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Background: There are limited data to assess pharmacodynamic (PD) profiles of patients with STEMI undergoing primary percutaneous coronary intervention (PCI) and receiving cangrelor after pretreatment with ticagrelor. Methods: The PharmacOdynaMic effects of cangrelor in PatiEnts wIth acute or chronIc coronary syndrome undergoing percutaneous coronary intervention (POMPEII) registry (NCT04790032) is a prospective study conducted at Federico II University of Naples enrolling all patients undergoing PCI receiving cangrelor at operator’s discretion. PD assessments were performed with 3 assays: (1) the gold standard light transmittance aggregometry (LTA) (20- and 5-μM adenosine diphosphate [ADP] stimuli); (2) VerifyNow P2Y12-test; (3) Multiplate electrode aggregometry (MEA), ADP-test. Results: We analyzed 13 STEMI patients pretreated with ticagrelor within 1 h at the time they underwent primary PCI receiving cangrelor. All patients showed low maximal platelet aggregation at 30-minute during cangrelor infusion, as well as at 3 h and 4–6 h (corresponding to 1 h and 2–4 h after stopping cangrelor infusion) with no cases of high residual platelet reactivity. These results were consistent with all assays. Conclusions: PD data show that in contemporary real-world STEMI patients pretreated within 1 h with ticagrelor undergoing primary PCI, adding cangrelor resulted in fast and potent platelet inhibition, thus suggesting that cangrelor may bridge the gap until ticagrelor reaches its effect.

An 84-year-old patient developed immediate thrombosis of his carotid stent in recovery after transcarotid artery revascularization. In the present report, the technical details about intraoperative management for neurovascular rescue using the transcarotid artery revascularization flow-reversal system are described. The patient was determined to have clopidogrel resistance. Intraoperative medical management is also discussed. The current alternative intravenous and oral antiplatelet therapies such as glycoprotein IIb/IIIa and P2Y12 inhibitors are explored. The debate regarding preoperative antiplatelet resistance testing remains ambiguous, and increasing studies have demonstrated the safety and efficacy of alternatives to clopidogrel. Despite an unpredictable and devastating complication, the patient’s outcome was successful using contemporary strategies.

Background: Pretreatment with a P2Y 12 inhibitor may be considered in patients with ST-segment elevation myocardial infarction (STEMI) referred to percutaneous coronary intervention (PCI). Intravenous cangrelor is an alternative in this setting, where oral absorption can be hindered. The aim of this study was to compare cangrelor administered after coronary angiography (i.e., "downstream") and ticagrelor pretreatment (i.e., "upstream")., Methods: STEMI patients undergoing PCI from October 2019 to June 2023 were included. The primary outcome was the composite of in-hospital major adverse cardiovascular events (MACE). Secondary outcomes included individual components of the primary outcome and in-hospital major bleeding. Univariable and multivariable regression analyses were performed in unmatched and propensity-matched cohorts., Results: Of 6086 patients enrolled in the prospective CAST registry, 761 were included: 383 (50.3 %) received downstream cangrelor and 378 (49.7 %) upstream ticagrelor. In the matched population, no between-group differences were observed in MACE (odds ratio [OR] 1.30; 95 % confidence interval [CI] 0.79-2.17; P 0.308), all-cause death (OR 1.91; 95 % CI 0.87-4.54; P 0.124), myocardial infarction (OR 2.64; 95 % CI 0.76-12.14; P 0.154), stent thrombosis (OR 0.38; 95 % CI 0.06-1.80; P 0.255), unplanned repeat revascularization (OR 1.22; 95 % CI 0.32-4.98; P 0.766) and major bleeding (OR 0.98; 95 % CI 0.50-1.93; P 0.955). Cardiogenic shock and bailout administration of glycoprotein IIb/IIIa inhibitors were independent predictors of MACE, while radial access showed an inverse association with the primary outc., Conclusions: In P2Y 12 -naïve STEMI patients undergoing primary PCI, no significant differences were noted in the risk of in-hospital ischemic and bleeding events between downstream cangrelor and upstream ticagrelor., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Tools for precise prediction of bleeding risk in patients undergoing percutaneous coronary intervention (PCI) with cangrelor are lacking., Methods: Consecutive patients undergoing PCI and treated with cangrelor in 7 centers were