Sage Journals: Discover world-class research

Abstract

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa receptors mediate platelet aggregation, representing the final common pathway of platelet-mediated thrombosis. Therefore, agents blocking this pathway may be desirable for the treatment of patients with ACS and PCI. Glycoprotein IIb/IIIa receptor inhibitors have been widely investigated and have been key to the pharmacological advancements in the field. However, although GPIs have been important to reduce ischemic complications, their elevated risk of bleeding complications remains a major limitation. The poor prognostic implications, including increased mortality, associated with bleeding complication underscores the need for alternative treatment options. Over the past years there have been several advancements in antithrombotic pharmacology which have led to changes in recommendations for GPI usage in clinical practice. This is an overview of the most recent clinical trial data on GPIs, and provides practical insight on their modern day use in ACS therapy.

Keywords

acute coronary syndrome antiplatelet therapy percutaneous coronary interventions

Introduction

An acute coronary syndrome (ACS) is the clinical manifestation of thrombus formation [Angiolillo et al. 2010]. This is caused by plaque rupture, fissure or erosion which in turn embraces both cellular (platelet adhesion, activation and aggregation) and plasma (activation of the coagulation cascade) components of thrombus formation. Notably, there is an important interplay between these two pathways, whereas thrombin is the most potent inducer of platelet activation and the activated platelet is the main source of thrombin generation, overall favoring the growth of the thrombus [Angiolillo et al. 2010; Freedman, 2005].

Occlusive thrombi generally lead to an ST-elevation myocardial infarction (STEMI), while nonocclusive thrombi lead to a non ST-elevation ACS [unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI)] [Davì and Patrono, 2007; Libby and Theroux, 2005]. Over the past decades there have been a plethora of trials supporting the role of antiplatelet therapy in preventing recurrent atherothrombotic events in these patients and currently there are three approved categories of antiplatelet targets [Angiolillo et al. 2010]. These include inhibitors of thromboxane A₂ mediated platelet activation via cyclooxygenase 1 (aspirin); adenosine diphosphate (ADP) P2Y₁₂ receptor mediated platelet activation (thienopyridine: ticlopidine, clopidogrel, and prasugrel; nonthienopyridine: ticagrelor); and glycoprotein (GP) IIb/IIIa receptor inhibitors (GPIs; abciximab, tirofiban, eptifibatide).

Platelet aggregation determined by cross-linking of fibrinogen and von Willebrand factor after the exposure of the activated GP IIb/IIIa receptor, the final common pathway leading to the platelet aggregate, is key in thrombus formation [Angiolillo et al. 2010; Freedman, 2005]. Therefore strategies inhibiting this final common pathway using GPIs are indeed appealing to minimize thrombotic risk in patients with ACS. Numerous studies have explored the role of GPIs in various clinical settings of patients presenting with an ACS and in those undergoing percutaneous coronary intervention (PCI). These include studies evaluating oral GPIs for long-term prevention of recurrent events, which however showed to be associated with worse outcomes, including increased mortality [Chew et al. 2001]. Currently, only parenteral GPIs are available for clinical use, which is mostly limited to high-risk patients with ACS undergoing PCI, given their limited ischemic benefit in patients managed conservatively. However, it is important to underscore that many of the trials supporting the use of GPIs were conducted in the earlier era of interventional cardiology, in which older devices were used (including balloon angioplasty only) or in which less efficacious antithrombotic regimens were used (e.g. ticlopidine or low clopidogrel dosing, indirect thrombin inhibitors) [Bhatt and Topol, 2000].

Further, the elevated rates of bleeding complications associated with GPIs and the ever raising understanding on the poor prognostic implications associated with bleeding have been reason to a decline in the use of GPIs in current clinical practice. This has led us to question the role of GPIs in the modern era of interventional cardiology. This article is an overview of the most recent clinical trial data on GPIs, and provides practical insights on modern day use of GPIs in light of recent advances in the field.

Glycoprotein IIb/IIIa receptor inhibitors: basic pharmacology

There are three parenteral GPIs available for clinical use: abciximab, eptifibatide, and tirofiban [Topol et al. 1999]. The latter two agents are also called ‘small molecule GPIs’ given their molecular structure that contrasts with abciximab, which is a chimeric murine molecule larger in size (Figure 1). These differences in chemical structure in turn lead to differences in their pharmacological properties, including their affinity of binding to the activated GP IIb/IIIa receptor, a process which is required for these molecules to exert their antiplatelet effects (Figure 2) [Wagner et al. 1996; Pytela et al. 1986; Coller et al. 1983; Coller, 1985]. Table 1 summarizes the key pharmacological differences between these compounds. In brief, the small molecule GPIs have lower affinity for the GP IIb/IIIa receptor, have a shorter half life, competitive binding, and are renally excreted (requiring dose adjustments in patients with impaired renal function). In contrast, abciximab has a higher affinity for the GP IIb/IIIa receptor, longer half life with noncompetitive binding, and does not require dose adjustments in patients with impaired renal function [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012].

Figure 1.

Glycoprotein (GP) IIb/IIIa inhibitors. Abciximab, a big chimeric monoclonal antibody, has high binding affinity to the GP IIb/IIIa receptor, which explains its very prolonged pharmacological effect. Abciximab blocks the GP IIb/IIIa receptor at different sites from the ligand-binding arginine–glycine–aspartic (RGD) sequence site (as a noncompetitive inhibition), in a different way than the small-molecule GP IIb/IIIa inhibitors, eptifibatide (peptide) and tirofiban (nonpeptide), which exert their effect through a competitive mechanism and with lower affinity for the GP IIb/IIIa receptor.

Figure 2.

The glycoprotein (GP) IIb/IIIa receptor. The structure of the GP IIb/IIIa receptor is a heterodimer (an integrin) which is made up of the noncovalent association of α IIb and β 3 subunits. Platelets are attracted and attached to the vessel wall by tissue factor, collagen, von Willebrand factor (VWF), and fibronectin, which activate them. There is also a conformational change in the platelet because of the binding of VWF, which causes its degranulation and the secretion of vasoconstrictive and chemoattractant substances. GP IIb/IIIa receptor inhibitors compete with fibrinogen and VWF for GP IIb/IIIa binding. In this way, they block platelet cross linking and platelet-derived thrombus formation. This is the reason why the inhibition of the platelet aggregation of these agents is so high; indeed, because it antagonizes the final common pathway leading to platelet aggregation preventing fibrinogen binding and causing ‘dethrombosis’. ADP, adenosine diphosphate. Reproduced with kind permission from Elsevier (Topol et al., 1999).

Table 1.

Characteristics of glycoprotein IIb/IIIa inhibitors.

	Abciximab	Eptifibatide	Tirofiban
Trade name	ReoPro	Integrilin	Aggrastat
Molecule	Fragment antigen binding (Fab)^7E3	Synthetic peptide	Nonpeptide mimetic
Molecular weight	~50,000	~800	~500
Stoichiometry (drug to GP IIb/IIIa)	~1.5:1	>>100:1	>>100:1
Binding	Noncompetitive	Competitive	Competitive
Half life	Plasma: 10–15 h	Plasma: 2–2.5 h	Plasma: 2–2.5 h
	Biologic: 12–24 h	Biologic = plasma	Biologic = plasma
PCI dosing	Bolus:	Bolus:	Bolus:
	0.25 mg/kg (10–60 min)	180 µg/kg (10 min) + 180 µg/kg	25 µg/kg (30 min)
	Infusion:	Infusion:	Infusion:
	0.125 µg/kg/min (12 h)	2 µg/kg/min (24–48 h)	0.10 µg/kg/min (48 h)
Renal adjustment	No	Bolus:	Bolus:
		180 µg/kg	12.5 µg/kg (30 min)
		Infusion:	Infusion:
		1 µg/kg/min (24–48 h)	0.10 µg/kg/min (48 h)

GP, glycoprotein; PCI, percutaneous coronary intervention.

