ticagrelor and cangrelor

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Administration, Intravenous; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Ticagrelor

The pharmacological and clinical differences of the three recommended oral P2Y

Topics: Adenosine Monophosphate; Administration, Intravenous; Administration, Oral; Blood Platelets; Cardiovascular Diseases; Clinical Decision-Making; Clopidogrel; Drug Substitution; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Treatment Outcome

Newer P2Y12 inhibitors have more rapid onset of platelet inhibition compared with clopidogrel, especially the intravenous P2Y12 inhibitor cangrelor. Direct comparisons between cangrelor and oral P2Y12 inhibitors ticagrelor and prasugrel do not exist. Thus, we performed a network meta-analysis to directly and indirectly compare different P2Y12 inhibitors in patients undergoing percutaneous coronary intervention (PCI).. MEDLINE/PubMed and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared at least two P2Y12 inhibitors including cangrelor, clopidogrel, prasugrel, and ticagrelor. Network meta-analysis with a Bayesian approach was performed to directly and indirectly compare the effects of the aforementioned P2Y12 inhibitors on clinical outcomes. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes.. This analysis included 15 RCTs with 54,025 patients randomized to cangrelor (n=12,475), clopidogrel (n=26,903), prasugrel (n=7455), or ticagrelor (n=7192) at time of PCI. Patients had a mean age of 63±10, 74% were male, and 82% underwent PCI for acute coronary syndrome. No significant differences between cangrelor and clopidogrel were found with respect to cardiovascular death (OR 1.01 [CrI 0.23-4.39]), myocardial infarction (OR 0.94 [CrI 0.69-1.25]), major adverse cardiac events (OR 0.91 [CrI 0.69-1.18]), stent thrombosis (OR 0.66 [CrI 0.37-1.19]), or major bleeding (OR 1.52 [CrI 0.79-2.98]). Rank probability data suggested that ticagrelor and prasugrel were better than cangrelor for reducing ischemic events, though these differences were not significant.. Despite rapid platelet inhibition provided by cangrelor, newer oral P2Y12 inhibitors such as ticagrelor and prasugrel have comparable clinical outcomes.

Topics: Adenosine; Adenosine Monophosphate; Clopidogrel; Humans; Myocardial Infarction; Network Meta-Analysis; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine; Treatment Outcome

Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.

Topics: Adenosine; Adenosine Monophosphate; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Diabetes Mellitus, Type 2; Drug Resistance; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Risk Factors; Ticagrelor; Ticlopidine; Treatment Outcome

Pretreatment with oral P2Y12 inhibitors occurs each time clopidogrel, prasugrel, ticagrelor are given to patients with suspected coronary artery disease before definition of the coronary anatomy. In acute coronary syndromes, the practice of administering oral P2Y12 inhibitors upstream has been the object of significant controversy in recent years, following the publication of two trials of pretreatment in non-ST-segment elevation acute coronary syndromes and ST-segment elevation myocardial infarction, respectively. The introduction in the market of cangrelor - the first intravenous P2Y12 inhibitor - represents a new opportunity but also a new challenge for clinicians. This article reviews current recommendations and supporting evidence surrounding pretreatment with oral and intravenous P2Y12 inhibitors in patients with acute coronary syndromes.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clopidogrel; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine

Acetylsalicylic acid and clopidogrel are two antiplatelet agents currently used in the therapy of peripheral arterial disease. Cilostazol also inhibits platelet aggegration. These agents present limitations that novel antiplatelet agents may overcome.. The aim of this manuscript is to review current data on the use of novel antiplatelet agents in peripheral arterial disease.. An extensive search in the English medical literature has yielded a number of publications on a number of novel antiplatelet agents; atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel, and prasugrel.. Data on atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel and prasugrel come mainly from cardiology publications. Limitations, side effects and effectiveness of each of these agents are studied, but their use in peripheral arterial disease is limited, especially for those agents that have not still been approved for this indication. As expected, main side effect of most of these agents is haemorrhage, but other important side effects limit the use of some of these agents in specific subgroups of patients.. Novel antiplatelet agents demonstrate a range of promising characteristics, but further study and clinical trials are necessary for them to be considered safe and effective.

Topics: Adenosine; Adenosine Monophosphate; Imines; Lactones; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Quinazolinones; Sulfonamides; Ticagrelor

It is estimated that in the United States, each year, approximately 620,000 persons will experience an acute coronary syndrome and approximately 70% of these will have non-ST-elevation acute coronary syndrome. Cardiovascular disease still accounts for 1 of every 3 deaths in the United States, and there is an urgent need to improve the prognosis of patients presenting with acute coronary syndrome. Cardiovascular mortality and ischemic complications are common after acute coronary syndrome, and the advent of newer antithrombotic therapies has reduced ischemic complications, but at the expense of greater bleeding. The new antithrombotic agents also raise the challenge of choosing between multiple potential therapeutic combinations to minimize recurrent ischemia without a concomitant increase in bleeding, a decision that often varies according to an individual patient's relative propensity for ischemia versus hemorrhage. In this review, we will synthesize the available information to arm health care providers with the contemporary knowledge on antithrombotic therapy and individualize treatment decisions.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Anticoagulants; Antithrombins; Clinical Trials as Topic; Cytochrome P-450 CYP2C19; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Genotype; Hemorrhage; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polymorphism, Genetic; Practice Guidelines as Topic; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor

Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet drugs (aspirin, ticlopidoine, clopidogrel, and prasugrel) or intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) do not increase the incidence of dyspnea in randomized trials. Dyspnea after oral reversible antiplatelet agents remains unexplained. A transfusion-related acute lung injury (TRALI) hypothesis has been proposed. The dyspnea risks after cangrelor, an intravenous reversible antiplatelet agent, are not well defined but may offer a universal mechanism linking TRALI, dyspnea, and reversible platelet inhibition.. We analyzed safety data from recent head-to-head randomized trials with reversible antiplatelet agents (ticagrelor, elinogrel, and cangrelor) compared to irreversible (clopidogrel/placebo) comparators.. All three reversible antiplatelet agents cause excess dyspnea. In contrast to the high double-digit rates after oral ticagrelor or elinogrel, the dyspnea risks after intravenous cangrelor were smaller (<2%) but still consistently and significantly higher than in the corresponding control arms.. The clinical utility of reversible antiplatelet strategies has been challenged. Despite a potential advantage of fewer bleeding events during heart surgery, reversible antiplatelet agents carry the risk of potential autoimmune reactions manifesting as dyspnea. Repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets are among the potential mechanism(s) responsible for dyspnea after reversible antiplatelet agents.

Topics: Acute Lung Injury; Adenosine; Adenosine Monophosphate; Administration, Oral; Clopidogrel; Dyspnea; Humans; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Sulfonamides; Ticagrelor; Ticlopidine; Transfusion Reaction

The dual antiplatelet therapy with acetylsalicylic acid and clopidogrel has been the mainstay of both acute and chronic phase coronary artery disease, reducing importantly the risk of adverse events. Despite a correct compliance, a non-negligible rate of adverse events still happens. New compounds, with improved properties, are now clinically available (such as prasugrel or ticagrelor) or under advanced development. The aim of the present review is the description of these new compounds, particularly prasugrel and ticagrelor.

