Platelet P2Y12 Research Articles

Switching From Ticagrelor or Prasugrel to Clopidogrel.

Ticagrelor and prasugrel are newer antiplatelet drugs which, like clopidogrel, block the P2Y12 platelet receptor to inhibit platelet aggregation. Compared with clopidogrel, both ticagrelor and prasugrel have greater clinical efficacy but also have a higher risk of bleeding and are much more costly. Therefore, some institutions and providers switch patients from ticagrelor or prasugrel to clopidogrel in an effort to lower bleeding risk, stem costs, or otherwise ensure that patients can safely adhere to long-term P2Y12 inhibitor therapy. From a pharmacodynamic perspective, switching patients from ticagrelor or prasugrel to clopidogrel comes at a cost of less antiplatelet efficacy. However, it is unclear if antiplatelet efficacy is diminished enough to affect clinical outcomes. This is because clinical trial data investigating such a switch is scant, leaving the clinician unsure as to the acceptability of this practice. Current clinical trial data have thus far not shown any clinical detriment from switching from ticagrelor or prasugrel to clopidogrel, but there are many limitations to these investigations. So although a large-scale switch of patients from ticagrelor or prasugrel to clopidogrel is not recommended, if the patient is unable to adhere to long-term ticagrelor or prasugrel therapy, switching him/her to clopidogrel seems to be a reasonable practice to maintain chronic suppression of platelet aggregation and minimize the risk of ischemic events.

Powerful P2Y12 inhibition after percutaneous coronary intervention for an acute coronary syndrome: “the times they are a changing”

DAPT using aspirin and a P2Y12 platelet ADP receptor blocker has been established since more than 20 years as the pharmacological background of percutaneous coronary intervention (PCI) and post-acute coronary syndrome (ACS) ( Table 1 ). First, the combination of aspirin and ticlopidine given for 30 days has shown superiority over aspirin and anticoagulant therapy in patients undergoing coronary artery stenting (1).

Abstract WP395: Verifynow P2Y12 Assay With Regard to Cytochrome P450 2C19 Polymorphisms and Stroke Recurrence

Background and Purpose: No evidence as yet that clopidogrel resistance (CR) on VerifyNow assay in relation to cytochrome P450 2C19 (CYP2C19) polymorphisms are more clinically informative at predicting recurrent vascular events during follow-up after ischemic stroke (IS). The aim of this study was to perform a subgroup analysis of MESTRO study to explore the relationship between VerifyNow P2Y12 assay with regard to CYP2C19 polymorphisms and stroke recurrence in patients with non-cardiogenic IS and clopidogrel treatment. Methods: The methods of the MAESTRO study have been published previously. For the study, CR was tested by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotype was classified as an ultrarapid metabolizer (UM; *1/*17, *17/*17), extensive metabolizer (EM; *1/*1), intermediate/unknown metabolizer (*1/*2, *1/*3 and *2/*17, *3/*17), or poor metabolizer (PM; *2/*2, *2/*3, *3/*3) based on CYP2C19 genotype status. UM or EM status patients were allocated into the good genotype group for clopidogrel metabolism, and intermediate/unknown metabolizer or PM status patients were allocated into the poor genotype group. Results: Of the 256 patients with clopidogrel treatment, 20 (7.8%) had a recurrent stroke: 15 (75%) experienced an IS and 5 (25%) experienced an ICH. Of the patients with percent inhibition (% INH) ≥40, the risk of recurrent stroke in the good genotype group was 2.2% and was not significantly different from that in the poor genotype group (6.7%) (P=0.400). There was also no significant reduction in the risk of a major vascular event between the groups (2.2% vs 6.7%, P=0.400). Of the patients with % INH <40, there was a trend towards reduction in risk for the recurrent stroke (2.1% vs 8.3%, p=0.142) and a major vascular event (2.1% vs 9.8%, p=0.081) in the good genotype group. Conclusions: Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel alone may not predict stroke recurrence.