Pivotal clinical trials

As previously mentioned, over the past decades there have been a large number of clinical trials testing the use of GPIs in various clinical settings. A comprehensive description of these trial data goes beyond the scope of the present review, which aims to analyze the most recent clinical trial data which in turn provide support to current practice guidelines in the United States and in Europe (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012]. Our accumulating experience with all three of the GPIs has now led to understand that these drugs are similar in efficacy. In fact, while head-to-head studies between abciximab and small molecule GPIs, in particular tirofiban, failed to show noninferiority of the latter, these have been shown to be attributed to inadequate dosing [Topol et al. 2001b; Kereiakes et al. 1996]. Subsequent dose-finding studies for both tirofiban and eptifibatide have identified the dose of these agents that is associated with similar pharmacodynamic effects as abciximab, for which there are more years of clinical testing experience, and which have also resulted in noninferiority of these drugs [ESPRIT Investigators, 2000; Valgimigli et al. 2010]. These have led to changes in the level of evidence of the use of small molecule GPIs in practice guidelines, which is now similar to that of abciximab (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012].

Table 2.

Guideline recommendations for available glycoprotein IIb/IIIa antagonists in the setting of percutaneous coronary intervention.

	Abciximab	Tirofiban	Eptifibatide
Dosing	IV bolus of 0.25 mg/kg, followed by 0.125 µg/kg/min (max 10 µg/min) for 12 h after PCI (no need for renal adjustment)	IV bolus of 25 µg/kg for 30 min followed by maintenance dose of 0.1 µg/kg/min for a minimum of 12 h and up to 18–24 h (dose reduction by 50% for IV bolus and maintenance dose if CrCl < 30 ml/min)	IV bolus of 180 µg/kg followed 10 min later by a second 180 µg/kg bolus, followed by maintenance dose of 2.0 µg/kg/min for a minimum of 12 h and up to 18–24 h (adjustment for maintenance dose to 1 µg/kg/min if CrCl < 50 ml/min)
2010 ESC/EACTS/EAPCI guidelines on myocardial revascularization* [Wijns et al. 2010]	Elective PCI: class IIa; LOE C NSTE-ACS: class I; LOE B STEMI: class IIa; LOE A	Elective PCI: class IIa; LOE C NSTE-ACS: class IIa; LOE B STEMI: class IIb; LOE B	Elective PCI: class IIa; LOE C NSTE-ACS: class IIa; LOE B STEMI: class IIa; LOE B
	Elective PCI: bail-out situations only (thrombus, slow flow, vessel closure, very complex lesions)NSTE-ACS: in patients with evidence of high intracoronary thrombus burdenUpstream: class III; LOE BSTEMI: in patients with evidence of high intracoronary thrombus burdenUpstream: class III; LOE B	Elective PCI: bail-out situations only (thrombus, slow flow, vessel closure, very complex lesions)NSTE-ACS: in patients with evidence of high intracoronary thrombus burden.Upstream: class III; LOE BSTEMI: in patients with evidence of high intracoronary thrombus burden.Upstream: class III; LOE B	Elective PCI: bail-out situations only (thrombus, slow flow, vessel closure, very complex lesions)NSTE-ACS: in patients with evidence of high intracoronary thrombus burdenUpstream: class III; LOE BSTEMI: in patients with evidence of high intracoronary thrombus burdenUpstream: class III; LOE B
2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention^$ [Levine et al. 2011]	No clopidogrel pretreatmentSIHD: class IIa; LOE BUA/NSTEMI: in patients with high-risk features (e,g. elevated troponin level) treated with UFH and not with bivalirudin. Class I; LOE ASTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE AIntracoronary abciximab. Class IIa; LOE ARoutine or upstream use is not beneficial. Class III; LOE B	No clopidogrel pretreatment High-bolus doseSIHD: class IIa; LOE BUA/NSTEMI: in patients with high-risk features (e.g. elevated troponin level) treated with UFH and not with bivalirudin. Class I; LOE ASTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE ARoutine or upstream use is not beneficial. Class III; LOE B	No clopidogrel pretreatment Double doseSIHD: class IIa; LOE BUA/NSTEMI: in patients with high-risk features (e.g. elevated troponin level) treated with UFH and not with bivalirudin. Class I; LOE ASTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE ARoutine or upstream use is not beneficial. Class III; LOE B
	Clopidogrel pretreatment SIHD: class IIb; LOE BUA/NSTEMI: in patients with high-risk features (e.g. elevated troponin level) treated with UFH and not with bivalirudin. Class IIa; LOE BSTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE CIntracoronary abciximab. Class IIb; LOE BRoutine or upstream use is not beneficial. Class III; LOE B	Clopidogrel pretreatment High-bolus-doseSIHD: class IIb; LOE BUA/NSTEMI: class IIa; LOE BSTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE CRoutine or upstream use is not beneficial. Class III; LOE B	Clopidogrel pretreatment Double bolusSIHD: class IIb; LOE BUA/NSTEMI: class IIa; LOE BSTEMI: in patients undergoing primary PCI treated with UFH. Class IIa; LOE CRoutine or upstream use is not beneficial. Class III; LOE B

2011 ESC guidelines for the management of ACS in patients presenting without persistent ST-segment elevation^‡ [Hamm et al. 2011]	High-risk patients: class I; LOE B	High-risk patients: class I; LOE B	High-risk patients: class I; LOE B

