cangrelor and Coronary-Artery-Disease

Inadequate antiplatelet effects can result in substantial morbidity and mortality in patients with acute coronary syndrome and percutaneous coronary intervention (PCI). Cangrelor is a rapid onset and potent intravenous P2Y12 inhibitor that has been shown in large randomized controlled trials to reduce periprocedural complications for PCI compared with clopidogrel, the most commonly used P2Y12 inhibitor. Cangrelor should be considered in the setting of PCI to reduce the risk of periprocedural complications such as myocardial infarction, repeat coronary revascularization and stent thrombosis in patients not yet treated with another P2Y12 inhibitor or glycoprotein IIb/IIIa inhibitor. In this review, the importance of adequate P2Y12 inhibition, cangrelor's pharmacology and clinical profiles, and future directions for the cangrelor are discussed.

Topics: Adenosine Monophosphate; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Risk Factors; Treatment Outcome

Dual antiplatelet therapy with aspirin and oral P2Y12-receptor inhibitors prevents ischemic events in patients undergoing Percutaneous Coronary Intervention (PCI). However, oral administration of antiplatelet drugs cause delay of onset of platelet inhibition in P2Y12-inhibitor naïve patients. Cangrelor is a novel P2Y12-receptor inhibitor which is administrated intravenously and thus allows immediate antiplatelet inhibition during PCI. Due to its unique pharmacokinetics with fast onset of platelet inhibition and very short plasma half-life it allows effective and controllable periprocedural platelet inhibition. It could reduce short-term ischemic events in large randomized clinical trials. The present article reviews the available evidence and application on cangrelor use in clinical practice.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Administration, Intravenous; Coronary Artery Disease; Coronary Thrombosis; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Factors; Treatment Outcome

Thrombotic events such as myocardial infarction or stent thrombosis are the major cause of adverse outcomes in patients undergoing percutaneous coronary intervention (PCI). While current antiplatelet agents, anticoagulants, and PCI techniques have reduced the risk of thrombotic events in PCI-treated patients, a considerable hazard still remains. Cangrelor is an intravenous P2Y12 receptor antagonist that provides a rapid onset and maximal platelet inhibition, which is quickly reversible. In the large-scale CHAMPION PHOENIX trial, cangrelor was shown to reduce ischemic events significantly, including myocardial infarction and stent thrombosis, without increasing the risk of severe bleeding across the full spectrum of patients undergoing PCI, with substantial benefits in all patient subgroups examined. The pharmacologic profile of cangrelor makes it a valuable addition to the armamentarium of physicians providing care to a broad range of patients with coronary artery disease. Cangrelor is currently approved for reducing thrombotic events in patients undergoing PCI who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. Future studies are needed to determine the role of cangrelor in other clinical settings, such as upstream therapy in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTE-ACS), and as a bridge to coronary artery bypass graft (CABG) or other non-cardiac surgeries in patients who require ongoing adenosine diphosphate receptor blockade.

Topics: Adenosine Monophosphate; Animals; Clinical Trials as Topic; Coronary Artery Disease; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis

Topics: Adenosine Monophosphate; Coronary Artery Disease; Humans; Injections, Intravenous; Percutaneous Coronary Intervention; Postoperative Complications; Purinergic P2Y Receptor Antagonists

Cangrelor is the first parenteral antagonist of the platelet P2Y12 receptor. This direct-acting antagonist of the platelet P2Y12 receptor should be considered an adjunct to a percutaneous coronary intervention in patients who have not been adequately pretreated with platelet P2Y12 receptor antagonists at the time of the procedure. The use of cangrelor requires transition to an oral platelet P2Y12 receptor antagonist. Transition strategies have been developed on the basis of pharmacologic characteristics of platelet P2Y12 receptor antagonists, results of pharmacodynamic studies, and results from clinical trials. Cangrelor blocks the binding to the platelet P2Y12 receptor of the active metabolite of the thienopyridines, clopidogrel and prasugrel. The active metabolite of thienopyridines is present in blood for a short interval after administration. For this reason, clopidogrel should be administered after cangrelor is stopped. Prasugrel can be administered at the end of the cangrelor infusion or up to 30 min before cangrelor is stopped. Ticagrelor is also a reversible direct-acting antagonist of the platelet P2Y12 receptor. Because there is no interaction between ticagrelor and cangrelor, ticagrelor can be administered before or during the infusion of cangrelor.

