vorapaxar and cangrelor

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

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

Acute coronary syndrome (ACS) encompasses acute myocardial infarction (MI) and unstable angina. Activation of platelets and coagulation cascade plays a central role in the development of ACS. Over the past decade, there have been substantial improvements in the strategies for secondary prevention of ACS, including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor. However, therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable.. This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents; cangrelor (an intravenous P2Y12 receptor antagonist), vorapaxar (protease-activated receptor-1 inhibitor) and rivaroxaban (an oral factor Xa inhibitor).. Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Fibrinolytic Agents; Humans; Lactones; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Thiophenes

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

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 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

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