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TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel. TRITON-TIMI 38 AHA 2007 Orlando, Florida.

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slide1

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel

TRITON-TIMI 38AHA 2007Orlando, Florida

Disclosure Statement: 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.

antiplatelet therapy for pci
Antiplatelet Therapy for PCI
  • Dual antiplatelet Rx (ASA + thienopyridine) is standard of care: Ticlopidine Clopidogrel
  • Clinical need to improve on benefits observed with clopidogrel
  • Prasugrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High IPA in clopidogrel“hyporesponders” Encouraging Phase 2 data
healthy volunteer crossover study
Healthy VolunteerCrossover Study

100

N=66

80

InterpatientVariability

60

IPA at 24 hours (%)

40

InterpatientVariability

20

Clopidogrel Responder

0

Clopidogrel Non-responder

-20

Response to Prasugrel 60 mg

Response to Clopidogrel 300 mg

From Brandt JT AHJ 153: 66e9,2007

study goals
Study Goals

To test the hypothesis that higher and less variable IPA prevents clinical ischemic events.

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 organization
Trial Organization

Trial Leadership: TIMI Study Group

Eugene Braunwald,Chairman, Elliott M. Antman,PI,

Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe,

Sabina A. Murphy, Susan McHale

Sponsors: Daiichi Sankyo and Eli Lilly

J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra

Data Center and Site Management: Quintiles Inc

Data Safety Monitoring Board

David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets

study design
Study Design

ACS (STEMI or UA/NSTEMI) & Planned PCI

N= 13,600

ASA

Double-blind

CLOPIDOGREL

300 mg LD/ 75 mg MD

PRASUGREL

60 mg LD/ 10 mg MD

Median duration of therapy - 12 months

1o endpoint: CV death, MI, Stroke

2o 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

enrollment criteria
Enrollment 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 nov 2004 jan 2007 n 13 608 itt
Enrollment: Nov 2004 - Jan 2007N = 13,608 (ITT)

30 Countries 707 Sites LTFU = 14 (0.1%)

slide11

Primary EndpointCV Death,MI,Stroke

15

Clopidogrel

12.1(781)

9.9 (643)

10

Primary Endpoint (%)

Prasugrel

HR 0.81(0.73-0.90)P=0.0004

HR 0.80P=0.0003

HR 0.77P=0.0001

5

NNT= 46

LTFU = 14 (0.1%)

ITT= 13,608

0

0

30

60

90

180

270

360

450

Days

slide12

Timing of Benefit(Landmark Analysis)

8

6.9

Clopidogrel

Clopidogrel

5.6

5.6

6

Primary Endpoint (%)

4.7

4

Prasugrel

Prasugrel

HR 0.82P=0.01

HR 0.80P=0.003

2

1

0

0

1

2

3

0

30

60

90

180

270

360

450

Days

Loading Dose

Maintenance Dose

stent thrombosis arc definite probable
Stent Thrombosis(ARC Definite + Probable)

3

Any Stent at Index PCI N= 12,844

2.4(142)

Clopidogrel

2

Endpoint (%)

1.1 (68)

1

Prasugrel

HR 0.48P <0.0001

NNT= 77

0

0

30

60

90

180

270

360

450

Days

slide14

Balance of Efficacy and Safety

15

138 events

Clopidogrel

HR 0.81(0.73-0.90)P=0.0004

12.1

CV Death / MI / Stroke

9.9

10

NNT = 46

Prasugrel

Endpoint (%)

5

35 events

TIMI Major NonCABG Bleeds

Prasugrel

2.4

HR 1.32(1.03-1.68)P=0.03

1.8

Clopidogrel

0

NNH = 167

0

30

60

90

180

270

360

450

Days

bleeding events safety cohort n 13 457
Bleeding EventsSafety Cohort(N=13,457)

ICH in Pts w Prior Stroke/TIA (N=518)

Clopidogrel

Prasugrel

Clop 0 (0) %Pras 6 (2.3)% (P=0.02)

% Events

ARD 0.6%HR 1.32P=0.03NNH=167

ARD 0.5%HR 1.52P=0.01

ARD 0.2%P=0.23

ARD 0.3%P=0.002

ARD 0%P=0.74

net clinical benefit death mi stroke major bleed non cabg
Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG)

Events per 1000 pts

+

Major Bleed(non CABG)

MI

15

Clopidogrel

13.9

ITT= 13,608

12.2

HR 0.87P=0.004

Prasugrel

10

Endpoint (%)

All CauseMortality

5

Clop 3.2%Pras 3.0 %P=0.64

0

0

30

60

90

180

270

360

450

Days

slide17

CV Death, MI, StrokeMajor Subgroups

Reduction in risk (%)

18

UA/NSTEMI

B

21

STEMI

21

Male

12

Female

25

<65

14

Age

65-74

6

>75

14

No DM

30

DM

20

BMS

18

DES

21

GPI

16

No GPI

14

CrCl < 60

20

CrCl > 60

Pinter = NS

19

OVERALL

0.5

1

2

Prasugrel Better

Clopidogrel Better

HR

diabetic subgroup
Diabetic Subgroup

N=3146

18

Clopidogrel

17.0

16

CV Death / MI / Stroke

14

12.2

12

HR 0.70P<0.001

Endpoint (%)

Prasugrel

10

NNT = 21

8

6

TIMI Major NonCABG Bleeds

Clopidogrel

4

2.6

2.5

2

Prasugrel

0

0

30

60

90

180

270

360

450

Days

net clinical benefit bleeding risk subgroups
Net Clinical BenefitBleeding Risk Subgroups

Post-hoc analysis

Risk (%)

+ 37

Yes

Prior Stroke / TIA

-16

No

Pint = 0.006

-1

>=75

Age

-16

Pint = 0.18

< 75

+3

< 60 kg

Wgt

Pint = 0.36

-14

>=60 kg

-13

OVERALL

0.5

1

2

Prasugrel Better

Clopidogrel Better

HR

bleeding risk subgroups therapeutic considerations
Bleeding Risk SubgroupsTherapeutic Considerations

Reduced MDGuided by PKAge > 75 or Wt < 60 kg

Avoid PrasugrelPrior CVA/TIA

16%

4%

Significant Net Clinical Benefit with Prasugrel80%

MD 10 mg

slide21

Comparison with Higher Dose Clopidogrel

IPA (%; 20 mM ADP)

IPA (%; 20 mM ADP)

P<0.0001

N=201

P<0.0001 for each

Prasugrel 60 mg

Clopidogrel 600 mg

Clopidogrel 150 mg

Prasugrel 10 mg

Hours

14 Days

Wiviott et al Circ 2007 (In Press)

conclusions higher ipa to support pci
ConclusionsHigher IPA to Support PCI

Efficacy

1. A significant reduction in: CV Death/MI/Stroke19% Stent Thrombosis 52% uTVR 34%       MI 24%

2. An early and sustained benefit

3. Across ACS spectrum

Safety

Significant increase in serious bleeding(32%increase)Avoid in pts with prior CVA/TIA

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

Net clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

antiplatelet therapy in acs
Antiplatelet Therapy in ACS

ASA

ASA + Clopidogrel

ASA + Prasugrel

Reduction inIschemicEvents

- 22%

- 20%

- 19%

Increase in Major Bleeds

+ 32%

+ 38%

+ 60%

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

publication of primary results
Publication of Primary Results

www.NEJM.org

NEJM 357: 2001-2015, 2007

Slides and Full Listing of Trial Participants at www.TIMI.org