	Among patients who are already treated with DAPT, the addition of a GPI for high-risk PCI (elevated troponin, visible thrombus) is recommended if the risk of bleeding is low	Among patients who are already treated with DAPT, the addition of a GPI for high-risk PCI (elevated troponin, visible thrombus) is recommended if the risk of bleeding is low.Class IIa; LOE C: tirofiban added to aspirin should be considered prior to angiography in high-risk patients not preloaded with P2Y₁₂ inhibitors.Class IIb; LOE C: in high-risk patients, tirofiban may be considered prior to early angiography in addition to DAPT, if there is ongoing ischemia and the risk of bleeding is low	Among patients who are already treated with DAPT, the addition of a GPI for high-risk PCI (elevated troponin, visible thrombus) is recommended if the risk of bleeding is lowClass IIa; LOE C: eptifibatide added to aspirin should be considered prior to angiography in high-risk patients not preloaded with P2Y₁₂ inhibitorsClass IIb; LOE C: in high-risk patients, eptifibatide may be considered prior to early angiography in addition to DAPT, if there is ongoing ischemia and the risk of bleeding is low
2012 ACCF/AHA focused update of the guidelines for the management of patients With UA/NSTEMI [Jneid et al. 2012]	Class IInvasive strategy: medium high risk Aspirin + second antiplatelet:Upstream: GPI (LOE A). Eptifibatide and tirofiban are the preferred, LOE BDownstream: GPI. LOE AConservative strategy: if recurrent symptoms of ischemia, HF or serious arrhythmias, diagnostic angiography should be performed with upstream IV administration of GPI [eptifibatide or tirofiban (LOE A)], clopidogrel or ticagrelor, in addition to aspirin and anticoagulant therapy (LOE C)	Class IInvasive strategy: medium high risk Aspirin + second antiplatelet:Upstream: GPI (LOE A). Eptifibatide and tirofiban are the preferred, LOE BDownstream: GPI. LOE AConservative strategy: if recurrent symptoms of ischemia, HF or serious arrhythmias, diagnostic angiography should be performed with upstream IV administration of GPI [eptifibatide or tirofiban (LOE A)], clopidogrel or ticagrelor, in addition to aspirin and anticoagulant therapy (LOE C)	Class IInvasive strategy: medium high risk Aspirin + second antiplatelet:Upstream: GPI (LOE A). Eptifibatide and tirofiban are the preferred, LOE BDownstream: GPI. LOE AConservative strategy: if recurrent symptoms of ischemia, HF or serious arrhythmias, diagnostic angiography should be performed with upstream IV administration of GPI [eptifibatide or tirofiban (LOE A)], clopidogrel or ticagrelor, in addition to aspirin and anticoagulant therapy (LOE C)
	Class IIaInvasive strategy: if ischemic discomfort with aspirin, a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor), and anticoagulant therapy, it is reasonable to add a GPI before diagnostic angiography (LOE C)Conservative strategy: omit GPI if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI (LOE B)	Class IIaInvasive strategy: if ischemic discomfort with aspirin, a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor), and anticoagulant therapy, it is reasonable to add a GPI before diagnostic angiography (LOE C)Conservative strategy: omit GPI if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered atleast 6 h earlier than planned catheterization or PCI (LOE B)	Class IIaInvasive strategy: if ischemic discomfort with aspirin, a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor), and anticoagulant therapy, it is reasonable to add a GPI before diagnostic angiography (LOE C)Conservative strategy: omit GPI if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI (LOE B)
	Class IIbInvasive strategy: high-ischemic-risk patients already receiving aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor) (elevated troponin levels, diabetes, or significant ST-segment depression), and who are not otherwise at high risk for bleeding (LOE B)	Class IIbInvasive strategy: high-ischemic-risk patients already receiving aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor) (elevated troponin levels, diabetes, or significant ST-segment depression), and who are not otherwise at high risk for bleeding (LOE B)	Class IIbInvasive strategy: high-ischemic-risk patients already receiving aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel or ticagrelor) (elevated troponin levels, diabetes, or significant ST-segment depression), and who are not otherwise at high risk for bleeding (LOE B)
	Class IIIAbciximab should not be administered to patients in whom PCI is not planned (LOE A)In low risk for ischemic events (e.g. TIMI risk score ≤2) or at high risk of bleeding and who are already receiving aspirin and a P2Y₁₂ receptor inhibitor, upstream GPI are not recommended (LOE B)	In low risk for ischemic events (e.g. TIMI risk score ≤2) or at high risk of bleeding and who are already receiving aspirin and a P2Y₁₂ receptor inhibitor, upstream GPI are not recommended (LOE B)	In low risk for ischemic events (e.g. TIMI risk score ≤2) or at high risk of bleeding and who are already receiving aspirin and a P2Y₁₂ receptor inhibitor, upstream GPI are not recommended (LOE B)
2012 ESC guidelines for the management of AMI in patients presenting with ST elevation^§[Steg et al. 2012]	LOE A for agentAngiographic evidence of massive thrombus, slow or no reflow or a thrombotic complication: bailout therapy. Class IIa; LOE CPrimary PCI: routine use with UFH (patients without contraindications). Class IIb; LOE BHigh-risk patients undergoing transfer for primary PCI: upstream use (versus in-lab use) Class IIb; LOE BBivalirudin (with use of GPI restricted to bailout) is recommended over UFH and a GPI. Class I; LOE BEnoxaparin (with or without routine GPI) may be preferred over UFH. Class IIb, LOE BUFH with or without routine GPI must be used in patients not receiving bivalirudin or enoxaparin. Class I, LOE C	LOE B for agent(with high bolus dose)Angiographic evidence of massive thrombus, slow or no reflow or a thrombotic complication: bailout therapy. Class IIa; LOE CPrimary PCI: routine use with UFH (patients without contraindications). Class IIb; LOE BHigh-risk patients undergoing transfer for primary PCI: upstream use (versus in-lab use). Class IIb; LOE BBivalirudin (with use of GPI restricted to bailout) is recommended over UFH and a GPI. Class I; LOE BEnoxaparin (with or without routine GPI) may be preferred over UFH. Class IIb, LOE BUFH with or without routine GPI must be used in patients not receiving bivalirudin or enoxaparin. Class I, LOE C	LOE B for agent(with double bolus)Angiographic evidence of massive thrombus, slow or no-reflow or a thrombotic complication: bailout therapy. Class IIa; LOE CPrimary PCI: routine use with UFH (patients without contraindications). Class IIb; LOE BHigh-risk patients undergoing transfer for primary PCI: upstream use (versus in-lab) Class IIb; LOE BBivalirudin (with use of GPI restricted to bailout) is recommended over UFH and a GPI. Class I; LOE BEnoxaparin (with or without routine GPI) may be preferred over UFH. Class IIb, LOE BUFH with or without routine GPI must be used in patients not receiving bivalirudin or enoxaparin. Class I, LOE C

General recommendations: 2010 ESC/EACTS/EAPCI guidelines on myocardial revascularization [Wijns et al. 2010]:

1. Adopt selective downstream use of GPI, as required in the catheterization laboratory, in preference to unselective upstream use.

General recommendations: 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention [Levine et al. 2011]:

1. GPI use in STEMI may be most appropriate in those with large anterior MI and/or large thrombus burden.

2, Recommendations apply to those patients not at high risk for bleeding complications.

‡

General recommendations: 2011 ESC Guidelines for the management of ACS in patients presenting without persistent ST-segment elevation [Hamm et al. 2011]:

1. Class I; LOE C: the choice of combination of oral antiplatelet agents, a GPI, and anticoagulants should be made in relation to the risk of ischemic and bleeding events.

2. Class III; LOE A:

a. GPIs are not recommended routinely before angiography in an invasive treatment strategy.

b. GPIs are not recommended for patients on DAPT who are treated conservatively.

3. Upstream use of GPIs may be considered if there is active ongoing ischemia among high-risk patients or when DAPT is not feasible. Patients who receive initial treatment with eptifibatide or tirofiban before angiography should be maintained on the same drug during and after PCI.

General recommendations: 2012 ESC guidelines for the management of AMI in patients presenting with ST elevation [Steg et al. 2012]:

1. In very-high-risk patients in whom cessation of antiplatelet therapy before surgery seems to carry a high risk (e.g. within the first weeks after stent implantation), it has been suggested to switch, before surgery, to a short half-life and reversible antiplatelet agent, for example, the glycoprotein IIb/IIIa receptor inhibitors tirofiban or eptifibatide, but there is no clinical evidence to support this approach based solely on pharmacokinetic or pharmacodynamic studies.

ACCF, American College of Cardiology Foundation; ACS, acute coronary syndrome; AHA, American Heart Association; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; EACTS, European Association for Cardio-Thoracic Surgery; EAPIC, European Association of Percutaneous Cardiovascular Interventions; ESC, European Society of Cardiology; HF, heart failure; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; LOE, level of evidence; MI, myocardial infarction; NSTE-ACS, non-ST-elevation ACS; PCI, percutaneous coronary intervention; SCAI, Society for Cardiac Angiography and Interventions; SIHD, stable ischemic heart disease; STEMI, ST-elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction; UA/NSTEMI, unstable angina/non-ST-elevation myocardial infarction; UFH, unfractionated heparin.

The currently approved dosing regimens for all agents, including renal adjustments for both tirofiban and eptifibatide, are summarized in Table 1. In general, while all agents can be started in the catheterization laboratory in patients with ACS undergoing PCI, when upstream therapy is considered, small molecule GPIs should be used, and abciximab should be considered only if the patient is imminently going to the catheterization laboratory. In the sections below, a description of the pivotal clinical trials according to clinical presentations of patients undergoing PCI [stable coronary artery disease (CAD), UA/NSTEMI, and STEMI) are described.

