TRITONTIMI 38 and PRINCIPLETIMI 44 Trials of Prasugrel

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TRITON-TIMI 38 and PRINCIPLE-TIMI 44 Trials of
Prasugrel

• Stephen D. Wiviott, MD
• Brigham and Womens Hospital
• Boston, MA, USA

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Farid N.A. et al. Drug Metab. Dispos. 35
1096-1104 (2007) Rehmel J.L.F. et al. Drug Metab.
Dispos. 34 600-607 (2006) Williams E.T. et al.
Drug Metab. Rev. 39(S1) 254 (2007)
Kurihara A. et al. Drug Metab. Rev. 37(S2) 99
(2005) Tang M. et al. JPET 319 1467-1476 (2006)
Thienopyridines Formation of Active Metabolite
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Principle TIMI 44 Study design
Planned elective PCI Baseline laboratory measures
Clopidogrel naïve No planned GP IIb/IIIa use
Loading phase n 201
Prasugrel 60 mg
Clopidogrel 600 mg
0.5 h Post-loading-dose labs
Coronary angiography Post-angiography labs
No PCI
PCI
Maintenance phase n 100
6 h labs, 15 day events
6 h labs, 1824 h labs
Prasugrel 10 mg 14 days
Clopidogrel 150 mg 14 days
Day 15 clinical events, labs, CROSSOVER
Clopidogrel 150 mg 14 days
Prasugrel 10 mg 14 days
Day 29 clinical events, labs
1º EPs Loading 6 h IPA (20 µM ADP)
Maintenance Day 15 or 29 IPA (20 µM ADP)
Reprinted with permission from Wiviott SD, Trenk
D, Frelinger AL, et al. Prasugrel compared with
high loading- and maintenance-dose clopidogrel
in patients with planned percutaneous coronary
intervention the Prasugrel in Comparison to
Clopidogrel for Inhibition of P latelet
Activation and Aggregation-Thrombolysis in
Myocardial Infarction 44 trial. Circulation. 2007
Dec 18116(25)2923-32.
4
Principle TIMI 44 PRIMARY EP acute phase IPA 20
mM ADP
P lt 0.0001 for each
Prasugrel 60 mg
IPA ( 20 mM ADP)
Hours
Reprinted with permission from Wiviott SD, Trenk
D, Frelinger AL, et al. Prasugrel compared with
high loading- and maintenance-dose clopidogrel
in patients with planned percutaneous coronary
intervention the Prasugrel in Comparison to
Clopidogrel for Inhibition of P latelet
Activation and Aggregation-Thrombolysis in
Myocardial Infarction 44 trial. Circulation. 2007
Dec 18116(25)2923-32.
5
Principle TIMI 44 IPA 20 uM ADP
Difference Between Treatments 14.9 95 CI 10.6
19.3, Plt0.0001
Prasugrel 10 mg
Prasugrel 10 mg
IPA ( 20 mM ADP)
Reprinted with permission from Wiviott SD, Trenk
D, Frelinger AL, et al. Prasugrel compared with
high loading- and maintenance-dose clopidogrel
in patients with planned percutaneous coronary
intervention the Prasugrel in Comparison to
Clopidogrel for Inhibition of P latelet
Activation and Aggregation-Thrombolysis in
Myocardial Infarction 44 trial. Circulation. 2007
Dec 18116(25)2923-32.
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Implications

• PRINCIPLE TIMI 44 extends the pharmacological
  superiority of the TRITON TIMI 38 dose of
  prasugrel (60 mg/10 mg) to higher doses of
  clopidogrel (600 mg/150 mg) in percutaneous
  coronary intervention
• TRITON TIMI 38 tested the hypothesis that an
  agent with higher and more consistent inhibition
  of platelet aggregation than standard approved
  clopidogrel (300 mg/75 mg) improves clinical
  outcomes

Wiviott SD, Braunwald E, McCabe CH, et al.
Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med. 2007 Nov
15357(20)2001-15.
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TRITON TIMI 38 Main Trial Design
ACS (STEMI or UA/NSTEMI) and planned PCI
n 13,608
ASA
Double-blind
Clopidogrel 300 mg LD/ 75 mg MD
Prasugrel 60 mg LD/ 10 mg MD
Duration of therapy 615 months
1o endpoint CV death, MI, stroke 2o endpoint
Stent thrombosis Safety endpoints TIMI
major bleeds, life-threatening bleeds
Reprinted with permission from Wiviott SD,
Antman EM, Gibson CM, et al. Evaluation of
prasugrel compared with clopidogrel in patients
with acute coronary syndromes design and
rationale for the TRial to assess Improvement in
Therapeutic Outcomes by optimizing platelet
InhibitioN with prasugrel Thrombolysis In
Myocardial Infarction 38 (TRITON-TIMI 38). Am
Heart J. 2006 Oct152(4)627-35.
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TRITON TIMI 38 Balance of efficacy and safety
Reprinted with permission Wiviott SD, Braunwald
E, McCabe CH, et al. Prasugrel versus clopidogrel
in patients with acute coronary syndromes. N
Engl J Med. 2007 Nov 15357(20)2001-15.
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TRITON TIMI 38 CV death, MI, strokeMajor
subgroups
Reprinted with permission Wiviott SD, Braunwald
E, McCabe CH, et al. Prasugrel versus clopidogrel
in patients with acute coronary syndromes. N
Engl J Med. 2007 Nov 15357(20)2001-15. .
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TRITON TIMI 38 Total Events Prevented First and
Recurrent
Total EventsPlt0.0001
896
-195
701
AdditionalEvents
Events
1st EventP0.0004
-138
Prasugrel
Clopidogrel


