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160 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Additional, although circumstantial, evidence to support the theory that it is the bolus
dose of tirofiban that may be inadequate can be found in a German study (48) that measured
the IPA in 60 patients undergoing coronary stenting for symptomatic coronary artery dis-
ease who were randomized to abciximab, eptifibatide, or tirofiban. The dose of tirofiban
was the same as that used in the TARGET trial. Platelet aggregometry using 20 µM ADP was
performed on serial blood samples obtained starting at 2 h following initial drug adminis-
tration. At the 2-h time interval, there were no significant differences in the mean inhibition
or in the percentage of patients achieving >80% inhibition with either drug. This degree
of platelet inhibition was subsequently maintained for the duration of the infusion. The
results of these two studies suggest that following a bolus of 10 µg/kg, tirofiban less effec-
tively inhibits platelet aggregation than does the corresponding abciximab bolus but by
1–2 h into the infusion the degree of platelet inhibition is equivalent. These observations may
also help explain the efficacy of tirofiban in the medical management of patients presenting
with an acute coronary syndrome who are pretreated with tirofiban prior to undergoing PCI.
PCI IN PATIENTS PRETREATED WITH TIROFIBAN
Two large-scale trials, PRISM-PLUS (42) and TACTICS-TIMI 18 (49), have involved
patients presenting with unstable angina or non-ST-elevation MI who were initially treated
with tirofiban and subsequently underwent PCI. A review of these trials will help to define
further the role of tirofiban in the cardiac catheterization laboratory, especially since many
patients are referred for coronary angiography and intervention only after having failed
aggressive medical therapy with aspirin, heparin, and a GPIIb/IIIa inhibitor such as tirofiban.
PRISM-PLUS
STUDY DESIGN
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited
by Unstable Signs and Symptoms (PRISM-PLUS) trial was a randomized, double-blind,
Fig. 11. Comparison of the extent of inhibition of platelet aggregation (20 µM ADP) by tirofiban and
abciximab as a function of time post bolus and anticoagulant. With citrate as anticoagulant, the inhi-
bition of platelet aggregation at 15 min is significantly lower with tirofiban than abciximab. (Adapted
from ref. 47, with permission.)
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Chapter 7 / Tirofiban: The RESTORE and TARGET Trials 161
multicenter study of 1915 patients with Canadian Cardiovascular Society class III or IV
angina and either ischemic ECG changes or elevated levels of cardiac enzymes who were
randomized to one of three dosing regimens: (1) tirofiban (0.6 µg/kg/min for 30 min,
followed by an infusion of 0.15 µg/kg/min) plus placebo heparin; (2) tirofiban (0.4 µg/
kg/min bolus over 30 min, followed by an infusion of 0.1 µg/kg/min) plus dose-adjusted
heparin; or (3) dose-adjusted heparin plus placebo tirofiban. Study medications were
infused for a minimum of 48 h, and all patients also received 325 mg of aspirin daily.
Between 48 and 96 h, all patients were encouraged to proceed with coronary angiography
and coronary intervention if indicated. In patients undergoing PCI, tirofiban (or tirofiban
placebo) was continued for 12–24 h following the procedure, whereas the heparin was
discontinued at the end of the procedure and the sheaths removed at least 2 h later. After
the first interim efficacy analysis, the tirofiban-only arm was discontinued because of an
excess mortality (4.6% vs 1.1%, tirofiban vs heparin, respectively).
The primary endpoint of the trial was the 7-d composite of all-cause mortality, new MI,
refractory ischemia, or rehospitalization for unstable angina. A prospectively defined anal-
ysis examined the occurrence of the composite endpoint at 30 d in the subgroup of 475
patients who underwent PTCA.
