A direct comparison of tirofiban and abciximab during percutaneous ...

Trial Design
A direct comparison of tirofiban and abciximab
during percutaneous coronary revascularization
and stent placement: Rationale and design of the
TARGET study
David J. Moliterno, MD, and Eric J. Topol, MD, for the TARGET International Steering Committee* Cleveland, Ohio
Background Trials testing intravenous platelet glycoprotein IIb/IIIa antagonists in the setting of percutaneous coronary
revascularization and empirically during acute coronary syndromes have consistently demonstrated a reduction in
ischemic events. These trials, however, have varied regarding patient population, type, duration and timing of IIb/IIIa therapy,
adjunct therapies, and methods for collection and adjudication of end points. All trials were placebo-controlled, and
none involved a direct comparison of IIb/IIIa inhibitors. Whether these agents produce a similar clinical outcome in the contemporary
practice of coronary interventions is uncertain.
Methods and Results To evaluate the efficacy of tirofiban in patients undergoing percutaneous revascularization
with stent placement, a randomized, multicenter, double-blind, double-dummy, abciximab-controlled study is currently underway.
All patients will receive preprocedural clopidogrel, weight-adjusted heparin, and aspirin. In 18 countries, 4750
patients undergoing nonemergency percutaneous coronary revascularization will be studied. The primary end point will be
the composite 30-day occurrence of death, myocardial infarction, or urgent target vessel revascularization. Secondary end
points will include 6-month death, myocardial infarction, or any myocardial revascularization and 1-year death.
Conclusion This is the first large-scale, head-to-head comparison of 2 established IIb/IIIa inhibitors in interventional cardiology.
Enrollment is expected to be complete by mid-2000. (Am Heart J 2000;140:722-6.)
Threatened and abrupt vessel closure during or shortly
after percutaneous coronary intervention (PCI) is known
to be caused by platelet-rich thrombus and vessel wall
disruption. 1,2 Intracoronary stent placement mechanically
lowers the incidence of abrupt vessel closure and
restenosis but can cause side-branch vessel closure and
atherothrombotic embolization. 3-5 These sequelae are
also associated with an increase in platelet activation,
periprocedural creatine kinase release, and late death. 5-7
Platelet glycoprotein IIb/IIIa inhibitors pharmacologically
block platelet aggregation and reduce the incidence of
ischemic events associated with acute coronary syndromes,
percutaneous coronary revascularization, and
intracoronary stent placement. 5,8-14 Several agents (abciximab
[ReoPro], eptifibatide [Integrilin], and tirofiban
[Aggrastat]) are now in widespread clinical use.
The largest trial studying intracoronary stent implanta-
From The Department of Cardiology and the Cleveland Clinic Cardiovascular Coordinating
Center, The Cleveland Clinic Foundation, Cleveland, Ohio.
*The Steering and Executive Committee members are listed in the Appendix.
Submitted April 11, 2000; accepted July 12, 2000.
Reprint requests: David J. Moliterno, MD, Department of Cardiology, F-25, The
Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
E-mail: molited@ccf.org
Copyright © 2000 by Mosby, Inc.
0002-8703/2000/$12.00 + 0 4/1/110094
doi:10.1067/mhj.2000.110094
tion randomly assigned patients to abciximab or
placebo. The Evaluation of Platelet IIb/IIIa Inhibitor for
Stenting (EPISTENT) trial randomly assigned 2399
patients to intracoronary stent with placebo, balloon
angioplasty with abciximab, or intracoronary stent with
abciximab. 5 This study was able to compare short-term
and long-term safety and efficacy outcomes of a
mechanical strategy, a pharmacologic strategy, and the
combination. The primary end point, 30-day composite
of death, myocardial infarction (MI), and urgent target
vessel revascularization, occurred in 10.8% of the
stent/placebo group, 6.9% of the balloon/abciximab
group, and 5.3% of the stent/abciximab group. The
reduction in ischemic events by the combination of
stent placement plus abciximab compared with stent
alone was highly significant (hazard ratio 0.48 [95% confidence
interval, 0.33-0.69], P < .001). The leading
reduction in events was for death and large MI, and the
treatment effect of abciximab persisted at 6-month follow-up.
Likewise, the 1-year mortality rate was 57%
lower for those assigned to stent/abciximab compared
with stent alone (1.0% vs 2.4%; P = .037). 7 Recently, the
Enhanced Suppression of Platelet Receptor GP IIb/IIIa
Using Integrilin Therapy (ESPRIT) investigators reported
results from the placebo-controlled trial testing eptifibatide,
a small-molecule, short-acting IIb/IIIa antagonist,

American Heart Journal
Volume 140, Number 5 Moliterno and Topol 723
among patients undergoing elective stent placement.
