P2Y12 Adenosine Diphosphate Receptor Research Articles

Efficacy of ticagrelor compared to clopidogrel in improving endothelial function in patients with coronary artery disease: a systematic review.

Ticagrelor and clopidogrel are antiplatelet drugs that act by binding to the adenosine diphosphate P2Y12 receptor. Previous studies have compared between them regarding the endothelial function effect. This systematic review aims to summarize the evidence comparing the efficacy of ticagrelor vs. clopidogrel in improving endothelial function in patients with coronary artery disease (CAD). In August 2021, the Scopus, PubMed, Web of Science, and Cochrane library were searched systematically for eligible trials. We included randomized controlled trials that compared the efficacy of ticagrelor vs. clopidogrel in improving endothelial function in patients with CAD. Seven trials (n = 511) were included in our systematic review. Ticagrelor resulted in a greater elevation of the level of progenitor cells CD34+ KDR+ and CD34+ 133+ (P = 0.036 and P = 0.019, respectively), with a lower rate of endothelial cell apoptosis rate (P < 0.001). Moreover, ticagrelor showed superiority regarding nitric oxide, radical oxygen species, and soluble P-selectin levels (P = 0.03, P = 0.02, and P = 0.019, respectively). Flow-mediated dilation findings differed between the studies (P = 0.004 vs. P = 0.39). Ticagrelor appears to exert an additional improvement in endothelial function compared with clopidogrel in patients with coronary heart disease.

Insights from Egyptian ticagrelor study in patients who presented with acute coronary syndrome (ETS in ACS)

BackgroundDual antiplatelet therapy with aspirin and a thienopyridine is used to prevent thrombotic complications of acute coronary syndrome (ACS) and percutaneous coronary interventions (PCI). Ticagrelor is an oral, reversible inhibitor of the adenosine diphosphate receptor P2Y12 with a faster onset and more potent platelet inhibition than clopidogrel. A study was needed to evaluate the efficacy and safety of generic ticagrelor in Egyptian patients.ResultsThis multicenter study included 830 patients aged above 40 years and diagnosed with ACS, with or without ST segment elevation during the preceding 6 months. They received generic ticagrelor (Thrombolinta, Global Napi Pharmaceutical Company, Egypt) (180 mg loading dose, 90 mg twice daily thereafter), added to aspirin 75–100 mg daily. The mean age of our study population was 57.5 (8.3) years and 38.3% were females. Hypertension, diabetes mellitus, dyslipidemia and previous coronary revascularization were present in 70.7%, 59.2%, 80.7% and 31% of the patients, respectively, and 42.5% were current smokers. The qualifying event was unstable angina, non-ST segment elevation myocardial infarction and ST segment elevation myocardial infarction in 54%, 21.8% and 24.2% of the patients, respectively. At 6 months, the primary efficacy end point—a composite of cardiovascular death, myocardial infarction and stroke—occurred in 3.4% of patients, while the secondary efficacy endpoint—a composite of the primary efficacy endpoints with the addition of hospitalization for unstable angina and urgent revascularization—occurred in 15.3%. Cardiovascular death occurred in 1.2% of the patients, myocardial infarction in 0.8%, stroke in 1.3%, hospitalization for UA in 8.1% and urgent revascularization in 3.9%. TIMI major bleeding occurred in 1.2% of patients, intracranial hemorrhage in 0.2% and TIMI minor bleeding in 13.3%. No significant difference was found between patients who underwent PCI at baseline and those who were treated conservatively regarding the primary (14 patients in each group, P = 0.931) and secondary (62 vs. 65 patients, P = 0.946) efficacy endpoints.ConclusionsIn patients who had an ACS during the 6 months preceding enrollment, treatment with generic ticagrelor led to a low rate of cardiovascular death, myocardial infarction and stroke with a minor increase in the risk of major bleeding.

