Glycoprotein IIb/IIIa receptor inhibitor-thrombolytic combination therapy for acute myocardial infarction

Over the past two decades, we have witnessed a large decrease in the death and complication rate of patients experiencing acute myocardial infarction (MI), due to our ability to restore blood flow to infarct-related arteries. Therapies include strategies to inhibit platelet function and induce fibrinolysis, and mechanical reperfusion with percutaneous intervention. Despite decreases in morbidity and mortality with thrombolytic therapy, reperfusion rates remain less than optimal. With standard fibrinolytic therapy in combination with aspirin, it is thought that thrombolyticinduced platelet activation may be an important reason for failure to induce perfusion, or maintain reperfusion in the infarct-related artery. In the past 10 years we have moved from platelet inhibition with aspirin to newer, more potent platelet inhibitors such as glycoprotein (GP) IIb/IIIa antagonists. Recent trials have evaluated the efficacy and safety of combining thrombolytic drugs with GP IIb/IIIa receptor antagonists. Future trends may use combination therapy as a part of a mechanical strategy, using these medications to induce early reperfusion as the patient is prepared for percutaneous intervention. This review summarizes recently published trials using combination thrombolytic and GP IIb/ IIIa receptor inhibitor therapy in the treatment of acute MI.     

Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: results of the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) Trial

Objectives. The trial was designed to assess the safety, pharmacodynamics and effects on reperfusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor lamifiban when given with thrombolysis to patients with ST segment elevation acute myocardial infarction.

Background. Studies of fibrinolytic agents in acute myocardial infarction have demonstrated a direct relationship between early complete reperfusion and survival. Blockade of the platelet GP IIb/IIIa receptor complex inhibits platelet aggregation and may speed reperfusion when given in conjunction with thrombolysis to patients with acute myocardial infarction.

Methods. Patients with ST segment elevation presenting within 12 h of symptom onset who were treated with either tissue-plasminogen activator or streptokinase were enrolled in this three-part Phase II dose exploration study. In Part A, all patients received the GP IIb/IIIa inhibitor lamifiban in an open-label, dose escalation scheme. Parts B and C were a randomized, double-blind comparison of a bolus plus 24-h infusion of lamifiban versus placebo with patients randomized in a 2:1 ratio. The goal was to identify a dose(s) of lamifiban that provided >85% adenosine diphosphate (ADP)-induced platelet aggregation inhibition. A composite of angiographic, continuous electrocardiographic and clinical markers of reperfusion was the primary efficacy end point, and bleeding was the primary safety end point.

Results. Platelet aggregation was inhibited by lamifiban in a dose-dependent manner with the highest doses exceeding 85% ADP-induced platelet aggregation inhibition. There was more bleeding associated with lamifiban (transfusions in 16.1% lamifiban-treated vs. 10.3% placebo-treated patients). Lamifiban induced more rapid reperfusion as measured by all continuous electrocardiographic (ECG) parameters.

Conclusions. Lamifiban given with thrombolytic therapy appears to be associated with more rapid and complete reperfusion than placebo. As expected in this small sample, there were no obvious clinical benefits to lamifiban over placebo. Reconciliation of ECG monitoring with clinical outcomes will require a larger, adequately powered clinical trial.     

Antiplatelet Therapy in AMI: Combining GP IIb/IIIa Inhibition with Reduced-dose Fibrinolytic Therapy

In the therapy of ST-segment elevation myocardial infarction (MI), the close relationship between early reperfusion of the infarct-related artery and improved outcomes has focused research on improving the speed and efficacy of pharmacologic reperfusion therapy. Recently, it has become appreciated that even among patients who achieve normal epicardial reperfusion after reperfusion therapy, myocardial and microvascular perfusion may be inadequate. Such patients are at increased risk for the development of death and congestive heart failure. The addition of glycoprotein (GP) IIb/IIIa antagonists to standard fibrinolytic therapy has been shown to improve both epicardial and myocardial reperfusion. This article focuses on emerging data regarding the combination of GP IIb/IIa antagonists and standard fibrinolytic agents for the treatment of acute ST-segment elevation MI.     