Topics: Adenosine; Adenosine Monophosphate; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Double-Blind Method; Dyspnea; Hemorrhage; Humans; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Receptors, Proteinase-Activated; Thiophenes; Ticagrelor; Treatment Outcome

New P2Y12 inhibitors can be classified as oral (prasugrel and ticagrelor) and intravenous drugs (cangrelor and elinogrel). These P2Y12 inhibitors might be superior to clopidogrel for reducing ischemic events in patients with coronary artery disease (CAD). We performed a meta-analysis of randomized trials that compared new oral or intravenous P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients.. Twelve randomized, placebo-controlled studies and two subgroup analyses of included studies on ST-segment elevation myocardial infarction (STEMI) were included. The database consisted of 82,784 patients, with 43,875 (53%) on new oral P2Y12 inhibitors and 38909 (47%) on intravenous P2Y12 inhibitors compared with clopidogrel. The primary efficacy endpoint was major adverse cardiac events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. New oral P2Y12 inhibitors significantly decreased MACEs (odds ratio: 0.85, p<0.0001 for the whole cohort; OR: 0.77, p=0.04 for STEMI) and all-cause death (OR: 0.88, p=0.04 for the whole cohort; OR: 0.77, p=0.01 for STEMI). Among new intravenous P2Y12 inhibitors, only cangrelor significantly decreased the risk of MACEs. An increase in TIMI major bleeding was observed only by prasugrel among the new P2Y12 inhibitors.. New oral P2Y12 inhibitors reduce ischemic events, but there is no obvious increase in major bleeding in patients with CAD, and the risk/benefit ratio is particularly favorable for STEMI patients. Moreover, only cangrelor is beneficial for ischemic events in patients on new intravenous P2Y12 inhibitors.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Administration, Oral; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Multicenter Studies as Topic; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Stents; Stroke; Sulfonamides; Thiophenes; Thrombolytic Therapy; Ticagrelor; Ticlopidine

Effective antagonism of the P2Y12 platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y12 antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-ST-segment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y12 receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clinical Trials as Topic; Clopidogrel; Combined Modality Therapy; Coronary Artery Bypass; Coronary Thrombosis; Diabetes Complications; Hemorrhage; Humans; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Precision Medicine; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Renal Insufficiency; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Dyspnea has been consecutively reported in some trials evaluating new P2Y₁₂ inhibitors.. We aimed to review and quantify the global risk of dyspnea of recent P2Y₁₂ inhibitor drugs, and evaluate its association with the reversibility profile of P2Y₁₂ inhibitors.. A database search (March 2013) retrieved randomized controlled trials (RCTs) comparing new antiplatelet drugs (ticagrelor, prasugrel, cangrelor, elinogrel) with clopidogrel. The primary outcome was the incidence of dyspnea. Placebo-controlled trials were excluded. Meta-analysis was performed and estimates were expressed as risk ratio (RR) and 95% confidence intervals (95% CIs). Dyspnea incidence was evaluated according to the reversibility profile of P2Y₁₂ antagonists.. We found eight RCTs including 41,289 patients. Prasugrel was not associated with an increased risk of dyspnea (RR 1.09, 95% CI 0.93-1.27), whereas ticagrelor (RR 1.95, 95% CI 1.37-2.77), cangrelor (RR 2.42, 95% CI 1.36-4.33), and elinogrel (RR 3.25, 95% CI 1.57-6.72) showed an increased risk of dyspnea. Reversible inhibitors significantly increased the risk of dyspnea compared with the irreversible inhibitor, prasugrel, through adjusted indirect comparison (RR 1.99, 95% CI 1.40-2.82).. The reversible P2Y₁₂ antagonists ticagrelor, cangrelor, and elinogrel have an increased incidence of dyspnea in increasing order when compared with irreversible P2Y₁₂ inhibitors such as clopidogrel or prasugrel.

Topics: Adenosine; Adenosine Monophosphate; Clopidogrel; Dyspnea; Humans; Incidence; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine

Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.

Topics: Adenosine; Adenosine Monophosphate; Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Clopidogrel; Drug Therapy, Combination; Humans; Off-Label Use; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Signal Transduction; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Mortality and morbidity in acute coronary syndromes (ACSs), caused principally by plaque erosion or rupture leading to thrombus formation and myocardial ischemia, have been reduced by a combination of antithrombotic agents (antiplatelet drugs and anticoagulants) and early revascularization. Aspirin is the foundation antiplatelet agent. New P2Y12 receptor inhibitors (prasugrel and ticagrelor) have clear benefits compared with clopidogrel for dual antiplatelet therapy, and cangrelor or vorapaxar, a thrombin receptor inhibitor, may be of value in specific settings. Anticoagulation uses 1 of 4 choices: bivalirudin, unfractionated heparin, enoxaparin, and fondaparinux. Moreover, some patients (such as those who have chronic atrial fibrillation) require triple therapy with aspirin, clopidogrel, plus an anticoagulant, frequently a vitamin K antagonist. New oral anticoagulants have been shown to be at least as effective as vitamin K antagonists in atrial fibrillation and led to fewer bleeding complications. Finally, the combination of aspirin, clopidogrel, and low-dose rivaroxaban has recently been approved by the European Medicines Agency (but not the Food and Drug Administration) for secondary prevention after ACS. Several strategies have been developed to balance the potential benefit of antithrombotic therapy against the risk of bleeding complications, for example, radial access in coronary angiography or restricted use of combination therapy, and others are under investigation, such as discontinuation of aspirin. This overview summarizes the current status of antithrombotic therapy in ACS and describes strategies currently explored to optimize its benefit/risk ratio.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Anticoagulants; Aspirin; Drug Therapy, Combination; Enoxaparin; Eptifibatide; Fondaparinux; Heparin; Hirudins; Humans; Lactones; Peptide Fragments; Peptides; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Receptors, Thrombin; Recombinant Proteins; Thiophenes; Ticagrelor; Tirofiban; Tyrosine; Warfarin

The considerable progress in P2Y12-platelet blockers has important perioperative implications due to a family of novel agents beyond clopidogrel. Although prasugrel is more potent than clopidogrel due to more efficient hepatic metabolism, it is limited clinically by its irreversibility and bleeding risks. Ticagrelor, as the first approved direct and reversible oral P2Y12 blocker, still is limited clinically by its novel side-effect profile. Intravenous reversible P2Y12 blockade is possible now with both cangrelor and elinogrel, although both agents are still in clinical development. Furthermore, elinogrel offers the possibility of both oral and parenteral P2Y12 blockade with a single agent. Future trials likely will continue to evaluate and compare the safety and efficacy of these agents in multiple clinical settings, including the perioperative period.

Topics: Adenosine; Adenosine Monophosphate; Humans; Perioperative Care; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thiophenes; Ticagrelor

Dual antiplatelet therapy is a guideline mandated for patients with acute coronary syndromes (ACS). Despite its use, thrombotic events continue to occur both early and late. Platelet function testing has been used to define the in vitro effects of new antiplatelet agents, and it has been suggested that it be used to choose therapy. The role of platelet function testing, particularly with newer antiplatelet agents, remains unclear.. We review the rationale for platelet function testing and its application in monitoring patients on antiplatelet therapy. We also review recent clinical trials of newer antiplatelet agents. On the basis of this review, we reach conclusions on the current role of antiplatelet function testing in monitoring modern antiplatelet therapy and the role of the new antiplatelet agents in the treatment of ACS.. We reviewed recent publications on platelet function testing and clinical trials of newer antiplatelet therapies compared with clopidogrel.. Platelet function testing is complex, but there is now a bedside test, VerifyNow. High platelet reactivity has been associated with worse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Recent clinical trials have not found any advantage in outcomes in patients who have their therapy adjusted by monitoring their platelet function. Newer agents, prasugrel, ticagrelor, and cangrelor, produce more rapid, complete, less variable effects on platelet function than clopidogrel. Prasugrel was found to improve outcomes compared with clopidogrel in patients with ACS undergoing percutaneous intervention. Ticagrelor is beneficial in all patients with ACS and reduces cardiovascular mortality compared with clopidogrel. Cangrelor improves outcomes in patients undergoing stenting. Recent studies to assess the role of platelet function monitoring of the effects of clopidogrel and modifying treatments have not been successful.. Recent clinical trials have indicated that newer antiplatelet agents have advantages over clopidogrel in the treatment of ACS. Platelet function testing gives us a guide to the timing, efficacy, and variability of therapy and can correlate with poor patient outcomes; however, the use of antiplatelet function testing to tailor therapy does not seem appropriate.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Blood Platelets; Clopidogrel; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Admissions to emergency care centres with acute coronary syndromes remain one of the principal burdens on healthcare systems in the Western world. Early pharmacological treatment in these patients is crucial, lessening the impact on both morbidity and mortality, with the cornerstone of management being antiplatelet agents. While aspirin and clopidogrel have been the drugs of choice for nearly a decade, an array of newer, more potent antiplatelet agents are now available or in late stage development. Data are rapidly gathering suggesting these agents have superior anti-ischaemic properties, improving patient outcomes, but that for some agents increased vigilance and appropriate patient selection may be necessary to guard against bleeding complications. In this review, the authors aim to deliver an overview of the changing field of antiplatelet therapy and provide information about the relative risks and benefits of these newer agents, many of which will be entering widespread clinical use imminently.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Emergency Treatment; Female; Humans; Male; Patient Selection; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Topics: Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Coronary Artery Bypass; Humans; Perioperative Care; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Ticagrelor; Ticlopidine

