drug loading dose
Pre-PCI (before 1st wire) 25 26
During PCI (1st wire to 1 hr after leaving lab) 74 73
Post-PCI (>1 h after leaving lab) 1 1
Pharmacotherapies (during index event)
Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker
75* 76
Beta-blocker 88 88
Statin 92 92
Calcium channel blocker 17 18
Aspirin 99 99
PCI=Percutaneous Coronary Intervention
*P=0.03 Wiviott SD et al. New Engl J Med 2007;357:2001-2015
ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat
10
15
Days
0
5
0 30 60 90 180 270 360 450
Prasugrel
Clopidogrel
Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%)
HR 0.81 (0.73-0.90)
P<0.001ARR=2.2NNT=46
12.1(n=781)
9.9 (n=643)
HR 0.77 (0.67-0.88)
P<0.001
HR 0.80 (0.71-0.90)
P<0.001
CV
Dea
th/M
I/S
tro
ke
(%)
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: Primary End Point All ACS Population
34
ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; RRR=Relative Risk Reduction
Days
CV
Dea
th/M
I/S
tro
ke (
%)
Loading Dose Maintenance Dose0 1 2 3 3 30 90 180 270 360 450
HR 0.82 (0.71-0.96)
P=0.01
RRR 18%ARR 0.9%
5.6
4.7
HR 0.80 (0.70-0.93)
P=0.003
RRR 20%ARR 1.3%
6.9
5.6Clopidogrel Clopidogrel
Prasugrel Prasugrel
0
2
4
6
8
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: Timing of Benefit (Primary Endpoint, All ACS– 3-Day Landmark Analysis)
CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction
Prasugrel
Clopidogrel
TRITON-TIMI 38: Rates of Key Study End Points (All ACS)
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
5
10
15
00 30 60 90 180 270 360 450
Days After Randomization
En
d P
oin
t (%
)
120
1.8 (n=111)
2.4(n=146)
Non-CABG TIMI Major Bleeds
CV Death, MI, Stroke
P=0.03
P<0.001↓138 events
↑ 35 events
12.1(n=781)
9.9 (n=643)
Prasugrel
Clopidogrel
Days After RandomizationMI=Myocardial Infarction; CABG=Coronary Artery Bypass Graft surgery; Hazard Ration; ITT=Intent To Treat; TIMI=Thrombolysis In Myocardial Infarction
0
5
10
15
0 30 60 90 180 270 360 450
En
d P
oin
t (%
)
HR 0.87 (0.79-0.95)
P=0.004
13.9
12.2
ITT=13,608
Prasugrel
Clopidogrel
TRITON-TIMI 38: Net Clinical Benefit(All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed)
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent
ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363
0 30 60 90 180 270 360 450
HR 0.48 (0.36-0.64)
P<0.001
RRR 52%ARR 1.22%
Prasugrel
Clopidogrel2.4
1.1
Days
Ste
nt
Th
rom
bo
sis
(%)
Any Stent at Index PCI n=12,844
0
1
2
3
NNT=77
TRITON-TIMI 38: Primary Endpoint (CVD/MI/Stroke) Not Related to Stent Thrombosis
Days
% o
f S
ub
ject
s
10.3%
8.7%
RRR 15%
HR 0.85p=0.005
Clopidogrel
Prasugrel
0
2
4
6
8
10
12
0 50 100 150 200 250 300 350 400 450
CVA=cerebrovascular accident; HR=hazard ratio; MI=myocardial infarction Wiviott SD et al. Lancet 2008;371:1353-1363
TRITON-TIMI 38: Net Clinical Benefit: MI and Non-CABG TIMI Major Bleeds
Myocardial Infarction
Non-CABG TIMI Major
Bleed
Events per 1,000 patients on prasugrelversus clopidogrel
CABG=Coronary Artery Bypass Graft surgery; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction
+6
-23
# o
f E
ven
ts
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146)
CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction
Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
d P
oin
t (%
)
CV Death, MI, Stroke
NNT=21
17.0
12.2
2.62.5
Non-CABG TIMI Major Bleeds
Prasugrel
Clopidogrel
Eff-SK-2-MENA-07/10
Cumulative Kaplan-Meier estimates of the rates of primary end points during the follow-up periodCV=Cardiovascular; HR=Hazard Ratio; NF=Nonfatal; MI=Myocardial Infarction; NNT=Number Needed to Treat ;STEMI=ST Segment Elevation Myocardial InfarctionMontalescot G et al. Lancet 2009 Feb 28;373(9665):723-31
STEMI Cohort: Primary End Point(CV Death, NF MI or NF Stroke)15
Days from Randomization
Pati
en
ts (
%)
5
10
00 50 100 150 200 250 300 350 400 450
9.5
6.5
12.4(n = 216)
10.0(n = 174)
Clopidogrel
Prasugrel
HR 0.68 (0.54–0.87) P = 0.0017
HR 0.79 (0.65–0.97) P = 0.0221
NNT = 41
30
TRITON TIMI 38
Eff-SK-2-MENA-07/10
