The Benefits of Platelet
Glycoprotein IIb/IIIa Receptor
Inhibition During Primary
Drug-Specific or Class Effect?*
Sorin J. Brener, MD
Brooklyn, New York
For patients with ST-segment elevation (acute) myocardial
infarction (STEMI), reperfusion with primary percutaneous
coronary intervention (PCI) results in excellent short- and
long-term outcome, predominantly because of the high rate
of restoration of normal flow at the epicardial and myocar-
dial levels (1). Despite its success, primary PCI remains
fraught with obstacles because of the high thrombus burden,
difficulty in initial assessment of lesion length and vessel
size, and consequences of distal embolization of plaque and
thrombus. Thus, adjunctive pharmacology has always been
an important tool for addressing these challenges. Oral and
intravenous platelet inhibitors and intravenous thrombin
inhibitors have been used in various combinations to reduce
thrombus size and prevent its reaccumulation after success-
See page 1668
After their introduction 2 decades ago, intravenous an-
tagonists of the platelet glycoprotein IIb/IIIa (GPIs) (2)
receptor quickly became the most researched intervention in
cardiology, with numerous studies performed in a variety of
clinical scenarios, ranging from adjunctive therapy to PCI in
stable patients to primary PCI for STEMI (3,4). Tens of
thousands of patients with varying clinical profile and acuity
have been enrolled in pre- and post-marketing studies of
GPIs. The prototypical agent, abciximab, is a large, chi-
meric antibody to the glycoprotein (GP) receptor, which
sterically hinders its binding to fibrinogen in a nearly
irreversible fashion, preventing platelet aggregation and
potentially promoting deaggregation of recently formed
platelet-rich thrombi, as occurs in STEMI (5,6). Initially,
there was considerable enthusiasm about the “pleiotropic”
effects of abciximab, such as inhibition of the vitronectin
receptor and prevention of white blood cells aggregation to
platelets and to the vascular wall (7). These interactions
were hypothesized to lead to less restenosis and inflamma-
tion after PCI. Subsequent laboratory work resulted in the
synthesis of smaller, cheaper molecules (peptides and non-
peptides), which bind specifically and reversibly to the
receptor and allow for quicker recovery of platelet function
after discontinuation of infusion. As compared with abcix-
imab’s long clearance time of 12 to 24 h, these small
molecules had a clearance time of only 2 to 2.5 h, making
them particularly attractive when urgent reversal of their
effect was desirable. When administered in a dose sufficient
to inhibit platelet aggregation by at least 80%, these com-
pounds proved equally able as abciximab to inhibit shedding
of soluble CD40 ligand, a compound associated with
increased inflammation and restenosis after PCI (8).
The use of abciximab in STEMI was first studied more
than 10 years ago in the RAPPORT (ReoPro and Primary
PTCA Organization and Randomized) trial (9). Compared
with placebo, abciximab reduced the incidence of death,
reinfarction, or urgent revascularization at 7 days (11.2% vs.
5.8%, respectively, p ? 0.03), but had no effect on late,
nonurgent repeat revascularization. The 30-day death (2.1%
vs. 2.5%) and reinfarction (4.1% vs. 3.3%) rates were similar
between the groups. Earlier administration of the drug, even
before angiography, seemed to result in the best outcome, in
a randomized study and in a large registry. With the
exception of 1 small study comparing eptifibatide with
placebo (10), most of the STEMI experience has been
accumulated with abciximab.
In this issue of the Journal, De Luca et al. (11) summarize
the results of 6 trials comparing the outcome of primary
PCI in 2,197 patients treated with abciximab, high-dose
tirofiban, or eptifibatide between 2002 and 2007. In 5
studies, abciximab was compared with high-dose tirofiban
(dosing regimen not approved by the Food and Drug
Administration), and in 1, eptifibatide was pitted against
abciximab. At 30 days death occurred in 2.2% of abciximab
patients and 2.0% of tirofiban or eptifibatide patients (p ?
0.66) and reinfarction occurred in 1.2% in each group (p ?