retrospectively enrolled. The primary endpoint was Bleeding Academic Research Consortium (BARC) BARC 2, 3, or 5 bleeding 48 h after PCI. Predictors of BARC 2-5 bleeding were identified in a derivation cohort and combined into a numerical risk score. Discrimination and calibration were assessed in the derivation and validation cohorts. A threshold to define high bleeding risk (HBR) was identified and its diagnostic accuracy was compared with that of currently recommended bleeding risk scores., Results: 1071 patients undergoing PCI with cangrelor were included. Fifty-four patients (5 %) experienced a BARC 2-5 bleeding, of whom 24 (44 %) from the access site. Age ≥ 75 years (odds ratio [OR] 2.58, 95 % confidence interval [CI] 1.21-5.48, p = 0.01), acute coronary syndrome at presentation (OR 8.14, 95 % CI 2.28-52, p = 0.01), and femoral access (OR 6.21, 95 % CI 2.71-14, p < 0.001) independently predicted BARC 2-5 bleeding at 48 h after PCI. The three items were combined to form a new risk score, the ICARUS score, showing good discrimination in both the derivation (area under the curve [AUC] 0.78) and internal validation (AUC 0.77) cohorts, and excellent calibration. An ICARUS score > 9 points accurately identified patients at HBR, showing better discrimination than other risk scores., Conclusions: A risk score based on age, clinical presentation and access site, predicts the risk of periprocedural bleeding in patients receiving cangrelor (ClinicalTrials.gov ID: NCT05505591)., (Copyright © 2024. Published by Elsevier B.V.)

Anxiety disorders are one of the most epidemic and chronic psychiatric disorders. An incomplete understanding of anxiety pathophysiology has limited the development of highly effective drugs against these disorders. GPR17 has been shown to be involved in multiple sclerosis and some acute brain injury disorders. However, no study has investigated the role of GPR17 in psychiatric disorders. In a well-established chronic restraint stress (CRS) mouse model, using a combination of pharmacological and molecular biology techniques, viral tracing, in vitro electrophysiology recordings, in vivo fiber photometry, chemogenetic manipulations and behavioral tests, we demonstrated that CRS induced anxiety-like behaviors and increased the expression of GPR17 in basolateral amygdala (BLA) glutamatergic neurons. Inhibition of GPR17 by cangrelor or knockdown of GPR17 by adeno-associated virus in BLA glutamatergic neurons effectively improved anxiety-like behaviors. Overexpression of GPR17 in BLA glutamatergic neurons increased the susceptibility to anxiety-like behaviors. What's more, BLA glutamatergic neuronal activity was required for anxiolytic-like effects of GPR17 antagonist and GPR17 modulated anxiety-like behaviors via BLA to ventral hippocampal CA1 glutamatergic projection. Our study finds for the first and highlights the new role of GPR17 in regulating anxiety-like behaviors and it might be a novel potential target for therapy of anxiety disorders., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Antiplatelet therapy involving aspirin and a P2Y 12 receptor inhibitor is fundamental in managing patients with atherothrombotic disease. Switching between P2Y 12 inhibitors is frequently observed in clinical settings for various reasons, such as safety, efficacy, patient adherence, or cost concerns. Although it occurs often, the optimal method for switching remains a concern owing to potential drug interactions, which can result in either inadequate platelet inhibition and subsequent thrombotic events or low platelet reactivity and increased bleeding risks due to therapy overlap. This review offers practical guidance on switching P2Y 12 inhibitors, drawing from pharmacodynamic and clinical data., Competing Interests: Disclosures Dr F. Franchi has received consulting fees or honoraria from AstraZeneca; and institutional grants from PLx Pharma and the Scott R. MacKenzie Foundation. Dr D.J. Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and has received institutional research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr D. Sibbing has received speaker fees and fees for advisory board activities from Bayer, Daiichi-Sankyo, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor is the standard of care for patients who undergo percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). Though this regimen reduces rates of ischemic events in patients with STEMI, the optimal strategy for P2Y 12 administration in STEMI patients is still evolving., Purpose: The purpose of this review is to summarize current evidence on optimal use of ticagrelor and prasugrel in the acute phase of STEMI., Summary: Due to high platelet activity in the acute setting of STEMI and PCI, adequate and rapid platelet inhibition is important. Strategies of increased ticagrelor/prasugrel loading dose or earlier administration in STEMI have not been successful in closing this platelet inhibition gap. Potential strategies for improving ticagrelor/prasugrel use early in STEMI include bridging with intravenous antiplatelet agents or crushed or chewed administration., Conclusion: Oral ticagrelor/prasugrel given before or immediately after STEMI PCI is usually sufficient to prevent thrombotic complications. When faster platelet inhibition is desired, or oral administration is compromised by inability to swallow tablets, crushing/chewing ticagrelor/prasugrel tablets is an alternative to intravenous P2Y 12 inhibitor therapy., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with STEMI receive dual antiplatelet therapy as soon as possible with aspirin and a P2Y12 receptor antagonist prior to PCI. A fraction of these patients may have multi-vessel disease needing emergent CABG surgery. The choice of a P2Y12 receptor antagonist plays a role in the timing of CABG surgery as it poses a bleeding risk until it is completely eliminated from the system. Oral P2Y12 receptor antagonists have a long duration of platelet inhibition which is difficult to reverse. Cangrelor is an intravenous P2Y12 receptor antagonist with a short half-life and rapid cessation of its effect after discontinuation. Methods: Three patients who presented to our emergency department with STEMI were started on cangrelor infusion prior to cardiac catheterization instead of other P2Y12 receptor antagonists like clopidogrel or ticagrelor. The study received ethical approval as it is part of the current standard of care for STEMI patients. Results: All three patients were found to have multi-vessel disease during coronary angiography requiring CABG surgery. As cangrelor was used in these patients they were able to have their surgery within 24–48 h. Intravenous cangrelor was stopped about an hour before surgery. No bleeding complications occurred and all three patients made a speedy recovery in the ICU. Conclusion: Cangrelor is a potent P2Y12 receptor antagonist which can be used in patients presenting with STEMI as one of the two anti-platelet agents along with aspirin without any dilemma that it would cause a delay in CABG surgery if the patients need one.

Tremendous progress has been made in the treatment of ST-segment elevation myocardial infarction (STEMI), the most severe and time-sensitive acute coronary syndrome. Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion, which has stimulated the development of regional STEMI systems of care with standardized protocols designed to optimize care. However, challenges remain for patients with cardiogenic shock, out-of-hospital cardiac arrest, an expected delay to reperfusion (>120 min), in-hospital STEMI, and more recently, those with Covid-19 infection. Ultimately, the goal is to provide timely reperfusion with primary PCI coupled with the optimal antiplatelet and anticoagulant therapies. We review the challenges and provide insights into the remaining knowledge gaps for contemporary STEMI care.

Ruptured blister type aneurysms are challenging to treat, and the ideal treatment remains debated. Recently, endovascular procedures, particularly flow diversion, gained popularity in treating blister aneurysms; however, the need for dual antiplatelet therapy remains a significant concern. Cangrelor is a novel intravenous P2Y12 platelet receptor antagonist with reversible binding and rapid onset and offset of action. These characteristics are appealing for use in endovascular procedures and may mitigate some concerns associated with other P2Y12 receptor antagonists. In this manuscript, we present the case of a ruptured blister aneurysm to highlight features of pathogenesis relevant to clinical course and patient management, describe current treatment paradigms, and illustrate the benefits of cangrelor in neurosurgical patients. Previously studied exclusively in the cardiac literature, this is one of the first reports of the use of cangrelor in neuro-endovascular procedures. This is important as cangrelor has the potential for improving the safety of endovascular procedures, especially in patients where treatment is associated with high risks of intraprocedural bleeding or other complications that may require further intervention.