Stable coronary artery disease

Although historical studies have shown a benefit of GPIs in patients with stable CAD undergoing elective PCI, as previously mentioned, these were conducted in earlier interventional pharmacology [Bhatt and Topol, 2000], therefore questioning whether GPIs still have a role in this clinical setting. To address this question, the most relevant trial was the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) trial [Kastrati et al. 2004]. In this trial low to intermediate risk patients undergoing elective PCI (n = 2159) were all pretreated with a 600 mg loading dose of clopidogrel at least 2 h prior to the procedure, and randomized to abciximab versus placebo. The trial demonstrated no benefit of abciximab therapy compared with placebo on the primary ischemic outcome [death, myocardial infarction (MI) and urgent target vessel revascularization at 30 days], and was associated with an increased risk of bleeding. Another important trial was the Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) trial [Mehilli et al. 2004], which had a similar trial design to ISAR-REACT but was conducted exclusively in patients with diabetes undergoing elective PCI. Importantly, historical trials have shown a particular benefit of GPIs in patients with diabetes, known to have enhanced platelet reactivity [Roffi et al. 2001]. However, this trial also showed that in patients with diabetes undergoing elective PCI pretreated at least 2 h previously, there was no benefit of abciximab [Mehilli et al. 2004]. Overall, these findings explain why, in practice guidelines, there has been a downgrade of the level of recommendation for the use of GPIs in patients with stable CAD (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012].

An area of emerging interest has been to understand whether patients with inadequate response to aspirin or clopidogrel may benefit from more potent antiplatelet treatment regimens, including GPIs. To this extent there are two small studies addressing this question and which have both shown that, in the catheterization laboratory, use of a GPI among poor aspirin or clopidogrel responders undergoing elective PCI is associated with a reduction in peri-procedural MI, without increased bleeding [Cuisset et al. 2008; Vagimigli et al. 2009]. However, the limited sample size of these studies should be considered as hypothesis driving for a large sample sized study to better address the safety and efficacy of this strategy, which currently is not considered within practice guidelines.

Unstable angina/non-ST-elevation myocardial infarction

During the last decades numerous clinical trials have been performed to better define the benefits associated with the use of GPIs in patients with ACS. Overall, these studies have shown that, in patients with ACS, the additive use of GPIs is associated with greater ischemic benefit in patients undergoing PCI, while there is limited benefit in patients who are medically managed [Boersma et al. 2002; Simoons, 2001; Topol, 2001a]. These findings are accordingly reflected in practice guidelines which provide a lower level of recommendation for GPI use in medically managed ACS (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012]. On the contrary, there have been a plethora of trials supporting the benefit of GPIs in patients with ACS undergoing PCI, particularly among high-risk settings [Kereiakes et al. 1996, EPIC Investigators, 1994; EPILOG Investigators, 1997; EPISTENT Investigators, 1998; Boersma and Simoons, 1997; CAPTURE Study Investigators, 1997; Hamm et al. 1999; Heeschen et al. 1999; PRISM-PLUS Study Investigators, 1998; PURSUIT Trial Investigators, 1998; Roffi et al. 2002; Kastrati et al. 2006]. However, many of the studies which have set the basis for the broad uptake of GPI use in patients with ACS undergoing PCI have limitations which have questioned whether these trial findings could apply to modern day interventional practice. In fact, many of these trials were conducted in the era of ticlopidine or with the use of a 300 mg loading dose of clopidogrel, rather than with a 600 mg clopidogrel loading dose or with novel P2Y₁₂ receptor inhibitors, such as prasugrel or ticagrelor. We therefore describe the more recent trials which are relevant to current day clinical practice and which have been considered in current guidelines as guidance for practice.

The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR REACT 2) trial [Kastrati et al. 2006] was a prospective randomized placebo controlled trial comparing the effects of abciximab on the incidence of death, MI, or target vessel revascularization at 30 days in patients with ACS (n = 2022) pretreated at least 2 h before PCI with clopidogrel 600 mg. Patients with an ACS could qualify if they had positive cardiac biomarkers (NSTEMI) or dynamic electrocardiogram changes with chest pain at rest in the absence of cardiac biomarkers (UA). Although the trial showed a significant reduction of the primary endpoint with abciximab in the overall trial population, a predefined subgroup analysis showed that this was confined to patients with elevated cardiac biomarkers. Based on these results [Kastrati et al. 2006] and those from other retrospective analyses [De Luca et al. 2011; Braunwald et al. 2008], the use of GPIs should be considered for high-risk patients with ACS with elevated cardiac biomarkers, as also reflected in practice guidelines (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012]. It has been questioned whether the introduction of the novel P2Y₁₂ receptor inhibitors prasugrel and ticagrelor can obviate the use of GPIs in patients with ACS undergoing PCI. However, in the pivotal Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON) trial [Wiviott et al. 2007] and the Platelet inhibition and patient Outcomes (PLATO) trial [Wallentin et al. 2009] showing the ischemic benefit of prasugrel over clopidogrel and ticagrelor over clopidogrel respectively, the benefit of these novel agents was irrespective of GPI use [O’Donoghue et al. 2009]. Nevertheless, further trials are needed to better address the adjunctive benefit of GPIs on top of novel antiplatelet agents.

Another major concern associated with GPI use is bleeding [Bhatt and Topol, 2000]. The very unfavorable short- and long-term prognostic implications of bleeding, including increased mortality, has underscored the need for treatment strategies associated with a more favorable safety profile [Halim and Rao, 2011]. Bivalirudin has been broadly investigated to this extent and has also been an important contributor for a reduction in the use of GPIs in clinical practice, including in the setting of patients with ACS undergoing PCI. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial [Stone et al. 2006] was performed in moderate- and high-risk patients with ACS managed invasively (n = 13,819) randomized to heparin, unfractionated heparin (UFH) or enoxaparin [low molecular weight heparin (LMWH)] plus GPI, bivalirudin plus GPI, or bivalirudin monotherapy. Similar rates of the composite ischemic end point (death, MI, or unplanned revascularization for ischemia) were found in both bivalirudin branches (bivalirudin monotherapy and bivalirudin plus GPI) compared with heparin plus GPI (7.7% and 7.8% versus 7.3%). However, bivalirudin monotherapy significantly reduced rates of major bleeding [3.0% versus 5.7%; p < 0.001; relative risk 0.53; 95% confidence interval (CI) 0.43–0.65] and the net clinical outcome end point (10.1% versus 11.7%; p = 0.02; relative risk 0.86; 95% CI 0.77–0.97) [Stone et al. 2006]. Bivalirudin plus GPI was not associated with significant differences in major bleeding (5.3% versus 5.7%, p = 0.38) and the net clinical outcome end point (11.8% versus 11.7%, p = 0.93) [Stone et al. 2006]. An analysis of the ACUITY trial showed that major bleeding was a powerful independent predictor of 30-day mortality and that several factors (age, female sex, diabetes, hypertension, renal insufficiency, anemia, no prior percutaneous coronary intervention, cardiac biomarker elevation, ST-segment deviation ≥ 1 mm) independently predict major bleeding, including treatment with heparin plus GPI compared with bivalirudin monotherapy [Manoukian et al. 2007; Mehran et al. 2009a].

Despite these encouraging findings, the ACUITY trial presented some important limitations: first, two-thirds of patients were already receiving some anticoagulant before randomization and not all patients were pretreated with clopidogrel (and used inconsistent dosing), with the consequent variability among the treatments before and during the study. Additionally the choice of GPI and UFH/LMWH was left to the discretion of the physician. Finally, the ACUITY trial has also been criticized because of its fairly liberal definition of bleeding, particularly regarding the definition of major bleeding [Stone et al. 2006].