Topics: Adenosine Monophosphate; Administration, Oral; Blood Platelets; Coronary Artery Disease; Humans; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Practice Guidelines as Topic

Pretreatment with oral P2Y12 inhibitors occurs each time clopidogrel, prasugrel, ticagrelor are given to patients with suspected coronary artery disease before definition of the coronary anatomy. In acute coronary syndromes, the practice of administering oral P2Y12 inhibitors upstream has been the object of significant controversy in recent years, following the publication of two trials of pretreatment in non-ST-segment elevation acute coronary syndromes and ST-segment elevation myocardial infarction, respectively. The introduction in the market of cangrelor - the first intravenous P2Y12 inhibitor - represents a new opportunity but also a new challenge for clinicians. This article reviews current recommendations and supporting evidence surrounding pretreatment with oral and intravenous P2Y12 inhibitors in patients with acute coronary syndromes.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clopidogrel; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine

Dual antiplatelet therapy is the standard of care for patients with acute coronary syndromes or with recent coronary stents implantation. P2Y12 receptor antagonists have shown to reduce the risk of recurrent ischemic events among these patients, at the expense of an increased risk of bleeding. Cangrelor is a novel, intravenous, short-acting, reversible platelet P2Y12 inhibitor, which has been evaluated for the treatment of arterial thrombosis.. Studies on the pharmacological characteristics of cangrelor and clinical trials were retrieved by a PubMed literature search.. Cangrelor has been tested in patients with coronary artery diseases undergoing percutaneous coronary intervention and as bridging therapy for patients undergoing coronary artery bypass graft. The rapid peak of action allows a fast and complete inhibition of platelet aggregation; the rapid offset is advantageous in case of bleeding complications; and finally, the intravenous administration also makes this drug suitable for patients unable to consume oral medications. Unfortunately, the large clinical trials evaluating cangrelor in percutaneous coronary intervention did not show superiority to the standard antiplatelet therapy, and its future use in this setting still needs to be better assessed. Conversely, when used as bridging therapy to coronary artery bypass graft, cangrelor showed promising results.

Topics: Adenosine Monophosphate; Coronary Artery Disease; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Thrombosis

To perform a systematic up-to-date review and critical discussion of potential clinical applications of cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies.. A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through December 2013.. Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid onset and quickly reversible action. In contrast to ticagrelor, cangrelor's interaction with thienopiridines requires termination of cangrelor infusion before switching to clopidogrel or prasugrel. According to randomized trials, a cangrelor-clopidogrel combination is relatively safe and more effective than the standard clopidogrel regimen in both urgent and elective percutaneous coronary intervention (PCI) settings, with the advantage of this drug combination fully evident when the universal definition of myocardial infarction is applied. In contrast to available antiplatelet drugs with delayed onset and offset of action, its favorable properties make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12 inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the trials favoring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of survival advantage.. With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12 inhibition, and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while maintaining a favorable safety profile. However, further studies, addressing the safety and efficacy of cangrelor on top of novel oral P2Y12 inhibitors, are warranted.

Topics: Adenosine Monophosphate; Animals; Coronary Artery Disease; Humans; Randomized Controlled Trials as Topic

Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y12 receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y12 receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding.. This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI.. Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naïve patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest).

Topics: Adenosine Monophosphate; Coronary Artery Disease; Coronary Thrombosis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Stents

The dual antiplatelet therapy with acetylsalicylic acid and clopidogrel has been the mainstay of both acute and chronic phase coronary artery disease, reducing importantly the risk of adverse events. Despite a correct compliance, a non-negligible rate of adverse events still happens. New compounds, with improved properties, are now clinically available (such as prasugrel or ticagrelor) or under advanced development. The aim of the present review is the description of these new compounds, particularly prasugrel and ticagrelor.

Topics: Adenosine; Adenosine Monophosphate; Clinical Trials, Phase III as Topic; Coronary Artery Disease; Double-Blind Method; Dyspnea; Hemorrhage; Humans; Multicenter Studies as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Receptors, Proteinase-Activated; Thiophenes; Ticagrelor; Treatment Outcome

New P2Y12 inhibitors can be classified as oral (prasugrel and ticagrelor) and intravenous drugs (cangrelor and elinogrel). These P2Y12 inhibitors might be superior to clopidogrel for reducing ischemic events in patients with coronary artery disease (CAD). We performed a meta-analysis of randomized trials that compared new oral or intravenous P2Y12 inhibitors with clopidogrel to determine their efficacy and safety in patients.. Twelve randomized, placebo-controlled studies and two subgroup analyses of included studies on ST-segment elevation myocardial infarction (STEMI) were included. The database consisted of 82,784 patients, with 43,875 (53%) on new oral P2Y12 inhibitors and 38909 (47%) on intravenous P2Y12 inhibitors compared with clopidogrel. The primary efficacy endpoint was major adverse cardiac events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding. New oral P2Y12 inhibitors significantly decreased MACEs (odds ratio: 0.85, p<0.0001 for the whole cohort; OR: 0.77, p=0.04 for STEMI) and all-cause death (OR: 0.88, p=0.04 for the whole cohort; OR: 0.77, p=0.01 for STEMI). Among new intravenous P2Y12 inhibitors, only cangrelor significantly decreased the risk of MACEs. An increase in TIMI major bleeding was observed only by prasugrel among the new P2Y12 inhibitors.. New oral P2Y12 inhibitors reduce ischemic events, but there is no obvious increase in major bleeding in patients with CAD, and the risk/benefit ratio is particularly favorable for STEMI patients. Moreover, only cangrelor is beneficial for ischemic events in patients on new intravenous P2Y12 inhibitors.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Administration, Oral; Clopidogrel; Coronary Artery Disease; Coronary Restenosis; Fibrinolytic Agents; Hemorrhage; Humans; Injections, Intravenous; Multicenter Studies as Topic; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Randomized Controlled Trials as Topic; Stents; Stroke; Sulfonamides; Thiophenes; Thrombolytic Therapy; Ticagrelor; Ticlopidine

Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions (PCI). Thienopyridines and ticagrelor are oral drugs developed for this purpose. Cangrelor is an intravenous, non-thienopyridine antagonist of the P2Y12 receptor with a rapid, potent, predictable, and quickly reversible effect. Cangrelor has been studied in a broad population intended to receive PCI in the CHAMPION program, where it was compared with different clopidogrel regimens. The first two trials, CHAMPION PCI and PLATFORM, failed their primary objective, likely for challenges in the adjudication of PCI-related myocardial infarction. In a third trial that implemented the universal definition of MI, CHAMPION PHOENIX, a reduction of thrombotic events, including stent thrombosis, was observed. In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery. Cangrelor appears a promising agent in patients who require PCI or when a rapid reversal is needed.

Topics: Adenosine Monophosphate; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Percutaneous Coronary Intervention; Purinergic P2Y Receptor Antagonists; Survival Analysis; Treatment Outcome

ADP plays a pivotal role in localized platelet activation and recruitment, and, with that, in the maintenance of thrombus integrity, making it a suitable target for the control of intravascular thrombosis. The limited distribution of one of its receptors, the P2Y12 receptor, primarily to platelets makes it an especially attractive pharmacologic target. For the last several decades the thienopyridine family of P2Y12 antagonists have provided the vast majority of clinical data confirming the clinical benefit of selective P2Y12 inhibition. Recently, new thienopyridine plus nonthienopyridine P2Y12 antagonists have become available or are being studied that will further improve our treatment of patients with coronary disease.

Topics: Acute Coronary Syndrome; Adenosine; Adenosine Monophosphate; Clopidogrel; Coronary Artery Disease; Humans; Myocardial Infarction; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Quinazolinones; Stents; Sulfonamides; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine

The use of oral antiplatelet therapy in reducing vascular events has been extensively studied. Currently available oral antiplatelet agents include aspirin and the thienopyridine P2Y12 receptor antagonists. These classes are combined frequently in the setting of acute coronary syndrome and percutaneous coronary intervention (PCI). Resistance to either or both of these agents is a major concern, as antiplatelet resistance has been linked to an increase in thrombotic events and worse clinical outcomes. As a result, there is a need for newer, more effective antiplatelet agents to address the limitations of currently available therapy. Prasugrel, a third generation thienopyridine, has been approved by both the FDA and European Commission. Two additional P2Y12 agents, ticagrelor and cangrelor are in advanced stages of development. The possible advantages of prasugrel over clopidogrel include a faster onset of action, reduced inter-patient variability and more potent platelet inhibition. Ticagrelor is an oral reversible P2Y12 antagonist with greater platelet inhibition compared with clopidogrel. Cangrelor is being developed as an intravenous P2Y12 antagonist with a very fast onset and offset, which may offer advantages particularly in the setting of coronary intervention. These emerging antiplatelet agents may offer advantages such as faster onset of action, greater potency and reversibility of platelet inhibition. This article summarizes the available clinical data on the upcoming P2Y12 antiplatelet agents in the treatment of coronary artery disease.

Topics: Adenosine; Adenosine Monophosphate; Animals; Coronary Artery Disease; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticagrelor

Antiplatelet therapy remains a cornerstone of modern management of atherothrombotic vascular disease. For many years, aspirin has been the mainstay of initial antiplatelet drug management in coronary heart disease, while the need for inhibition of other platelet activation pathways has led to the development of various other antiplatelet drugs, such as clopidogrel. An improved understanding of the underlying mechanisms involved in thrombogenesis has paved the way for further development of newer antiplatelet drug therapies. Various clinical studies have probed the effectiveness and risk profile of the newer antiplatelet drugs, such as prasugrel, in comparison with currently available drugs. Some newer agents such as prasugrel are close to being approved for clinical use, whereas other agents such as cangrelor and AZD6140 are in phase 3 clinical trials. New drug classes, such as the thromboxane receptor antagonists (such as NCX-4016 and S18886), as well as platelet adhesion antagonists and thrombin receptor antagonists are similarly being evaluated for their efficacy and risk profile in phase I and II trials.

Topics: Adenosine; Adenosine Monophosphate; Aspirin; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Drug Design; Humans; Imines; Lactones; Naphthalenes; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Propionates; Purinergic P2 Receptor Antagonists; Pyridines; Thiophenes; Ticagrelor; Ticlopidine

There are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor.. This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor.. Compared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite.. Compared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162).

