Trial Design

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)
Stephen D. Wiviott, MD,a Elliott M. Antman, MD,a C. Michael Gibson, MD,a Gilles Montalescot, MD,b
Jeffrey Riesmeyer, MD,c Govinda Weerakkody, PhD,c Kenneth J. Winters, MD,c Jeffrey W. Warmke, PhD,d
Carolyn H. McCabe, BS,a and Eugene Braunwald, MD,a for the TRITON-TIMI 38 Investigators Boston, MA; Paris,
France; Indianapolis, IN; and Parsippany, NJ

Background Dual antiplatelet therapy with aspirin and clopidogrel is standard for prevention of thrombotic
complications of percutaneous coronary intervention (PCI). Prasugrel is a thienopyridine that is more potent, more rapid in
onset, and more consistent in inhibition of platelets than clopidogrel. TRITON-TIMI 38 is designed to compare prasugrel with
clopidogrel in moderate to high-risk patients with acute coronary syndrome (ACS).

Study Design TRITON-TIMI 38 is a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial.
Approximately 13 000 patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/nonST-segment
elevation myocardial infarction [MI], 3500 ST-segment elevation MI) will be randomized to prasugrel 60 mg loading dose
followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end
point is the time of the first event of cardiovascular death, MI, or stroke. Analyses will be performed first in the unstable
angina/nonST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points
include TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery.

Conclusions TRITON-TIMI 38 is a phase 3 comparison of prasugrel versus clopidogrel in patients with moderate to
high-risk ACS undergoing PCI. In addition, it is the first large-scale clinical events trial to assess whether a thienopyridine
regimen that achieves a higher level of inhibition of platelet aggregation than the standard therapy results in an improvement
in clinical outcomes. (Am Heart J 2006;152:627235.)

Background established the benefit of long-term clopidogrel for up to

Dual antiplatelet therapy with aspirin and a thieno-
pyridine is standard therapy for prevention of thrombotic
complications of percutaneous coronary intervention
(PCI).1,2 Clopidogrel has largely replaced ticlopidine
because of a better side-effect profile.3,4 Studies have
From the aTIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham
and Womens Hospital, Boston, MA, bGroupe Hospitalier Pitie-Salpetriere, Paris, France,
c
Eli Lilly and Company, Indianapolis, IN, and dSankyo Pharma Inc, Parsippany, NJ.
The TRITON-TIMI 38 trial is supported by Eli Lilly and Company, Indianapolis, IN, and
Daiichi Sankyo Co., Parsippany, NJ.
Submitted December 23, 2005; accepted April 13, 2006.
Reprint requests: Stephen D. Wiviott, MD, TIMI Study Group, Cardiovascular Division,
Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115.
E-mail: swiviott@partners.org
0002-8703/$ - see front matter
n 2006, Published by Mosby, Inc.
doi:10.1016/j.ahj.2006.04.012
1 year in subjects with an acute coronary syndrome
(ACS), including those who undergo PCI.5,6
Several important issues remain regarding this current
standard. Most of the acute effect seen in reducing
periprocedural events in the CREDO trial was observed in
patients who received a loading dose (LD) of clopidogrel
at least 6 hours before the procedure.6,7 Significant
variability in the response to clopidogrel has been
observed, with some individuals having minimal inhibi-
tion of adenosine diphosphateinduced platelet aggre-
gation8-12, leading to the concern that some patients may
be at increased risk for thrombotic events.11,13,14
Background on prasugrel
Prasugrel (CS-747, LY640315) is a thienopyridine that
has been shown in preclinical studies to be more potent

