Glycoprotein IIb-IIIa Inhibitors

Authors


Giuseppe De Luca, M.D., Ph.D.,
Chief Interventional Cardiology, “Maggiore della Carità” Hospital, Università del Piemonte Orientale “A. Avogadro,” Novara, Italy.
Tel: +39-0321-3733141;
Fax: +39-0321-3733407;
E-mail: giuseppe.deluca@maggioreosp.novara.it

SUMMARY

Platelets play a pivotal role in the pathogenesis of coronary artery disease and myocardial infarction. Therefore, great interests have been focused in the last decades on improvement in antiplatelet therapies, that currently are regarded as main pillars in the prevention and treatment of coronary artery disease, with special attention to glycoprotein IIb-IIIa (GP IIb-IIIa) receptors, that mediates the final stage of platelet activation. GP IIb-IIIa inhibitors, especially abciximab, have been shown to improve clinical outcome in patients undergoing primary angioplasty for STEMI. Upstream administration cannot routinely recommended, but may potentially be considered among high-risk patients within the first 4 h from symptoms onset. In case of periprocedural administration of antithrombotic therapy, Bivalirudin should be considered, especially in patients at high risk for bleeding complications. Among high-risk patients with acute coronary syndromes, an early invasive strategy with selective downstream administration of GP IIb-IIIa inhibitors is the strategy of choice, whereas bivalirudin should be considered in patients at high risk for bleeding complications. Among patients with unstable angina GP IIb-IIIa inhibitors should be considered only in case of evidence of intracoronary thrombus or in case of thrombotic complications (as provisional use). Further, randomized trials are certainly needed in the era of new oral antiplatelet therapies, and with strategies to prevent bleeding complications such as larger use of radial approach, mechanical closure devices, bivalirudin, or postprocedural protamine administration to promote early sheat removal.

Introduction

Platelets play a pivotal role in the pathogenesis of coronary artery disease and myocardial infarction. Therefore, great interests have been focused in the last decades on improvement in antiplatelet therapies that currently are regarded as main pillars in the prevention and treatment of coronary artery disease, with special attention to glycoprotein IIb-IIIa (GP IIb-IIIa) receptors, that mediates the final stage of platelet activation (Figure 1). Thus, pharmacotherapy that may block this receptor is expected to strongly inhibit platelet aggregation and represents a very attractive strategy, especially in the era of coronary angioplasty in the setting of acute coronary syndromes.

Figure 1.

This figure shows platelet receptors and mechanisms of action of several antiplatelet therapies. GP IIb-IIIa inhibitors mediates the final stage of platelet activation and therefore represent the most powerful antiplatelet therapy.

Pharmacokinetics/Pharmacology

The platelet GP IIb-IIIa inhibitors differ markedly in their pharmacokinetics, pharmacodynamics, and differential receptor affinities (Table 1). Abciximab and the small-molecule GP IIb-IIIa inhibitors (eptifibatide, tirofiban) have separate, distinct binding sites on the GP IIb-IIIa receptor complex [1–3].

Table 1. Characteristics of intravenous GP IIb-IIIa inhibitors
 AbciximabEptifibatideTirofiban
TypeAntibodyCyclic peptideNonpeptide
Molecular weight (Da)47.600832495
InhibitionNoncompetitiveCompetitiveCompetitive
BindingIrreversibleCompetitiveCompetitive
Platelet affinityHighLowLow
Plasma half-life10–30 min2.5 h2 h
Recovery of platelet functionSlow (24–48 h)Fast (<4 h)Fast (4–8 h)
AntigenicityPresentAbsentAbsent
ClearancePlatelet binding, unbound substance via proteolytic cleavageRenal (60–70%) Biliar (20–30%)Renal (98%)
Recommended dosage
 Bolus0.25 μg/kg180 μg/kg X 225 μg/kg
 Infusion0.125 μg/kg/min (12 h)2 μg/kg/min0.15 μg/kg/min
StudiesGUSTO-V, ASSENT 3,IN-TAMISchneider et al., STRATEGY,
RAPPORT, CADILLACTITAN TIMI-34On-TIME-2, MultiSTRATEGY
ADMIRAL, ISAR, ACE,  
Petronio et al.,  
Petronio et al.,  
Zorman et al.,  
Petronio et al.,  
Lee et al.  

