From the Cardiovascular Institute, Mount Sinai Medical Center, New York,
NY.
Correspondence to Valentin Fuster, MD, PhD, Director, Cardiovascular Institute, Mount Sinai Medical Center, 1 Gustave Levy Place, Box 1030, New York, NY 10029-6574. E-mail Valentin-Fuster{at}SMTPLINK.MSSM.edu
An indisputable body
of angiographic,1 2
angioscopic,3
pathological,4 and
biochemical5 evidence supports the role of
thrombus in the pathogenesis of acute myocardial infarction, unstable
angina, and percutaneous coronary
intervention.6 Compelling data from large-scale
trials and analyses have established the role of platelet
inhibitors in reducing coronary events in patients
with the acute coronary syndromes and in maintaining patency of
vascular grafts in the long term.7 8 Persistent
reports of high clinical event rates in the modern era of acute
coronary syndromes despite aggressive medical therapy have
spurred the development of more effective antiplatelet agents.
Despite its efficacy, aspirin is a relatively weak antiplatelet
agent, inhibiting only thromboxane
A2–mediated platelet aggregation. The final
common pathway of platelet aggregation involves activation of the
platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor
to allow fibrinogen binding.9 Studies involving a
number of intravenous inhibitors of GP IIb/IIIa
receptors have demonstrated efficacy in reducing ischemic
complications after percutaneous
angioplasty10 11 12 and in the acute
coronary syndromes.13 14 15 16
In patients who have survived an episode of unstable angina or
myocardial infarction, activation of the hemostatic system may persist
for several months after the acute event.5
Studies with GP IIb/IIIa
inhibitors12 16 and with specific
antithrombins17 have demonstrated efficacy of
these agents during the short-term period coinciding with
intravenous administration, with subsequent decay in
clinical benefit after cessation of parenteral treatment so that no
demonstrable clinical benefit is evident at late (1 month) follow-up.
Hence, there exists a compelling rationale for long-term
antiplatelet treatment, including GP IIb/IIIa inhibition. More than
one dozen oral GP IIb/IIIa inhibitors are in clinical
trials, and early reports from several phase II studies are
appearing.
The Present Study
In the present issue of Circulation, Cannon et
al18 conducted a dose-ranging study of
sibrafiban, an orally active peptidomimetic GP IIb/IIIa
antagonist. In the pharmacokinetic/pharmacodynamic study,
seven dosing regimens of sibrafiban were assessed with serial
evaluations of platelet aggregation; four doses that achieved at
least minimum-grade platelet inhibition (defined as >50%
inhibition of ADP-induced platelet aggregation for >75% of the
day) were then chosen for evaluation in the safety study, and aspirin
served as control. In the safety cohort, 223 patients with documented
coronary artery disease after an acute coronary
syndrome (unstable angina, non–Q-wave myocardial infarction [MI],
Q-wave MI) were studied for 28 days.
High levels of platelet inhibition were achieved (mean peak values,
47% to 97% inhibition of 20 µmol/L ADP-induced platelet
aggregation on day 28). Good correlations between blood level and
degree of platelet inhibition were noted. Major hemorrhage
occurred in 1.5% of sibrafiban-treated and 1.9% of aspirin-treated
patients. Protocol-defined minor bleeding occurred in 0% to 32% of
the sibrafiban groups and in no patient treated with aspirin alone.
Between 6% and 10% of patients experienced a clinically significant
major or minor hemorrhage at the doses that achieved
Efficacy
Major questions must be resolved before oral agents enter
routine clinical practice. In this study and in other dose-ranging
studies,19 a clear-dose response relationship was
seen, with higher drug levels correlating with higher levels of
platelet inhibition and higher levels of bleeding complications. In
trials of intravenous GP IIb/IIIa receptor
antagonists, agents with effective (ie, >80%) receptor
blockade are more effective than those with more limited receptor
blockade in reducing clinical events.10 11 It is
unknown what degree of receptor inhibition is needed in the long-term
setting to prevent recurrent ischemic cardiac events, without
the hazard of hemorrhagic complications. Although the development of
reliable bedside assays for measurement of degree of platelet
inhibition may ultimately prove helpful in optimizing the safety of GP
IIb/IIIa therapy,20 an effective and safe level
of receptor blockade must first be established. Similarly, it is
unknown whether the degree of platelet inhibition required changes
over time after the acute coronary syndrome. It is interesting
to note that in the present study, in patients who underwent
complete pharmacokinetic evaluation, the drug concentration required to
give 50% inhibition was similar on days 1 and 28, suggesting that the
patients' platelets did not change over time with respect to
platelet surface GP IIb/IIIa receptor number or activation state.