628 Wiviott et al
Figure 1
Design schema for TRITON-TIMI 38.
*TIMI Risk Score for UA/NSTEMI.21
and rapid in onset than clopidogrel.15 Phase 1 studies in
healthy human subjects showed greater inhibition of
platelet aggregation (IPA) with a 60-mg dose of
prasugrel than 300 mg of clopidogrel16 and repeat
dosing with 10 mg of prasugrel compared with 75 mg of
clopidogrel.17 There is also evidence that poor IPA
response may be less frequent with an LD of 60 mg of
prasugrel than 300 mg of clopidogrel.16,18 The differ-
ences in response appear to be based largely on a more
efficient generation of the active metabolite of prasugrel
because the active metabolites of the 2 drugs appear to
have similar in vitro potency.19
These favorable properties of prasugrel led to the
interest in the development of the drug for the
prevention of ischemic events in patients undergoing
PCI. The JUMBO-TIMI 26 trial was a double-blind, dose-
ranging, safety study of prasugrel compared with
clopidogrel in 904 patients undergoing elective or
urgent PCI with stenting and followed for 30 days.20 The
primary end point of TIMI major plus minor bleeding
was similar between prasugrel- and clopidogrel-treated
patients. At the highest dose of prasugrel (60 mg
followed by 15 mg daily), there was a trend toward more
TIMI minimal bleeding. There was a trend toward the
reduction of clinical ischemic events in the prasugrel-
treated patients.20 Whether these features will result in
improved clinical outcomes will be studied in the
TRITON-TIMI 38.
Study objectives
The primary objective of TRITON-TIMI 38 is to test the
hypothesis that prasugrel is superior to clopidogrel on a
background of aspirin in the treatment of subjects with
American Heart Journal
October 2006
Table I. Disease diagnostic criteria for TRITON-TIMI 38
I. Moderate to high risk UA:
A history of chest discomfort or ischemic symptoms of 10 min or
longer at rest, 72 h or less before randomization, with persistent
or transient ST-segment deviation 1 mm or higher in one or more
electrocardiogram (ECG) leads without elevation of creatine
kinaseMB (CK-MB) or troponin T or I but with a TIMI risk score
321 or greater
II. Moderate to high-risk NSTEMI:
A history of chest discomfort or ischemic symptoms of 10 min or
longer at rest, 72 h or less before randomization with no evidence
of persistent ST-segment elevation. Subjects must also have CK-MB
or troponin T or I greater than the upper limit of normal (ULN) and
a TIMI risk score 3 or greater. If CK-MB or troponin is not available,
total CK 2 times or greater ULN is acceptable
III. STEMI:
A history of chest discomfort or ischemic symptoms of greater than
20 minutes duration at rest, within 14 days or less randomization
with one of the following ECG features:
(a) ST-segment elevation 1 mm or higher in 2 or more contiguous
ECG leads
(b) New or presumably new left bundle branch block
(c) ST-segment depression 1 mm or greater in 2 anterior precordial
leads (V1 through V4) with clinical history and evidence
suggestive of true posterior infarction
ACS who are to undergo PCI measured by the composite
end point of cardiovascular (CV) death, nonfatal myo-
cardial infarction (MI), or nonfatal stroke. Additional
efficacy hypotheses include that prasugrel reduces the
occurrence of (1) the primary composite at 30 or 90 days
and (2) CV death, nonfatal MI, or urgent target vessel
revascularization at 30 or 90 days.
The safety hypotheses for TRITON-TIMI 38 are that
compared with clopidogrel, prasugrel will have similar
rates of (1) noncoronary artery bypass graft (CABG)
surgery-related TIMI major bleeding, (2) life-threatening
bleeding (a subset of nonCABG-related TIMI major