0.88), without heterogeneity among the trials or evidence
for publication bias. Furthermore, there was no evidence for
superiority of either type of drug with respect to angio-
graphic (restoration of Thrombolysis In Myocardial Infarc-
tion flow grade 3) or electrocardiographic (ST-segment
resolution) parameters, which occurred in a high proportion
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the New York Methodist Hospital, Department of Cardiology, Brooklyn,
Journal of the American College of Cardiology
© 2009 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 53, No. 18, 2009
of the patients. Major bleeding was low and comparable
among the 2 groups. The authors elegantly discuss the
implications of their findings and recognize that their study
is significantly underpowered to detect even a 1% absolute
reduction in mortality between the groups, the difference
observed between lytic regimens in a landmark reperfusion
Currently, in the American College of Cardiology/
American Heart Association guidelines abciximab use as
adjunct to primary PCI carries a Class IIA (Level of
Evidence: B) recommendation, while the small molecules
received a Class IIB (Level of Evidence: C) recommenda-
tion (12). Are the guidelines correct? How should one
interpret these results?
Using the data shown in Table 1, we can conclude that
GPIs in general, and abciximab in particular (the others
have not been extensively studied), are superior to placebo in
improving the outcome of primary PCI. The benefit is small
in absolute terms, particularly when the patients studied are
relatively low-risk and cardiogenic shock is excluded. Mor-
tality can be reduced more significantly in higher-risk
patients, as shown in 1 study (13). The effect on myocardial
infarction is most obvious in patients receiving percutaneous
transluminal coronary angioplasty only, who are at higher
risk of abrupt vessel closure soon after the procedure.
Despite the putative advantages of abciximab with respect
to inhibition of additional proinflammatory pathways, the
small molecules appear to do as well as abciximab as far as
ischemic events are concerned and the less enthusiastic
recommendation for their use stems from a lack of compar-
ative data to placebo. Finally, it is possible that on the
background of aspirin and thienopyridine, the use of GPIs
can be replaced completely with bivalirudin without any
disadvantage in prevention of ischemic events (14).
Ultimately, when the mortality is as low as that observed
in contemporary randomized clinical trials of primary PCI,
it is very difficult to demonstrate added benefit from one
intervention, particularly when it is compared with another
with similar effect. Mortality cannot be completely elimi-
nated in STEMI patients. The lack of statistical power of
the current meta-analysis underscores this concept. It is
unlikely, in the current era of primary PCI, that additional
studies, large enough to detect small differences in rare
events, will be performed. The use of surrogate end points,
such as extent of angiographic or electrocardiographic
reperfusion, is not likely to overcome this fact, even if
differences between compounds were found.
The information we currently possess is sufficient to guide
our practice in that GPIs are likely to improve outcome,
compared with placebo or control therapy, particularly in
high-risk STEMI patients, receiving the drug as early as
possible after diagnosis and before primary PCI (15–17).
The choice of GPI is more dependent on cost and consid-
erations of reversibility rather than on efficacy, as long as
drugs with similar ability to inhibit platelet aggregation are
given. STEMI is probably the last segment of the PCI
population for which GPI has a defined role, until addi-
tional studies with alternative antithrombotic regimens are
Reprint requests and correspondence: Dr. Sorin J. Brener, New
York Methodist Hospital, Department of Cardiology, 506 6th
Street, Brooklyn, New York 11215. E-mail: firstname.lastname@example.org.
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Recent Studies and Meta-Analysesof Reperfusion With Primary PCI for STEMI
Recent Studies and Meta-Analyses
of Reperfusion With Primary PCI for STEMI
De Luca et al.
De Luca et al.
Stone et al.
Period 1995–2002 2002–20072005–2007
30-day death 2.4% vs. 3.4% 2.2% vs. 2.0%2.1% vs. 3.1%
Change vs. control therapy29%§
30-day MI1.0% vs. 1.9%1.2% vs. 1.2%1.8% vs. 1.8%
Change vs. control therapy47%§ 0%0%
*Meta-analysis (8 studies) of abciximab versus placebo; †meta-analysis (6 studies) of abciximab
versus small-molecule glycoprotein IIb/IIIa inhibitors; ‡randomization to bivalirudin versus abcix-
imab or small-molecule glycoprotein IIb/IIIa inhibitors; §signifies p ? 0.05.
MI ? myocardial infarction; PCI ? percutaneous coronary intervention; STEMI ? ST-segment
elevation myocardial infarction.
JACC Vol. 53, No. 18, 2009
May 5, 2009:1674–6
GP Receptor Inhibitors in STEMI
12. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines Download full-text
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myocardial infarction: a meta-analysis of randomized trials. JAMA
Key Words: primary angioplasty y meta-analysis y abciximab y
STEMI y small molecules.
GP Receptor Inhibitors in STEMI
JACC Vol. 53, No. 18, 2009
May 5, 2009:1674–6