Antithrombotic therapies in primary angioplasty: rationale, results and future directions

Despite the improvement in outcome observed with primary angioplasty compared with thrombolysis, there is still room for improvement. Indeed, despite restoration of optimal epicardial flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a relatively large proportion. The aim of this article is to provide an up-to-date review of adjunctive antithrombotic therapy for primary angioplasty for ST-segment elevation myocardial infarction (STEMI).The HORIZONS trial has shown a significant reduction in mortality and major bleeding complications in patients treated with bivalirudin compared with those treated with glycoprotein (GP) IIb-IIIa inhibitors. Thus, bivalirudin may be considered as an alternative strategy to heparin plus GPIIb-IIIa inhibitors in primary angioplasty, especially in patients at high risk for bleeding complications. However, despite the negative results of the FINESSE trial, a large amount of evidence has been observed in favour of early administration of GPIIb-IIIa inhibitors, which should still be considered a reasonable strategy.Non-responsiveness to aspirin and clopidogrel is relatively common. However, future trials are needed to evaluate whether the routine assessment for non-responsiveness and a consequent change in therapy (to higher dosages of clopidogrel or a switch to another adenosine diphosphate [ADP]-receptor antagonist) may improve clinical outcome. Even though not yet demonstrated, it is conceivable that the greatest benefits of clopidogrel may come from early administration, and that this might be considered as part of a pharmacological facilitation strategy, together with early administration of GPIIb-IIIa inhibitors. As a result of better and faster inhibition of platelet aggregation, further benefits might be expected from the early administration of one of the new oral platelet ADP-receptor antagonists.As a consequence of the very low mortality currently achieved by primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, should be considered when exploring the potential benefits of adjunctive antithrombotic therapies in future randomized trials among patients undergoing mechanical revascularization for STEMI.     

Ticagrelor: Positive,negative and misunderstood properties as a new antiplatelet agent

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Importance of potent P2Y(12) receptor blockade in acute myocardial infarction: focus on prasugrel

INTRODUCTION: Prasugrel therapy is recommended in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). AREAS COVERED: This article reviews the efficacy and safety profile of prasugrel, cost considerations, and its role in clinical practice based on published data. The authors searched PubMed and Ovid databases for English language clinical trial articles involving the use of prasugrel in human subjects and patients, published through June 2012. The keyword "prasugrel" was used. The review focuses on clinical trials, but other articles including Food and Drug Administration documents are also reviewed. EXPERT OPINION: Prasugrel has a more rapid and greater pharmacodynamic (PD) effect than clopidogrel. No significant drug - drug interactions have been reported. In a large-scale randomized clinical trial, prasugrel was associated with better protection against ischemic event occurrence compared to clopidogrel, but more bleeding in ACS patients undergoing PCI. Adverse outcomes outweighed the benefit of prasugrel in certain subgroups, including patients over the age of 75, those weighing less than 60 kg, and patients with a prior history of stroke or transient ischemic attack. In subsequent PD studies, prasugrel therapy showed suboptimal platelet inhibition in selected patients. In addition, "hyper-responsiveness" to prasugrel may increase the risk of serious bleeding in high-risk patients. More detailed studies are warranted to explore antiplatelet regimens tailored to optimally limit ischemic and bleeding event occurrences. A Phase-III TRILOGY trial (NCT00699998) will indicate the clinical efficacy and safety of prasugrel in patients with non-ST-segment elevation ACS, who are medically managed without coronary revascularization.     

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.     

Antithrombotic therapy in ST-segment elevation myocardial infarction

INTRODUCTION: Anticoagulation is an integral part of both fibrinolytic therapy and percutaneous intervention (PCI) in the reperfusion treatment of ST-segment elevation AMI (STEMI). AREAS COVERED: This article reviews the choices of adjunctive anticoagulation regimens. Readers will appreciate the complexities of anticoagulation and the variable risk of clotting with ischemic/thrombotic complications versus that of bleeding. Antiplatelet therapy with aspirin and clopidogrel is recommended with fibrinolysis and PCI. Newer P2Y(12) inhibitors such as prasugrel and ticagrelor have been shown to reduce cardiovascular death, myocardial infarction (MI), stroke and stent thrombosis, as compared with clopidogrel. Ticagrelor has also been shown to reduce mortality. Glycoprotein IIb/IIIa inhibitors, by blocking the final pathway of platelet clumping with each other through bridging with fibrinogen, have the ability to disaggregate platelets, hence the potential for reducing thrombotic complications as well as increasing bleeding in patients undergoing PCI bleeding risks. Enoxaparin reduces death and MI compared with unfractionated heparin (UFH) with fibrinolytic therapy. There was a trend for a reduction in death, MI procedural failure or non-coronary artery bypass grafting (CABG) major bleeding compared with UFH in primary PCI. In primary PCI, bivalirudin has the advantage over UFH of inhibiting clot bound thrombin and reduces bleeding and mortality compared with the use of UFH plus glycoprotein IIb/IIIa inhibitors. Combinations of P2Y(12) antagonists and bivalirudin need to be tested to optimize the balance between efficacy and bleeding. EXPERT OPINION: This field is rapidly evolving with multiple appropriate approaches.     