bleeding), and (3) nonCABG-related TIMI minor bleeding.
Study design and population
TRITON-TIMI 38 is a randomized, double-blind, dou-
ble-dummy, parallel-group, clinical trial with an active
comparator (Figure 1). The study population includes
subjects with moderate to high-risk ACS (Table I).
Patients with unstable angina (UA) and nonST-segment
elevation MI (NSTEMI) and TIMI risk score21 of 3 or
higher may be enrolled within 72 hours of symptom
onset. Patients with ST-segment elevation MI (STEMI)
may be enrolled either within 12 hours of the onset of
symptoms (primary PCI) or more than 12 hours to
14 days after the onset of symptoms if primary PCI is not
planned (post-STEMI). The evaluation of patients for
enrollment is summarized in Figure 2. Major exclusion
criteria include any thienopyridine within 5 days of
randomization, cardiogenic shock, recent fibrinolytic
administration (24 hours for fibrin specific and 48 hours
for nonfibrin specific), and bleeding diathesis (Table II).
American Heart Journal
Volume 152, Number 4
Figure 2
Enrollment schema for TRITON-TIMI 38.
TRS = TIMI Risk Score.21
Treatment protocol and follow-up
procedures
A loading dose of study medication is administered
anytime after randomization until the completion of the
PCI procedure (within 1 hour after the patient leaves the
cardiac catheterization laboratory). Randomization may
occur immediately after obtaining informed consent
from patients with STEMI when primary PCI is planned.
For patients with UA/NSTEMI or those enrolled post-
STEMI, coronary angiography may reveal an anatomy
that is not amenable to PCI, and therefore, randomiza-
tion may occur only after the coronary anatomy is
known to be suitable for PCI. For patients in whom the
coronary anatomy is known, an LD may be administered
up to 24 hours before planned PCI. The choice of vessels
instrumented, adjunctive medications, devices, and
staging of multivessel interventions is at the discretion of
the treating physician. Visits to assess clinical end points
and adverse events are planned for hospital discharge,
day 30 (28-35 days), day 90 (F2 weeks), and every
90 days (F2 weeks) thereafter for up to 15 months.
Study closeout procedures
The analysis of the primary efficacy composite end
point will include events occurring for each subject
Wiviott et al 629
during the study period, defined as the day of random-
ization through the end of the study period (maximum
464 days, ie, 450+14 days), which is after randomization,
as clarified hereinafter.
The completion date of the study will be determined by
the executive committee as a specific date when the
following are expected to be met: (1) 875 subjects with a
primary end point in the UA/NSTEMI arm and (2) median
duration of follow-up for subjects of at least 12 months.
Four groups of subjects must be considered for the
determination of the end of the study period (Table III).
All end points occurring after randomization, before the
end of the study period for a given patient, and those
reported to the data coordinating center before database
lock will be included in the primary efficacy and safety
analyses. End points occurring before the end of the study
period but reported after the database lock and before the
publication of the primary results will be incorporated, as
much as possible, into the manuscript. End points
occurring before the end of the study period for a given
subject but reported after publication of the primary
results will be included in regulatory updates only.
Dosing regimens
The dosing regimen of prasugrel in TRITON-TIMI 38 is
an LD of 60 mg and daily 10 mg of maintenance dose.

