trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel...

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%)


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


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


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


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%


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


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


trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel...

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