TRITON-TIMI 38: STEMI Cohort Efficacy Endpoints at 15

Report
Montalescot G et al. Lancet 2008;372:1-9
Mid- and long-term outcomes of STEMI
patients treated with prasugrel,
compared with clopidogrel and
undergoing PCI: Observations from the
TRITON-TIMI 38 trial
Elsa Margarita Arrieta, MD1 and Hyunah Caroline Choi , MD2
1. Eli Lilly and Company Mexico; Mexico City, United Mexican States
2 . Eli Lilly and Company Korea; Seoul, Korea
Study funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company.
TRITON-TIMI 38: Introduction
 As use of stents has grown, thienopyridines—
especially clopidogrel—have become increasingly
important for treatment of STEMI1-6
 No randomized controlled trials have been undertaken
to compare clopidogrel (or the first-generation
thienopyridine, ticlopidine) with placebo in patients
undergoing PCI for STEMI
 The effectiveness of clopidogrel in this setting has
been presumed on the basis of results of studies of
scheduled PCI7-9
PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction
1Bertrand ME et al. Circulation 1998;98:1597-1603
2Schörnig A et al. N Engl J Med 1996;334:1084-1089
3Urban P et al. Circulation 1998;98:2126-2132
4Leon MB et al. N Engl J Med 1998;339:1665-1671
5Bertrand ME et al. Circulation 2000;102:624-629
6Mandelzweig L et al. Eur Heart J 2006;27:2285-2293
7Mehta SR et al. Lancet 2001;358:527-533
8Steinhubl SR et al. JAMA 2002;288:2411-2420
9Sabatine MS et al. JAMA 2005;294:1224-1232
TRITON-TIMI 38: Introduction cont’
 Prasugrel is a novel third-generation thienopyridine and a
more potent blocker of the platelet P2Y12 receptor than
clopidogrel, producing consistent platelet inhibition10
 The TRial to assess Improvement in Therapeutic Outcomes
by optimizing platelet inhibitioN with prasugrel–
Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38
was designed to compare clopidogrel with prasugrel
• In a previous report, prasugrel was superior to clopidogrel in
reduction of ischaemic events in patients undergoing PCI for the
entire spectrum of acute coronary syndrome (ACS), albeit with
increased bleeding11
10Wiviott SD et
11Wiviott SD et
al. Circulation 2007;116:2923-2932
al. Am Heart J 2006;152:627-635
TRITON-TIMI 38: Objective
 To assess prasugrel vs. clopidogrel in the STEMI
population
• This report represents the first large experience for
prasugrel in mechanical reperfusion of STEMI
STEMI = ST-segment elevation myocardial infarction
TRITON-TIMI 38: Study Design – Distribution
of Patients in STEMI Cohort
Double-blind, double-dummy, parallel, randomized controlled trial
All ACS/PCI patients
N = 13608
UA/NSTEMI
n = 10074
Randomised patients with STEMI
N = 3534
Clopidogrel 300 mg LD/75 mg MD
n = 1765
Prasugrel 60 mg LD/10 mg MD
n = 1769
2 patients did not receive study
drug or undergo PCI
Primary PCI
n = 2438
Clopidogrel
n = 1235
Prasugrel
n = 1203
Secondary PCI
n = 1094
Clopidogrel
n = 530
Prasugrel
n = 564
ACS = acute coronary syndrome; LD = loading dose; MD = maintenance dose; NSTEMI = non-STsegment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = STsegment elevation myocardial infarction; UA = unstable angina
TRITON-TIMI 38: Enrollment Criteria
 Participants divided into two strata
• Those enrolled within 12 hours of onset of symptoms
(primary PCI)
• Those enrolled between 12 hours and 14 days after onset
of symptoms (secondary PCI)
 Major exclusion criteria
•
•
•
•
•
Any thienopyridine treatment within 5 days of randomization
Need for chronic oral anticoagulants
Cardiogenic shock