Comparison of Safety and Efficacy Between Clopidogrel and Ticagrelor in Elderly Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

Background: Dual antiplatelet therapy combining aspirin with a P2Y12 adenosine diphosphate receptor inhibitor is a therapeutic mainstay for acute coronary syndrome (ACS). However, the optimal choice of P2Y12 adenosine diphosphate receptor inhibitor in elderly (aged ≥65 years) patients remains controversial. We conducted a meta-analysis to compare the efficacy and safety of ticagrelor and clopidogrel in elderly patients with ACS. Methods: We comprehensively searched in Web of Science, EMBASE, PubMed, and Cochrane databases through 29th March, 2021 for eligible randomized controlled trials (RCTs) comparing the efficacy and safety of ticagrelor or clopidogrel plus aspirin in elderly patients with ACS. Four studies were included in the final analysis. A fixed effects model or random effects model was applied to analyze risk ratios (RRs) and hazard ratios (HRs) across studies, and I2 to assess heterogeneity. Results: A total number of 4429 elderly patients with ACS were included in this analysis, of whom 2170 (49.0%) patients received aspirin plus ticagrelor and 2259 (51.0%) received aspirin plus clopidogrel. The ticagrelor group showed a significant advantage over the clopidogrel group concerning all-cause mortality (HR 0.78, 95% CI 0.63–0.96, I2 = 0%; RR 0.79, 95% CI 0.66–0.95, I2 = 0%) and cardiovascular death (HR 0.71, 95% CI 0.56–0.91, I2 = 0%; RR 0.76, 95% CI 0.62–0.94, I2 = 5%) but owned a higher risk of PLATO major or minor bleeding (HR 1.46, 95% CI 1.13–1.89, I2 = 0%; RR 1.40, 95% CI 1.11–1.76, I2 = 0%). Both the groups showed no significant difference regarding major adverse cardiovascular events (MACEs) (HR 1.06, 95% CI 0.68–1.65, I2 = 77%; RR 1.04, 95% CI 0.69–1.58, I2 = 77%). Conclusion: For elderly ACS patients, aspirin plus ticagrelor reduces cardiovascular death and all-cause mortality but increases the risk of bleeding. Herein, aspirin plus ticagrelor may extend lifetime for elderly ACS patients compared with aspirin plus clopidogrel. The optimal DAPT for elderly ACS patients may be a valuable direction for future research studies.

The pleiotropic effects of antithrombotic drugs in the metabolic-cardiovascular-neurodegenerative disease continuum: impact beyond reduced clotting.

Antithrombotic drugs are widely used for primary and secondary prevention, as well as treatment of many cardiovascular disorders. Over the past few decades, major advances in the pharmacology of these agents have been made with the introduction of new drug classes as novel therapeutic options. Accumulating evidence indicates that the beneficial outcomes of some of these antithrombotic agents are not solely related to their ability to reduce thrombosis. Here, we review the evidence supporting established and potential pleiotropic effects of four novel classes of antithrombotic drugs, adenosine diphosphate (ADP) P2Y12-receptor antagonists, Glycoprotein IIb/IIIa receptor Inhibitors, and Direct Oral Anticoagulants (DOACs), which include Direct Factor Xa (FXa) and Direct Thrombin Inhibitors. Specifically, we discuss the molecular evidence supporting such pleiotropic effects in the context of cardiovascular disease (CVD) including endothelial dysfunction (ED), atherosclerosis, cardiac injury, stroke, and arrhythmia. Importantly, we highlight the role of DOACs in mitigating metabolic dysfunction-associated cardiovascular derangements. We also postulate that DOACs modulate perivascular adipose tissue inflammation and thus, may reverse cardiovascular dysfunction early in the course of the metabolic syndrome. In this regard, we argue that some antithrombotic agents can reverse the neurovascular damage in Alzheimer's and Parkinson's brain and following traumatic brain injury (TBI). Overall, we attempt to provide an up-to-date comprehensive review of the less-recognized, beneficial molecular aspects of antithrombotic therapy beyond reduced thrombus formation. We also make a solid argument for the need of further mechanistic analysis of the pleiotropic effects of antithrombotic drugs in the future.

Method Development Technologies for Clopidogrel Bisulphate by Improving Solubility and Bioavailability

Clopidogrel bisulphate (CB) is a crystalline, poorly water-soluble drug of bioavailability less than 50%. The drug is an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor found on the membranes of platelet cells. The present work was performed using different polymers such as Polyvinylpyrrolidone (PVP) K-30 and polyvinyl alcohol with varied surfactants such as Tween 80 in comparison by using superdisintegrants like Sodium Starch Glycolate (SSG) and Microcrystalline Cellulose (MCC). By performing the particle size distribution, the size ranges from 232.6 nm to 995.6 nm and the polydispersity index ranges from 0.11 to 0.96, these ranges indicating the good physical nature of nanoparticles. The drug entrapment efficiency (DEE) of clopidogrel bisulphate nanoparticles was found to be in the range of 30.10% to 94.4%. From the study, it was found that F2 formulation containing PVP K-30 and L-arginine has given the best release in 80mins and the maximum cumulative drug release was 96.8% in comparison with other formulation, and the dissolution studies were performed for the seven formulations of prepared clopidogrel bisulphate granules among which F5 formulation containing crospovidone has given maximum drug release of 91.6% within 80mins. Here we state that the method development technologies improve the solubility and bioavailability studies by producing the nanoparticles.