ADP plays a pivotal role in localized platelet activation and recruitment, and, with that, in the maintenance of thrombus integrity, making it a suitable target for the control of intravascular thrombosis. The limited distribution of one of its receptors, the P2Y12 receptor, primarily to platelets makes it an especially attractive pharmacologic target. For the last several decades the thienopyridine family of P2Y12 antagonists have provided the vast majority of clinical data confirming the clinical benefit of selective P2Y12 inhibition. Recently, new thienopyridine plus nonthienopyridine P2Y12 antagonists have become available or are being studied that will further improve our treatment of patients with coronary disease.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clopidogrel; Coronary Artery Disease; Humans; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Stents; Sulfonamides; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

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.

Topics: Adenosine; Adenosine Monophosphate; Animals; Clopidogrel; Humans; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thienopyridines; Thiophenes; Ticagrelor; Ticlopidine

Inhibiting platelet function is a key therapeutic principle in cardiology because platelets play a pivotal role in triggering cardiovascular events. In addition to acetylsalicylic acid, a cyclooxygenase inhibitor, ADP-receptor blockers are frequently used for anti-platelet therapy. This therapy does not abolish platelet activation and aggregation. Platelets may still be activated by alternative routes such as the thrombin receptor-mediated pathway. New, more potent inhibitors of platelet function continue to lower the risk of ischaemic events but several trials and clinical registries have also shown that this advantage was frequently offset by an increased risk of bleeding complications. As a consequence, the individual risk of ischaemia and bleeding of a patient must be taken into consideration to select the platelet inhibitor offering the best benefit-risk ratio. Modern laboratory diagnostics may help to achieve this goal by complementing functional platelet tests with pharmacogenomic analyses consistent with the idea of "personalized medicine".

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Coronary Thrombosis; Drug Interactions; Hemorrhage; Humans; Piperazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor; Ticlopidine

P2Y12, one of the two platelet receptors for adenosine diphosphate (ADP), plays a central role in platelet function. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥10 µM), is unable to induce full, irreversible platelet aggregation. Patients with congenital P2Y12 defects display a mild-to-moderate bleeding diathesis of variable severity, characterised by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA). Its most important drawback is the inability to inhibit adequately P2Y12-dependent platelet function in about 1/3 of patients, at the recommended therapeutic doses. The incidence of bleeding events is similar in ASA-treated and clopidogrel-treated patients; however, the combination of ASA and clopidogrel causes more bleeding than each drug in monotherapy. Compared to clopidogrel, new drugs inhibiting P2Y12, such as prasugrel and ticagrelor, decrease the risk of cardiovascular events and increase the risk of bleeding complications, because they adequately inhibit P2Y12-dependent platelet function in the vast majority of treated patients.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Animals; Clinical Trials, Phase III as Topic; Clopidogrel; Hemorrhage; Humans; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine

The important role of the P2Y12 receptor in amplification of platelet activation and associated responses and the limitations associated with clopidogrel therapy have led to the development of novel inhibitors of this receptor. Three reversibly-binding P2Y12 inhibitors are in phase 3 development, ticagrelor, cangrelor and elinogrel. The pharmacology and clinical trial data for each of these inhibitors are discussed and compared with relevant data for the thienopyridines clopidogrel and prasugrel.

Topics: Adenosine; Adenosine Monophosphate; Animals; Clinical Trials, Phase III as Topic; Clopidogrel; Humans; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Protein Binding; Purinergic P2Y Receptor Antagonists; Quinazolinones; Sulfonamides; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

Thienopyridines have become the cornerstone of treatment of percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y(12) inhibitors are more potent, more predictable and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk PCI. Four new P2Y(12) inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral prodrug leading to irreversible blockade of the P2Y(12) receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y(12) receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y(12) receptor providing the highest level of inhibition and elinogrel is an intravenous and oral P2Y(12) antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y(12) inhibition led respectively to significant 19 % and 16 % relative risk reduction of a similar primary endpoint combining cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Both drugs showed a significant 0.6 % absolute excess of TIMI major bleeding not related to CABG surgery. The effect of these new compounds is prompt, predictable and powerful as compared to clopidogrel. Their net benefit is particularly marked in PCI for STEMI patients, in which there is no significant increase in major bleeding when compared with clopidogrel. However, because in clinical trials patients perceived to be at higher risk for bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a "real-world" setting i.e. in the elderly patient with comorbidities.

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Clinical Trials as Topic; Clopidogrel; Combined Modality Therapy; Disease Management; Drug Resistance; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Multicenter Studies as Topic; Myocardial Infarction; Myocardial Reperfusion; Myocardial Revascularization; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine; Time Factors

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: i) it is a pro-drug that needs to be metabolized to its active metabolite; ii) it has a delayed onset and offset of action; iii) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG (Coronary Artery Bypass Grafting) related bleeding complications. Two direct and reversible P2Y12 antagonists, cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor did not prove superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor proved to be superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but was, like prasugrel, was associated with higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery was necessary in ticagrelor-treated patients compared to clopidogrel-treated patients to limit the severity of post-surgical bleeding.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Catheter Ablation; Clinical Trials as Topic; Clopidogrel; Coronary Artery Bypass; Humans; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

Dual antiplatelet therapy with aspirin and clopidogrel is a well-established standard of care for patients with acute coronary syndromes. Whether there are other drug strategies or therapies that will achieve fewer ischemic events, and at the same time be associated with fewer bleeding complications, is a question recurrently asked. Finding the appropriate pharmacologic calibration of antiplatelet potency and applying such a pharmacodynamic effect to all patients has only been partially successful. The shadow of this one-size-fits-all dilemma is now being recast with the arrival of newer antiplatelet agents, which are attempting to decouple antithrombotic potency from bleeding liability. Novel antiplatelet agents that act faster and have more consistent pharmacokinetics and higher potency are steadily emerging. Additionally, newer agents that target unique sites, such as the thrombin receptor on platelets, are being studied in large-scale clinical trials. Each of these new agents has the potential to extend net clinical benefits beyond those provided by aspirin and clopidogrel.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Cilostazol; Clopidogrel; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Tetrazoles; Thiophenes; Ticagrelor; Ticlopidine

Use of the ADP (P2Y(12))-receptor antagonist clopidogrel is a cornerstone of dual platelet inhibition in acute coronary syndromes and following stent implantation. Because of the metabolization into its active form and the irreversible inhibition of the ADP receptor there are disadvantages to clopidogrel which could limit its efficacy in reducing clinical events. This is particularly problematic in so-called poor responders with reduced metabolizing activity and hence reduced platelet inhibition. Two novel drugs for platelet inhibition in acute coronary syndrome could become relevant in clinical practice. The irreversible ADP-receptor antagonist prasugrel led to stronger platelet inhibition, fewer ischemic events but more bleeding complications compared to clopidogrel in the TRITON-TIMI-38 trial. The reversibly binding, direct-acting ADP-receptor antagonist ticagrelor, which is effective without metabolization, is also superior over clopidogrel in reducing platelet aggregation and decreased the number of ischemic events in the PLATO-trial. However, it did not increase the rate of overall major bleeding and was shown to reduce total mortality. This review article summarizes current data on novel platelet inhibitors and delineates their potential influence on clinical practice.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Humans; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Precision Medicine; Thiophenes; Thrombolytic Therapy; Ticagrelor