Recent fibrinolytic administration
Increased bleeding risk or anaemia
TRITON-TIMI 38: Procedures
 The randomization procedure was stratified by presenting
syndrome (STEMI vs unstable angina [UA] or non-STEMI
[NSTEMI])
 In patients with STEMI who presented within 12 hours of
onset of symptoms and for whom primary PCI was planned,
randomization could take place without knowledge of
coronary anatomy, just after informed consent was obtained
 In individuals undergoing secondary PCI, knowledge of
coronary anatomy was required before randomization
PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction
TRITON-TIMI 38: Study Endpoints
 Primary endpoint: cardiovascular (CV) death, non-fatal (NF)
myocardial infarction (MI), or NF stroke
 Key secondary endpoint: CV death, NF MI, or urgent target vessel
revascularisation (UTVR) at 30 days, follow-up was out to 15
months12-16
 Other prespecified efficacy analyses included stent thrombosis
(clinically adjudicated according to definite or probable Academic
Research Consortium definitions)17,18 the composite of CV death or
NF MI, and all individual components of the composite endpoints
 Safety endpoints: thrombolysis in myocardial infarction (TIMI) major
bleeding unrelated to coronary artery bypass graft (CABG) surgery,
TIMI life-threatening bleeding, and TIMI major or minor bleeding
unrelated to CABG surgery
 Net clinical outcome endpoint: all-cause death, NF MI, NF stroke,
or NF TIMI major bleeding unrelated to CABG surgery
16Antoniucci D et al. J Am Coll Cardiol 2003;42:1879-1885
12Brener SJ et al. Circulation 1998;98:734-741
17Mauri et al. N Engl J Med 2007;356:1020-1029
13Neumann FJ et al. J Am Coll Cardiol 2000;35:915-921
14Montalescot G et al. N Engl J Med 2001;344:1895-1903 18Wiviott et al. Lancet 2008;371:1353-1363
15Stone GW et al. N Engl J Med 2002;346:957-966
TRITON-TIMI 38: Statistical Analyses
 The sample size for the main trial was calculated to have
90% power to detect a 20% reduction in relative risk of
the primary endpoint in patients with UA or NSTEMI
 The number of participants with STEMI was capped at
3500 to ensure the overall TRITON-TIMI 38 trial would
have a distribution of presentations of ACS similar to
that seen in the general population19
 The trial was not prospectively designed or powered to
show superiority of prasugrel over clopidogrel in the
STEMI cohort alone
 Efficacy comparisons by time-to-first event with the
intention-to-treat principle
ACS = acute coronary syndrome; NSTEMI = non-ST-segment elevation myocardial infarction; STEMI =
ST-segment elevation myocardial infarction; TRITON-TIMI 38 = TRial to assess Improvement in
Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial
Infarction; UA = unstable angina
19Rosamond
W et al. Circulation 2008;117:e25-e146
TRITON-TIMI 38: Statistical Analyses
 Safety analyses in patients who received at least one
dose of study drug and in whom an event took place
while on active treatment or within 7 days of
treatment discontinuation
 Event rates are expressed as Kaplan-Meier
estimates, and estimates are compared with hazard
ratios (HRs) and two-sided 95% confidence intervals
(CIs)
 P < 0.05 was judged significant
 Numbers needed to treat and corresponding CIs
were calculated with event rate estimates in the
clopidogrel arm
TRITON-TIMI 38: Baseline Characteristics of the
STEMI Cohort – Prasugrel vs Clopidogrel
Clopidogrel
(N = 1765)
Prasugrel
(N = 1769)
59 (52-69)
58 (51-67)
Age  75 years, n (%)
222 (13)
185 (10)
Gender, male, n (%)
1346 (76)
1389 (79)
82 (5)
