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

Study funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company.

Elsa Margarita Arrieta, MD1 and Hyunah Caroline Choi , MD2

1. Eli Lilly and Company Mexico; Mexico City, United Mexican States2 . Eli Lilly and Company Korea; Seoul, Korea

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

1Bertrand ME et al. Circulation 1998;98:1597-16032Schörnig A et al. N Engl J Med 1996;334:1084-10893Urban P et al. Circulation 1998;98:2126-21324Leon MB et al. N Engl J Med 1998;339:1665-16715Bertrand ME et al. Circulation 2000;102:624-629

6Mandelzweig L et al. Eur Heart J 2006;27:2285-22937Mehta SR et al. Lancet 2001;358:527-5338Steinhubl SR et al. JAMA 2002;288:2411-24209Sabatine MS et al. JAMA 2005;294:1224-1232

PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction

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 al. Circulation 2007;116:2923-293211Wiviott SD et 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

ACS = acute coronary syndrome; LD = loading dose; MD = maintenance dose; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina

Double-blind, double-dummy, parallel, randomized controlled trial

All ACS/PCI patientsN = 13608

All ACS/PCI patientsN = 13608

UA/NSTEMIn = 10074

UA/NSTEMIn = 10074

Randomised patients with STEMI N = 3534

Randomised patients with STEMI N = 3534

Prasugrel 60 mg LD/10 mg MDn = 1769

Prasugrel 60 mg LD/10 mg MDn = 1769

Clopidogrel 300 mg LD/75 mg MDn = 1765

Clopidogrel 300 mg LD/75 mg MDn = 1765

2 patients did not receive study drug or undergo PCI

2 patients did not receive study drug or undergo PCI

Primary PCI n = 2438

Primary PCI n = 2438

Secondary PCI n = 1094

Secondary PCI n = 1094

Clopidogreln = 1235

Clopidogreln = 1235

Prasugreln = 1203

Prasugreln = 1203

Clopidogreln = 530

Clopidogreln = 530

Prasugreln = 564

Prasugreln = 564

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

12Brener SJ et al. Circulation 1998;98:734-74113Neumann FJ et al. J Am Coll Cardiol 2000;35:915-92114Montalescot G et al. N Engl J Med 2001;344:1895-190315Stone GW et al. N Engl J Med 2002;346:957-966

16Antoniucci D et al. J Am Coll Cardiol 2003;42:1879-188517Mauri et al. N Engl J Med 2007;356:1020-102918Wiviott et al. Lancet 2008;371:1353-1363

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

19Rosamond W et al. Circulation 2008;117:e25-e146

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

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

VariableClopidogrel (N = 1765)

Prasugrel (N = 1769)

Age, years, median (IQR) 59 (52-69) 58 (51-67)

Age 75 years, n (%) 222 (13) 185 (10)

Gender, male, n (%) 1346 (76) 1389 (79)

Weight < 60 kg, n (%) 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)

IQR = interquartile range; STEMI = ST-segment elevation myocardial infarction

TRITON-TIMI 38: Baseline Characteristics of the STEMI Cohort – Prasugrel vs Clopidogrel

VariableClopidogrel (N = 1765) %

Prasugrel (N = 1769) %

Previous MI, n (%) 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)

Killip class II-IV, n (%) 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)

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

VariableClopidogrel (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)

Access, n (%)

Femoral 1598 (91) 1598 (91)

Radial 155 (9) 158 (9)

Other 2 (<1) 2 (<1)

Multivessel PCI, n (%) 136 (8) 132 (8)

BMS = bare metal stent; DES = drug-eluting stent; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction

VariableClopidogrel (N = 1765) %

Prasugrel (N = 1769)

%Anti-thrombin, n (%)

Unfractionated heparin 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)

Timing of study drug administration, n (%)

Before PCI 453 (27) 455 (27)

During PCI 1213 (72) 1221 (72)

After PCI 21 (1) 15 (1)

TRITON-TIMI 38: Baseline Characteristics of the STEMI Cohort – Prasugrel vs Clopidogrel

GP = glycoprotein; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction

Clopidogrel

Prasugrel

*p < 0.05

StentThrombosis†

CV Death/NF MI

CV Death/NF MI/UTVR

CV Death/NF MI/NF Stroke

All-cause Death

NF MI UTVR

Pat

ien

ts (

%)

*

0

2

4

6

8

10

* *

***

9.5

6.5

8.8

6.7

8.8

6.2

2.6

1.6

7.0

4.9

1.91.3

2.4

1.2

12

†Clinically adjudicated according to definite or probable Academic Research Consortium definitionsCV = cardiovascular; MI = myocardial infarction; NF = non-fatal; STEMI = ST-segment elevation myocardial infarction; UTVR = urgent target vessel revascularisation

TRITON-TIMI 38: STEMI Cohort Efficacy Endpoints at 30 Days

TRITON-TIMI 38: STEMI Cohort Primary Efficacy Endpoint at 30 Days (CV Death, NF MI, NF Stroke)

CV = cardiovascular; NF = non-fatal; MI = myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction

*p < 0.05

Clopidogrel

Prasugrel

*

*8.2

12.3

6.5 6.6 6.4

9.5

0

5

10

15

All STEMI Primary PCI Secondary PCI

Pat

ien

ts (

%)

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 = ST-segment elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction

† Clinically adjudicated according to definite or probable Academic Research Consortium definitionsCV = cardiovascular; MI = myocardial infarction; NF = non-fatal; STEMI = ST-segment elevation myocardial infarction; UTVR = urgent target vessel revascularisation

TRITON-TIMI 38: STEMI Cohort Efficacy Endpoints at 15 Months

Clopidogrel

StentThrombosis†

CVDeath/NF MI

CV Death/NF MI/UTVR

CV Death/NF MI/NF Stroke

Prasugrel

*p < 0.05

All-causeDeath

NF MI UTVR

*

0

2

4

6

8

10

12

14

Pat

ien

ts (

%)

12.4

10.0

12.0

9.6

11.5

8.8

4.3

3.3

9.0

6.8

3.22.2 2.8

1.6

**

*

*

16

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

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: STEMI Cohort Net Clinical Benefit at 30 Days and 15 Months

All-cause Death/NF MI/NF Stroke/

Non-CABG TIMI MajorBleeding at 15 Months

Death/NF MI/NF Stroke/Non-CABG and CABGTIMI Major Bleeding

at 15 Months

Death/MI/Stroke/Non-CABG TIMI Major

Bleeding at 30 Days

*p < 0.05

*

* *

*

* *

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

¨ 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: Summary STEMI Cohort

¨ 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

TRITON-TIMI 38: Discussion

23Rosamond W et al. Circulation 2008;117:e25-14624Wiviott SD et al. N Engl J Med 2007;357:2001-2015