The role of concomitant aspirin treatment has not been studied
prospectively; some trials have added an oral GP IIb/IIIa
inhibitor to background aspirin
treatment,19 and others, including the
present study,18 compared the oral GP
IIb/IIIa receptor antagonist to aspirin.
Safety
The safety of prolonged GP IIb/IIIa inhibition is similarly
unknown. Patients with Glanzmann thrombasthenia lack GP IIb/IIIa
function on the basis of a genetic defect. Although the generally
favorable clinical outcome of Glanzmann patients (largely
mucocutaneous bleeding with rare spontaneous central nervous system
bleeding)21 has served as the theoretical model
for the development of pharmacologic interruption of the GP IIb/IIIa
receptor, the long-term outcome of patients with pharmacologically
mediated inhibition of GP IIb/IIIa is unknown. Moreover, the optimal
duration of treatment after an acute coronary syndrome is also
unknown.
A major concern with the long-term use of oral GP IIb/IIIa
antagonists is bleeding. Thus, in the present study of
Cannon et al,18 6% of patients experienced
gastrointestinal bleeding with sibrafiban; whether this effect can be
reduced or eliminated with concomitant antacid or
H2 blocker is also unknown. Although patients
with creatinine >1.5 mg/dL were excluded from the
present study, a higher rate of major or minor hemorrhage
was observed in patients with even moderate impairment of renal
function (creatinine clearance <67 mL/min) in
multivariate analysis. In regard to low
platelet count, acute profound thrombocytopenia has been reported
with abciximab.22 However, the observation that
elevated reactivity to human antichimeric antibody before the first
dose of abciximab was not associated with an increased incidence of
thrombocytopenia,23 and the consistent
finding of thrombocytopenia with other nonantibody GP IIb/IIIa receptor
antagonists18 19 suggests the
existence of mechanisms other than direct
reticuloendothelial binding of the platelet/drug
complex. For example, binding of a number of molecules to the GP
IIb/IIIa receptor produces a conformational change in the receptor
resulting in the expression of new epitopes, known as ligand-induced
binding sites. A preexisting IgG type antibody that binds to the GP
IIb/IIIa receptor in the presence of an experimental GP IIb/IIIa
receptor antagonist causes profound thrombocytopenia. This
antibody was detected in about 1% of human
samples.24
Ultimately, it would be presumed that a rapid acting
intravenous agent would be administered acutely during the
hospitalization for the acute coronary syndrome or
revascularization procedure, with outpatient
conversion to an orally active preparation of the same compound;
indeed, several such products are in
development.25 However, it has been shown that
the pharmacodynamic response to an oral GP IIb/IIIa receptor
antagonist is potentiated by antecedent treatment with
abciximab.26 Whether this finding will be
observed with other combinations of oral and parenteral GP IIb/IIIa
receptor antagonists is unknown. This observation may have
important implications regarding safety of sequential GP IIb/IIIa
blocker therapy, particularly considering that in the present study
by Cannon et al,18 patients had not received
prior treatment with an intravenous preparation.
Conclusions
Footnotes
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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© 1998 American Heart Association, Inc.
Editorial
Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety
Key Words: Editorials • glycoproteins • platelets • platelet aggregation inhibitors • drugs
70% to
80% platelet inhibition. One patient (0.3%) developed severe
thrombocytopenia (nadir platelet count, 6000 per 1 µL) that
required cessation of study drug. The overall cardiac event rate was
low (1.8% death, 1.4% recurrent MI, 4.0% recurrent
ischemia), and the study was not statistically powered to
detect differences in clinical events among the treatment groups.
For cardiologists at the dawn of a new century, antiplatelet
therapy is at a crossroads. Aspirin celebrated its centenary this past
summer and remains the mainstay of the therapeutic arsenal due to its
efficacy, safety profile, and cost effectiveness. Although some degree
of optimism should prevail about future potential efficacy for chronic
oral GP IIb/IIIa inhibitors, the major challenge to be
pursued at this time is safety.
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