630 Wiviott et al
Table II. Inclusion/exclusion criteria
Inclusion criteria
(1) Acute coronary syndrome based on the disease diagnostic
criteria with planned PCI
(2) Legal age (and z18 y) and competent mental condition to
provide written informed consent
(3) For women of childbearing potential only, test negative for
pregnancy between ACS presentation and enrollment (based on a
urine or serum pregnancy test) and agree to use a reliable method
of birth control during the study
Exclusion criteria
Cardiovascular exclusion criteria
(1) Cardiogenic shock at the time of randomization
(2) Refractory ventricular arrhythmias
(3) New York Heart Association class IV congestive heart failure
Bleeding risk exclusion criteria
(4) Fibrin-specific fibrinolytic therapy less than 24 h before
randomization
(5) Nonfibrin-specific fibrinolytic therapy less than 48 h
before randomization
(6) Active internal bleeding or history of bleeding diathesis
(7) Clinical findings, in the judgment of the investigator, associated
with an increased risk of bleeding
(8) Any of the following:
(a) History of hemorrhagic stroke
(b) Intracranial neoplasm, arteriovenous malformation, or aneurysm
(c) Ischemic stroke within 3 months prior to screening
(9) International normalized ratio known to be greater than 1.5 at
the time of screening
(10) Platelet count of less than 100 000/mm3 at the time of screening
(11) Anemia (hemoglobin b10 g/dL) at the time of screening
Prior/concomitant therapy exclusion criteria
(12) One or more doses of a thienopyridine 5 d or less before PCI
(13) Oral anticoagulation or other antiplatelet therapy that cannot
be safely discontinued for the duration of the study
(14) Daily treatment with nonsteroidal antiinflammatory drugs or
cyclooxygenase-2 inhibitors
General exclusion criteria
(15) Investigative site personnel directly affiliated with the study or
immediate family
(16) Employed by Eli Lilly and Company; Ube Industries Limited,
Daiichi Sankyo Co.; The TIMI Study Group; Quintiles
(17) Treatment within the last 30 d with an investigational drug or
are presently enrolled in another drug or device study
(18) Previously completed or withdrawn from this study or any
other study investigating prasugrel
(19) Women who are known to be pregnant, have given birth within
the past 90 d, or are breast-feeding
(20) Concomitant medical illness that in the opinion of the
investigator is associated with reduced survival over the expected
treatment period
(21) Known severe hepatic dysfunction
(22) Any condition associated with poor treatment compliance,
including alcoholism, mental illness, or drug dependence
(23) Intolerance of or allergy to aspirin, ticlopidine, or clopidogrel
(24) May be unable to cooperate with protocol requirements
and follow-up procedures
These doses have been selected on the basis of
nonclinical thrombosis models, nonclinical toxicology
studies,22 dose escalation studies in healthy subjects,23
American Heart Journal
October 2006
dose ranging versus clopidogrel in subjects with
stable coronary artery disease,18 and the JUMBO-TIMI
26 study.20 These studies have demonstrated that
prasugrel can achieve an increase in the inhibition of
adenosine diphosphateinduced platelet aggregation of
approximately 30% compared with the level of IPA
obtained with standard doses of clopidogrel.17,18 In
clinical studies of higher maintenance doses of prasugrel
(z15 mg), there were suggestions of higher rates of
TIMI minimal bleeding.18,20
The dosing regimen of clopidogrel selected for TRI-
TON-TIMI 38 is the standard, approved, labeled LD of
300 mg followed by 75 mg daily. Some contemporary
clinical trials have used higher LDs as part of an
experimental treatment strategy,24,25 or compared
higher to standard doses of clopidogrel in patients using
platelet function measures.26,27 Small-scale clinical stud-
ies have suggested that post-PCI biomarker release may
be less with higher doses of clopidogrel than standard
dosing.26,28 Though many physicians have used these
data to justify the use of higher doses of clopidogrel in
their daily practice, it was determined that there were
insufficient data regarding the efficacy or safety of higher
doses of clopidogrel to justify the comparison between a
nonapproved agent (prasugrel) with a nonapproved off-
label dose of clopidogrel in this registration pathway
trial. Furthermore, TRITON-TIMI 38 will be the first study
adequately powered for clinical end points to formally
test the hypothesis that higher levels of inhibition of
platelets result in improved clinical outcomes, the
inference that is made by providers choosing 600 mg of
clopidogrel. Additional studies are planned to compare
prasugrel with higher-dose clopidogrel with pharmaco-
dynamic end points, though indirect comparisons with
public data suggest that prasugrel 60 mg results in higher
levels of IPA than clopidogrel 600 mg or even 900 mg.
Concomitant medications
All decisions regarding concomitant medications are
left to the treating physician. It is recommended that
long-term aspirin therapy be 75 to 162 mg. Patients may
receive unfractionated heparin, lowmolecular-weight
heparin, any approved direct thrombin inhibitor, and/or
GPIIb/IIIa receptor antagonist. Because of a lack of
information regarding the safety of thienopyridines in