As shown in Table 1, abciximab is an antibody with non-competitive, irreversible inhibition. This might appear a limitation in case of bleeding complications or need to undergo bypass surgery. However, with advances in technology, only a minority of patients in the setting of ACS need to undergo urgently bypass surgery soon after angioplasty (due to complications or unsuccessful PTCA). Remarkably, abciximab does not need dose adjustment in case of renal failure, whereas a dose adjustment is strongly recommended in case of small molecules.

Rationale for Adjunctive use of GP IIB-IIIA Inhibitors

Time-to-treatment and survival: “time is muscle”

A major factor that has leaded to the large consensus in favor of an extensive application of primary angioplasty to the vast majority of patients, when logistics allow, was the supposed time-independence in restoration of TIMI-3 flow and clinical outcome of primary angioplasty as compared to thormbolysis. This was strongly supported by an individual patient's data meta-analysis by Zijlstra et al. [4]. However, a large series of investigations published in the last years have demonstrated that time-to-treatment is a relevant issue in primary angioplasty, with a significant impact on mortality [5–10]. The Zwolle group provided a clear demonstration that restoration of optimal epicardial flow does not overcome the deleterious effect of time-delay on myocardial perfusion and infarct size [5]. Stone et al have recently shown the impact of time-to-treatment and prepdocedural TIMI flow on infarct size as evaluated by SPECT with 99Tc sestamibi [9]. The vast majority of STEMI patients currently present to non-PCI hospital, with the need of transportation with subsequent longer delay to treatment. Even though GP IIb-IIIa inhibitors do not have lythic properties and therefore should not be considered as a solo reperfusion therapy, the potential early restoration of optimal TIMI flow that can be achieved by early administration of antithrombotic therapies during transportation towards the cath lab seems attractive in STEMI patients, particularly among high-risk patients and within the first hours from symptom onset [11], when the larger amount of myocardium at risk and viable myocardium may justify this approach.

Incidence and prognostic impact of reinfarction

Several reports have demonstrated the prognostic impact of reinfarction after STEMI in patients treated with thrombolysis or primary angioplasty [12,13]. Despite the larger use observed in the last years, coronary stenting has not reduced reinfarction as compared to balloon angioplasty [14], with even large concerns about late in-stent thrombosis among patients receiving drug-eluting stents [15]. The incidence of in-stent thrombosis after coronary stenting in primary angioplasty is not so futile as commonly believed. In fact, it seems that a larger unrestricted use of coronary stenting is associated with a poorer outcome in terms of reinfarction, particularly when GP IIb-IIIa inhibitors are not administered [16,17], ranging between 5% and 10%.

Incidence and prognostic impact of distal embolization

Despite successful mechanical revascularization, suboptimal reperfusion may occur, resulting in unfavorable outcome [18–20]. In the last years, growing interest has been focused on the role of distal embolization as major determinant of poor reperfusion.

