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Contemporary use of glycoprotein IIb/IIIa inhibitors

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Review Article © Schattauer 2012 215

Contemporary use of glycoprotein IIb/IIIa inhibitors

Steen Dalby Kristensen1; Morten Würtz1; Erik Lerkevang Grove1; Raffaele De Caterina2; Kurt Huber3; David J. Moliterno4;
Franz-Josef Neumann5
1Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; 2Institute of Cardiology and Center of Excellence on Aging, ‘G. d’Annunzio’ University – Chieti and ”G.
Monasterio” Foundation, Pisa, Italy; 33rd Department of Internal Medicine, Cardiology and Emergency Medicine, Wilhelminenhospital, Vienna, Austria; 4Division of Cardiovascular
Medicine and Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA; 5Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany

Summary Nonetheless, GPI may still be beneficial during coronary interventions

Platelet glycoprotein IIb/IIIa inhibitors (GPI) are antithrombotic agents
preventing the binding of fibrinogen to GP IIb/IIIa receptors. Thus, GPI
interfere with interplatelet bridging mediated by fibrinogen. Currently,
three generic GPI with different antithrombotic properties are available
for intravenous administration: abciximab, eptifibatide, and tirofiban.
The development of oral GPI was abandoned, whereas intravenous GPI
were introduced in various clinical settings during the 1990s, yielding
substantial benefit in the treatment of acute coronary syndromes, par-
ticularly during percutaneous coronary interventions. Results of the
many randomised trials evidenced the efficacy of this drug class,
though these trials were conducted prior to the emergence of modern
oral antiplatelet therapy with efficient P2Y12 inhibitors. Subsequent
trials failed to consolidate the strongly favourable impression of GPI,
and indications for their use have been more restricted in recent years.
among high-risk patients including acute ST-elevation and non-ST-elev-
ation myocardial infarctions, particularly in the absence of adequate
pretreatment with oral antiplatelet drugs or when direct thrombin in-
hibitors are not utilised. Intracoronary GPI administration has been sug-
gested as adjunctive therapy during primary percutaneous coronary in-
tervention, and the results of larger ongoing trials are expected to eluci-
date its clinical potential. The present review outlines the key mile-
stones of GPI development and provides an up-to-date overview of the
clinical applicability of these drugs in the era of refined coronary stent-
ing, potent antithrombotic drugs, and novel thrombin inhibiting agents.
Keywords
Abciximab, acute coronary syndrome, antiplatelet agents, glycoprotein
IIb/IIIa inhibitors, percutaneous coronary intervention

Correspondence to: Received: July 8, 2011

Steen Dalby Kristensen, MD, DMSc Accepted after minor revision: November 12, 2011
Department of Cardiology, Aarhus University Hospital, Skejby Prepublished online: January 11, 2012
Brendstrupgaardsvej 100, 8200 Aarhus, Denmark doi:10.1160/TH11-07-0468
Tel.: +45 7845 2030, Fax: +45 7845 2260 Thromb Haemost 2012; 107: 215–224
E-mail: steendk@dadlnet.dk

Introduction
The discovery of the platelet glycoprotein (GP) IIb/IIIa receptor
marked a breakthrough in the understanding of platelet physiol-
ogy and pharmacotherapy. During the late 1990s, the introduction
of specific GP IIb/IIIa inhibitors (GPI) yielded a substantial clini-
cal benefit in the setting of acute coronary syndromes (ACS), par-
ticularly during percutaneous coronary intervention (PCI), as ver-
ified by several large-scale randomised trials (1–6). Currently,
three different drugs are clinically available for intravenous admin-
istration: abciximab, eptifibatide, and tirofiban. These drugs differ
with respect to pharmacodynamics and pharmacokinetics, includ-
ing antithrombotic properties (씰Table 1).
Inhibition of the GP IIb/IIIa receptor and its clinical impli-
cations were originally recognised during the investigation of
Glanzmann thrombasthenia, an autosomal recessive bleeding dis-
order characterised by quantitative and/or qualitative defects of
the GP IIb/IIIa receptor. During the 1970s an increasing under-
standing of the receptor was gained, ultimately leading to the de-
velopment of monoclonal mouse antibodies against GP IIb/IIIa
used to induce a transient state of controlled thrombasthenia (7).
Background
Platelet physiology
Platelet activation can occur from a variety of different stimuli, all
with mechanisms converging towards the GP IIb/IIIa complex
(씰Fig. 1). Non-covalent Ca2+-dependent association between the
GP IIb (αIIb) and GP IIIa (β3) subunits leads to the formation of a
heterodimeric integrin receptor (8). The majority of the GP IIb/
IIIa complexes are present on the platelet surface, whereas a minor
part is stored within the canalicular system and cytoplasmatic
α-granules and is distributed to the surface upon platelet acti-
vation (inside-out signalling). The function of the GP IIb/IIIa re-
ceptor is prominent during physiological haemostasis as well as
during pathological thrombus formation, and GP IIb/IIIa is often
termed the final common pathway of platelet aggregation. The af-
finity of the GP IIb/IIIa receptor for its ligands is low in resting pla-
telets, but increases during platelet activation by agonists such as
ADP, epinephrine, collagen, von Willebrand factor, thromboxane
A2, thrombin etc. (씰Fig. 1) (8). A polymorphism in the gene en-
coding this receptor might be linked with an increased risk of myo-