Background: A drug-drug interaction (DDI) may occur when transitioning from intravenous P2Y 12 inhibition with cangrelor to oral P2Y 12 inhibition with prasugrel. However, this has never been tested in patients undergoing percutaneous coronary intervention (PCI)., Objectives: This study sought to rule out a DDI when cangrelor and prasugrel are concomitantly administered in PCI patients., Methods: SWAP-6 (Switching Antiplatelet-6) was a prospective, randomized, 3-arm, open-label pharmacokinetic (PK) and pharmacodynamic (PD) study. Patients (N = 77) were randomized to 1) prasugrel only at the start of PCI, 2) cangrelor plus prasugrel concomitantly at the start of PCI, or 3) cangrelor at the start of PCI plus prasugrel at the end of infusion. Cangrelor infusion was maintained for 2 hours. PK/PD assessments were performed at baseline and 6 time points postrandomization. The primary endpoint was noninferiority in VerifyNow (Werfen) P2Y 12 reaction units measured at 4 hours after randomization between cangrelor plus prasugrel concomitantly administered vs prasugrel only. PK assessments included plasma levels of the active metabolite of prasugrel., Results: Compared with prasugrel, cangrelor further enhances P2Y 12 inhibitory effects. At 4 hours postrandomization, P2Y 12 reaction unit levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (least squares means difference = 130; 95% CI: 85-176), failing to meet the prespecified noninferiority margin. Findings were corroborated by multiple PD assays. The active metabolite of prasugrel levels were not affected by concomitant administration of cangrelor and were low at the end of cangrelor infusion., Conclusions: In patients undergoing PCI, concomitant administration of prasugrel with cangrelor leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI. (Switching Antiplatelet Therapy-6 [SWAP-6]; NCT04668144)., Competing Interests: Funding Support and Author Disclosures This study was funded by an investigator-initiated grant from the Scott R. MacKenzie Foundation. The Scott R. MacKenzie Foundation had no role in the study design conception, conduct of the study, or decision to publish these results. Dr Franchi has received payment as an individual for consulting fees or honoraria from AstraZeneca, Bayer, and Sanofi; and has received institutional payments for grants from PLx Pharma and the Scott R. MacKenzie Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, Celo-Nova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: 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., Objectives: This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor., Methods: In this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y 12 reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points., Results: 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., Conclusions: 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)., Competing Interests: Funding Support and Author Disclosures The present study was funded by an investigator-initiated grant from The Scott R. MacKenzie Foundation. The Scott R. MacKenzie Foundation had no role in the study design conception, conduct of the study, or decision to publish these results. Dr Franchi has received consulting fees or honoraria from AstraZeneca, Bayer, and Sanofi; and has received institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and has received research grants to the institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and The Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with STEMI receive dual antiplatelet therapy as soon as possible with aspirin and a P2Y 12 receptor antagonist prior to PCI. A fraction of these patients may have multi-vessel disease needing emergent CABG surgery. The choice of a P2Y 12 receptor antagonist plays a role in the timing of CABG surgery as it poses a bleeding risk until it is completely eliminated from the system. Oral P2Y 12 receptor antagonists have a long duration of platelet inhibition which is difficult to reverse. Cangrelor is an intravenous P2Y 12 receptor antagonist with a short half-life and rapid cessation of its effect after discontinuation., Methods: Three patients who presented to our emergency department with STEMI were started on cangrelor infusion prior to cardiac catheterization instead of other P2Y 12 receptor antagonists like clopidogrel or ticagrelor. The study received ethical approval as it is part of the current standard of care for STEMI patients., Results: All three patients were found to have multi-vessel disease during coronary angiography requiring CABG surgery. As cangrelor was used in these patients they were able to have their surgery within 24-48 h. Intravenous cangrelor was stopped about an hour before surgery. No bleeding complications occurred and all three patients made a speedy recovery in the ICU., Conclusion: Cangrelor is a potent P2Y 12 receptor antagonist which can be used in patients presenting with STEMI as one of the two anti-platelet agents along with aspirin without any dilemma that it would cause a delay in CABG surgery if the patients need one., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Tremendous progress has been made in the treatment of ST-segment elevation myocardial infarction (STEMI), the most severe and time-sensitive acute coronary syndrome. Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion, which has stimulated the development of regional STEMI systems of care with standardized protocols designed to optimize care. However, challenges remain for patients with cardiogenic shock, out-of-hospital cardiac arrest, an expected delay to reperfusion (>120 min), in-hospital STEMI, and more recently, those with Covid-19 infection. Ultimately, the goal is to provide timely reperfusion with primary PCI coupled with the optimal antiplatelet and anticoagulant therapies. We review the challenges and provide insights into the remaining knowledge gaps for contemporary STEMI care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Essentials An optimal therapeutic strategy has yet to be established to prevent early shunt thrombosis. A phase 1 study of cangrelor was performed in neonates after palliation of congenital heart disease. PD endpoint of >90% platelet inhibition in 60% of patients was achieved at 0.5 µg/kg/min dosing. No serious adverse events related to drug administration were observed, including bleeding. ABSTRACT: Background Systemic-to-pulmonary artery shunt thrombosis is a significant cause of early postoperative mortality in neonates after palliation of congenital heart disease. In the context of thromboprophylaxis, an optimal therapeutic strategy has yet to be established before aspirin administration. Cangrelor, a fast-acting, reversible P2Y 12 inhibitor, may fill this unmet need. Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of cangrelor in neonates undergoing stage 1 palliation. Methods This prospective, open-label, single-arm study evaluated two cangrelor dosing cohorts following placement of a systemic-to-pulmonary artery shunt, right ventricle-to-pulmonary artery shunt, or ductal stent. Drug concentrations and platelet reactivity, assessed by light transmission aggregometry and in microfluidic assays (MF), were measured. Results Twenty-two patients were consented and 15 received a 1-hour infusion of cangrelor at either 0.5 µg/kg/min (cohort 1) or 0.25 µg/kg/min (cohort 2). Whereas the primary PD endpoint was achieved at the higher dose (ie, reduction in maximal platelet aggregation by ≥90% in 60% of participants), only 29% of those in cohort 2 attained this goal. Comparable and statistically significant results were obtained in MF assays (P < .0001 vs. baseline). Drug levels during infusion were 3-fold higher in cohort 1 vs. cohort 2 (P < .001). Most participants (70%) had undetectable drug levels by 10 minutes postinfusion with full recovery in platelet function at 1 hour. No drug-related bleeding events occurred. Conclusions Favorable PK/PD properties of cangrelor 0.5 µg/kg/min dosing and safety profile warrant further evaluation in neonates following palliative cardiac procedures., (© 2020 International Society on Thrombosis and Haemostasis.)

Several platelet P2Y 12 inhibiting agents, both oral and intravenous, are available for clinical use. The oral P2Y 12 inhibitors comprise clopidogrel, prasugrel, and ticagrelor. Cangrelor is the only intravenous P2Y 12 inhibitor. Numerous pharmacodynamic studies have been performed to assess the impact of P2Y 12 inhibitor switching on platelet reactivity profiles and to define the optimal strategy if switching is needed, with the goal of minimizing the risk of having inadequate platelet inhibition due to potential drug-drug interactions occurring during the drug overlap phase. This article provides an overview of pharmacodynamic studies assessing switching between P2Y 12 inhibitors and recommendations on switching modalities based on these findings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Controversies exist over the appropriate definition for peri-procedural myocardial infarction (PPMI) and its association with mortality. This study aims to evaluate one-year survival following percutaneous coronary intervention (PCI) and the association of different definitions of PPMI with survival among patients with stable angina (SA) or acute coronary syndrome (ACS) in the contemporary era., Methods: We used data from the CHAMPION PLATFORM and CHAMPION PCI trials of patients undergoing PCI and conducted univariable and multivariable Cox proportional hazard regression models to evaluate mortality risk during the first year after PCI. A blinded events committee adjudicated suspected PPMI defined by biomarker elevations ≥3× the upper limit of normal (ULN) or new Q-waves. We further analyzed PPMI by the magnitude of CK-MB elevation ([a] 3 to <5× ULN, [b] 5 to <10× ULN, [c] ≥10× ULN) or by the 2 nd universal definition of myocardial infarction (UDMI CK-MB ) excluding patients with evidence of myocardial infarction (MI) prior to PCI., Results: Of 13,968 patients, 11% initially presented with SA, and 89% with ACS. One-year mortality was 3.4% (SA: 1.5%; ACS: 3.6%). PPMI occurred in 6.3% of the patients (3 to <5× ULN: 2.5%; 5 to <10× ULN: 2.1%; ≥10× ULN: 1.6%; UDMI