combination with warfarin, blinded study drug is
discontinued in patients requiring anticoagulation with
warfarin, and open-label thienopyridine use is left to the
discretion of the treating physician.
Study end points
The primary end point of the trial is the time of first
occurrence of any element of the composite of CV
death, nonfatal MI, or nonfatal stroke. Cardiovascular
American Heart Journal
Volume 152, Number 4
Table III. Timing of end of study period
Group Subject characteristics at the time of study completion
1 Subjects who have completed 15 m (z436 d)
2 Subjects who have completed at least 6 m but less than 15 m
3 Subjects who have completed fewer than 6 m
(maximum 165 d) at the time of study completion
4 Subjects who have withdrawn consent for
follow-up during the study period
death is considered as any death with a demonstrable CV
cause or any death that is not clearly attributable to a
non-CV cause. Myocardial infarction must be distinct
from the index event and is defined by symptoms
suggestive of ischemia/infarction, electrocardiographic
data, cardiac biomarker, or pathologic evidence of
infarction dependent on the clinical situation using
criteria (Figure 3) adapted from the definition developed
by the American College of Cardiology (Bethesda, MD).29
Stroke is defined as the rapid onset of new, persistent,
neurologic deficit lasting at least 24 hours (or resulting
in death before 24 hours). Major safety end points
include TIMI major bleeding, TIMI major plus minor
bleeding, and life-threatening bleeding (Table IV).
Statistical considerations
Determination of sample size
The study is designed to continue until 875 subjects
with UA/NSTEMI reach one of the components of the
primary end point. This provides 90% power to establish
superiority relative to the primary composite end point
of CV death, nonfatal MI, or nonfatal stroke in the
UA/NSTEMI group. These calculations are based on the
following assumptions: (1) 10.5% of subjects in the
clopidogrel group will develop the primary end point
within 1 year based on extrapolation from CURE and PCI
CURE,5,30,31 (2) an average hazard ratio of 0.80, and
(3) the time-to-first-event analysis based on a 2-sided
log-rank test used at a 2-sided significance level (alpha)
of .05 to assess superiority.
Because of an anticipated lack of proportionality of
hazards, the Gehan-Wilcoxon test will be used for the
primary analysis. The overall power for establishing
superiority is in excess of 90%. Superiority of prasugrel
in all subjects with ACS (UA/NSTEMI/STEMI) will be
evaluated contingent on successfully demonstrating
superiority in subjects with UA/NSTEMI.
For the necessary number of subjects to attain the
primary end point, it is anticipated that 9500 subjects
with UA/NSTEMI will be enrolled. The number of
subjects with STEMI will be capped at 3500 subjects.
Wiviott et al 631
End of study period
Date and time of final visit or day 464, whichever is sooner
Date and time of final study visit or 30 d after
study completion date, whichever is sooner
Date of final visit (minimum 166 d) or 194 d, whichever is sooner
Date consent is withdrawn
This will provide experience with prasugrel across the
entire spectrum of ACS and will allow for direct
comparison of prasugrel to clopidogrel in STEMI and
for the assessment of whether there is a difference of
effect in UA/NSTEMI compared with STEMI. However,
the trial is not designed or powered to demonstrate
superiority in the STEMI population alone.
When 650 subjects with UA/NSTEMI have reached
the primary end point, the pooled blinded event rate
will be used to conservatively predict the number of
additional subjects with UA/NSTEMI that need to be
enrolled in the trial so that 875 subjects with UA/
NSTEMI will reach the primary end point at the end of
the study.
Statistical and analytical plans
Primary analyses will be conducted on end points
adjudicated by an independent clinical events committee.
Efficacy analyses will be carried out using an intention-to-
treat data set. Safety analyses will be carried out using the
treated data set. Safety events that occur after discontin-
uation of study drug and that are considered to be
unrelated to study drug will not be included in the
analyses. All analyses are to be carried out for subjects
with UA/NSTEMI, and all ACS (UA/NSTEMI/STEMI). As an
exploratory analysis, events will be evaluated in all
subjects with ACS enrolled within 72 hours of
symptom onset.
Comparison of the treatment groups relative to
primary and secondary efficacy end points will be
carried out using time-to-first-event analysis via the
Gehan-Wilcoxon test. The potential influence of base-
line risk factors will be assessed in an exploratory
manner using the Cox proportional hazards model.
Comparison of the proportions of events accounting for
repeated occurrences of events within a subject will be
carried out using Poisson regression analysis. All CIs will
be 2 sided with a 95% confidence level, and all
hypothesis tests will be 2 sided carried out using a
P value b.05 as evidence of significance. If the primary
end point fails to achieve superiority by the above
definition, an exploratory noninferiority analysis will be
 American Heart Journal
632 Wiviott et al
October 2006