Cumulative Kaplan-Meier estimates of the safety end point non-CABG TIMI major bleedingCABG=Coronary Artery Bypass Graft; HR=Hazard Ratio; NNH=Number Needed to Harm;STEMI=ST Segment Elevation Myocardial Infarction; TIMI=Thrombolysis in Myocardial InfarctionMontalescot G et al. Lancet 2009 Feb 28;373(9665):723-31
STEMI Cohort:Non-CABG TIMI Major Bleeding
2.4(n = 38)
Pati
en
ts (
%)
Days from Randomization
0.5
1.0
2.0
2.5
1.5
2.1(n = 34)
HR 1.11 (0.70–1.77)P = 0.6451
0 100 200 300 4000
Clopidogrel
Prasugrel
15050 250 350 450
TRITON TIMI 38
TRITON-TIMI 38: Net Clinical BenefitPost-hoc Analyses in Selected Subgroups
Prasugrel Better Clopidogrel Better
P* value
P**interaction
0.04 -
<0.001 0.006
0.43 -
<0.001 0.006
MI=Myocardial infarction; HR=Hazard Ratio; TIA=Transient Ischemic Attack; TIMI=Thrombolysis In Myocardial Infarction
HR0.8 1.3 1.8 2.30.5 1.0 1.5 2.0 2.5
History of stroke or TIA
Yes
No
Any of the following:
Age >75 y, Body wt. <60 kg, History stroke/TIA
Yes
No
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
*Tests hazard ratio =1.0 within subgroups; **Tests equality hazard ratio between subgroups
All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed
CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction
TRITON-TIMI 38: Clinical Implications
¨ For every 1,000 patients treated with prasugrel compared with clopidogrel• 23 MI’s are prevented
• 6 more non-CABG TIMI major bleeds are experienced
¨ Over 15 months • Number needed to treat is 46 to prevent one CV
death, nonfatal MI or nonfatal stroke
• Number needed to harm is 167 to cause one non-CABG TIMI major bleed
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
Conclusions
¨ The TRITON-TIMI 38 Trial demonstrated that prasugrel is more effective at preventing ischemic events than clopidogrel in moderate to high-risk patients with ACS with scheduled PCI
¨ Prasugrel was also more effective at preventing stent thrombosis
¨ The beneficial effect of intensive inhibition of platelet aggregation is accompanied by increased risk of major bleeding
¨ Analysis of net clinical benefit favored prasugrel over clopidogrel
¨ In patients with STEMI and those with Diabetes the superiority of prasugrel compared to clopidogrel was more important with SAME bleeding risk
ACS= Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention Wiviott SD et al. New Engl J Med 2007;357:2001-2015
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
47
ACC/AHA 2009 STEMI/PCI Guidelines Focused Update
Based on the ACC/AHA Guidelines for the Management of Patients With ST-Elevation
Myocardial Infarction (STEMI) and the ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (PCI): A Report of the ACC/AHA Task Force on Practice Guidelines
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
48
Recommendations for the use of Thienopyridines STEMI
A loading dose of thienopyridine is recommended for STEMI patients for
whom PCI is planned. Regimens should be one of the following:
MODIFIED Recommendation
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Clopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Prasugrel 60 mg should be given
as soon as possible for primary
PCI.
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
49
Recommendations for the timing of Angiography and
Antiplatelet Therapy in UA/NSTEMI
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive
The choice of a second antiplatelet therapy to be added to ASA on presentation includes 1 of the following:
Before PCI:
● Clopidogrel; or
● An IV GP IIb/IIIa inhibitor. (Level of Evidence: A) IV eptifibatide or tirofiban
are the preferred GP IIb/IIIa inhibitors.
At the time of PCI:
● Clopidogrel if not started before PCI; or
● Prasugrel; or
● An IV GP IIb/IIIa inhibitor (Level of Evidence: A)
50JACC Vol. 57, No. 18, March 2011
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
…dual-antiplatelet therapy on presentation, ASA should be initiated on presentation
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII