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