Topics: Blood Platelets; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome

Reticulated platelets are associated with impaired antiplatelet response to irreversibly acting P2Y. This study randomized 110 patients undergoing elective percutaneous coronary intervention with use of cangrelor to different oral transitioning strategies loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (. Platelet inhibition is not influenced by levels of reticulated platelets during infusion of cangrelor independent of oral P2Y

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Clopidogrel; Coronary Artery Disease; Female; Flow Cytometry; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thienopyridines; Ticagrelor

To examine the safety and efficacy of cangrelor in patients with single-vessel disease (SVD) and multi-vessel disease (MVD).. Cangrelor, an intravenous, rapidly acting P2Y. We studied a modified intention to treat population of patients with SVD and MVD from the CHAMPION PHOENIX trial. The primary efficacy outcome was the composite of death, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) at 48hours. The key safety outcome was non-coronary artery bypass grafting GUSTO severe bleeding at 48hours.. Among 10,921 patients, 5,220 (48%) had SVD and 5,701 (52%) had MVD. MVD patients were older and more often had diabetes, hyperlipidemia, hypertension, prior stroke, and prior MI. After adjustment, MVD patients had similar rates of 48-hour death/MI/IDR/ST (6.3% vs 4.2%, adjusted odds ratio [OR] 1.6 [95% CI 0.42-6.06]) and GUSTO severe bleeding (0.1% vs 0.2%, P=.67) compared with SVD patients. Consistent with overall trial findings, cangrelor use reduced ischemic complications in patients with both SVD (3.9% vs 4.5%; OR 0.86, 95% CI 0.65-1.12) and MVD (5.5% vs 7.2%; OR 0.74, 95% CI 0.6-0.92, P-interaction=.43). GUSTO severe bleeding outcomes were not significantly increased with cangrelor or clopidogrel in either SVD or MVD patients.. In the CHAMPION PHOENIX trial, MVD and SVD patients had similar ischemic outcomes at 48hours and 30days. Cangrelor consistently reduced ischemic complications in both SVD and MVD patients without a significant increase in GUSTO severe bleeding. CLINICAL PERSPECTIVES.

Topics: Adenosine Monophosphate; Administration, Oral; Aged; Cause of Death; Clopidogrel; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Global Health; Humans; Incidence; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Postoperative Complications; Purinergic P2Y Receptor Antagonists; Survival Rate; Ticlopidine; Time Factors

The aim of this study was to determine the impact of cangrelor and prasugrel on the pharmacodynamic effects of each agent.. The development of an intravenous P2Y12 antagonist necessitates transition between intravenous and oral therapy.. Patients (n=15) with stable coronary artery disease who were taking 81 mg aspirin daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 60 mg dose of prasugrel at 1 h (n=3), 1.5 h (n=6), 2 h (n=3), or 2.5 h (n=3). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 μmol/l ADP, VerifyNow, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 10 mg of prasugrel daily for either 5 days (n=6) or 6 days (n=6). On study day 8, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor.. During cangrelor infusion (days 1 and 8), extensive inhibition of platelet function, reflected by limited residual platelet reactivity, was apparent. On day 1, transient (limited to the first hour after cangrelor was stopped) but substantial (>50%) recovery of platelet reactivity was observed. This recovery was attenuated when prasugrel was given at 1.5 h (30 min before cangrelor was stopped).. Prasugrel did not alter the antiplatelet effects of cangrelor, but transient recovery of platelet reactivity was apparent during the transition from cangrelor to prasugrel. Recovery of platelet reactivity was limited when prasugrel was administered 30 min before the end of the cangrelor infusion.

Topics: Adenosine Monophosphate; Administration, Oral; Aged; Coronary Artery Disease; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Drug Substitution; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Time Factors; Treatment Outcome

The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.. Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.. In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.. At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).. Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

Topics: Adenosine Monophosphate; Aged; Anticoagulants; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Double-Blind Method; Female; Hemorrhage; Hirudins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Peptide Fragments; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Recombinant Proteins; Risk Factors; Stents; Ticlopidine; Time Factors; Treatment Outcome

To determine whether initiation of clopidogrel before discontinuation of cangrelor would impact on the recovery of platelet reactivity.. The active metabolite of clopidogrel cannot bind to P2Y12 when cangrelor occupies the receptor. Pharmacodynamic studies have shown that this interaction is avoided when clopidogrel is given at the end of the cangrelor infusion. We found that antiplatelet effects of another thienopyridine, prasugrel, were apparent when prasugrel was administered 0.5 hour before cangrelor was stopped.. Platelet function studies (light transmission aggregometry, VerifyNow, and flow cytometry) were performed on blood from patients with stable coronary artery disease who were taking aspirin when a loading dose of clopidogrel (600 mg) was given during a cangrelor infusion (0.5 and 1 hour before cangrelor was stopped). Results were compared with those obtained when clopidogrel was given immediately after cangrelor was stopped.. Administration of clopidogrel 0.5 and 1 hour before discontinuation of the cangrelor infusion did not prevent recovery of platelet reactivity more effectively than administration at the end of the infusion.. Our results support the previously established strategy of administering clopidogrel immediately after discontinuation of cangrelor. Earlier administration increases the recovery of platelet function.

