Common Pathway Of Platelet Aggregation Research Articles

Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use.

Oral antiplatelet drugs are crucially important for patients with acute coronary syndrome or stable coronary artery disease undergoing percutaneous coronary intervention (PCI). In recent decades, several clinical trials have focused on reducing periprocedural ischemic events in patients undergoing PCI by means of more rapid platelet inhibition with the use of intravenous antiplatelet drugs. Glycoprotein IIb/IIIa receptor inhibitors (GPIs) block the final common pathway of platelet aggregation and enable potent inhibition in the peri-PCI period. In recent years, however, the use of GPIs has decreased due to bleeding concerns and the availability of more potent oral P2Y12 inhibitors. Cangrelor is an intravenous P2Y12 receptor antagonist. In a large-scale regulatory trial, cangrelor administration during PCI allowed for rapid, potent and rapidly reversible inhibition of platelet aggregation, with an anti-ischemic benefit and no increase in major bleeding. This article aims to provide an overview of general pharmacology, supporting evidence and current status of intravenous antiplatelet therapies (GPIs and cangrelor), with a focus on contemporary indications for their clinical use.

Norcantharidin, a clinical used chemotherapeutic agent, acts as a powerful inhibitor by interfering with fibrinogen-integrin αIIb β3 binding in human platelets.

During platelet activation, fibrinogen binds to its specific platelet receptor, integrin αII bβ3, thus completing the final common pathway for platelet aggregation. Norcantharidin (NCTD) is a promising anticancer agent in China from medicinal insect blister beetle. In this study, we provided the evidence to demonstrate NCTD (0.1–1.0 μM) possesses very powerful antiplatelet activity in human platelets; nevertheless, it had no effects on surface P‐selectin expression and only slight inhibition on ATP‐release reaction in activated platelets. Moreover, NCTD markedly hindered integrin αII bβ3 activation by interfering with the binding of FITC‐labelled PAC‐1. It also markedly reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as clot retraction. Additionally, NCTD attenuated phosphorylation of proteins such as integrin β3, Src and FAK in platelets spreading on immobilized fibrinogen. These results indicate that NCTD restricts integrin αII bβ3‐mediated outside‐in signalling in human platelets. Besides, NCTD substantially prolonged the closure time in human whole blood and increased the occlusion time of thrombotic platelet plug formation and prolonged the bleeding time in mice. In conclusion, NCTD has dual activities, it can be a chemotherapeutic agent for cancer treatment, and the other side it possesses powerful antiplatelet activity for treating thromboembolic disorders.

A comparative study of tirofiban plus enoxaparin versus enoxaparin alone along with dual antiplatelet blockade in the management of patients with non-ST elevation acute coronary syndrome

Introduction: Antithrombotic therapy in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) includes dual antiplatelet therapy (DAPT) along with enoxaparin. However, resistance to antiplatelet action of aspirin and clopidogrel is well known and is about 27% (0-57%) and 30%, respectively. Hence the use of GPIIb/IIIa inhibitor appears to be a reasonable option as they act on the final common pathway of platelet aggregation. Though frequently used in patients undergoing percutaneous intervention (PC1), their use in patients not undergoing such procedure is not popular despite evidence in literature. Materials and Methods: This study was done on 44 patients of NSTE-ACS managed conservatively. The patients were randomized in a 1:1 fashion in two groups. The patients in group 1 received tirofiban(0.4μg/kg/min i.v for 30 min followed by 0.1μg/kg/min for 48 hours) in addition to aspirin (325 mg stat followed by 75 mg P.O. daily), clopidogrel (300 mg stat followed by 75 mg P.O. daily) and enoxaparin (1 mg/kg S.C bid for 5 days). The group 2 patients received DAPT and enoxaparin only, in similar doses. Both the groups received antianginal therapy as appropriate and statins. Results: The study showed the benefits of adding tirofiban to enoxaparin and DAPT irrespective of age, sex, presence or absence of diabetes and dyslipidemia, ECG changes, troponin positivity and TIMI score in patients with NSTE-ACS. There was a significant reduction {Risk reduction (RR) of 45.4% P Conclusion: Thus, we conclude that tirofiban in addition to DAPT and enoxaparin reduces the risk of refractory ischemia, MI and death in patients with NSTE-ACS without any additional risk of major or minor bleeding. Therefore, we advocate this regimen in patients with NSTE-ACS managed conservatively. Large randomized study is needed to recommend this regimen.