The use of oral antiplatelet therapy in reducing vascular events has been extensively studied. Currently available oral antiplatelet agents include aspirin and the thienopyridine P2Y12 receptor antagonists. These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention (PCI). Resistance to either or both of these agents is a major concern, as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes. As a result, there is a need for newer, more effective antiplatelet agents to address the limitations of currently available therapy. Prasugrel, a third generation thienopyridine, has been approved by both the FDA and European Commission. Two additional P2Y12 agents, ticagrelor and cangrelor are in advanced stages of development. The possible advantages of prasugrel over clopidogrel include a faster onset of action, reduced inter-patient variability and more potent platelet inhibition. Ticagrelor is an oral reversible P2Y12 antagonist with greater platelet inhibition compared with clopidogrel. Cangrelor is being developed as an intravenous P2Y12 antagonist with a very fast onset and offset, which may offer advantages particularly in the setting of coronary intervention. These emerging antiplatelet agents may offer advantages such as faster onset of action, greater potency and reversibility of platelet inhibition. This article summarizes the available clinical data on the upcoming P2Y12 antiplatelet agents in the treatment of coronary artery disease.

Topics: Adenosine; Adenosine Monophosphate; Animals; Coronary Artery Disease; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor

Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current 'gold standard' antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factor-dependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.

Topics: Adenosine; Adenosine Monophosphate; Benzofurans; Blood Platelets; Carbamates; Clinical Trials as Topic; Clopidogrel; Humans; Lactones; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Receptor, PAR-1; Receptors, Proteinase-Activated; Thiophenes; Ticagrelor; Ticlopidine; von Willebrand Factor

The interaction of ADP with its platelet receptor P2Y12 plays a crucial role in platelet activation and thrombogenesis. This article reviews the pharmacology and clinical trials of specific antagonists of P2Y12. Clopidogrel is a thienopyridine with proven antithrombotic efficacy, but it has some important drawbacks: (a) it is a pro-drug that needs to be metabolized to its active metabolite; (b) it has a delayed onset and offset of action and (c) there is high inter-individual variability in pharmacological response. Prasugrel is also a thienopyridine, with faster onset of action and a more uniform inhibition of platelet function compared to clopidogrel, accounting for lower incidence of ischemic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and higher incidence of both non-CABG-related bleeding complications. Two direct and reversible P2Y12 antagonists, Cangrelor and ticagrelor, are characterized by rapid onset and reversal of platelet inhibition. Cangrelor is not superior to clopidogrel in preventing thrombotic events in patients undergoing PCI. Ticagrelor is superior to clopidogrel in preventing major adverse cardiac events in ACS patients, but, like prasugrel, is associated with a higher frequency of non-CABG-related bleeding complications. A shorter period of drug discontinuation before surgery is necessary in ticagrelor-treated patients compared to clopiodgrel-treated patients to limit the severity of post-surgical bleeding.

Topics: Adenosine; Adenosine Monophosphate; Clopidogrel; Humans; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Receptors, Purinergic P2Y12; Sulfonamides; Thiophenes; Ticagrelor; Ticlopidine

Antiplatelet therapy is the cornerstone of management of acute coronary syndromes. Currently used antiplatelet drugs present several limitations that provoke new searches. These limitations include resistance, delay in the onset of action, risk for bleeding, variations in the individual response, and interaction with other medications (i.e. proton pump inhibitors, calcium channel blockers). New concepts and medications have emerged for the effective inhibition of platelets. Prasugrel, AZD6140 (ticagrelor), cangrelor, and SCH 530348 (thrombin receptor antagonist) are among some of the novel agents that survived randomized trials. In this review, we aimed to summarize novel concepts and agents in antiplatelet therapy.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Pyridines; Receptors, Thrombin; Thiophenes; Ticagrelor; Ticlopidine

The role of antiplatelet therapy in the management of coronary artery disease and its sequalae is of great significance. Acetil Salycilic Acid (ASA) has continued to dominate the field as a potent antiplatelet agent, due to its ease of use and cost effectiveness. In addition to this, clopidogrel has also been widely used with better long term administration results in patients with atherosclerotic disease. However, interpatient variability and resistance to clopidogrel has opened the doors for further investigative research to find another agent which potentially meets the pharmacokinetic demands whilst having a satisfactory safety profile. Prasugrel and other novel nonthienopyridine derivatives are currently under investigation, with previous trials showing very reassuring outcomes. Patented inventions along with large trials have shown that prasugrel significantly reduces ischemic end points, ultimately resulting in a decrease in Myocardial infarctions, thromboocculusive episodes and death. Further studies are required to support these findings before we are aware of all clinical effects of Prasugrel.

Topics: Adenosine; Adenosine Monophosphate; Cardiovascular Diseases; Clinical Trials as Topic; Clopidogrel; Humans; Imines; Lactones; Patents as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptor, PAR-1; Receptors, Purinergic P2Y12; Receptors, Thrombin; Thiophenes; Ticagrelor; Ticlopidine

Antiplatelet agents are the cornerstone of treatment for patients with acute coronary syndromes and patients undergoing percutaneous coronary intervention. The current "gold standard" consists of a combination of aspirin and clopidogrel administered orally shortly before invasive procedures and then continued in the form of maintenance doses. Not all patients respond optimally to standard therapy. Resistance to the antiplatelet activity of both drugs when used either singly or in combination has been observed and may lead to treatment failure, including further atherothrombotic events. Potential limitations associated with the combined use of aspirin and clopidogrel have inspired clinical investigation into several promising new antiplatelet agents as potential additions or alternatives to standard therapy. The candidates include prasugrel, which has a mechanism similar to that of clopidogrel but with superior pharmacokinetics; ticagrelor, a nonthienopyridine that binds reversibly to the platelet P2Y(12) receptor; cangrelor, an intravenously administered analogue of ticagrelor; and various thrombin receptor antagonists.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Signal Transduction; Thiophenes; Ticagrelor; Treatment Outcome

Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX-4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.

Topics: Adenosine; Adenosine Monophosphate; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Drug Design; Humans; Imines; Lactones; Naphthalenes; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Propionates; Purinergic P2 Receptor Antagonists; Pyridines; Thiophenes; Ticagrelor; Ticlopidine

A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome (ACS). This article reviews the pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and ticagrelor. Prasugrel, a third-generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analog of adenosine triphosphate, is a potent direct platelet P2Y12 antagonist. In development as an intravenous agent, cangrelor is currently being evaluated in two phase III studies in patients requiring PCI. Ticagrelor is the first of a new class of orally available antiplatelet agents antagonizing the effects of ADP mediated by P2Y12; it is currently being studied in a phase III trial in patients with ACS.