GP IIb/IIIa inhibitors during primary percutaneous coronary intervention for STEMI: New trial and registry data

Primary percutaneous coronary intervention (PCI) with adjunctive glycoprotein (GP) IIb/IIIa receptor inhibitor therapy administered in the cardiac catheterization laboratory is the optimal reperfusion strategy for patients with ST-elevation myocardial infarction. Most available data regarding these agents are from trials comparing abciximab to placebo alone. Noninferiority trials comparing small-molecule GP IIb/IIIa receptor inhibitors, such as tirofiban and eptifibatide with abciximab, have used markers for myocardial reperfusion as primary end points but are underpowered to detect significant differences in hard clinical outcomes. Such a trial would need to enroll a very large number of patients and thus make it practically impossible to perform. Registry data reveal that most patients undergoing primary PCI are treated with small-molecule GP IIb/IIIa receptor inhibitors in clinical practice, and no observed difference is observed in safety and efficacy when compared with patients treated with abciximab therapy.     

Bridging the Gap with New Strategies in Acute ST Elevation Myocardial Infarction: Bolus Thrombolysis,Glycoprotein IIb/IIIa Inhibitors,Combination Therapy,Percutaneous Coronary Intervention,and “Facilitated” PCI

Achieving early reperfusion with thrombolytic agents or primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) is the cornerstone of current therapy. Two advances in pharmacologic therapy are: (1) bolus thrombolysis, which simplifies therapy, reduces door-to-needle time, and reduces the potential for medication errors, and (2) Low-dose fibrinolytic therapy combined with a glycoprotein (GP) IIb/IIIa inhibitor which can achieve higher rates of reperfusion than fibrinolytic therapy alone. In addition, the IIb/IIIa inhibitor as part of the reperfusion regimen will support any acute-phase interventions that are performed. The combination of fibrinolytic therapy and GP IIb/IIIa inhibition to facilitate PCI is being examined in TIMI-14, SPEED, and GUSTO IV. Early findings in the SPEED trial have shown promising results with facilitated PCI when patency is achieved before PCI is attempted. Results of these trials will further define the role of combination therapy in facilitating mechanical interventions.     

Update on Glycoprotein IIb/IIIa Blockade in Endovascular Interventions

Platelet aggregation plays a central role in the ischemic complications of percutaneous coronary interventions (PCI) and the acute coronary syndromes (ACS). Although aspirin and heparin have been effective at decreasing adverse events in these settings, the perceived need for more potent inhibition of platelet aggregation has led to targeting of the platelet surface membrane glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Several agents have been developed; four: abciximab, tirofiban, eptifibatide, and lamifiban have been tested in clinical trials. Overall, the positive findings of these studies have supported the hypothesis that enhanced platelet blockade leads to improved clinical outcomes in the settings of PCI and ACS. In this article, an overview of the various GP IIb/IIIa receptor inhibitors is presented. The clinical trials of these agents as adjunctive therapy for patients undergoing PCI and in treatment of acute myocardial infarction are reviewed. Practical considerations relating to clinical efficacy, drug safety, and economic issues are discussed.     

Platelet glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction

There are many limitations to reperfusion therapy for acute myocardial infarction. Preliminary studies have explored the potential of using more potent antiplatelet therapy. Abciximab, eptifibatide, and lamifiban are new agents that inhibit platelet glycoprotein IIb/IIIa, which serves as the final common pathway for platelet aggregation. Infarct artery patency occurs more rapidly, normal coronary blood flow is more often restored, and reperfusion is more stable when these agents are used with standard- or reduced-dose fibrinolytic therapy. Moreover, abciximab monotherapy has thrombolytic activity and facilitates primary angioplasty or stenting. Further studies are needed to define safety, efficacy, and cost effectiveness.     

Systematic review of fibrinolytic-facilitated percutaneous coronary intervention: Potential benefits and future challenges

BACKGROUND:

Facilitated percutaneous coronary intervention (PCI) is defined as the administration of fibrinolytic therapy and/or glycoprotein (GP) IIb/IIIa inhibitors to minimize myocardial ischemia time while waiting for PCI. A pooled meta-analysis suggested that facilitated PCI was associated with higher rates of mortality and morbidity compared with nonfacilitated PCI.

OBJECTIVE:

The heterogeneous and complex trials of facilitated PCI were systematically reviewed to identify where this strategy may be beneficial and deserving of further research.

METHODS:

MEDLINE, EMBASE, the Cochrane database, the Internet and conference proceedings were searched to obtain relevant trials. Human studies that randomly assigned patients to fibrinolytic-facilitated PCI (administration of fibrinolytic therapy alone or in combination with GP IIb/IIIa inhibitors before angiography) versus nonfacilitated PCI were included.