Figure 3

Schema for definition of MI in TRITON-TIMI 38. Five major sets of criteria will be used for the diagnosis of nonfatal MI:

! ST = elevation or reelevation of ST segment and one of the following:

o ischemic chest pain or equivalent longer than 20 minutes,

o hemodynamic decompensation.

! Spont = spontaneous: CK-MB or troponin greater than the ULN and one of the following:
o ischemic chest pain (or anginal equivalent) greater than 20 minutes

o ST-segment deviation 1 mm or more in one or more leads

! P = PCI: CK-MB greater than 3 times ULN on 2 samples post-PCI, or greater than 5 times ULN on 1 sample,
provided it is the final sample and is greater than 12 hours after PCI.
! C = CABG: CK-MB greater than 10 times ULN on 1 sample after CABG.
! New Q waves 0.04 seconds or longer, or pathology distinct from prior MI.

performed with a boundary of 1.15. Quintiles Corpora-
tion (Research Triangle Park, NC), a contract research
organization, and the TIMI Study Group, Boston, MA,
will have full access to the complete study database and
will independently perform key analyses including
primary efficacy analyses.
The trial is monitored by an independent data-
monitoring committee (DMC) empowered to assess
safety, futility, or overwhelming efficacy. The DMC
consists of a physician chairman, statistician, and
3 physician members. The DMC is supported by an
independent statistician from Quintiles isolated from
the operations of the trial. Tabular summaries of major
safety end points divided by treatment will be sent to
the DMC chairman after 500, 1500, 3000, and
5000 subjects have completed 1 month of therapy,
with review intervals not to exceed 6 months.
Additional safety reviews by the DMC chairman may be
scheduled if judged necessary by the chairman or
operations committee.
Three planned, unblinded, interim analyses will be
conducted by the complete membership of the DMC
when 250, 450, and 650 subjects with UA/NSTEMI have
reached the primary composite end point. All interim
American Heart Journal
Wiviott et al 633
Volume 152, Number 4

Table IV. Major safety end points

TIMI hemorrhage criteria

ICH Clinically overt (including imaging) Hemoglobin drop4

4 (gm/dL)

Major X X z5
Minor X 3 to b5
Minimal X b3

Life-threatening bleeding is a TIMI major bleeding event that meets any of the following criteria: is fatal; leads to hypotension requiring treatment with intravenous inotropic agents;
requires surgical intervention for ongoing bleeding; necessitates the transfusion of 4 or more units of blood (whole blood or packed red blood cells) over a 48-hour period; is a
symptomatic intracranial hemorrhage (ICH).
4To account for transfusions measurements will be adjusted for transfusions. A transfusion of 1 unit of blood will be assumed to result in an increase by 1 g/dL in hemoglobin or 3%
in hematocrit.

regulatory agencies and are set to be achieved only with

Table V. Baseline characteristics
overwhelming superiority, because it is necessary to
Characteristic (N = 7197) have adequate safety data from this study. Because of the
Age in years, median 60
extreme nature of these boundaries and the late period
Age z 75 13 at which they will be assessed, the effects on splitting of
Female 25 the a for the main analyses are so small as to be
Hypertension 59 negligible, and no adjustment in the final analysis is
Diabetes mellitus 21
made. Algorithms for study termination due to safety or
Dyslipidemia 56
Current smoker 40 futility are guided by Herson.32
UA/NSTEMI 56
STEMI 44
Prior MI 16 Study organization
Prior PCI 11 The TRITON-TIMI 38 trial is sponsored by Eli Lilly and
Prior CABG 7 Company (Indianapolis, IN) and Daiichi Sankyo Co.
Region of enrollment
(Parsippany, NJ), and is coordinated by the TIMI Study
North America 33
Western Europe 27 Group. Quintiles Corporation serves as the contract
Eastern Europe 24 research organization and provides data and site man-
Middle East 10 agement services. The steering committee is responsible
Africa 3 for the scientific content of the protocol, protocol
Asia Pacific 2
implementation, results presentation, and written
South America 0
manuscripts. Trial operations are monitored and coor-
Results are in percentage unless otherwise stated. dinated by the operations committee (Appendix A).

