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A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients. [ABSTRACT FROM AUTHOR]

Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety. [ABSTRACT FROM AUTHOR]

The increasing use of antiplatelet therapy, particularly aspirin and oral P2Y12 inhibitors, in the prevention and management of arterial thrombosis, has stimulated extensive pharmacodynamic studies and research into tailored antiplatelet regimens. Many different methodologies have been studied for monitoring antiplatelet drugs and some are now well validated and used in clinical practice. However, clinical studies of tailored antiplatelet therapy have not convincingly demonstrated a benefit of this approach in patients treated with aspirin and clopidogrel, coupled with the fact that more potent antiplatelet therapies have more consistent effects compared with clopidogrel and so may reduce the rationale for monitoring. On the other hand, the optimum timing of urgent surgery after cession of oral antiplatelet therapy may be informed by platelet function testing. This review discusses the differentmethodologies that have been used to monitor the effects of antiplatelet therapy and highlights the current position of platelet function testing in clinical practice. [ABSTRACT FROM AUTHOR]

Cangrelor is a rapid-acting, direct-binding, and reversible P2Y12antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y12antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y12antagonist 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. Thisin vitrostudy evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y12receptor number using a33P-2MeSADP binding assay. All P2Y12antagonists studied resulted in strong P2Y12receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y12receptor 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(% P2Y12receptor 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 vitrocangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y12receptor, 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. [ABSTRACT FROM PUBLISHER]

Thrombin-induced platelet activation is initiated by PAR1 and PAR4 receptors. Vorapaxar, a PAR1 antagonist, has been assessed in patients with acute coronary syndromes (ACS) and stable atherosclerotic disease in addition to standard-of-care treatment. In clinical trials, vorapaxar has been observed to reduce the frequency of ischaemic events in some subgroups though in others has increased the frequency of bleeding events. Among patients undergoing CABG surgery, which is associated with excess thrombin generation, bleeding was not increased. The aim of these studies was to investigate the effects of selective PAR1 antagonism on thrombin-induced platelet activation in patients receiving vorapaxar or placebo in the TRACER trial and to explore the roles of PAR1 and PAR4 in thrombin-induced platelet activation in healthy volunteers. ACS patients receiving vorapaxar or placebo in the TRACER trial were studied at baseline and 4 hours, 1 and 4 months during drug administration. Thrombin-induced calcium mobilisation in platelet-rich plasma was assessed by flow cytometry. In vitro studies were performed in healthy volunteers using the PAR1 antagonist SCH79797 or PAR4 receptor desensitisation. Vorapaxar treatment significantly inhibited thrombin-induced calcium mobilisation, leaving a residual, delayed response. These findings were consistent with calcium mobilisation mediated via the PAR4 receptor and were reproduced in vitro using SCH79797. PAR4 receptor desensitization, in combination with SCH79797, completely inhibited thrombin-induced calcium mobilisation confirming that the residual calcium mobilisation was mediated via PAR4. In conclusion vorapaxar selectively antagonises the PAR1-mediated component of thrombin-induced platelet activation, leaving the PAR4-mediated response intact, which may explain why vorapaxar is well tolerated in patients undergoing CABG surgery since higher thrombin levels in this setting may override the effects of PAR1 antagonism through PAR4 activation, thus preserving haemostasis. Further assessment may be warranted. [ABSTRACT FROM AUTHOR]

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel ( p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel ( p = 0.015) and clopidogrel ( p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy. [ABSTRACT FROM AUTHOR]

The aim of these studies was to investigate the extent of platelet P2Y12 receptor inhibition by the thienopyridine active metabolite of prasugrel, R-138727. Blood was taken from healthy volunteers and pre-incubated with R-138727 or cangrelor (AR-C66931MX). Platelet aggregation was assessed in platelet rich plasma (PRP) and whole blood (WB). Vasodilator stimulated phosphoprotein (VASP) phosphorylation, platelet procoagulant activity (annexin V binding and microparticle formation) and calcium mobilisation were measured by flow cytometry. Platelet-leukocyte co-aggregate formation and sCD40L release, both pro-inflammatory responses of platelets, were measured by flow cytometry and ELISA, respectively. P2Y12 receptor antagonism was determined using a radioligand binding assay (33P 2-MeSADP) in resting and stimulated platelets and the effects of clopidogrel administration were also assessed. R-138727 yielded concentration-dependent inhibition of platelet aggregation, VASP phosphorylation inhibition, procoagulant activity and pro-inflammatory responses. In the presence of R-138727 or cangrelor there was increased calcium reuptake following agonist stimulation. R-138727 30 µmol/L and cangrelor 1 µmol/L completely inhibited 33P 2-MeSADP binding, compared to partial inhibition following clopidogrel administration. Platelet activation and granule secretion did not expose an additional pool of P2Y12 receptors. Prasugrel's active metabolite effectively blocks the P2Y12 receptor with the highest concentrations tested yielding complete inhibition of P2Y12-mediated amplification of several important platelet responses. [ABSTRACT FROM AUTHOR]

The efficacy of the platelet P2Y 12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y 12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G&ThickSpace;>&ThickSpace;A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4&ThickSpace;h post clopidogrel 300&ThickSpace;mg, and 10 and 28 days following clopidogrel 75&ThickSpace;mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4&ThickSpace;h post clopidogrel 600&ThickSpace;mg. Patients were genotyped for P2Y 12 haplotype and the CYP3A5 6986G&ThickSpace;>&ThickSpace;A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y 12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy. [ABSTRACT FROM AUTHOR]

Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, including abciximab and tirofiban, are administered concurrently with clopidogrel, a P2Y12 antagonist, and aspirin in some patients undergoing percutaneous coronary intervention. We studied the effects of, and interactions between, abciximab, tirofiban, aspirin and the P2Y12 antagonist cangrelor on platelet aggregation, α and dense granule secretion and procoagulant responses in vitro. Blood was obtained from healthy volunteers. Platelet aggregation, dense granulesecretion, α granule secretion (PAI-1 and soluble CD40 ligand levels) and procoagulant responses (annexin-V and microparticle formation) were assessed using collagen and thrombin receptor activating peptide (TRAP) as agonists. All the antagonists used singularly inhibited collagen-induced responses. Combinations of abciximab or tirofiban with aspirin and/or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor. Cangrelor inhibited TRAP-induced responses and, again, there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor. The GPIIb/IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between GPIIb/IIIa antagonists and inhibitors of both P2Y12 receptor activation and, to a lesser extent, thromboxane A2 generation. These interactions are likely to have important influences on the safety and efficacy of combination anti-platelet therapies. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the stability of VerifyNow P2Y12 assay results with citrate anticoagulation as compared to hirudin anticoagulation over a period of 20 minutes.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y 12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor ( n = 10), clopidogrel ( n = 8) or no drug ( n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y 12 inhibitors. Sepsis patients with fatal outcomes ( n = 12) had reduced miR-150 levels compared with survivors ( n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y 12 inhibition. While P2Y 12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.