TRITON-TIMI 38 AHA 2007 Orlando, Florida
description
Transcript of TRITON-TIMI 38 AHA 2007 Orlando, Florida
TRial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet InhibitioN with Prasugrel
TRITON-TIMI 38TRITON-TIMI 38AHA 2007AHA 2007
Orlando, FloridaOrlando, Florida
Disclosure StatementDisclosure Statement: : The TRITON-TIMI 38 trial was supported by a research grant to the The TRITON-TIMI 38 trial was supported by a research grant to the
Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
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
Healthy VolunteerHealthy VolunteerCrossover StudyCrossover Study
-20-20
00
2020
4040
6060
8080
100100
IPA
at
24 h
ou
rs (
%)
IPA
at
24 h
ou
rs (
%)
Response to Response to Prasugrel 60 mgPrasugrel 60 mg
Response to Response to Clopidogrel 300 mgClopidogrel 300 mg
Clopidogrel ResponderClopidogrel Responder
Clopidogrel Non-responderClopidogrel Non-responder
Inte
rpat
ien
tIn
terp
atie
nt
Var
iab
ility
Var
iab
ility
Interp
atient
Interp
atient
Variab
ilityV
ariability
From Brandt JT AHJ 153: 66e9,2007
N=66
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.
Trial Trial OrganizationOrganization
Trial Leadership: TIMI Study GroupTrial Leadership: TIMI Study GroupEugene Braunwald,Chairman, Elliott M. Antman,PI, Eugene Braunwald,Chairman, Elliott M. Antman,PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Sabina A. Murphy, Susan McHale Sabina A. Murphy, Susan McHale
Sponsors: Daiichi Sankyo and Eli Lilly Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Tomas Bocanegra
Data Center and Site Management: Quintiles IncData Center and Site Management: Quintiles Inc
Data Safety Monitoring BoardData Safety Monitoring Board David Williams (Chair) , Christophe Bode, Spencer King, David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets Ulrich Sigwart, David DeMets
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
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
Enrollment: Enrollment: Nov 2004 - Jan 2007Nov 2004 - Jan 2007N = 13,608 (ITT)N = 13,608 (ITT)
30 Countries30 Countries 707 Sites707 Sites LTFU = 14 (0.1%) LTFU = 14 (0.1%)
Argentina (195)Argentina (195) Finland (116)Finland (116) New Zealand (49)New Zealand (49)
Australia (217)Australia (217) France (146)France (146) Poland (1938)Poland (1938)
Austria (182)Austria (182) Germany (999)Germany (999) Portugal (67)Portugal (67)
Belgium (287)Belgium (287) Hungary (695)Hungary (695) Slovakia (140)Slovakia (140)
Brazil (225)Brazil (225) Iceland (10)Iceland (10) South Africa (404)South Africa (404)
Canada (251)Canada (251) Israel (1219)Israel (1219) Spain (178)Spain (178)
Chile (114)Chile (114) Italy 782)Italy 782) Sweden (154)Sweden (154)
Czech Rep (340)Czech Rep (340) Latvia (21)Latvia (21) Switzerland (136)Switzerland (136)
Denmark (33)Denmark (33) Lithuania (54) Lithuania (54) United Kingdom (73)United Kingdom (73)
Estonia 134)Estonia 134) Netherlands (390)Netherlands (390) United States (4059)United States (4059)
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
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 Procedure
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%)
0
2
4
6
8
0 1 2 3
1
0
3060 90 180 270 360 450
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)(Landmark Analysis)
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
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
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)
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
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
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
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
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%
PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel
P<0.0001 for each
IPA (%; 20 M ADP)
Hours 14 Days
IPA (%; 20 M ADP)
P<0.0001
Prasugrel 10 mg
Clopidogrel 150 mg
Wiviott et al Circ 2007 (In Press)
N=201
Prasugrel 60 mg
Clopidogrel 600 mg
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
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
Publication of Primary ResultsPublication of Primary Results
Slides and Full Listing of Trial Participants at Slides and Full Listing of Trial Participants at www.TIMI.orgwww.TIMI.org
NEJM 357: 2001-2015, 2007 www.NEJM.org