Interval From Initiation of Prasugrel to Coronary Angiography in Patients With Non–ST-Segment Elevation Myocardial Infarction

Background

In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial, the prasugrel pre-treatment strategy versus placebo was associated with excess bleeding complications and no improved ischemic outcome in non–ST-segment elevation myocardial infarction (MI). Whether patients with the longest pre-treatment duration had an ischemic benefit is unknown.

Pharmacokinetic,pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

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.     

Antiplatelet function variability in clopidogrel-treated patients: need for new antiplatelet agents

Antiplatelet therapy is obligatory in patients with coronary artery disease (CAD) both in acute coronary syndromes (ACS) and in secondary prevention. Aspirin in combination with clopidogrel has been recommended as the main therapeutic regimen for many years. However, the high inter-individual variability of platelet aggregation seen with clopidogrel, caused by the underlying disease (more pronounced in diabetic patients and patients with ACS), drug interactions as well as by genetic variants leading to a reduced formation of the active metabolite of the prodrug clopidogrel, has confronted clinical practice with increasing numbers of adverse clinical events in patients following an ACS. Therefore, new antiplatelet agents have been investigated showing a more favorable efficacy/safety profile. Prasugrel as well as ticagrelor are meanwhile part of the recently published revascularization guidelines of the European Society of Cardiology based on their favorable results with respect to reducing a combined ischemic efficacy endpoint in patients with ACS in the TRITON-TIMI-38 (prasugrel) and PLATO (ticagrelor) trials. Different to clopidogrel, their effects are independent of genetic variants and also drug interactions seem neglectable. This article discusses the reasons for antiplatelet function variability of clopidogrel and presents clinical data of the new ADP-receptor inhibitors by reviewing the recently published trials and prespecified post hoc analyses of these trials as well as the potential use of the new antiplatelet agents in the near future.     

Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats

Introduction

Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y₁₂ antagonists on the reactivity of vascular smooth muscle cells.

Materials and methods

Wistar rats (n = 30) were pretreated with an investigated drug or placebo. Clopidogrel (50 mg/kg, n = 7), prasugrel (10 mg/kg, n = 7), ticagrelor (10 mg/kg, n = 7) or placebo (n = 9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1 μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y₁₂ receptor.

Results

Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response.

Conclusions

Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.     

A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

AIMS: This double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y(12) ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. METHODS: Thirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. RESULTS: Inhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 microm) ADP was significantly higher in the prasugrel 10 mg group (58.2 +/- 4.9% vs. 9.2 +/- 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 +/- 6.8% vs. 9.2 +/- 4.0%, P = 0.78). With 5 microm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 +/- 4.7%; clopidogrel 75 mg, 36.5 +/- 9.0%; vs. placebo, 11.3 +/- 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 +/- 252 s vs. placebo, 221 +/- 38 s, P = 0.05) but not with clopidogrel (283 +/- 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. CONCLUSIONS: Compared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.     

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12 receptors in vitro

Cangrelor is a rapid-acting, direct-binding, and reversible P2Y₁₂ antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y₁₂ antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y₁₂ antagonist following PCI, such as the thienopyridines clopidogrel, and prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. This in vitro study evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y₁₂ receptor number using a ³³P-2MeSADP binding assay. All P2Y₁₂ antagonists studied resulted in strong P2Y₁₂ receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y₁₂ receptor blockade by the AM (clopidogrel AM: 7%, prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y₁₂ (% P2Y₁₂ receptor blockade after co-incubation with cangrelor 1000?nmol/L: 11.7% for clopidogrel AM 3?µmol/L; 34.1% for prasugrel AM 3?µmol/L). In conclusion, in vitro cangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y₁₂ receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI.     

Prasugrel vs. clopidogrel for cytochrome P450 2C19‐genotyped subgroups: integration of the TRITON‐TIMI 38 trial data

Summary. Background: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON‐TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced‐function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non‐ST segment elevation myocardial infarction is currently uncertain. Methods and Results: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON‐TIMI 38 trial. Individuals with a CYP2C19 reduced‐metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39–0.83]. For CYP2C19 extensive metabolizers (～ 70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80–1.20). Conclusions: Integration of the TRITON‐TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.     

抗血小板治疗的最新进展

大量临床研究已证实抗血小板药物：阿司匹林、噻吩吡啶类药物、血小板膜糖蛋白受体桔抗剂、西洛他唑等在预防和治疗心脑血管疾病以及外周动脉血管病变中具有十分重要的作用。洞悉药物的作用机理、应用现状、进展和存在的争议,对于更好地运用该类药物具有十分重要的作用。现就相关内容进行简要综述。