Topics: Adenosine; Adenosine Monophosphate; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Treatment Outcome

Despite recent advances in the treatment of acute coronary syndromes (ACS), including dual antiplatelet therapy with aspirin and a thienopyridine during the acute phase and for secondary prevention, this condition remains a leading cause of morbidity and mortality. The limitations of the currently available antiplatelet agents have triggered the development of newer drugs. In this review we summarize the mechanisms of actions and results of current clinical trials of novel antiplatelet agents. These include prasugrel, a thienopyridine prodrug which has a mechanism similar to that of clopidogrel but superior pharmacokinetic features; ticagrelor, a non-thienopyridine that binds reversibly to the platelet P2Y(12) receptor; cangrelor, an intravenously administered analog of ticagrelor; the thrombin receptor antagonist SCH 53048; and terutroban (S18886), a thromboxane A(2) receptor inhibitor.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Humans; Lactones; Naphthalenes; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Propionates; Pyridines; Thiophenes; Ticagrelor

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Clopidogrel, is a pro-drug that needs to be metabolized in the liver and intestines to form active metabolites. Prasugrel, a third generation thienopyridine, was approved for use in Europe in February 2009, and is currently available in the United Kingdom. All thienopyridines however, have pharmacological limitations that lead to a search for more effective non-thienopyridine P2Y12 inhibitors. Promising results have been reported with ticagrelor, an oral first reversible, direct-acting inhibitor of the P2Y12 receptor. Ticagrelor is the first oral P2Y12 receptor binding antagonist that does not require metabolic activation. Furthermore, ticagrelor has at last 1 active metabolite, which has very similar pharmacokinetics to the parent compound. Therefore, ticagrelor has more rapid onset and more pronounced platelet inhibition than other antiplatelet agents. The safety and efficacy of ticagrelor compared with clopidogrel in ACS patient has been recently evaluated by the PLATelet inhibition and patient Outcomes (PLATO) trial. Ticagrelor compared with clopidogrel had a significantly greater reduction in the death rate from vascular causes, myocardial infarction, or stroke without major bleeding. There was however, an increase in non-procedure related bleeding, dyspnoea and ventricular pauses in the first week of treatment. Further studies on new antiplatelet agents are needed to establish a new "gold standard" antiplatelet therapy.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Biotransformation; Clinical Trials as Topic; Clopidogrel; Hemorrhage; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

The incidence of new coronary events in patients receiving dual antiplatelet therapy (e.g. cyclo-oxygenase inhibitors such as aspirin [acetylsalicylic acid; ASA]) and ADP receptor blockers (e.g. clopidogrel) is high. Therefore, it is critical to identify patients who require more intense treatment such as those with poor tolerance to existing drugs, those with genotypes that predict treatment resistance, diabetic patients, and smokers. The new ADP receptor blockers (prasugrel, cangrelor, Ticagrelor) can provide greater efficacy but it should not be associated with increased bleeding. Thrombin receptor antagonists (e.g. SCH530348) are another alternative that is currently being tested in randomized trials.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Clopidogrel; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prasugrel Hydrochloride; Pyridines; Thiophenes; Ticagrelor; Ticlopidine

A number of promising antiplatelet therapies currently in advanced clinical testing offer hope for improving cardiovascular outcomes in patients with acute coronary syndromes and those undergoing percutaneous interventions. We review the preclinical pharmacology and selected ongoing clinical trials of promising novel platelet inhibitor therapies.

Topics: Adenosine; Adenosine Monophosphate; Humans; Lactones; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thrombin; Thiophenes; Ticagrelor

Three novel nonthienopyridine antiplatelet agents--cangrelor, ticagrelor (AZD6140), and SCH 530348--are in advanced clinical testing in patients with coronary artery disease. Cangrelor and ticagrelor are direct and reversible inhibitors of the platelet adenosine 5'-diphosphate P2Y12 receptor, whereas SCH 530348 is a thrombin receptor antagonist. Clinical data available to date for each of these compounds suggest that they have safety and efficacy profiles that will be advantageous to patients with acute coronary syndromes or undergoing percutaneous intervention. We review the clinical features of these new platelet inhibition therapies.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Coronary Disease; Drug Therapy, Combination; Humans; Lactones; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Receptors, Thrombin; Ticagrelor

Aspirin is the foundation antiplatelet therapy for patients at risk of cardiovascular events. The thienopyridine, clopidogrel, is modestly more effective than aspirin and in patients with stroke seems to be as effective as the combination of aspirin and dipyridamole. The addition of clopidogrel to aspirin further reduces the risk of cardiovascular events in patients with acute coronary syndromes and those who undergo percutaneous coronary intervention, but uncertainty remains about whether this combination has incremental efficacy over clopidogrel monotherapy in patients with stroke or peripheral arterial disease. Clopidogrel has pharmacological limitations that have prompted the search for more effective ADP-receptor antagonists. Promising results have been achieved with the thienopyridine, prasugrel, which has been compared with clopidogrel in patients treated with aspirin. The nonthienopyridine P2Y(12) inhibitors AZD6140 and cangrelor are presently being evaluated in phase III, randomized, controlled trials.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; History, 20th Century; History, 21st Century; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Stents; Thiophenes; Ticagrelor; Ticlopidine; Treatment Outcome

Platelets possess three P2 receptors for adenine nucleotides: P2Y1 and P2Y12, which interact with ADP, and P2X1, which interacts with ATP. The interaction of adenine nucleotides with their platelet receptors plays an important role in thrombogenesis. The thienopyridine ticlopidine, an antagonist of the platelet P2Y12 ADP receptor, reduces the incidence of vascular events in patients at risk, but it also has some important drawbacks: a relatively high incidence of toxic effects; delayed onset of action; high inter-individual variability in response. Another thienopyridine, clopidogrel, has superseded ticlopidine, because it is an efficacious antithrombotic drug and is less toxic than ticlopidine. However, the high inter-patient variability in response still remains an important issue. These drawbacks justify the continuing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, have very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, P2Y1, and of the receptor for ATP, P2X1, are under development and may prove to be effective antithrombotic agents.

Topics: Adenosine; Adenosine Monophosphate; Angina, Unstable; Animals; Blood Platelets; Clopidogrel; Coronary Disease; Coronary Thrombosis; Drug Interactions; Fibrinolytic Agents; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Receptors, Purinergic P2X; Syndrome; Thiophenes; Ticagrelor; Ticlopidine

Platelets play a central role in the pathophysiology of acute coronary syndromes (ACS). Dual antiplatelet therapy has resulted in significant advances in the treatment of ACS; however, ACS remains an important cause of morbidity and mortality. Important limitations exist among the current antiplatelet agents and therefore a pressing need for the development of improved antiplatelet agents exists. Three antiplatelet agents currently under investigation (prasugrel, AZD6140, and cangrelor) in clinical trials for the treatment of ACS appear promising.

Topics: Adenosine; Adenosine Monophosphate; Angina, Unstable; Blood Platelets; Humans; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; Ticagrelor; Treatment Outcome

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.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Blood Platelets; Clopidogrel; Coronary Disease; Humans; Membrane Proteins; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

The efficacy with aspirin and clopidogrel treatment has been demonstrated in various clinical trials. Laboratory evaluation of platelet response in recent studies revealed that a distinctive response variability and nonresponsiveness/resistance in selected patients were associated with these antiplatelet agents. Moreover, some studies have correlated this nonresponsiveness/resistance phenomenon to the occurrence of thrombotic events. At this time there are no uniformly established methods to quantify exvivo platelet reactivity after clopidogrel and aspirin treatment of the extent of platelet inhibition by clopidogrel and aspirin. Therefore, specific treatment recommendations for patients exhibiting high platelet reactivity or poor platelet inhibition during clopidogrel or aspirin therapy are not established. A higher aspirin dose and strict compliance to therapy may overcome the occurrence of "aspirin resistance" in selected patients. A higher clopidogrel dose may be considered in patients exhibiting clopidogrel nonresponsiveness.

Topics: Adenosine; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Restenosis; Drug Resistance; Humans; Membrane Proteins; Myocardial Ischemia; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor; Ticlopidine

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration. In preclinical use, these compounds predictably and effectively inhibited platelet aggregation without significant increases in bleeding time. In clinical use, these compounds may have significant advantages over current antiplatelet agents. This article summarizes preclinical and clinical data on cangrelor and AZD6140 and discusses the potential of these compounds as novel antiplatelet therapies.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Animals; Arterial Occlusive Diseases; Clinical Trials as Topic; Dogs; Double-Blind Method; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Humans; Injections, Intravenous; Male; Membrane Proteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Pyridines; Rabbits; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor

There are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor.. This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor.. Compared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite.. Compared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162).