Topics: Adenosine Monophosphate; Adult; Aged; Biological Availability; Blood Platelets; Clopidogrel; Coronary Artery Disease; Drug Interactions; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Ticlopidine

The purpose of this study was to assess the in vitro P2Y12 receptor inhibitory effects of cangrelor on platelets from patients on maintenance prasugrel therapy treated with 2 reloading dose regimens.. Despite its more potent and rapid antiplatelet effects compared with clopidogrel, recent studies have shown variability in prasugrel-mediated P2Y12 receptor inhibition, particularly in high-risk settings. Cangrelor is a potent intravenous P2Y12 receptor inhibitor.. A total of 60 patients with coronary artery disease on maintenance prasugrel (10 mg/day) therapy were randomized to a 30- or 60-mg reload of prasugrel. The platelet reactivity index (PRI), as assessed by whole-blood vasodilator-stimulated phosphoprotein, was measured with and without in vitro incubation of cangrelor (500 nM) at baseline, and at 1 and 4 h after reload.. In the absence of cangrelor, prasugrel reloading reduced PRI (p < 0.001 for both doses), although a 60-mg reload had greater platelet inhibition compared with a 30-mg reload at 4 h (p = 0.001). Cangrelor was associated with a reduction in PRI values during the overall study time course in patients reloaded with 30 mg (p = 0.001) and 60 mg (p < 0.001) of prasugrel. In patients reloaded with 30 mg prasugrel, cangrelor decreased PRI at each time point (baseline, p < 0.001; 1 h, p = 0.013; 4 h, p = 0.001). In patients reloaded with 60 mg prasugrel, cangrelor decreased PRI at baseline (p < 0.001) and 1 h (p = 0.002); levels of platelet reactivity comparable to those achieved with cangrelor were observed only at 4 h (p = 0.325). The intergroup comparisons with cangrelor were not significant at any time point.. In patients on maintenance prasugrel therapy exposed to a reloading dose (30 or 60 mg) of prasugrel, in vitro cangrelor is associated with further platelet P2Y12 receptor inhibitory effects.

Topics: Adenosine Monophosphate; Aged; Blood Platelets; Cell Adhesion Molecules; Coronary Artery Disease; Drug Administration Schedule; Female; Florida; Humans; Male; Microfilament Proteins; Middle Aged; Percutaneous Coronary Intervention; Phosphoproteins; Phosphorylation; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Thiophenes; Time Factors

This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor.. Cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents.. Patients (n = 12) with stable coronary artery disease who were taking aspirin 81 mg daily were recruited. On study day 1, they received a bolus plus 2-h infusion of cangrelor plus a 180-mg dose of ticagrelor at either 0.5 h (n = 6) or 1.25 h (n = 6). Pharmacodynamic effects (light transmission platelet aggregation in response to 20 and 5 μmol/l adenosine diphosphate, VerifyNow, P2Y12 assay (Accumetrics, San Diego, California), vasodilator-stimulated phosphoprotein index, and flow cytometry) were assessed during and after the cangrelor infusion. Patients took 90 mg of ticagrelor twice daily for either 6 (n = 6) or 7 (n = 6) doses. On study day 5, pharmacodynamic effects were assessed before and during a bolus plus 2-h infusion of cangrelor.. During cangrelor infusion, extensive inhibition of platelet function reflected by limited residual platelet reactivity was apparent. After cangrelor was stopped, the antiplatelet effects of ticagrelor were preserved despite a modest increase in platelet reactivity.. Ticagrelor given before or during infusion of cangrelor did not attenuate the pharmacodynamic effects of cangrelor. The pharmacodynamic effects of ticagrelor were preserved when ticagrelor was given during infusion of cangrelor. Consistent with the reversible binding of ticagrelor, this oral P2Y12 antagonist can be administered before, during, or after treatment with cangrelor.

Topics: Adenosine; Adenosine Monophosphate; Administration, Oral; Aged; Blood Platelets; Cell Adhesion Molecules; Coronary Artery Disease; Drug Administration Schedule; Drug Interactions; Drug Substitution; Female; Humans; Infusions, Intravenous; Male; Microfilament Proteins; Middle Aged; Phosphoproteins; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Time Factors; Vermont

Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5 to 7 days prior to surgery to minimize bleeding.. To evaluate the use of cangrelor, an intravenous, reversible P2Y(12) platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery.. Prospective, randomized, double-blind, placebo-controlled, multicenter trial, involving 210 patients with an acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n = 11) conducted between January 2009 and April 2011. Interventions Thienopyridines were stopped and patients were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery.. The primary efficacy end point was platelet reactivity (measured in P2Y(12) reaction units [PRUs]), assessed daily. The main safety end point was excessive CABG surgery-related bleeding.. The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 μg/kg per minute. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3-8.1] P < .001). Excessive CABG surgery-related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5-2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.. Among patients who discontinue thienopyridine therapy prior to cardiac surgery, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition.. clinicaltrials.gov Identifier: NCT00767507.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Adult; Aged; Aged, 80 and over; Blood Loss, Surgical; Coronary Artery Bypass; Coronary Artery Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Purinergic P2Y Receptor Antagonists; Stents; Thienopyridines; Thrombosis

