Antiplatelet and Anticoagulant Therapy for Atherothrombotic Disease: The Role of Current and Emerging Agents

Coronary atherothrombotic disease, including chronic stable angina and acute coronary syndromes (ACS), is associated with significant global burden. The acute clinical manifestations of atherothrombotic disease are mediated by occlusive arterial thrombi that impair tissue perfusion and are composed of a core of aggregated platelets, generated by platelet activation, and a superimposed fibrin mesh produced by the coagulation cascade. Long-term antithrombotic therapies, namely oral antiplatelet agents and anticoagulants, have demonstrated variable clinical effects. Aspirin and P2Y₁₂ adenosine diphosphate (ADP) receptor antagonists have been shown to reduce the risk for thrombosis and ischaemic events by blocking the thromboxane (Tx) A₂ and platelet P2Y₁₂ activation pathways, respectively, whereas the benefits of oral anticoagulants have not been consistently documented. However, even in the presence of aspirin and a P2Y₁₂ receptor antagonist, the risk for ischaemic events remains substantial because platelet activation continues via pathways independent of TxA₂ and ADP, most notably the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antithrombotic therapies include those targeting the platelet, such as the new P2Y₁₂ antagonists and a novel class of oral PAR-1 antagonists, and those inhibiting the coagulation cascade, such as the new direct factor Xa antagonists, the direct thrombin inhibitors, and a novel class of factor IX inhibitors. The role of emerging antiplatelet agents and anticoagulants in the long-term management of patients with atherothrombotic disease will be determined by the balance of efficacy and safety in large ongoing clinical trials.     

急性冠脉综合征患者接受经皮冠状动脉介入治疗前后抗血小板策略

急性冠脉综合征(ACS)是一组由急性心肌缺血引起的临床综合征,包括不稳定型心绞痛(UA)、非ST段抬高型心肌梗死(NSTEMI)和ST段抬高型心肌梗死(STEMI).ACS主要发病机制是动脉粥样硬化斑块破裂后,血小板激活和凝血酶的形成,最终导致血栓形成.目前抗血小板治疗和抗凝治疗是ACS患者抗栓治疗的两大重要组成部分.随着经皮冠状动脉介入治疗(PCI)的广泛应用,ACS患者PCI围手术期抗栓药物的安全性及有效性备受关注.本文就ACS患者有关接受PCI前后的抗血小板治疗策略的一些大型临床试验及抗血小板药物在当今早期侵入性冠状动脉治疗时代中的应用现状作一综述.     

Novel Antiplatelet Therapy in Acute Coronary Syndromes: What is New in the Pipeline?

Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an "one-size fits all" concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients' groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role.     

Oral antiplatelet therapy for acute coronary syndromes: aspirin, P2Y12 inhibition and thrombin receptor antagonists

The platelet is central to the pathophysiology of acute coronary syndromes (ACS) via its direct participation in the formation of the thrombotic occlusion and its participation in the coagulation cascade that results in the formation of thrombin. Antiplatelet therapy is a cornerstone of therapy in the setting of ACS. Unfortunately, many patients who receive intensive antiplatelet therapy remain at high risk for recurrent events. Current efforts to reduce this "residual risk" include lifestyle modifications, cardiac rehabilitation, and intensive therapy for dyslipidemia. Also being investigated are methods of individualizing and intensifying antiplatelet therapy. Novel compounds that promise to reduce recurrent ischemic events without an increase in bleeding events are being evaluated in clinical trials. This review summarizes ongoing efforts to improve the effectiveness of antiplatelet therapy among patients with ACS.     

Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments

Introduction: There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors.

Areas covered: In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2Y₁₂ receptor blockers, PAR-1 inhibitors, direct thrombin inhibitors and factor Xa inhibitors from PubMed since 2008.

