INTRODUCTION — Platelets play a pivotal role in normal hemostasis, maintaining vascular integrity and preventing continued blood loss after vascular injury. However, they also contribute directly to pathologic vascular thrombosis of the arterial circulatory system. This relationship constitutes the rationale for the use of antiplatelet agents in the treatment of coronary heart disease (CHD). (See "The role of platelets in coronary heart disease".)
Three intravenous platelet glycoprotein (GP) IIb/IIIa inhibitors have been studied extensively. Abciximab is a monoclonal antibody directed against the receptor, while tirofiban and eptifibatide are high affinity non-antibody receptor inhibitors. Only tirofiban and eptifibatide are widely available for clinical use
Antiplatelet therapy with intravenous GP IIb/IIIa inhibitors has been evaluated in patients with acute coronary syndrome (ACS) and in those undergoing intracoronary stent implantation. Dual oral antiplatelet therapy with aspirin and a platelet P2Y12 receptor blocker has decreased the role of GP IIb/IIIa therapy in these settings, although it continues to be important for provisional use during percutaneous coronary intervention.
This topic summarizes the early trials of GP IIb/IIIa inhibitors performed before the routine use of intracoronary stents in patients undergoing percutaneous coronary intervention and P2Y12 receptor blocker therapy in patients with ACS or those undergoing stenting. These early trials collectively formed the basis of a high-intensity, platelet-directed approach (in addition to aspirin) to pharmacotherapy for patients at high risk for myocardial infarction (MI), recurring MI, intra-coronary thromboembolism, and, with the increasing deployment of stents in routine clinical practice, acute stent thrombosis.
The role of platelet GP IIb/IIIa inhibitors in patients who receive currently recommended treatment with dual (oral) antiplatelet therapy is discussed elsewhere. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)
THE PLATELET GLYCOPROTEIN IIB/IIIA RECEPTOR — Platelet activation and aggregation is preceded by rolling, tethering, transient adhesion, and firm adhesion, and occurs following exposure to several biochemical and mechanical stimuli (table 1 and figure 1). The ability of platelets to adhere to abnormal surfaces and aggregate is mediated by surface membrane glycoprotein (GP) receptors that can be expressed in greater numbers (10-fold or more) and assume a more ligand-binding conformation upon platelet activation. Accordingly, they represent attractive targets for pharmacologic inhibition.
The platelet GP IIb/IIIa receptor is of particular interest because of its central role in platelet adhesion and aggregation. Following platelet activation, GP IIb/IIIa undergoes a conformational change, rendering it competent to bind protein ligands, including Von Willebrand factor in general and fibrinogen in particular [1]. This allows for a bridge to be formed between two adjacent platelets.
ABCIXIMAB — Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. (See "Structure of immunoglobulins", section on 'Immunoglobulin fragments/regions'.)
Pharmacokinetics and pharmacodynamics — Following intravenous bolus administration, free plasma concentrations of abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of 30 minutes, owing to rapid binding to the platelet glycoprotein (GP) IIb/IIIa receptor. Platelet function generally recovers over the course of 48 hours; however, abciximab remains in the circulation for up to 10 days in the platelet-bound state. Upon completion of a constant infusion, free plasma concentrations fall rapidly over the next six hours then decline at a slower rate. The low concentration of free drug in plasma becomes important if serious bleeding occurs and a platelet transfusion is given. More precisely, there is little drug to bind and inhibit new platelets introduced, endogenously or exogenously, to the circulation.
Intravenous administration of abciximab in doses ranging from 0.15 to 0.3 mg/kg produces a rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or thrombin receptor-activated peptide (TRAP). At the highest dose, 80 percent of the platelet GP IIb/IIIa receptors are occupied within two hours and platelet aggregation is near completely inhibited. Sustained inhibition is achieved with continuous infusions, and low-level receptor blockade is present for up to 10 days following cessation of the infusion. Platelet aggregation in response to 5.0 mmol ADP returns to ≥50 percent of baseline within 24 hours in the majority of patients.
Acute coronary syndrome patients undergoing PCI — A number of randomized trials were performed with abciximab in patients undergoing percutaneous coronary intervention (PCI) before the routine practice of stent insertion. This was referred to at that time as percutaneous transluminal coronary angioplasty (PTCA). The pre-stent era was also characterized by an absence of routine P2Y12 receptor blocker therapy. In a meta-analysis of over 5400 (predominantly) acute coronary syndrome (ACS) patients enrolled in the EPIC [2-4], EPILOG [5,6], RAPPORT, EPISTENT [7], and CAPTURE [8-13] trials who underwent PTCA, abciximab significantly reduced the 30-day rate of death and myocardial infarction (MI) (hazard ratio 0.52, 95% CI 0.41-0.65) [14].
STEMI patients undergoing PCI with stenting — Outcomes after either abciximab or placebo were evaluated in several randomized trials of patients with ST-elevation MI (STEMI) undergoing primary PCI with (primarily) stent placement, including RAPPORT [7], ADMIRAL [15,16], ISAR-2 [17], CADILLAC [18], and ACE [19]. In a meta-analysis of these trials, abciximab was associated with significant reductions in mortality at 30 days (2.4 versus 3.4 percent with placebo) and 6 to 12 months (4.4 versus 6.2 percent) and in reinfarction at 30 days (1.0 versus 1.9 percent) [20]. In addition, there was no increase in bleeding. This analysis provided support for the benefit of abciximab as adjunctive therapy to reduce acute ischemic events among patients undergoing primary PCI with stenting.
Stable patients — In contrast to the benefit of abciximab observed among patients with ACS, including those with STEMI, two trials (EPISTENT and ISAR-REACT) included some patients with stable coronary artery disease undergoing PCI with stenting and came to different conclusions:
●EPISTENT randomly assigned 2399 patients undergoing elective (about 40 percent) or emergent PCI to therapy with stenting alone, stenting plus abciximab, or PTCA plus abciximab [21,22]. Ticlopidine, in addition to aspirin, was given to all patients receiving stents. The 30-day and six-month incidence of the primary end point (death, MI, and need for urgent revascularization) was significantly lower with the use of abciximab (10.8, 5.3, and 6.9 percent, respectively and 11.4, 5.6 and 7.8 percent, respectively) (figure 2), primarily because of a reduced incidence of death and large non-STEMI (figure 3). The overall benefit derived from abciximab was predominantly observed in patients with ACS.
●In the ISAR-REACT trial of 2159 stable patients undergoing PCI with stenting (90 percent) and treated with aspirin and a P2Y12 receptor blocker, patients were randomly assigned to either abciximab or placebo [23]. At 30 days, there was no difference in the incidence of death, MI, or urgent target vessel revascularization between the treatment groups (4 percent in each group). Major bleeding complications occurred in 1 percent of each group. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Efficacy and safety'.)
Patients not undergoing reperfusion — The GUSTO 4-ACS trial evaluated the role of abciximab in 7800 patients with unstable angina or non-ST elevation MI (NSTEMI) who did not undergo revascularization; patients were randomly assigned to abciximab bolus plus 24-hour infusion, abciximab bolus plus 48-hour infusion, or placebo [24]. The primary end point, death, or MI at 30 days, was the same in the three groups (8.2 and 9.1 versus 8 percent for placebo), as was the rate of revascularization with PCI or coronary artery bypass graft surgery (CABG) (30 percent of patients in each group). Bleeding rates were higher in patients randomized to abciximab and increased with the duration of administration. Thrombocytopenia was also more common with abciximab.
This lack of benefit of abciximab in the GUSTO 4-ACS trial persisted at one year [25]. The findings from GUSTO 4-ACS are different from those observed in other trials with intravenous GP IIb/IIIa inhibitors, in which benefit was observed in patients who received medical therapy alone, with additional protection in those who underwent revascularization. The reason for this difference is uncertain but may be related to dosing, the overall degree of platelet inhibition, and possibly paradoxical platelet GP IIb/IIIa activation with prolonged infusion.
TIROFIBAN — Tirofiban is a nonpeptide inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor and interferes with platelet aggregation.
Pharmacokinetics — There is a dose-dependent inhibition of ex vivo platelet aggregation within minutes of bolus administration of tirofiban. The inhibitory effect is maintained during continuous drug infusion [26].
UA/NSTEMI patients undergoing PCI — Several trials compared tirofiban (bolus plus continuous infusion) with placebo or with heparin in patients with unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI) scheduled to undergo percutaneous coronary intervention (PCI) without stent insertion, and in whom P2Y12 receptor blockers were not routinely used:
●The RESTORE trial randomly assigned 2139 patients within 72 hours of presenting to the hospital to either tirofiban or placebo [27]. The primary composite end point (death, MI, angioplasty failure requiring coronary artery bypass graft surgery [CABG] or unplanned stenting, recurrent ischemia requiring repeat PCI) at 30 days was reduced by tirofiban (10.3 versus 12.2 percent in the placebo group).
