Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Sten

1
Prasugrel Compared to Clopidogrel in Patients
with Acute Coronary Syndromes Undergoing PCI with
Stenting the TRITON - TIMI 38 Stent Analysis
STENT ANALYSIS

• Stephen D. Wiviott, Elliott M. Antman, Ivan
  Horvath, Matyas Keltai, Jean-Paul R. Herrman,
  Frans van de Werf, William Downey, Benjamin M.
  Scirica, Sabina A. Murphy, Carolyn H. McCabe,
  Eugene Braunwald
• SCAI ACCi2 2008Chicago, Illinois

Disclosure Statement The TRITON-TIMI 38 trial
was supported by a research grant to the Brigham
and Womens Hospital from Daiichi Sankyo Co. Ltd
and Eli Lilly Co.
2
Main Trial Design
STENT ANALYSIS
ACS (STEMI or UA/NSTEMI) 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 6-15 months
1o endpoint CV death, MI, Stroke 2o endpoint
Stent Thrombosis Safety endpoints TIMI
major bleeds, Life-threatening bleeds
Wiviott SD, Antman EM et al AHJ 2006
3
Trial Organization
STENT ANALYSIS
Trial Leadership TIMI Study Group Eugene
Braunwald,Chairman, Elliott M. Antman, PI,
Carolyn H. McCabe, Director, Stephen D. Wiviott,
Gilles Montalescot, Sabina A. Murphy, Susan
McHale Sponsors Daiichi Sankyo and Eli
Lilly J. Anthony Ware, Jeffrey Riesmeyer,
William Macias, James Croaning, Govinda
Weerakkody, Francis Plat, Tomas Bocanegra Data
Center and Site Management Quintiles Inc Data
Safety Monitoring Board David Williams (Chair) ,
Christophe Bode, Spencer King, Ulrich Sigwart,
David DeMets
4
Main Trial Primary Results

15
Clopidogrel
HR 0.81(0.73-0.90)P0.0004
12.1
CV Death / MI / Stroke
9.9
10
Prasugrel
Endpoint ()
5
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32(1.03-1.68)P0.03
1.8
Clopidogrel
0
0
30
60
90
180
270
360
450
Days
Wiviott SD, Braunwald E, McCabe CH et al NEJM2007
5
Goals of Stent Analysis
STENT ANALYSIS

• To compare the efficacy and safety of PRASUGREL
  and CLOPIDOGREL in 12,844 patients with at least
  one stent as part of the index procedure with
  respect to
• Stent Thrombosis (ARC definitions)
• Ischemic Events, Bleeding
• Overall and stratified by stent type received

6
Patient Population
STENT ANALYSIS
Randomized 13,608
Stent Placed 12,844 (94)
BMS Only 6461 (47)
DES Only 5743 (42)
Both BMS/DES 640 (5)
PES Only 2766 (20)
SES Only 2454 (18)
Other/Mixed 523 (4)
7
Baseline Characteristics
STENT ANALYSIS
8
Key Efficacy, Safety EPStratified by Stent Type
STENT ANALYSIS

• CVD/MI/CVA

• Non-CABG TIMI Major Bleeding

HR 0.80 (0.69-0.93) p0.003
HR 0.82 (0.69-0.97) p0.02
CLOPIDOGREL
PRASUGREL
of Subjects
HR 1.37 (0.95-1.99) p0.09
HR 1.19 (0.83-1.72) p0.34
N6461
N5743
9
ARC ST Definitions
STENT ANALYSIS
Blinded CEC review of using source documents incl
imaging reports Definite total occlusion w/in
or lt 5 mm of the stent or thrombus w/in orlt 5 mm
of the stent AND a clinical syndrome lt48
h. Probable unexplained death lt 30 days or MI
in stented territory w/o angiographic
confirmation ST AND w/o alternative
cause Possible unexplained death gt 30 days
following stenting Early 0 30 days after
randomization Late gt 30 days after randomization
(landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
10
Death Following ST
STENT ANALYSIS

• Mortality During Follow up () Post-Stent
  Thrombosis

HR 13.1 (9.8 17.5) Plt0.0001
of Subjects
N210
N12634
11
Definite/Probable ST Any Stent (N12844)
STENT ANALYSIS
2.35