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216 Kristensen et al. Glycoprotein IIb/IIIa inhibitors
cardial infarction (MI) (9–12). GPI exert their antithrombotic ef-
fect by preventing the binding of fibrinogen to adjacent GP IIb/IIIa
receptors, thus interfering with interplatelet bridging mediated by
fibrinogen (씰Fig. 1) (13). By this mechanism, the final common
pathway of platelet aggregation is blocked. Other adhesive proteins
may interact with the receptor (i.e. von Willebrand factor, fibro-
nectin, and vitronectin); however, fibrinogen serves as the primary
ligand (8). GPI must maintain ≥80% receptor occupancy to
achieve sufficient therapeutic efficacy (14). Such platelet inhibition
is particularly important in ACS and PCI, during which platelets
adhere and aggregate at sites of plaque rupture and potentially on
metallic stent struts.
Pharmacology of GP IIb/IIIa inhibitors
Differences between GPI are outlined in 씰Table 1. Abciximab, the
first GPI approved for clinical use, is a non-competitive inhibitor
of GP IIb/IIIa. Abciximab is the humanised chimeric Fab-frag-
ment of the monoclonal mouse antibody 7E3 against GP IIb/IIIa
(15). Free plasma abciximab is cleared from the circulation within
minutes, while platelet-bound drug persists for up to one week de-
pending on the rate of platelet turnover (14). Abciximab cross-
reacts with the αvβ3 integrin on endothelial cells and smooth
muscle cells, as well as the αMβ2 integrin (Mac-1) on granulocytes
and monocytes (16). Two small-molecule GPI acting specifically
on the αIIb-chain of the GP IIb/IIIa complex have been approved
for clinical use: eptifibatide (plasma half-life 2.5 hours [h]), an
RGD mimetic blocking aggregation by occupying the RGD (Arg-
Gly-Asp acid) binding site of GP IIb/IIIa, and tirofiban (plasma
half-life 2 h), a non-peptide tyrosine derivative also blocking the
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Figure 1: Platelet activation pathways and
platelet aggregation. Platelet activation is
induced by the interaction of several agonists
with receptors expressed on the platelet sur-
face. Agonists induce a conformational change
of the GP IIb/IIIa complex allowing fibrinogen
to ensure permanent linkage between activated
GP IIb/IIIa complexes on adjacent platelets to
consolidate the formation of stable platelet ag-
gregates. The antithrombotic properties of GPI
rely on non-competitive (abciximab) or com-
petitive (eptifibatide and tirofiban) inhibition of
GP IIb/IIIa. ADP, adenosine diphosphate; Epi,
epinephrine; GP, glycoprotein; GPI, glycoprotein
IIb/IIIa inhibitor; PAF, platelet activation factor;
TxA2, thromboxane A2; vWF, von Willebrand
factor.
RGD binding site. Unlike abciximab, eptifibatide and tirofiban are
competitive inhibitors of GP IIb/IIIa. Their effect on platelet ag-
gregation is closely related to plasma concentrations and, due to
short plasma half-lives, continuous infusion is needed for sus-
tained platelet inhibition (17). Accordingly, the antiaggregatory ef-
fect of these drugs decreases within hours after infusion, since re-
covery of platelet function occurs as soon as the active drug has
been renally excreted.
Differences between GPI agents in terms of antiplatelet potency
have been reported (18). Furthermore, substantial inter-individual
variability in the level of platelet inhibition obtained by GPI has
been demonstrated in patients undergoing PCI and may predict
cardiovascular events (19).
Oral administration
The breakthrough of GPI was driven by the remarkable results of
trials assessing the effect of intravenous agents. In the wake of these
results, oral GPI (xemilofiban, orbofiban, sibrafiban, and lotrafi-
ban) were developed and tested against placebo on top of aspirin to
investigate a potential role for GPI in long-term secondary preven-
tion. However, in large-scale clinical studies these drugs increased
bleeding and thrombosis and generated an excess overall mortality
of approximately 30% (20). The excess mortality was not clearly
caused by an increase in MIs and was observed despite a reduction
in the need for urgent revascularisation, thus arguing against a
pure prothrombotic mechanism. Several potential explanations
for this disappointing outcome were suggested, including drug
toxicity, inadequate drug plasma levels, paradoxical receptor acti-
vation, diversity in patient-specific factors (e.g. individual vari-
© Schattauer 2012
 Kristensen et al. Glycoprotein IIb/IIIa inhibitors 217

Table 1: Characteristics of intravenous gly- Abciximab Eptifibatide Tirofiban

coprotein IIb/IIIa inhibitors. Modified from
Type Monoclonal antibody Small molecule Small molecule
Brown et al. (85).
fragment (cyclic peptide) (non-peptide)
Platelet-bound half-life Hours Seconds Seconds
Plasma half-life Minutes 2.5 hours 2.0 hours
Drug-to-receptor ratio 1.5–2.0 250–2,500 >250
Percent of dose in bolus 75% <2.5% <2.5%
Cost €€ € €
Specificity/Selectivity
IIb/IIIa +++ +++ +++
αvβ3 +++ +
Mac-1 +
Anticoagulant properties
↓ thrombin generation ++ + +
↑ activated clotting time 30 seconds 20 seconds 0 seconds
Reversibility without platelets 24–48 hours 4 hours 4 hours
Reversibility with platelets Yes No No
Route of elimination (22) Spleen Renal (50%) Renal (40–70%)
Renal dose adjustment (22) None CrCl < 50 ml/min; CrCl < 30 ml/min;
180 μg/kg/bolus 0.2 μg/kg/min x 30 min
+ 1.0 μg/kg/min + 0.05 μg/kg/min
CrCl, creatinine clearance.