83 (5)
White ethnic origin, n (%)
1705 (97)
1688 (96)
History of hypertension, n (%)
881 (50)
875 (49)
History of hypercholesterolaemia, n (%)
722 (41)
725 (41)
History of diabetes, n (%)
344 (19)
330 (19)
Current tobacco use, n (%)
772 (44)
834 (47)
Variable
Age, years, median (IQR)
Weight < 60 kg, n (%)
IQR = interquartile range; STEMI = ST-segment elevation myocardial infarction
TRITON-TIMI 38: Baseline Characteristics of the
STEMI Cohort – Prasugrel vs Clopidogrel
Clopidogrel
(N = 1765) %
Prasugrel
(N = 1769) %
184 (10)
175 (10)
Previous CABG surgery, n (%)
40 (2)
41 (2)
Previous stroke or transient ischaemic
attack, n (%)
64 (4)
49 (3)
Creatinine clearance < 60, mL/min, n (%)
199 (11)
168 (10)
Anterior MI, n (%)
680 (39)
698 (40)
113 (6)
156 (9)
Time from symptom onset to
randomisation, hours, median (IQR)
5.6 (2.8-26.9)
6.4 (2.9-27.8)
Time from symptom onset to PCI, hours,
median (IQR)
6.0 (3.1-27.5)
6.8 (3.3-29.2)
Variable
Previous MI, n (%)
Killip class II-IV, n (%)
CABG = coronary artery bypass graft; IQR = interquartile range; MI = myocardial infarction; PCI =
percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction
TRITON-TIMI 38: Baseline Characteristics of the
STEMI Cohort – Prasugrel vs Clopidogrel
Clopidogrel
(N = 1765) %
Prasugrel
(N = 1769) %
PCI performed, n (%)
1714 (97)
1711 (97)
Stent used for index PCI, n (%)
1633 (93)
1624 (92)
BMS (only) used for index PCI, n (%)
1059 (60)
1040 (59)
DES (only) used for index PCI, n (%)
574 (33)
584 (33)
1598 (91)
1598 (91)
Radial
155 (9)
158 (9)
Other
2 (<1)
2 (<1)
136 (8)
132 (8)
Variable
Access, n (%)
Femoral
Multivessel PCI, n (%)
BMS = bare metal stent; DES = drug-eluting stent; PCI = percutaneous coronary intervention; STEMI
= ST-segment elevation myocardial infarction
TRITON-TIMI 38: Baseline Characteristics of the
STEMI Cohort – Prasugrel vs Clopidogrel
Clopidogrel
(N = 1765) %
Prasugrel
(N = 1769) %
1200 (71)
1201 (72)
Low-molecular weight heparin
108 (6)
137 (8)
Other, or a combination
374 (22)
332 (20)
GPIIb/IIIa inhibitor used during index
hospitalisation, n (%)
1124 (64)
1102 (62)
Fibrinolytic treatment, n (%)
184 (10)
187 (11)
Before PCI
453 (27)
455 (27)
During PCI
1213 (72)
1221 (72)
21 (1)
15 (1)
Variable
Anti-thrombin, n (%)
Unfractionated heparin
Timing of study drug administration, n (%)
After PCI
GP = glycoprotein; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation
myocardial infarction
12
10
TRITON-TIMI 38: STEMI Cohort Efficacy
Endpoints at 30 Days
9.5
*
8.8
*
8.8
Clopidogrel
*
Prasugrel
Patients (%)
8
6.5
6.7
6
7.0
*
6.2
4.9
*p < 0.05
4
*
2.6
2
2.4
1.9
1.6
1.3
*
1.2
0
CV Death/
CV Death/
NF MI/NF Stroke NF MI/UTVR
†Clinically
CV Death/
NF MI
All-cause
Death
NF MI
UTVR
Stent
Thrombosis†
adjudicated according to definite or probable Academic Research Consortium definitions
CV = cardiovascular; MI = myocardial infarction; NF = non-fatal; STEMI = ST-segment elevation
myocardial infarction; UTVR = urgent target vessel revascularisation
TRITON-TIMI 38: STEMI Cohort Primary Efficacy
Endpoint at 30 Days (CV Death, NF MI, NF Stroke)
15
12.3
*
Clopidogrel
Patients (%)
Prasugrel
10
9.5
*
8.2
6.5
6.6
6.4
5
0
All STEMI
Primary PCI
Secondary PCI
CV = cardiovascular; NF = non-fatal; MI = myocardial infarction; PCI = percutaneous
coronary intervention; STEMI = ST-segment elevation myocardial infarction
*p < 0.05
TRITON-TIMI 38: STEMI Cohort Primary Safety Endpoint
at 30 Days (Non-CABG TIMI Major Bleeding)
Differences between treatment groups are not statistically significant
CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention; STEMI = STsegment elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction
TRITON-TIMI 38: STEMI Cohort Efficacy
Endpoints at 15 Months
16
14
*
12.4
Patients (%)
12
10
10.0
12.0 *
9.6
Clopidogrel
Prasugrel
*
11.5
*
9.0
8.8
8
6.8
*p < 0.05
6
4
4.3
3.2
3.3
2.2
2
2.8
*
1.6
0
CV Death/
CV
All-cause
CV Death/
Death
NF MI/NF Stroke NF MI/UTVR Death/NF MI
† Clinically
NF MI
UTVR
Stent
Thrombosis†
adjudicated according to definite or probable Academic Research Consortium definitions
CV = cardiovascular; MI = myocardial infarction; NF = non-fatal; STEMI = ST-segment elevation
myocardial infarction; UTVR = urgent target vessel revascularisation
TRITON-TIMI 38: STEMI Cohort Primary Efficacy
Endpoint at 15 Months (CV Death, NF MI, NF Stroke)
*
*
*p < 0.05
CV = cardiovascular; NF = non-fatal; MI = myocardial infarction; PCI = percutaneous
coronary intervention; STEMI = ST-segment elevation myocardial infarction
TRITON-TIMI 38: STEMI Cohort Primary Safety Endpoint
at 15 Months (Non-CABG TIMI Major Bleeding)
Differences between treatment groups are not statistically significant
CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention; STEMI =
ST-segment elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction
TRITON-TIMI 38: STEMI Cohort Net
Clinical Benefit at 30 Days and 15 Months
*
*
*
*
*
*
*p < 0.05
Death/MI/Stroke/
All-cause Death/NF MI/ Death/NF MI/NF Stroke/
Non-CABG TIMI Major
NF Stroke/
Non-CABG and CABG
Bleeding at 30 Days Non-CABG TIMI Major
TIMI Major Bleeding
Bleeding at 15 Months
at 15 Months
MI = myocardial infarction; CABG = coronary artery bypass graft; NF = non-fatal; STEMI = ST-segment
elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction
TRITON-TIMI 38: Summary STEMI Cohort
 Efficacy
• Prasugrel: greater relative treatment effect
compared to clopidogrel
 Primary endpoint (CV death, NF MI, or NF stroke)
significantly reduced (10.0% vs 12.4%, p = 0.02)
 Safety
• Prasugrel: no more significant bleeding events
compared to clopidogrel
 Non-CABG TIMI major bleeding (2.4% vs 2.1%, p = NS)
 Life-threatening bleeding (1.3% vs 1.1%, p = NS)
 Non-CABG TIMI major or minor bleeding (5.1% vs 4.7%,
p = NS)
NS = non-significant
TRITON-TIMI 38: Summary STEMI Cohort
 Net Clinical Benefit
• Outcome endpoint of all deaths, NF MI, NF stroke, or
NF non-CABG TIMI major bleeding significantly
favouring prasugrel both at 30 days and 15 months
• Prasugrel compared to clopidogrel in patients
undergoing PCI for STEMI: greater efficacy in
preventing ischaemic events without an apparent
increased risk of bleeding
TRITON-TIMI 38: Discussion
 In STEMI patients, prasugrel compared with clopidogrel
• Significant risk reduction in the primary composite endpoint of
CV death, NF MI, or NF stroke for the trial duration
• Significant reduction in the key secondary composite endpoint of
CV death, NF MI, or UTVR at 30 days
 Consistent with those of TRITON-TIMI 38, in the cohort
presenting with UA or non-STEMI23,24
 TRITON-TIMI 38 was not designed or powered for all
clinical endpoints in the STEMI population alone
• In view of the capped sample size, we believe it is noteworthy
that there was a benefit of prasugrel on ischaemic events
• With a larger sample size, differences could possibly have been
noted for low frequency events, including major bleeding
23Rosamond W et
24Wiviott SD et al.
al. Circulation 2008;117:e25-146
N Engl J Med 2007;357:2001-2015

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