Abstract TP84: Safety and Effectiveness of Ticagrelor in Patients With Clopidogrel Resistance Undergoing Angioplasty, Stent or Flow Diverter Placement

Background and Purpose: Nearly 30% of the patients have clopidogrel resistance and are at high risk for in-stent thrombosis and adverse ischemic events. Ticagrelor is an allosteric platelet antagonist that reversibly inhibits the P2Y12 platelet receptor more potently than clopidogrel. We report upon the safety and effectiveness of ticagrelor in patients with cerebrovascular diseases and clopidogrel resistance undergoing angioplasty and/or stent or flow diverter placement. Methods: We analyzed data from our prospectively maintained endovascular database and identified patients treated with ticagrelor and underwent treatment with a stent or flow diverter. The patients were divided into an acutely loaded dose group and those converted from clopidogrel due to clopidogrel resistance, defined by platelet aggregation value of 200 PRU VerifyNow P2Y12 test. Patients received standard dual antiplatelet therapy, however, despite repeat clopidogrel loading doses, were found to be clopidogrel non-responders and were then administered ticagrelor 180mg loading dose and maintained on 90mg BID dosing. We ascertained occurrence of any bleeding complications, classified as major (hgb decrease >5 g/dl), minor (hgb decrease 3-5 g/dl), or insignificant. Results: A total of 36 (13.8%) patients (mean age 64.7±13.8 years; 58.3% females) had clopidogrel resistance out of 260 patients screened. Of those, 29 patients were switched from clopidogrel to ticagrelor due to an elevated PRU (avg 294.76±41.32 PRU) and 7 patients without previous antiplatelet use received a bolus and maintenance dose. Only one patient experienced a transient ischemic event within 24 hours after starting ticagrelor. Patients who were acutely loaded did not experience any ischemic events. No patient experienced symptomatic or asymptomatic hemorrhage on ticagrelor in the post-op period. A total of 43 procedures were performed in 36 patients with clopidogrel resistance: 26 pipeline placements, 8 wingspan stent placements, 2 LVIS stents, 1 neuroform stent with pipeline, and 7 angioplasties. Conclusions: Our study demonstrates the safety and effectiveness of loading or switching patients to ticagrelor with cerebrovascular diseases undergoing angioplasty, stent or flow diverter placement.

Designing Natural Product Hybrids Bearing Triple Antiplatelet Profile and Evaluating Their Human Plasma Stability.

Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustiblesource of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities thattake advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.

Ticagrelor - toward more efficient platelet inhibition and beyond.

Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor’s adverse effects, including dyspnea and bradycardia. Large-scale clinical trials demonstrated that both standard 12-month therapy and long-term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug–drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor.

Percutaneous coronary intervention of lesions with in-stent restenosis: A report from the ADAPT-DES study

There is a paucity of data from large contemporary cohorts of patients with in-stent restenosis (ISR) treated with drug-eluting stents (DESs), and no studies have examined the impact of high platelet reactivity (HPR) on the occurrence of ischemic events after ISR percutaneous coronary intervention (PCI) with DESs. We sought to report outcomes after PCI of ISR lesions and its association with HPR. Patients in the prospective, multicenter ADAPT-DES study were stratified according to whether they had ISR versus non-ISR PCI. Two-year outcomes were compared between the groups using Cox proportional hazards models. HPR was defined as on-clopidogrel P2Y12 platelet reaction units >208 as measured by the VerifyNow assay; target vessel failure (TVF) was defined as the composite of all-cause death, myocardial infarction, or ischemia-driven target vessel revascularization. Among the 8,582 patients included in the ADAPT-DES study, 840 (9.8%) patients underwent successful ISR PCI. ISR PCI was independently associated with a higher 2-year risk of TVF (adjusted hazard ratio [HR] 1.95; 95% CI 1.68-2.27; P<.001) and stent thrombosis (adjusted HR 1.95; 95% CI 1.08-3.51; P=.027) but not bleeding (adjusted HR 0.94; 95% CI 0.73-1.21; P=.64). There was no statistical interaction between HPR and ISR versus non-ISR PCI in regard to TVF (adjusted Pinteraction=.81). ISR PCI is associated with a considerably higher risk of 2-year adverse ischemic events, with HPR conferring similar risk in ISR and non-ISR PCI. More effective therapeutic strategies for managing ISR lesions are necessary.