RESULTS:

Nine trials encompassing 3836 patients were reviewed. The facilitated PCI strategy was fibrinolytic therapy alone in seven trials and half-dose fibrinolytic therapy plus GP IIb/IIIa inhibitors in two trials. In patients who had fibrinolysis less than 2 h after symptom onset (mainly in the prehospital setting) and/or slightly delayed PCI 3 h to 24 h after fibrinolysis, facilitated PCI was associated with the greatest Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow and a trend toward reduced mortality. Overall, facilitated PCI was associated with increased intracranial hemorrhage and reinfarction. Combining half-dose fibrinolytic therapy and GP IIb/IIIa inhibitors reduced reinfarction but increased major bleeding.

CONCLUSIONS:

Facilitated PCI cannot be recommended outside of experimental protocols at this time. Further research should focus on selecting patients with higher benefit-to-risk ratios and performing prehospital fibrinolysis with optimal antiplatelet or antithrombin therapy, as well as slightly delayed PCI in patients who are stable or geographically removed from PCI facilities.     

Contemporary management of ST elevation myocardial infarction

Management of acute ST elevation myocardial infarction (MI) has become increasingly complex. Third-generation fibrinolytic agents have provided simpler bolus administration and enhanced arterial patency rates but have not lowered mortality. Prehospital fibrinolysis reduces time to treatment, and studies continue to better define the clinical benefits. Combining glycoprotein (GP) IIb/IIIa inhibitors with reduced-dose fibrinolytic therapy thus far has not reduced mortality; improvements in secondary outcomes such as recurrent infarction have been offset by increases in bleeding complications, particularly in elderly patients. In contrast to fibrinolytic trial results, outcomes are improved in patients who promptly undergo primary percutaneous coronary intervention (PCI). Meta-analyses demonstrate a significant reduction in mortality compared with patients who receive fibrinolytic therapy. Accessibility of primary intervention remains an important limitation, although recent trials suggest superiority of intervention even when hospital transfer is necessary. Conflicting trends include the development of regional centers for interventional treatment of MI as well as the dissemination of limited interventional programs to smaller hospitals. Facilitated PCI, a hybrid of pharmacological reperfusion (typically combination therapy) followed by intervention, may bridge the delay when primary intervention is not immediately available. Optimal therapy for acute MI must be individualized based on both patient characteristics and resource availability.     

Current perspectives on reperfusion therapy for acute ST-segment elevation myocardial infarction: integrating pharmacologic and mechanical reperfusion strategies

The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.     

Glycoprotein IIb/IIIa inhibition in the setting of acute ST-segment elevation myocardial infarction

Glycoprotein (GP) IIb/IIIa inhibitors have been extensively studied in the setting of percutaneous coronary intervention (PCI) and in the management of non-ST-segment elevation acute coronary syndromes. However, the use of GP IIb/IIIa inhibitors is less well established in the setting of acute ST-segment elevation myocardial infarction (MI). Multiple nonrandomized studies suggest that combination therapy with GP IIb/IIIa inhibitors and thrombolytic agents leads to increased rates of TIMI 3 flow. However, two clinical trials involving over 22,000 patients demonstrated that combination therapy is associated with only modest reductions in major adverse cardiac events, does not reduce mortality, and is associated with an increase in bleeding. In the setting of primary PCI, four clinical trials involving over 3,000 patients demonstrated that GP IIb/IIIa inhibition results in a significant decrease in the need for urgent target vessel revascularization but not in reductions of death or recurrent MI. Thus, GP IIb/IIIa inhibition may provide only limited benefits in the setting of acute ST-segment elevation MI.     

A Review of Clinical Trials with Eptifibatide in Cardiology

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit the binding of ligands to activated platelet GP IIb/IIIa receptors and, therefore, prevent the formation of platelet thrombi. Additional antithrombin therapy should be given in connection with GP IIb/IIIa administration. Eptifibatide is a small heptapeptide, which is highly selective and rapidly dissociates from its receptor after cessation of therapy. In clinical trials (IMPACT‐II and ESPRIT) concomitant administration of eptifibatide to patients undergoing percutaneous coronary intervention (PCI) reduced thrombotic complications. In the PURSUIT trial, in patients with non‐ST‐elevation acute coronary syndromes, eptifibatide, compared to placebo, significantly reduced the primary endpoint of death and nonfatal myocardial infarction at 30 days. In patients with STEMI eptifibatide has been studied as an adjunct to fibrinolysis and primary PCI; it improved epicardial flow and tissue reperfusion. Current studies are evaluating eptifibatide as upstream therapy in high‐risk patients with NSTE‐ACS, in the EARLY‐ACS and in comparison with abciximab in patients with primary PCI in the EVA‐AMI trial.     

