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

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y₁₂ 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 P2Y₁₂ 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.     

Interactions between clopidogrel and proton pump inhibitors: a review of evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.     

Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia

Introduction: After acute coronary syndromes (ACS), the so-called dual antiplatelet therapy (DAPT), which usually consists of low-dose of aspirin in combination with a thienopyridine (clopidogrel, prasugrel) or with a cyclopentyltriazolopyrimidine (ticagrelor), reduces the risk of ischemic events. Ticagrelor, un particular, is an effective drug as it isn’ a prodrug, doesn’t require metabolic activation and demonstrates a rapid onset and faster offset of action.

Areas covered: This article evaluates the pharmacokinetics, efficacy, safety and tolerability of ticagrelor during DAPT after ACS and its potential use beyond the canonical twelve months after PCI. The review discusses studies comparing: ticagrelor and clopidogrel (DISPERSE, DISPERSE-2, PLATO, RESPOND Trial, ONSET/OFFSET Trials), ticagrelor and placebo (PEGASUS TIMI 54 Trial).

Expert opinion: For ACS patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. PEGASUS TIMI 54 showed that patients in whom ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based dual antiplatelet therapy, over 12 months. This strategy has been recently approved by the ACC/AHA guidelines. Further studies are needed to evaluate and eventually validate the role of the prolonged DAPT in patients treated with new generation stents.     

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.     

Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.     

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.     

Novel situations of endothelial injury in stroke--mechanisms of stroke and strategy of drug development: protective effects of antiplatelet agents against stroke

Stroke is the second cause of mortality worldwide, and intravenous administration of tissue plasminogen activator (t-PA) within 3 h of symptom onset is the only treatment proven effective for re-establishment of cerebral blood flow following acute ischemic stroke. However, its widespread application remains limited by its narrow therapeutic time window and the related risks of intracranial hemorrhage. On the other hand, in patients with atherothrombotic risk, antiplatelet agents are widely used to decrease the risk of occlusive arterial events. All of these drugs are used during coronary interventions and in the medical management of acute coronary syndromes. In contrast, only aspirin, cilostazol, and thienopyridine derivatives (ticlopidine and clopidogrel) are used in the long-term prevention of cerebrovascular events in patients with risk of recurrence. In this paper, we introduce recent clinical findings on antiplatelet therapies for secondary prevention after ischemic stroke and describe basic research that has focused on cerebrovascular protection by cilostazol, which has a unique pharmacological profile.     

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.     

氯吡格雷与质子泵抑制剂的相互作用

氯吡格雷能够降低冠心病患者再次发生心肌梗死的风险,故广泛用于急性冠脉综合征和经皮冠脉介入术后的患者。临床相关指南建议,氯吡格雷应与质子泵抑制剂（proton pump inhibitor,PPI）合用以减少氯吡格雷的胃肠道不良反应。但是,氯吡格雷需经肝脏细胞色素P450酶的同功酶CYP2C19代谢才能转化为活性产物发挥作用,而PPI同样主要由CYP2C19代谢。药代动力学研究显示,氯吡格雷与奥美拉唑合用会发生药物相互作用、由此降低氯吡格雷的抗血小板作用,而泮托拉唑与氯吡格雷的相互作用不明显。发表于2009年的系列回顾性病例对照研究表明,氯吡格雷与PPI合用会增加心血管不良事件的发生风险。但这一研究结果并未得到前瞻性的随机、对照研究和荟萃分析的证实。因此,目前仍需进行大规模的前瞻性的随机、对照试验来分析氯吡格雷和PPI合用与心血管不良事件风险间的相关性。鉴于临床上有大量服用氯吡格雷的患者需合用PPI来降低胃肠道出血风险,建议现最好选用与氯吡格雷相互作用较小的泮托拉唑。     

Prasugrel during primary percutaneous coronary intervention: evidence from clinical data

Primary percutaneous coronary intervention (PCI) encompassing stent implantation is a mainstay in the management of acute ST-elevation myocardial infarction (STEMI). Despite refinements in techniques and devices, peri- and post-procedural antithrombotic therapy remains pivotal to prevent early and late thrombotic events, without unduly increasing bleeding risk. Concomitant dual antiplatelet therapy with aspirin and clopidogrel has been considered until recently the standard of care in terms of oral antiplatelet agents. However, most recently a novel and more potent thienopyridine, prasugrel, has been tested in randomized trials including patients with STEMI, and subsequently approved for clinical practice in Europe and North America. Despite its potent antithrombotic effect, prasugrel also carries a statistically significant increase in the risk of bleeding, especially in the elderly, those with low body weight, and previous stroke or transient ischemic attack. Thus, the use of prasugrel, as well as that of clopidogrel or ticagrelor, should best be individualized to maximize clinical benefits and minimize hazards.     