Thrombocytopenia Associated with Antithrombotic Therapy in Patients with Cardiovascular Diseases

Agents with antiplatelet and anticoagulant activity have been proved to be effective in reducing the incidence of complications following acute coronary syndrome, percutaneous coronary intervention, and cardiopulmonary bypass. However, these agents, including heparin, glycoprotein IIb/IIIa receptor inhibitors, and thienopyridines, are associated with increased risk of bleeding and thrombocytopenia and have been administered together with increasing frequency in a variety of cardiovascular settings. Therefore, clinicians must be familiar with the safety and rational use of these potent antithrombotic agents. Clinical features of thrombocytopenia range from bleeding to thrombosis, even death, and therapy is very different depending on the underlying cause. Additionally, patients may sometimes need urgent intervention or surgery. Thus, it is essential to quickly discriminate the etiology and start appropriate therapy. This review highlights the pathogenesis, clinical and laboratory manifestation, differential diagnosis, and treatment of antithrombotic drug-induced thrombocytopenia in cardiovascular diseases.     

Ticagrelor,prasugrel, or clopidogrel in ST-segment elevation myocardial infarction: which one to choose?

Introduction: Clopidogrel, prasugrel, and ticagrelor are the currently available oral P2Y12 inhibitors for the treatment of ST-segment elevation myocardial infarction (STEMI), in association with aspirin. These agents bind the P2Y12 platelet receptor and thus inhibit platelet aggregation. Large randomized clinical trials have provided efficacy and safety data on P2Y12 inhibitors in STEMI patients.

Areas covered: This review focuses on key pharmacologic and clinical aspects of clopidogrel, prasugrel, and ticagrelor, highlighting their differences. Results from the main clinical trials are discussed, as well as the current STEMI guideline recommendations, to help inform agent selection for patients presenting with STEMI.

Expert opinion: Clinical trials studying newer P2Y12 inhibitors with increased potency have shown further reduction of cardiovascular events compared with clopidogrel, therefore suggesting the use of ticagrelor or prasugrel as a first-line agent for STEMI treatment. There are still clinical situations – such as fibrinolysis, high risk of bleeding, use of oral anticoagulant, and financial hurdles – in which clopidogrel maintains a role in the treatment of STEMI.     

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.     

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.     

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.     

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.     

Guidelines for stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is most commonly associated with nonvalvular cardiovascular disease and is especially frequent among the elderly. The annual risk for stroke in patients with AF is approximately 5% with a wide range depending on the presence of additional risk factors. For patients who cannot successfully be converted and maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective method for preventing stroke. The 2 drugs which are indicated for stroke prophylaxis in patients with AF are warfarin and aspirin. For primary prevention, warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less effective, resulting in a 20 to 30% risk reduction. Combination therapy with aspirin and low intensity warfarin adjusted to an International Normalised Ratio (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history of stroke or transient ischaemic attack (TIA), the absolute risk reduction with warfarin is even greater because of the high risk of stroke in this population. In contrast, aspirin has not been shown to significantly reduce the risk of stroke in patients with AF when used for secondary prevention. When appropriately managed, warfarin is associated with a low risk of major bleeding. In controlled trials of highly selected patients, the annual rate of intracranial haemorrhage (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty anticoagulation clinics can achieve similar low rates of major bleeding. However, these results cannot be extrapolated to the general population. Factors which have been identified as predictors of bleeding include advanced age, number of medications and most importantly, the intensity of anticoagulation. INR values above 4.0 have been associated with an increased risk of major bleeding while values below 2.0 have been associated with thrombosis. Slow careful dosage titration, regular laboratory monitoring and patient education can substantially reduce the risk of complications. In patients with AF, antithrombotic therapy has been shown to be cost effective. For high risk patients, warfarin is the most cost-effective therapy, provided the risks for bleeding are minimised. In contrast, aspirin is the most cost-effective agent for low risk patients. Current practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5: range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75 years of age or younger patients with additional risk factors. Aspirin should be reserved for low risk patients or those unable to take warfarin. Although these recommendations are strongly supported by the clinical trial evidence, studies show that many patients are not receiving appropriate antithrombotic therapy. In particular, warfarin is underutilised in high risk elderly patients. Additional studies are needed to identify barriers that prevent implementation of the clinical trial findings into clinical practice.     