Current Role of Platelet Glycoprotein IIb/IIIa Inhibition in the Therapeutic Management of Acute Coronary Syndromes in the Stent Era

The pathophysiology of acute coronary syndromes (ACS) is characterized by disruption of atherosclerotic plaques, activation and aggregation of platelets, and formation of an arterial thrombus. Thrombus formation can result in either transient or persistent occlusion giving rise to the spectrum of ACS. This syndrome defines rapidly evolving symptoms of myocardial ischemia ranging from unstable angina pectoris to non-Q-wave myocardial infarction to Q-wave myocardial infarction. An early pharmacological strategy to reduce ischemic complications of PCI was the use of parenteral glycoprotein (GP) IIb/IIIa inhibitors. The benefit of GP IIb/IIIa inhibitors in early studies was driven primarily by reductions in periprocedural myocardial infarction. Advances in both stent design and adjunct pharmacology have led to improved outcomes in ACS and a diminished role for GP IIb/IIIa inhibitors as reflected in current PCI guidelines. Current medical therapy with aspirin, clopidogrel, ticagrelol, prasugrel, and heparin provides important therapeutic benefits. The platelet GP IIb/IIIa receptor antagonists, by blocking the final common pathway of platelet aggregation, are a breakthrough in the management of ACS. Several large multicenter trials have evaluated the platelet GP IIb/IIIa antagonists with and without heparin undergoing PCI or not. There was a significantly reduced incidence in the cardiac ischemic events. The clinically important benefit persisted at 3 years of followup. In addition to maintaining epicardial wall vessel patency, it was shown an improvement in microvascular perfusion and myocardial function as assessed by peak coronary flow velocity and regional wall motion. Despite the success of abciximab in preventing ischemic events after PCI, the use of intravenous, small-molecule GP IIb/IIIa antagonists, and the intention to broaden the clinical indication have produced varied results. Mechanisms contributing to these heterogeneous outcomes may include the possibility of prothrombotic events, as well as, normal variation in platelet or receptor number, differences in receptor activity, and interpatient variation in pharmacological dose response. Trials investigating the role of intravenous small-molecule GP IIb/IIIa antagonists underline the importance of adequate higher and effective dosing. These trials highlight the use of suboptimal dose as the cause for the poor outcome in some instances. Despite the heterogeneous outcome, these agents still have potential advantages in patients with high clinical risk but low bleeding risk. Adjunctive platelet GP IIb/IIIa receptor inhibition has proved beneficial effects in the setting of PCI, and still has a place as bailout therapy for periprocedural PCI complications in ACS patients, such as those patients with large thrombus, with stent thrombosis, and refractory no-reflow phenomenon following PCI.

Discovery of novel antagonists of glycoprotein IIb/IIIa-mediated platelet aggregation through virtual screening.

The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking thrombus formation. RUC-2 is a novel glycoprotein IIb/IIIa inhibitor of adenosine-5'-diphosphate (ADP)-induced platelet aggregation, importantly which exhibits a unique mode of binding with respect to classical Arg-Gly-Asp (RGD)-based glycoprotein IIb/IIIa antagonists. To identify new chemotypes that inhibit glycoprotein IIb/IIIa-mediated platelet aggregation like RUC-2, we performed a combination of structure-based pharmacophore screening and structure-based virtual screening approach to screen over 7.3 million small molecules based on the RUC-2-glycoprotein IIb/IIIa crystal structure. Three of the eleven hit compounds identified by virtual screening showed promising activity with IC50 values between 16.9 and 90.6μmolL(-1) in a human platelet aggregation assay induced by ADP and thrombin. The binding conformations of these three were analyzed to provide a rationalization of their activity profile. These compounds may serve as potential novel scaffolds for further development of glycoprotein IIb/IIIa antagonists.

Clinical and economic studies of eptifibatide in coronary stenting.

