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420 Part IV / Practical Issues and Future Applications
Fig. 7.
Fig. 8.
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Chapter 20 / Cerebrovascular Aspects of GPIIb/IIIa Receptor Inhibitors 421
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424 Part IV / Practical Issues and Future Applications
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Chapter 21 / Summary and the Future 425
425
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
21 Evolution of Drug Development
in Evidence-Based Medicine
Summary and the Future
David E. Kandzari, MD,
David F. Kong,
MD,
and Robert M. Califf,
MD
CONTENTS
INTRODUCTION
PATHOPHYSIOLOGY OF UNSTABLE ATHEROSCLEROTIC PLAQUES
AND
THERAPEUTIC TARGETS
CONTEMPORARY CLINICAL TRIALS OF GPIIb/IIIa INHIBITION IN ACS
P
ROGRESSION AND REGRESSION: DEVELOPMENT AND FAILURE
OF
ORAL GPIIb/IIIa INHIBITORS
ALTERNATIVE ANTIPLATELET AND ANTITHROMBOTIC THERAPIES
FUTURE DIRECTIONS
CONCLUSIONS
REFERENCES
INTRODUCTION
Clinical medicine has entered a new era, characterized by dramatic advances in the
understanding of disease biology and a new focus on the organization of medical practice.
Identification of receptors, agonists, and antagonists permits development of therapies tar-
geted against specific biologic processes. Development of new therapies has consumed
substantial resources from government and industry. The estimated cost to develop and
market a new prescription drug averaged $802 million for the year 2000, three times higher
than estimates from a decade ago (1). Despite these daunting costs, the world will accrue
long-standing benefit from these huge investments in biomedical research as the number
of medical treatments for chronic diseases increases exponentially.
Shortly after investigators clarified the role of the glycoprotein (GP) IIb/IIIa receptor
in thrombosis, they rapidly turned their attention from its physiologic function to its thera-
peutic potential. As a result, several promising molecular targets have been identified.
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426 Part IV / Practical Issues and Future Applications
Recent discoveries have provided insight into the influence of genetic variants on the
development of atherosclerotic disease and arterial thrombosis, enhancing our understand-
ing of ischemic heart disease. Unprecedented efforts are under way to identify variations
of single nucleotides and complex polymorphisms. Ongoing translational research seeks to
establish the genotypic and phenotypic bases for ischemic heart disease susceptibility and
drug response. Many therapeutic agents will be derived from the Human Genome Project
and computer simulations of receptors, genes, and gene products. Sophisticated receptor
models allow synthesis of agonists and antagonists even before their biologic functions
are known. Before clinicians and scientists are led astray by technology that outpaces the
application of proven therapies, however, the GPIIb/IIIa receptor experience should serve
as an educational template for this more complex future.
The continuing rigorous evaluation of the safety and efficacy of GPIIb/IIIa inhibitors
reflects the clinical and scientific communities’ changing approach to new cardiovascular
therapies. Before therapies such as fibrinolytics or GPIIb/IIIa inhibitors were scrutinized
in large, randomized clinical trials, health care providers would have embraced any major
therapeutic advance after studies of a relatively few patients and would have eagerly applied
it to various indications. Today, regulatory authorities apply immensely higher standards
for proof of safety and efficacy, requiring definitive evidence that a new agent does not
cause potential harm in trials involving thousands of patients. Furthermore, health care sys-
tems are concerned about not only the potential benefits of a new therapy but also the incre-
mental costs. Compared with aspirin, possibly the most effective and yet inexpensive
therapy for ischemic heart disease, these new antiplatelet therapies face a challenging stan-
dard. As an example, although investigations of GPIIb/IIIa inhibitors now have random-
ized over 60,000 patients, only a few agents have been approved and marketed (Table 1).
PATHOPHYSIOLOGY OF UNSTABLE
ATHEROSCLEROTIC PLAQUES AND THERAPEUTIC TARGETS
Our understanding of the pathophysiology, therapeutic applications, and clinical out-
comes of patients with acute coronary syndromes (ACS) continues to evolve. Envisaging
the future of GPIIb/IIIa antagonists requires an understanding of the rationale for their
application and the measures of their clinical effects.