The preliminary 30-day results showed a 35% relative
risk reduction in the composite end point of death, MI,
and urgent revascularization with eptifibatide (10.4% vs
6.8%). 15
Tirofiban, also a small-molecule IIb/IIIa inhibitor, has
been studied in both PCI 12 and in acute coronary syndromes.
13,14 The Randomized Efficacy Study of Tirofiban
for Outcomes and Restenosis (RESTORE) trial randomly
assigned 2141 patients to placebo or a bolus and 36-hour
infusion of tirofiban. The 30-day occurrence of death, MI,
or any target vessel revascularization for ischemia was
nonsignificantly reduced by 16% with tirofiban compared
with placebo (10.3% vs 12.2%; P = .169). Death or
MI was reduced 19%, and using the same 30-day composite
end point as the abciximab trials (ie, including only
target vessel revascularization procedures which were
urgent), end point events were reduced 24% by tirofiban
(8.0% vs. 10.5%, P = .052). The Platelet Receptor Inhibition
for Ischemic Syndrome Management in Patients Limited
by Unstable Signs and Symptoms (PRISM-PLUS) trial
studied patients with an acute coronary syndrome. Of
the 1915 patients in the trial, 475 underwent PCI after
receiving 48 hours of heparin and aspirin (control group)
versus tirofiban, heparin, and aspirin. In this PCI subgroup,
the probability of death or MI at 30 days was
reduced by 44% with tirofiban (relative risk = 0.56; 95%
confidence interval, 0.29-1.09).
Because the large-scale clinical trials testing tirofiban
were completed before the widespread use of intracoronary
stents, there are limited data regarding their
combination. With this in mind, we undertook the current
study. The purpose of this study, the Do Tirofiban
and ReoPro Give Similar Efficacy Outcomes Trial (TAR-
GET), is to assess the efficacy of tirofiban in patients
undergoing planned PCI with an intracoronary stent
and to compare the efficacy of tirofiban versus abciximab
in this population.
Patient population and entry criteria
Patients from 18 countries scheduled to undergo nonemergency
PCI with stent placement to a native coronary
artery or arterial or venous coronary bypass graft
are eligible for study entry. The percutaneous revascularization
strategy may include any approved (noninvestigational)
angioplasty catheter, atherectomy device, or
stent. If multivessel PCI is being performed, stent placement
should be planned for all sites. Study exclusion
criteria include direct or rescue PCI for acute MI or
planned staged procedure. Patients are excluded if they
have received low-molecular-weight heparin, tirofiban,
or eptifibatide within 10 hours or fibrinolytic therapy
within 24 hours; undergone PCI or received abciximab
within 14 days; had prolonged cardiopulmonary resuscitation
within 2 weeks; major surgery (including noncutaneous
biopsy, any ophthalmologic or coronary
bypass surgery) or an investigation drug or device
within 1 month; severe physical trauma within 6
weeks; gastrointestinal or genitourinary bleeding within
3 months; transient neurologic ischemic attack within 6
months; or nonhemorrhagic stroke within 2 years.
Patients are also excluded for allergy, intolerance, or
contraindication to any study medication. Other exclusions
are pregnancy, pericarditis, significant retinopathy,
persistent systolic blood pressure 180 mm
Hg or diastolic blood pressure >105 mm Hg, coagulopathy
or clinically important abnormal laboratory findings
(including protime international normalized ratio >1.5,
platelet count

724 Moliterno and Topol
American Heart Journal
November 2000
Figure 1
TARGET study schematic.
venously within 24 hours of the procedure and 75 to
325 mg daily throughout the study follow-up. An oral
loading dose of clopidogrel will be administered within
2 to 6 hours before the procedure when possible. If the
coronary anatomy is unknown (ie, ad hoc PCI after
diagnostic angiography), clopidogrel may be given as
late as immediately before the procedure. For patients
having taken 75 mg of clopidogrel daily (or ticlopidine
250 mg twice daily) for ≥3 days or who have otherwise
received ≥300 mg within the previous 48 hours, only
75 mg clopidogrel will be given before the procedure.
All patients (even those in whom a stent cannot be
placed) will receive 75 mg clopidogrel daily for 30 days
after the procedure.