The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4 (ISAR REACT 4) trial [Kastrati et al. 2011] was a double-blind randomized trial designed trying to avoid the mentioned limitations of the ACUITY trial design. In this study the same GPI (abciximab) was used, all patients were pretreated with 600 mg of clopidogrel and the trial used hard definitions of major bleeding (presence of intracranial, intraocular, or retroperitoneal hemorrhage; a decrease in the hemoglobin level of more than 40 g per liter plus either overt bleeding or the need for transfusion of 2 or more units of packed red cells or whole blood). In particular, the ISAR REACT 4 trial compared abciximab and heparin with bivalirudin in patients with NSTEMI undergoing PCI (n = 1721) and found that such a regimen compared with bivalirudin failed to decrease the rate of ischemic events (12.8% with abciximab versus 13.4% with bivalirudin; relative risk 0.96; 95% CI 0.74–1.25; p = 0.76) and increased the risk of bleeding in patients with NSTEMI undergoing PCI (major bleeding 4.6% with abciximab versus 2.6% with bivalirudin; relative risk 1.84; 95% CI 1.10–3.07; p = 0.02) [Kastrati et al. 2011].

Despite the more favorable safety profile associated with bivalirudin use, there have been differences in uptake of this drug in Europe compared with the United States. This has been largely driven by the broader use of a radial approach in Europe, which is associated with a lower risk of bleeding complications [Biondi-Zoccai et al. 2011]. Since, to date, trials showing a more favorable safety profile of bivalirudin, without compromise in ischemic benefit have been mostly conducted via a femoral approach, this has inevitably led us to question the benefits of bivalirudin in patients undergoing PCI using a radial approach. At present, the Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of angioX (MATRIX) trial [ClinicalTrials.gov identifier: NCT01433627] is ongoing. This is a randomized single-blind study designed to compare intended transradial versus transfemoral intervention and bivalirudin monotherapy versus current European standards of care consisting of UFH plus provisional use of GPIs (e.g. abciximab, tirofiban or eptifibatide) in patients with ACS (≥18 years) undergoing PCI.

Indeed, it may be argued that the increased risk of bleeding associated with GPI use may be associated with their prolonged duration of infusion. This has advocated the potential that shorter duration of treatment may be a safer treatment option. The Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention (BRIEF-PCI) trial [Fung et al. 2009] evaluated the possibility of shortening the eptifibatide infusion (18 h) recommended in patients with ACS or recent STEMI (less than 48 h) who underwent successful and uncomplicated nonemergent PCI (n = 624). The trial demonstrated noninferiority between a standard 18 h infusion (mean 16.8 ± 3.4) and early discontinuation of eptifibatide infusion (< 2 h, mean 1.4 ± 0.78) without any compromise in ischemic benefit, measured as periprocedural myonecrosis, but with a lower incidence of major bleeding (1.0% versus 4.2%, p = 0.02) [Fung et al. 2009]. Indeed, larger studies are warranted to support the concept of short duration of GPI treatment. The ongoing Shortened Aggrastat Versus Integrilin in Percutaneous Coronary Intervention (SAVI-PCI) trial [ClinicalTrials.gov identifier: NCT01522417] was designed to evaluate the possible association of a high-dose bolus of tirofiban plus a shortened infusion duration versus label-dosing eptifibatide in patients undergoing PCI, with a noninferior composite rate of death, PCI-related MI, urgent target vessel revascularization or in-hospital major bleeding within 48 h following PCI or hospital discharge.

Finally, the optimal timing of GPI administration (‘upstream’ versus ‘downstream’) in patients with ACS has been a topic of debate, given the paucity of trials designed to address this question. This was recently specifically assessed in the Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial [Giugliano et al. 2009] which analyzed routine upstream administration of eptifibatide (two boluses of 180 µg/kg administered 10 min apart, and a standard infusion ≥ 12 h before angiography) or placebo infusion versus provisional eptifibatide after angiography in patients with UA/NSTEMI invasively managed (n = 9492). This trial found no differences between groups in the primary ischemic end point (a composite of death, MI, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during PCI that required bolus therapy opposite to the initial study group assignment, ‘thrombotic bailout’, at 96 h): 9.3% of patients in the early-eptifibatide group versus 10.0% in the delayed-eptifibatide group (odds ratio 0.92; 95% CI 0.80–1.06; p = 0.23). At 30 days, the rate of death or MI was 11.2% in the early-eptifibatide group compared with 12.3% in the delayed-eptifibatide group (odds ratio 0.89; 95% CI 0.79–1.01; p = 0.08). A significantly higher rate of bleeding and red-cell transfusion in the early eptifibatide group was found, without significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events [Giugliano et al. 2009]. Parallel findings were observed in the Acute Catheterization and Urgent Intervention Triage strategy Timing (ACUITY Timing) analysis [Stone et al. 2007] designed to assess the noninferiority of deferred GPI versus upstream in prevention of ischemic events in moderate- and high-risk patients with ACS undergoing PCI (n = 9207). This trial showed no statistically significant differences in ischemic events at 20 days, 7.9% for in-lab versus 7.1% for upstream (relative risk 1.12; 95% CI 0.97–1.29; p = 0.044 for noninferiority; p = 0.13 for superiority). A significant reduction of 30-day rates of major bleeding (4.9% versus 6.1%, respectively; p < 0.001 for noninferiority; p = 0.009 for superiority) and similar rates of net clinical outcomes (11.7% versus 11.7%; p < 0.001 for noninferiority; p = 0.93 for superiority) were also found in the deferred use compared with upstream use [Stone et al. 2007]. These findings advocate against routine upstream GPI use, particularly if patients have been pretreated with a P2Y₁₂ receptor inhibitor (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012].

ST elevation myocardial infarction

GPIs have been widely studied in the setting of patients with STEMI undergoing primary PCI. In line with the enhanced thrombotic burden which characterizes these patients, GPIs have shown a clinical benefit in this setting. A meta-analysis of 11 randomized trials (n = 27,115) showed a significant decrease in the rate of reinfarction and mortality rates at 30 days [De Luca et al. 2005]. Most clinical experience with GPIs in the setting of patients with STEMI undergoing primary PCI is with abciximab. However, recent trials also support the benefit of eptifibatide and tirofiban which yield similar outcomes to abciximab [Akerblom et al. 2010; Ottani et al. 2010; De Luca et al. 2009].