Platelet activation in acute myocardial infarction and the rationale for combination therapy

Current fibrinolytic regimens fail to fully restore coronary blood flow in slightly less than 50% of patients with acute myocardial infarction. Platelet activation and aggregation may be responsible for a large proportion of these therapeutic failures. Therefore, platelet inhibition may enhance thrombolysis. Experimental and early clinical evidence suggest that glycoprotein IIb/IIIa antagonists may enhance reperfusion when combined with reduced doses of thrombolytic agents. However, the clinical benefit of combination therapy will depend on the outcomes of a number large clinical trials that are currently being performed.     

Overcoming thrombolytic resistance: rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction.

OBJECTIVES: We sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI). BACKGROUND: Although thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the "thrombolytic ceiling" in infarct-related artery (IRA) patency. METHODS: Recent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed. RESULTS: A new approach toward improving current thrombolytic-antithrombotic regimens focuses on "targeted therapy" for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk. CONCLUSIONS: Given the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming "thrombolytic resistance."     

Small peptide GP IIb/IIIa receptor inhibitors as upstream therapy in non-ST-segment elevation acute coronary syndromes: results of the PURSUIT, PRISM, PRISM-PLUS, TACTICS, and PARAGON trials.

The primary pathophysiologic mechanism underlying all non-ST-segment elevation acute coronary syndromes (NSTE ACS) is the formation of platelet-rich coronary thrombi in response to spontaneous or intervention-induced endothelial damage with exposure of subendothelial substrates. Antagonists of the glycoprotein (GP) IIb/IIIa receptor ameliorate this process by blocking the final common pathway for platelet aggregation. Based upon collective data in over 24,000 patients, clinical trials have demonstrated that treatment of NSTE ACS patients with GP IIb/IIIa agents results in an approximate 12% relative risk reduction in the incidence of death or myocardial infarction at 30 days. The magnitude of this clinical benefit is increased in patients who are troponin-positive and who are referred for early percutaneous intervention. Potential benefits of GP IIb/IIIa inhibitor use must be weighed against an increased risk of bleeding. Ongoing controversies exist concerning the relative efficacy of different GP IIb/IIIa antagonists, the accurate use of platelet function tests to define safe and efficacious drug dosing, the adjunctive use of additional anti-thrombotic agents, and the optimal timing of upstream therapy before diagnostic cardiac catheterization and revascularization.     

Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention

BACKGROUND: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting. METHODS AND RESULTS: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab. CONCLUSIONS: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.     

Multimodality reperfusion therapy for acute myocardial infarction

With the strong and direct relation between early reperfusion in acute myocardial infarction (AMI) and improved clinical outcomes, attention has focused on new means of improving rates of reperfusion and accelerating every stage of AMI evaluation and management, from the onset of symptoms of myocardial infarction to the achievement of reperfusion. Critical pathways to streamline the evaluation and management of AMI have cut minutes and even hours off in-hospital treatment times for patients with AMI; public health initiatives focus on educational efforts to shorten time to hospital arrival. The latest advance in fibrinolytic therapy is the availability of bolus fibrinolytic agents with safety and efficacy in large phase III trials comparable to accelerated intravenous infusion regimens. Faster and simpler fibrinolytic regimens may shorten door-to-needle time, reduce medication errors, and facilitate prehospital thrombolysis. Bolus fibrinolytic agents are being evaluated for use in combination with other interventions to open occluded coronary arteries, including acute percutaneous coronary intervention, the glycoprotein IIb/IIIa platelet inhibitors, or both. The goal of this "multimodality" approach to AMI management is to minimize time to reperfusion and maximize the percentage of patients who achieve complete arterial patency and myocardial perfusion without bleeding complications.     