Precision Medicine for Poor Metabolizers of Clopidogrel

Clopidogrel, an inhibitor of the platelet adenosine diphosphate P2Y12 receptor, is a prodrug that needs to be processed into an active metabolite by

Optimal Timing of Intervention in NSTE-ACS Without Pre-Treatment: The EARLY Randomized Trial

ObjectivesThe aim of this study was to compare a delayed and a very early invasive strategy in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) without pre-treatment. BackgroundThe optimal delay of the invasive strategy in patients with NSTE-ACS remains debated and has never been investigated in patients not pre-treated with P2Y12–adenosine diphosphate receptor antagonists. MethodsA prospective, open-label, randomized controlled trial was conducted. Altogether, 741 patients presenting with intermediate- or high-risk NSTE-ACS intended for an invasive strategy were included. The modified intention-to-treat analysis was composed of 709 patients after 32 withdrew consent. Patients were randomized 1:1 to the delayed invasive group (DG) (n = 363) with coronary angiography (CA) performed 12 to 72 h after randomization or the very early invasive group (EG) (n = 346) with CA within 2 h. No pre-treatment with a loading dose of a P2Y12–adenosine diphosphate receptor antagonist was allowed before CA. The primary endpoint was the composite of cardiovascular death and recurrent ischemic events at 1 month, as determined by a blinded adjudication committee. ResultsMost patients had high-risk NSTE-ACS in both groups (93% in the EG vs. 92.5% in the DG). The median time between randomization and CA was 0 h (interquartile range [IQR]: 0 to 1 h) in the EG group and 18 h (IQR: 11 to 23 h) in the DG. The primary endpoint rate was significantly lower in the EG (4.4% vs. 21.3% in the DG; hazard ratio: 0.20; 95% confidence interval: 0.11 to 0.34; p < 0.001), driven by a reduction in recurrent ischemic events (19.8% vs. 2.9%; p < 0.001). No difference was observed for cardiovascular death. ConclusionsWithout pre-treatment, a very early invasive strategy was associated with a significant reduction in ischemic events at the time of percutaneous coronary intervention in patients with intermediate- and high-risk NSTE-ACS. (Early or Delayed Revascularization for Intermediate and High-Risk Non ST-Elevation Acute Coronary Syndromes; NCT02750579)

Novel Antiplatelet Agents in Cardiovascular Disease.

Antiplatelet therapy reduces atherothrombotic risk and has therefore become a cornerstone in the treatment of cardiovascular disease. Aspirin, adenosine diphosphate P2Y12 receptor antagonists, glycoprotein IIb/IIIa inhibitors, and the thrombin receptor blocker vorapaxar are effective antiplatelet agents but significantly increase the risk of bleeding. Moreover, atherothrombotic events still impair the prognosis of many patients with cardiovascular disease despite established antiplatelet therapy. Over the last years, advances in the understanding of thrombus formation and hemostasis led to the discovery of various new receptors and signaling pathways of platelet activation. As a consequence, many new antiplatelet agents with high antithrombotic efficacy and supposedly only moderate effects on regular hemostasis have been developed and yielded promising results in preclinical and early clinical studies. Although their long journey from animal studies to randomized clinical trials and finally administration in daily clinical routine has just begun, some of the new agents may in the future become meaningful additions to the pharmacological armamentarium in cardiovascular disease.

Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3)

BackgroundAn unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y12 receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD. MethodsApproximately 180 patients (aged ≥ 2 to <18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes. ConclusionsHESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients.Trial Identifier: NCT03615924; EudraCT2017-002421-38.