Because novel direct acting anticoagulants are being tested in the secondary prevention of cardiovascular events, we assessed potential effects of a direct acting antagonist of Factor Xa on platelet function. Blood from patients with known coronary artery disease who were treated with aspirin but no other antithrombotic agent was spiked in vitro with rivaroxaban alone or in combination with a direct acting P2Y12 antagonist (cangrelor). To limit cofounding effects of anticoagulants and to enable interaction between coagulation factors, blood was anticoagulated only with a specific inhibitor of Factor XIIa, corn trypsin inhibitor. Polymerization of fibrin was prevented with the peptide GPRP. Activation of platelets was determined with the use of flow cytometry in response to lipidated tissue factor, thrombin, the collagen mimetic convulxin, and adenosine diphosphate (ADP). Rivaroxaban inhibited the activation of platelets induced by tissue factor and to a lesser extent activation induced by thrombin, effects that were accentuated when combined with cangrelor. Rivaroxaban did not attenuate convulxin-induced activation of platelets; however, a limited but consistent attenuation of ADP-induced platelet activation was seen with blood anticoagulated with rivaroxaban. Effects of rivaroxaban on ADP-induced platelet activation were not mediated by thrombin, tissue factor, or platelet-leukocyte aggregation. In conclusion, rivaroxaban attenuated in vitro the activation of platelets mediated by thrombin. In light of the pivotal role of thrombin in platelet activation after rupture of an atherosclerotic plaque, rivaroxaban should attenuate platelet activation in vivo, an effect that is accentuated by combination with a P2Y12 antagonist.

Topics: Adenosine Monophosphate; Aged; Anticoagulants; Aspirin; Blood Platelets; Coronary Artery Disease; Crotalid Venoms; Factor Xa; Factor Xa Inhibitors; Female; Humans; Lectins, C-Type; Male; Middle Aged; Morpholines; Plant Proteins; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Rivaroxaban; Thiophenes

Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI.. The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales.. The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

Topics: Adenosine Monophosphate; Adult; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk Assessment; Survival Analysis; Ticlopidine; Treatment Outcome

Topics: Adenosine Monophosphate; Aged; Coronary Artery Disease; Heart Transplantation; Humans; Infusions, Intravenous; Male; Platelet Aggregation Inhibitors; Preoperative Care

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y

Topics: Adenosine Monophosphate; Aged; Aspirin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Female; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Thrombosis; Ticagrelor

The effect of perioperative bridging therapy on risks of ischemic cardiac events and major bleeding complications in patients on dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) remains undefined.. We report on 60 consecutive patients between 2010 and 2017 who required cardiac (CS; n = 15) or non-cardiac (NCS; n = 45) surgeries following PCI at our institution. Short-acting intravenous (IV) antiplatelet (APT) bridging with eptifibatide, tirofiban and cangrelor were instituted after DAPT interruption.. All patients were men with multiple atherosclerosis risk factors. An acute coronary syndrome indication (56.7%) was the most common PCI indication in the CS and NCS groups. Drug-eluting stents were used in 93.33% and 95.56% of the above groups, respectively. The median duration from PCI to CS and NCS were 11.17 and 18.25 months, respectively and 38.33% of all surgeries were performed within 6 months of the index PCI. Most patients were on background aspirin (83.33%) and clopidogrel (81.67%) and median duration of DAPT interruption was 7 days. Median duration of perioperative IV APT bridging was 3 days for CS and 5 days for NCS groups. In the CS group, two patients (13.33%) had non-fata myocardial infarction (MI), and four (26.67%) had clinically significant bleeding. No patients had perioperative stent thrombosis. In the NCS group, one patient (2.22%) had stent thrombosis; four (6.67%) had myocardial infarction, and five (11.11%) clinically significant bleeding.. Despite using IV APT as bridging therapy during perioperative DAPT interruption in post-PCI patients, postoperative cardiac events and bleeding complications can still occur.

Topics: Adenosine Monophosphate; Administration, Intravenous; Aged; Aspirin; Cardiac Surgical Procedures; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Drug-Eluting Stents; Eptifibatide; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Perioperative Care; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Factors; Time Factors; Tirofiban; Treatment Outcome

Topics: Adenosine Monophosphate; Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Female; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Stents; Thrombosis; Treatment Outcome

In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs).. Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67-0.97; P=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52-1.01; P=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56-11.2; P<0.001; SI: 9.08 [4.01-20.5]; P<0.001; CEC and SI: 10.9 [3.23-36.6]; P<0.001; CEC but not SI: 4.69 [1.94-11.3]; P<0.001; SI but not CEC: 15.4 [5.26-44.9]; P<0.001).. In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

Topics: Adenosine Monophosphate; Coronary Artery Disease; Coronary Thrombosis; Humans; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Adenosine Monophosphate; Aged; Coronary Artery Disease; Drug Approval; Female; Humans; Injections, Intravenous; Intraoperative Period; Male; Middle Aged; Percutaneous Coronary Intervention; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Tertiary Care Centers; United States; United States Food and Drug Administration

Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding.. CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81).. Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial.