R
ESULTS
The addition of tirofiban to heparin therapy significantly decreased the occurrence of
the composite endpoint at 7 d from 17.9% in the heparin-only arm to 12.9% in the tiro-
fiban plus heparin arm (RR = 0.68, 95% CI = 0.53-0.88, p = 0.004). Although the absolute
difference decreased over time, the reduction in the composite endpoint remained statis-
tically significant at 30 d and 6 mo. This reduction was primarily driven by a 47% reduc-
tion in the incidence of MI and a 50% reduction in the incidence of refractory ischemia.
The mortality rate at all time points was similar in both groups. The beneficial effect of tiro-
fiban on the incidence of MI was apparent as early as 48 h into therapy, coincident with
the duration of the medical stabilization phase of the trial.
During the initial hospitalization 90% of patients underwent coronary angiography,
and angioplasty was subsequently performed on 30.5% of all patients, at the discretion of
the attending physician. In this subgroup, the 30-d composite endpoint occurred in 8.8%
of patients in the tirofiban plus heparin group and in 15.3% of patients in the heparin-only
group, suggesting that patients with an acute coronary syndrome who undergo PCI derive
particular benefit from pretreatment with tirofiban in addition to aspirin and heparin.
The mechanism of this benefit is most likely a reduction in intracoronary thrombus
burden and improved coronary flow. In an angiographic substudy of PRISM-PLUS, 1491
angiograms were analyzed at the core angiographic laboratory for the extent of intracor-
onary thrombus, Thrombolysis in Myocardial Infarction (TIMI) flow grade, and lesion
severity (50). The clot burden was classified using the TIMI thrombus grading system, in
which grade 1 is defined as a possible thrombus, grade 2 a small thrombus [<0.5× normal
lumen diameter (NLD)], grade 3 a medium-sized thrombus (0.5–1.5× NLD), grade 4 a
large thrombus (>1.5× NLD), grade 5 a recent thrombotic occlusion, and grade 6 a chronic
occlusion. The primary angiographic endpoint was the proportion of patients with each
grade of TIMI thrombus excluding grade 6, since chronic occlusions were unlikely to be
the cause of the presenting acute coronary syndrome. Predefined secondary endpoints
included TIMI flow grade and lesion severity. Compared with heparin alone, tirofiban
plus heparin significantly reduced intracoronary thrombus burden by 23% (OR = 0.77,
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162 Part II / GPIIb/IIIa Blockade During Coronary Intervention
p = 0.022) and significantly increased the proportion of patients with TIMI 3 flow (OR =
0.65 for TIMI 2 or less vs TIMI 3, p = 0.002). Persistence of thrombus was associated with
a twofold increase in the composite endpoint at 30 d.
A
NALYSIS
The results of the PRISM-PLUS study suggest that significant clinical benefit can be
anticipated from the early initiation of tirofiban in patients with acute coronary syndrome.
This benefit was evident as early as 48 h into therapy, implying that tirofiban is effective
in patients who are treated medically. These results are consistent with a recent metaanal-
ysis of trials of GPIIb/IIIa inhibitors in acute coronary syndrome: an overall 34% reduc-
tion in the incidence of death or nonfatal MI was noted during the initial period of medical
stabilization prior to PCI (51).
A reduction in the composite endpoint in PRISM-PLUS was also present at 7 d, 30 d,
and 6 mo in the combination therapy group. Most of the benefit at these time points was
conferred on the subset of patients who underwent PCI. In fact, the incidence of the com-
posite endpoint at 30 d in the group of patients treated with medical management alone,
although favoring combination therapy, was not significantly different from that in the hep-
arin-only group (RR = 0.87, 95% CI = 0.6-1.25).
Based on the results of the angiographic substudy, it is evident that the mechanism
responsible for the observed clinical benefit is a reduction in the thrombus burden and an
improvement in coronary flow. Mechanistically, this may also explain why some of the
initial comparative trials of early invasive or conservative therapy for patients with acute
coronary syndrome, which did not include GPIIb/IIIa inhibitor therapy, demonstrated a
worse outcome in the invasive arms (52). In light of this apparent paradox, the TACTICS-
TIMI 18 trial was designed to compare directly an early invasive or conservative treat-
ment strategy in acute coronary syndrome patients treated with tirofiban combination
therapy.