Expert opinion: Since thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y₁₂ inhibitors plus aspirin, the degree of adverse event reduction compared to clopidogrel therapy in large scale trials is modest along with significantly greater bleeding. Recent studies suggest that targeting the thrombin pathway in addition to antiplatelet agents in high risk patients may further mitigate the risk of ischemic event occurrences with improved safety profiles.     

Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y₁₂ receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.     

Developments in antiplatelet therapy for acute coronary syndromes and considerations for long-term management

ABSTRACT

Objective: This article reviews the currently available antiplatelet therapies and emerging investigational drugs in the treatment of acutecoronary syndrome (ACS), and considerations for primary and secondary prevention in the long-term management of ACS patients undergoing percutaneous coronary intervention (PCI).

Research design and methods: Primary studies and reviews in the peer-reviewed, English-language literature were identified through searches of MEDLINE (1966–2008) using the terms ‘acute coronary syndrome’, ‘antiplatelet’, ‘aspirin’, ‘long-term management’, ‘P2Y₁₂ receptor’, and ‘thienopyridine’. Additional references were obtained by searching the reference lists of the identified articles. Articles were included if they were recently published and pertinent, patient-focused, and authors were recognized as leaders in the field. Current review is limited by literature search on single database.

Results: Platelets play a major role in atherogenesis and the formation of thrombi, the main events in the pathogenesis of ACS. Although aspirin is an effective antiplatelet agent, efficacy and safety data from a number of randomized clinical trials on atherothrombotic disease support the use of dual antiplatelet therapies such as aspirin and thienopyridines over single antiplatelet therapy for ACS and up to 1?year following ACS. Antiplatelet agents reduce, but do not eliminate, ischemic events after ACS due, in part, to variable individual response (or resistance) in antiplatelet agents, non-compliance, progression of atherosclerosis, modest inhibition of platelet aggregation (IPA) levels and other factors. Several antiplatelet agents, including novel P2Y₁₂-receptor antagonists and thrombin-receptor antagonists, are currently under investigation for ACS and primary and secondary prevention in the long-term management of patients undergoing PCI.

Conclusions: Current antiplatelet therapies have clinical benefits such as reducing immediate and long-term cardiovascular risk, but substantial residual risk remains indicating a need for new therapeutic agents. Additional large randomized trials are necessary to determine the most appropriate treatment regimens for ACS patients.     

Thrombin receptor antagonism –the potential of antiplatelet medication SCH 530348

Importance of the field: Coronary artery disease is a leading cause of morbidity and mortality worldwide. Platelet activation and subsequent thrombus formation play a central role in disease progression and development of acute coronary syndromes (ACS). Despite widespread use of single and dual antiplatelet therapies in atherothrombotic disease, ischemic complications remain common. Therefore, the need exists for new antiplatelet agents that are more effective, but with acceptable safety profiles (i.e., do not increase risk of bleeding). Antiplatelet agents available at present are effective in blocking the cyclo-oxygenase, ADP-mediated and final common (IIb/IIIa receptor) pathways for platelet activation. Recently, there has been more interest in inhibition of the proteinase-activated receptor-1 (PAR-1), which blocks thrombin-mediated platelet activation.

Areas covered in this review: This review covers the pharmacology, pharmacokinetics and development of the new PAR₁ antagonist, SCH 530348 in a review of all publications relevant to the topic over the last 10 years. Phase II clinical trials indicate that addition of this agent to current antiplatelet regimens may provide additional antithrombotic protection without an increase in bleeding. Results of the ongoing Phase III trials, examining the use of SCH 530348 in patients with ACS and for secondary prevention of ischemic events are anxiously awaited.

What the reader will gain: The review is a summary of all pharmacologic properties and current clinical data available on the PAR1 antagonist SCH 530348. The readers will be introduced to its novel mechanism of action, advantages over current antiplatelet agents and potential future applications should ongoing clinical trials confirm its efficacy in reducing platelet activity.

