1) The TRITON-TIMI 38 trial compared the antiplatelet drug prasugrel to clopidogrel in 13,608 patients with acute coronary syndrome undergoing percutaneous coronary intervention. 2) Prasugrel was found to significantly reduce the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel, from 12.1% to 9.9%. However, prasugrel was also associated with an increased risk of bleeding. 3) In the overall study population, the superior efficacy of prasugrel in reducing ischemic events outweighed the increased risk of bleeding, representing a net clinical benefit. However, prasugrel appeared to have less benefit or

1. TRITON - TIMI 38
AHA 2007
Orlando, Florida
TRIAL TO ASSESS IMPROVEMENT IN THERAPEUTIC
OUTCOMES BY OPTIMIZING PLATELET INHIBITION
WITH PRASUGREL – THROMBOLYSIS IN MYOCARDIAL
INFARCTION 38
DR. SBAM. MUJAHITH
MEDICAL REGISTRAR
NHSL

2. Why this study was needed in the first place ?

3. Clopidogrel limitations
Hyporesponders
Slow onset
Too much variability

4. Prasugrel
Novel thienopyridine
Efficient generation of active metabolite
High levels of mean IPA achieved rapidly - 30mins vs 6hrs
High mean IPAs in clopidogrel “hyporesponders”
Encouraging Phase 2 data

5. TRITON – TIMI 38
TRIAL

6. Inclusion Criteria
Planned PCI for :
Mod-High Risk UA/NSTEMI
STEMI: Primary PCI
STEMI: < 14 days

7. Major Exclusion Criteria
Severe comorbidity
Increased bleeding risk
Prior hemorrhagic stroke or any stroke < 3 months
Any thienopyridine within 5 days
No exclusion for advanced age or renal function

8. Enrollment: Nov 2004 - Jan 2007
Argentina (195) Finland (116) New Zealand (49)
Australia (217) France (146) Poland (1938)
Austria (182) Germany (999) Portugal (67)
Belgium (287) Hungary (695) Slovakia (140)
Brazil (225) Iceland (10) South Africa (404)
Canada (251) Israel (1219) Spain (178)
Chile (114) Italy (782) Sweden (154)
Czech Rep (340) Latvia (21) Switzerland (136)
Denmark (33) Lithuania (54) United Kingdom (73)
Estonia (134) Netherlands (390) United States (4059)
30 Countries 707 Sites

9. Median duration of therapy – 14.5 months
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL
60 mg LD/ 10 mg MD
CLOPIDOGREL
300 mg LD/ 75 mg MD
N= 13,608
Study Design

10. End Points
Primary efficacy end points: CV death/MI/stroke
Secondary efficacy end points: CV death, MI, Stroke,
Rehospitalization due to cardiac ischaemic event, UTVR
Key safety end point: TIMI major bleeding not related to CABG

11. Baseline Characteristics
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
88
12
89
11

12. Index Procedure
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
25
74
1
26
73
1

13. All ACS/PCI
patients
N=13608
UA/NSTEMI patients
N=10074
STEMI patients
N=3534
Primary PCI
N=2438 (69%)
Secondary PCI
N=1094 (31%)*
Clopidogrel
N=1235
Prasugrel
N=1203
Clopidogrel
N=530
Prasugrel
N=564
TRITON-TIMI 38 STEMI

14. Results of the study
1. Prasugrel compared with clopidogrel significantly reduced
the incidence of the primary endpoint, the composite of the rate
of cardiovascular death, myocardial infarction, or stroke from
12.1 to 9.9% (hazard ratio: 0.81; P < 0.001)

15. 2. Significant benefit of prasugrel was found during the first 3
days (hazard ratio: 0.82; P = 0.01) and from day 4 to the end of
the study (hazard ratio: 0.8; P = 0.003)

16. 3. Of the patients treated with prasugrel, 2.4% experienced
at least one TIMI major haemorrhage unrelated to coronary
artery bypass graft, compared with 1.8% treated with
clopidogrel (hazard ratio: 1.32; P = 0.03)

17. 4. Thus, in the entire study group, the balance of efficacy
and safety was in favour of prasugrel with an absolute
2.2% reduction in the primary efficacy endpoint by
prasugrel when compared with clopidogrel that was
opposed by an only 0.6% increase in major haemorrhage.