Further analysis of the data showed that patients with elevated levels of serum troponin I or T benefited from tirofiban [28]. Among the 28 percent of patients who had elevated serum troponin I (≥1 µg/L) on admission, tirofiban significantly reduced the 30-day risk of death (1.6 versus 6.2 percent for heparin) and MI (2.7 versus 6.8 percent); this benefit was seen in patients managed either medically or with revascularization (figure 4).
●The PRISM-PLUS trial randomly assigned 1915 patients to tirofiban, heparin, or tirofiban plus heparin [29]. At seven days the frequency of the composite primary end point (death, MI, or refractory ischemia) was significantly lower in the group receiving tirofiban plus heparin compared to heparin alone (12.9 versus 17.9 percent), primarily due to a reduction in MI.
●The ADVANCE trial evaluated the potential benefit of a higher bolus dose of tirofiban (25 mcg/kg over 3 min) than had been used in the RESTORE, PRISM, or PRISM-PLUS trials [30]. A total of 202 patients (56 percent with an acute coronary syndrome [ACS]) were randomly assigned to tirofiban or placebo. At six months, the primary end point (death, MI, target vessel revascularization, or bailout use of a GP IIb/IIIa inhibitor) was significantly lower with tirofiban (20 versus 35 percent) than placebo. The benefit of tirofiban was significant among patients with ACS but not among those with stable angina.
Acute coronary syndrome patients treated medically — Two studies have evaluated ACS patients managed with medical therapy.
●The TETAMI trial randomly assigned 1224 patients with an acute ST elevation MI (STEMI) who did not undergo reperfusion to either tirofiban or placebo [31]. At 30 days, there was no significant difference in the combined end point of death, reinfarction, or recurrent angina (16.6 versus 16.4 percent, respectively). As discussed previously, patients participating in the PRISM trial (UA/NSTEMI) who were treated medically derived benefit from tirofiban if they were troponin positive.
●The PRISM trial randomly assigned 3232 patients to either tirofiban or heparin. In the trial, routine PCI was discouraged [32]. The primary composite end point (death, MI, refractory ischemia) at 48 hours was reduced significantly with tirofiban (3.8 versus 5.6 percent in heparin treated patients). However, at 30 days, the composite end point was similar in the two groups (15.9 versus 17.1 percent), although there was a significant reduction in mortality (2.3 versus 3.6 percent) (figure 5).
ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention — The TIGER-PA pilot, On-TIme, and On-TIME 2 trials investigated angiographic or electrocardiographic surrogates rather than clinical outcomes [33-37]. The three trials generally showed that treatment with tirofiban improved these surrogate end points compared with placebo.
Stable patients — As discussed previously, stable patients in the ADVANCE trial had better outcomes with tirofiban than placebo.
EPTIFIBATIDE — Eptifibatide is a heptapeptide inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor that interferes with platelet aggregation [38].
Pharmacokinetics and pharmacodynamics — The plasma half-life of eptifibatide is 10 to 15 minutes and clearance is predominantly renal (75 percent) and hepatic (25 percent). The antiplatelet effect has a rapid onset of action and is rapidly reversible. Boluses of 180 or 135 µg/kg produce greater than 80 percent inhibition of adenosine diphosphate (ADP)-mediated platelet aggregation within 15 minutes of administration in more than 75 percent of patients [39].
Acute coronary syndrome patients — The IMPACT-II trial of 4010 patients undergoing elective, urgent, or emergency PCI who were randomly assigned to two dosing schedules of eptifibatide or placebo did not show a benefit from GP IIb/III inhibition [40]. However, benefit was detected in the PURSUIT trial of almost 11,000 patients with unstable angina or non-ST elevation myocardial infarction (NSTEMI). In PURSUIT, which included patients who were managed medically or with PCI, eptifibatide was associated with a significantly lower 30-day event rate of death or nonfatal MI (14.2 versus 15.7 percent with placebo) [41]. The benefit with eptifibatide was equivalent in those who underwent early PCI or were managed medically [42].
Stable patients — The ESPRIT trial randomly assigned 2064 stable patients to placebo or eptifibatide immediately before PCI [43]. The trial was prematurely terminated because eptifibatide reduced the primary end point (48-hour rate of death, MI, urgent revascularization, or need for "bail-out" GP IIb/IIIa inhibitor) by 37 percent (6.6 versus 10.5 percent for placebo).
