the triton-timi 38 trial is supported by daiichi sankyo co. ltd. and eli lilly and co

TRITON TIMI-38 STEMI cohort

Clopidogrel Under Fire: Is Prasugrel in Primary PCI or Recent MI Superior?

Insights From TRITON-TIMI-38

Gilles Montalescot, Stephen D. Wiviott, Eugene Braunwald, Sabina A. Murphy, C. Michael Gibson,

Carolyn H. McCabe and Elliott M. Antman, for the TRITON–TIMI 38 Investigators

The TRITON-TIMI 38 Trial is supported by Daiichi Sankyo Co. Ltd. and Eli Lilly and Co. G. Montalescot, disclosure: Institutional research grant, consulting and speaker fees from

Daiichi Sankyo, Eli Lilly, Sanofi Aventis, BMS.


Clopidogrel limitations

• Slow onset

• Low level of inhibition

• Too much variability


Trial Clopi PreRx No PreRx

PCI-CURE 27/1039 (2.6) 39/988 (3.9)

CREDO 26/473 (5.5) 34/519 (6.6)

PCI-CLARITY 22/639 (3.4) 30/615 (4.9)

OVERALL 75/2151 (3.5) 103/2122 (4.9)

Trial Clopi PreRx No PreRx

PCI-CURE 14/274 (5.1) 23/357 (6.4)

CREDO 29/427 (6.8) 32/396 (8.1)

PCI-CLARITY 12/288 (4.2) 28/310 (9.0)

OVERALL 55/989 (5.6) 83/1063 (7.8)

Clopidogrel PreRxClopidogrel PreRx

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)

P=0.03P=0.03

OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)

P=0.03P=0.03

FavorsPreRx

FavorsNo PreRx

OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)

P=0.05P=0.05

OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)

P=0.05P=0.05

Without GPIWithout GPIWithout GPIWithout GPI

P=0.85 for P=0.85 for heterogeneityheterogeneity

by GPI useby GPI use

With GPIWith GPIWith GPIWith GPI

Sabatine MS et al. ESC 2006


High clopidogrel dosesHigh clopidogrel doses

0

20

40

60

80

100

120

IRP

A (

20 µ

Mo

l AD

P,

%)

900 mg600 mg300 mg

p=0.34

p=0.0008

p=0.017

First reloading dose

The RELOAD The RELOAD studystudy

Inhibition of RPA 4 Inhibition of RPA 4 hourshours afterafter the the first first reloadingreloading dosedose

The RELOAD study - Circulation 2008

The ALBION study

The ALBION study - JACC 2006

Maximum Inhibition of Platelet Aggregation Maximum Inhibition of Platelet Aggregation

(ADP 20 (ADP 20 µµmol/ Lmol/ L))

P<.05 vs 300 mg LD

0

5

10

15

20

25

30

35

40

(%) Inhibition

1 2 3 4 5 6

300 mg LD 600 mg LD 900 mg LD

Time (hours)24

% I

PA

0

20

40

60

80

100

120

IRP

A (

20 µ

Mo

l AD

P,

%)

900 mg600 mg300 mg

p=0.34

p=0.0008

p=0.017

First reloading dose

The RELOAD The RELOAD studystudy

Inhibition of RPA 4 Inhibition of RPA 4 hourshours afterafter the the first first reloadingreloading dosedose

The RELOAD study - Circulation 2008

The ALBION study

The ALBION study - JACC 2006



P<.05 vs 300 mg LD

0

5

10

15

20

25

30

35

40

(%) Inhibition

1 2 3 4 5 6


Time (hours)24

% I

PA



P<.05 vs 300 mg LD

0

5

10

15

20

25

30

35

40

(%) Inhibition

1 2 3 4 5 6


Time (hours)24

% I

PA


TRITON-TIMI 38TRITON-TIMI 38

TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom

onset or secondary PCI when they presented late

0

1

2

3

4

5

6

TIMI majorbleed

Lifethreatening

TIMI majoror minor

clopidogrel

prasugrel

P=0.03P=0.03

P=0.01P=0.01

P=0.002P=0.002

Wiviott et al.Wiviott et al. New Engl J Med New Engl J Med 2007;357:2001-20152007;357:2001-2015

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)

Days

CV

Dea

th, M

I, S

tro

ke (

%)

12.1

9.9

NNT= 46

Prasugrel

Clopidogrel

P<0.001


All ACS/PCI patientsN=13608

UA/NSTEMI patients

N=10074

STEMI patients

N=3534

Primary PCIN=2438 (69%)

Secondary PCIN=1094 (31%)*

ClopidogrelClopidogrel

N=1235N=1235

PrasugrelPrasugrel

N=1203N=1203

ClopidogrelClopidogrel

N=530N=530

PrasugrelPrasugrel

N=564N=564

Montalescot et al. ESC 2008

TRITON-TIMI 38 STEMI

* 2 patients were missing data for primary or secondary


• Baseline characteristics were well matched between the treatment groups, with the exception of:

