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The TRITON-TIMI 38 Trial is supported by Daiichi Sankyo Co. Ltd. and Eli Lilly and Co.
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Transcript of 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.
TRITON TIMI-38 STEMI cohort
Clopidogrel limitations
• Slow onset
• Low level of inhibition
• Too much variability
TRITON TIMI-38 STEMI cohort
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
TRITON TIMI-38 STEMI cohort
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
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
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
TRITON TIMI-38 STEMI cohort
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
TRITON TIMI-38 STEMI cohort
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
TRITON TIMI-38 STEMI cohort
• 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
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Baseline characteristics of patients with primary or secondary PCI
Montalescot et al. ESC 2008
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
TRITON TIMI-38 STEMI cohort
Primary EP (CV death, MI and stroke at 15 months)
Montalescot et al. ESC 2008
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)
TRITON TIMI-38 STEMI cohort
Montalescot et al. ESC 2008
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
Age-adjusted HR=0.77 (0.60-0.97)
TRITON TIMI-38 STEMI cohort
Efficacy endpoints at 30 days
Montalescot et al. ESC 2008
* 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
TRITON TIMI-38 STEMI cohort
Montalescot et al. ESC 2008
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
TRITON TIMI-38 STEMI cohort
Montalescot et al. ESC 2008
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
Age-adjusted HR=0.59 (0.37-0.96)
TRITON TIMI-38 STEMI cohort
TIMI major non-CABG bleeding
Montalescot et al. ESC 2008
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
Age-adjusted HR=1.19 (0.75-1.89)
TRITON TIMI-38 STEMI cohort
TIMI life-threatening non-CABG bleeding
Montalescot et al. ESC 2008
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
Age-adjusted HR=1.20 (0.63-2.26)
TRITON TIMI-38 STEMI cohort
Bleeding events over 15 months
Montalescot et al. ESC 2008
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
TRITON TIMI-38 STEMI cohort
Net clinical benefit at 15 months
Montalescot et al. ESC 2008
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 (
%)
TRITON TIMI-38 STEMI cohort
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