TACTICS-TIMI 18
STUDY DESIGN
The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or
Conservative Strategy (TACTICS-TIMI 18) trial randomized 2220 patients with unstable
angina or non-ST-elevation MI to early invasive or conservative therapy. All patients
were treated with aspirin and unfractionated heparin (5000 U bolus followed by a 1000
U/h infusion for 48 h), and tirofiban was administered as a 0.4 µg/kg/min bolus over 30 min
followed by a maintenance infusion of 0.1 µg/kg/min for 48 h or until revascularization.
For patients undergoing percutaneous revascularization, the tirofiban infusion was con-
tinued for at least 12 h after the procedure. Patients were eligible for inclusion if they had
experienced either a prolonged episode of angina or recurrent episodes at rest or with
minimal exertion within the previous 24 h that were associated with ischemic ECG changes,
abnormal cardiac enzymes, or prior evidence of documented coronary artery disease.
Patients were excluded if they presented with persistent ST-segment elevation, had under-
gone a PCI or CABG within the previous 6 mo, had evidence of severe congestive heart
failure or cardiogenic shock, or were felt to be at increased risk of bleeding.
Patients randomized to an early invasive strategy were to undergo diagnostic catheteri-
zation between 4 and 48 h after randomization, followed by PCI or CABG as appropriate.
Patients randomized to early conservative therapy underwent invasive procedures only
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Chapter 7 / Tirofiban: The RESTORE and TARGET Trials 163
if they failed medical therapy, as defined by the occurrence of any of the following: refrac-
tory angina, hemodynamic instability, documented ischemia on routine or nuclear stress test-
ing, rehospitalization for recurrent angina, or new MI. The primary endpoint was the 6-mo
composite of death, nonfatal MI, and rehospitalization for an acute coronary syndrome.
R
ESULTS
In the group of patients randomized to an early invasive therapy, diagnostic catheter-
ization was performed in 97%, a median (25th, 75th percentiles) of 22 (18, 39) h after ran-
domization. Subsequent revascularization with PCI or CABG was performed in 60% of
patients, a median of 25 (19, 46) and 89 (48, 142) h after randomization, respectively. Coro-
nary stents were used in 83% of coronary interventions in the invasive group. Tirofiban
therapy was administered in 94% of cases.
At 6 mo, the primary endpoint had occurred in 15.9% of patients in the invasive group
as opposed to 19.4% of patients in the conservative group (OR = 0.78, 95% CI = 0.62–0.97,
p = 0.025). This reduction was evident as early as 30 d after randomization (7.4% vs
10.5%, p = 0.009). The predominant benefit was seen in the reduction of nonfatal MI and
rehospitalization for recurrent angina and not in a reduction in mortality.
A
NALYSIS
The many similarities between the patients in the TACTICS trial and those in the TARGET
trial allow for several important comparisons. The difference in the incidence of death
or nonfatal MI (an endpoint chosen for comparison given the different definitions of the
primary endpoint in each study) between abciximab and tirofiban at 30 d in TARGET is
no longer evident when the event rate in the abciximab arm in TARGET (5.7%) is com-
pared with the event rate in the invasive arm of TACTICS (4.7%). The fact that the patients
in the invasive arm of TACTICS underwent PCI later than those in TARGET suggests
several hypotheses that may explain the above observation. It is possible that suboptimal
bolus dosing of tirofiban contributed to its reduced efficacy in TARGET, or that a longer
tirofiban infusion is required prior to PCI in order to passivate the lesion and reduce
complications. The preponderance of evidence to date clearly shows that several hours
into an infusion of tirofiban the inhibition of platelet aggregation is similar to that pro-
vided by abciximab and well above the accepted cutoff of 80% (see TARGET section).