– Age (59 [IQR 52, 69] for clopidogrel and 58 [IQR 51, 67] for prasugrel, p=0.04)

– Tobacco (43.7% clopidogrel and 47.2% prasugrel, p=0.04) and

– Killip class >1 (6.4% clopidogrel and 8.8% prasugrel, p= 0.007)

• The median treatment duration was 15.2 months

• PCI was performed on 97% of patients: 92% received 1 intracoronary stent, 59% received bare metal stent only and 33% received drug eluting stent

• The follow-up rate was > 99%

Baseline demographics and disposition



Baseline characteristics of patients with primary or secondary PCI


Variable Primary PCI(%)

Secondary PCI(%)

p

Age (years) 59 58 0.01

History of diabetes 16.8 24.1 0.001

Prior CABG 1.9 3.2 0.02

Multivessel PCI 6.5 11.0 0.001

GPIIb/IIIa inhibitor 64.5 59.8 0.01

Creatinine clear. < 60mL/min 11.4 8.8 0.02


Primary EP (CV death, MI and stroke at 15 months)


Time (Days)

5

10

15

00 50 100 150 200 250 300 350 400 450

Pro

po

rtio

n o

f p

atie

nts

(%

)

9.5

6.5

12.4

10.0

HR=0.79 (0.65–0.97) NNT=42

p=0.02RRR=21%

p=0.002RRR=32%

Clopidogrel

Prasugrel

Age-adjusted HR=0.81 (0.66-0.99)



Key secondary EP (CV death, MI, and UTVR at 30 days)

HR=0.75 (0.59–0.96) NNT=48

5 10 250 15 25 30

10

5

0

Time (Days)

Pro

po

rtio

n o

f p

atie

nts

(%

) p=0.02RRR=25%

8.8

6.7

Clopidogrel

Prasugrel



Efficacy endpoints at 30 days


* ARC def/probable

0

2

4

6

8

10

All Death MI UTVR StentThrombosis*

CV Death/MI

CV Death/MI/UTVR

CV Death/MI/Stroke

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

p= 0.04

p= 0.01

p= 0.13p= 0.008

p= 0.004 p= 0.02p= 0.002

Clopidogrel

Prasugrel



Efficacy endpoints at 15 months

Clopidogrel

Prasugrel

0

2

4

6

8

10

12

14

p= 0.11

p= 0.02

p= 0.09p= 0.02

p= 0.007 p= 0.03 p= 0.02

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

All Death MI UTVR StentThrombosis*

CV Death/MI

CV Death/MI/UTVR

CV Death/MI/Stroke

* ARC def/probable



Stent thrombosisARC Definite/probable

HR=0.58 (0.36–0.93) NNT=83

p=0.02 RRR=42%

0 100 200 300 4000

1

2

3

Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (Days)

2.4

1.2

2.8

1.6p=0.008RRR=51%

Clopidogrel

Prasugrel



TIMI major non-CABG bleeding


0.5

1.0

2.0

2.5

1.5

2.1

2.4

HR=1.11 (0.70–1.77) NNH=333Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (Days)

p=0.65

0 100 200 300 4000

ClopidogrelPrasugrel



TIMI life-threatening non-CABG bleeding


0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480

HR=1.11 (0.59–2.10) NNH=500Lif

e th

reat

enin

g b

leed

ing

(%

)

Time (Days)

p=0.75

Clopidogrel

Prasugrel



Bleeding events over 15 months


Majornon-CABG

Lifethreatening

Intra-cranialhaemorrhage

Minornon-CABG

Major or minornon-CABG

Major or minorCABG/non-CABG

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

2.1

1.1

0.3

2.7

4.7 4.8

2.4

1.3

0.2

2.8

5.1

5.9

0

1

2

3

4

5

6

7

Clopidogrel

Prasugrel

p=NS

p=NS

p=NS

p=NS

p=NS

p=NS


Net clinical benefit at 15 months


14.6 14.7

12.2 12.5

0

2

4

6

8

10

12

14

16

18p=0.02

NNT=42

Death / non-fatal MI /non-fatal stroke or

major non-CABG bleeding

Death / MI /stroke/major bleeding

(CABG and non-CABG)

p=0.04NNT=45

Clopidogrel

Prasugrel

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)


Conclusions In STEMI patients undergoing PCI

Montalescot et al ESC 2008

• Prasugrel was superior to standard dose clopidogrel to prevent ischaemic events

• Prasugrel did not have more bleeding events compared to those who were treated with clopidogrel, and this was equally true for:– Primary PCI– Secondary PCI– Major bleeding– Minor bleeding

• These data make prasugrel an especially attractive alternative to clopidogrel in PCI for STEMI

the triton-timi 38 trial is supported by daiichi sankyo co. ltd. and eli lilly and co

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