Several studies have shown the implications of distal embolization as major determinant of infarct size and poor reperfusion after primary angioplasty. Sakuma et al. [21] have shown that the presence of distal embolization is associated with an increase in the perfusion defect and final infarct size by 139% and 70%, respectively, as compared to control group. Several reports in humans have shown that distal embolization is a relatively common phenomenon in primary angioplasty. Based on a histological three-dimensional reconstruction of the retrieved emboli, Limbruno et al. [22] observed that the embolic load was >2 mm3 in 15% of patients and >6 mm3 in 5% of patients, which could be detectable by angiography. Yip et al. [23] observed in 794 patients undergoing primary angioplasty that the incidence of no-reflow was significantly higher in patients with high thrombus burden. It was observed in a recent report, by the use of intravascular ultrasound, that plaque volume reduction (an indirect sign of distal embolization when excluding distal or proximal plaque shifting) was nine times higher in patients with postprocedural TIMI perfusion grades 0–2, as compared to TIMI perfusion grade 3 [24]. Based on the histological analysis of retrieved debris, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) trial [25] showed visible debris in 78% of patients. Henriques et al. [26] reported that the incidence of angiographically detectable distal embolization was 16%, and this was associated with poor reperfusion, larger infarct size and unfavorable 5 years survival, as compared to patients without angiographic signs of distal embolization. Similar findings were also observed by Napodano et al. [27] in a population of 400 STEMI patients undergoing primary angioplasty. However, it must be recognized that the thrombotic burden may be extremely variable among patients. The identification of those patients at higher risk for distal embolization would be crucial, especially when the decision to administrate adjunctive antithormbotic therapy is undertaken after diagnostic angiography. In a recent analysis by the Zwolle group, a poor myocardial perfusion was more often observed in small vessels despite less distal embolization, as compared to larger vessel [28].

Inflammation and no-reflow phenomenon

Among the several proposed mechanisms, in addition to distal embolization, inflammation plays a major role in no-reflow phenomenon. Soon after IRA recanalization, it has been demonstrated neutrophil activation and accumulation in the damaged myocardium [29,30]. In fact, after neutrophil activation, cellular deformability is further attenuated and this may contribute to leukocyte entrapment in the capillaries, leading to microvascular plugging. Even if capillary leukocyte trapping is prominent in the area of no-reflow, the effects of leukocytes probably are not solely confined to mechanical plugging, but may involve complex interactions with the endothelium and platelets. This interaction is mediated by the selectin family of glycoprotein adhesion molecules, including P-selectin, E-selectin, and L-selectin, the b2 integrin family and its principal ligand, the endothelial intercellular adhesion molecule-1 (ICAM-1). Adhesion of activated neutrophils to platelets involves both platelet P-selectin and neutrophil CD18 integrins, further solidifying the association between thrombotic and inflammatory systems [31–33].

The complement cascade may further modulate these interactions. Activation of neutrophils by the activated factor C5a of the complement system was shown to produce myocardial ischemia when given directly into the coronary artery [34,35]. Systemic activation of inflammatory cells might enhance no-reflow, as suggested by the observation that raised serum levels of C-reactive protein are associated with impaired coronary microvascular response to both endothelium-dependent and endothelium-independent vasodilator stimuli [36,37] and with enhanced transcardiac neutrophil activation [38,39].

The affinity of abciximab for the platelet GP IIb-IIIa integrin receptor, together with non-platelet-receptor mediated effects achieved through its affinity for the aVb3 and CD11b/18 receptors [40–42], may contribute to larger clinical benefits in terms of myocardial reperfusion with the use of abciximab during primary angioplasty. Still controversial is the impact of GP IIb-IIIa blockers on Thrombin and coagulation cascade [40].

Interindividual variability in the response to conventional antiplatelet therapies

It has been described a large interindividual variability in the response to antiplatelet therapies [43–49]. The importance of being able to identify individuals who are aspirin- or clopidogrel nonresponders [45] is supported by emerging evidence that laboratory aspirin or clopidogrel resistance predicts cardiovascular events [43–49]. The percentage of nonresponders ranges between 5% and 50% (according to different laboratory tests) for aspirin, and between 20% and 30% for clopidogrel [43–49]. Several mechanisms have been proposed [50–68].

However, improvement in pharmacology have contributed to reduce this limitation with new oral antiplatelet therapy such as prasugrel [69,70] and ticagrelor [71,72].