Additionally, pretreatment with tirofiban, which, in PRISM-PLUS, was shown to decrease
the thrombus burden and improve coronary flow, may prevent the occurrence of distal
microembolization that often results in small myocardial infarctions. Prevention of these
periprocedural infarcts is consistent with the observation that the main benefit observed
in these trials was in a lower incidence of nonfatal MI.
In light of the increased use of tirofiban in the initial treatment of patients with acute
coronary syndrome, the results of the TARGET trial raise the question of whether to switch
to abciximab in patients on tirofiban who are referred for PCI. Although a small, single-
center study of 50 patients did document a further reduction in platelet function without
a higher incidence of bleeding or thrombocytopenia when abciximab was substituted for
tirofiban in acute coronary syndrome patients undergoing PCI (53), our practice is to con-
tinue the tirofiban during the intervention. This strategy is supported by the low incidence
of adverse outcomes in the patients randomized to the early invasive arm of the TACTICS
trial and by the pharmacodynamic studies showing equivalent degrees of platelet inhibi-
tion between abciximab and tirofiban after the first 2 h of drug infusion.
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164 Part II / GPIIb/IIIa Blockade During Coronary Intervention
CONCLUSIONS
Tirofiban is a specific antagonist of the GPIIb/IIIa receptor with unique pharmacologic
properties that distinguish it from the other agents in its class that have been approved
by the Food and Drug Administration. A wealth of evidence from well-designed, large-
scale trials now exists confirming that therapy with tirofiban reduces the incidence of
adverse cardiac events in acute coronary syndrome patients treated medically as well as
in patients undergoing PCI directly. In both groups, the observed benefits include a
reduction in the combined incidence of death or MI as well as a reduction in the incidence
of refractory ischemia or need for urgent repeat revascularization. Furthermore, it is evi-
dent that in patients with acute coronary syndrome who are initially treated medically, the
ones who derive the greatest benefit are those who subsequently proceed to cardiac cathe-
terization and coronary intervention.
Inevitable comparisons with abciximab suggest that for younger acute coronary syn-
drome patients, abciximab is the superior agent, resulting in a reduced incidence of non-
fatal MI within 30 d after intervention. However, for nonacute coronary syndrome patients
undergoing elective stenting, there appears to be no discernable difference in outcomes
between the two agents, and the shorter half-life, lower incidence of profound thrombo-
cytopenia, and lower cost of tirofiban make it an attractive alternative to abciximab. More-
over, multiple small-scale studies have suggested that the difference in efficacy between
the two agents may be a result of an inadequate bolus dose of tirofiban, resulting in sub-
optimal platelet inhibition at the time of coronary intervention. A multicenter, dose-escala-
tion study of the bolus dose of tirofiban is currently under way to address this issue.
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Chapter 8 / Overview of the GPIIb/IIIa Interventional Trials 167
167
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
8 Overview of the Glycoprotein
IIb/IIIa Interventional Trials
CONTENTS
INTRODUCTION
THE AGENTS
THE RANDOMIZED TRIALS
SYNTHESIS OF THE RANDOMIZED TRIALS
RECOMMENDATIONS
SUMMARY
REFERENCES
A. Michael Lincoff, MD and Eric J. Topol, MD
INTRODUCTION
Plaque rupture and vascular thrombosis are key initiating factors in the pathogenesis
of ischemic complications of percutaneous coronary revascularization (1,2). The central
role of platelet activity in this setting is highlighted by the unequivocal benefit of aspirin
in preventing death or myocardial infarction among patients undergoing coronary inter-
vention (3). Newer strategies for more potent inhibition of platelet activity at the injured
coronary plaque focus on the integrin glycoprotein (GP) IIb/IIIa receptor on the platelet
surface membrane, which binds circulating fibrinogen or von Willebrand factor and cross-
links adjacent platelets as the final common pathway to platelet aggregation (4). Pharma-
cologic compounds directed against GPIIb/IIIa block this receptor, prevent binding of
circulating adhesion molecules, and potently inhibit platelet aggregation.
