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.     

Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors

Dual anti-platelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for patients with acute coronary syndromes (ACS) and for patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is associated with increased risk of high on-treatment platelet reactivity (HTPR) compared to ticagrelor and prasugrel. Investigators have therefore sought to “escalate” clopidogrel dosing to overcome HTPR to reduce ischemic/thrombotic events. In this review, we will summarize the evidence for dose escalation in the context of genetic determinants of resistance and platelet function data. We will review contemporary clinical trials that have sought to improve delivery of dual antiplatelet therapy to patients with coronary artery disease and discuss the potential of clopidogrel dose escalation in specific populations.     

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) P2Y(12) 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.     

Genetics of platelet inhibitor treatment

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y₁₂ receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel.     

Ticagrelor: a review of its use in the management of acute coronary syndromes

Ticagrelor (Brilique?; Brilinta?), a cyclopentyl-triazolo-pyrimidine antiplatelet agent, is the first oral antagonist of the P2Y(12) receptor to offer reversible receptor binding. It is indicated in the EU for the prevention of atherothrombotic events in adults with acute coronary syndromes (ACS) [unstable angina pectoris, ST-segment elevation myocardial infarction [STEMI] or non-STEMI), including those managed medically or with percutaneous coronary intervention or coronary artery bypass grafting (CABG). Ticagrelor provides selective and reversible inhibition of adenosine diphosphate-induced platelet aggregation, with a faster onset and offset of action than that of clopidogrel, and is effective in the treatment of patients with ACS, with or without ST-segment elevation. In the large, randomized, double-blind, multicentre PLATO trial conducted in this patient population, ticagrelor was more effective than clopidogrel in terms of preventing ischaemic events over 12 months, providing a significantly lower risk of the primary composite endpoint of myocardial infarction, stroke or death from vascular causes, and was associated with an overall mortality benefit. The risk of major bleeding with ticagrelor, including bleeds related to CABG, did not differ from that seen with clopidogrel in this study, although ticagrelor was associated with more non-CABG-related major bleeds and fatal intracranial bleeding, albeit the latter bleeding events were rare. Further long-term and comparative efficacy and tolerability data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel. However, the clinical data currently available indicate that ticagrelor is a promising option for the treatment of patients with ACS and may be of particular use in those at high risk of ischaemic events or unresponsive to clopidogrel.     

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.     

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.     

ADP Receptor Antagonism

ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y(12) receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y(12) receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y(12) receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y(12) receptor antagonists - such as prasugrel, ticagrelor (AZD 6140) and cangrelor - will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y(12) receptor antagonism and the projected developments in this field.     

Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.     

Efficacy and safety of ticagrelor in patients with acute coronary syndrome: A meta‐analysis of randomized controlled trials

Acute coronary syndrome (ACS) is a dangerous and urgent clinical pattern of coronary artery disease. Aspirin and adenosine diphosphate P2Y₁₂ receptor antagonists are the standard dual anti‐platelet therapy for patients with ACS. Ticagrelor is a new oral antagonist of the adenosine diphosphate P2Y₁₂ receptor. Randomized controlled trials (RCTs) have evaluated the efficacy and safety of ticagrelor compared to clopidogrel or prasugrel in patients with ACS, obtaining conflicting results. Thus, we conducted a meta‐analysis of these RCTs to determine the efficacy and safety of ticagrelor in patients with ACS. Results of the meta‐analysis indicate that ticagrelor decreased the risk of major adverse cardiovascular events (MACE) and all‐cause death, but increased the risk of bleeding events. In Asiatic patients, analysis indicates that ticagrelor did not decrease the risk of MACE and all‐cause death, while increasing the risk of bleeding events. Together, this meta‐analysis suggests that ticagrelor was more effective, but less safe than clopidogrel and prasugrel in patients with ACS. Subgroup analysis indicates that ticagrelor was not more effective, although less safe than clopidogrel in Asiatic patients, thus more evidence is needed to further evaluate the efficacy and safety of ticagrelor in Asiatic patients.     