Take home message: SCH 530348 is a new, orally administered antiplatelet agent that blocks the protease-activated thrombin receptor on the platelet. Early clinical data indicate that it is associated with a lower risk of bleeding. However, its efficacy in improving clinical outcomes in patients with coronary disease remains to be confirmed in ongoing Phase III clinical trials.     

Protease-activated receptors differentially regulate human platelet activation through a phosphatidic acid-dependent pathway

Pathological conditions such as coronary artery disease are clinically controlled via therapeutic regulation of platelet activity. Thrombin, through protease-activated receptor (PAR) 1 and PAR4, plays a central role in regulation of human platelet function in that it is known to be the most potent activator of human platelets. Currently, direct thrombin inhibitors used to block platelet activation result in unwanted side effects of excessive bleeding. An alternative therapeutic strategy would be to inhibit PAR-mediated intracellular platelet signaling pathways. To elucidate the best target, we are studying differences between the two platelet thrombin receptors, PAR1 and PAR4, in mediating thrombin's action. In this study, we show that platelet activation by PAR1-activating peptide (PAR1-AP) requires a phospholipase D (PLD)-mediated phosphatidic acid (PA) signaling pathway. We show that this PAR1-specific PA-mediated effect is not regulated through differential granule secretion after PAR-induced platelet activation. Perturbation of this signaling pathway via inhibition of lipid phosphate phosphatase-1 (LPP-1) by propranolol or inhibition of the phosphatidylcholine-derived phosphatidic acid (PA) formation by PLD with a primary alcohol significantly attenuated platelet activation by PAR1-AP. Platelet activation by thrombin or PAR4-AP was insensitive to these inhibitors. Furthermore, these inhibitors significantly attenuated activation of Rap1 after stimulation by PAR1-AP but not thrombin or PAR4-AP. Because PA metabolites such as diacylglycerol play an important role in intracellular signaling, identifying crucial differences in PA regulation of PAR-induced platelet activation may lead to a greater understanding of the role of PAR1 versus PAR4 in progression of thrombosis.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

The role of antiplatelet therapy in the management of acute coronary syndromes

The benefit of aspirin use in the emergent care of acute coronary syndromes (ACS) has been well-established. Recent studies have further demonstrated the importance of antiplatelet therapy in the acute setting, primarily with the use of intravenous glycoprotein IIb/IIIa receptor inhibitors. Aspirin and the thienopyridines (ticlopidine and clopidogrel) are oral antiplatelet agents that interfere with platelet activation in complementary, but separate pathways. Combination therapy of aspirin with other antiplatelet agents has demonstrated a benefit for the management of ACS. This article reviews the pathophysiology of platelet activation in ACS, landmark trials regarding antiplatelet agents, and the current recommendations for the use of both intravenous and oral antiplatelet agents in the management of patients with ACS.     

Platelet hyperreactivity and stent thrombosis in patients undergoing coronary stenting

Stent thrombosis (ST) is a rare but very serious event complicating percutaneous coronary intervention (PCI) procedures. Both procedure- and patient-related factors, including inadequate platelet inhibition are well known predictors of ST. According to the present guidelines, a dual antiplatelet treatment regimen consisting of aspirin and a P2Y12 receptor inhibitor such as clopidogrel, prasugrel or ticagrelor is routinely administered to ACS patients and to patients undergoing PCI in order to prevent thrombotic vessel occlusions. In recent years, evidence has grown that patients showing high on-treatment platelet reactivity (HPR) under clopidogrel intake exhibit a higher risk for the occurrence of ischemic events including ST. For assessing HPR, different platelet function assays are currently available and have already found their way into routine clinical practice in several centers. Along with this development, more potent P2Y12 receptor inhibitors like prasugrel and ticagrelor are substitutes for clopidogrel in specific circumstances such as in ACS patients or in patients who do not adequately respond to standard clopidogrel treatment. Utilizing platelet function monitoring, patients showing HPR can be identified and an optimized antiplatelet treatment regime can be tailored for these patients. This review paper aims to summarize the important facts in relation to ST and antiplatelet therapy with a particular focus on P2Y12 receptor inhibition and its ex vivo assessment in patients undergoing coronary stent placement.     

