trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel...
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TRial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet InhibitioN with Prasugrel
TRITON-TIMI 38TRITON-TIMI 38
Elliott M. Antman, MDElliott M. Antman, MD
TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo.TRITON-TIMI 38 was supported by Eli Lilly and Daiichi Sankyo.
Antiplatelet Therapy Antiplatelet Therapy for PCIfor PCI
• Dual antiplatelet Rx (ASA + thienopyridine) is standard of Dual antiplatelet Rx (ASA + thienopyridine) is standard of care:care:
Ticlopidine Ticlopidine ClopidogrelClopidogrel• Clinical need to improve on benefits observed with Clinical need to improve on benefits observed with
clopidogrelclopidogrel• PrasugrelPrasugrel
Novel thienopyridineNovel thienopyridineEfficient generation of active metaboliteEfficient generation of active metaboliteHigh levels of IPA achieved rapidlyHigh levels of IPA achieved rapidlyHigh IPA in High IPA in clopidogrelclopidogrel “hyporesponders”“hyporesponders”Encouraging Phase 2 dataEncouraging Phase 2 data
Study GoalsStudy Goals
1. To test the hypothesis that higher and less variable IPA prevents clinical ischemic events.
2. To evaluate the safety of a regimen that produces higher IPA.
These goals were achieved by evaluating the efficacy and safety of prasugrel compared to clopidogrel in mod/high risk patients with ACS undergoing PCI on a background of ASA.
Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Wiviott SD et al AHJ 152: 627,2006
Enrollment CriteriaEnrollment Criteria
•Inclusion Criteria Planned PCI for :
Mod-High Risk UA/NSTEMI (TRS > 3)STEMI: < 14 days (ischemia or Rx strategy)STEMI: Primary PCI
•Major Exclusion Criteria:– Severe comorbidity– Increased bleeding risk– Prior hemorrhagic stroke or any stroke < 3 mos– Any thienopyridine within 5 days– No exclusion for advanced age or renal function
KnownAnatomy
Wiviott SD et al AHJ 152: 627,2006
Clopidogrel (N=6795)
%
Prasugrel (N=6813)
%
UA/NSTEMI 74 74
STEMI 26 26
Age, median (IQR)
> 75 y
61 (53,69) y
13
61 (53, 70) y
13
Wgt, median (IQR) < 60 kg
83 kg (72, 92)5.3
84 kg (73, 93)4.6
Female 27 25*
Diabetes 23 23
Prior MI 18 18
CrCl (ml/min)>60<60
8812
8911
Baseline CharacteristicsBaseline Characteristics
*P<0.05
Wiviott SD et al NEJM 357: 2001, 2007
Clopidogrel (N=6795)
%
Prasugrel (N=6813)
%
PCI / CABG 99 / 1 99 / 1
Any Stent 95 94
BMS 47 48
DES 47 47
Multivessel PCI 14 14
UFH / LMWH / Bival 65 / 8 / 3 66 / 9 / 3
GP IIb/IIIa 55 54
LD of Study Rx Pre PCI
During PCI Post PCI
25741
26731
Index ProcedureIndex ProcedureWiviott SD et al NEJM 357: 2001, 2007
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 0.80P=0.0003
HR 0.77P=0.0001
Days
Pri
ma
ry E
nd
po
int
(%) 12.1
(781)
9.9 (643)
Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke
NNT= 46
ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)
Wiviott SD et al NEJM 357: 2001, 2007
781643
115
58
0
200
400
600
800
1000
1100 Endpoint Events Endpoint Events PreventedPrevented
Post-hoc AnalysisPost-hoc Analysis
# # E
ven
tsE
ven
ts
25/180 6/189
896896
701701
Clopidogrel Prasugrel
1st EventP=0.0004
AdditionalEvents
Total EventsP<0.0001
-138
-195
ITT N= 13,608 TIMI Study Group, Data on File
CV Death,MI,StrokeCV Death,MI,StrokeTiming of LDTiming of LD
< 1 hr post lab< 1 hr post lab (N=3552) (N=3552)
Post PCI in lab Post PCI in lab (N=3833)(N=3833)
During PCI During PCI (N=2380)(N=2380)
Pre PCIPre PCI (N=3370) (N=3370)
0.5 1 2Prasugrel Better Clopidogrel Better
HR
0.75 (0.60-0.93)0.75 (0.60-0.93)
0.76 (0.62-0.93)0.76 (0.62-0.93)
0.93 (0.73-1.19)0.93 (0.73-1.19)
0.87 (0.71-1.07)0.87 (0.71-1.07)
PPintint = 0.40 = 0.40TIMI Study Group, Data on File
0
2
4
6
8
0 1 2 3
1
0
306090 180 270 360 450
HR 0.82P=0.01
HR 0.80P=0.003
5.6
4.7
6.9
5.6
Days
Pri
ma
ry E
nd
po
int
(%)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of BenefitTiming of Benefit(Landmark Analysis - 3 days)(Landmark Analysis - 3 days)
Components of EndpointsComponents of EndpointsClopidogrel HRPrasugrel
12.1 0.819.9
2.4 0.892.1
9.5 0.767.3
1.0 1.021.0
uTVR
Nonfatal Stroke
Nonfatal MI
CV Death
CV Death, MI, Stroke
0.5 1 2
3.7 0.662.5
Prasugrel Better Clopidogrel Better
All Cause Mortality3.2 0.953.0
Stent Thrombosis
2.4 0.481.1
HR Wiviott SD et al NEJM 357: 2001, 2007
Myocardial Infarction 0 - 450 days
0
2
4
6
8
10
0 30 60 90 180 270 360 450
Days
MI (
%)
Prasugrel
Clopidogrel 9.7
7.4
HR 0.76P<0.0001
TIMI Study Group-- Data on fileTIMI Study Group-- Data on file