Enoxaparin: a review of its use in ST-segment elevation myocardial infarction

Enoxaparin (enoxaparin sodium; Lovenox) is a low-molecular-weight heparin (LMWH) that has recently been approved by the US FDA for use in patients with medically managed ST-segment myocardial infarction (STEMI), or STEMI with subsequent percutaneous coronary intervention (PCI). It binds to and potentiates the action of antithrombin, and inhibits coagulation factors XIa, IXa, Xa and IIa (thrombin), thereby preventing formation of blood clots. Unfractionated heparin (UFH) has long been regarded as the antithrombotic agent of choice in the adjunctive treatment of patients with STEMI. However, compared with UFH, enoxaparin has many advantages in terms of its pharmacodynamic profile and, potentially, also its efficacy. Enoxaparin was significantly more effective than UFH in patients presenting with STEMI who underwent fibrinolytic therapy in terms of the 30-day combined incidence of all-cause mortality plus recurrent nonfatal myocardial infarction (MI) [primary endpoint], and all-cause mortality plus recurrent nonfatal MI plus urgent revascularization (secondary endpoint) in the ExTRACT-TIMI 25 trial. The significant difference in the incidence of the composite primary endpoint between these two groups was maintained at the 1-year follow-up. Although bleeding was reported more frequently with enoxaparin than with UFH in the ExTRACT-TIMI 25 trial, enoxaparin was associated with a net clinical benefit relative to UFH. Patients in this trial received enoxaparin as an initial 30 mg intravenous bolus, followed by 1 mg/kg subcutaneously within 15 minutes and then every 12 hours for up to 8 days; the first two subcutaneous dosages were not to exceed 100 mg. Patients > or =75 years of age did not receive the initial bolus of enoxaparin and the 12-hourly dosages were reduced to 0.75 mg/kg; the dose was also reduced to 1 mg/kg every 24 hours in patients of any age who had an estimated creatinine clearance (CL(CR)) of <30 mL/min. Data from several earlier randomized, multicentre, phase III trials support these results.     

心力衰竭患者高凝状态与抗栓治疗

心力衰竭(HF)患者脑卒中、肺栓塞及外周静脉血栓等血栓栓塞事件的发生率明显高于非HF患者。其抗栓治疗一直存在争议,主要权衡抗栓(抗凝和抗血小板)治疗、血栓栓塞风险降低的获益和出血的风险。多项研究已证实,有心房颤动或血栓栓塞史的HF患者需要进行常规抗凝治疗,但窦性心律HF患者是否需要进行预防性抗栓治疗目前还没有达成共识。     

一例联合应用华法林和氯吡格雷导致消化道出血患者的药学监护

目的 探讨1例联合抗栓治疗导致消化道出血患者的抗栓治疗方案优化及临床药师的作用.方法 临床药师结合患者疾病史、临床特征、实验室检查等多方面因素,通过文献查阅,比较不同抗血小板药物特点,针对患者不同临床疾病进展,合理选用抗栓治疗药物并进行药学监护.结果 患者的消化道出血与华法林+氯吡格雷联合抗栓治疗有关,临床药师建议华法...     

Vorapaxar: a novel protease-activated receptor-1 inhibitor

INTRODUCTION: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. AREAS COVERED: Only 20% relative risk (～ 2% absolute risk) reduction associated with newer P2Y(12) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombin-protease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations - vorapaxar and atopaxar. In preclinical and Phase I - II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. EXPERT OPINION: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.     

Prasugrel: A Guide to Its Use in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention in the US

Oral prasugrel (Effient®; Efient®) provides rapid, potent inhibition of platelet aggregation. It is indicated (in combination with aspirin) for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In the pivotal clinical trial in this patient population, prasugrel-based therapy was associated with a significantly lower incidence of ischemic events than clopidogrel-based therapy. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. Prasugrel appears to have an overall favorable risk: benefit ratio in ACS patients undergoing PCI who do not have these three easily identifiable clinical characteristics. Limited pharmacoeconomic analyses suggest that prasugrel-based therapy is an economically attractive treatment strategy relative to clopidogrel-based therapy from a US healthcare payer perspective.     

