thienopyridine and cangrelor

Adenosine diphosphate (ADP)-induced platelet activation plays a pivotal role in the thrombocyte aggregation and pathogenesis of ischemic heart disease. The long-term benefit of dual anti-platelet therapy with ADP-receptor antagonists, such as clopidogrel, in combination with aspirin is well established for patients following coronary stent implantation. This review discusses latest developments in the field of ADP-receptor antagonists.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Aspirin; Clopidogrel; Combined Modality Therapy; Humans; Myocardial Ischemia; Platelet Aggregation Inhibitors; Pyridines; Receptors, Purinergic P2; Stents; Ticlopidine

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

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

Oral P2Y₁₂ platelet receptor inhibitors are a cornerstone of reducing complications in patients with acute coronary syndromes or coronary stents. Guidelines advocate discontinuing treatment with P2Y₁₂ platelet receptor inhibitors before surgery. Cangrelor, a short-acting, reversible, intravenously administered P2Y₁₂ platelet inhibitor is effective in achieving appropriate platelet inhibition in patients who are awaiting coronary artery bypass grafting (CABG) and require P2Y₁₂ inhibition. The objective of this study was to assess the effects of preoperative cangrelor on the incidence of perioperative complications, which are currently unknown.. Patients (n = 210) requiring preoperative clinical administration of thienopyridine therapy were randomized in a multicenter, double-blinded study to receive cangrelor or placebo while awaiting CABG after discontinuation of the thienopyridine. Optimal platelet reactivity, which was defined as <240 P2Y₁₂ platelet reaction units, was measured with serial point-of-care testing (VerifyNow). Pre- and postoperative outcomes, bleeding values, and transfusion rates were compared. To quantify potential risk factors for bleeding, we developed a multivariate logistic model.. The differences between the groups in bleeding and perioperative transfusion rates were not significantly different. The rate of CABG-related bleeding was 11.8% (12/102) in cangrelor-treated patients and 10.4% (10/96) in the placebo group (P = .763). Transfusion rates for the groups were similar. Serious postoperative adverse events for the cangrelor and placebo groups were 7.8% (8/102) and 5.2% (5/96), respectively (P = .454).. Compared with placebo, bridging patients with cangrelor prior to CABG effectively maintains platelet inhibition without increasing post-CABG complications, including bleeding and the need for transfusions. These data suggest cangrelor treatment is a potential strategy for bridging patients requiring P2Y₁₂ receptor inhibition while they await surgery.

Topics: Adenosine Monophosphate; Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Transfusion; Coronary Artery Bypass; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Injections, Intravenous; Male; Middle Aged; Placebo Effect; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Premedication; Prevalence; Purinergic P2Y Receptor Antagonists; Pyridines; Risk Assessment; Treatment Outcome; United States