Hemostasis Management of Patients Undergoing Emergency Cardiac Surgery After Ticagrelor Loading

Summary Ticagrelor, a direct and reversible inhibitor of P2Y12 adenosine diphosphate (ADP) receptor, has become one of the most commonly used oral antiplatelet agents in the treatment of acute coronary syndrome (ACS). Consequently, an increasing number of patients are presenting for emergent cardiac surgery with extensive platelet inhibition, and a potential risk for major perioperative bleeding. Herein, we describe the management of 3 patients, each of whom required an emergent cardiac surgical procedure following a loading or maintenance dose of ticagrelor for presumed ACS. Preoperative platelet function assessment was performed using a whole blood platelet aggregation test to confirm the extent of platelet P2Y12 inhibition. Platelet transfusion in the presence of therapeutic drug levels of ticagrelor have minimal impact on cessation of bleeding. Appropriate timing of surgery, and use of adjunctive hemostatic therapies is therefore imperative to achieve intraoperative hemostasis, and to minimize the need for allogeneic blood transfusion.

Microvesicles generated following traumatic brain injury induce platelet dysfunction via adenosine diphosphate receptor.

Traumatic brain injury (TBI) can result in an acute coagulopathy including platelet dysfunction that can contribute to ongoing intracranial hemorrhage. Previous studies have shown adenosine diphosphate (ADP)-induced platelet aggregation to be reduced after TBI. In addition, circulating microvesicles (MVs) are increased following TBI and have been shown to play a role in post-TBI coagulopathy and platelet function. We hypothesized that post-TBI MVs would affect platelet aggregation in a murine head injury model. Moderate TBI was performed using a weight-drop method in male C57BL6 mice. Whole blood, plasma, MVs, and MV-poor plasma were isolated from blood collected 10 minutes following TBI and were mixed separately with whole blood from uninjured mice. Platelet aggregation was measured with Multiplate impedance platelet aggregometry in response to ADP. The ADP P2Y12 receptor inhibitor, R-138727, was incubated with plasma and MVs from TBI mice, and platelet inhibition was again measured. Whole blood taken from 10-minute post-TBI mice demonstrated diminished ADP-induced platelet aggregation compared with sham mice. When mixed with normal donor blood, post-TBI plasma and MVs induced diminished ADP-induced platelet aggregation compared with sham plasma and sham MVs. By contrast, the addition of post-TBI MV-poor plasma to normal blood did not change ADP-induced platelet aggregation. The observed dysfunction in post-TBI ADP platelet aggregation was prevented by the pretreatment of post-TBI plasma with R-138727. Treatment of post-TBI MVs with R-138727 resulted in similar findings of improved ADP-induced platelet aggregation compared with nontreated post-TBI MVs. Adenosine diphosphate-induced platelet aggregation is inhibited acutely following TBI in a murine model. This platelet inhibition is reproduced in normal blood by the introduction of post-TBI plasma and MVs. Furthermore, observed platelet dysfunction is prevented when post-TBI plasma and MVs are treated with an inhibitor of the P2Y12 ADP receptor. Clinically observed post-TBI platelet dysfunction may therefore be partially explained by the presence of the ADP P2Y12 receptor within post-TBI MVs. Level III.

Update in Glycoprotein IIb/IIIa Receptor Antagonist Clopidogrel: Use in Cerebrovascular Accidents

Acute ischemic stroke is the most common manifestation of cerebrovascular disease, which ranks the first to make an adult become bedridden and/or out of productive life. Antiplatelet therapy has long been demonstrated to alleviate the risks of recurrent untoward events, especially in the setting of secondary prevention. In the last decade it has been proved that dual antiplatelet therapy (DAPT) appears to be more efficacious than monotherapy with aspirin. Clopidogrel (CLP) -an irreversible inhibitor of the platelet P2Y12 adenosine diphosphate receptor- is licensed in adults for the prevention of atherothrombotic events in patients suffering from MI, ischemic stroke (from 7 days to 6 months) or peripheral arterial disease. The recommended dose is 75 mg as a single daily dose, taken with or without food. This review is designed to encompass use of the agent comprehensively and delineates a frame in which clinicians can view as a guide in their routine clinical practice.