Clinical Data

ST-Segment elevation myocardial infarction

Cath lab administration

Several randomized trials have been conducted in primary angioplasty, the vast majority of them on abciximab [73–86]. Several small studies have shown that abciximab administration is associated with improved perfusion and left ventricular functional recovery [73,74]. In the largest trial, the CADILLAC [81], a total of 2082 patients were randomized to stent or balloon with or without periprocedural administration of abciximab. Abciximab did not improve myocardial perfusion as evaluated by myocardial blush grade and ST-segment resolution. Some benefits in mortality with abciximab were observed in patients undergoing balloon angioplasty only, whereas no benefits were observed in terms of reinfarction. Abciximab did not increase the risk of bleeding complications. However, a major limitation of this study was the relatively low risk population. In fact, in trials without strict patient selection, as conducted by Antoniucci et al., abciximab was associated with benefits in terms of death and reinfarction [17].

A recent meta-analysis of randomized trials has shown that periprocedural abciximab administration is associated with a significant reduction in mortality and reinfarction, without an increased risk of major bleeding complications [83] (Figure 2). However, data from the BRAVE-3 trial [84] have shown no benefits in infarct size and 30-day mortality when a clopidogrel loading dose of 600 mg was administrated. Keeping in mind the relationship between the risk profile and mortality benefits from abciximab administration [85], it may be claimed that absence of benefits would have been expected in a population with a mortality lower than 3%, as observed in the BRAVE-3 trial [84]. In fact, this relationship has been recently confirmed in an updated meta-analysis of 14 randomized trials [86].

Figure 2.

Bar graphs show the results (mortality rate) of meta-analyses on: (A) periprocedural abciximab as compared to control group (first and second graphs); (B) early versus late administration of GP IIb-IIIa inhibitors (abciximab, third graph; small molecules, fourth graph); and (C) facilitation with combined therapy (half-dose lythic therapy with GP IIb-IIIa inhibitors) versus GP IIb-IIIa inhibitors only.

Few data have been reported on eptifibatide and tirofiban (small molecules) [87–94]. Steen et al. [88] did show in a small randomized trial (53 patients) a significantly improved epicardial and myocardial perfusion by adjunctive tirofiban. Data from a randomized trial conducted in Zwolle [89] have shown that high-dose tirofiban was associated with a better platelet inhibition as compared to abciximab or standard dose of tirofiban. In the STRATEGY trial [91], no difference in death and or reinfarction was observed between high-dose tirofiban and abciximab. Data from the MultiSTRATEGY trial [92], have shown among 745 STEMI patients undergoing primary angioplasty a similar outcome (non-inferiority) between tirofiban and abciximab, and no difference in major bleeding complications, whereas data from the FATA trial [93] showed an inferiority of Tirofiban as compared to abciximab in terms of myocardial reperfusion (as evaluated by ST-segment resolution).

In the EVA-AMI trial [94], 400 STEMI patients were randomly assigned to periprocedural administration of eptifibatide or abciximab, with similar outcome between the two molecules. The major limitation of the study is that the primary endpoint (ST resolution at 60–90 min.) was available in only 50% of patients.

Recent meta-analyses [95,96] showed similar outcome between abciximab and small molecules (Tirofiban in five of six trials). However, it must be recognized that despite the proven safety and benefits, high-dose Tirofan still remains an “off-label” practice. Current European Guidelines provide class IIa for Eptifibatide and Class IIb for Tirofiban.

Further benefits may be expected by adjunctive intracoronary administration of GP IIb-IIIa inhibitors. A small randomized trial [97] showed that selective intracoronary administration of abciximab distally to the occlusion (through an over-the-wire balloon) was associated with a significant improvement in myocardial perfusion and smaller infarct size. These data have been confirmed in another small randomized trial [98], showing among 144 STEMI patients that intracatheter administration of abciximab bolus was associated with improved myocardial perfusion and reduced infarct size as compared to intravenous bolus administration.

Large randomized trials [99,100] will hopefully provide definitive conclusions on the potential superiority of the intracoronary as compared to intravenous administration.

