Glycoprotein Iib/Iiia Inhibitors During Percutaneous Coronary Interventions

REVIEW Glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions Intravenous glycoprotein IIb/IIIa inhibitors are widely used during percutaneous coronary interventions (PCIs). There are three commercially available pharmacological agents: abciximab, eptifibatide and tirofiban. This article presents the evidence indicating their use in connection with PCI, and focuses on the differences between the three regimens, as well as on their use in special clinical conditions. The documentation for their use in high-risk PCI (in other words, for acute coronary syndromes and complex coronary anatomy), and in primary PCI for ST-elevation myocardial infarction will be scrutinized, as well as the use of intracoronary administration. Furthermore, the role of glycoprotein IIb/IIIa inhibitors as opposed to, or in combination with, thienopyridines and thrombin inhibitors will be analyzed, as will their use in diabetics, in patients with renal insufficiency and when performing PCI in vein grafts. Finally, the possible effects of glycoprotein IIb/IIIa inhibitors on restenosis and inflammation, as well as dosing and bleeding issues will be discussed. †1 KEYWORDS: abciximab n eptifibatide n glycoprotein IIb/IIIa inhibitor n myocardial Michael Koutouzis infarction n percutaneous coronary intervention n tirofiban & Lars Grip1 1Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden Percutaneous coronary intervention, to be developed and brought forward for clini- †Author for correspondence: coronary thrombosis & development cal use [6,7]. Abciximab has a high molecular Tel.: +46 313 427 565 Fax: +46 3182 0062 of glycoprotein IIb/IIIa inhibitors weight of more than 47,000 Da, a high affinity [email protected] Percutaneous coronary intervention (PCI) was to the GP IIb/IIIa receptor and a relatively short introduced as balloon dilatation by Grüntzig in plasma half-life (20–30 min). Its high affinity 1977 – a revolution with respect to revasculariza- is responsible for the slow recovery of platelet tion of coronary artery disease. However, it soon function, taking days after administration. became evident that the intra coronary trauma With more than 80% of the receptors occupied and tissue injury, and the resulting exposure of minutes after a bolus administration, approxi- subendothelial tissue, was very thrombogenic. mately 30% receptor occupancy is observed after Antithrombotic regimens based on platelet inhibi- 8 days and 10% is observed 15 days after drug tion by aspirin in combination with anticoagula- discontinuation [8]. In addition to the binding to tion by heparin were therefore established early [1]. the platelet GP IIb/IIIa receptor, this molecule Despite these agents, thrombotic complications demonstrates affinity to the CD11b/18(amb2 or remained substantial hazards, especially when MAC 1) receptor [9], inhibiting inflammatory performing PCI in high-risk patients with com- leukocyte–platelet interaction and anb3 (vitro- plicated coronary artery disease or with increased nectin) receptors [10], with possible beneficial thrombus burden, such as those with acute coro- effects on e ndothelial dysfunction and r estenosis nary syndromes [2,3]. Thus, there was a need for after PCI. more effective a ntithrombotic agents. n Eptifibatide & tirofiban n Abciximab Abciximab carries some potential drawbacks. Its Upon platelet activation, the glycoprotein (GP) use is associated with an increased risk of bleed- IIb/IIIa receptor is activated and exposed on the ing, and the tight binding and long-standing platelet surface. It binds to fibrinogen and the inhibition of platelet aggregation make this dif- von Willebrand factor and is thus essential for ficult to manage. Furthermore, as a fragment and, in a sense, constitutes the final common of a foreign antibody, it is potentially aller- pathway of platelet aggregation [4,5]. A murine– genic, causing thrombocytopenia in a number human chimeric fragment of a monoclonal anti- of patients severe enough to mandate platelet body against the GP IIb/IIIa receptor, c7E3 Fab count monitoring and, in some cases, platelet (abciximab) was the first GP IIb/IIIa inhibitor substitution is necessary to prevent bleeding. 