2.5
HR 0.48 0.36-0.64 Plt0.0001
2
CLOPIDOGREL
52
1.5
of Subjects
1.13
1
PRASUGREL
1 year 1.06 vs 2.15 HR 0.48 0.36-0.65,
Plt0.0001
0.5
0
0
50
100
150
200
250
300
350
400
450
DAYS
12
Definite/Probable ST Any Stent (N12844)
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.41 0.29-0.59 Plt0.0001
HR 0.60 0.37-0.97 P0.03
CLOPIDOGREL
PRASUGREL
1.56
of Subjects
59
0.82
40
0.64
0.49
DAYS
13
Stent Thrombosis By ARC Category (N12844)
STENT ANALYSIS
CLOPIDOGREL
PRASUGREL
DEF/PROB/POSS HR 0.56 (0.43-0.73) Plt0.0001
DEF/PROB HR 0.48 (0.36-0.64) Plt0.0001
DEFINITE HR 0.42 (0.31-0.59) Plt0.0001
of Subjects
14
Stent Thrombosis Subgroups
STENT ANALYSIS
PRAS
CLOP
RISK ()
1.6
2.8
42
1.0
2.2
57
1.4
2.9
53
0.9
1.9
52
1.1
2.2
50
1.4
4.6
69
1.1
2.1
51
1.1
3.9
70
1.2
2.1
45
0.8
3.4
75
0.9
2.0
54
1.3
2.6
51
2.0
3.6
48
0.9
2.0
55
1.8
3.4
44
1.0
2.2
54
0.9
2.3
61
1.2
2.4
50
PRASUGREL BETTER
CLOPIDOGREL BETTER
15
Definite/Probable ST DES Only (N5743)
STENT ANALYSIS
2.31
HR 0.36 0.22-0.58 Plt0.0001
CLOPIDOGREL
64
of Subjects
0.84
PRASUGREL
1 year 0.74 vs 2.05 HR 0.35 0.21-0.58,
Plt0.0001
DAYS
16
Definite/Probable ST DES Only (N5743)
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.29 0.15-0.56 P0.0001
HR 0.46 0.22-0.97 P0.04
CLOPIDOGREL
PRASUGREL
1.44
of Subjects
0.91
71
54
0.42
0.42
DAYS
17
Stent Thrombosis DES SubtypesTrial Duration
STENT ANALYSIS
CLOPIDOGREL
PRASUGREL
Sirolimus Only HR 0.33 (0.15-0.73) p0.004
Paclitaxel Only HR 0.33 (0.16-0.68) p0.002
of Subjects
67
67
N2454
N2766
18
Definite/Probable ST BMS Only (N6461)
STENT ANALYSIS
2.41
HR 0.52 0.35-0.77 P0.0009
CLOPIDOGREL
48
of Subjects
1.27
PRASUGREL
1 year 1.22 vs 2.27 HR 0.53 0.36-0.79,
P0.0014
DAYS
19
Definite/Probable ST BMS Only (N6461)
STENT ANALYSIS
EARLY ST
LATE ST
HR 0.45 0.28-0.73 P0.0009
HR 0.68 0.35-1.31 P0.24
CLOPIDOGREL
1.66
PRASUGREL
of Subjects
55
0.78
32
0.75
0.53
DAYS
20
Summary
STENT ANALYSIS

• Intensive antiplatelet therapy with PRASUGREL in
  stented patients compared to CLOPIDOGREL
• Substantial reduction in ST
• Regardless of stent type or ST definition
• Early and Late
• A broad range of clinical/procedural
  characteristics
• Fewer ischemic events, more major bleeding

21
Balance of Efficacy and Safety (Stented
Population)
STENT ANALYSIS
Stent Thrombosis
CVD/MI/CVA w/o ST
Events per 1000 patients treated
22
Conclusions/Implications
STENT ANALYSIS
www.thelancet.com

• Stent Thrombosis is a rare, but devastating
  complication of PCI associated with a high
  mortality. Efforts to reduce ST have focused on
  compliance w/ and duration of ASA/clopidogrel
• Our data indicate that an agent w/ more rapid,
  consistent, and greater inhibition of platelet
  aggregation (prasugrel) results in major
  reductions (50) in ST across a broad array of
  clinical procedural characteristics

23
STENT ANALYSIS
24
Clinical Endpoints
STENT ANALYSIS

• Net Clinical Benefit

HR 0.84 (0.72-0.98) p0.025
HR 0.88 (0.77-1.01) p0.07
HR 0.86 (0.77-0.95) p0.002
of Subjects
N6461
N12844
N5743
25
Primary EP (D/MI/CVA) Not Related to ST
STENT ANALYSIS
HR 0.85, P0.005
10.3
15
CLOPIDOGREL
8.7
of Subjects
PRASUGREL
DAYS
26
Key Efficacy, Safety EPStratified by Stent Type
STENT ANALYSIS

• CVD/MI/CVA

• Major Bleeding

HR 0.82 (0.69-0.97) p0.02
HR 0.80 (0.69-0.93) p0.003
HR 0.81 (0.72-0.90) p0.0001
CLOPIDOGREL
PRASUGREL
HR 1.27 (0.99-1.63) p0.06
HR 1.37 (0.95-1.99) p0.09
HR 1.19 (0.83-1.72) p0.34
N12844
N6461
N5743