Topics: Blood Platelets; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10 min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10 min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6 h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48 h and 3 months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).

Topics: Adenosine Monophosphate; Contrast Media; Gadolinium; Humans; Pancreatic Elastase; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Ticagrelor; Treatment Outcome

The platelet inhibitory effects induced by oral P2Y. This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y. In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y. URL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738.

Topics: Adenosine Monophosphate; Aged; Biomarkers; Blood Platelets; Cell Adhesion Molecules; Double-Blind Method; Drug Therapy, Combination; Female; Florida; Humans; Male; Microfilament Proteins; Middle Aged; Percutaneous Coronary Intervention; Phosphoproteins; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; ST Elevation Myocardial Infarction; Ticagrelor; Time Factors; Treatment Outcome

 Oral P2Y12 inhibitors take more than 2 hours to achieve full effect in healthy subjects and this action is further delayed in patients with acute myocardial infarction. Intravenous P2Y12 inhibition might lead to more timely and potent anti-platelet effect in the context of emergency primary angioplasty, improving myocardial recovery..  This article compares the efficacy of intravenous cangrelor versus ticagrelor in a ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI)..  In an open-label, prospective, randomized controlled trial, 100 subjects with STEMI were assigned 1:1 to intravenous cangrelor or oral ticagrelor. The co-primary endpoints were platelet P2Y12 inhibition at infarct vessel balloon inflation time, 4 and 24 hours. Secondary endpoints included indices of coronary microcirculatory function: index of microvascular resistance (IMR), initial infarct size (troponin at 24 hours) and final infarct size at 12 weeks (cardiac magnetic resonance). Secondary endpoints included indices of coronary microcirculatory function (index of microvascular resistance [IMR]), initial infarct size (troponin at 24 hours), final infarct size at 12 weeks (cardiac magnetic resonance), corrected thrombolysis in myocardial infarction (TIMI) frame count, TIMI flow grade, myocardial perfusion grade, and ST-segment resolution (ClinicalTrials.gov NCT02733341)..  P2Y12 inhibition at first balloon inflation time was significantly greater in cangrelor-treated patients (cangrelor P2Y12 reaction unit [PRU] 145.2 ± 50.6 vs. ticagrelor 248.3 ± 55.1). There was no difference in mean PRU at 4 and 24 to 36 hours post-dosing. IMR, final infarct size, angiographic and electrocardiographic measures of reperfusion were all similar between groups..  Cangrelor produces more potent P2Y12 inhibition at the time of first coronary balloon inflation time compared with ticagrelor. Despite this enhanced P2Y12 inhibition, coronary microvascular function and final infarct size did not differ between groups.

Topics: Adenosine Monophosphate; Aged; Blood Platelets; Blood Vessels; Cells, Cultured; Female; Humans; Male; Microcirculation; Middle Aged; Myocardial Infarction; Myocardium; Percutaneous Coronary Intervention; Platelet Activation; Platelet Function Tests; Receptors, Purinergic P2Y12; Regional Blood Flow; Ticagrelor

Reticulated platelets are associated with impaired antiplatelet response to irreversibly acting P2Y. This study randomized 110 patients undergoing elective percutaneous coronary intervention with use of cangrelor to different oral transitioning strategies loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (. Platelet inhibition is not influenced by levels of reticulated platelets during infusion of cangrelor independent of oral P2Y

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Clopidogrel; Coronary Artery Disease; Female; Flow Cytometry; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thienopyridines; Ticagrelor

Topics: Adenosine Monophosphate; Blood Platelets; Drug Therapy, Combination; Humans; Middle Aged; Percutaneous Coronary Intervention; Prospective Studies; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Ticagrelor

Topics: Adenosine Monophosphate; Biomarkers; Blood Platelets; Cell Adhesion Molecules; Drug Synergism; Humans; Microfilament Proteins; Phosphoproteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor; Time Factors

This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor.. Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition.. This trial randomized 110 P2Y. The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups.. Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739).

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Clopidogrel; Coronary Disease; Drug Substitution; Female; Germany; Humans; Infusions, Intravenous; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor.. Cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents.. Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 μmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor.. During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity.. Ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor. Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Cell Adhesion Molecules; Coronary Artery Disease; Drug Administration Schedule; Drug Interactions; Drug Substitution; Female; Humans; Infusions, Intravenous; Male; Microfilament Proteins; Middle Aged; Phosphoproteins; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Time Factors; Vermont

Background In clinical trials, cangrelor has been shown to reduce percutaneous coronary intervention-related ischemic complications without increasing major bleeding. This study was performed to examine cangrelor use and transition to oral P2Y

Topics: Adenosine Monophosphate; Clopidogrel; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Registries; Ticagrelor; Treatment Outcome

Dual antiplatelet therapy (DAP) is necessary to prevent thromboembolic events during carotid stenting, stent-assisted coil embolization, and implant of flow diverters (FD). However, DAP in the acute phase may be challenging. An intravenous alternative, cangrelor, has rapid onset, short plasma half-life, and more reliable antiplatelet action for acute interventions. The study objective was to evaluate feasibility and safety of IV cangrelor during acute neuroendovascular surgery procedures.. We performed a retrospective analysis of our database of patients treated with stent-assisted coil embolization, FD placement for aneurysmal subarachnoid hemorrhage (aSAH), or stenting for acute internal carotid artery (ICA) occlusion where IV cangrelor was used. Morbidity, mortality, incidence of thromboembolic events, hemorrhages, and 90-day outcomes were reported.. Ten patients were found in our database from June 2018 through January 2019. Four patients had aSAH, four had middle cerebral artery strokes with tandem lesions, one had an ICA occlusion, and one had a vertebral artery aneurysm. One of the ten patients experienced a thrombotic event. One patient developed new post-procedural bleeding and two had worsening intracranial hemorrhage. Five patients were discharged home in stable condition, two to acute rehabilitation, one to a nursing facility, and two others expired (likely the result of the severe and evolving strokes). Of the eight who were discharged, six (75%) had a good 90-day functional outcome (modified Rankin Scale 0-2).. Acute administration of IV cangrelor with or without oral ticagrelor is a feasible antiplatelet treatment option for acute neuroendovascular procedures.

Topics: Adenosine Monophosphate; Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Clopidogrel; Endovascular Procedures; Female; Humans; Male; Middle Aged; Purinergic P2Y Receptor Antagonists; Retrospective Studies; Self Expandable Metallic Stents; Stroke; Subarachnoid Hemorrhage; Ticagrelor; Treatment Outcome

Topics: Adenosine Monophosphate; Aged; Anxiety; Chest Pain; Coronary Angiography; Coronary Occlusion; Drug Substitution; Drug-Eluting Stents; Drug-Related Side Effects and Adverse Reactions; Dyspnea; Electrocardiography; Humans; Inferior Wall Myocardial Infarction; Male; Percutaneous Coronary Intervention; Purinergic P2Y Receptor Antagonists; ST Elevation Myocardial Infarction; Ticagrelor; Treatment Outcome; Withholding Treatment

Dual antiplatelet therapy (DAPT) remains the cornerstone management for the prevention of acute stent thrombosis after percutaneous intervention (PCI). Situations mandating early interruption of DAPT carry a high risk of ischemic complications. Perioperative bridge therapy using Cangrelor, an intravenous P2Y2 inhibitor, may offer a potential solution. Unfortunately, evidence for its use in non-cardiac procedures is limited.. Our protocol demonstrates successful off-label use of IV Cangrelor bridge therapy in a non-cardiac surgery patient. We describe a case of a 77-year old male; triple therapy with Aspirin, Apixaban, and Ticagrelor for recent drug-eluting stent placement required immediate surgical resection of stage I colonic adenocarcinoma.. Cangrelor bridge therapy was utilized both preoperatively and postoperatively without ischemic or bleeding complications. The patient tolerated exploratory laparoscopic colectomy with minimal bleeding and good post-op recovery.. Minimizing the interruption of DAPT therapy in high-risk patients is achievable. However, careful planning with a team-based approach involving surgeons, cardiologists and pharmacists, along with close clinical follow-up and vigilant management of anti-platelet therapy is recommended.