ation in dose-response), and the lack of concurrent aspirin treat-
ment in some study arms. Thus, GPI were never adopted into clini-
cal practice.
Intravenous administration
Numerous clinical trials have established the clinical benefit of in-
travenous GP IIb/IIIa inhibition in patients undergoing PCI in-
cluding non-ST-elevation acute coronary syndromes (NSTE-
ACS) and ST-elevation MIs (STEMI). However, many of these
trials were conducted prior to the emergence of contemporary
antithrombotic agents like clopidogrel and, thus, should be inter-
preted as such. In addition, new antithrombotic drugs, such as new
generation P2Y12 receptor antagonists and anticoagulant drugs,
have further challenged the current position of GPI and ques-
tioned their relevance in a broad range of clinical settings.
Dosing and administration
Since the first clinical trials, attempts have been made to optimise
the dosing regimen of abciximab and, in particular, of the small
molecule agents by doubling bolus doses or extending infusion
periods.
Abciximab is administered as a 0.25 mg/kg bolus dose followed
by a 12-h maintenance infusion of 10 μg/minute (min). Dosing is
based on the EPIC trial that showed the superiority of bolus abcixi-
mab plus infusion as compared with bolus alone (1). In EPILOG,
the successor to EPIC, heparin doses were reduced to the currently
recommended bolus dose of 70 IU/kg (2). A recent study even
showed that withholding abciximab maintenance infusion does
not impair platelet inhibition in patients receiving a high loading
dose of clopidogrel (21). Abciximab is eliminated through the reti-
culoendothelial system, including the spleen, and does not require
dose adjustment in the setting of renal insufficiency (씰Table 1)
(22). Platelet aggregation returns to baseline after approximately
48 h (17). Recently, intracoronary bolus administration into the
infarct-related artery during primary PCI has been investigated as
detailed below.
Eptifibatide is administered as a 180 μg/kg bolus dose followed
by a maintenance infusion of 2.0 μg/kg/min for 18 to 24 h or until
discharge. In the setting of PCI, a second bolus of 180 μg/kg is given
10 min after administration of the first bolus. Current recommen-
dations for dosing are based on the results of the ESPRIT trial that
demonstrated the clinical benefit of high-dose versus low-dose ep-
tifibatide (23). These findings were consolidated, and perhaps
pharmacologically explained, in the PRIDE study that showed the
necessity of high-dose eptifibatide to obtain sufficient GP IIb/IIIa
receptor occupancy (24).
Previous recommendations on dosing of tirofiban were based
on the RESTORE trial (25); however, they were changed according