Platelet adhesion and aggregation at the site of coronary stenting can have catastrophic clinical and economic consequences. Therefore, effective platelet inhibition is vital during and after percutaneous coronary intervention. Eptifibatide is an intravenous antiplatelet agent that blocks the final common pathway of platelet aggregation and thrombus formation by binding to glycoprotein IIb/IIIa receptors on the surface of platelets. In clinical studies, eptifibatide was associated with a significant reduction of mortality, myocardial infarction, or target vessel revascularization in patients with acute coronary syndrome undergoing percutaneous coronary intervention. However, recent trials conducted in the era of dual antiplatelet therapy and newer anticoagulants failed to demonstrate similar results. The previously seen favorable benefit of eptifibatide was mainly offset by the increased risk of bleeding. Current American College of Cardiology/American Heart Association guidelines recommend its use as an adjunct in high-risk patients who are undergoing percutaneous coronary intervention with traditional anticoagulants (heparin or enoxaparin), who are not otherwise at high risk of bleeding. In patients receiving bivalirudin (a newer safer anticoagulant), routine use of eptifibatide is discouraged except in select situations (eg, angiographic complications). Although older pharmacoeconomic studies favor eptifibatide, in the current era of P2Y12 inhibitors and newer safer anticoagulants, the increased costs associated with bleeding make the routine use of eptifibatide an economically nonviable option. The cost-effectiveness of eptifibatide with the use of strategies that decrease the bleeding risk (eg, transradial access) is unknown. This review provides an overview of key clinical and economic studies of eptifibatide well into the current era of potent antiplatelet agents, novel safer anticoagulants, and contemporary percutaneous coronary intervention.

Antiplatelet characteristics of Z4A5, a novel selective platelet glycoprotein IIb/IIIa inhibitor, under long‐term infusion (837.13)

Introduction:Glycoprotein IIb/IIIa inhibitors are important in the treatment of acute coronary syndromes (ACS) and percutaneous coronary interventions due to their effects on the final common pathway of platelet aggregation. Z4A5 is a new hexapeptide IIb/IIIa inhibitor with antiplatelet and antithrombotic effects. This study was performed to assess the stability of the antiplatelet effects and characteristics of Z4A5 with long‐term infusion. Materials and Methods:Light‐transmission aggregometry was used to measure platelet aggregation to assess the antiplatelet efficacy of Z4A5 in vitro and ex vivo. The activity of Z4A5against platelet aggregation and template bleeding time were evaluated after 8‐hour intravenous infusions in Beagle dogs following a 3 × 3 Latin square design. The recovery of platelet function after suppression by Z4A5 was compared with the recovery following eptifibatide and tirofiban administration 4h after termination. Results:Z4A5 completely inhibited Adenosine diphosphate (ADP)‐ and thrombin‐induced in vitro platelet aggregation with an IC50 of 265.8±22.9 nM and 180.3±58.2 nM. It also markedly and stably prevented ADP‐induced ex vivo platelet aggregation and prolonged the bleeding time throughout the 8‐hour infusion. Platelet function suppressed by long‐term infusion of Z4A5 recovered significantly faster than after eptifibatide infusion.Conclusions: Z4A5 has a stable antiplatelet effect and can be more readily controlled by physicians to monitor platelet function in ACS patients compared with two other GP IIb/IIIa inhibitors.Grant Funding Source: Supported by the Ministry of Science and Technology New Drug Major Project (No. 2012ZX09103‐301‐039)

Does the Inhibition of the Final Common Pathway of Platelet Aggregation Reduce the No-Reflow Phenomenon During Primary Percutaneous Coronary Intervention? Tirofiban no Infarto Agudo do miocárdio e a não Reperfusão (TIARA)