Topics: Adenosine Monophosphate; Aged; Aspirin; Colectomy; Colonic Neoplasms; Drug-Eluting Stents; Factor Xa Inhibitors; Humans; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Thrombosis; Ticagrelor

Several studies have reported the beneficial effects of anti-platelet drugs in cardioprotection against ischaemia-reperfusion injuries. To date, no studies have focused on the indirect cytoprotective effects of ticagrelor via adenosine receptor on the endothelium.. By evaluating cell viability and cleaved caspase 3 expression, we validated a model of endothelial cell apoptosis induced by hypoxia. In hypoxic endothelial cells treated with ticagrelor, we quantified the extracellular concentration of adenosine, and then we studied the involvement of adenosine pathways in the cytoprotective effect of ticagrelor.. Our results showed that 10 µM ticagrelor induced an anti-apoptotic effect in our model associated with an increase of extracellular adenosine concentration. Similar experiments were conducted with cangrelor but did not demonstrate an anti-apoptotic effect. We also found that A2B and A3 adenosine receptors were involved in the anti-apoptotic effect of ticagrelor in endothelial cells exposed to 2 h of hypoxia stress.. we described an endothelial cytoprotective mechanism of ticagrelor against hypoxia stress, independent of blood elements. We highlighted a mechanism triggered mainly by the increased extracellular bioavailability of adenosine, which activates A2B and A3 receptors on the endothelium.

Topics: Adenosine; Adenosine Monophosphate; Apoptosis; Biomarkers; Cell Hypoxia; Extracellular Space; Human Umbilical Vein Endothelial Cells; Humans; Nitric Oxide Synthase; Phosphatidylinositol 3-Kinases; Prostaglandin-Endoperoxide Synthases; Receptors, Purinergic P1; RNA, Messenger; Signal Transduction; Stress, Physiological; Ticagrelor

Although premature discontinuation of dual antiplatelet therapy (DAPT) is associated with an increased risk of ischemic complications, patients may present with an urgent need for surgery that would require interruption of DAPT. Antiplatelet bridge therapy using cangrelor, an intravenous P2Y

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Aged; Aspirin; Biopsy; Bronchoscopy; Clopidogrel; Drug Therapy, Combination; Drug-Eluting Stents; Dual Anti-Platelet Therapy; Female; Hemorrhage; Humans; Perioperative Care; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticagrelor

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y

Topics: Adenosine Monophosphate; Aged; Aspirin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Female; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

Topics: Adenosine Monophosphate; Humans; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Ticagrelor

Topics: Adenosine Monophosphate; Biological Availability; Coma; Female; Humans; Male; Middle Aged; Out-of-Hospital Cardiac Arrest; Percutaneous Coronary Intervention; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome

Patients pretreated with ticagrelor with less than 1 hour from percutaneous coronary intervention (PCI) or receiving ticagrelor in cath lab were prospectively included and received cangrelor. Cangrelor was infused for 2 hours and platelet function was assessed as P2Y12 reactivity units (PRU) with the VerifyNow P2Y12 function assay before start of infusion, 15 min after the start of infusion, and 30 min after the end of infusion. A total of n = 32 patients with an average age of 68 (±13) years with n = 22 (69%) males were included. The level of P2Y12 inhibition before cangrelor infusion was started was 249 PRU (IQR 221-271). After 15 min of cangrelor infusion the P2Y12 reactivity was markedly decreased to 71 PRU (IQR 52-104, p < 0.001). At 30 min after end of infusion PRU remained within the therapeutic range, 89 PRU (IQR 50-178; p < 0.001 for comparison with preinfusion) with only n = 4 (12.5%) patients with PRU >225. Results were consistent between patients receiving ticagrelor prehospital or in the cath lab and no statistical differences in PRU were noted between the two groups in any of the three measurements. In conclusion, cangrelor in combination with ticagrelor results in consistent and strong P2Y12 inhibition during and after infusion and cangrelor may bridge the gap until oral P2Y12 inhibitors achieve effect in real-world STEMI patients undergoing primary PCI.

Topics: Adenosine; Adenosine Monophosphate; Female; Humans; Male; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Ticagrelor

Essentials Irreversible platelet inhibition persists after reversibly-binding ticagrelor is discontinued. Reversibility of platelet inhibition by ticagrelor and its active metabolite was assessed. Incomplete recovery was observed after prolonged exposure to ticagrelor. Activated GPIIb-IIIa and P-selectin, not platelet reactivity index, showed irreversibility.. Introduction Ticagrelor is described as a reversible P2Y

Topics: Adenosine; Adenosine Monophosphate; Blood Platelets; Cell Adhesion Molecules; Dose-Response Relationship, Drug; Humans; Kinetics; Microfilament Proteins; P-Selectin; Phosphoproteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor

Pairing orphan G protein–coupled receptors (GPCRs) with their cognate endogenous ligands is expected to have a major impact on our understanding of GPCR biology. It follows that the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into the pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as a dualistic uracil nucleotide/cysteinyl leukotriene receptor and by others as inactive toward these stimuli altogether. Whereas regulation of central nervous system myelination by GPR17 is well established, verification of activity of its putative endogenous ligands has proven elusive so far. Herein we report that uracil nucleotides and cysteinyl leukotrienes do not activate human, mouse, or rat GPR17 in various cellular backgrounds, including primary cells, using eight distinct functional assay platforms based on labelfree pathway-unbiased biosensor technologies, as well as canonical second-messenger or biochemical assays. Appraisal of GPR17 activity can neither be accomplished with co-application of both ligand classes, nor with exogenous transfection of partner receptors (nucleotide P2Y12, cysteinyl-leukotriene CysLT1) to reconstitute the elusive pharmacology. Moreover, our study does not support the inhibition of GPR17 by the marketed antiplatelet drugs cangrelor and ticagrelor, previously suggested to antagonize GPR17. Whereas our data do not disagree with a role of GPR17 per se as an orchestrator of central nervous system functions, they challenge the utility of the proposed (ant)agonists as tools to imply direct contribution of GPR17 in complex biologic settings.

Topics: Adenosine; Adenosine Monophosphate; Animals; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Cysteine; HEK293 Cells; Humans; Leukotrienes; Ligands; Mice; Nerve Tissue Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Small Molecule Libraries; Ticagrelor; Uracil Nucleotides

We report the development of a microfluidic device for the rapid assay in whole blood of interfacial platelet-protein interactions indicative of the efficacy of antiplatelet drugs, for example, aspirin and Plavix, two of the world's most widely used drugs, in patients with cardiovascular disease (CVD). Because platelet adhesion to surface-confined protein matrices is an interfacial phenomenon modulated by fluid shear rates at the blood/protein interface, and because such binding is a better indicator of platelet function than platelet self-aggregation, we designed, fabricated, and characterized the performance of a family of disposable, self-powered microfluidic chips with well-defined flow and interfacial shear rates suitable for small blood volumes (≤200 μL). This work demonstrates that accurate quantification of cell adhesion to protein matrices, an important interfacial biological phenomenon, can be used as a powerful diagnostic tool in those with CVD, the world's leading cause of death. To enable such measurements, we developed a simple technique to fabricate single-use self-powered chips incorporating shear control (SpearChips). These parallel-plate flow devices integrate on-chip vacuum-driven blood flow, using a predegassed elastomer component to obviate active pumping, with microcontact-printed arrays of 6-μm-diameter fluorescently labeled fibrinogen dots on a cyclic olefin polymer base plate as a means to quantitatively count platelet-protein binding events. The use of SpearChips to assess in whole blood samples the effects of GPIIb/IIIa and P2Y12 inhibitors, two important classes of "antiplatelet" drugs, is reported.