The primary goal in STEMI is to obtain early reperfusion. This has led us to question whether early upstream use of GPIs as a facilitating strategy to early reperfusion can improve clinical outcomes. Indeed, very encouraging results from a series of pilot, small-sized studies evaluated the safety and efficacy of different protocols of facilitated PCI using GPI alone or in combination with a reduced-dose fibrinolytic [Eitel et al. 2010]. These studies analyzed surrogate markers of ischemic benefit, such as angiographic flow or ST-segment resolution. However, this was not confirmed in all studies. The Third Bavarian Reperfusion Alternatives Evaluation (BRAVE 3) trial [Mehilli et al. 2009] did not support the upstream use of abciximab in patients with STEMI within the last 24 h undergoing primary PCI pretreated with a high loading dose of clopidogrel (n = 800), not showing any reduction in the primary end point of infarct size (measured by single-photon emission computed tomography) before hospital discharge or the ischemic endpoint at 30 days [Mehilli et al. 2009]. Further, larger-scale clinical investigations have consistently failed to show any benefit of facilitated PCI, which was actually associated with increased risk of bleeding. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial [Ellis et al. 2008] evaluated the use of a facilitated pharmacologic strategy for reperfusion, with either abciximab alone or abciximab plus reduced-dose reteplase, in anticipation of urgent PCI for patients with STEMI presenting early (≤ 6 h) (n = 2452). This trial showed a significantly higher rate of early ST-segment resolution with combination-facilitated PCI (43.9%) compared with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; p = 0.01 and 0.003 respectively), but it did not find statistically significant differences among the three groups either in the occurrence of the primary end point (a composite of death from all causes, ventricular fibrillation occurring more than 48 h after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization) or 90-day mortality rates (5.2%, 5.5%, and 4.5% respectively; p = 0.49). An increase in the rates of bleeding, intracranial hemorrhage, and transfusions in the PCI-facilitated groups was observed. Even the rate of death (in all the groups) was associated with the grade of bleeding [18.2% with thrombolysis in myocardial infarction (TIMI) major bleeding, 6.1% with TIMI minor bleeding, and 2.6% with little or no bleeding; p < 0.001]. This study concluded that in STEMI neither facilitation strategy of PCI significantly improved the clinical outcomes compared with abciximab given at the time of PCI with an important increase in bleeding risk [Ellis et al. 2008]. Overall, these findings explain why a facilitated PCI is not recommended and considered a class III recommendation according to the majority of practice guidelines (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012]. However, a recent subanalysis of the FINESSE trial [Herrmann et al. 2009] of a small subgroup of patients with a TIMI risk score of at least 3 presenting to non-PCI hospitals within 4 h of symptom onset demonstrated a significantly better 1-year survival if treated with combination-facilitated PCI (p = 0.01) as well as 90-day composite outcome (p = 0.009). These findings suggested that facilitation of a PCI with a combination of abciximab and half-dose reteplase improved survival at 1 year in high-risk patients presenting to a hospital with symptom-to-randomization time up to 4 h. In line with this, the recent 2012 European guidelines for STEMI recommend (as a class IIb recommendation, level of evidence B) the upstream use (versus in-lab use) of GPIs in high-risk patients undergoing transfer for primary PCI (Table 2) [Steg et al. 2012].

Despite the proven efficacy of GPIs in the setting of primary PCI, high bleeding rates remain a concern. Similarly to patients with UA/NSTEMI, this has led us to investigate the effects of bivalirudin because of its more favorable safety profile in patients with STEMI undergoing primary PCI. The Harmonizing Outcomes with Revascularization and Stents in Acute myocardial Infarction (HORIZONS AMI) trial [Stone et al. 2008] showed that in patients with STEMI undergoing primary PCI (n = 3602), bivalirudin versus heparin plus GPI results in significantly decreased 30-day rates of major bleeding, with no trade-off in ischemic benefit, resulting in a significant decrease in net adverse clinical events. More importantly, bivalirudin was also associated with a significant reduction in mortality at 1 and 3 years, which is likely attributed to the protective effects associated with reduced bleeding complications [Mehran et al. 2009b; Stone et al. 2011]. The main concern with bivalirudin however is the increased risk of acute (<24 h) stent thrombosis, which appears to be mitigated with the early use of P2Y₁₂ inhibitors and upstream heparin bolus administration [Dangas et al. 2012].

These observations overall lead us to question the current role of GPIs in patients with STEMI undergoing primary PCI. In particular, questions that have emerged include the benefits associated with GPIs if given by intracoronary injection instead of systemically; if used as a bolus-only strategy; if used in conjunct with bivalirudin; and their role in the era of more potent P2Y₁₂ receptor inhibitors. The pivotal clinical trials analyzing these aspects are outlined below.

Several small-scale studies and meta-analyses have suggested the potential benefits of intracoronary over intravenous administration of abciximab [Gu et al. 2010; De Luca et al. 2012]. Given the inherent limitations to small-sized studies and meta-analyses, the larger-scale Abciximab Intracoronary versus Intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial [Thiele et al. 2012] was specifically designed to evaluate the safety and efficacy of intracoronary versus intravenous abciximab bolus (0.25 mg/kg bodyweight) during PCI with a subsequent 12 h intravenous infusion 0.125 μg/kg per min (maximum 10 μg/min). The trial randomized 2065 patients with recent STEMI (< 24 h) and failed to show statistical differences in the combined primary ischemic endpoint of all-cause mortality, recurrent MI, or new congestive heart failure at 90 days, although there was a reduction in reducing rates of congestive heart failure [Thiele et al. 2012]. Accordingly, current guidelines provide a weak recommendation for intracoronary GPI use (Table 2) [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012].

The role of the administration of a bolus only of a GPI was evaluated in the Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction (INFUSE AMI) trial [Stone et al. 2012]. This trial randomized high-risk patients within 4 h of STEMI undergoing primary PCI (n = 452) with bivalirudin anticoagulation in an open-label, 2 by 2 factorial design to bolus intracoronary abciximab delivered locally at the infarct lesion site versus no abciximab and to manual aspiration thrombectomy versus no thrombectomy. The trial demonstrated that an intracoronary bolus of abciximab delivered to the infarct lesion site significantly reduced infarct size at 30 days (assessed by cardiac magnetic resonance imaging) in patients with large anterior STEMI with bivalirudin anticoagulation in comparison with manual aspiration thrombectomy [Stone et al. 2012]. The role of GPIs in patients treated with prasugrel was evaluated in the Facilitation through Aggrastat by Dropping or Shortening Infusion Line in Patients with ST-segment Elevation Myocardial Infarction Compared to or on top of Prasugrel given at Loading Dose (FABOLUS PRO) trial [Valgimigli et al. 2012]. This trial evaluated patients with STEMI (n = 100) who randomly received prasugrel 60 mg versus 25 µg/kg tirofiban bolus with or without post-bolus 2 h infusion of tirofiban, with or without concomitant prasugrel. The primary endpoint was the inhibition of platelet aggregation (IPA) stimulated with 20 µmol/liter ADP at 30 min. The study concluded that prasugrel alone provides suboptimal platelet inhibition for at least 2 h in patients with STEMI and that prasugrel associated with a bolus only of tirofiban eludes the necessity of post-bolus infusion and practically eliminates residual variability of IPA after treatment, reaching the higher and more consistent IPA level after both agents [Valgimigli et al. 2012].

Practical considerations

The plethora of trial data on GPIs and emerging antithrombotic therapies in the setting of ACS and PCI has changed the landscape for the clinical use of these drugs. Therefore, after analyzing the most important clinical trials relevant to modern day clinical practice, we provide below our personal view on the optimal use of GPIs according to different clinical settings.

Stable coronary artery disease

In general, we agree with the current guidelines and believe that there is a limited role for the use of GPIs in patients with stable CAD undergoing elective PCI. However, recent trial data have shown that these patients have a very low risk of ischemic complications, particularly on a background of aspirin and clopidogrel therapy, which does not rationalize the increased bleeding risk associated with GPI.

Unstable angina or non-ST elevation myocardial infarction

In general, GPI use should be reserved for patients with UA/NSTEMI undergoing PCI, and has limited benefit in medically managed patients as reflected in current guidelines. Although, bivalirudin has emerged as a safer (i.e. lower risk of bleeding) treatment alternative, in our opinion GPI use remains a reasonable treatment to consider, particularly in high-risk patients with ACS and those with elevated cardiac biomarkers, not pretreated with a P2Y₁₂ receptor inhibitor. The more potent P2Y₁₂ receptor inhibitors (prasugrel and ticagrelor) should not prevent GPI use as these agents have different pharmacodynamic profiles and trial data have shown them to be of additive benefit irrespective of GPI use. Trial data do not support ‘routine’ upstream use of GPIs, which therefore should be started in the catheterization laboratory if deemed clinically indicated. However, we believe that upstream treatment is still a reasonable option if patients are not pretreated with a P2Y₁₂ receptor inhibitor.