ABSTRACT Background Primary percutaneous coronary intervention is currently the preferred method to treat patients with STsegment elevation acute myocardial infarction. The no-reflow phenomenon, which is the inability to reperfuse a region of the myocardium after restoration of patency of a previously occluded epicardial coronary artery, is observed in a considerable proportion of these patients. The benefit of IIb/IIIa glycoprotein inhibitors, blocking the final common pathway of platelet aggregation, has been suggested in studies of acute coronary syndromes, but their actual efficacy in the context of no-reflow in patients treated with primary percutaneous coronary intervention remains unclear. Methods The aim of this multicenter, double-blinded, placebo controlled study is to assess the impact of the early administration of the low molecular weight glycoprotein IIb/ IIIa inhibitor tirofiban on the incidence of no-reflow using angiographic and electrocardiographic methods to determine: (1) the epicardial coronary flow, using the TIMI score, and the microcirculatory flow, using the MBG score of opacification and myocardial flow; (2) the resolution of the ST segment elevation, as the final index of the success of reperfusion. Conclusions If the decrease in no-reflow incidence at 90 minutes and 24 hours after primary percutaneous coronary intervention is confirmed, this pilot study should guide the implementation of a larger study to investigate the possible impact of the systematic inhibition of the final common pathway of platelet aggregation on the mortality of ST-segment elevation acute myocardial infarction patients.

Does the Inhibition of the Final Common Pathway of Platelet Aggregation Reduce the No-Reflow Phenomenon During Primary Percutaneous Coronary Intervention? Tirofiban no Infarto Agudo do miocárdio e a não Reperfusão (TIARA)

Primary percutaneous coronary intervention is currently the preferred method to treat patients with STsegment elevation acute myocardial infarction. The no-reflow phenomenon, which is the inability to reperfuse a region of the myocardium after restoration of patency of a previously occluded epicardial coronary artery, is observed in a considerable proportion of these patients. The benefit of IIb/IIIa glycoprotein inhibitors, blocking the final common pathway of platelet aggregation, has been suggested in studies of acute coronary syndromes, but their actual efficacy in the context of no-reflow in patients treated with primary percutaneous coronary intervention remains unclear. The aim of this multicenter, double-blinded, placebo controlled study is to assess the impact of the early administration of the low molecular weight glycoprotein IIb/ IIIa inhibitor tirofiban on the incidence of no-reflow using angiographic and electrocardiographic methods to determine: (1) the epicardial coronary flow, using the TIMI score, and the microcirculatory flow, using the MBG score of opacification and myocardial flow; (2) the resolution of the ST segment elevation, as the final index of the success of reperfusion. If the decrease in no-reflow incidence at 90 minutes and 24 hours after primary percutaneous coronary intervention is confirmed, this pilot study should guide the implementation of a larger study to investigate the possible impact of the systematic inhibition of the final common pathway of platelet aggregation on the mortality of ST-segment elevation acute myocardial infarction patients. A Inibição da Via Final Comum da Agregação Plaquetária Reduz o Fenômeno de Não Reperfusão Durante a Intervenção Coronária Percutânea Primária? Tirofiban no Infarto Agudo do miocárdio e a não Reperfusão (TIARA) A intervenção coronária percutânea primária é hoje o método preferencial de reperfusão na abordagem de pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST. Em boa parte desses casos, ocorre o fenômeno de não reperfusão, que é a incapacidade de se reperfundir uma região do miocárdio após o restabelecimento da patência de uma artéria coronária epicárdica previamente ocluída. O benefício de inibidores da glicoproteína IIb/IIIa, bloqueando a via final comum da agregação plaquetária, tem sido sugerido em estudos de síndromes coronárias agudas, mas persistem pontos obscuros quanto à sua real eficácia, no contexto da não reperfusão, em pacientes tratados com intervenção coronária percutânea primária. Investigação multicêntrica que avaliou o impacto da administração precoce do inibidor da glicoproteína IIb/IIIa de baixo peso molecular tirofiban, em forma duplo-mascarada, controlada por placebo, sobre a ocorrência de não reperfusão, empregando métodos angiográficos e eletrocardiográfico para documentar (1) os fluxos coronário epicárdico, pelo escore TIMI, e microcirculatório, pelo escore MBG de opacificação e escoamento miocárdicos; (2) a resolução do supradesnivelamento do segmento ST, como índice final do sucesso da reperfusão. Se comprovada redução da incidência de não reperfusão tanto 90 minutos como 24 horas após a intervenção coronária percutânea primária, este estudo-piloto, deve nortear a implementação de estudo mais abrangente, para investigar o possível impacto do bloqueio.