CK-MB : 2.7%). After multivariable adjustment, a significantly higher risk of one-year mortality was observed for patients with PPMI compared with patients without PPMI (HR 2.35 [1.74-3.18], p < 0.001; 3 to <5× ULN: 1.55 [0.92-2.62], p = 0.10; 5 to <10× ULN: 1.22 [0.67-2.20], p = 0.52; ≥10× ULN: 4.78 [3.06-7.47], p < 0.001; UDMI CK-MB : 2.19 [1.29-3.73], p = 0.004)., Conclusion: PPMI occurred in 6.3% of the patients and was associated with increased risk of death within one year. Survival was not significantly impacted by PPMI if defined by periprocedural CK-MB elevations <10× ULN alone and without additional evaluation of symptoms or evidence of ischemia. These findings highlight the importance of PPMI for long-term outcome in the contemporary era and of its definition in the planning and interpretation of clinical trials., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients who have had a prior myocardial infarction (MI) are at increased risk for adverse outcomes after subsequent percutaneous coronary intervention (PCI)., Objective: The objective of this study is to examine the efficacy and safety of cangrelor, a potent intravenous P2Y 12 inhibitor, in patients with prior MI., Methods: Pooled data from the CHAMPION trials were examined. Prior MI was defined as a history of MI, excluding MI events at baseline. The primary endpoint was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48-h post-randomization. The primary safety endpoint was GUSTO-defined severe bleeding at 48h., Results: Out of 24,691 patients, 5699 (23%) had a prior MI. The primary endpoint was higher in patients with vs. without prior MI (4.9% vs. 4.0%, p=0.002). The primary endpoint was 4.2% with cangrelor vs. 5.7% with clopidogrel (absolute risk reduction=1.5%; OR 0.72 [95%CI 0.57-0.92]) in patients with prior MI and 3.7% with cangrelor vs. 4.3% with clopidogrel (absolute risk reduction=0.6%; OR 0.85 [95%CI 0.74-0.99]) in patients without prior MI (P-interaction=0.25). The rate of GUSTO-defined severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR 1.39 [95%CI 0.31-6.24]) in patients with prior MI, and 0.2% with cangrelor vs. 0.2% with clopidogrel (OR 1.18 [95%CI 0.65-2.14]) in patients without prior MI (P-interaction=0.84)., Conclusion: In the CHAMPION trials, patients with prior MI had higher rates of ischemic outcomes within 48h after PCI. Cangrelor reduced ischemic events with no significant increase in GUSTO-defined severe bleeding in patients with or without prior MI., (Copyright © 2017. Published by Elsevier B.V.)

Background: Newer P2Y12 inhibitors have more rapid onset of platelet inhibition compared with clopidogrel, especially the intravenous P2Y12 inhibitor cangrelor. Direct comparisons between cangrelor and oral P2Y12 inhibitors ticagrelor and prasugrel do not exist. Thus, we performed a network meta-analysis to directly and indirectly compare different P2Y12 inhibitors in patients undergoing percutaneous coronary intervention (PCI)., Methods: MEDLINE/PubMed and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared at least two P2Y12 inhibitors including cangrelor, clopidogrel, prasugrel, and ticagrelor. Network meta-analysis with a Bayesian approach was performed to directly and indirectly compare the effects of the aforementioned P2Y12 inhibitors on clinical outcomes. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes., Results: This analysis included 15 RCTs with 54,025 patients randomized to cangrelor (n=12,475), clopidogrel (n=26,903), prasugrel (n=7455), or ticagrelor (n=7192) at time of PCI. Patients had a mean age of 63±10, 74% were male, and 82% underwent PCI for acute coronary syndrome. No significant differences between cangrelor and clopidogrel were found with respect to cardiovascular death (OR 1.01 [CrI 0.23-4.39]), myocardial infarction (OR 0.94 [CrI 0.69-1.25]), major adverse cardiac events (OR 0.91 [CrI 0.69-1.18]), stent thrombosis (OR 0.66 [CrI 0.37-1.19]), or major bleeding (OR 1.52 [CrI 0.79-2.98]). Rank probability data suggested that ticagrelor and prasugrel were better than cangrelor for reducing ischemic events, though these differences were not significant., Conclusion: Despite rapid platelet inhibition provided by cangrelor, newer oral P2Y12 inhibitors such as ticagrelor and prasugrel have comparable clinical outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: This randomized trial tested whether early loading with prasugrel can provide sufficient platelet inhibition even when given at the start of a 2-h infusion of cangrelor., Background: Effective platelet inhibition with intravenous cangrelor reduces the risk of ischemic complications during percutaneous coronary intervention (PCI). Transitioning to oral therapy with clopidogrel or prasugrel is only recommended after discontinuation of cangrelor due to drug interactions. Given the long half-life of prasugrel, this drug could achieve effective platelet inhibition even when given early under cangrelor and thereby prevent a transient gap in platelet inhibition., Methods: This trial randomized 110 P2Y 12 -receptor blocker-naive patients undergoing PCI with use of cangrelor