Guidelines for intravenous unfractionated heparin
administration will be given, but dosing may be modified
based on investigators’ clinical assessment. A targeted
activated clotting time (ACT) of 250 seconds is
recommended. For patients not receiving heparin
within 4 hours of the procedure, a 70-U/kg bolus will
be given. For patients receiving heparin within 4 hours
and a preprocedural ACT

American Heart Journal
Volume 140, Number 5 Moliterno and Topol 725
mine the overall rate of patients reaching an end point.
Since this rate was below 5.3%, the sample size was
increased to 4750.
Discussion
Several features of this study are worth highlighting.
To begin, this will be the first trial directly comparing 2
IIb/IIIa antagonists. Previous placebo-controlled PCI trials
testing the various agents have substantially differed,
and these dissimilarities confound even indirect comparisons
of agents. Considering the cost differences
among agents, a head-to-head trial has both scientific
and financial importance. Second, this will be the
largest prospective study involving coronary stents.
Other than EPISTENT (1603 patients with stents), most
prospective stent studies have been for new device
approval, and they have been relatively small. Third,
unlike EPISTENT, which primarily included the first
generation Johnson & Johnson coronary stent, this trial
will involve second and third generation coronary
stents. Fourth, the TARGET trial will be the first largescale
IIb/IIIa trial to allow any approved revascularization
device (eg, rotational, laser, and extraction atherectomy).
Finally, the trial will allow and incorporate
practical aspects of real-world interventional procedures,
including preprocedural clopidogrel as well as
ad hoc interventions with procedural clopidogrel loading,
vascular closure devices, and ambulation during
study drug infusion.
Because TARGET is comparing 2 approved and established
drugs (ie, an active comparator trial), the statistical
design and sample size are based on a noninferiority
hypothesis. As such, tirofiban tested as an adjunct to
intracoronary stenting is hypothesized to prevent
ischemic events within the range of effect observed
with abciximab. In clinical trials several factors affect
sample size, including the expected end point event
rate in the study group and the statistical design. For
example, phase III cardiovascular pharmacologic trials
testing new agents are often placebo-controlled, have a
low primary end point event rate, are large in scale, and
are based on a superiority hypothesis. Other trials, testing
a modification of a pharmacologic agent, may be
statistically based on equivalency, such as the testing of
recombinant tissue plasminogen activator versus TNKtissue
plasminogen activator (tenecteplase) and are
moderately large in size. These and other factors are
importantly influencing clinical trials in the new millennium.
17
Considering interagent differences, abciximab and
tirofiban are respectively distinguishable by structural
characteristics (antibody vs peptidomimetic), molar
concentration per IIb/IIIa receptor (2 vs >250), receptor
specificity (α IIb β 3 , α v β 3 , and MAC-1 vs α IIb β 3 –specific),
and duration of antiplatelet effect (days vs
hours). The doses of abciximab and tirofiban administered
in this study have been shown to inhibit ADPinduced
platelet aggregation potently to a similar
degree (>80% to 90%) and in a similar proportion of
patients. 18,19 Abciximab has been shown to lower the
occurrence of ischemic events at 30 days in PCI trials
by approximately 35% to 50% 5,10,11 compared with an
approximate 20% lowering observed in most small-molecule
PCI studies. 12,20 Most recently, the preliminary
30-day results from the ESPRIT trial show a 35% reduction
in the composite end point of death, MI, and
urgent revascularization with eptifibatide, 15 but again
leave uncertainty whether this is comparable to the
55% reduction in the same end point as seen with
abciximab in EPISTENT. 5 Also, the early benefits of
abciximab have been shown to be durable at 6 months,
and more recently a 1-year mortality rate benefit has
been observed for patients receiving a coronary stent
with abciximab. Regardless, it remains unclear if these
results reflect potential differences among agents, trial
designs, or both.
The TARGET trial should provide valuable insight into
the clinical importance of potent α IIb β 3 antagonism by
different inhibitory mechanisms. It will also provide
additional information on the durability of clinical benefit
and impact on late death. Beyond this needed information,
a key insight will be available for the outcome
of patients treated with a contemporary, real-world
approach. The trial is expected to complete its enrollment
in mid-2000.
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Appendix
International Steering and Executive Committees
Topol EJ (chair), Ardissino D, Bassand J-P, Beauchamp
GD, Bertrand M, Bunt T, Chronos NA, Cohen E, Cohen
M, Demopoulos L, DiBattiste P, Hamm C, Herrmann
HC, Kristensen SD, Lange RA, Miguel CM, Meier B,
Moliterno DJ, Neumann FJ, Stone GW, Yakubov SJ,
Yeung AC