To minimize the risk of bleeding complications, the recent HORIZONS trial evaluated the benefits from Bivalirudin administration as compared to periprocedural administration of abciximab or eptifibatide [101]. In this trial, a total of 3602 STEMI patients undergoing primary angioplasty have been randomized to bivalirudin or GP IIb-IIIa inhibitors (Abciximab in 49.9% and Eptifibatide in 44.4%) plus UFH. Bivalirudin was associated with a significant reduction in overall net clinical outcome (9.3% vs. 12.2%, P = 0.006), mainly due to a significant reduction of major bleeding complications (5.0% vs. 8.4%, P < 0.0001). Surprisingly, bivalirudin significantly reduced the incidence of cardiac-related mortality by 38% (1.8% vs. 2.9%, P = 0.035), despite a higher rate of 24-h in-stent thrombosis with bivalirudin (1.3% vs. 0.3%, P = 0.0009). The benefits in mortality have been confirmed at 2-year follow-up, with associated significant benefits in reinfarction. Some limitations may be taken into account. Despite the attempts of investigators, a low-risk population was finally included, with a median age less than 60 years, and a short-term mortality rate ranging between 2% and 3%. The benefits in terms of bleeding complications may be a consequence of the study design that apparently may have favored bivalirudin in that sense. In fact, as per protocol, the administration of bivalirudin was stopped at the end of the procedure, whereas infusion of GP IIb-IIIa inhibitors continued up to 12–18 h after the procedure, suggesting that in low-risk patients the risk of bleeding complications may outweight the risk of thrombotic complications and thus the benefits from aggressive antithrombotic therapy. A larger use of radial approach, mechanical closure devices, potential postprocedural administration of protamin with subsequent early sheath removal [102,103] could certainly reduce the risk of bleeding complications while preserving the benefits from GP IIb-IIIa inhibitors in terms of thrombotic complications.

Early upstream administration

GP IIb-IIIa inhibitors

Several randomized trials have been conducted to evaluate the benefits from early GP IIb-IIIa inhibitors administration in patients undergoing primary angioplasty [104–116]. In the On-TIME trial [105], a total of 507 STEMI patients transferred to a PCI center, were randomized to early, prehospital initiation of tirofiban (early) or to its initiation in the catheterization laboratory (late). Early tirofiban was associated with a better preprocedural TIMI 2–3 flow (43% vs. 34%, P = 0.04), and myocardial perfusion (myocardial blush grades 2 and 3: 30% vs. 22%, P = 0.04). However, no benefits were observed in postprocedural TIMI 3 flow, myocardial perfusion, mortality (4.5% vs. 3.7%, P = 0.66) and reinfarction (2.4% vs. 3.7%, P = 0.43) at 1-year follow-up. Similar results have been observed in the TITAN-TIMI 34, where 316 STEMI patients were randomized to early or late eptifibatide [106]. Several small randomized trials [110–114] have been conducted with abciximab, showing benefits in terms of preprocedural TIMI flow and myocardial perfusion.

Data from the large FINESSE trial have been published [116]. In this trial, up to 2500 STEMI patients were randomized within 6 h from symptom onset to facilitation with half lythic and abciximab, early or periprocedural abciximab administration. As compared to late administration, early abciximab did improve neither preprocedural TIMI 2–3 flow (26% vs. 25%) or 90-day mortality (5.5% vs. 4.5%), with a nonsignificantly higher risk of major bleeding complications (4.1% vs. 2.6%, P = 0.13). Several limitations should be taken into account in the interpretation of the results of this trial. First of all, it was prematurely stopped after 4 years due to slow recruitment. Thus, the very low enrollment rate per center per year certainly leaded to a selection bias. In addition, despite the study was focused on facilitation (and therefore drug administration during transportation), more than 50% of patients were enrolled in primary PCI centers. In fact, subgroup analyses have shown larger benefits in terms of outcome among patients included within the first 3 h and in high-risk patients.

