Transcript Document

STENT ANALYSIS
Prasugrel Compared to Clopidogrel in
Patients with Acute Coronary Syndromes
Undergoing PCI with Stenting:
the TRITON - TIMI 38 Stent Analysis
Stephen D. Wiviott, Elliott M. Antman, Ivan Horvath, Matyas Keltai, JeanPaul R. Herrman, Frans van de Werf, William Downey, Benjamin M.
Scirica, Sabina A. Murphy, Carolyn H. McCabe, Eugene Braunwald
SCAI – ACCi2 2008
Chicago, Illinois
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the
Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.
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
STENT ANALYSIS
Trial
Organization
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
Main Trial:
Primary Results
15
Clopidogrel
12.1
Endpoint (%)
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
Prasugrel
5
TIMI Major
NonCABG Bleeds
Prasugrel
2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
P=0.03
0
0 30 60 90
180
270
Days
360
450
Wiviott SD, Braunwald E, McCabe CH et al NEJM2007
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
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%)
Baseline Characteristics
STENT ANALYSIS
Any Stent
(N=12844)
94 %
UA/NSTEMI
75
STEMI
25
Age, median (IQR)
> 75 y
60 (53,69) y
13
Female
26
Diabetes
23
Smoker
38
North America
32
Prior MI
17
CrCl (ml/min)
>60
<60
89
11
Key Efficacy, Safety EP:
Stratified by Stent Type
STENT ANALYSIS
CVD/MI/CVA
HR 0.82
(0.69-0.97)
p=0.02
% of Subjects
HR 0.80
(0.69-0.93)
p=0.003
Non-CABG TIMI Major Bleeding
CLOPIDOGREL
PRASUGREL
HR 1.37
(0.95-1.99)
p=0.09
N=6461
N=5743
HR 1.19
(0.83-1.72)
p=0.34
ARC ST Definitions
STENT ANALYSIS
Blinded CEC review of using source documents incl imaging
reports:
Definite: total occlusion w/in or < 5 mm of the stent or thrombus
w/in or< 5 mm of the stent AND a clinical syndrome <48 h.
Probable: unexplained death < 30 days or MI in stented territory
w/o angiographic confirmation ST AND w/o alternative cause
Possible: unexplained death > 30 days following stenting
Early: 0 – 30 days after randomization
Late > 30 days after randomization (landmark analysis)
Based on ARC Definitions Mauri L et al NEJM 2007
Death Following ST
STENT ANALYSIS
Mortality During Follow up (%) Post-Stent Thrombosis
% of Subjects
HR 13.1 (9.8 – 17.5)
P<0.0001
N=210
N=12634
Definite/Probable ST:
Any Stent (N=12844)
STENT ANALYSIS
2.5
2
% of Subjects
2.35%
HR 0.48 [0.36-0.64]
P<0.0001
CLOPIDOGREL
52%
1.5
1.13%
1
PRASUGREL
0.5
1 year: 1.06 vs 2.15%
HR 0.48 [0.36-0.65], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
Definite/Probable ST:
Any Stent (N=12844)
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.41 [0.29-0.59]
P<0.0001
HR 0.60 [0.37-0.97]
P=0.03
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.56%
1.5
1.5
59%
1
0.82%
1
40%
0.5
0.64%
0
0
5
10
15
20
25
30
0.5
0.49%
0
30
DAYS
90
150
210
270
330
390
450
STENT ANALYSIS
Stent Thrombosis By
ARC Category (N=12844)