Prasugrel versus Clopidogrel Antiplatelet Therapy after Acute Coronary Syndrome

Antithrombotic therapy is imperative in the management of patients presenting with an acute coronary syndrome (ACS). The combination of antiplatelet therapy in conjunction with antithrombotic therapy has become the standard of care in improving the morbidity and mortality of patients with an ACS and in reducing ischemic complications of percutaneous coronary intervention. Patients with an ACS are at increased risk for a recurrent event, both in-hospital and for several months afterward. Secondary prevention to reduce these events is accomplished through the establishment of appropriate medical therapy. Dual antiplatelet therapy with aspirin and adenosine 5'-diphosphate P2Y(12) receptor blockers such as ticlopidine or clopidogrel are integral components of this regimen; however, both of these thienopyridines have a relatively slow onset of action and variable bioavailability. Prasugrel, a third-generation thienopyridine approved by the US FDA in 2009, has a more rapid onset of platelet inhibition than clopidogrel and ticlopidine because of increased efficiency of prodrug-to-active metabolite conversion. The result is higher and less variable concentration of the active metabolite within 60 minutes following oral dosing. Phase II and III trials assessing the safety and efficacy of prasugrel have been completed, including JUMBO-TIMI 26, PRINCIPLE-TIMI 44, and TRITON-TIMI 38. These trials demonstrated greater inhibition of platelet aggregation and lower rates of the composite endpoint of death, non-fatal myocardial infarction, and stroke compared with clopidogrel. However, major bleeding occurred more frequently with prasugrel treatment than with clopidogrel. This review highlights the current state of evidence-based antiplatelet therapy and provides guidance on appropriate use of prasugrel in cardiovascular medicine.     

Prasugrel

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.     

Prasugrel hydrochloride for the treatment of acute coronary syndromes

Introduction: P2Y12 receptor antagonists, by inhibiting platelet activation and subsequent aggregation, are critical to prevent ischemic event recurrence after an acute coronary syndrome (ACS). Prasugrel is a third-generation thienopyridine whose metabolites target the P2Y12 receptor. Compared with clopidogrel, prasugrel has a more potent, faster in onset, and more consistent P2Y12 receptor inhibition.

Areas covered: This review describes prasugrel chemistry, pharmacokinetics, pharmacodynamics and clinical studies. In a Phase III randomized clopidogrel-controlled trial, prasugrel improved cardiovascular outcome (risk reduction of cardiovascular death, non-fatal heart attack and non-fatal stroke) at the cost of increased major and fatal bleeding complications. Prasugrel, in combination with aspirin, has been approved by European and American regulatory agencies for the prevention of atherothrombotic events in patients with ACS who undergo percutaneous coronary intervention (PCI).

Expert opinion: Prasugrel is effective for managing ACS patients with planned PCI and it offers an alternative with potential benefits over clopidogrel. Prasugrel is currently challenged by ticagrelor, a P2Y12 receptor antagonist with different pharmacokinetic/pharmacodynamic properties. The superiority of one drug to the other cannot be reliably estimated from the current trials. Ongoing randomized and observational studies may help to provide valuable information on the safety and efficacy of these two drugs and their respective places with ACS patients.     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

P2Y12 receptor inhibitors: an evolution in drug design to prevent arterial thrombosis

Introduction: P2Y12 inhibitors are a critical component of dual antiplatelet therapy (DAPT), which is the superior strategy to prevent arterialthrombosis in patients with acute coronary syndromes (ACS) and undergoing stent implantation..

Areas covered: Basic science articles, clinical studies, and reviews from 1992–2017 were searched using Pubmed library to collet impactful literature. After an introduction to the purinergic receptor biology, this review summarizes current knowledge on P2Y12 receptor inhibitors. Furthermore, we describe the subsequent improvements of next-generation P2Y12 receptor inhibitors facing the ambivalent problem of bleeding events versus prevention of arterial thrombosis in a variety of clinical settings. Therefore, we summarize data from relevant preclinical and clinical trials of currently approved P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) and provide strategies of drug switching and management of bleeding events.