Prasugrel as a safe alternative for clopidogrel-induced polyarthralgias

Clopidogrel is an oral thienopyridine that has been shown to reduce the risk of vascular death in patients with acute coronary syndrome, ischemic stroke, and peripheral vascular disease. The drug is associated with rare adverse effects such as thrombotic thrombocytopenia purpura, acute hepatotoxicity, and neutropenia. Only six cases have been reported that link acute arthritis with the use of clopidogrel. We describe a 64-year-old Caucasian man with sudden onset of severe arthritis, erythema, and swelling after starting clopidogrel therapy; he had no history of arthralgias while taking prasugrel during the previous 8?months. The patient was hospitalized for 3?days, and after cessation of clopidogrel therapy and conservative management, he improved dramatically, showing resolution of his joint erythema and swelling. The patient started prasugrel therapy at discharge, and no arthritic development was noted 8?weeks later. Although clopidogrel is commonly well tolerated, this case report demonstrates that clinicians should be aware that acute arthritis may be a possible adverse effect of clopidogrel. Additionally, polyarthralgias may not be a class effect of thienopyridines; patients who experience acute arthralgias during clopidogrel therapy may not experience similar adverse effects with prasugrel.     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

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.     

The value of clopidogrel in addition to standard therapy in reducing atherothrombotic events

The recent multinational, randomised, prospective studies Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Percutaneous Coronary Intervention substudy of CURE (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) have demonstrated the clinical efficacy and safety of clopidogrel for the treatment of patients with non-ST-segment elevation acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention. In these settings, clopidogrel significantly reduces the risk of atherothrombotic events, with relative risk reductions of 20-30% (absolute risk reduction 1.9-3.0%). Health economic evaluations based on data from these studies conducted in Europe and the United States have clearly demonstrated the cost-effectiveness of clopidogrel in combination with aspirin compared with aspirin alone for the management of ACS. Within-trial evaluations based on CURE and PCI-CURE data showed that treatment with clopidogrel on top of standard therapy reduced the cost of initial hospitalisation as well as the total cost associated with hospitalisations. Long-term economic analyses based on the CURE study demonstrate that clopidogrel is cost saving in the Netherlands and that the cost per life-year gained (LYG) in other European countries is between Euros 549 and Euros 5048. In the United States, the cost per LYG for clopidogrel has been assessed at US dollars 6173 on the basis of CURE, US dollars 5910 for PCI-CURE and US dollars 3685 for CREDO, all of which are considerably lower than that associated with common cardiovascular benchmarks. The results are robust and consistent across different countries using varying costing strategies and estimates of survival. In conclusion, these data demonstrate that clopidogrel in combination with aspirin for the management of ACS is both clinically effective and cost-effective in this setting.     

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.     

Clopidogrel: an updated and comprehensive review

The risk of adverse events in patients with acute coronary syndrome remains substantial despite the use of regular aspirin. The addition of clopidogrel to regular aspirin therapy has been shown to be associated with significantly better outcomes in a variety of clinical settings within the spectrum of acute coronary syndromes. In this article, the evidence and therapeutic implications for the use of clopidogrel in patients with non-ST-elevation and ST elevation acute coronary syndromes is discussed, and also in those undergoing percutaneous coronary intervention. The use of clopidogrel in combination with other antithrombotics in the acute setting is considered, including glycoprotein IIb/IIIa receptor antagonists and direct thrombin inhibitors. Clopidogrel has changed the way in which patients with non-ST-elevation and, more recently, ST elevation acute coronary syndromes are treated.     

Safety of clopidogrel and aspirin for stroke prevention: implications of the CHARISMA trial.

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage.The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone.Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.     

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.     

The discovery and development of prasugrel

Introduction: Prasugrel (CS-747, LY640315) is a third-generation thienopyridine, which gained approval by the FDA in 2009 for its use in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Areas covered: This article focuses on the preclinical profile of prasugrel. Using published preclinical and clinical studies, the authors summarize the pharmacokinetics, pharmacodynamics, and pharmacogenomics of prasugrel and their distinguishing features in efficacy and safety.

Expert opinion: Prasugrel has a more rapid, more potent antiplatelet effect with less interindividual response variability when compared to clopidogrel. Those therapeutic advantages are attributed to features of its chemical structure that favor the metabolic conversion of prasugrel to its active metabolite. However, the increased risk of bleeding has been associated with a greater antiplatelet effect and dosing profile; this is especially the case in those patients who are at a higher risk of bleeding complications. It is therefore important for an optimal dosing strategy of prasugrel to be identified to provide a formulation that has the best balance for efficacy and safety.