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
Clopidogrel PreRx
Without GPI
Favors Favors
PreRx No PreRx
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)
OR 0.72
0.25
(0.53-0.98)
P=0.03
0.5
1.0
OR (95% CI)
With GPI
P=0.85 for
heterogeneity
by GPI use
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)
OR 0.69
0.25
Sabatine MS et al. ESC 2006
2.0
(0.47-1.00)
P=0.05
0.5
1.0
OR (95% CI)
2.0
TRITON TIMI-38 STEMI cohort
High clopidogrel doses
The RELOAD study
The ALBION study
Inhibition of RPA 4 hours after the
first reloading dose
Maximum Inhibition of Platelet Aggregation
(ADP 20 µmol/ L)
600 mg
300 mg
300 mg LD
600 mg LD
900 mg LD
35
% IPA
30
to
ib
h
)In
(%
25
20
15
10
P<.05 vs 300 mg LD
p=0.0008
120
IRPA (20 µMol ADP, %)
40
900 mg
p=0.017
100
p=0.34
80
60
40
20
5
0
0
1 2 3 4 5 6
24
Time (hours)
The ALBION study - JACC 2006
First reloading dose
The RELOAD study - Circulation 2008
TRITON TIMI-38 STEMI cohort
TRITON-TIMI 38
6
CV Death, MI, Stroke (%)
15
Clopidogrel
12.1 5
9.9
4
Prasugrel P<0.001
3
10
5
HR 0.81
(0.73-0.90)
NNT= 46
0
0 30 60 90
180
270
360
Days
Wiviott et al. New Engl J Med 2007;357:2001-2015
450
P=0.002
clopidogrel
prasugrel
P=0.03
P=0.01
2
1
0
TIMI major
bleed
Life
TIMI major
threatening or minor
TRITON allowed recruitment of STEMI patients undergoing
primary PCI when they presented < 12 hours of symptom
onset or secondary PCI when they presented late
TRITON TIMI-38 STEMI cohort
TRITON-TIMI 38 STEMI
All ACS/PCI
patients
N=13608
UA/NSTEMI
patients
N=10074
STEMI patients
N=3534
Primary PCI
Secondary PCI
N=2438 (69%)
N=1094 (31%)*
Clopidogrel
Prasugrel
Clopidogrel
Prasugrel
N=1235
N=1203
N=530
N=564
* 2 patients were missing data for primary or secondary
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Baseline demographics and disposition
• 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%
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Baseline characteristics of patients with
primary or secondary PCI
Primary PCI
(%)
Secondary PCI
(%)
p
59
58
0.01
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
Variable
Age (years)
History of diabetes
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Primary EP (CV death, MI and stroke at 15 months)
Clopidogrel
Prasugrel
15
Proportion of patients (%)
12.4
p=0.02
10.0 RRR=21%
10
9.5
p=0.002
RRR=32%
6.5
5
HR=0.79 (0.65–0.97) NNT=42
Age-adjusted HR=0.81 (0.66-0.99)
0
0
50
100
150
200
250
300
350
400
450
Time (Days)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Key secondary EP (CV death, MI, and UTVR at 30 days)
Clopidogrel
Prasugrel
10
Proportion of patients (%)
8.8
6.7
p=0.02
RRR=25%
5
HR=0.75 (0.59–0.96) NNT=48
Age-adjusted HR=0.77 (0.60-0.97)
0
0
5
10
15
25
25
30
Time (Days)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Efficacy endpoints at 30 days
Clopidogrel
Proportion of population (%)
Prasugrel
p= 0.002
10
p= 0.004
8
p= 0.02
p= 0.01
6
4
p= 0.04
p= 0.13
p= 0.008
2
0
All Death
MI
UTVR
Stent
CV Death/ CV Death/ CV Death/
Thrombosis*
MI
MI/UTVR MI/Stroke
* ARC def/probable
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Efficacy endpoints at 15 months
Clopidogrel
Proportion of population (%)
Prasugrel
14
p= 0.007
12
10
p= 0.03
p= 0.02
p= 0.02
8
6
p= 0.11
p= 0.09
4
p= 0.02
2
0
All Death
MI
UTVR
Stent
CV Death/ CV Death/ CV Death/
Thrombosis*
MI
MI/UTVR MI/Stroke
* ARC def/probable
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Stent thrombosis
ARC Definite/probable
Clopidogrel
Prasugrel
3
Proportion of patients (%)
2.8
p=0.02
RRR=42%
2.4
2
p=0.008
1.6
RRR=51%
1.2
1
HR=0.58 (0.36–0.93) NNT=83
Age-adjusted HR=0.59 (0.37-0.96)
0
0
100
200
300
400
Time (Days)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
TIMI major non-CABG bleeding
Clopidogrel
Prasugrel
2.5
Proportion of patients (%)
2.4
2.0
p=0.65
2.1
1.5
1.0
0.5
HR=1.11 (0.70–1.77) NNH=333
Age-adjusted HR=1.19 (0.75-1.89)
0
0
100
200
300
400
Time (Days)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
TIMI life-threatening non-CABG bleeding
Clopidogrel
Prasugrel
Life threatening bleeding (%)
1.6
1.4
p=0.75
1.2
1.0
0.8
0.6
0.4
HR=1.11 (0.59–2.10) NNH=500
Age-adjusted HR=1.20 (0.63-2.26)
0.2
0.0
0
30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480
Time (Days)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Bleeding events over 15 months
p=NS
7
p=NS
Proportion of population (%)
Clopidogrel
6
5.9
Prasugrel
5.1
4.7
5
4
4.8
p=NS
p=NS
2.7 2.8
3
2.1
2.4
p=NS
2
1.1
1.3
p=NS
1
0.3 0.2
0
Major
non-CABG
Life
threatening
Intra-cranial
haemorrhage
Minor
non-CABG
Major or minor Major or minor
non-CABG CABG/non-CABG
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Net clinical benefit at 15 months
p=0.02
NNT=42
Proportion of population (%)
18
16
14
p=0.04
NNT=45
Clopidogrel
Prasugrel
14.7
14.6
12.2
12.5
12
10
8
6
4
2
0
Death / non-fatal MI /
non-fatal stroke or
major non-CABG bleeding
Death / MI /stroke/
major bleeding
(CABG and non-CABG)
Montalescot et al. ESC 2008
TRITON TIMI-38 STEMI cohort
Conclusions
In STEMI patients undergoing PCI
• 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
Montalescot et al ESC 2008