Antithrombotic effect of Z4A5 on coronary thrombosis in a canine model of acute unstable angina

The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti-platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina. Z4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 μg·kg⁻¹ + 1 μg·kg⁻¹·min⁻¹, 30 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹ or 300 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet-dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet-rich plasma and platelet poor plasma respectively. The Z4A5 infusion induced a dose-dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP-induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion. Z4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid-on and rapid-off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes.

Intracoronary Use of GP IIb/IIIa Inhibitors in Percutaneous Coronary Interventions

The glycoprotein (GP) IIb/IIIa receptor is critical to the process of platelet aggregation and thrombus formation as it serves as the final common pathway for platelet aggregation. For this reason, the development of GP IIb/IIIa inhibitors that block fibrinogen binding to the receptor has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. Presently, there are three commercially available GP IIb/IIIa inhibitors: abciximab, eptifibatide and tirofiban. All three drugs are commonly administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in patients at high risk, especially those undergoing percutaneous coronary interventions (PCI). Recently, several studies tested the intracoronary (IC) route for GP IIb/IIIa inhibitors in order to verify its safety and its possible superiority as compared to the intravenous (IV) route. The majority of the studies testing the IC route were conducted using abciximab and in patients with STEMI with better results in terms of myocardial reperfusion and infarct size and also promising results in terms of clinical outcome. On the IC administration of eptifibatide and tirofiban only some, even if promising, data are available. Larger and randomized studies are warranted to confirm the superiority of the IC route of administration of the GP IIb/IIIa inhibitors to the IV one in patients with coronary artery disease undergoing PCI.

Bleeding risk and safety profile related to the use of eptifibatide: a current review

Introduction: Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks the final common pathway of platelet aggregation. Its major adverse effect is bleeding. Balancing its safety and efficacy is paramount for its appropriate usage. Areas covered: The development of eptifibatide and its mechanism of action are explored. Clinical trials evaluating its efficacy and safety in a variety of clinical settings, as well as newer dosing regimens, are discussed. Readers will be able to understand the bleeding risks of eptifibatide in specific patient populations. Expert opinion: The risk of bleeding with eptifibatide needs to be weighed against the potential benefits. Understanding which patients are at higher risk of bleeding will help the clinician make appropriate decisions.

The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors

BackgroundPlatelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (∼9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.Methodology/Principal FindingsWe studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6–17% peak-trough amplitudes; p≤0.01). These circadian peaks occurred at a circadian phase corresponding to 8–9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3–8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.Conclusions/SignificanceThese data demonstrate robust effects of the endogenous circadian system on platelet activation in humans—independent of the sleep/wake cycle, other behavioral influences and the environment. The ∼9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.

Prescribing glycoprotein IIb/IIIa inhibitors in ACS

The advent of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes and in those undergoing percutaneous coronary intervention has added a new dimension to antiplatelet therapy. These agents work by blocking the final common pathway of platelet aggregation in thrombus formation. This is achieved by preventing the binding of fibrinogen to the activated glycoprotein IIb/IIIa receptors on the platelet surface. Three agents are currently licensed for use: abciximab, eptifibatide and tirofiban. Clinical trials have demonstrated a reduction in death, myocardial infarction and urgent or repeat coronary revascularization in those who received these agents, compared with placebo. Two potential complications with these agents are bleeding, particularly from the femoral artery access point, and thrombocytopenia. For nurses working in cardiac catheterization laboratories and cardiovascular wards, there needs to be an awareness of the benefits of receiving these agents, of which patients should receive them, and of their effect on platelets.

Propiedades de los diferentes inhibidores de la glucoproteína IIb/IIIa: ¿se puede aceptar el efecto de clase?