Topics: Adenosine Monophosphate; Aged; Brain Ischemia; Chi-Square Distribution; Clopidogrel; Coronary Artery Disease; Coronary Thrombosis; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Ticlopidine; Time Factors; Treatment Outcome

In three comparative trials in a total of about 25,000 patients requiring coronary angioplasty, IV cangrelor was not more effective in reducing mortality than oral clopidogrel, and it only improved cardiovascular morbidity in a biased trial. Cangrelor can provoke bleeding, kidney failure and dyspnea.

Topics: Adenosine Monophosphate; Administration, Intravenous; Clopidogrel; Coronary Artery Disease; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Treatment Outcome

Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y(12) receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y(12) reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y(12) receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.

Topics: Adenosine Monophosphate; Aged; Coronary Artery Disease; Diabetes Complications; Female; Humans; Male; Middle Aged; Prospective Studies; Purinergic P2Y Receptor Antagonists; Treatment Outcome

Insufficient response on antiplatelet medication has become an intensively discussed issue because of the risk factor of recurrent adverse cardiovascular events. However, the monitoring of antiplatelet therapy requires appropriate, robust and reliable test methods. For the measurement of thienopyridine effects, the manufacturer of the PFA-100® System provides the INNOVANCE® PFA P2Y * cartridge. We tested this cartridge for its capacity to detect the inhibition of the P2Y₁₂ receptor, which is the target for thienopyridine medication (e.g. clopidogrel). We compared the INNOVANCE® PFA P2Y * results with those obtained by the receptor specific flow cytometric vasodilator stimulated phosphoprotein (VASP) assay that expresses the status of the P2Y₁₂ receptor as "platelet reactivity index" (PRI). The in vitro addition of the P2Y₁₂ receptor antagonist cangrelor (AR-C69931MX) to citrated human whole blood resulted in a dose-dependent prolongation of closure times (CTs) of the INNOVANCE® PFA P2Y * cartridge correlating with decreased PRI levels. In volunteers, the intake of a 600 mg clopidogrel loading dose caused an increase of the CTs in all volunteers, although some of these volunteers were identified as "poor responders" by the VASP assay (no significant reduction of PRI levels). In 50 patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) and under dual antiplatelet therapy, the new cartridge had a detection rate of 84% (CT 106 s as cut-off) for clopidogrel medication. After dividing the 50 patients into two groups according to their response to clopidogrel INNOVANCE® PFA P2Y * recognized all "responders" (defined by a PRI > 50%) using >106 s as cut-off but the specificity for a "good response" was only 42% because several "poor responders" (defined by a PRI > 50%) also showed CTs above the cut-off. The best correlation (substantial agreement) between the results of INNOVANCE® PFA P2Y * and of the VASP phosphorylation assay was achieved using CT > 200 s and PRI < 55% as cut-offs. Then, the sensitivity of INNOVANCE® PFA P2Y * was 97% and the specificity for a "good response" 65%. In summary, INNOVANCE® PFA P2Y * showed a high sensitivity for the detection of P2Y₁₂ receptor blockade, but had only a limited specificity for a "good response" to clopidogrel. Therefore, this new cartridge is a useful tool to rule out P2Y₁₂ receptor inhibition, if normal or only slightly prolonged CTs are obtained. Its predictive value for ri

Topics: Adenosine Monophosphate; Adult; Aged; Aged, 80 and over; Biological Assay; Biomarkers; Blood Platelets; Case-Control Studies; Cell Adhesion Molecules; Clopidogrel; Coronary Artery Disease; Female; Flow Cytometry; Humans; Male; Microfilament Proteins; Middle Aged; Phosphoproteins; Phosphorylation; Platelet Aggregation Inhibitors; Predictive Value of Tests; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Sensitivity and Specificity; Ticlopidine; Young Adult

Topics: Adenosine Monophosphate; Angioplasty, Balloon, Coronary; Clopidogrel; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Research Design; Ticlopidine

Though antiplatelet drugs are proven beneficial to patients with coronary heart disease and stroke, more effective and safer antiplatelet drugs are still needed. In this study we report the antiplatelet effects and mechanism of BF0801, a novel adenine derivative. BF0801 dramatically inhibited platelet aggregation and ATP release induced by ADP, 2MeSADP, AYPGKF, SFLLRN or convulxin without affecting shape change in vitro . It also potentiated the inhibitory effects of adenosine-based P2Y12 antagonist AR-C69931MX or phosphodiesterase (PDE) inhibitor IBMX on platelet aggregation. The cAMP levels in both resting and forskolin-stimulated platelets were increased by BF0801 suggesting its PDE inhibitor activity, which is further confirmed by the concentration-dependent suppression of BF0801 on the native and recombinant PDE. Similar to AR-C69931MX, BF0801 drastically inhibited 2MeSADP- induced adenylyl cyclase inhibition in platelets indicating its P2Y12 antagonism activity, which is substantiated by the inhibition of BF0801 on the interaction between ADP and P2Y12 receptor expressed in CHO-K1 cells measured by atomic force microscopy. Moreover, we confirmed the antiplatelet effects of BF0801 using platelets from rats intravenously given BF0801. In summary, for the first time we developed a novel adenine derivative bearing dual activities of PDE inhibition and P2Y12 antagonism, which may have therapeutic advantage as a potential antithrombotic drug.