ST-elevation myocardial infarction or primary percutaneous coronary intervention

According to the current guidelines, GPI use has shown to be beneficial in patients with STEMI undergoing primary PCI, although recent data have shown a mortality benefit with bivalirudin likely linked to the reduced bleeding risk. From our point of view, if a GPI is considered, this should be administered in the catheterization laboratory, as most trial data have not shown any benefit with upstream use (‘facilitation’ strategy). Intracoronary administration with standard infusion does not offer any benefit over systemic infusion, although a locally delivered bolus only intracoronary administration in adjunct to bivalirudin has proven beneficial.

Glycoprotein IIb/IIIa receptor inhibitors as a ‘bridging’ therapy

It is important to underscore that GPIs represent the only antiplatelet agents available for intravenous infusion. This has become particularly relevant for patients who require antiplatelet protection while awaiting surgery when GPIs have been considered as a ‘bridging’ strategy [Singla et al. 2012]. It is well established that dual antiplatelet therapy with aspirin and an oral P2Y₁₂ receptor inhibitor is the standard of care to prevent recurrent atherothrombotic events in patients with ACS and undergoing PCI [Wijns et al. 2010; Levine et al. 2011; Hamm et al. 2011; Jneid et al. 2012; Steg et al. 2012]. However, these patients have an increased risk of bleeding when undergoing surgical procedures, which is why discontinuation of antiplatelet therapy for a time period that allows recovery of platelet function is needed [Singla et al. 2012]. However, premature discontinuation of antiplatelet therapy in these settings has been associated with an increase in ischemic complications, including stent thrombosis. These findings underscore the need to define strategies of platelet inhibition that allow safe ‘bridging’ of patients to their surgical procedure with minimum risk of ischemic events or bleeding complications. Small-molecule GPIs have a very fast onset of action (immediate effect) and relatively quick offset of action (~4 h). These drugs have been studied in several registries and proven to be a plausible bridging option [Savonitto et al. 2010]. However, to date there are no randomized studies with GPIs in this setting. In the future, the clinical application of small-molecule GPIs as a bridging strategy for patients undergoing surgery requiring platelet blockade will likely depend on emerging antiplatelet agents under clinical investigation. To this extent cangrelor is an intravenous antiplatelet agent which selectively inhibits P2Y₁₂ receptor mediated signaling, thus representing a more natural bridging strategy characterized by very fast onset of action (immediate) and very fast offset (<60 min). This agent has been tested in a prospective randomized double-blind clinical trial and has been shown to be pharmacologically effective and safe [Angiolillo et al. 2012].

Conclusion

During the past decades numerous clinical trials have evaluated the role of GPIs in various settings of patients with CAD manifestations. The evolving landscape of antithrombotic pharmacotherapy has led to a less prominent role of GPIs in clinical treatment algorithms. However, GPIs still represent very important and useful agents, particularly for the treatment of high-risk patients with ACS undergoing PCI. Although other intravenous antiplatelet therapies are under investigation and may be of potential benefit in clinical practice, GPIs remain the only available antiplatelet therapy for intravenous infusion. Indeed, ongoing clinical trials will provide further insights into the role of GPIs as developments in the field of antithrombotic pharmacotherapy continue to expand.

Footnotes

Acknowledgements

Ana Muñiz-Lozano is a recipient of a training grant from the Spanish Society of Cardiology (‘Beca de la Sección de Cardiopatía Isquémica para Formación e Investigación Post Residencia en el Extranjero’, Sociedad Española de Cardiología).

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Dominick J. Angiolillo reports receiving honoraria for lectures from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichi Sankyo, Inc., Astra Zeneca; consulting fees from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Novartis, Accumetrics, Abbott Vascular, Astra Zeneca, Merck, Evolva; research grants from Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli Lilly Co., Daiichi Sankyo, Inc., The Medicines Company, Portola, Accumetrics, Astra-Zeneca, Eisai, Evolva. Ana Muñiz-Lozano, Fabiana Rollini and Francesco Franchi have no conflict of interest to report.

References

Akerblom

James

Koutouzis

Lagerqvist

Stenestrand

Svennblad

. (2010) Eptifibatide is noninferior to abciximab in primary percutaneous coronary intervention: results from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). J Am Coll Cardiol 56: 470–475.

Angiolillo

Firstenberg

Price

Tummala

Hutyra

Welsby

. (2012) Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 307: 265–274.

Angiolillo

Ueno

Goto

(2010) Basic principles of platelet biology and clinical implications. Circ J 74: 597–607.

Bhatt

Topol

(2000) Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 284: 1549–1558.

Biondi-Zoccai

Sciahbasi

Bodí

Fernández-Portales

Kanei

Romagnoli

. (2011) Right versus left radial artery access for coronary procedures: an international collaborative systematic review and meta-analysis including 5 randomized trials and 3210 patients. Int J Cardiol 20 December (Epub ahead of print).

Boersma

Harrington

Moliterno

White

Théroux

Van

Werf

. (2002) Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 359: 189–198.

Boersma

Simoons

(1997) Reperfusion strategies in acute myocardial infarction. Eur Heart J 18: 1703–1711.

Braunwald

Angiolillo

Bates

Berger

Bhatt

Cannon

. (2008) Antiplatelet strategies: evaluating their current role in the setting of acute coronary syndromes. Clin Cardiol 31: 2–9.

CAPTURE Study Investigators (1997) Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349: 1429–1435.

10.

Chew

Bhatt

Sapp

Topol

(2001) Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 103: 201–206.

11.

Coller

(1985) A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex. J Clin Invest 76: 101–108.

12.

Coller

Peerschke

Scudder

Sullivan

(1983) A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 72: 325–338.

13.

Cuisset

Frere

Quilici

Morange

Mouret

Bali

. (2008) Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. JACC Cardiovasc Interv 1: 649–653.

14.

Dangas

Claessen

Mehran

Brener

Brodie

Dudek

. (2012) Clinical outcomes following stent thrombosis occurring in-hospital versus out-of-hospital: results from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol 59: 1752–1759.

15.

Davì

Patrono

(2007) Platelet activation and atherothrombosis. N Engl J Med 357: 2482–2494.

16.

De Luca

Navarese

Cassetti

Verdoia

Suryapranata

(2011) Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy. Am J Cardiol 107: 198–203.

17.

De Luca

Suryapranata

Stone

Antoniucci

Tcheng

Neumann

. (2005) Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 293: 1759–1765.

18.

De Luca

Ucci

Cassetti

Marino

(2009) Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-analysis. J Am Coll Cardiol 53: 1668–1673.

19.

De Luca

Verdoia

Suryapranata

(2012) Benefits from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: a meta-analysis of 8 randomized trials. Atherosclerosis 222: 426–433.

20.

Eitel

Franke

Schuler

Thiele

(2010) ST-segment resolution and prognosis after facilitated versus primary percutaneous coronary intervention in acute myocardial infarction: a meta-analysis. Clin Res Cardiol 99: 1–11.

21.

Ellis

Tendera

de Belder

van Boven

Widimsky

Janssens

. (2008) Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 358: 2205–2217.

22.

EPIC Investigators (1994) Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 330: 956–961.

23.

EPILOG Investigators (1997) Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 336: 1689–1696.

24.

EPISTENT Investigators (1998) Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 352: 87–92.

25.

ESPRIT Investigators (2000) Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 356: 2037–2044.

26.

Freedman

(2005) Molecular regulation of platelet-dependent thrombosis. Circulation 112: 2725–2734.

27.

Fung

Saw

Starovoytov

Densem

Jokhi

Walsh

. (2009) Abbreviated infusion of eptifibatide after successful coronary intervention: the BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) randomized trial. J Am Coll Cardiol 53: 837–845.

28.

Giugliano

White

Bode

Armstrong

Montalescot

Lewis

. (EARLY ACS Investigators) (2009) Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 360: 2176–2190.

29.

Kampinga

Wieringa

Fokkema

Nijsten

Hillege

. (2010) Intracoronary versus intravenous administration of abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration: the Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) trial. Circulation 122:2709–2017.