Los tres agentes inhibidores de la glucoproteína IIb/IIIa actualmente en uso clínico, abciximab, eptifibatida y tirofibán, comparten como diana terapéutica el bloqueo de la vía final común de la agregación plaquetaria, pero difieren significativamente en su estructura química, en la forma de bloquear la integrina α2bβ3 plaquetaria y en la especificidad por el receptor. Como consecuencia de ello, el patrón de inhibición de cada uno de estos fármacos en la funcionalidad plaquetaria varía y la equivalencia de beneficio clínico para una misma indicación es cuestionable. Hoy por hoy, no se dispone de ensayos clínicos de equivalencia que nos permitan aceptar o excluir un efecto de clase para los inhibidores de la glucoproteína IIb/IIIa en una determinada indicación clínica. Los resultados de los metaanálisis realizados en las diversas indicaciones clínicas tampoco han sido concluyentes, ya que no siempre muestran beneficios clínicos similares en magnitud y dirección para cada uno de los inhibidores de la glucoproteína IIb/IIIa. Por lo tanto, no podemos recomendar el intercambio o sustitución de un inhibidor por otro más allá de la indicación particular para la que se lo haya estudiado y aprobado. The three glycoprotein-IIb/IIIa inhibitors currently in clinical use, abciximab, eptifibatide and tirofiban, all share the same therapeutic target, namely blockade of the final common pathway of platelet aggregation. However, they differ significantly in chemical structure, in the way in which they block platelet integrin α2bβ3, and in specificity for the receptor. Consequently, each drug inhibits platelet function in a different way and it is unclear whether they offer equivalent clinical benefits for the same indication. To date, there have been no clinical trials on the equivalence of these drugs that would enable us to conclude that glycoprotein-IIb/IIIa inhibitors either do or do not exhibit a class effect for any particular clinical indication. Moreover, the findings of meta-analyses carried out for various indications have been inconclusive because the magnitude and direction of the clinical benefits associated with different glycoprotein-IIb/IIIa inhibitors have often diverged. Therefore, the exchange or substitution of one glycoprotein-IIb/IIIa inhibitor for another cannot be recommended beyond the specific indication for which the drug has been investigated and approved.

Actual Role of Platelet Glycoprotein IIb/IIIa Receptor Inhibitors as Adjunctive Pharmacological Therapy to Primary Angioplasty in Acute Myocardial Infarction: In the Light of Recent Randomized Trials and Observational Studies with Bivalirudin

Strategies for preventing ischemic complications during percutaneous coronary interventions (PCI) in the setting of acute myocardial infarction (AMI) have focused on the platelet surface-membrane glycoprotein (GP) IIb/IIIa receptor. The platelet GP IIb/IIIa receptor inhibitors, by blocking the final common pathway of platelet aggregation, have become a breakthrough in the management of acute coronary syndromes. Current adjuvant pharmacological therapy of AMI with aspirin, clopidogrel, unfractionated heparin (UH), and platelet GP IIb/IIIa inhibitors provides useful therapeutic benefits. Although the use of more potent antithrombin and antiplatelet agents during PCI in AMI has reduced the rate of ischemic complications, in parallel, the rate of bleeding has increased. Several studies have reported an association between bleeding after PCI and an increase in morbidity and mortality. Therefore, investigational studies have focused in pharmacological agents that would reduce bleeding complications without compromising the rate of major adverse cardiovascular events. Based on the results of several randomized trials, abciximab with UH, aspirin and clopidogrel have become a standard adjunctive therapy with primary PCI for AMI. However, some of the trials were done before the use of stents and the widespread use of thienopyridines. In addition, GP IIb/IIIa inhibitors use have been associated with thrombocytopenia, high rates of bleeding, and the need for transfusions, which increase costs, length of hospital stay, and mortality. On the other hand, in the stent era, bivalirudin, a semi-synthetic direct thrombin inhibitor, has recently been shown to provide similar efficacy with less bleeding compared with unfractionated heparin plus platelet GP IIb/IIIa inhibitors in AMI patients treated with primary PCI. The impressive results of this recent randomized trial and other observational studies make a strong argument for the use of bivalirudin rather than heparin plus GP IIb/IIIa inhibitors for the great majority of patients with AMI treated with primary PCI. However, some controversial results and limitations in the studies with bivalirudin exert some doubts in the future widespread use of this drug.