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218 Kristensen et al. Glycoprotein IIb/IIIa inhibitors
to the more recent On-TIME 2 trial that demonstrated the clinical
benefit of an early high-dose bolus of tirofiban as compared with
placebo in STEMI patients (26). In On-TIME 2, tirofiban was ad-
ministered as a 25 μg/kg bolus dose followed by an 18-h mainten-
ance infusion of 0.15 μg/kg/min.
From the ESPRIT (23) and On-TIME 2 (26) trials it appears
that the platelet inhibitory effect of eptifibatide and tirofiban has
been optimised by implementing an approximately two-fold in-
crease of the loading dose. The effect of these drugs on platelet ag-
gregation dissipates rapidly once infusion has been discontinued
(17). Eptifibatide and tirofiban are renally eliminated and thus
require dose adjustments in the setting of renal insufficiency
(씰Table 1) (22).
Safety
The large amount of clinical trials involving the use of GPI has re-
vealed an overall acceptable bleeding safety profile of GPI, al-
though depending on the clinical setting in which they are used.
Severe non-intracranial bleeding remains a concern when GPI are
utilised along with fibrinolytic therapy as demonstrated in
GUSTO V (27). In this trial, however, the use of GPI (abciximab)
did not confer an increased risk of intracranial haemorrhage. In
the setting of PCI, the bleeding risk is acceptable provided that he-
parin is given in appropriate doses.
When surgery is needed, the reversibility and short half-life of
the small molecule agents is advantageous, and they are not con-
sidered to confer an increased risk of perioperative bleeding. In
contrast, the risk of peri- and postoperative bleeding expectedly
increases when abciximab is used.
GPI, in particular abciximab, carry a small risk of thrombocy-
topenia, which may even occur weeks after administration (28, 29).
This should be considered, since GPI-induced thrombocytopenia
increases the risk of bleeding (30). Thus, it is recommended to
measure platelet counts prior to initiation of GPI treatment and
within 2–4 h of abciximab administration and 24 h of eptifibatide
and tirofiban administration.
GP IIb/IIIa inhibitors in non-acute patients
GP IIb/IIIa inhibition in the setting of elective and subacute NSTE-
ACS PCI has been evaluated in the EPIC, EPILOG, and EPISTENT
trials (abciximab), the IMPACT-II and ESPRIT trials (eptifiba-
tide), and in the RESTORE (tirofiban) and TARGET trials (abcixi-
mab vs. tirofiban). TARGET is the only trial to directly compare
two GPI (31). This study showed superiority of abciximab over ti-
rofiban in patients undergoing PCI. In TARGET, a total of 4,809
elective and NSTE-ACS patients undergoing PCI were randomly
assigned to abciximab or tirofiban (low-dose bolus) in addition to
aspirin and, in many cases, clopidogrel prior to urgent or elective
PCI. Importantly, as the On-TIME 2 trial was yet to be initiated, a
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low-dose bolus of 10 μg/kg was used in the tirofiban arm of TAR-
GET. Overall abciximab proved superior to tirofiban. Only when
analyses were restricted to diabetic patients event rates were equal.
Thus, abciximab has been widely used during PCI, especially in pa-
tients at particularly high risk of ischaemic complications.
ISAR-REACT (32) tested the effect of abciximab in 2,159 pa-
tients undergoing low-risk elective PCI after pretreatment with a
high loading dose (600 mg) of clopidogrel. Abciximab provided no
reduction in the 30-day incidence of major adverse cardiac events
compared with placebo, but caused an increased need for sub-
sequent blood transfusion. Similar results were obtained from 701
diabetic patients in the ISAR-SWEET trial (33). Thus, pretreat-
ment with clopidogrel appears to neutralise the particular benefit
of abciximab in diabetic patients undergoing elective PCI that was
well documented in earlier studies on GP IIb/IIIa inhibition in
clopidogrel naïve patients (31, 34). An ongoing trial is further ex-
ploring the role of GPI (eptifibatide) during elective PCI for the
treatment of complex lesions (≥2 stents) in patients pretreated
with aspirin and clopidogrel (35).
In REPLACE-2 (36), including 2,999 high-risk patients, pro-
cedural anticoagulation with bivalirudin, a direct thrombin in-
hibitor, plus provisional GP IIb/IIIa inhibition proved superior to
heparin and systematic GP IIb/IIIa inhibition in reducing bleeding
rates while preventing major adverse cardiac events similarly.
Recently, tirofiban has been evaluated in the setting of tailored
antiplatelet therapy by the 3T/2R investigators (37). In this study
on 1,277 patients undergoing elective PCI, initial screening was
performed to identify those with a low platelet response to aspirin,
clopidogrel, or both as determined by a point-of-care platelet
function test. Low-responders were randomly assigned to tirofiban
or placebo on top of aspirin and clopidogrel, the former conferring
a significant reduction in peri-procedural MI and major adverse
cardiovascular events at 30 days. This benefit was sustained during
one-year follow-up (38). Previously, eptifibatide has been shown
to enhance platelet inhibition compared to aspirin and clopidogrel
alone resulting in reduced myocardial necrosis (39). Another trial,
still ongoing, investigates whether administration of a GPI in the
catheterisation laboratory will improve clinical outcome in pa-
tients on dual antiplatelet therapy (aspirin and clopidogrel) re-
sponding inadequately to aspirin. All study participants have stable
angina and are undergoing elective PCI (ClinicalTrials.org,
NCT01103440).
In the era of P2Y12 receptor antagonists, no clear evidence sup-
ports the routine use of GPI during elective PCI, not even in dia-
betic patients. Previously, GPI were widely used in diabetic pa-
tients, but given the results of ISAR-SWEET this strategy is no
longer common practice. Thus, when upstream administration of
a P2Y12 receptor antagonist is feasible, the European Society of
Cardiology (ESC) guidelines state that use of GPI should generally
be restricted to bail-out situations caused by coronary thrombus
formation, vessel closure, etc. (22). In this setting, most clinicians
prefer the use of abciximab (씰Table 2). A recent meta-analysis by
Winchester et al. evaluated the use of GPI during elective PCI with
stenting from studies of which the vast majority employed pre-
treatment with thienopyridines. The study concluded that GPI
© Schattauer 2012