Compared efficacy of clopidogrel and ticagrelor in treating acute coronary syndrome: a meta-analysis

Background & AimsTicagrelor has been acknowledged as a new oral antagonist of P2Y12-adenosine diphosphate receptor, as a strategy with more rapid onset as well as more significant platelet inhibition function in acute coronary syndrome (ACS) patients. The clinical benefit of ticagrelor compared with clopidogrel remains controversial. The current meta-analysis was conducted to better evaluate the role of ticagrelor in comparison of clopidogrel in treating ACS patients.MethodsThe publications involving the safety as well as the efficacy of clopidogrel versus ticagrelor were screened and identified updated to June 2018. After rigorous review, eligible randomized controlled trials (RCTs) were extracted and propensity score matching (PSM) analysis was conducted. To analyze the summary odds ratios (ORs) of the endpoints of interest, we applied Meta-analysis Revman 5.3 software.ResultsThere were a total of 10 studies that met our inclusion criteria, of which the risk of bleeding rate (P = 0.43), MI (P = 0.14), and stroke (P = 0.70) had no association with significant differences between patients receiving ticagrelor or clopidogrel. Nonetheless, higher rate of dyspnea was observed in ticagrelor group (OR = 1.87, 95% CI: 1.70–2.05, P<0.00001 = .ConclusionsOur present findings suggest similar efficacy and safety profiles for clopidogrel and ticagrelor Ticagrelor should be considered as a valuable option to reduce the risk of bleeding, MI and stroke, whereas potentially increases the incidence of dyspnea. Given the metabolic process, ticagrelor may be a valid and even more potent antiplatelet drug than clopidogrel, as an alternative strategy in treating patients with clopidogrel intolerance or resistance.

Efficacy of P2Y12 Receptor Blockers After Myocardial Infarction and Genetic Variability of their Metabolic Pathways.

Various antiplatelet drugs are used following Acute Coronary Syndromes (ACS). Of them, adenosine diphosphate receptor P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are currently used for post-ACS long-term treatment. Although they act on the same receptor, they differ in pharmacodynamics and pharmacokinetics. Several enzymes and transporters involved in the metabolism of P2Y12 inhibitors show genetic variability with functional impact. This includes Pglycoprotein, carboxylesterase 1 and, most notably, CYP2C19 that is important in clopidogrel activation. Common gain-of-function or loss-of-function alleles of CYP2C19 gene are associated with lower or higher platelet reactivity that may impact clinical outcomes of clopidogrel treatment. Prasugrel is considered to be less dependent on CYP2C19 variability as it is also metabolized by other CYP450 isoforms. Some studies, however, showed the relevance of CYP2C19 variants for platelet reactivity during prasugrel treatment as well. Ticagrelor is metabolized mainly by CYP3A4, which does not show functionally relevant genetic variability. Its concentrations may be modified by the variants of Pglycoprotein gene ABCB1. While no substantial difference between the clinical efficacy of prasugrel and ticagrelor has been documented, both of them have been shown to be superior to clopidogrel in post-ACS treatment. This can be partially explained by lower variability at each step of their metabolism. It is probable that factors influencing the pharmacokinetics of both drugs, including genetic factors, may predict the clinical efficacy of antiplatelet treatment in personalized medicine. We summarize the pharmacokinetics and pharmacogenetics of P2Y12 inhibitors with respect to their clinical effects in post-myocardial infarction treatment.

GLS-409, an Antagonist of Both P2Y1 and P2Y12, Potently Inhibits Canine Coronary Artery Thrombosis and Reversibly Inhibits Human Platelet Activation

Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor antagonist reduces ischemic events in patients with acute coronary syndrome. Previous evidence from our group, obtained in a preclinical model of recurrent platelet-mediated thrombosis, demonstrated that GLS-409, a diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12 ADP receptors, may be a novel and promising antiplatelet drug candidate. However, the salutary antiplatelet effects of GLS-409 were accompanied by a trend toward an unfavorable increase in bleeding. The goals of this study were to: 1) provide proof-of-concept that the efficacy of GLS-409 may be maintained at lower dose(s), not accompanied by an increased propensity to bleeding; and 2) establish the extent and kinetics of the reversibility of human platelet inhibition by the agent. Lower doses of GLS-409 were identified that inhibited in vivo recurrent coronary thrombosis with no increase in bleeding time. Human platelet inhibition by GLS-409 was reversible, with rapid recovery of platelet reactivity to ADP, as measured by platelet surface activated GPIIb-IIIa and platelet surface P-selectin. These data support the concept that GLS-409 warrants further, larger-scale investigation as a novel, potential therapy in acute coronary syndromes.