Supporting the benefits from early abciximab administration, data from the Eurotransfer registry [117] showed among up to 1000 STEMI patients transferred for primary angioplasty that early abciximab administration improved preprocedural TIMI 3 flow (17.7% vs. 8.9%, P < 0.05) and was independently associated with better 30-day survival (3.8% vs. 5.8%, P = 0.007). Similar findings have been observed in the REAL registry [118], especially among high-risk patients. In the MISSION study, despite the small number of patients (n = 180), early in-ambulance abciximab administration was associated with smaller infarct size and better left ventricular functional recovery [119].

In addition, in a retrospective analysis from the large APEX-MI trial [120], early GP IIb-IIIa inhibitors administration was associated with improved preprocedural TIMI 2–3 flow (27.8% vs. 21%), postprocedural reperfusion (complete ST-resolution: 53.9% vs. 49.5%), and reduced 90-day mortality (3.2% vs. 4.8%), as compared to periprocedural administration.

A recent individual patients’ data meta-analysis (including 1662 patients) of randomized trials comparing early versus late administration of GP IIb-IIIa inhibitors in primary angioplasty [121] has demonstrated significant benefits in preprocedural TIMI flow with all the molecules. However, only abciximab was associated with significant benefits in postprocedural TIMI flow, myocardial blush, distal embolization, and survival. Of note, facilitation did not significantly increase the risk of major bleeding complications (3.2% vs. 2.9%).

Further evidence of benefits from early GP IIb-IIIa inhibitors (Tirofiban) has been observed in the On-TIME 2 trial [122]. In this study, 984 patients have been randomized to early, prehospital administration of high-dose tirofiban (25-μg/kg bolus followed by a 0.15-μg/kg-per-minute maintenance infusion) or placebo. Of note, all patients received early high-dose (600 mg) clopidogrel administration. Early tirofiban was associated with improved pre- and postprocedural reperfusion, with reduced mortality (2.3% vs. 4.0%, P = 0.14).

Thus, despite the negative results of the FINESSE trial [116] and the negative recommendation from recent European guidelines [123], there is still some evidence of beneficial effects from early GP IIb-IIIa inhibitors administration that may still be considered a potential strategy, especially in high-risk patients and within the first hours from symptom onset.

Combined GP IIb-IIIa inhibitors and half-dose lythic therapy

For years, there have been concerns about the combination of thrombolysis and mechanical reperfusion in STEMI due to the fact that thrombolytic therapy may induce platelet aggregation and impair the results of adjunctive mechanical revascularization [124]. However, the results of trials on adjunctive thrombolytic therapy have been negative [125–130]. These data may be explained by the higher rates of early reocclusion and re-infarction, potentially due to the low rate of abciximab administration.

The combination of GP IIb-IIIa inhibitors with half-dose lysis has been shown to provide a higher rate of reperfusion and may reduce the risk of thrombotic complications. This strategy may be appealing particularly when long-distance transportation to cath lab is needed. Few small trials have been so far conducted comparing combination therapy versus upstream GP IIb-IIIa inhibitors alone for PCI [131–134], showing no benefits in terms of myocardial salvage [131] and clinical outcome, despite the significantly improved preprocedural epicardial recanalization. Data from the FINESSE trial [116] showed that, despite improvement in preprocedural TIMI flow, combotherapy did not confer any benefit in terms of survival, but was associated with higher risk of major bleeding complications (4.8% vs. 2.6%, P = 0.025). These data have been confirmed in a recent meta-analysis of six randomized trials, conducted by De Luca et al. [135], including 2684 STEMI patients, where combotherapy, even though significantly increased the rate of preprocedural TIMI 3 flow (44.3% vs. 15.2%, P < 0.0001), it did not improve postprocedural TIMI 3 flow (91.5% vs. 91.2%, P = 0.12), 30-day mortality (4.2% vs. 4.6%, P = 0.66, Phet= 0.22) or 30-day reinfarction (1.3% vs. 1.3%, P = 0.84). Furthermore, combotherapy was associated with higher risk of major bleeding complications (5.8% vs. 3.9%, P = 0.03).