The studies and trials evaluating the roles of specific GPIIb/IIIa inhibitors in the setting
of percutaneous coronary intervention (PCI) have been described in detail in Chapters
5–7. Trials evaluating the efficacy of GPIIb/IIIa blockade during primary angioplasty for
acute myocardial infarction are discussed in Chapter 12. The present chapter reviews the
body of clinical data regarding this class of agents during coronary revascularization and
provides a perspective on the efficacy, safety, patient selection, and optimal use of this
new therapeutic strategy.
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168 Part II / GPIIb/IIIa Blockade During Coronary Intervention
THE AGENTS
Three intravenous GPIIb/IIIa antagonists have undergone large-scale Phase III and
Phase IV trial evaluation in the setting of percutaneous coronary revascularization, and
all are currently approved for clinical use by the United States Food and Drug Administra-
tion. Abciximab (c7E3 Fab, ReoPro
™
, Centocor, Malvern, PA), the first agent of this class,
is a human-murine chimeric monoclonal Fab antibody fragment that binds with high
affinity and a slow dissociation rate to the GPIIb/IIIa receptor (5,6). Abciximab is cleared
rapidly from the plasma (half-life of approx 25 min) (7) but remains bound to circulating
platelets for as long as 21 d (8). Binding of abciximab is not specific for the platelet GPIIb/
IIIa receptor; this agent has equal affinity for the vitronectin receptor (α
v
β
3
), which appears
to play a role in cell adhesion, migration, and proliferation. Eptifibatide (Integrilin
™
, COR
Therapeutics, South San Francisco, CA), a cyclic heptapeptide based on the Lys-Gly-
Asp (KGD) amino acid sequence, is a highly specific, competitive inhibitor of the GPIIb/
IIIa complex. Blockade of the receptor by eptifibatide is rapidly reversible, with a plasma
half-life in humans of about 2.5 h (9). Tirofiban (Aggrastat
™
, Merck, White House Station,
NJ) is a tyrosine-derivative nonpeptide mimetic inhibitor of GPIIb/IIIa, which also spe-
cifically and competitively binds to the receptor in a rapidly reversible fashion (10) and
has a short (approx 1.6 h) serum half-life. Platelet aggregation is inhibited by all these
agents in a dose-related manner, with nearly complete abolition of platelet thrombosis at
levels of receptor occupancy >80% (6). After discontinuation of abciximab, platelet aggre-
gation returns toward baseline over the subsequent 12–36 h (6), whereas normalization
of platelet function occurs much more quickly (over 30 min to 4 h) following discontinu-
ation of the reversible eptifibatide or tirofiban (9,10).
THE RANDOMIZED TRIALS
The role of GPIIb/IIIa inhibitors administered as periprocedural intravenous therapy
in the setting of PCI has been tested in 12 large-scale, randomized, controlled trials enroll-
ing in total over 25,000 patients. Six of these trials were placebo-controlled evaluations
during elective or urgent PCI: EPIC of abciximab among patients considered to be at high
risk, EPILOG of abciximab in a broad spectrum of patients undergoing elective or urgent
revascularization, EPISTENT of abciximab among patients suitable for stent implantation,
IMPACT-II of lower dose eptifibatide in a broad patient population undergoing balloon
angioplasty, ESPRIT of a high-dose, double-bolus eptifibatide regimen during elective
or urgent stenting, and RESTORE of tirofiban during balloon angioplasty for unstable
ischemic syndromes. Four trials have tested abciximab vs placebo or “conventional
care” among patients with acute myocardial infarction undergoing balloon angioplasty
(RAPPORT) or stenting (ISAR-2, ADMIRAL) or in a 2-by-2 factorial design randomized
to angioplasty or stenting (CADILLAC). CAPTURE tested the role of abciximab as treat-
ment prior to angioplasty among patients with refractory unstable angina. TARGET is the
only direct comparative trial carried out thus far, testing the relative efficacy of abciximab
and tirofiban during PCI among patients outside the setting of acute myocardial infarction.
