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100 Part I / Basic Principles
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Chapter 4 / Development and Pharmacology of GPIIb/IIIa Antagonists 101
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102 Part I / Basic Principles
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Chapter 5 / Abciximab During Percutaneous Coronary Intervention 103
II GLYCOPROTEIN IIb/IIIa BLOCKADE
DURING CORONARY INTERVENTION
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104 Part II / GPIIb/IIIa Blockade During Coronary Intervention
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Chapter 5 / Abciximab During Percutaneous Coronary Intervention 105
105
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
5 Abciximab During
Percutaneous Coronary Intervention
EPIC, EPILOG, and EPISTENT Trials
A. Michael Lincoff, MD
CONTENTS
INTRODUCTION
PHARMACOLOGY OF ABCIXIMAB
PIVOTAL TRIALS OF ABCIXIMAB DURING CORONARY INTERVENTION
CONCLUSIONS
REFERENCES
INTRODUCTION
Blockade of the platelet glycoprotein (GP) IIb/IIIa receptor as a therapy for ischemic
heart disease was introduced into clinical practice by demonstration that the first of these
agents, abciximab, reduces periprocedural complications among patients undergoing
high-risk coronary angioplasty. From this initial “proof of concept,” subsequent clinical
evaluation of this agent progressed through a series of large-scale trials, establishing the
broad applicability, marked clinical efficacy, and acceptable safety profile of this thera-
peutic strategy in the setting of percutaneous coronary revascularization. This chapter
reviews the clinical experience with this agent as a pharmacologic adjunct to elective or
urgent coronary intervention.
PHARMACOLOGY OF ABCIXIMAB
Preclinical Data
The development and pharmacology of abciximab are reviewed in detail in Chapter 4
by Dr. Coller. In brief, abciximab (ReoPro
™
, Centocor, Malvern, PA) is a chimeric Fab
monoclonal antibody fragment that binds to the platelet GPIIb/IIIa receptor. A murine
antibody (7E3) was produced by immunization of mice with human platelets and isolated
from hybridoma supernatants by its inhibition of the interaction between platelets and
fibrinogen-covered beads. To limit the risk of thrombocytopenia owing to clearance of
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106 Part II / GPIIb/IIIa Blockade During Coronary Intervention
7E3-coated platelets by binding of the Fc region of the IgG molecule to the reticuloendo-
thelial system, 7E3 was cleaved with pepsin into F(ab')
2
fragments. Animal experiments
and initial human studies were carried out using this F(ab')
2
form. Because of continued
concerns regarding the potential for thrombocytopenia by crosslinking of platelets with
the bivalent F(ab')
2
antibody, an Fab antibody fragment was produced by papain digestion
of m7E3 and subsequently evaluated. Finally, to reduce the risk of immunogenicity to
murine protein, genetic reconstruction was used to produce the chimeric c7E3 Fab antibody
fragment currently in clinical use (abciximab), which consists of human constant regions
and murine variable regions of the IgG antibody.
In preclinical canine and primate animal models (see Chapter 4), 7E3 F(ab')
2
or c7E3
Fab were shown to markedly diminish thrombus formation and platelet-mediated cyclic
flow reductions in injured and stenosed coronary arteries, to facilitate tissue plasmino-
gen activator (t-PA)-induced thrombolysis, and to abolish reocclusion. These antithrom-
botic effects were observed at doses that achieved blockade of >60–80% of GPIIb/IIIa
receptors.
Clinical Studies
Murine 7E3 and abciximab bind with high affinity to both activated and unactivated
platelet GPIIb/IIIa, with inhibition of platelet aggregation observed at levels of receptor
blockade >50% and nearly complete abrogation of aggregability at >80% receptor occu-
pancy. Although binding is reversible, dissociation of the agent from the receptor is slow,
and normalization of platelet aggregation does not occur until 24–36 h following discont-
inuation of abciximab infusion (1,2). By flow cytometry, decreasing but measurable levels
of platelet-bound abciximab are present for as long as 15 d, beyond the normal circulating
platelet lifespan, indicating redistribution of abciximab to new platelets entering the cir-
culation (3).
Phase II clinical studies confirmed dose-related inhibition of platelet aggregation and
prolongation of bleeding time by 7E3 in the setting of percutaneous coronary interven-
tion. In a pilot study of 23 patients undergoing elective angioplasty, escalating bolus
doses ranging from 0.15 to 0.35 mg/kg of m7E3 Fab produced levels of receptor blockade
ranging from approx 50–90% (4). Doses of ≥0.20 mg/kg led to >70–80% inhibition of
platelet aggregation, with partial recovery of platelet function noted by 6 h. Marked pro-
longation of bleeding times were observed at all doses, with normalization by 24 h.
Chimeric 7E3 Fab (abciximab) was evaluated in a multicenter, open-label, dose-esca-
lation study of 56 patients undergoing elective percutaneous transluminal coronary angio-
plasty (PTCA) (2). Levels of receptor blockade and inhibition of platelet aggregation
following bolus doses of 0.15, 0.20, and 0.25 mg/kg are detailed in Table 1; although wide
variability was observed among patients, particularly at the lowest dose, platelet aggre-
gation was consistently suppressed to the theoretical target of ≤20% of baseline by the
abciximab bolus dose of 0.25 mg/kg. In the second phase of this study, GPIIb/IIIa recep-
tor blockade, platelet aggregation, and bleeding times were measured following a 0.25
mg/kg bolus dose, with and without a subsequent 12-h infusion at a rate of 10 µg/min (Fig.