Triple antithrombotic therapy in patients with atrial fibrillation who have undergone percutaneous coronary intervention with stent implantation

Purpose The efficacy and safety of triple antithrombotic therapy in patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) with stent implantation are reviewed. Summary A systematic literature search of PubMed, EMBASE, and International Pharmaceutical Abstracts identified a total of 10 cohort studies and one meta-analysis investigating triple antithrombotic therapy in this patient population. With respect to efficacy, evidence from nonrandomized studies supports the superiority of triple antithrombotic therapy over dual antiplatelet therapy at preventing major adverse cardiac events and all-cause mortality. With respect to safety, the heterogeneous methodology and definitions for bleeding in the studies do not allow for easy interpretation and quantification of bleeding risk. There appears to be qualitative consistency that the rate of bleeding is higher with triple antithrombotic therapy compared with dual antiplatelet therapy. The meta-analysis, as well as a recent large registry data cohort study, demonstrated a twofold increase in the risk of major bleeding with triple antithrombotic therapy. Conclusion The heterogeneous methodology of the available studies does not allow for conclusive interpretation and quantification of the efficacy and safety of triple antithrombotic therapy in patients with AF undergoing PCI with stent implantation compared with dual antiplatelet therapy. Evidence from small cohort studies support the benefit of triple antithrombotic therapy at reducing major adverse cardiac events and all-cause mortality with higher rates of bleeding.     

Repeat oral dosing of prasugrel, a novel P2Y12 receptor inhibitor, results in cumulative and potent antiplatelet and antithrombotic activity in several animal species

Antiplatelet and antithrombotic activity of multiple oral dosing of prasugrel were evaluated in several animal species. Prasugrel's active metabolite concentration-relatedly inhibited in vitro ADP-induced aggregation of rat, rabbit, dog, monkey and human platelets. Oral administration of prasugrel to dogs (0.03-0.3 mg/kg/day) and monkeys (0.1 and 0.3 mg/kg/day) once a day for 14 days resulted in potent, dose-related and cumulative inhibition of ADP-induced platelet aggregation. The inhibitory effects reached a plateau on days 3 to 5 and thereafter were maintained during dosing. Inhibition decreased gradually after cessation of dosing with near full recovery by 7 days after last dose. Antiplatelet and antithrombotic activity of prasugrel and clopidogrel were further examined in rats. Multiple oral dosing of prasugrel (0.3-3 mg/kg/day) to rats resulted in more potent inhibition of platelet aggregation compared to clopidogrel (3-30 mg/kg/day) and ticlopidine (30-300 mg/kg/day). Separate experiments confirmed that platelet inhibition was associated with inhibition of [(3)H]-2-methylthio-ADP binding to rat platelets. In a rat model of electrically-induced arterial thrombosis, prasugrel (0.1-1 mg/kg/day, p.o.) significantly prolonged the time to arterial occlusion and increased the duration of arterial patency. The inhibition of platelet aggregation of prasugrel was about 10 and 300 times more potent than clopidogrel and ticlopidine, respectively. Overall these results show that in several species multiple oral administration of prasugrel results in more potent inhibition of platelet aggregation and thrombus formation than clopidogrel and ticlopidine, and that these effects are mediated by inhibition of platelet ADP receptors.     

Nitric oxide-releasing non-steroidal anti-inflammatory drugs: a new generation of antithrombotics?

Long-term use of aspirin as an antithrombotic agent is limited by its toxicity in the gastrointestinal tract. Even very low doses of aspirin can markedly increase the risk of gastrointestinal bleeding and ulceration. Addition of a nitric oxide (NO)-releasing moiety to non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to greatly reduce their ulcerogenic properties as well as their renal toxicity. We proposed that similar derivatisation of aspirin may yield a potent, gastrointestinal-sparing antithrombotic drug. Two prototype compounds (NCX-4215 and NCX-4016; Nicox SA) have been evaluated thus far. Each shows comparable or better anti-aggregatory activity to aspirin while not inducing detectable gastric damage. Current studies are aimed at determining what the optimal balance is between nitric oxide release and inhibition of thromboxane synthesis to achieve good antithrombotic activity with low toxicity. NO-aspirin derivatives appear to offer great potential as gastrointestinal-sparing antithrombotic drugs.