Potential target-related proteins in rabbit platelets treated with active monomers dehydrocorydaline and canadine from Rhizoma corydalis

BackgroundDehydrocorydaline (DHC) and canadine (THB) are two active alkaloid compounds in Corydalis yanhusuo (Y.H. Chou & Chun C. Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu (Papaveraceae) (Rhizoma Corydalis). DHC and THC were previously shown to exert anti-platelet aggregation effect dose-dependently, but their exact mechanisms had not yet been addressed. Therefore, it is essential to study the mechanisms of DHC and THB affecting on platelet's function. PurposeTo investigate the anti-platelet effects and corresponding signal cascades of DHC and THB on platelet aggregation. MethodsFirstly, in vitro anti-platelet aggregation of DHC and THB induced by different agonists including thrombin (THR), adenosine diphosphate (ADP) and arachidonic acid (AA) were determined through turbidimetry method. Then the possible target-related platelet proteins after treated with DHC/THB were separated and identified by two dimensional gel electrophoresis (2-DE) and MALDI-TOF-MS/MS analysis, respectively. Finally, the signal cascades network induced by DHC/THB were predicted through functional analysis of these proteins along with the determination of platelet DAG concentration. ResultsThe platelet aggregation stimulated by THR, ADP and AA were inhibited by DHC and THB dose-dependently to a certain degree. Meanwhile, DHC and THB had the strongest effect on ADP- and THR-induced platelet aggregation respectively. In addition, treatment of these two compounds caused regulations of about sixty proteins in platelet, including cytoskeleton proteins, cell signaling proteins, proteins related to material energy metabolism, etc. ConclusionsUsing proteomic analysis combined with platelet aggregation test and ELISA, this study was successful in exploring the possible mechanisms of DHC/THB on platelet aggregation. DHC might inhibit platelet aggregation by a mechanism involving the ADP receptors P2Y1 and P2Y12, and the effect of THB on platelet function may be related to its binding to THR receptor PAR1 for mediated Gi signaling pathway. These results provide fundamental information for the anti-thrombotic effect of RC.

Trends in Platelet Adenosine Diphosphate P2Y12 Receptor Inhibitor Use and Adherence Among Antiplatelet-Naive Patients After Percutaneous Coronary Intervention, 2008-2016

Current guidelines recommend prasugrel hydrochloride and ticagrelor hydrochloride as preferred therapies for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). However, it is not well known how frequently these newer agents are being used in clinical practice or how adherence varies among the platelet adenosine diphosphate P2Y12 receptor (P2Y12) inhibitors. To determine trends in use of the different P2Y12 inhibitors in patients who underwent PCI from 2008 to 2016 in a large cohort of commercially insured patients and differences in patient adherence and costs among the P2Y12 inhibitors. A retrospective cohort study used administrative claims from a large US national insurer (ie, UnitedHealthcare) from January 1, 2008, to December 1, 2016, comprising patients aged 18 to 64 years hospitalized for PCI who had not received a P2Y12 inhibitor for 90 days preceding PCI. The P2Y12 inhibitor filled within 30 days of discharge was identified from pharmacy claims. Proportion of patients filling prescriptions for P2Y12 inhibitors within 30 days of discharge by year, as well as medication possession ratios (MPRs) and total P2Y12 inhibitor copayments at 6 and 12 months for patients who received drug-eluting stents. A total of 55 340 patients (12 754 [23.0%] women; mean [SD] age, 54.4 [7.1] years) who underwent PCI were included in this study. In 2008, 7667 (93.6%) patients filled a prescription for clopidogrel bisulfate and 521 (6.4%) filled no P2Y12 inhibitor prescription within 30 days of hospitalization. In 2016, 2406 (44.0%) patients filled clopidogrel prescriptions, 2015 (36.9%) filled either prasugrel or ticagrelor prescriptions, and 1045 (19.1%) patients filled no P2Y12 inhibitor prescription within 30 days of hospitalization. At 6 months, mean MPRs for patients who received a drug-eluting stent filling clopidogrel, prasugrel, and ticagrelor prescriptions were 0.85 (interquartile range [IQR], 0.82-1.00), 0.79 (IQR, 0.66-1.00), and 0.76 (IQR, 0.66-0.98) (P < .001), respectively; mean copayments for a 6 months' supply were $132 (IQR, $47-$203), $287 (IQR, $152-$389), and $265 (IQR, $53-$387) (P < .001), respectively. At 12 months, mean MPRs for clopidogrel, prasugrel, and ticagrelor were 0.76 (IQR, 0.58-0.99), 0.71 (IQR, 0.49-0.98), and 0.68 (IQR, 0.41-0.94) (P < .001), respectively; mean total copayments were $251 (IQR, $100-$371), $556 (IQR, $348-$730), and $557 (IQR, $233-$744) (P < .001), respectively. Between 2008 and 2016, increased use of prasugrel and ticagrelor was accompanied by increased nonfilling of prescriptions for P2Y12 inhibitors within 30 days of discharge. Prasugrel and ticagrelor had higher patient costs and lower adherence in the year following PCI compared with clopidogrel. The introduction of newer, more expensive P2Y12 inhibitors was associated with lower adherence to these therapies.