1). With a bolus only (Fig. 1A), peak receptor blockade and inhibition of platelet aggrega-
tion to ≤20% occurred by the first (2-h) measurement, with prolongation of bleeding time
to >30 min. Bleeding time returned nearly to normal by 12 h, although recovery of platelet
aggregability occurred more gradually, remaining approx 40% and approx 30% inhibited
by 12 and 24 h, respectively. Addition of an infusion of abciximab (10 µg/min) following
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Chapter 5 / Abciximab During Percutaneous Coronary Intervention 107
the bolus dose produced consistent levels of receptor occupancy of approx 80%, with
inhibition of platelet aggregation to approx 20% and prolongation of bleeding time to >30
min during the 12-h infusion period (Fig. 1B). Following discontinuation of the infusion,
recovery of these parameters occurred at rates similar to those following administration of
the bolus only. The effectiveness of the 12-h abciximab infusion (10 µg/min or 0.125 µg/
kg min) in maintaining receptor blockade >80% and platelet aggregability <20% in the
majority of treated patients was confirmed in a subsequent study of 41 normal volunteers (3).
Kleiman and coworkers (5) evaluated the influence of different agonists on measured
inhibition of platelet aggregation by abciximab among 32 patients undergoing coronary
angioplasty. Receptor blockade was approx 80% at 2 h following the single abciximab
bolus of 0.25 mg/kg, declining to approx 50% by 24 h. This level of receptor occupancy
was associated with nearly complete inhibition of platelet aggregation in response to the
traditional agonists ADP (20 and 5 µM concentrations) and collagen (mean 76%, 88%,
and 85% inhibition at 2 h, respectively). The circulating plasma half-life of abciximab
was very short, calculated at <26 min. Inhibition of platelet aggregation at various time
points in response to ADP and collagen was significantly correlated with the extent of
receptor blockade by abciximab but was not at all related to circulating abciximab plasma
concentrations (which were very low by 2 h following the drug bolus). Platelet aggrega-
tion in response to stimulation with thrombin receptor-activating peptides (TRAPs), an
agonist that mimics platelet activation by thrombin, was significantly less inhibited 2 h fol-
lowing abciximab than was aggregation in response to ADP or collagen. Addition of exoge-
nous abciximab to the platelet-rich plasma, however, led to more complete inhibition of
aggregation in response to TRAP.
These investigators postulated that the continued ability of platelets to aggregate in
response to TRAP 2 h following the bolus of abciximab may have been related to the
“release reaction” induced by thrombin stimulation, in which GPIIb/IIIa receptors in the
α-granule membranes and perhaps other sites of the platelet are externalized to the plate-
let membrane. Given the brief circulating half-life of abciximab, plasma levels of this
agent would be insufficient to bind such newly exposed receptors shortly after the bolus
is administered. These findings suggested that a continued infusion of abciximab follow-
ing a bolus would be required to provide complete inhibition of platelet aggregation in the
setting of intense stimulation by agonists such as thrombin, in which additional unbound
GPIIb/IIIa receptors are externalized to the platelet membrane.
Table 1
GPIIb/IIIa Receptor Blockade
and Inhibition of Platelet Aggregation after Abciximab Bolus Doses
GPIIb/IIIa Platelet aggregation
receptor blockade to 20 µM ADP
Bolus dose (% blocked) (% of baseline)
(mg/kg body weight) [median (interquartile range)] [median (interquartile range)]
0.15 54 (15–94) 46 (34–80)
0.20 80 (67–89) 45 (19–71)
0.25 87 (62–96) 18 (9–25)
Data from ref. 2.
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108 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Fig. 1. Pharmacodynamics of a 0.25 mg/kg bolus dose only (A) or a 0.25 mg/kg bolus dose followed
by a 10 µg/min infusion for 12 h (B) of abciximab. The bolus was given at time 0, with the infusion
between time 0 and 12 h. Effects were followed for 24 h. Data points for each patient are shown in
open circles; median values are in solid squares, and lines join the median values. For each panel:
top graph, percentage of GPIIb/IIIa receptors blocked by abciximab; middle graph, inhibition of plate-
let aggregation, expressed as percentage of baseline aggregation in response to 20 µmol/L ADP; bot-
tom graph, bleeding time. (From ref. 2 with permission.)
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Chapter 5 / Abciximab During Percutaneous Coronary Intervention 109
Fig. 1. (Continued)
Subsequent studies performed since the availability of point-of-care devices to measure
platelet aggregation have documented substantial interpatient variability in the degree
of platelet inhibition during abciximab administration. In one study of 100 patients under-
going percutaneous coronary revascularization, all but one achieved >80% inhibition
following the bolus of abciximab (6). At 8 h after the bolus, however, during the 12-h abcix-
imab infusion, 13% of patients demonstrated inhibition levels below the 80% target.
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