Topics: Abciximab; Adenosine; Adenosine Monophosphate; Animals; Antibodies, Monoclonal; Cattle; Clopidogrel; Dimethylpolysiloxanes; Equipment Design; Fibrinogen; Humans; Immunoglobulin Fab Fragments; Lab-On-A-Chip Devices; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Powders; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Serum Albumin, Bovine; Ticagrelor; Ticlopidine

Cangrelor, a P2Y12 receptor blocker, administered just prior to reperfusion reduced but did not eliminate myocardial infarction in rabbits. Combining cangrelor with ischemic postconditioning offered no additional protection suggesting they protected by a similar mechanism. To determine if cangrelor's protection might be additive to other cardioprotective interventions we tested cangrelor in combination with ischemic preconditioning, cariporide, a sodium-hydrogen exchange blocker, and mild hypothermia.. Open-chest rats underwent 30-min coronary occlusion/2-h reperfusion.. Cangrelor, administered as a bolus (60 μg/kg) 10 min before reperfusion and continued as an infusion (6 μg/kg/min) for the duration of the experiment, decreased infarction from 45.3 % of risk zone in control hearts to 25.0 %. Combining cangrelor and ischemic preconditioning offered no additional protection. Mild hypothermia (32-33 °C) instituted by peritoneal lavage with cold saline just prior to coronary occlusion resulted in 25.2 % infarction, and combining cangrelor and hypothermia nearly halved infarction to 14.1 % of risk zone. Cariporide (0.5 mg/kg) just prior to occlusion resulted in 27.2 % infarction and 15.8 % when combined with cangrelor. Combining cangrelor, hypothermia and cariporide further halved infarction to only 6.3 %. We also tested another P2Y12 inhibitor ticagrelor which is chemically similar to cangrelor. Ticagrelor (20 mg/kg) fed 1 h prior to surgery reduced infarct size by an amount similar to that obtained with cangrelor (25.6 % infarction), and this protective effect was abolished by chelerythrine and wortmannin, thus implicating participation of PKC and PI3-kinase, resp., in signaling.. Cardioprotection from a P2Y12 receptor antagonist can be combined with at least 2 other strategies to magnify the protection. Combining multiple interventions that use different cardioprotective mechanisms could provide powerful protection against infarction in patients with acute coronary thrombosis.

Topics: Adenosine; Adenosine Monophosphate; Animals; Anti-Arrhythmia Agents; Cardiotonic Agents; Guanidines; Hypothermia, Induced; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Purinergic P2Y Receptor Antagonists; Rats; Rats, Sprague-Dawley; Sulfones; Ticagrelor

Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y12 receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y12 receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y12 receptor-directed compounds can lead to very different clinical effects.

Topics: Adenosine; Adenosine Monophosphate; Humans; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thienopyridines; Thiophenes; Ticagrelor

As ticagrelor, clopidogrel and cangrelor therapies may be used in the same clinical setting, their potential pharmacodynamic interactions are of interest. Hence, we investigated possible interactions between these agents in dogs using a variety of switching protocols.. Six male dogs all received 7 different dosing regimens separated by 1-5week washout periods: cangrelor (1μg/kg/min, intravenous infusion); ticagrelor (0.8mg/kg, oral); clopidogrel (3mg/kg, intravenous injection); cangrelor together with ticagrelor initiated 10minutes after cangrelor infusion start or clopidogrel given 30minutes after cangrelor infusion start; ticagrelor followed by clopidogrel given 3 or 7hours after ticagrelor dosing. ADP-induced whole blood platelet aggregation was measured by impedance aggregometry.. Mean maximum inhibition of platelet aggregation (IPA) was 81-87% at 6minutes (cangrelor), 3hours (ticagrelor) and 4hours (clopidogrel) postdosing and platelet function recovered after 1.5hours, 12hours, and 9days, respectively. IPA at 2hours post clopidogrel was reduced to 39% when clopidogrel was given during cangrelor infusion versus 69% for clopidogrel alone. With clopidogrel dosed 3hours after ticagrelor, IPA was reduced after washout of ticagrelor to 38% at 24hrs vs. 68% for clopidogrel alone, but an interaction was not seen when clopidogrel was dosed 7hours after ticagrelor. No pharmacodynamic interaction occurred between ticagrelor and cangrelor.. The extent of the pharmacodynamic drug-drug interactions observed between clopidogrel and cangrelor or ticagrelor apparently depends on the level of receptor occupancy when clopidogrel is administered. Importantly, no significant pharmacodynamic interaction occurred between ticagrelor/clopidogrel when clopidogrel was given at clinical trough IPA levels with ticagrelor. No significant pharmacodynamic interaction occurred with cangrelor and ticagrelor.

Topics: Adenosine; Adenosine Monophosphate; Animals; Blood Platelets; Clopidogrel; Dogs; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Ticlopidine

P2Y(12) receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y (12)receptors. However, some P2Y(12) receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y(12) antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y(12) receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y(12) antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y(12) antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y(12) antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y (12)antagonists enhanced VASP-phosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y(12)receptors and not through another G-protein-coupled receptor.

Topics: Adenosine; Adenosine Monophosphate; Blood Platelets; Cell Adhesion Molecules; Cells, Cultured; Humans; Microfilament Proteins; Phosphoproteins; Phosphorylation; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, G-Protein-Coupled; Thiophenes; Ticagrelor

To investigate whether adenosine diphosphate (ADP)-derived adenosine might inhibit platelet aggregation, especially in the presence of a P2Y₁₂ antagonist, where the effects of ADP at the P2Y₁₂ receptor would be prevented.. Platelet aggregation was measured in response to thrombin receptor activator peptide by platelet counting in platelet-rich plasma (PRP) and whole blood in the presence of ADP and the P2Y₁₂ antagonists cangrelor, prasugrel active metabolite, and ticagrelor. In the presence of a P2Y₁₂ antagonist, preincubation of PRP with ADP inhibited aggregation; this effect was abolished by adenosine deaminase. No inhibition of aggregation occurred in whole blood except when dipyridamole was added to inhibit adenosine uptake into erythrocytes. The effects of ADP in PRP and whole blood were replicated using adenosine and were directly related to changes in cAMP (assessed by vasodilator-stimulated phosphoprotein phosphorylation). All results were the same irrespective of the P2Y₁₂ antagonist used.. ADP inhibits platelet aggregation in the presence of a P2Y₁₂ antagonist through conversion to adenosine. Inhibition occurs in PRP but not in whole blood except when adenosine uptake is inhibited. None of the P2Y₁₂ antagonists studied replicated the effects of dipyridamole in the experiments that were performed.

Topics: Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Blood Platelets; Cell Adhesion Molecules; Erythrocytes; Humans; Microfilament Proteins; Phosphoproteins; Phosphorylation; Piperazines; Platelet Aggregation; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Receptors, Thrombin; Thiophenes; Ticagrelor

Acute coronary syndromes (ACS), characterized by unstable angina or a non-ST-segment elevation myocardial infarction, are caused by rupture of an atherosclerotic plaque, leading to platelet activation and aggregation, thrombus formation, and microembolization. Antiplatelet therapy is a cornerstone of therapy. Combined with aspirin, clopidogrel provides significant benefit for patients across the ACS spectrum. However, clopidogrel has limitations given its slow onset and the inconsistent level of inhibition that it achieves. Newer thienopyridine and non-thienopyridine P2Y12 receptor agonists offer the advantages of a rapid onset of action and greater and more consistent platelet inhibition.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Aspirin; Clopidogrel; Drug Therapy, Combination; Humans; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prasugrel Hydrochloride; Thiophenes; Ticagrelor; Ticlopidine