However, the recently published 1-year follow-up data of the FINESSE trial [136,137] showed benefits from combotherapy in terms of survival. As expected, in a post hoc analysis, the benefits were mostly pronounced in high-risk patients and when the therapy was started within 4 h from symptoms onset.

In fact, it must be recognized that even though in several randomized trials the time window for enrollment has been restricted to the first 6 h from symptoms onset, a large proportion of patients did receive facilitation after the first 3–4 h, when clinical benefits are certainly low, and the risk of bleeding complications outweights the benefits from early pharmacological reperfusion, due to less myocardium that can be saved, in addition to reduced drug effectiveness.

Remarkably, data from CARESS (including 600 patients) [138] and the TRANSFER-AMI (including 1060 patients) [139] have recently shown the safety and benefits (in terms of reinfarction and recurrent ischemia) of early routine angiography (within 6 h) soon after combotherapy (CARESS) or full-dose lysis (TRANSFER-AMI), without a significant increase in the risk in TIMI major bleeding complications (2.7% vs. 2.3% in the CARESS and 4.6% vs. 4.3% in the TRANSFER-AMI). These data will probably contribute to modify current ACC/AHA recommendation and hopefully promote future trials to address whether the type of pharmacological facilitation should be selected according to the time from symptom onset to presentation. In fact, complete reperfusion within the first two hours has a high probability of abortion of myocardial infarction that should still be considered the target in the treatment of STEMI, independently from whether mechanical reperfusion is planned or not [140].

Acute Coronary Syndromes (UA/NSTEMI)

Several randomized trials and meta-analysis have shown the beneficial effects from adjunctive GP IIb-IIIa inhibitors in the setting of ACS only in case of invasive approach and in high-risk patients, identified according to troponin increase or ST-segment deviation [141]. However, the major limitation of previous trials was the suboptimal use of oral antiplatelet therapy, being almost all the studies conducted with ticlopidine or standard dose of clopiodgrel. The recent randomized trial ISAR-REACT 2 [142] clearly showed benefits in clinical outcome from abciximab administration even with high-dose (600 mg) clopidogrel. In fact, in this study, periprocedural abciximab administration was associated with a significant reduction in 30-day and 1-year occurrence of combined death–myocardial infarction. No benefits were observed among patients with negative troponin (unstable angina), who therefore should not routinely treated with adjunctive GP IIb-IIIa inhibitors, but only in case of procedural thrombotic complications (provisional use).

Upstream versus downstream administration of GP IIb-IIIa inhibitors

Still a matter of debate what should be the preferred strategy, with upstream, prolonged administration of small molecules or downstream, potentially selective, administration of GP IIb-IIIa inhibitors. The rationale for upstream administration is the plaque passivation that may minimize the occurrence of microembolization and poor myocardial perfusion during coronary angioplasty. This has been investigated by a small randomized study conducted by Bolognese et al. [143], who found in a small population (90 patients) that upstream administration of tirofiban was associated with improved myocardial perfusion and smaller infarct size. Similar findings have been observed in the ELISA II trial [144] conducted by Rasoul et al., who found lower infarct size by upstream administration of GP IIb-IIIa inhibitors as compared to a fast-track strategy. Several additional small trials have been conducted on this issue with contrasting results [145,146].

It must be recognized that 30–40% of initial population do not undergo angioplasty, but conservative therapy or bypass surgery. Conversely, a downstream selective administration of GP IIb-IIIa inhibitors only in patients undergoing coronary angioplasty may reduce costs and bleeding complications, as compared to its upstream unselective administration. Two recent trials have compared these two strategies. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial patients randomized to GP IIb-IIIa inhibitors with or without bivalirudin were subsequently randomized to an upstream or selective downstream strategy [147]. Upstream strategy did not improve clinical outcome, but was associated with a significantly higher occurrence of major bleeding complications (Figure 3).