Thienopyridines and Other ADP-Receptor Antagonists

Platelet P2Y12 receptor inhibition plays a pivotal role in preventing thrombotic vascular events in patients with ACS and in patients undergoing percutaneous coronary intervention (PCI). Among the P2Y12 receptor inhibitors, the group of thienopyridines include ticlopidine, clopidogrel and prasugrel, all of which are orally administered prodrugs leading to irreversible P2Y12 receptor inhibition. Non-thienopyridine derivatives including ticagrelor, cangrelor and elinogrel do not require metabolic activation and lead to a reversible P2Y12 receptor inhibition in contrast to thienopyridines. The extend of platelet inhibition is subject to the administered antiplatelet agent and influenced by individual genetic and clinical factors. Insufficient platelet inhibition, termed high platelet reactivity (HPR) is associated with an increased risk for ischemic events after PCI whereas exceeding platelet inhibition results in an increased bleeding risk. Pharmacologic properties and clinical outcome data differ substantially between the existing P2Y12 receptor inhibitors. Whether individualized antiplatelet treatment incorporating different P2Y12 receptor inhibitors improves patients' clinical outcomes warrants further investigation.     

Antiplatelet therapy in acute coronary syndromes

Introduction: Coronary thrombosis is a frequent cause of death and myocardial infarction most often explained by superimposition of a platelet-rich thrombus on existing coronary artery disease. Therefore, antiplatelet drugs are essential in the treatment and secondary prevention of acute coronary syndromes (ACS) and during percutaneous coronary intervention. Several novel antiplatelet drugs are now available.

Areas covered: For several years, aspirin and clopidogrel remained the cornerstone of treatment for ACS. However, prasugrel and ticagrelor have a more consistent, faster-acting and more potent antiplatelet effect than clopidogrel, which translates into improved clinical outcomes, although at the expense of an increased bleeding risk. Importantly, some patients experience cardiovascular events despite current antiplatelet treatment, because platelet activation may occur via pathways not inhibited by these agents. Therefore, improved antiplatelet strategies are warranted.

Expert opinion: Despite undisputable benefits of current antiplatelet strategies, a considerable number of patients continue to experience adverse thrombotic events, although clinical outcomes have been improved with new oral P2Y₁₂ antagonists. New drugs have been developed, including intravenous P2Y₁₂ antagonists and oral antagonist targeting the protease-activated receptor-1 platelet activation pathway stimulated by thrombin. This review provides an overview of current and novel antiplatelet strategies and also discusses unmet needs related to antiplatelet therapy for ACS.     

Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor

Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor.     

Platelets in atherothrombosis--diagnostic and prognostic value of platelet activation in patients with atherosclerotic diseases

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept?, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.     

New perspectives in antiplatelet therapy

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbβ3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.     