provide some clinical benefit by reducing the risk of non-fatal MI
without a notable increase in major bleeding, but at the expense of
more minor bleeding and a higher rate of thrombocytopenia (30).
Unstable angina and non-ST elevation MI
(NSTEMI)
A number of large-scale randomised clinical trials have tested the
effect of GP IIb/IIIa inhibition in the setting of unstable angina
pectoris and NSTEMI. The inherent heterogeneity of patients
presenting with NSTE-ACS and the diversity of their symptoms
renders the risk-benefit outcome more variable than in the case of
elective PCI. Some patient subgroups have been shown to receive
substantial benefit, whereas others have tended toward more harm
from routine use of GPI.
The CAPTURE trial investigated the effect of abciximab in the
setting of PCI for high-risk ACS as evidenced by electrocardio-
graphic changes compatible with ischaemia (3). In CAPTURE, pa-
tients derived a substantial benefit from abciximab, which could be
attributed to a benefit in cardiac troponin-positive patients only.
Pursuing a strictly conservative strategy with revascularisation
being discouraged during the acute phase, the GUSTO IV-ACS
trial yielded results contrasting those observed in CAPTURE (40).
Although in GUSTO IV-ACS patients were selected prospectively
by use of both cardiac troponin and electrocardiographic changes,
abciximab actually led to an increased risk of death at 30 days.
Thus, comparison of the results of GUSTO IV-ACS and CAP-
TURE suggests that the benefit of abciximab in cardiac troponin-
positive patients is linked to an invasive strategy. Both studies were
conducted prior to the era of routine coronary stenting and before
clopidogrel became standard therapy.
The effect of upstream therapy with small-molecule agents was
examined in PURSUIT (eptifibatide) and in PRISM-PLUS and
PRISM (tirofiban). In PURSUIT (6), a large prospective study en-
compassing 10,948 patients presenting with either electrocardio-
graphic changes indicative of ischaemia or creatinine kinase MB
elevation, eptifibatide proved superior to placebo on top of aspirin
and heparin. In PRISM-PLUS (4), tirofiban and heparin were con-
comitantly administered and compared with heparin alone, and
reduced the 30-day death and MI rate. In PRISM (5), the larger
successor to PRISM-PLUS, tirofiban was directly compared with
heparin on top of aspirin revealing a significant clinical benefit of
tirofiban that was, however, not sustained beyond 30 days. Based
on these large, but now remote, clinical trials, eptifibatide and ti-
rofiban were previously recommended for upstream therapy in
certain cases of NSTE-ACS (41). In NSTE-ACS patients, an early
invasive strategy accompanied by intense antithrombotic treat-
ment, including tirofiban, also proved beneficial (42, 43). However,
results of the more recent ACUITY-timing (44) and EARLY ACS
(45) trials, evaluating the benefit of upstream GP IIb/IIIa therapy
in the setting of P2Y12-blockade and refined stenting techniques,
showed no benefit. Accordingly, the present ESC guidelines on
myocardial revascularisation do not recommend this strategy (22).
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Kristensen et al. Glycoprotein IIb/IIIa inhibitors 219
Table 2: Common indications for the use of glycoprotein IIb/IIIa
inhibitors during percutaneous coronary intervention.
Clinical setting Indications
Non-acute ● No pretreatment with aspirin and a P2Y12 receptor
patients antagonist.
● Bail-out situations (coronary thrombus formation,
vessel closure, etc.), preferably abciximab.
● Poor compliance with dual antiplatelet therapy.
NSTE-ACS ● No pretreatment with aspirin and a P2Y12 receptor
antagonist.
● High-risk patients (complex lesions, large thrombi,
elevated troponin levels).
STEMI ● High-risk patients (complex lesions, large thrombi,
haemodynamically compromised patients).
NSTE-ACS, non-ST-elevation myocardial infarction acute coronary syndromes;
STEMI, ST-elevation myocardial infarction.
Given the observation that clopidogrel pretreatment eradicated
most of the benefit of abciximab in elective PCI, the value of ab-
ciximab in urgent PCI for ACS seen in CAPTURE had to be re-
visited in the era of high-loading dose clopidogrel. Thus, abcixi-
mab was re-examined in the recent ISAR-REACT-2 trial (46). In
this study, abciximab was administered in the catheterisation lab-
oratory after preloading with clopidogrel in patients subjected to
PCI following admission with NSTE-ACS. Abciximab significantly
reduced the 30-day primary endpoint and one-year incidence of
major adverse cardiac events without increasing the rate of bleed-
ing complications. A pre-specified subgroup analysis revealed that
the 30-day benefit of abciximab was confined to patients with elev-
ated cardiac troponin levels.
The more recent EARLY ACS trial (45) investigated the effect of
eptifibatide in patients with high-risk NSTE-ACS undergoing an-
giography and provisional PCI. The study included 9,492 patients
presenting within 24 h of symptom debut. Patients were randomly
assigned to either early routine eptifibatide (double bolus followed
by infusion) or delayed provisional eptifibatide at the time of PCI.
The primary endpoint (a 30-day composite of all-cause death, MI,
recurrent ischaemia requiring urgent revascularisation, or throm-
botic bailout at 96 h) did not differ between groups. Systematic up-
stream eptifibatide even carried an increased risk of bleeding.
However, a recent EARLY ACS substudy showed that the use of
routine early eptifibatide, compared with delayed provisional use,
may be associated with a lower 30-day ischaemic risk in NSTE-ACS
patients also treated with clopidogrel (47).
Bivalirudin has been suggested as an alternative to GPI in pa-
tients with ACS. In ACUITY (48), comprising 13,819 patients pres-
enting with NSTE-ACS, systematic GP IIb/IIIa inhibition on top of
heparin was compared with bivalirudin plus bail-out GP IIb/IIIa
inhibition. Bivalirudin proved non-inferior to heparin plus GP
IIb/IIIa inhibition in preventing the ischaemic endpoint, but con-
ferred a significant reduction in the primary endpoint of net clini-
cal outcome including the occurrence of bleeding. Thus, bivaliru-
din appears an appropriate alternative to GPI, particularly in pa-
Thrombosis and Haemostasis 107.2/2012
220 Kristensen et al. Glycoprotein IIb/IIIa inhibitors
tients preloaded with clopidogrel. Some minor uncertainties re-
main since patients in the non-bivalirudin arms of ACUITY were
predominantly treated with small-molecule agents, which may