Table 1
Pharmacologic Properties
of Food and Drug Administration (FDA)-Approved Platelet GPIIb/IIIa Inhibitors
Abciximab Eptifibatide Tirofiban
Chemical nature Antibody Peptide Nonpeptide
Size Large (48 kDa) Small (1 kDa) Small (<1 kDa)
Onset of effect Rapid Rapid Rapid
Reversibility Slow Rapid Rapid
Binds other integrins? Yes No No
Antibody response? Yes No No
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Chapter 21 / Summary and the Future 427
Role of the GPIIb/IIIa Receptor in ACS
The pathophysiology of ACS is defined by atherosclerotic plaque rupture, platelet acti-
vation, and resultant thrombus formation (2,3). In atherosclerotic coronary vessels, plaque
rupture exposes the subendothelium, precipitating clot formation. Platelets first adhere
to the subendothelium by binding to class I glycoproteins. The presence of thrombin or
other agonists such as adenosine or epinephrine activates platelets, causing a conforma-
tional change in the GPIIb/IIIa receptor and platelet degranulation. These changes cause
the release of serotonin, adenosine diphosphate (ADP), and other vasoactive substances,
which stimulate further platelet activation and recruitment. The conformational change
in the GPIIb/IIIa receptor allows crossbinding of fibrinogen and von Willebrand factor with
other platelets, resulting in platelet aggregation and thrombus formation. The associated
clinical presentation depends on whether the clot is occlusive, subocclusive, or nonobstruc-
tive and is influenced by collateral flow, baseline left ventricular function, amount of jeop-
ardized myocardium, diabetes, and other factors. Patients therefore may have severe angina
with ST-segment elevation, mild angina, or no symptoms at all.
The role of the GPIIb/IIIa receptor as the final common pathway for platelet aggre-
gation made its inhibition a pivotal transition from bench work to clinical practice (4,5).
In 1983, Coller and coworkers (6) first reported a murine monoclonal antibody that blocked
this receptor. These findings led to the engineering of a chimeric monoclonal antibody,
abciximab (ReoPro
™
), which was first studied in patients undergoing high-risk percuta-
neous coronary intervention (PCI) (Table 1) (7). Since then, several other inhibitors that
mimic the arginine-glycine-aspartic acid (RGD) binding sequences of the GPIIb/IIIa recep-
tor have undergone extensive clinical investigation. These include the synthetic cyclic hep-
tapeptide eptifibatide (Integrilin
®
) as well as peptidomimetics such as tirofiban (Aggrastat
®
)
and lamifiban (Ro 44-9883) (Table 1). Despite differences in pharmacodynamics, the com-
mon mechanism of these drugs is to inhibit platelet aggregation by occupying the fibrino-
gen binding site.
CONTEMPORARY
CLINICAL TRIALS OF GPIIb/IIIa INHIBITION IN ACS
GPIIb/IIIa Inhibition in PCI
For the past 30 years, the animal model for atherosclerosis was predicated on mechanical
abrasion of the arterial endothelial surface, coupled with a high-cholesterol diet. Balloon
dilation and mechanical debulking cause similar biologic reactions, creating a human
model for cellular proliferation and thrombotic vascular occlusion. Platelets often provide
a protective barrier in response to vascular injury, but when this process becomes exces-
sive, vessel occlusion or embolism can result. Therefore, the acute thrombotic reaction
to PCI creates an ideal opportunity for platelet inhibitors. Prevention of platelet aggrega-
tion during and after intentional vessel injury reduced clinical complications by antago-
nizing a molecular target.
In the past decade, advances in interventional drugs and devices have improved out-
comes significantly for patients undergoing elective PCI. Stenting has reduced the inci-
dence of abrupt vessel closure to <0.5% and the need for repeat revascularization by
30–50% (8–10). In addition, several randomized trials have shown that GPIIb/IIIa inhi-
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428 Part IV / Practical Issues and Future Applications
bition during elective PCI reduces the composite incidence of death, nonfatal myocardial
infarction (MI), or target-vessel revascularization (TVR) at both 30 d and 6 mo (7,11). The
synergy between PCI and GPIIb/IIIa blockade is especially prominent for patients with
ACS without ST-segment elevation, although similar clinical benefit has been observed
for patients with acute ST-elevation MI.
GPIIb/IIIa I
NHIBITION AND PCI IN NON-ST-ELEVATION ACS
The application of GPIIb/IIIa inhibitors as adjuncts to PCI has been modeled after an
initial series of large, randomized, placebo-controlled trials (Fig. 1) (12–16). A system-
atic overview of these trials has shown a highly significant reduction in the endpoint of
death, nonfatal MI, or urgent revascularization at 48–96 h (p < 0.001), 30 d (p < 0.001),
and 6 mo (p < 0.003) (11). Furthermore, the addition of GPIIb/IIIa antagonists to coronary
stenting is supported by the significant reduction in 30-d death, MI, or urgent revascu-
larization observed in the EPISTENT (17) trial (5.3% in the stent-plus-abciximab group
versus 10.8% in the stent-only group; p < 0.001) (see Appendix for definitions of all trials).