Effect of intravenous fentanyl on ticagrelor absorption and platelet inhibition among patients undergoing percutaneous coronary intervention: Design, rationale, and sample characteristics of the PACIFY randomized trial

IntroductionMorphine reduces and delays the absorption of oral P2Y12 platelet inhibitors. Fentanyl is another opiate often administered during percutaneous coronary interventions (PCI). The PACIFY study will test whether intravenous fentanyl also impairs the absorption and action of oral P2Y12 inhibitors. MethodsPACIFY is a single-center trial randomizing adults undergoing clinically-indicated coronary angiography to have the procedure with or without fentanyl. All patients will receive local anesthetic and intravenous midazolam. Doses of all drugs are at the discretion of treating providers. Patients that require PCI receive 180mg of oral ticagrelor during the angiography procedure. The primary outcome is area under the ticagrelor plasma concentration-time curve. Secondary outcomes include platelet inhibition 2-h after loading, measured both by VerifyNow® (Accriva Diagnostics, San Diego, California) and by light-transmission platelet aggregometry. We will also survey patient comfort and measure high-sensitivity troponin levels. Patients and outcomes assessors are blinded, treating providers are not. ResultsA total of 212 patients are participating, 70 of whom required PCI. Baseline characteristics are numerically well balanced in both study arms. Mean age is 63years and 27% are female. There were no differences in total midazolam dose during the index PCI procedure, whereas mean total fentanyl dose was 9 mcg in the no-fentanyl arm (2 participants in this arm required fentanyl for bailout treatment of pain) versus 96 mcg in the fentanyl arm. ConclusionsThis study will provide important information on the impact of fentanyl administered during PCI on the absorption of ticagrelor and its antiplatelet activity.Trial Registration: clinicaltrials.gov Identifier: NCT02683707.

Oral Antiplatelet Therapy in Coronary Disease.

Ischemic heart disease is the major isolated cause of death worldwide, responsible for 7,249,000 deaths in 2008, 12.7% of deaths from any causes. The inhibition of platelet activation and aggregation is an important therapeutic target. Cyclooxygenase inhibitors and thienopyridines are currently the 2 most used pharmacological classes, but novel antiplatelet agents have currently an important role. The most recent thienopyridine, prasugrel, allows an irreversible inhibition of the P2Y12 platelet receptor associated to a faster and more consistent onset of action rather the previous antiplatelet agents of the same class. Cyclopentyl-triazolo-pyrimidines, a newer pharmacological class from which ticagrelor is an example, also act at the P2Y12 platelet receptor, and like prasugrel, ticagrelor inhibits platelet aggregation in a fast and consistent manner, however, in a reversible way. This article aims to conduct a review on the literature about the most recent information and guidelines on oral antiplatelet agents available for the management of coronary disease.

The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions.

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.

Efficacy and safety of potent platelet P2Y12 receptor inhibitors in elderly versus nonelderly patients with acute coronary syndrome: A systematic review and meta-analysis

The use of the potent oral P2Y12 inhibitors prasugrel and ticagrelor in patients with acute coronary syndromes (ACS) has a favorable net clinical effect compared with clopidogrel and is recommended as first-line therapy. However, the impact of these agents on ischemic and bleeding events in elderly ACS patients is not well defined. We performed a systematic review of articles comparing potent P2Y12 inhibitors to clopidogrel in elderly and nonelderly patients (defined according to each study) with ACS in terms of efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (major bleeding) end points. A total of 7,860 elderly and 37,857 nonelderly patients from 7 studies (5 randomized control trials and 2 observational studies) were included. Potent P2Y12 inhibitors significantly reduced efficacy end point in nonelderly patients (relative risk [RR] 0.85, 95% CI 0.79-0.93) and less so in elderly patients (RR 0.95, 95% CI 0.86-1.05). No significant differences were found between potent P2Y12 inhibitors and clopidogrel in terms of safety end point in both elderly (RR 1.19, 95% CI 0.95-1.49) and nonelderly patients (RR 1.16, 95% CI 0.95-1.41). There were no significant interactions between age and treatment effect in both analyses (efficacy Pint=.16; safety Pint=.83). The effect of more potent P2Y12 inhibitors compared with clopidogrel on efficacy and safety end points is consistent in elderly and younger patients. These data imply that potent P2Y12 inhibitors should not be withheld from eligible patients solely because of advanced age.

P2Y12 receptor inhibitor resistance and coronary artery disease: a bench to bedside primer for cardiovascular specialists.