ITT N 13,608
Reprinted with permissionfrom Murphy SA, Antman
EM, Wiviott SD, et al. Reduction in recurrent
cardiovascular events with p rasugrel compared
with clopidogrel in patients with acute coronary
syndromes from the TRITON-TIMI 38 trial. Eur
Heart J. 2008 Aug 21
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TRITON TIMI 38 Bleeding eventsSafety cohort
n 13,457
Clopidogrel
Prasugrel
ICH in patients with prior stroke/TIA (n 518)
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Clopidogrel 0 (0) Prasugrel 6 (2.3)(P 0.02)
2.4
Events ()
1.8
2
1.4
1.1
0.9
0.9
0.4
0.3
0.3
0.1
0
TIMI major
Life-
Non-fatal
Fatal
ICH
bleeds
threatening
ARD 0.6HR 1.32P 0.03NNH 167
ARD 0.5HR 1.52P 0.01
ARD 0P 0.74
ARD 0.3P 0.002
ARD 0.2P 0.23
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TRITON TIMI 38 Net clinical benefit Bleeding
risk subgroups
Post-hoc analysis
Risk ()
Yes

37
Prior stroke/TIA
No
16
Pint 0.006
1
75
Age
16
lt75
Pint 0.18
lt60 kg
3
Weight
60 kg
Pint 0.36
14
13
OVERALL
0.5
1
2
Prasugrel better
Clopidogrel better
HR
Wiviott SD, Braunwald E, McCabe CH, et al.
Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med. 2007 Nov
15357(20)2001-15.
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Definite/probable ST Any stent (n 12,844)
TRITON TIMI 38 STENT ANALYSIS
2.5

HR 0.48 0.360.64 P lt 0.0001
2.35
2.0
Clopidogrel
52
1.5
Subjects ()
1.13
1.0
Prasugrel
1 year 1.06 vs 2.15 HR 0.48 0.360.65 P lt
0.0001
0.5
0
0
50
100
150
200
250
300
350
400
450
Days
Reprinted with permission Wiviott SD, Braunwald
E, McCabe CH, et al. Intensive oral antiplatelet
therapy for reduction of ischaemic events
including stent thrombosis in patients with acute
coronary syndromes treated with percutaneous
coronary intervention and stenting in the
TRITON-TIMI 38 trial a subanalysis of a
randomised trial. Lancet. 2008 Apr
19371(9621)1353-63
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Stent thrombosis subgroups
TRITON TIMI 38 STENT ANALYSIS
Pras
Clop
Risk ()
1.6
2.8
42
STEMI
1.0
2.2
57
UA/NSTEMI
1.4
2.9
53
Stent gt20 mm
0.9
1.9
52
Stent ?20 mm
B
1.1
2.2
50
No bifurcation stent
1.4
4.6
69
Bifurcation stent
1.1
2.1
51
CrCl 60
1.1
3.9
70
CrCl lt60
1.2
2.1
45
No prior MI
0.8
3.4
75
Prior MI
0.9
2.0
54
No GPI
1.3
2.6
51
GPI
2.0
3.6
48
DM
0.9
2.0
55
No DM
1.8
3.4
44
Age 75
1.0
2.2
54
Age lt75
B
0.9
2.3
61
Female
1.2
2.4
50
Male
B
0.1
1
2
Prasugrel better
Clopidogrel better
Reprinted with permission Wiviott SD, Braunwald
E, McCabe CH, et al. Intensive oral antiplatelet
therapy for reduction of ischaemic events
including stent thrombosis in patients with acute
coronary syndromes treated with percutaneous
coronary intervention and stenting in the
TRITON-TIMI 38 trial a subanalysis of a
randomised trial. Lancet. 2008 Apr
19371(9621)1353-63
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Clinical trials of prasugrel Summary

• Prasugrel (60 mg LD/10 mg MD) achieves more
  rapid, more consistent and higher levels of
  inhibition of platelet aggregation than standard
  or higher dose clopidogrel
• These features resulted in a significant
  reduction in ischaemic events, including MI and
  ST, across a broad range of patient and
  procedural characteristics
• Bleeding, including serious bleeding, was
  increased