META-ANALYSES — Meta-analyses have evaluated the use of intravenous glycoprotein (GP) IIb/IIIa inhibitors in a variety of settings related to coronary disease. The impact of the intravenous GP IIb/IIIa inhibitors on clinical outcomes was assessed in a pooled analysis of 21 trials involving various groups of patients with ischemic heart disease [44]. The GP IIb/IIIa inhibitor significantly reduced the combined end point of death, nonfatal myocardial infarction (MI), or urgent revascularization at 30 days in the following groups of patients:
●Those undergoing a percutaneous coronary intervention (PCI) (7.8 versus 11.6 percent for placebo, relative risk reduction 33 percent)
●Those with non-ST elevation myocardial infarction (NSTEMI) (11.4 versus 12.8 percent, relative risk reduction 11 percent)
●Those with an ST elevation MI (STEMI) treated with percutaneous transluminal coronary angioplasty (PTCA) (3.9 versus 7.8 percent, relative risk reduction 49 percent).
ADVERSE EFFECTS
Bleeding — The primary concern with antithrombotic therapy (and antiplatelet therapy in particular) is the increase in bleeding risk. This issue is discussed in detail elsewhere. (See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)
The rate of bleeding between glycoprotein (GP) IIb/IIIa inhibitor and placebo has been higher with the former in some [7,8,26] but not all studies performed before the routine use of dual oral antiplatelet therapy [32,39-41].
Whether this includes an increased incidence of intracerebral hemorrhage was addressed by a pooled analysis of 14 randomized trials involving almost 28,000 patients treated with one of these agents or placebo [45]. The incidence of intracerebral hemorrhage with heparin plus any GP IIb/IIIa inhibitor was similar to that seen with heparin plus placebo (0.12 versus 0.09 percent, odds ratio 1.3), and there was no difference in incidence with a GP IIb/IIIa inhibitor alone compared to heparin alone (0.07 versus 0.06 percent).
Thrombocytopenia — Thrombocytopenia, at times profound, has been observed within 24 hours, and occasionally within several hours, of administration of a GP IIb/IIIa inhibitor. This subject, as well as the management of thrombocytopenia in patients treated with these agents, is discussed separately. (See "Drug-induced immune thrombocytopenia".)
Allergy — There has been concern that since a first course of abciximab can result in the generation of human antichimeric antibodies, readministration might lead to serious allergic or hypersensitivity reactions. However, the risk of such reactions does not appear to be increased [46,47].
COMPARISON OF AGENTS FOR PCI — A meta-analysis of eight prospective trials including a total of 14,644 patients undergoing a percutaneous coronary intervention (PCI) compared the efficacy and safety of abciximab, eptifibatide, and tirofiban [48]. Although differences were reported, a major limitation of this analysis was that each of the trials compared one of the drugs with placebo; none directly assessed the drugs against each other. Thus, differences in study design and end points likely contributed to the differences in outcome. In addition, and as discussed previously, these studies included patients treated with PCI, but no stents, and many who did not receive P2Y12 receptor blockers. Our interpretation of all available comparative evidence from these early studies is that at optimal doses, abciximab, tirofiban, and eptifibatide have comparable efficacy [43,48-55].
SUMMARY
●Platelets play a pivotal role in normal hemostasis, preventing continued blood loss after vascular injury. However, they also contribute directly to pathologic vascular thrombosis. This relationship constitutes the rationale for the use of aggressive antiplatelet therapy, including glycoprotein (GP) IIb/IIIa agents, in the treatment of coronary heart disease. (See 'Introduction' above.)
●Platelet activation can be accomplished via a variety of pharmacologic and mechanical mediators, leading to platelet adhesion and ultimately aggregation. The ability of platelets to adhere to abnormal surfaces and aggregate is mediated by surface membrane GP receptors that are expressed in greater numbers with platelet activation and serve as potential targets for therapy. (See 'The platelet glycoprotein IIb/IIIa receptor' above.)
●Two intravenous platelet GP IIb/IIIa inhibitors are widely available for clinical use: tirofiban and eptifibatide. (See 'Abciximab' above and 'Tirofiban' above and 'Eptifibatide' above.)
The early trials of these agents were performed before the routine use of dual oral antiplatelet therapy and deployment of stents in most patients who underwent percutaneous coronary intervention (PCI). These early trials provided evidence of improved outcomes from the use of aggressive antiplatelet therapy in many patients with acute coronary syndromes and some patients undergoing elective stenting. (See 'Meta-analyses' above.)
The use of these agents in the current era dual oral antiplatelet therapy and PCI with stenting is discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Our approach' and "Percutaneous coronary intervention after fibrinolysis for acute ST-elevation myocardial infarction", section on 'Facilitated PCI (with fibrinolytic therapy)' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Intravenous agents' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors'.)