have inferior efficacy compared with abciximab as seen in the ACS
patients of the TARGET trial (49). Also, the use of low-molecular-
weight heparin in about half of the patients may have impacted the
GPI-arm of ACUITY. In an attempt to clarify these issues, the
ISAR-REACT-4 trial (ClinicalTrials.org, NCT00373451) is com-
paring unfractionated heparin plus abciximab to bivalirudin in
clopidogrel-pretreated patients undergoing PCI for NSTEMI.
ACUITY Timing (44), a substudy of ACUITY, showed no signifi-
cant advantage of upstream GP IIb/IIIa inhibition compared with
administration in the catheterisation laboratory. In general, up-
stream administration of GPI is not recommended for the treat-
ment of NSTE-ACS (22).
Currently, GP IIb/IIIa inhibition is not recommended as rou-
tine therapy for patients with NSTE-ACS (22). The combination of
aspirin, clopidogrel, and anticoagulation simply carries a better
risk/benefit-ratio and at a lower cost. Results from EARLY ACS
(45) highlight the potential risk of bleeding with upstream GPI as
part of triple-antiplatelet therapy. However, the use of GPI, in par-
ticular abciximab, may be considered in the catheterisation labora-
tory in high-risk patients or if oral antiplatelet pretreatment has
not been given in due time (씰Table 2). In these cases, though, bi-
valirudin serves as a strong alternative to GPI due to a lower bleed-
ing risk. Furthermore, the use of GPI is likely to further decrease
given the advent of the new potent thienopyridine prasugrel and
the non-thienopyridine P2Y12 receptor antagonist ticagrelor. Both
have proved superior to clopidogrel in TRITON-TIMI 38 (50) and
PLATO (51), respectively, and a TRITON-TIMI 38 substudy
showed that the superiority of prasugrel was independent of the
periprocedural use of GPI (52).
STEMI
Primary PCI is superior to fibrinolysis for the immediate reperfu-
sion of patients with STEMI if performed within a certain time
limit (53–55). However, fibrinolysis still plays an important role in
the treatment of STEMI in areas with inadequate access to cathe-
terisation facilities. Thus, GPI have been tested as adjunctive ther-
apy to fibrinolysis in the GUSTO V (27) and ASSENT-3 (56) trials.
According to these studies, the combination regimen carried an in-
creased bleeding risk and provided no additional benefit in terms
of thrombotic complications. Therefore, the combination of fibri-
nolysis and GPI is not recommended.
In patients undergoing primary PCI, administration of abcixi-
mab in the catheterisation laboratory has proved beneficial in a
number of trials; RAPPORT (57), ISAR-2 (58), ADMIRAL (59),
CADILLAC (60), and ACE (61). Thus, this strategy may be used
during coronary interventions except in patients at high risk of
bleeding. Recently, the EVA-AMI trial addressed the question
whether eptifibatide may serve as an equally effective and less
costly alternative to abciximab (62). The study demonstrated the
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non-inferiority of eptifibatide with respect to the primary end-
point of complete ST-segment resolution one hour post-PCI. Im-
portantly, the power of the EVA-AMI trial (n = 400) did not allow
any firm conclusions to be drawn on the potential differences be-
tween the two agents in terms of efficacy and safety. Large-scale da-
tasets have added to the evidence of comparability of small-mol-
ecule agents to abciximab for primary angioplasty (63).
Smaller studies, including registries, have previously shown
promising results of upstream therapy with abciximab at first
medical contact (initiated in the emergency room or in the ambu-
lance) (64, 65). Furthermore, a large substudy of the APEX-AMI
trial supported the pre-procedural administration of GPI in the
setting of STEMI (66). In the APEX-AMI trial, 3,969 of 5,707 pa-
tients with STEMI received one of three GPI at the operator’s dis-
cretion administered either early (pre-sheath) or late (in-lab). GPI,
in particular abciximab, conferred a significant reduction in
90-day clinical outcome when administered pre-procedurally
compared with the administration in the catheterisation labora-
tory or no administration. This benefit was mainly seen in patients
with a symptom-to-PCI duration of less than 3 h. However, in the
large randomised FINESSE trial abciximab fell short of expec-
tations (67). In FINESSE, 1,624 patients with STEMI were ran-
domly assigned to abciximab administered upstream or in the ca-
theterisation laboratory. No difference in the primary composite
endpoint (death from all causes, ventricular fibrillation, cardio-
genic shock, and congestive heart failure) was reported, but up-
stream abciximab increased the risk of bleeding in patients with a
symptom-to-PCI time of less than 3 h. Importantly, the adminis-
tration of GPI in FINESSE was initiated with a notable time delay
from symptom onset compared with the studies summarised in
the EGYPT meta-analysis (65). The findings of FINESSE also
somewhat contrast with those reported in the On-TIME 2 trial
(26). In that study, 984 STEMI patients were randomised to tirofi-
ban or placebo administered pre-hospital before being transferred
for primary PCI. Importantly, patients were pretreated with a load-
ing dose of clopidogrel in On-TIME 2, but not in FINESSE. The
On-TIME 2 study showed improved ST-segment resolution with
tirofiban 1 h after PCI. Nevertheless, the study was unable to dem-
onstrate a statistically significant survival benefit or a diminished
risk of re-infarction. However, a recent post-hoc analysis of On-
TIME 2 revealed a reduction in the incidence of early stent throm-
bosis (0–30 days) and urgent revascularisation with tirofiban.
Early stent thrombosis and prehospital tirofiban were reported as
independent predictors of 30-day mortality (68). The FATA trial,
however, failed to demonstrate equivalence of high-dose bolus ti-
rofiban to abciximab as adjunctive therapy to primary PCI for
achieving effective reperfusion as measured by the incidence of
complete ST-segment resolution (69). The MULTISTRATEGY
trial compared a high bolus dose of tirofiban (25 mg/kg) plus stan-
dard infusion with abciximab in 725 STEMI patients. In this trial,
tirofiban proved non-inferior with respect to the primary end-
point of at least 50% ST-segment-elevation resolution at 90 min
after PCI (70). An ongoing trial is evaluating whether upstream ti-
rofiban may improve outcome in patients pretreated with prasu-
grel (ClinicalTrials.org, NCT01336348).
© Schattauer 2012