Topics: Adenine; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Platelets; CHO Cells; Coronary Artery Disease; Cricetinae; Cricetulus; Humans; Mice; Mice, Knockout; Phosphoric Diester Hydrolases; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2Y12

Platelets are activated in vivo by multiple agonists; however, platelet function testing in vitro has been performed predominantly with only one or two agonists of platelet activation. Greater insight into anticipated effects of antithrombotic regimens should enhance the design of successful clinical trials. To test this concept, we assessed platelet activation induced by multiple agonists and two antithrombotic regimens, unfractionated heparin (UFH) and eptifibatide compared with bivalirudin and cangrelor. Blood samples from 10 patients with coronary artery disease were spiked with pharmacologic concentrations achieved in vivo of either UFH (1.2 U/ml) and eptifibatide (1.7 microg/ml), or with bivalirudin (8 microg/ml) and cangrelor (500 nmol/l). Platelet function was assessed with the use of flow cytometry. Agonists included thrombin (50 nmol/l), adenosine diphosphate (1 micromol/l), the collagen-mimetic convulxin (5 ng/ml), and platelet-activating factor (10 nmol/l). When platelet activation was identified by the surface expression of P-selectin in response to multiple agonists, the combination of bivalirudin and cangrelor suppressed activation more than UFH and eptifibatide. When platelet activation was identified by the activation of glycoprotein IIb-IIIa (PAC-1 binding), the combination of bivalirudin and cangrelor was more effective in suppressing activation in response to thrombin and adenosine diphosphate, whereas UFH and eptifibatide more effectively prevented binding of PAC-1 when platelets were activated with the collagen-mimetic convulxin. In conclusion, bivalirudin and cangrelor suppressed platelet activation in response to diverse agonists in vitro more than UFH and eptifibatide. These results and this approach to selection of promising interventions should be helpful in streamlining the design of clinical trials.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Animals; Blood Platelets; Clinical Trials as Topic; Coronary Artery Disease; Crotalid Venoms; Drug Evaluation, Preclinical; Drug Therapy, Combination; Eptifibatide; Fibrinolytic Agents; Flow Cytometry; Heparin; Hirudins; Humans; Lectins, C-Type; P-Selectin; Peptide Fragments; Peptides; Pilot Projects; Platelet Activating Factor; Platelet Activation; Platelet Function Tests; Recombinant Proteins; Research Design; Thrombin

Combined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited. Born aggregometry was performed with adenosine diphosphate (ADP), collagen and epinephrine. To verify platelet adrenergic activity, potentiation by low-dose epinephrine and inhibition by selective alpha-2 receptor blocker atipamezole were determined. To assess the P2Y(12)-specific residual activity, cangrelor was used. Plasma norepinephrine, soluble CD40-ligand, high-sensitivity-C-reactive protein (hsCRP) - and in 24 subjects platelet P-selectin positivity were measured. Epinephrine - at very low concentration (10(-9)g/ml) - significantly potentiates (1.25 microM ADP: 26.5% vs. 43%; 5 microM ADP: 53% vs. 64.5%; collagen: 17% vs 42%, p < 0.001) while atipamezole inhibits ADP- and collagen-induced platelet aggregations (1.25 microM ADP: 26.5% vs. 23%; 5 microM ADP: 53% vs. 47%; collagen: 17% vs. 11%, p < 0.001). Patients with high adrenergic activity have significantly increased baseline ADP- and collagen-induced platelet aggregation. Based on cangrelor's efficacy, these patients have significantly more residual P2Y(12) activity as well. HsCRP and soluble CD40-ligand levels were similar. In conclusion, stable coronary heart disease patients with prominent adrenoceptor activity in vitro have significantly increased platelet aggregability and more functional P2Y(12) receptor, indicating poor inhibitory response to thienopyridines. Therefore, platelet adrenergic receptor represents a considerable, dynamic factor of high residual platelet reactivity and might contribute to cardiovascular events indicating failure of antiplatelet therapy.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adrenergic alpha-Antagonists; Aged; Aspirin; Blood Platelets; Clopidogrel; Collagen; Coronary Artery Disease; Drug Resistance; Drug Therapy, Combination; Female; Humans; Imidazoles; Male; Middle Aged; Norepinephrine; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Receptors, Adrenergic, alpha-2; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Ticlopidine; Treatment Failure