Pharmacosimulation of interruptions and its solution in intravenous administration of cangrelor.

Cangrelor is an intravenous adenosine diphosphate (ADP) P2Y12 receptor antagonist, which has to be administered as a bolus followed by immediate infusion. Nevertheless, in clinical routine deviations from the correct practice, such as delayed infusion onset or interruptions during infusion, may occur. The objective of the present study was to investigate the impact of administration delays on cangrelor concentration in a pharmacological simulation setting and to give possible solutions for the clinical practice. We simulated the effects of different delays in administration of cangrelor in a model based on known pharmacokinetic parameters. Additionally, we calculated the optimal dosage of a second bolus. We demonstrate that already a short delay between the bolus and begin of infusion as well as short infusion interruptions considerably affect the serum concentration of cangrelor. Additionally, we estimate the dosage of a possible second bolus which highly depends on the duration of the delay. Our results emphasize that continuous administration of cangrelor is crucial to avoid the critical time frame of increased thrombosis risk. We suggest a strategy for dealing with interruptions by demonstrating that a second bolus allows to reach rapidly an effective but not excessive cangrelor serum concentration.

Differential impact of diabetes mellitus on antiplatelet effects of prasugrel and clopidogrel

BackgroundAlthough prasugrel exerts stronger antiplatelet effects compared with clopidogrel, the factors affecting platelet reactivity under prasugrel have not been fully determined. This study aimed to find the novel mechanistic differences between two thienopyridines and identify the factor that influence platelet reactivity to each drug.MethodsForty patients with stable angina who underwent elective percutaneous coronary intervention were randomly assigned to receive either prasugrel (20 mg) or clopidogrel (300 mg) as a loading dose. Platelet function (light transmission, laser light scattering, and vasodilator-stimulated phosphoprotein phosphorylation) and plasma active metabolite levels were measured after the loading dose.ResultsPrasugrel consistently inhibited adenosine diphosphate receptor P2Y12 signalling to abolish amplification of platelet aggregation. Prasugrel abolished even small platelet aggregates composed of less than 100 platelets. On the other hand, clopidogrel inhibited large aggregates but increased small and medium platelet aggregates. Diabetes was the only independent variable for determining antiplatelet effects and active metabolite concentration of prasugrel, but not clopidogrel. Sleep-disordered breathing was significantly correlated with platelet reactivity in patients who had clopidogrel.ConclusionsPrasugrel efficiently abolishes residual P2Y12 signalling that causes small platelet aggregates, but these small aggregates are not inhibited by clopidogrel. Considering the differential effect of diabetes on antiplatelet effects between these two drugs, the pharmacokinetics of prasugrel, other than cytochrome P450 metabolism, might be affected by diabetes.Trial registrationUMIN-CTR UMIN000017624, retrospectively registered 21 May 2015.

GLS-409, a Synergistic Inhibitor of Both P2Y1 and P2Y12: Efficacy in a Canine Model of Recurrent Coronary Thrombosis and Reversibility of Human Platelet Inhibition