BRAVE-3 (71) tested upstream abciximab against unfraction-
ated heparin (up to 5,000 U) after preloading with a high dose of
clopidogrel (600 mg). The BRAVE-3 investigators randomly as-
signed 800 patients presenting with STEMI within 24 h of symp-
tom onset to either abciximab (bolus followed by a 12-h infusion)
or placebo and employed infarct-size imaging by Tc-99m-sestami-
bi as the primary endpoint. The study failed to show a reduction in
infarct size in the abciximab arm. Moreover, no difference was ob-
served in the combined secondary endpoint (30-day incidence of
death, myocardial reinfarction, urgent revascularisation, and
stroke). There was, however, an increased incidence of thrombocy-
topenia and a slightly higher rate of TIMI minor bleeding in the
abciximab arm.
The HORIZONS-AMI trial (72) tested bivalirudin plus bail-out
GP IIb/IIIa inhibition against heparin plus systematic GP IIb/IIIa
inhibition in 3,602 patients presenting with STEMI and a symp-
tom onset of less than 12 h. The reduced rate of net adverse clinical
events at 30 days reported in the bivalirudin arm was ascribed pri-
marily to a lower bleeding rate and was accompanied by a reduc-
tion in mortality. The mortality benefit prevailed and remained
statistically significant during three years of follow-up (73). In pa-
tients who underwent coronary stent implantation, an excess of
acute stent thrombosis within the first 24 h was seen in the bival-
irudin arm. Subsequent incidences of stent thrombosis were, how-
ever, higher in the GPI arm. Accordingly, during three-year follow-
up, the incidence of stent thrombosis was similar between the two
arms of HORIZONS-AMI (73). Overall, according to the results of
HORIZONS-AMI, bivalirudin is a favorable alternative to abcixi-
mab in STEMI patients undergoing primary PCI. Thus, current
ESC guidelines highly recommend (class I) the use of bivalirudin
in the setting of STEMI (22). Also in diabetic patients bivalirudin is
safe and may reduce cardiac mortality at 30 days and one year (74).
Moreover, the ongoing EUROMAX trial (ClinicalTrials.org,
NCT01087723) is investigating whether early administration of
bivalirudin during transport improves 30-day outcome compared
with treatment with unfractionated heparin and optional GP IIb/
IIIa inhibition in patients with STEMI intended for primary PCI.
The study is expected to provide further insight into the potential
of bivalirudin in the management of STEMI patients.
In BRAVE-3, the routine use of abciximab given in the intensive
care prior to catheterisation showed no benefit in STEMI patients
(71). However, when administered in the catheterisation labora-
tory this drug remains a justifiable option in high-risk patients
(씰Table 2). Given the results of FINESSE, the use of GP IIb/IIIa in-
hibition in facilitated PCI is not recommended at present, al-
though an early use in patients with short symptom duration (<3
h) has been suggested beneficial in the recent APEX-AMI substudy
(66) and a meta-analysis (65). Still, bivalirudin is a strong alter-
native to GP IIb/IIIa inhibition, also in diabetic patients.
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Kristensen et al. Glycoprotein IIb/IIIa inhibitors 221
Intracoronary administration of GP IIb/IIIa
inhibitors
Antithrombotic therapy is an inherent companion to PCI. No-
netheless, PCI is often complicated by distal microembolisation,
either catheter-induced or by spontaneous plaque rupture. During
recent years, the intracoronary delivery of the first bolus of GPI has
been shown to preserve perfusion of the microvascular bed during
PCI. This capacity is attributed to the ability of GPI to inhibit pla-
telet aggregation and dissolve newly formed platelet aggregates by
displacement of fibrinogen from its receptors (75).
Abciximab has been the predominant agent used to investigate
a potential clinical role for intracoronary GPI administration, but
a few studies on eptifibatide (76) and tirofiban (77) have recently
been carried out as well. In a randomised trial by Thiele et al., pa-
tients with STEMI were randomly assigned to a bolus of intra-
venous or intracoronary abciximab followed by intravenous infu-
sions. The study showed a benefit of intracoronary bolus adminis-
tration in terms of less microvascular obstruction, reduced infarct
size, and improved myocardial perfusion (78). Employing intra-
coronary eptifibatide administration, the ICE trial supported these
findings revealing an excess local GP IIb/IIIa receptor occupancy
and improved microvascular perfusion with intracoronary versus
intravenous administration (76). However, the recent CICERO
trial, a larger randomised trial investigating intracoronary abcixi-
mab administration, failed to show any difference with respect to
the primary endpoint of restored myocardial reperfusion assessed
by complete ST-segment resolution. Conversely, when myocardial
reperfusion was assessed by myocardial blush grade or enzymatic
infarct size, intracoronary administration proved superior (79). A
recent randomised trial employed a clinical endpoint to demon-
strate the benefit of intracoronary versus intravenous delivery of
abciximab (80). The ongoing INFUSE-AMI trial is evaluating the