to loading with prasugrel 60 mg or ticagrelor 180 mg at the start of cangrelor (n = 45 each) or loading with clopidogrel 600 mg after discontinuation of cangrelor (n = 20). The primary endpoint was the proportion of patients without high on-treatment platelet reactivity 1 h after stopping cangrelor., Results: The 3 groups were well balanced with respect to clinical parameters. One hour following discontinuation of cangrelor, the primary endpoint was seen in 65.0% of patients on clopidogrel versus 95.6% with ticagrelor and 93.3% with prasugrel (p for superiority of prasugrel vs. clopidogrel = 0.003; p of prasugrel vs. ticagrelor = 0.65). The 30-day incidence of ischemic and bleeding events was similar in all groups., Conclusions: Prasugrel 60 mg given at the start of a 2-h infusion of cangrelor can provide a sufficient platelet inhibition post-cangrelor. This approach prevents the transient gap in platelet inhibition seen with oral loading after discontinuation of cangrelor. (Impact of Extent of Clopidogrel-Induced Platelet Inhibition during Elective Stent Implantation on Clinical Event Rate - Advanced Loading Strategies [ExcelsiorLOAD2]; DRKS00009739)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Antiplatelet therapy with aspirin and a P2Y 12 receptor inhibitor is the cornerstone of treatment of patients with atherothrombotic disease manifestations. Switching between P2Y 12 inhibitors occurs commonly in clinical practice for a variety of reasons, including safety, efficacy, adherence, and economic considerations. There are concerns about the optimal approach for switching because of potential drug interactions, which may lead to ineffective platelet inhibition and thrombotic complications, or potential overdosing due to overlap in drug therapy, which might cause excessive platelet inhibition and increased bleeding. This review provides practical considerations of switching based on pharmacodynamic and clinical data available from the literature., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Administering antiplatelet agents before coronary angiography to patients referred to elective or urgent percutaneous coronary intervention (PCI) requires a careful evaluation of advantages and disadvantages associated with platelet inhibition to avoid overtreatment on one side and undertreatment on the other. The delicate balance between ischemic protection and bleeding demands the ability to undertake risk stratification and individualized decisions, which is particularly challenging in the setting of ad hoc PCI and urgent procedures. This review analyzes the current evidence on pretreatment with oral and intravenous P2Y 12 inhibitors in patients undergoing coronary angiography with intent to undergo PCI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In clinical trials that assessed the safety and efficacy of cangrelor during percutaneous coronary intervention (PCI), cangrelor was administered as a 30-μg/kg bolus followed by a 4-μg/kg/min infusion for at least 2 hours or the duration of the PCI, whichever was longer. Cangrelor is currently indicated as an adjunct to PCI to reduce the risk of myocardial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y 12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Effective inhibition of platelet aggregation during PCI in high risk patients with ACS is of utmost importance. The new intravenous short acting P2Y 12 -receptor inhibitor cangrelor is available for use in PCI-treated patients. We aimed to study platelet inhibition during treatment with cangrelor and transition phase with oral P2Y 12 -receptor inhibitors in patients with acute coronary syndromes (ACS)., Methods: Cangrelor was administered during PCI to 21 P2Y 12 -inhibitor naïve patients with ACS. Patients received a loading dose of ticagrelor at the time of procedure or prasugrel 30min before end of the cangrelor infusion. Platelet inhibition was measured by multiple electrode aggregometry (MEA) and thromboelastography (TEG), before and after PCI, immediately and 2h after stopping the infusion. Platelet inhibition after PCI was compared to a matched cohort of patients treated with oral P2Y 12 -inibitors only., Results: There was a significant reduction of platelet reactivity measured by MEA-ADP from 46.7U to 17.9U and by TEG MA ADP from 43.1mm to 22.0mm before infusion and after PCI respectively (p<0.001). There was also sustained platelet inhibition after stopping of cangrelor infusion and 2h later. Significant higher platelet inhibition was observed at the end of PCI in comparison to control cohort without cangrelor (MEA 17.9U vs. 54.2U, p=0.001)., Conclusion: We demonstrate significantly improved platelet inhibition during PCI in ACS patients treated with cangrelor in comparison to early treatment with potent oral P2Y 12 -inhibitors. Cangrelor should be considered for periprocedural treatment of high risk patients with acute coronary syndrome., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The purpose of this study was to examine the safety and efficacy of cangrelor in patients with stable angina (SA) or acute coronary syndrome (ACS)., Background: The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial demonstrated that cangrelor significantly reduced periprocedural ischemic events in all-comer percutaneous coronary intervention with a modest increase in mild and moderate bleeding. Whether this benefit is consistent across SA and ACS has not been explored fully., Methods: The CHAMPION PHOENIX trial compared periprocedural administration of cangrelor or clopidogrel, with either a 300- or 600-mg loading dose for the prevention of periprocedural complications in patients undergoing percutaneous coronary intervention. Among the 10,942 patients in the modified intention to treat population, 6,358 patients were classified as having SA, and 4,584 patients had ACS (including unstable angina, non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction) at randomization. The primary composite endpoint was death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h. A key secondary endpoint was stent thrombosis, and the primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding., Results: Cangrelor consistently reduced the primary endpoint in SA and ACS (odds ratio [OR]: 0.83 [95% confidence interval (CI): 0.67 to 1.01] and OR: 0.71 [95% CI: 0.52 to 0.96], respectively; interaction p = 0.41). Cangrelor also consistently reduced stent thrombosis in SA and ACS (OR: 0.55 [95% CI: 0.30 to 1.01] and OR: 0.67 [95% CI: 0.42 to 1.06], respectively; interaction p = 0.62). The impact of cangrelor on GUSTO severe/moderate bleeding was also similar for SA and ACS (OR: 1.49 [95% CI: 0.67 to 3.33] and OR: 1.79 [95% CI: 0.79 to 4.07], respectively; interaction p = 0.75)., Conclusions: The benefits and risks of cangrelor were consistent in patients with SA and ACS. (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]; NCT01156571)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: 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., Background: 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., Methods: 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., Results: 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)., Conclusions: Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine pharmacodynamic effects during transition from intravenous cangrelor to oral ticagrelor and from oral ticagrelor to intravenous cangrelor., Background: Cangrelor is an intravenous antagonist of P2Y12 and its use will require transition to and from oral agents., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: 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., Background: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: Aggressive antiplatelet strategies unquestionably cause extra hemorrhagic risks. Bleeding episodes are associated with poor outcomes including increased mortality. However, lack of uniform reporting and adjudication of bleeding events might prevent objective evaluation of the efficacy/safety profile of antithrombotic agents., Objective: We analyzed the bleeding rates by several previously used bleeding scales (TIMI, GUSTO, ACUITY, and BARC) after cangrelor in recent head-to-head randomized, controlled clinical trials (RCTs)., Results: Data for meta-analyses were pooled from 3 RCTs (CHAMPION-PLATFORM, CHAMPION-PCI and CHAMPION-PHOENIX) including 25,106 patients. In addition, the bleeding risks were also assessed from the small (n=210) BRIDGE RCT. Cangrelor caused a significantly increased risk for major bleeding at 48 h according to the ACUITY scale (RR: 1.51, 95% CI: 1.32-1.72, p<0.00001); however, this impact was less prominent according to less sensitive bleeding scales (GUSTO severe: RR: 1.21, 95% CI: 0.70-2.11, p=0.49; TIMI major: RR: 1.00, 95% CI: 0.59-1.68, p=0.99). There was also an obvious trend towards an increased risk for any transfusions (RR: 1.31, 95% CI: 0.97-1.77, p=0.08) and TIMI major+minor bleeding events (RR: 1.30, 95% CI: 0.96-1.76, p=0.09)., Conclusions: Cangrelor on top of aspirin or/and clopidogrel increases the risk for early bleeding events after PCI; however, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured. The bleeding hazard needs to be verified in the ongoing FDA secondary cangrelor review., (© 2013.)

Recurrent atherothrombotic events in patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI) are essentially platelet-driven processes, underscoring the need for effective pharmacological platelet inhibition. Dual antiplatelet therapy with aspirin and clopidogrel has been, for over a decade, the mainstay of antiplatelet management in ACS/PCI. However, atherothrombotic events continue to occur in a relevant proportion of subjects despite the benefit of this combination, which has led to the clinical development of newer and more potent antiplatelet drugs. Two of these, prasugrel and ticagrelor, have been recently approved for clinical use. The scope of this manuscript is to provide an up-to-date overview on new antiplatelet drugs in the setting of ACS and PCI, including the most recent advances on newly approved agents as well as on emerging compounds in clinical development., (© 2013 International Society on Thrombosis and Haemostasis.)