Understanding the complexity of abciximab-related thrombocytopenia

Patients with a rare bleeding disorder characterised by skin and mucosal bleeding – typical of thrombocytopenia – but with a normal platelet count, and later characterised by a defective aggregation to all agonists, described as Glanzmann thrombasthenia, have mutations in a platelet membrane glycoprotein (GP) called GP IIb/IIIa, also known as the integrin αIIbβ3 (1). Such discovery paved the road to a molecular understanding of how platelets aggregate, with GPIIb/IIIa acting as a main ligand for fibrinogen, which in turn provides the main molecular bridge between two adjacent platelets. This was the basis, now more than 15 years ago, for starting the development of a new class of antiplatelet agents directed against GP IIb/IIIa, blocking the final common pathway of platelet aggregation. The first such drug was derived from a murine monoclonal antibody (7E3) recognising activated, but not resting platelets, and binding to an epitope on the GPIIb/IIIa complex close to a critical binding site for fibrinogen (2). To decrease the immunogenicity of the antibody, the pharmaceutical abciximab (ReoPro, developed by Centocor and Eli Lilly), was produced. Abciximab is a chimeric (human/mouse) Fab fragment derived from 7E3, where the N-terminal sequences that control its specificity were incorporated into a human IgG1 framework. The intact chimeric IgG molecule was then cleaved by papain to produce the Fab fragment abciximab. Abciximab is therefore a Fab chimera that retains the mouse-derived variable portion of murine 7E3 joined to the constant region of human IgG Fab. Out of several other molecules developed for intravenous and oral use to target GP IIb/IIIa, two other compounds of this class have become available for intravenous use only. One is the Lys-Gly-Asp (KGD)containing cyclic heptapeptide eptifibatide (Integrilin, developed by ScheringPlough), derived from disintegrins, a class of proteins found in snake venoms and interfering with the binding of Arg-Gly-Asp (RGD)-containing adhesive proteins to cellular integrins. The other is tirofiban (Aggrastat, developed by Merck), developed by engineered synthesis to mimic the charge and spatial conformation of the RGD sequence. These compounds, which are small molecules not per se immunogenic, are collectively termed ligand-mimetic. Abciximab, eptifibatide and tirofiban are currently approved and recommended for therapeutic use in acute coronary syndromes (both ST-elevation myocardial infarction and non-ST elevation acute coronary syndromes), especially in the setting of percutaneous coronary interventions (PCI) (3, 4). Here, in patients with complex anatomy and receiving coronary stents, in the highly thrombogenic setting of acute coronary syndromes, abciximab is currently, within the category, the agent of choice when given at the time of PCI, having shown superiority in one face-to-face trial against tirofiban (5). In earlier clinical trials (6, 7) and in immediate post-marketing surveillance of abciximab, it was found that about 1% of patients develop thrombocytopenia. Thrombocytopenia (nadir platelet count <100x109 cells/l) developed actually in 2.4% of patients treated with abciximab and 0.5% of those treated with tirofiban (p<0.001) in a large series of patients undergoing coronary stenting in the setting of the TARGET study. Here abciximab use was independently associated with the risk of thrombocytopenia Correspondence to: Raffaele De Caterina, MD, PhD Institute of Cardiology and Center of Excellence on Aging “G. d’Annunzio” University – Chieti C/o Ospedale SS. Annunziata Via dei Vestini, 66013 Chieti, Italy Tel.: +39 0871 41512, Fax: +39 0871 402817 E-mail: rdecater@unich.it

Eptifibatide: The evidence for its role in the management of acute coronary syndromes