Expert opinion: An enormous amount of pharmacologic and clinical data is available for the application of P2Y12 receptor inhibitors. Today prasugrel, ticagrelor and clopidogrel are the standard of care drugs during dual antiplatelet therapy for ACS patients, but have considerable rates of bleeding. Recent and future clinical trials will provide evidence for subsequent escalation and de-escalation strategies of P2Y12 receptor inhibition. These data may pave the way for an evidence-based, individualized P2Y12 receptor inhibitor therapy.     

Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile

Prasugrel (CS-747, LY640315) is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Like other thienopyridines, prasugrel is a prodrug that is inactive in vitro. Prasugrel's distinct chemical structure permits efficient conversion to its active metabolite with a less rigorous dependence on specific cytochrome P-450 enzymes. Prasugrel is rapidly converted in vivo to an active metabolite (R-138727) that binds specifically and irreversibly to the platelet P2Y 12 purinergic receptor inhibiting ADP-mediated platelet activation and aggregation. Preclinical studies indicated that prasugrel is approximately 10- and 100-fold more potent at inhibiting ex vivo platelet aggregation and in vivo thrombus formation than clopidogrel and ticlopidine, respectively. Early clinical data in healthy subjects confirmed the greater platelet inhibition and consistency with prasugrel compared to clopidogrel. While the active metabolites of prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo was quite different-prasugrel (60 mg) resulting in an approximately 12-fold greater exposure to its active metabolite compared with clopidogrel (300 mg). This observation provides a mechanistic basis for the faster, greater, and more consistent inhibition of platelet aggregation observed with prasugrel. Clinical studies in patients with cardiovascular disease confirmed the potent antiplatelet effect of prasugrel compared with clopidogrel. Collectively, these phase 1/1b studies and a phase 2 study (JUMBO-TIMI 26) aided in dose selection for the recently completed phase 3 trial (TRITON-TIMI 38) in patients with acute coronary syndrome undergoing percutaneous coronary intervention.     

Role of platelet function testing in clinical practice: current concepts and future perspectives

Oral antiplatelet therapy is routinely administered to ACS patients as well as to patients undergoing percutaneous coronary intervention (PCI) with the primary aim of inhibiting platelet-mediated thrombus formation and subsequent abrupt vessel occlusion. Individual platelet response to aspirin and especially to clopidogrel is highly variable and evidence has grown in recent years linking an attenuated response to therapy with the occurrence of ischemic events. At present, the antiplatelet therapy landscape is changing with the emergence of prasugrel and ticagrelor as alternative and more potent treatment options. In addition, tests for near-patient monitoring of platelet function in clinical practice are available and are being increasingly employed for the optimization of antiplatelet treatment. It is hypothesized that platelet function testing may prove useful for achieving an optimized balance of proven platelet inhibition at a cost of moderate bleeding risk. This is also why first centers have already included testing in day-to-day routine. Extensive clinical evaluations with a range of currently-available assays for platelet function testing are ongoing and the current and future role of platelet function testing in clinical practice is a topic of much debate. Widespread adoption of this practice and its incorporation into clinical guidelines awaits the results of ongoing trials where treatment is changed based on platelet function testing data. This review paper summarizes the key characteristics of platelet function tests available, presents an overview of relevant studies and examines the present role of platelet function testing in clinical practice with a focus on antiplatelet therapy in patients undergoing coronary stent placement.     

Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications

Over the last two decades or more, anti-platelet therapy has become established as a cornerstone in the treatment of patients with ischaemic cardiovascular disease, since such drugs effectively reduce arterial thrombotic events. The original agent used in this context was aspirin (acetylsalicylic acid) but, with the advent of adenosine diphosphate (ADP) receptor antagonists, the use of dual anti-platelet therapy has resulted in further improvement in cardiovascular outcomes when compared with aspirin alone. The first group of platelet ADP receptor antagonists to be developed was the thienopyridine class, which comprise inactive pro-drugs that require in vivo metabolism to their active metabolites before exerting their inhibitory effect on the P2Y(12) receptor. Clopidogrel has been the principal ADP receptor antagonist in use over the past decade, but is limited by variability in its in vivo inhibition of platelet aggregation (IPA). The pharmacokinetics of clopidogrel are unpredictable due to their vulnerability to multiple independent factors including genetic polymorphisms. Expression of the 3435T/T genetic variant encoding the MDR1 gene for the P-glycoprotein efflux transporter results in a significantly reduced maximum drug concentration and area under the plasma concentration-time curve as intestinal absorption of clopidogrel is reduced; and the expression of the mutant *2 allele of CYP2C19 results in similar pharmacokinetic effects as the two cytochrome P450 (CYP)-mediated steps required for the production of the active metabolite of clopidogrel are impaired. These variable pharmacokinetics lead to erratic pharmacodynamics and cannot reliably be overcome with increased dosing. Both prasugrel, a third-generation thienopyridine, and ticagrelor, a cyto-pentyl-triazolo-pyrimidine, have more predictable pharmacokinetics and enhanced pharmacodynamics than clopidogrel. Neither appears to be affected by the same genetic polymorphisms as clopidogrel; prasugrel requires only a single CYP-mediated step to produce its active metabolite and ticagrelor is not a pro-drug. Enhanced IPA by both prasugrel and ticagrelor is achieved at the expense of increased major bleeding, although this is partially mitigated in the case of ticagrelor due to its reversible IPA. However, the reversible binding of ticagrelor to the P2Y(12) receptor requires a twice-daily dosing regimen. Due to limited data from clinical studies, the use of prasugrel is currently restricted to individuals undergoing percutaneous coronary intervention who are ≤75 years old and have a body weight ≥60 kg. The clinical data for ticagrelor are more comprehensive and this drug therefore has a place in the management of patients with acute coronary syndrome at moderate-to-high risk of ischaemic events, irrespective of treatment strategy. Here we review in detail the pharmacokinetics and pharmacodynamics of clopidogrel, prasugrel and ticagrelor, and explore the implications of the differences in these parameters for their clinical use.     

Ticagrelor for acute coronary syndrome?

Current guidelines from the National Institute for Clinical Excellence (NICE) recommend antiplatelet therapy comprising aspirin plus either clopidogrel or prasugrel for patients with acute coronary syndrome (ACS). However, such dual therapy increases the likelihood of bleeding compared to that with aspirin alone. Ticagrelor (Brilique - Astra-Zeneca) is a new oral antiplatelet drug recently licensed in the UK (since publication of the NICE guidelines) for use with aspirin in patients with ACS, including those managed medically or undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Here we review the place of ticagrelor in the management of people with ACS, and whether it offers advantages over standard therapy in terms of greater efficacy or lower likelihood of bleeding complications.     

Clopidogrel

Dual antiplatelet therapy with acetylsalicylic acid (aspirin) and clopidogrel is a guideline-recommended standard of care for patients with acute coronary syndromes (ACS) and those who undergo percutaneous coronary intervention (PCI). Despite a large body of clinical evidence obtained from randomized clinical trials and patient registries supporting the efficacy and safety of aspirin plus clopidogrel therapy in these patients, questions concerning the optimal use of dual antiplatelet therapy remain. Widely debated topics pertaining to dual antiplatelet therapy in patients with ACS or undergoing PCI include (i) the appropriate clopidogrel loading dose; (ii) the optimal time to initiate the clopidogrel loading dose; (iii) the optimal duration of dual antiplatelet therapy following ACS or PCI; (iv) impact of variability of platelet response on patient outcomes; and (v) the role of other recommended and emerging P2Y₁₂ antagonists. This review discusses these ongoing controversies regarding the optimal use of dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS or those undergoing PCI.