Introduction

Platelet reactivity plays a pivotal role in the pathogenesis of ischemic cardiovascular disorders. Among the proposed pharmacological targets for antiplatelet therapy, the glycoprotein IIb/IIIa (GPIIb/IIIa) continues to be a very attractive pathway as it represents the common final mechanism, which leads to platelet aggregation. The GPIIb/IIIa receptor binds several substrates, most notably fibrinogen, which forms a bridge between platelets, directly mediating aggregation. GPIIb/IIIa is the most abundant GP on the platelet surface; however, in the inactivated state, approximately 70% of GPIIb/IIIa complexes are distributed on the surface of the platelet, while the remaining receptors remain stealth [1]. Following platelet activation, the number of GPIIb/IIIa receptors on the cell surface increases exponentially. GPIIb/IIIa inhibitors, which include abciximab, tirofiban, and eptifibatide, selectively block the GPIIb/IIIa receptor on the surface of the platelet thus preventing the binding of fibrinogen to the receptor and have been regarded as the most potent inhibitors of platelet activity [2]. The first agent in this class introduced to clinical practice was abciximab, a chimeric human–murine monoclonal antibody Fab fragment (c7E3) [2].

Tirofiban

Tirofiban is a potent GPIIb/IIIa inhibitor that has been well studied and used clinically in a variety of settings including STEMI, non-ST-segment-elevation acute coronary syndromes (NSTE-ACS), and elective procedures. Similar to abciximab, tirofiban is a competitive GPIIb/IIIa inhibitor with high specificity and affinity for the GPIIb/IIIa receptor [3]. Unlike abciximab, tirofiban is a small-molecule, nonpeptide tyrosine derivative [4]. Tirofiban further differs from abciximab in that it dissociates from the GPIIb/IIIa receptor relatively rapidly and, with a half-life of 2–4 h, therefore is reversed within hours after the completion of the infusion [4]. Abciximab rather binds irreversibly to the IIb/IIIa receptor producing an effect that persists for the lifespan of the platelet [5]. Such reversibility may have significant implications with regard to bleeding, particularly in patients who require the need for emergent coronary artery bypass graft surgery.

Dosing of tirofiban

The dosing of tirofiban has evolved over time. It has been established that different dosing regimens may be required based on the patient’s diagnosis and the timing of percutaneous coronary intervention (PCI). A regimen utilizing a loading infusion of 0.4 µg/kg/min run over 30 min followed by a 0.10 µg/kg/min maintenance infusion has proven quite effective in the management of patients with NSTE-ACS when administered at least 4 h prior to PCI [6, 7, 8]. Studies conducted in similar patient populations who rather than receiving tirofiban prior to PCI were administered immediately prior to PCI [9, 10] employed a dosing regimen including a bolus of 10 µg/kg administered over 3 min followed by an infusion of 0.15 µg/kg/min. Given the benefit seen with the upstream dosing regimen, one might assume that this dose would achieve adequate platelet inhibition even when administered immediately prior to initiation of PCI. Yet, results of such studies were not as favorable for tirofiban, revealing an increase in clinical events as compared to abciximab [10]. Follow-up studies have suggested that a higher incidence of myocardial infarction (MI) after PCI seen in these studies was likely due to suboptimal platelet inhibition from 15 to 60 min after onset of treatment [11]. These studies also indicated that this suboptimal platelet inhibition could be overcome by a regimen including a higher-dose bolus of tirofiban (25 µg/kg) and revealed that a high-dose bolus of tirofiban results in a level of platelet inhibition necessary for coronary intervention [12]. Therefore, a regimen using a 25 µg/kg bolus dose of tirofiban followed by a maintenance infusion of 0.15 µg/kg/min (high-dose bolus regimen) is considered more appropriate when administration immediately prior to PCI is warranted.

Likewise, a high-dose bolus regimen of tirofiban may potentially induce a potent effect on platelets as compared to abciximab. When platelet inhibition was compared in 112 STEMI patients who were either administered the standard dose of abciximab or one of two doses of tirofiban (10 µg/kg bolus or the regimen or the high-dose bolus regimen), mean periprocedural platelet inhibition exceeding 80% was seen only with the high-dose tirofiban regimen [13]. A separate study involving 66 patients with STEMI undergoing PCI provided comparable results [14]. The high-dose bolus regimen of tirofiban produced significantly higher levels of platelet inhibition than abciximab when measured immediately after PCI 30, 60, and 120 min. Given its similar effect on platelet function to abciximab, tirofiban administered using the high-dose bolus regimen may indeed be considered a beneficial cost-effective alternative for abciximab in patients suffering from thrombus-containing lesion undergoing PCI.