Acute coronary syndromes and non-Q-wave myocardial infarction are often initiated by platelet activation. Eptifibatide is a cyclic heptapeptide and is the third inhibitor of glycoprotein (Gp) IIb/IIIa that has found broad acceptance after the specific antibody abciximab and the nonpeptide tirofiban entered the global market. Gp IIb/IIIa inhibitors act by inhibiting the final common pathway of platelet aggregation, and play an important role in the management of acute coronary syndromes. This review assesses the evidence for therapeutic value of eptifibatide as a Gp IIb/IIIa inhibitor in patients with acute coronary syndromes. Several large, randomized controlled trials show that eptifibatide as adjunctive therapy to standard care in patients with non-ST segment elevation acute coronary syndrome is associated with a significant reduction in the incidence of death or myocardial infarction. Data are limited regarding the use of eptifibatide in patients with ST segment elevation myocardial infarction. Cost-effectiveness analysis indicates that eptifibatide is associated with a favorable cost-effectiveness ratio relative to standard care. According to US cost-effectiveness analysis about 70% of the acquisition costs of eptifibatide are offset by the reduced medical resource consumption during the first year. Eptifibatide was well tolerated in most of the trials. Bleeding is the most commonly reported adverse event, with most major bleeding episodes occurring at the vascular access site. Major intracranial bleeds, stroke, or profound thrombocytopenia rarely occurred during eptifibatide treatment. Eptifibatide has gained widespread acceptance as an adjunct to standard anticoagulation therapy in patients with acute coronary syndromes, and may be particularly useful in the management of patients with elevated troponin or undergoing percutaneous coronary interventions.

Herman Kalman Gold, MD

Dr Herman K. Gold, Associate Professor of Medicine, Harvard Medical School, Boston, Mass, died on March 1, 2008, at the Massachusetts General Hospital (MGH) of complications related to acute myelogenous leukemia. He was 67 years old. Dr Gold served for 37 years as staff physician and interventional cardiologist in the Department of Cardiology at MGH and was responsible for groundbreaking research in the use of fibrinolytic agents and subsequently glycoprotein IIb/IIIa inhibitors in the treatment of myocardial infarction. Dr Gold was born in Newport News, Va, the son of Jonah and Miriam Gold. His life was from early childhood shaped by medicine, a recognition of the role it played in saving his own life, which drove his passion, hope, and tireless energy in the pursuit of medical advances and clinical excellence to save others. Two indelible childhood events fueled his desire to become a physician. As a child, he contracted scarlet fever. During wartime, penicillin was rationed, and the family was only able to obtain enough for a few doses. He recalled that every night, his parents would boil his urine to collect enough penicillin for the next day’s treatment. Later, at the age of 9, he contracted bulbar polio, which prevented him from swallowing properly for nearly 2 years. These two experiences imprinted in him an appreciation for good health and a feeling of personal obligation as a physician to try sometimes unconventional treatments in an effort to cure patients’ ills. Dr Gold received his BS from the College of William and Mary in 1961. It was there he …

Glycoprotein IIb/IIIa Inhibitors in Patients With Renal Insufficiency Undergoing Percutaneous Coronary Intervention

Glycoprotein IIb/IIIa receptor antagonists (GPRAs) are agents that block the final common pathway in platelet aggregation by inhibiting the binding of fibrinogen to the GPR on the surface of activated platelets, which then decreases crosslinking of platelets and thus platelet aggregation. Treatment guidelines recommend that patients undergoing percutaneous coronary intervention (PCI) be treated with a regimen of antithrombotic therapy that includes a GPRA to decrease the risk of ischemic events. Three GPRAs are currently available for use in the United States: abciximab (ReoPro), tirofiban (Aggrastat), and eptifibatide (Integrilin). Tirofiban and eptifibatide are renally cleared and thus must have dosage adjustment if used in patients with renal insufficiency (RI). Abciximab is not renally eliminated and does not require dosage adjustment in RI. Bleeding has been associated with worse outcomes after PCI and is the major risk associated with the use of GPRAs. Approximately 30% of PCI patients have RI, and RI increases the risk of bleeding. Unfortunately, clinical trials of GPRAs in PCI have excluded patients with moderate to severe RI. Several subgroup analyses and single center cohort analyses have analyzed the safety of GPRAs in patients with RI. These analyses have confirmed that bleeding is increased in patients with RI and in patients receiving GPRAs; however, the risk does not seem to be magnified by the combination of RI and GPRA therapy. These results are limited by the small study sample sizes and the varying definitions of RI and bleeding. An important finding of recent studies is that doses of eptifibatide and tirofiban are not always adjusted for RI, resulting in an increased risk of bleeding. The presence of RI in patients undergoing PCI should not preclude the use of GPRAs; however, the dose should be adjusted (eptifibatide and tirofiban) if pertinent and bleeding should be closely monitored.