CLOPIDOGREL
% of Subjects
PRASUGREL
DEFINITE
HR 0.42 (0.31-0.59)
P<0.0001
DEF/PROB
HR 0.48 (0.36-0.64)
P<0.0001
DEF/PROB/POSS
HR 0.56 (0.43-0.73)
P<0.0001
Stent Thrombosis
Subgroups
STENT ANALYSIS
PRAS CLOP
1.4
0.9
2.9
1.9
53%
52%
B
1.1
1.4
2.2
4.6
50%
69%
B
1.1
1.1
2.1
3.9
51%
70%
1.2
0.8
0.9
1.3
2.0
0.9
1.8
1.0
0.9
1.2
2.1
3.4
2.0
2.6
3.6
2.0
3.4
2.2
2.3
2.4
45%
75%
54%
51%
48%
55%
44%
54%
61%
50%
B
CrCl >=60
CrCl< 60
0.1
42%
57%
B
B
No Bifurcation Stent
Bifurcation Stent
No Prior MI
Prior MI
No GPI
GPI
DM
No DM
Age >=75
Age < 75
Women
Men
2.8
2.2
B
Stent > 20 mm
Stent <= 20 mm
(%)
1.6
1.0
B
STEMI
UA/NSTEMI
RISK
B
B
B
B
B
B
B
B
B
B
B
PRASUGREL
BETTER
1
2
CLOPIDOGREL
BETTER
Definite/Probable ST:
DES Only (N=5743)
STENT ANALYSIS
2.31%
HR 0.36 [0.22-0.58]
P<0.0001
2.5
% of Subjects
2
CLOPIDOGREL
64%
1.5
0.84%
1
PRASUGREL
0.5
1 year: 0.74% vs 2.05%
HR 0.35 [0.21-0.58], P<0.0001
0
0
50
100
150
200 250
DAYS
300
350
400
450
Definite/Probable ST:
DES Only (N=5743)
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.29 [0.15-0.56]
P=0.0001
HR 0.46 [0.22-0.97]
P=0.04
2.5
2.5
2
2
CLOPIDOGREL
PRASUGREL
1.44%
1.5
1.5
71%
1
0.91%
1
54%
0.5
0.5
0.42%
0
0
5
10
15
20
25
30
0.42%
0
30
DAYS
90
150
210
270
330
390
450
Stent Thrombosis
DES Subtypes
STENT ANALYSIS
Trial Duration
CLOPIDOGREL
PRASUGREL
% of Subjects
Sirolimus Only
HR 0.33 (0.15-0.73)
p=0.004
Paclitaxel Only
HR 0.33 (0.16-0.68)
p=0.002
67%
N=2454
67%
N=2766
Definite/Probable ST:
BMS Only (N=6461)
STENT ANALYSIS
CLOPIDOGREL
2
% of Subjects
2.41%
HR 0.52 [0.35-0.77]
P=0.0009
2.5
48%
1.5
1.27%
PRASUGREL
1
0.5
1 year: 1.22 vs 2.27%
HR 0.53 [0.36-0.79], P=0.0014
0
0
50
100
150
200 250
DAYS
300
350
400
450
Definite/Probable ST:
BMS Only (N=6461)
STENT ANALYSIS
EARLY ST
LATE ST
% of Subjects
HR 0.45 [0.28-0.73]
P=0.0009
HR 0.68 [0.35-1.31]
P=0.24
2.5
2.5
2
2
1.66%
1.5
CLOPIDOGREL
PRASUGREL
1.5
55%
1
0.78%
1
32%
0.75%
0.5
0.5
0.53%
0
0
5
10
15
20
25
30
0
30
DAYS
90
150
210
270
330
390
450
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
Events per 1000 patients treated
STENT ANALYSIS
Stent
Thrombosis
Balance of Efficacy and
Safety (Stented Population)
CVD/MI/CVA
w/o ST
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
STENT ANALYSIS
Clinical Endpoints
STENT ANALYSIS
Net Clinical Benefit
HR 0.88
(0.77-1.01)
p=0.07
HR 0.84
(0.72-0.98)
p=0.025
% of Subjects
HR 0.86
(0.77-0.95)
p=0.002
N=12844
N=6461
N=5743
Primary EP (D/MI/CVA)
Not Related to ST
STENT ANALYSIS
12
HR 0.85, P=0.005
10.3%
% of Subjects
10
15%
CLOPIDOGREL
8
8.7%
6
PRASUGREL
4
2
0
0
50 100 150 200 250 300 350 400 450
DAYS
STENT ANALYSIS
Key Efficacy, Safety EP:
Stratified by Stent Type
CVD/MI/CVA
HR 0.81
(0.72-0.90)
p=0.0001
HR 0.80
(0.69-0.93)
p=0.003
Major Bleeding
HR 0.82
(0.69-0.97)
p=0.02
CLOPIDOGREL
PRASUGREL
HR 1.27
(0.99-1.63)
p=0.06
N=12844
N=6461
N=5743
HR 1.37
(0.95-1.99)
p=0.09
HR 1.19
(0.83-1.72)
p=0.34