The recent ESPRIT trial not only confirmed that treatment with a GPIIb/IIIa inhibitor
before stenting was the superior approach but also showed improved outcomes among
low-risk patients treated with more modern stenting techniques, thereby broadening the
applicability of the therapy to nearly all patients undergoing PCI (18). In the ESPRIT
trial, the control arm was “rescue” or “bailout” GPIIb/IIIa blockade therapy. Among 2064
patients undergoing elective (nonurgent) angioplasty with stenting, treatment with double-
bolus eptifibatide was associated with a 37% relative reduction in the composite rate of
death, MI, urgent revascularization, or “bailout” GPIIb/IIIa inhibitor therapy at 48 h (p =
0.0015). The benefit of preprocedural eptifibatide was consistent across all components
of the primary endpoint and was maintained at 30-d and 6-mo follow-up (18,19). At 1 yr,
Fig. 1. Odds ratios for death or MI at 30 d with GPIIb/IIIa inhibition vs placebo; all published trials
in routine PCI (12–16).
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Chapter 21 / Summary and the Future 429
the eptifibatide group showed continued benefit, with a significantly lower rate of death
or MI (8.0% vs 12.4% with placebo; p = 0.001) (20).
For patients undergoing PCI, a large portion of the benefit of GPIIb/IIIa inhibition
reflects a reduction in periprocedural MI. New angiographic techniques, including the
Thrombolysis In Myocardial Infarction (TIMI) myocardial blush score, and noninvasive
diagnostic tests (e.g., continuous ST-segment monitoring) have shown that epicardial
TIMI grade 3 flow may be an incomplete measure of reperfusion success (21). Depending
on the clinical setting, up to 40% of patients develop myocardial necrosis with elevation
of creatine kinase-MB (CK-MB). Although most of these events can be identified by angio-
graphy, a substantial number of “angiographically silent” events occur at the cellular level
of myocardial perfusion. Despite epicardial vessel patency, disrupted microvascular func-
tion and inadequate myocardial perfusion often result from thromboembolic debris. Use
of balloon occlusion and filter devices to prevent distal embolization during high-risk PCI
has reduced the occurrence of periprocedural MI in recent studies. To date, these devices have
not been systematically compared with GPIIb/IIIa inhibition. Although elevated cardiac
enzymes clearly reflect myocardial injury and necrosis, the clinical significance of peri-
procedural myocardial necrosis has been debated. The relative contribution of myocardial
necrosis to mortality has been difficult to discern, given the confounding fact that patients
with more severe disease are more likely to have such necrosis.
Collectively, these investigations have shown markedly improved outcomes with a vari-
ety of GPIIb/IIIa inhibitors in thousands of patients undergoing PCI and in an array of clin-
ical settings. Whether GPIIb/IIIa inhibitors improve survival after elective intervention
remains a topic of great debate (22), although the inability of GPIIb/IIIa inhibition to influ-
ence restenosis appears more certain. By 6 mo after initial PCI, restenosis, unimpeded by
GPIIb/IIIa inhibition, accounts for most repeat procedures. Thus, clinical events accrue
equally after 6 mo independent of earlier GPIIb/IIIa inhibition, and the relative differ-
ence between groups diminishes (23–25).
Further uncertainty exists about the selection of adjunctive GPIIb/IIIa inhibition in PCI.
Despite a lack of interest from industry, additional comparative studies are needed. In the
only comparative trial of GPIIb/IIIa inhibition in PCI to date, the TARGET study showed
a significant 26% reduction in the composite of death, MI, or urgent revascularization at
30 d with abciximab compared with tirofiban (6.01% vs 7.55%; p = 0.038) (Fig. 2) (26).
Although this difference deserves further exploration, one potential explanation is inade-
quate platelet inhibition with the tirofiban regimen used (see Dosing and Intensity of Plate-
let Inhibition section). Other continuing uncertainties for GPIIb/IIIa inhibitors in PCI include
optimal dosing and monitoring (27), immunogenicity (28), and selection of patients based
on underlying risk, to optimize the economic outlay relative to benefits achieved (29).
GPIIb/IIIa Inhibition and PCI in ST-Elevation MI
Recent trials have established evidence supporting GPIIb/IIIa inhibition for acute ST-
segment elevation MI. Given the abundant platelet-rich thrombus present in almost all
patients with acute MI, it is intuitive that these agents might be effective in this syndrome.
Furthermore, a “reperfusion ceiling” has been reached, given that no more than 55% of
patients achieve TIMI grade 3 flow after fibrinolytic monotherapy (Fig. 3). Addition of
GPIIb/IIIa inhibition to PCI for ST-elevation MI has substantially reduced recurrent ische-
mic events and improved early survival, ventricular function, and vessel patency.
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