Significant reductions in :Landmark Analyses at 3, 30 daysPeri-Procedural MI’sSpontaneous MI’s during followupNew development of STEMICV Death after MI
Urgent Target Vessel Urgent Target Vessel RevascularizationRevascularization
0
2
4
6
0 30 60 90 180 270 360 450
HR 0.66P=0.0001
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
3.7(233)
NNT= 83
2.5 (156)
ITT= 13,608ITT= 13,608
Wiviott SD et al NEJM 357: 2001, 2007
Reductions in uTVR with Reductions in uTVR with Prasugrel in Landmark Analyses at 3, 30 daysPrasugrel in Landmark Analyses at 3, 30 days
Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48P <0.0001
Prasugrel
Clopidogrel2.4
(142)
NNT= 77
1.1 (68)
Days
En
dp
oin
t (%
)
Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844
Wiviott SD et al NEJM 357: 2001, 2007
Significant reductions both with BMS, DESSignificant reductions both with BMS, DESSignificant reductions in early and late stent thrombosesSignificant reductions in early and late stent thromboses
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.82.4
138 events
35 events
Balance of Balance of Efficacy and SafetyEfficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
Wiviott SD et al NEJM 357: 2001, 2007
1.8
0.9 0.9
0.10.3
2.4
1.41.1
0.4 0.3
0
2
4
TIMI MajorBleeds
LifeThreatening
Nonfatal Fatal ICH
Bleeding EventsBleeding EventsSafety CohortSafety Cohort
(N=13,457)(N=13,457)
% E
ven
ts%
Eve
nts
ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03
NNH=167 NNH=167
ClopidogrelClopidogrel
PrasugrelPrasugrel
ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01
ARD 0.2%ARD 0.2%P=0.23P=0.23
ARD 0%ARD 0%P=0.74P=0.74
ARD 0.3%ARD 0.3%P=0.002P=0.002
ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA
(N=518)(N=518)
Clop 0 (0) %Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)
Wiviott SD et al NEJM 357: 2001, 2007
Net Clinical BenefitNet Clinical BenefitDeath, MI, Stroke, Death, MI, Stroke,
Major Bleed (non CABG)Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450Days
En
dp
oin
t (%
)
HR 0.87P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608ITT= 13,608
-23
6
-25
-20
-15
-10
-5
0
5
10
Events per 1000 ptsEvents per 1000 pts
MIMI Major BleedMajor Bleed(non CABG)(non CABG)
++All CauseAll CauseMortalityMortality
Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %
P=0.64P=0.64
Wiviott SD et al NEJM 357: 2001, 2007
B
OVERALL
No GPIGPI
DESBMS
DMNo DM
>7565-74<65
FemaleMale
STEMIUA/NSTEMI
0.5 1 2Prasugrel Better Clopidogrel BetterHR
Age
Reduction in risk (%)18
2112
25146
1430
2018
2116
19
21
Pinter = NS
CV Death, MI, StrokeCV Death, MI, StrokeMajor SubgroupsMajor Subgroups
CrCl > 60CrCl < 60 14
20
Wiviott SD et al NEJM 357: 2001, 2007
Diabetic SubgroupDiabetic Subgroup
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
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 21
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
Wiviott SD et al NEJM 357: 2001, 2007
Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 54
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisPost-hoc analysis
Wiviott SD et al NEJM 357: 2001, 2007
Bleeding Risk SubgroupsBleeding Risk SubgroupsTherapeutic ConsiderationsTherapeutic Considerations
Significant Net Clinical Benefit
with Prasugrel80%
MD MD 10 mg10 mg
Reduced MD
Guided by PK
Age > 75 or
Wt < 60 kg
16%
Avo
id
Prasu
grel
Prio
r
CV
A/T
IA4%4%
Wiviott SD et al NEJM 357: 2001, 2007
Dose Reduction for Patients <60kg or ≥75 yrs
Decreased Exposure
Time
Co
nce
ntr
atio
n
Ris
k o
f B
lee
din
g
DecreasedRisk
Eff
ica
cy RetainEfficacy
AUC (ng*hr/mL)
0 50 100 150 200 250 300
0
20
40
60
80
100
MP
A
AUC
Maintain PD> Clopidogrel
Clopidogrel
Prasugrel
Safety
Significant increase in
serious bleeding(32% increase)
Avoid in pts with prior CVA/TIA
Efficacy
1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%
MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
ConclusionsConclusionsHigher IPA to Support PCIHigher IPA to Support PCI
Net clinical benefit significantly favored PrasugrelNet clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balancemay help improve the benefit : risk balance
Wiviott SD et al NEJM 357: 2001, 2007
Antiplatelet Therapy in ACSAntiplatelet Therapy in ACS
Placebo APTC CURE TRITON-TIMI 38Single
Antiplatelet RxDual
Antiplatelet RxHigher
IPA
ASAASA +
Clopidogrel ASA + Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction in
IschemicEvents
Increase in
Major Bleeds
Wiviott SD et al NEJM 357: 2001, 2007
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