Introduction. Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) P2Y12 receptor inhibitor is a mainstay of pharmacological therapy in acute coronary syndromes. GLS-409 is a novel diadenosine tetraphosphate derivative that inhibits both P2Y1 and P2Y12platelet ADP receptors.Aims. 1) Determine the minimal dose of GLS-409 for in vivo inhibition of recurrent coronary thrombosis in a canine model. 2) Characterize the effects of the minimal antithrombotic dose of GLS-409 on the bleeding time. 3) Determine the extent and kinetics of the reversibility of platelet inhibition by GLS-409.Methods. (1) Canine Model of Recurrent Coronary Thrombosis. Recurrent platelet-mediated coronary thrombosis was initiated in anesthetized dogs by application of a stenosis at a site of vessel injury. At 1 h post-injury + stenosis, dogs were randomized to receive either GLS-409 or matched volumes of vehicle (saline). Three doses of GLS-409 were assessed: A) 0.054 mg/kg bolus + 0.00018 mg/kg/min infusion maintained for 2 hours; B) 1/10th bolus + 1/10th infusion; C) 1/100th bolus + 1/100th infusion. Coronary blood flow was monitored throughout the 2 hours post-treatment. Primary endpoints were: (i) area of the flow-time profile (index of coronary patency, expressed as % of baseline flow); and (ii) template bleeding time. (2) Reversibility of platelet inhibition following 30 minutes exposure to GLS-409. Sodium citrate 3.2% anticoagulated whole blood from healthy human volunteers (n=9) was treated with 80% inhibitory dose of GLS-409 for 30 minutes and assessed for recovery of response to ADP by flow cytometric analysis of platelet surface P-selectin and activated GPIIb-IIIa (reported by binding of the activation-dependent monoclonal antibody, PAC-1), at specified times before and after 300-fold dilution in drug-free, platelet-poor plasma.Results. (1) All dogs developed spontaneous episodes of recurrent thrombosis following coronary injury + stenosis. In the saline control group, there was no change in coronary patency during the 2 hour treatment period versus the pretreatment phase. Administration of GLS-409 at Doses A and B was associated with significant increases in % flow-time area, while Dose C had no significant effect on patency (Figure A). GLS-409 at Doses A and B which effectively inhibited recurrent coronary thrombosis, had no effect on the template bleeding time.(2) Incubation of human whole blood with GLS-409 for 30 min at room temperature, produced strong, concentration-dependent inhibition of the ADP-stimulated increases in platelet surface P-selectin and activated GPIIb-IIIa; 80% inhibition was obtained with 1.56 nM GLS-409. Blood exposed for 30 minutes to the 80% inhibitory concentration of GLS-409, then diluted 300-fold in drug-free, platelet-poor plasma (thereby reducing GLS-409 to 0.0052 nM, final concentration) showed a time-dependent recovery of reactivity to ADP as measured by both platelet surface P-selectin and activated GPIIb-IIIa (Figure B). However, while ADP-stimulated activated GPIIb-IIIa fully recovered within 60 min to levels seen in vehicle-treated samples, ADP-stimulated P-selectin response recovered to only 75% of the response seen in the vehicle-treated control (Figure B).Conclusions. (1) GLS-409 improved coronary patency in this canine model of recurrent coronary thrombosis without an accompanying increase in the bleeding time. (2) The time required after exposure of platelets to GLS-409 in whole blood for 50% recovery of ADP-stimulated PAC-1 reactivity (~26 min) is longer than published (J Thromb Haemost . 2017. 10.1111/jth.13627) recovery times after exposure to cangrelor (1.8 min), ticagrelor (4.4 min), and ticagrelor active metabolite (6.3 min), suggesting a slower off-rate for GLS-409. Incomplete reversibility of ADP-stimulated P-selectin following exposure to GLS-409 is similar to published results for cangrelor, but different from ticagrelor, both of which are selective for P2Y12. This relatively slow reversibility of GLS-409 inhibition offers another explanation, in addition to its dual specificity for P2Y1 and P2Y12, for the presently-described high potency of GLS-409 observed in the animal model. These properties suggest that GLS-409 could become a useful addition to the current drugs used in acute coronary syndromes. Further evaluation of the potential clinical utility of GLS-409 is warranted. [Display omitted] DisclosuresMichelson:Ionis: Research Funding; Sysmex: Research Funding; Baxalta: Research Funding; GLSynthesis: Research Funding; Eisai: Research Funding; Elsevier: Patents & Royalties; Ironwood: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratory: Consultancy; Pfizer: Research Funding. Yanachkov:GLSynthesis: Employment. Yanachkova:GLSynthesis: Employment. Wright:GLSynthesis: Employment. Przyklenk:GLSynthesis: Research Funding. Frelinger:Pfizer: Research Funding; Ionis: Research Funding; Sysmex: Research Funding; Baxalta: Research Funding; GLSynthesis: Research Funding; Ironwood: Research Funding.