30.

Halim

Rao

(2011) Bleeding and acute coronary syndromes: defining, predicting, and managing risk and outcomes. Curr Drug Targets 12: 1831–1835.

31.

Hamm

Bassand

Agewall

Bax

Boersma

Bueno

. (2011) ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 32: 2999–3054.

32.

Hamm

Heeschen

Goldmann

Vahanian

Adgey

Miguel

. (1999) Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels: c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study. N Engl J Med 340: 1623–1629.

33.

Heeschen

Hamm

Goldmann

Deu

Langenbrink

White

(1999) Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban: Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study. Lancet 354: 1757–1762.

34.

Herrmann

Brodie

Armstrong

Montalescot

Betriu

. (2009) Benefit of facilitated percutaneous coronary intervention in high-risk ST-segment elevation myocardial infarction patients presenting to nonpercutaneous coronary intervention hospitals. JACC Cardiovasc Interv 2: 917–924.

35.

Jneid

Anderson

Wright

Adams

Bridges

Casey

. (2012) 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 126: 875–910.

36.

Kastrati

Mehilli

Neumann

Dotzer

ten Berg

Bollwein

. (2006) Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 295: 1531–1538.

37.

Kastrati

Mehilli

Schuhlen

Dirschinger

Dotzer

ten Berg

. (2004) A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 350: 232–238.

38.

Kastrati

Neumann

Schulz

Massberg

Byrne

Ferenc

. (2011) Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. ISAR REACT 4 trial. N Engl J Med 365: 1980–1989.

39.

Kereiakes

Kleiman

Ambrose

Cohen

Rodriguez

Palabrica

. (1996) Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 27: 536–542.

40.

Levine

Bates

Blankenship

Bailey

Bittl

Cercek

. (2011) 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 58: 2550–25583.

41.

Libby

Theroux

(2005) Pathophysiology of coronary artery disease. Circulation 111: 3481–3488.

42.

Manoukian

Feit

Mehran

Voeltz

Ebrahimi

Hamon

. (2007) Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 49: 1362–1368.

43.

Mehilli

Kastrati

Schuhlen

Dibra

Dotzer

von Beckerath

. (2004) Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 110: 3627–3635.

44.

Mehilli

Kastrati

Schulz

Frungel

Nekolla

Moshage

. (2009) Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial. Circulation 119: 1933–1940.

45.

Mehran

Lansky

Witzenbichler

Guagliumi

Peruga

Brodie

. (2009a) Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 374: 1149–1159.

46.

Mehran

Pocock

Stone

Clayton

Dangas

Feit

. (2009b) Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 30: 1457–1466.

47.

O’Donoghue

Antman

Braunwald

Murphy

Steg

Finkelstein

. (2009) The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) analysis. J Am Coll Cardiol 54: 678–685.

48.

Ottani

La Vecchia

De Vita

Catapano

Tarantino

Galvani

. (2010) Comparison by meta-analysis of eptifibatide and tirofiban to abciximab in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 106: 167–174.

49.

PRISM-PLUS Study Investigators (1998) Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Qwave myocardial infarction: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 338: 1488–1497.

50.

PURSUIT Trial Investigators (1998) Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 339: 436–443.

51.

Pytela

Pierschbacher

Ginsberg

Plow

Ruoslahti

(1986) Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp-specific adhesion receptors. Science 231: 1559–1562.

52.

Roffi

Chew

Mukherjee

Bhatt

White

Heeschen

. (2001) Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment elevation acute coronary syndromes. Circulation 104: 2767–2771.

53.

Roffi

Chew

Mukherjee

Bhatt

White

Moliterno

. (2002) Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy. Eur Heart J 23: 1441–1448.

54.

Savonitto

D’Urbano

Caracciolo

Barlocco

Mariani

Nichelatti

. (2010) Urgent surgery in patients with a recently implanted coronary drug-eluting stent: a phase II study of ’bridging’ antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth 104: 285–291.

55.

Simoons

(2001) Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularization. The GUSTO IV-ACS randomised trial. Lancet 357: 1915–1924.

56.

Singla

Sachdeva

Uretsky

(2012) The risk of adverse cardiac and bleeding events following noncardiac surgery relative to antiplatelet therapy in patients with prior percutaneous coronary intervention. J Am Coll Cardiol 60: 2005–2016.

57.

Steg

James

Atar

Badano

Blömstrom-Lundqvist

Borger

. (2012) ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 33: 2569–2619.

58.

Stone

Bertrand

Moses

Ohman

Lincoff

Ware

. (2007) Routine upstream initiation vs. deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA 297: 591–602.

59.

Stone

Maehara

Witzenbichler

Godlewski

Parise

Dambrink

. (2012) Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI trial. JAMA 307: 1817–1826.

60.

Stone

McLaurin

Cox

Bertrand

Lincoff

Moses

. (2006) Bivalirudin for patients with acute coronary syndromes. N Engl J Med 355: 2203–2216.

61.

Stone

Witzenbichler

Guagliumi

Peruga

Brodie

Dudek

. (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358: 2218–2230.

62.

Stone

Witzenbichler

Guagliumi

Peruga

Brodie

Dudek

. (2011) Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 377: 2193–2204.

63.

Thiele

Wöhrle

Hambrecht

Rittger

Birkemeyer

Lauer

. AIDA STEMI Trial Team (2012) Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial. Lancet 379: 923–931.

64.

Topol

GUSTO V Investigators (2001a) Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 357: 1905–1914.

65.

Topol

Byzova

Plow

(1999) Platelet GP IIb-IIIa blockers. Lancet 353: 227–231.

66.

Topol

Moliterno

Herrmann

Powers

Grines

Cohen

. (2001b) Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 344: 1888–1894.

67.

Valgimigli

Biondi-Zoccai

Tebaldi

van’t Hof

Campo

Hamm

. (2010) Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coronary intervention: a meta-analysis of randomized trials. Eur Heart J 31: 35–49.

68.

Valgimigli

Campo

de Cesare

Meliga

Vranckx

Furgieri

. (2009) Intensifying platelet inhibition with yirofiban in poor responders to ASA, clopidogrel, or both agents undergoing elective coronary intervention: results from the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to ASA and/or Resistance to Clopidogrel Study. Circulation 119: 3215–3222.

69.

Valgimigli

Tebaldi

Campo

Gambetti

Bristot

Monti

. (2012) Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By Dropping or Shortening Infusion Line in Patients with ST-segment Elevation Myocardial Infarction Compared to or on top of Prasugrel given at Loading Dose) trial. JACC Cardiovasc Interv 5: 268–277.

70.

Wagner

Mascelli

Neblock

Weisman

Coller

Jordan

. (1996) Analysis of GP IIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 88: 907–914.

71.

Wallentin

Becker

Budaj

Cannon

Emanuelsson

Held

. (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361: 1045–1057.

72.

Wijns

Kolh

Danchin

Di Mario

Falk

Folliguet

. (2010) Guidelines on myocardial revascularization. Eur Heart J 31: 2501–2555.

73.

Wiviott

Braunwald

McCabe

Montalescot

Ruzyllo

Gottlieb

. (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357: 2001–2015.

Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice

Abstract

Keywords

Introduction

Glycoprotein IIb/IIIa receptor inhibitors: basic pharmacology

Pivotal clinical trials

Stable coronary artery disease

Unstable angina/non-ST-elevation myocardial infarction

ST elevation myocardial infarction

Practical considerations

Stable coronary artery disease

Unstable angina or non-ST elevation myocardial infarction

ST-elevation myocardial infarction or primary percutaneous coronary intervention

Glycoprotein IIb/IIIa receptor inhibitors as a ‘bridging’ therapy

Conclusion

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References