Glycoprotein IIb/IIIa antagonism and fibrinolytic therapy for acute myocardial infarction

Fibrinolytic therapy for the treatment of ST-segment elevation myocardial infarction unquestionably reduces mortality when administered within 12 hours of symptom onset. By promptly restoring antegrade perfusion, infarct size is limited, ventricular function is less compromised, and mortality rates are lowered. Although fibrinolytic therapy initially restores antegrade flow in the infarct vessel in the majority of patients, sustained, tissue-level reperfusion occurs in only approximately one fourth of patients. Thrombin and platelets associated with a coronary thrombus are not specifically targeted by fibrinolytic agents, but rather have paradoxically increased activity. These components contribute to the tendency for vessel reocclusion after initially successful reperfusion. Thus, adjunctive therapy with antithrombins and antiplatelet agents are essential in the successful treatment of a coronary thrombus. Although aspirin has been shown to reduce mortality in acute myocardial infarction, it is a weak antiplatelet agent that is pathway specific. Glycoprotein IIb/IIIa inhibitors are potent antiplatelet agents that block the final common pathway for platelet aggregation. Thus, the growing evidence of platelet preeminence in the pathophysiology of failed thrombolysis has lead to the study of combination drug therapy with glycoprotein IIb/IIIa inhibition and reduced dose fibrinolytic agents in the treatment of acute ST-segment elevation myocardial infarction. This article reviews the rationale, results, and clinical implications of the major trials of combination drug therapy in acute myocardial infarction.     

Early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocardial infarction: observations from the National Registry of Myocardial Infarction 4

OBJECTIVES: We sought to identify patient and hospital features associated with early glycoprotein (GP) IIb/IIIa inhibitor therapy for non-ST-elevation (NSTE) myocardial infarction (MI) and to relate this treatment to in-hospital outcomes. BACKGROUND: Glycoprotein IIb/IIIa inhibitors have improved outcomes in randomized trials of NSTE MI, leading national treatment guidelines to recommend their use. Their actual use, safety, and effectiveness have not been well characterized beyond trial populations. METHODS: We studied 60,770 patients with NSTE MI treated between July 2000 and July 2001 at 1,189 hospitals in a U.S. registry. Using logistic regression, we identified patient and hospital features associated with GP IIb/IIIa inhibition within 24 h after presentation. We also compared outcomes by early treatment versus no treatment after adjusting for patient and hospital characteristics and treatment propensity. RESULTS: Only 25% of eligible patients received early GP IIb/IIIa therapy. Elderly patients, women, minority patients, and those without private insurance received such therapy less often than their counterparts. Treated patients had lower unadjusted in-hospital mortality (3.3% vs. 9.6%, p < 0.0001) remaining significantly lower after adjustment for patient risk, treatment propensity, and hospital characteristics (adjusted odds ratio, 0.88; 95% confidence interval, 0.79 to 0.97). Hospitals that adopted early GP IIb/IIIa inhibition more rapidly also had lower adjusted mortality rates than those slower to adopt such therapy. CONCLUSIONS: Glycoprotein IIb/IIIa inhibitor therapy appears to be underused in early management of NSTE MI patients. Because this therapy is associated with better outcomes, it represents a target for quality improvement.     

Combination antiplatelet treatment in coronary artery disease patients: A necessary evil or an overzealous practice?

In seeking to improve care in coronary artery disease patients, further platelet inhibition has been occasionally applied beyond that provided by aspirin and a P2Y₁₂ receptor antagonist. This review aims to offer insights about the rationale, the efficacy and safety of combination antiplatelet therapy, involving three or more agents. Overall, the use of glycoprotein (GP) IIb/IIIa inhibitors did not significantly modify the treatment effect of different antiplatelet strategies, including double vs standard clopidogrel, prasugrel vs clopidogrel, ticagrelor vs clopidogrel, cangrelor vs clopidogrel, and vorapaxar vs placebo. With the caveat that the use of GP IIb/IIIa inhibitor was not randomized, adding such an agent to aspirin and a P2Y₁₂ receptor antagonist appears to carry a significantly increased bleeding potential. Moreover, adding vorapaxar to aspirin- and clopidogrel-treated patients is associated with more bleeding events, while the bleeding potential is further exacerbated in cases of quadruplicate antiplatelet treatment including aspirin, clopidogrel, vorapaxar, and a GP IIb/IIIa inhibitor. In ST-segment elevation, myocardial infarction patients’ administration of an intravenous antiplatelet agent (GP IIb/IIIa inhibitor or cangrelor), in addition to aspirin and a P2Y₁₂ receptor antagonist, efficiently bridges the pharmacodynamic gap of oral agents. Cilostazol on top of aspirin and clopidogrel appears to be safe, although of questionable clinical benefit. In conclusion, combination antiplatelet therapy should be reserved only for selected cases and following thoughtful consideration of the associated risk/benefit ratio.