effect on the infarct size of site-specific abciximab delivered with a
local perfusion catheter using bivalirudin as anticoagulation (81).
The combination of intracoronary bolus abciximab and aspiration
thrombectomy is also being evaluated at present (Clinical-
Trials.org, NCT01404507). Another ongoing clinical trial, the
AIDA STEMI trial, is expected to provide further information as to
whether intracoronary delivery of GPI will translate into a better
clinical outcome (82).
At present, no sufficiently powered clinical trials have been
undertaken to justify the routine use of intracoronary adminis-
tration. Moreover, all trials conducted so far compared intracoron-
ary with intravenous administration, which might be of limited
clinical relevance given the onward march of bivalirudin.
Key areas for future research
● Novel oral antiplatelet agents like prasugrel and ticagrelor
might not provide optimal platelet inhibition within two hours
in all clinical settings. Thus, intravenous, and perhaps intracor-
onary, GPI administration may still serve as an important op-
Thrombosis and Haemostasis 107.2/2012
222 Kristensen et al. Glycoprotein IIb/IIIa inhibitors
tion given the rapid onset of platelet inhibition, especially in
STEMI patients with short symptom duration or considerable
treatment delay.
● Existing pharmacodynamic and pharmacokinetic data on pra-
sugrel and ticagrelor are primarily obtained from healthy indi-
viduals and might not reflect absorption and metabolism in pa-
tients with ACS. Thus, precaution is needed with respect to their
clinical use in acute settings.
● The increasing use of strong P2Y12 receptor antagonists in pa-
tients with ACS is likely to reduce the benefit of GPI and might
even obviate the need for these drugs. Nonetheless, high on-
treatment platelet reactivity persists even in the era of these new
agents (83).
● In light of the increasing use of strong P2Y12 receptor antago-
nists, GPI treatment might confer a higher risk of bleeding than
reported in previous studies.
● The potential benefit of tailored GPI dosing by platelet function
testing during high-risk PCI needs to be established. The T3/R2
trial (37) has provided important insight into this field in low-
responders to aspirin and/or clopidogrel. Moreover, tailored
GPI dosing is interesting given the importance of inter-individ-
ual differences in intrinsic platelet reactivity for the effect of
antiplatelet drugs (84).
● It remains to be elucidated whether GPI are beneficial during
PCI in high-risk NSTEMI patients pre-treated with new anti-
platelet drugs such as ticagrelor or prasugrel.
● Upstream therapy with GPI in STEMI patients transferred for
primary PCI should be further investigated.
Conclusion
Intravenous GP IIb/IIIa inhibition during elective PCI is not rec-
ommended as routine therapy, but may still be considered when a
P2Y12 receptor antagonist has not been given in advance. GP IIb/
IIIa inhibition is also worth consideration in bail-out situations
even after preloading with clopidogrel in patients undergoing very
complex PCI, and if dissection, coronary thrombus formation,
troponin-positivity, or other severe complications occur.
In NSTEMI patients, GPI may be considered in the catheteri-
sation laboratory in high-risk patients, in patients with significant
intracoronary thrombus burden, or in the absence of timely anti-
platelet pre-treatment. In these cases, the strongest evidence sup-
ports the use of abciximab (22).
Also, in the setting of STEMI, GP IIb/IIIa inhibition should be
considered in high-risk patients during PCI. Routine upstream
therapy with GPI is not recommended at present.
Current antithrombotic strategies are subject to important
changes encouraged by the success of P2Y12 receptor antagonists
like clopidogrel and its promising potent successors, prasugrel and
ticagrelor. Bivalirudin, a direct thrombin inhibitor, is another im-
portant alternative to GPI, especially in patients at increased risk of
bleeding undergoing PCI, but also in the setting of NSTE-ACS and,
in particular, during primary PCI (22).
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Abbreviations
ACS, acute coronary syndrome(s); CAD, coronary artery disease; GP,
glycoprotein; GPI, glycoprotein IIb/IIIa inhibitor(s); NSTE-ACS, non-ST-
elevation acute coronary syndrome(s); NSTEMI, non-ST-elevation
myocardial infarction; PCI, percutaneous coronary intervention;
STEMI, ST-elevation myocardial infarction.
Acknowledgement
Dr. Kristensen is supported by a grant from The A.P Møller Foun-
dation for the Advancement of Medical Science. Dr. Kristensen, Dr.
Huber, and Dr. Neumann are members of the European Platelet
Academy, which is funded by an unrestricted grant from Eli Lilly
and Daichii-Sankyo.
Conflict of interest
Dr. Kristensen has received lecturing fees from AstraZeneca, Eli
Lilly, Merck Sharp & Dohme, and The Medicines Company; Dr.
De Caterina has received lecturing fees from Eli Lilly and Merck
Sharp & Dohme; Dr. Huber has received lecturing fees from Eli
Lilly; Dr. Moliterno, consultant and research grants from Merck-
Schering-Plough.
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