Figure 3.

Bar graphs show mortality, recurrent myocardial infarction, and major bleeding complication in the two largest randomized trials conducted in ACS patients undergoing an invasive strategy comparing upstream versus downstream administration of GP IIb-IIIa inhibitors.

Similar findings were observed in the large EARLY ACS [148] where 9492 patients were randomized to upstream Eptifibatide versus downstream selective Eptifibatide administration. An upstream strategy was associated with a slightly better primary endpoint (combined death and myocardial infarction), without reaching the statistical significance. Conversely, the strategy significantly increased the rate of major bleeding complications as compared to a selective downstream eptifibatide administration (Figure 3).

A recent meta-analysis of five randomized trials by De Luca et al., including 19,929 patients, have shown that selective administration provide similar clinical benefits as compared to early administration, with a significant reduction in major bleeding complications [149].

Therefore, according to current available data there is no indication for upstream administration of GP IIb-IIIa inhibitors.

The strategy of selective downstream administration of GP IIb-IIIa inhibitors is certainly reinforced by an early invasive strategy, that may shorten the time from hospital admission to optimal antithrombotic (periprocedural) therapy, and therefore the risk of thrombotic complications while waiting for mechanical plaque stabilization. Data from the Early ACS [148], TIMACS [150], and ACUITY [147] showed that the early intervention strategy with downstream administration results in better safety and much lower use of GP IIb/IIIa (from 23% TIMACS to 26% Early ACS to 55% Acuity).

GP IIB-IIIA Inhibitors in the Era of Bivalirudin and New Oral Antiplatelet Therapies

A larger widespread use of new oral antiplatelet therapies, such as prasugrel and ticagrelor, will certainly keep burning the question whether still persist the benefits from deferred GP IIb-IIIa inhibitors. It must be recognized that even recent oral antiplatelet therapies reach peak effect no earlier than 2 h. Therefore, while protecting postprocedural occurrence of thrombotic complications, they cannot completely protect from procedural complications such as distal microembolization, especially among STEMI patients. Among ACS patients, further stratification according to coronary anatomy and the angiographic information on plaque stability and intracoronary thrombus, will probably further help, in addition to risk stratification based on troponin or ECG changes at admission, in the identification of patients who may mostly benefit from a deferred administration of GP IIb-IIIa even in the era of new powerful oral antiplatelet therapies [69–72]. The use of Bivalirudin has been shown to reduce the risk of bleeding complications among ACS patients (ACUITY trial) [148], and significant reduction in major bleeding complication, mortality, and reinfarction in the setting of STEMI [101]. Therefore, the combination between new thienopyridines and bivalirudin may appear an appealing strategy and may reduce the clinical benefits from adjunctive GP IIb-IIIa inhibitors. Ongoing randomized trials will hopefully provide further insights on this issue [151–153].

Conclusions

GP IIb-IIIa inhibitors, especially abciximab, have been shown to improve clinical outcome in patients undergoing primary angioplasty for STEMI. Upstream administration cannot routinely recommended, but may potentially be considered among high-risk patients within the first 4 h from symptoms onset. In case of periprocedural administration of antithrombotic therapy, bivalirudin should be considered, especially in patients at high risk for bleeding complications. Among high-risk patients with acute coronary syndromes, an early invasive strategy with selective downstream administration of GP IIb-IIIa inhibitors is the strategy of choice, whereas bivalirudin should be considered in patients at high risk for bleeding complications. Among patients with unstable angina GP IIb-IIIa inhibitors should be considered only in case of evidence of intracoronary thrombus or in case of thrombotic complications (as provisional use). Further randomized trials are certainly needed in the era of new oral antiplatelet therapies, and with strategies to prevent bleeding complications such as larger use of radial approach, mechanical closure devices, bivalirudin, or postprocedural protamine administration to promote early sheat removal.

Conflict of interest

The authors have no conflict of interest.

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