Elsevier

The Lancet

Volume 353, Issue 9148, 16 January 1999, Pages 227-231
The Lancet

New Drug Classes
Platelet GPIIb-IIIa blockers

https://doi.org/10.1016/S0140-6736(98)11086-3Get rights and content

Summary

Regardless of the event that stimulates the aggregation of platelets, the receptor αllbβ3-one of a family of adhesion receptors known as integrins–has a key role in the process. The past decade has seen the publication of 10 phase III (randomised) clinical trials of four members of a new class of antiplatelet drugs, the GPIIb-IIIa blockers, targeted at this important receptor. Three (abciximab, eptifibatide, and tirofiban) are licensed for human use. 10 other GbIIb-IIIa blockers are in phase II or III human studies. In all 10 placebo-controlled trials, done in the clinical settings of percutaneous coronary intervention or acute coronary syndrome in patients on aspirin, the endpoints favoured the active drug, with a risk reduction for death or non-fatal myocardial infarction of about 21% overall. With attention to heparin dose the risk of bleeding is not a major concern with these agents. The GPIIb-IIIa blockers are taking the clinician and patient out of the era of aspirin monotherapy when platelet inhibition is required.

Section snippets

αllbβ3the molecule

To understand the biology of GPIIb-IIIa blockers requires a brief consideration of the structure and function of their target. Of the many families of adhesion receptors, the integrins are among the largest; and αIIIbβ3 is one of the more than twenty integrins.4 All integrins are noncovalently linked α/β heterodimers (figure 1). The aminoacid sequence of αIIIbβ3 indicates that each subunit has a large extracellular domain, a single transmembrane region, and a short cytoplasmic tail. The αIIIb

αIIIbβ3 function

Under conditions of normal haemostasis, platelets circulate freely in the blood without interacting with the vessel wall or with each other. Vascular injury, such as rupture of an atherosclerotic plaque, perturbs the non-thrombogenic properties of the endothelium and exposes the subendothelial matrix, including collagens, fibronectins, laminin, and von Willebrand factor (vWF). These ground substances are recognised by adhesion receptors, notably GPIb-IX-V and GPVI and integrins α2β1, α5β1 and α6

αIIbβ3 antagonism

The participation of αIIIbβ3 in platelet aggregation, whatever the initiating event or agonist, provides the molecular logic for therapeutic blockade of this receptor. The feasibility of such blockade was demonstrated in the early 1980s by the development of peptides and antibodies that could interact with αIIIbβ3, block ligand binding to the receptor, and inhibit platelet aggregation.24 In theory, this blockade should not compromise platelet adhesion to the subendothelial matrix so that

Clinical efficacy

Over the past decade considerable experience with inhibition of αIIIbβ3 has been accrued in clinical trials. The results of 10 large, placebo-controlled randomised trials, superimposed on aspirin background therapy, are summarised in figure 4.30, 31, 32, 33, 34, 35, 36, 37, 38, 39 Four parenterally administered GPIIb-IIIa blockers (abciximab, eptifibatide, and tirofiban and lamifiban) have been tested in two different clinical indications–namely, percutaneous coronary intervention and the acute

Safety

In the early trials, GPIIb-IIIa blockade was associated with a significantly higher rate of bleeding complications30, 33 but this proved to be largely attributable to excessive and prolonged concurrent heparin administration. All of the later trials, incorporating reduced, weight-adjusted heparin regimens, have demonstrated no excess in major bleeding, as defined by need for transfusion or by a 5 g/dL or greater fall in haemòglobin.31, 32, 35, 36, 39 Importantly, there has been no excess in

Unresolved issues

Despite the impressive progress in our understanding of αIIIbβ3 and its role in platelet function and the promising entry of GPIIb-IIIa blockers into patient care, much remains to be learned. Critical questions are:

  • Precisely how do ligands and antagonists bind to αIIIbβ3 A three-dimensional structure of αIIIbβ3 is vital to our understanding of the receptor and to drug design.

  • How does αIIIbβ3 become activated and can specific activation events be targets for new antithrombotic drugs? Such

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