analyses will be conducted in view of terminating the
trial because of excessive mortality in prasugrel-treated
patients or excessive life-threatening bleeding due to
prasugrel versus clopidogrel, and if the predicted
incidence of life-threatening bleeding for prasugrel
exceeds historic levels.
Discontinuation of the study because of futility will be
considered at the time of the second and third interim
analyses if the accumulating data suggest a very low
likelihood (b1%) of a statistically significantly lower
primary end point event rate for prasugrel in the
subjects with UA/NSTEMI at the conclusion of the study.
Discontinuation of the study because of overwhelming
efficacy will be considered at the time of the third
interim analysis only if all of the following are observed
in the UA/NSTEMI cohort: (1) a P value b.000 01 for the
primary end point, (2) a P value b.0001 for CV death/MI,
(3) a P value b.001 significance for CV death. The
efficacy stopping rules have been endorsed by the
Baseline characteristics
TRITON-TIMI 38 began enrollment in November
2004. Patients have been enrolled at more than 450 sites
in 21 countries. The baseline characteristics are listed
in Table V.
Summary
TRITON-TIMI 38 is a phase 3, randomized, double-
blind, double-dummy, parallel-group, clinical trial that
assesses the efficacy and safety of prasugrel compared
with that of clopidogrel in patients with an ACS
undergoing PCI. This trial will provide important infor-
mation regarding the safety and efficacy of prasugrel and
whether this agent is superior to the current standard of
care. Furthermore, this is the first large-scale clinical
events trial that assesses whether a thienopyridine
regimen that achieves a higher level of IPA than
the standard clopidogrel therapy results in
improved outcomes.

634 Wiviott et al
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American Heart Journal
Volume 152, Number 4
Appendix A
Trial Operations
OPERATIONS COMMITTEE
TIMI Study Group, Brigham and Womens
Hospital, Boston, MA
Eugene Braunwald, Chairman; Carolyn H. McCabe, Director;
Elliott M. Antman, Principal Investigator; C. Michael Gibson,
CoPrincipal Investigator; Stephen D. Wiviott, Coinvestigator;
Amy McCagg, Project Coordinator; Susan McHale, Project
Coordinator.
Data Coordinating Center, Randomization, and
Site Management: Quintiles Incorporated, Research
Triangle, NC
Timothy Bidgood, Gary Shorter.
Eli Lilly and Company, Indianapolis, IN (Sponsor)
Jeffery Riesmeyer, J. Anthony Ware, Govinda Weerakkody,
William Macias, Elena Moscarelli.
Daiichi Sankyo Co. (Sponsor)
Jeffrey Warmke, Francis Plat, Indu Patel, Tomas Bocanegra,
Laurent Kassalow.
STEERING COMMITTEE
Members of the Operations Committee and Gilles Mon-
telescot, France; CoPrincipal Investigator, Lars Aaberge,
Norway; Henning Rud Anderson, Denmark; Diego Ardissino,
Italy; Phillip Aylward, Australia; Ramon Corbalan, Chile;
Anthony Dalby, South Africa; Stefano DeServi, Italy; Viliam
Fridrich, Slovak Republic; Mark Furman, United States; Shaun
Goodman, Canada; Shmuel Gottlieb, Israel; Enrique Gurfinkel,
Argentina; Kurt Huber, Austria; Matyas Keltai, Hungary; Dean
Wiviott et al 635
Keriakes, United States; Neal Kleiman, United States; Jose
Lopez-Sendon, Spain; Thomas Luscher, Switzerland; Franz-
Josef Neumann, Germany; Jose Nicolau, Brazil; Jeffrey
Popma, United States; Witold Ruzyllo, Poland; Fredrik
Schersten, Sweden; Albert Schomig, Germany; Ricardo Sea-
bra-Gomes, Portugal; Axel Sigurdsson, Iceland; Philippe
Gabriel Steg, France; Mikko Syvanne, Finland; Frans Van de
Werf, Belgium; Freek Verheugt, Netherlands; Harvey White,
New Zealand; Petr Widimsky, Czech Republic; Robert
Wilcox, United Kingdom.
Data Monitoring Committee
Chairman: David William, United States
Statistician: David DeMets, United States
Members: Christoph Bode, Germany; Spencer King, United
States; Ulrich Sigwart, Switzerland
Clinical Events Committee
Chairman: Benjamin Scirica, United States
Core Laboratories
! Sample Bank: Sandra Close-Kirkwood
! ECG: TIMI Ambulatory ECG Core Laboratory, Brigham and
Womens Hospital, Boston, MA; Benjamin M. Scirica
! Platelet Function: Center for Platelet Studies, University of
Massachusetts, Alan Michelson, Director; Mark Furman,
Andrew Frelinger III
! Angiographic: TIMI angiographic core laboratory,
C. Michael Gibson, Director
! Economic and Quality of Life: Economic and Quality of Life
Assessment Group: David J. Cohen, Harvard Clinical
Research Institute, United States; Elizabeth Mahoney, New
England Research Group, United States