18. Primary Endpoints - CV Death, MI , Stroke
Time (Days)
5
10
15
0
0 50 100 150 200 250 300 350 400 450
Proportionofpatients(%)
9.5
6.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=42
p=0.02
RRR=21%
p=0.002
RRR=32%
Clopidogrel
Prasugrel
Age-adjusted HR=0.81 (0.66-0.99)

19. 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)
Proportionofpatients(%)
p=0.02
RRR=25%
8.8
6.7
Clopidogrel
Prasugrel
Age-adjusted HR=0.77 (0.60-0.97)

20. * ARC def/probable
0
2
4
6
8
10
All Death MI UTVR Stent
Thrombosis*
CV Death/
MI
CV Death/
MI/UTVR
CV Death/
MI/Stroke
Proportionofpopulation(%)
p= 0.04
p= 0.01
p= 0.13
p= 0.008
p= 0.004 p= 0.02
p= 0.002
Clopidogrel
Prasugrel
Efficacy endpoints at 30 days

21. Clopidogrel
Prasugrel
0
2
4
6
8
10
12
14
p= 0.11
p= 0.02
p= 0.09
p= 0.02
p= 0.007 p= 0.03 p= 0.02
Proportionofpopulation(%)
All Death MI UTVR Stent
Thrombosis*
CV Death/
MI
CV Death/
MI/UTVR
CV Death/
MI/Stroke
Efficacy endpoints at 15 months

22. Stent thrombosis
ARC Definite/probable
HR=0.58 (0.36–0.93) NNT=83
p=0.02
RRR=42%
0 100 200 300 400
0
1
2
3
Proportionofpatients(%)
Time (Days)
2.4
1.2
2.8
1.6
p=0.008
RRR=51%
Clopidogrel
Prasugrel
Age-adjusted HR=0.59 (0.37-0.96)

23. 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=333
Proportionofpatients(%)
Time (Days)
p=0.65
0 100 200 300 400
0
Clopidogrel
Prasugrel
Age-adjusted HR=1.19 (0.75-1.89)

24. Bleeding events over 15 months
Major
non-CABG
Life
threatening
Intra-cranial
haemorrhage
Minor
non-CABG
Major or minor
non-CABG
Major or minor
CABG/non-CABG
Proportionofpopulation(%)
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

25. Net clinical benefit at 15 months
14.6 14.7
12.2 12.5
0
2
4
6
8
10
12
14
16
18
p=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=0.04
NNT=45
Clopidogrel
Prasugrel
Proportionofpopulation(%)

26. In post hoc subgroup analyses, following major
subgroups showed less clinical benefit or clinical
harm:
1. Patients with a history of stroke or transient
ischemic attack before enrollment
2. The elderly (age ≥75 years)
3. Those with a body weight of less than 60 kg

27. Significant
Net Clinical Benefit
with Prasugrel
80%
16%
4%
Bleeding Risk Subgroups
Therapeutic Considerations
MD
10 mg

28. B
OVERALL
No GPI
GPI
DES
BMS
DM
No DM
>75
65-74
<65
Female
Male
STEMI
UA/NSTEMI
0.5 1 2
Prasugrel Better Clopidogrel BetterHR
Age
Reduction in risk (%)
18
21
12
25
14
6
14
30
20
18
21
16
19
21
CrCl > 60
CrCl < 60 14
20
CV Death, MI, Stroke
Major Subgroups
Pinter = NS

29. Conclusion
In conclusion, in patients with acute coronary syndromes undergoing
PCI, prasugrel significantly reduced the incidence of ischaemic
events, both in the acute and long term. Prasugrel was associated
with an increased risk of bleeding. In the entire cohort, the
superior efficacy of prasugrel outweighed the increased risk
of bleeding.

30. "Prasugrel appears to be particularly potent, with the danger of
serious bleeding in patients who undergo CABG or who have
cerebrovascular disease. It will also be interesting to see how well
this drug is tolerated in the real treatment world."
Dr Eric Topol

31. "The holy grail of antithrombotic drug development is
balancing improved efficacy against the risk of increased
bleeding. It appears that prasugrel has fallen short in this
regard."
Dr Sanjay Kaul

32. THANK YOU