Triple antiplatelet therapy in acute coronary syndromes

Heightened platelet activity plays a critical role in thrombus formation, which is central to acute coronary syndromes (ACS), including non-ST-segment elevation (NSTE)-ACS (comprising unstable angina pectoris and non-ST-segment elevation myocardial infarction [NSTEMI]) and ST-segment elevation myocardial infarction (STEMI), and has been implicated in poor clinical outcome. Platelets not only impact coronary thrombus but are major contributors to microcirculatory dysfunction and vascular inflammation. Efforts to inhibit platelet function, including antiplatelet therapy, are paramount to the management of ACS; thus, a growing recognition of the various pathways driving platelet activity has given rise to the need for multiple agents that impart complimentary mechanisms of action. While only inhibiting platelet activation will still allow for aggregation, i.e. the binding of glycoprotein (GP) IIb/IIIa receptors to fibrinogen, solely blocking aggregation may leave platelet-activating pathways free to sustain the production and release of various pro-inflammatory and pro-thrombotic compounds. The benefit of 'triple antiplatelet therapy', referring to the combination of aspirin, a thienopyridine or non-thienopyridine adenosine diphosphate (ADP)/P2Y12 receptor blocker and a GPIIb/IIIa inhibitor (GPI), has been demonstrated in patients with NSTE-ACS who ultimately undergo percutaneous coronary intervention (PCI) and are determined to be at an elevated risk for ischaemic events, and in patients undergoing primary PCI. It is therefore recommended by the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association. Furthermore, the rationale for adding a GPI, particularly in patients with STEMI, is backed by studies that have shown negligible effects of a 600?mg clopidogrel loading dose, despite being administered 4 hours prior to PCI. Moreover, it has been observed that the physiological state of STEMI may deem dual antiplatelet therapy ineffective, because during an acute event the absorption of clopidogrel may be impaired. Nonetheless, there is still considerable variability with respect to the use of triple antiplatelet therapy such as that documented in the Euro Heart Survey. The perception that the mortality benefit afforded by adding a GPI to dual oral antiplatelet therapy does not outweigh the risk is a likely factor. This may be fuelled by results of trials such as BRAVE-3, which, inconsistent with those for On-TIME 2, failed to prove the value of adding a GPI to dual oral antiplatelet therapy in patients with STEMI. Subsequent analyses have indeed demonstrated the positive benefit-risk ratio associated with adding a GPI and determined that the timing of GPI administration could have an impact on clinical outcome related to its impact on infarct size in patients with STEMI. Additionally, it has been presumed that a synergistic effect exists between P2Y12 inhibitors and GPIs. Triple antiplatelet therapy has a significant role to play in the management of patients with ACS managed with PCI. An understanding of patient risk status and timing of symptoms and bleeding risk is crucial to patient selection and ensuring that this therapy is optimized. Though no interaction has been noted in trials of newer, more potent antiplatelet agents, future studies are key to determining the role of this strategy in the era of these more potent agents.     

Platelet activation, and antiplatelet targets and agents: current and novel strategies

Platelets play a key role in thrombosis and haemostasis, which can be either beneficial or deleterious depending on the circumstances. Multiple factors, such as genetic polymorphisms, pathological state and lifestyle, are thought to be associated with platelet hyperreactivity. Platelet activation occurs through the complex process of transmembrane signalling, with a cascade of biochemical interactions leading to platelet activation. Transmembrane signalling involves many different molecules with different enzymatic activity and/or function. Based on the signalling pathways involved in platelet activation, there are four possible targets of antiplatelet drugs: (i) inhibition of agonist generation; (ii) receptor inhibition; (iii) G-protein inhibition; and (iv) inhibition of enzymatic cascades. However, both established and novel antiplatelet drugs have their own advantages and disadvantages. Because of the problems associated with the use of current antiplatelet drugs, such as resistance, optimal dosage and safety, future strategies for the development of new antiplatelet drugs and new treatment regimens may include consideration of the following: (i) a shift from single targets within the signalling cascade to multiple targets; (ii) a shift from therapy with a single drug to combination therapy; and (iii) investigating drugs in current clinical use for novel antiplatelet properties.     

Antiplatelet Mechanism of 2‐Chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an Antithrombotic Agent

Abstract: The effects of 2‐chloro‐3‐(4‐hexylphenyl)‐amino‐1,4‐naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin‐, arachidonic acid‐ and thapsigargin‐induced aggregation of washed human platelets with the IC₅₀ values of 22.2±0.7, 6.5±0.2, and 7.6±0.1 μM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate‐conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen‐glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin‐induced increase in intracellular Ca²⁺ mobilization at the dose of 30 μM and ATP secretion in a dose‐dependent manner. It also inhibited thrombin‐ and arachidonic acid‐induced thromboxane A₂ formation in human platelet dose‐dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A₂ formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.