Platelet P2Y12 receptor inhibitors are routinely prescribed for patients after acute coronary syndromes and percutaneous coronary interventions. Patients may have underresponsiveness (or resistance) to these drugs and in particular to clopidogrel, the most often used type. This review aims to focus on the concept of P2Y12 receptor inhibitor resistance and discuss incidence, mechanisms, novel diagnostic techniques and past and future clinical trials on the topic. Patients treated with P2Y12 receptor inhibitors may develop high on-treatment platelet reactivity (HPR), a phenomenon of impaired response toward the drug, which has been associated with ischemic complications. Although potent P2Y12 inhibitors provide better ischemic protection, this must be balanced with increased bleeding risk. Several clinical factors, including common genetic variants such as Cytochrome P450 2C19 loss-of-function alleles, have been shown to predispose to HPR among patients on clopidogrel. Platelet function tests and genotyping platforms have enabled identification of patients at-risk for HPR. Past studies using platelet testing and tailoring therapy among patients with HPR have failed to provide conclusive data to support its routine use. Ongoing studies using genotyping and novel antiplatelet regimens may identify potential strategies to minimize ischemic and bleeding risks concurrently. Until definitive studies demonstrate clear benefit of a personalized approach to P2Y12 inhibitor prescription, the choice of P2Y12 inhibitors should continue to be based on best evidence from previous large clinical trials.

Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus.

Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y12 receptor expression in megakaryocytes. Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P<0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y12 receptor expression in diabetes mellitus. Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.

Tailoring naringenin conjugates with amplified and triple antiplatelet activity profile: Rational design, synthesis, human plasma stability and in vitro evaluation

BackgroundThe current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y12 antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y12 receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways. MethodsComputational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates. ResultsIn silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) – naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists. ConclusionsThe DHA – naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y12 and COX-1 platelet activation pathways. General significanceNatural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs.

Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary syndrome.

Statin use is associated with enhanced pharmacodynamic response to clopidogrel in patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI). However, the impact of statin therapy on clopidogrel response profiles in patients with acute coronary syndrome (ACS) undergoing PCI has not been established and represents the objective of this investigation. On-treatment P2Y12 platelet reactivity was measured using the vasodilator stimulated phosphoprotein (VASP) phosphorylation assay before PCI, at hospital discharge, and at 1month after PCI in ACS patients enrolled in the multicenter, prospective GEne polymorphisms, Platelet Reactivity, and Syntax Score (GEPRESS) study (n = 962). High platelet reactivity (HPR) was defined as platelet reactivity index ≥50%. Statins were prescribed at hospital discharge in 87% (n = 835) of patients. All patients were followed for 1year. The 1-month HPR rate was lower in statin than in non-statin treated patients (39.6 vs 52%, respectively, p = 0.009). This finding was confirmed also among statin-treated patients with high Syntax score (≥15). After adjustment for differences in baseline characteristics, statin use at discharge was independently associated with 1-month HPR rate (odds ratio, 0.58, 95% confidence interval, 0.38-0.89; p = 0.015). In ACS patients undergoing PCI treated with clopidogrel the use of statins at discharge was associated with significantly lower 1-month HPR rates compared with patients not treated with statins.

P4438Mortality after oral platelet p2y12 inhibitors in the food and drug administration adverse event reporting system

P4438Mortality after oral platelet p2y12 inhibitors in the food and drug administration adverse event reporting system

Ferro reports robust 1Q 2017 performance

Morphine reduces and delays the absorption of oral P2Y12 platelet inhibitors. Fentanyl is another opiate often administered during percutaneous coronary interventions (PCI). The PACIFY study will test whether intravenous fentanyl also impairs the absorption and action of oral P2Y12 inhibitors.PACIFY is a single-center trial randomizing adults undergoing clinically-indicated coronary angiography to have the procedure with or without fentanyl. All patients will receive local anesthetic and intravenous midazolam. Doses of all drugs are at the discretion of treating providers. Patients that require PCI receive 180 mg of oral ticagrelor during the angiography procedure. The primary outcome is area under the ticagrelor plasma concentration-time curve. Secondary outcomes include platelet inhibition 2-h after loading, measured both by VerifyNow® (Accriva Diagnostics, San Diego, California) and by light-transmission platelet aggregometry. We will also survey patient comfort and measure high-sensitivity troponin levels. Patients and outcomes assessors are blinded, treating providers are not.A total of 212 patients are participating, 70 of whom required PCI. Baseline characteristics are numerically well balanced in both study arms. Mean age is 63 years and 27% are female. There were no differences in total midazolam dose during the index PCI procedure, whereas mean total fentanyl dose was 9 mcg in the no-fentanyl arm (2 participants in this arm required fentanyl for bailout treatment of pain) versus 96 mcg in the fentanyl arm.This study will provide important information on the impact of fentanyl administered during PCI on the absorption of ticagrelor and its antiplatelet activity.Trial Registration: clinicaltrials.gov Identifier: NCT02683707.