10.2217/ICA.10.33 © 2010 Future Medicine Ltd Interv. Cardiol. (2010) 2(3), 301–318 ISSN 1755-5302 301 REVIEW Koutouzis & Grip Lastly, as previously mentioned, it is not very inhibition by abciximab, compared with heparin selective. These properties served as an impetus and aspirin only, reduced thrombotic complica- for developing more selective drugs with shorter tions associated with high-risk PCI [19]. It was half-lives. also evident that a bolus at the time of PCI The amino acid sequence that accounts for the was not enough, but that the therapy had to binding of the GP IIb/IIIa receptor to fibrinogen be prolonged with a postprocedural infusion. is constituted of arginine, glycine and aspartic A drawback was the increased rate of bleeding acid. The small molecules developed to block that, according to post hoc ana lysis, was related this sequence should theoretically be very selec- to greater age, female sex and lower weight [20]. tive for the binding of the GP IIb/IIIa receptor to From this, it was hypothesized that the excess in fibrinogen (in other words, the target when aim- bleedings was attributed to the concomitant use ing at blocking aggregation), the final common of non-weight-adjusted unfractionated heparin pathway of platelet activation. Two molecules, as an adjunctive anticoagulant regimen. the cyclic heptapeptide eptifibatide (Integrilin™, This led to the design of the following Millennium Pharmaceuticals, Inc., MA, USA) Evaluation of PTCA to Improve Long-Term and the nonpeptide tirofiban (Aggrastat®, Iroko Outcomes by c7E3 GP IIb/IIIa Receptor Pharmaceuticals, PA, USA) were thus developed Blockade (EPILOG) study in which abciximab and introduced for c linical use. in combination with a weight-adjusted heparin, in Eptifibatide is a synthetic heptapeptide with a lower dose than previously used, was compared low molecular weight (less than 1000 Da) that with either heparin alone or the combination of is modeled on a compound isolated from the abciximab with the hitherto used standard dose venom of the pygmy rattlesnake [11]. It is revers- of heparin [21]. The positive effects from the EPIC ibly bound to the b3 subunit of the GP IIb/IIIa study of abciximab compared with heparin only receptor, causing a platelet inhibition correlated were confirmed. Furthermore, this study demon- to the plasma level of the drug. Eptifibatide is strated that with a weight-adjusted and lower excreted through the kidneys with a plasma half- dose of heparin, the bleeding rate was no longer life of approximately 2–3 h. increased compared with the heparin-only group. Tirofiban is a tyrosine derivative nonpeptide However, it is worth noting that in the EPILOG that has a structure modeled on a compound iso- study, as well as in all subsequent studies with lated from saw-scaled viper venom [12]. It has sim- abciximab, the postbolus abciximab infusion dose ilarities to the amino acid sequence of fibrinogen, was, as with heparin, weight-adjusted, as opposed making it possible to bind to the GP IIb/IIIa to the fixed infusion dose used in the EPIC study. receptor. Its affinity is between those of abcixi- A further development was the use of abciximab and eptifibatide and it has a plasma half-life mab as a pretreatment for 20–24 h before a of between 1.5 and 2 h. Tirofiban is excreted PCI for unstable angina (UA). In the c7E3 Fab through the kidneys (60–70%) and metabolized Antiplatelet Therapy in Unstable Refractory through the biliary system (30–40%). Angina (CAPTURE) trial, this was demonstrated to reduce the combined end point of Role of GP IIb/IIIa receptor death, myocardial infarction (MI) and urgent antagonists in high-risk PCI revascularization at both 30 days and 6 months Both the American College of Cardiology after the intervention compared with pla- and the European Society of Cardiology cebo [22], an effect observed only among patients recommend the use of GP IIb/IIIa inhibi- with elevated troponin T levels [23]. tors in patients undergoing PCI for different In all three of the aforementioned studies, indications (TABLE )1 [13–18]. usage of stents was either discouraged or established as an exclusion criterion. To bring therapy GP IIb/IIIa inhibitors in connection up to modern standards of PCI, the Evaluation with PCI for patients without of IIb/IIIa Platelet Inhibitor for Stenting ongoing ST-elevation MI (EPISTENT) study was conducted in which n Abciximab patients were randomly assigned to either stenting The first of a number of pivotal studies with placebo, stenting with abciximab or balloon (TABLE ) 2 that broke the ground for current dilatation with abciximab alone [24]. The stent GP IIb/IIIa receptor antagonist regimens was plus abciximab group was shown to be superior the Evaluation of 7E3 for the Prevention of to the other groups, but an interesting aspect of Ischemic Complications (EPIC) study, which this study was that even balloon dilatation with demonstrated that the addition of GP IIb/IIIa abciximab was safer than stenting with placebo. 302 Interv. Cardiol. (2010) 2(3) future science group Table 1. Extracts of the American and European guidelines for the use of glycoprotein inhibitors in patients undergoing percutaneous future sciencegroup coronary interventions. American College of Cardiology/American Heart Association Guidelines European

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