TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 TRITON-TIMI 38 Elliott M. Antman, MD Elliott 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.
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TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38 TRITON-TIMI 38 Elliott M. Antman, MD.
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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.
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
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
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
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