Incidence and outcome of switching of oral platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: the SCOPE registry

In patients with acute coronary syndromes (ACS) undergoing a percutaneous coronary intervention (PCI), switching of oral P2Y12 receptor inhibitors may frequently occur. We aimed to assess the current incidence of switching of oral P2Y12 receptor inhibitors and its safety in consecutive ACS patients undergoing PCI over a three-month period. The SCOPE registry was a multicentre, observational, prospective study. A total of 1,363 consecutive patients were enrolled in 39 PCI centres across Italy. Switching of oral antiplatelet therapies occurred in 2.3% in the cathlab, 3.3% at discharge and 5.1% at follow-up. The cumulative incidence of major adverse cerebrovascular events (MACE) and net adverse cerebrovascular events (NACE: a combination of MACE and bleeding events) was 1.6% and 5.6%, respectively. Among patients receiving an upgrade switching (change from old to novel P2Y12 receptor inhibitors), no ischaemic or bleeding events occurred during the whole study period. On the other hand, downgrade switching (from novel to old P2Y12 receptor inhibitors) was an independent predictor of NACE (OR 5.3; CI: 2.1-18.2; p=0.04). Switching of oral antiplatelet therapies is not uncommon among ACS patients undergoing PCI. Notably, switching from clopidogrel to novel P2Y12 receptor inhibitors appears safe, while a downgrade switching in early phases of ACS is associated with adverse clinical events.

Impact of platelet inhibition level on subsequent no-reflow in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction

High P2Y12 platelet reactivity (PR) level after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) affects prognosis and may induce the no-reflow phenomenon. To investigate the role of PR in the genesis of microvascular obstruction. Patients with STEMI undergoing PPCI within 12hours of symptoms onset were included prospectively. All patients received a 600mg clopidogrel-loading dose before PPCI and 250mg aspirin. PR was measured thereafter during PPCI while wiring the culprit lesion and before coronary dilatation, using the P2Y12 VerifyNow® assay. No-reflow was defined as ST-segment regression<50% observed 90minutes after PPCI. Between January 2014 and November 2015, 140 STEMI patients were included, and divided into two groups: a low PR group (LPR) defined as PR<209P2Y12 reaction units (PRU); and a high PR group (HPR) defined as PR≥209PRU. There were no differences in baseline characteristics between LPR and HPR groups, including age (57.8±11.9 vs. 59.4±13.2 years, respectively; P=0.44) and weight (76.1±15.1 vs. 74.8±10.9kg, respectively; P=0.55). Delay to revascularization was 270.1±175.5 vs. 295.6±206.2minutes (P=0.49) and time between clopidogrel-loading and PR measurement was 53±37 vs 65±54minutes (P=0.29) in the LPR and HPR groups, respectively. No-reflow was more frequent in the HPR group (44 [47.3%] vs. 9 [19.1%]; P=0.0012). Mean PR was higher in patients with no-reflow: 268.3±53 vs. 223.8±50.1 PRU (P=0.002). In multivariable analysis, HPR was an independent predictor of no-reflow. Area under the receiver operating characteristic curve was 0.745 (0.654, 0.835); the cut-off value predicting no-reflow was 254PRU. High PR level measured at PPCI is independently associated with no-reflow.

Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant‐induced inflammatory pain

Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain was induced in wild-type and P2ry12 gene-deficient (P2ry12-/- ) mice, and the potent, direct-acting and reversible P2Y12 receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12-/- mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-α and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1β, IL-6, TNF-α and KC levels were attenuated in P2ry12-/- mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12-/- mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12-/- mice on day 14. Conclusions In conclusion, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.