Trial Designs
Study algorithms are summarized in Fig. 1, enrollment details provided in Table 1, and
details regarding heparin dosing listed in Table 2. Individual trial protocols are described,
and efficacy and safety findings are detailed in subsequent sections.
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Chapter 8 / Overview of the GPIIb/IIIa Interventional Trials 169
Trial Protocols
THE EPIC TRIAL
EPIC is described in detail in Chapter 5. This trial provided the “proof of concept” of
the efficacy of GPIIb/IIIa blockade in improving clinical outcome among patients under-
going coronary balloon angioplasty or directional atherectomy. A total of 2099 patients
deemed to be at high risk for ischemic complications on the basis of acute ischemic syn-
dromes (myocardial infarction or unstable angina) or adverse clinical and lesion morpho-
logic characteristics were enrolled between 1992 and 1993 (11). Given the prolonged
duration of abciximab’s binding to the GPIIb/IIIa receptor, this trial assessed whether a
single bolus of the agent would be effective or if a more prolonged period of administra-
tion would be required. Patients were therefore randomized to treatment with placebo,
an abciximab 0.25 mg/kg bolus administered immediately prior to initiation of the
interventional procedure, or an abciximab bolus followed by a 10 µg/min infusion for 12
h. All patients received aspirin; concomitant heparin was administered as a preprocedural
bolus of 10–12,000 U [with additional boluses as necessary to achieve and maintain an
activated clotting time (ACT) of 300–350 s], followed by a postprocedural infusion for
at least the 12-h duration of the abciximab study drug. Vascular access sheaths were left
in place during the heparin and study drug infusions and were removed 6 h after the hep-
arin was discontinued. The primary efficacy endpoint was death, myocardial infarction,
urgent repeat revascularization, or stent or intraaortic balloon pump placement; double
blinding was maintained and clinical assessments were also performed at 6 mo and 3 yr
following randomization.
T
HE EPILOG TRIAL
EPILOG is described in detail in Chapter 5. This study was designed to extend the
findings of the EPIC trial in two ways. First, to determine whether the clinical benefits
of abciximab therapy observed among high-risk patients in EPIC could be extrapolated
to all patients treated by percutaneous coronary revascularization, regardless of their per-
ceived risk for ischemic complications, a broad spectrum of patients undergoing elective
or urgent intervention was enrolled. The second objective was to determine whether the
substantial increase in bleeding complications associated with abciximab therapy in
EPIC (see below) could be attenuated by modification of conjunctive heparin dosing. The
EPILOG trial design was based on the findings of the pilot PROLOG study (12), which
suggested that hemorrhagic complications of abciximab could be reduced without loss
of clinical efficacy by weight adjustment and reduction of heparin dose and by early
sheath removal during the abciximab infusion (with no postprocedural heparin). Patients
were randomized to placebo with standard-dose, weight-adjusted heparin; abciximab with
standard-dose, weight-adjusted heparin; or abciximab with low-dose, weight-adjusted
heparin (Table 2) (13). Abciximab was administered as a bolus of 0.25 mg/kg, followed
by an infusion of 0.125 µg/kg/min (maximum 10 µg/min) for 12 h. Postprocedural hep-
arin was not given, and vascular sheaths were removed 2–6 h after the procedure. Planned
sample size was 4800 patients, but the trial was terminated early after the first interim anal-
ysis demonstrated an unexpectedly marked treatment efficacy of abciximab therapy; at that
point, a total of 2792 patients had been enrolled between February and December, 1995. The
primary efficacy endpoint was death, myocardial infarction, or urgent repeat revascular-
ization by 30 d; patients were also followed in a double-blinded fashion to 6 mo and 1 yr.
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