Reversible P2Y12 Inhibitor Research Articles

Prevalence of adverse events during ticagrelor versus clopidogrel treatment and its association with premature discontinuation of dual antiplatelet therapy in East Asian patients with acute coronary syndrome.

Clinical evidence raises the issues regarding the high risk of adverse events and serious bleeding in East Asian patients receiving standard-dose ticagrelor treatment. We sought to evaluate the association between adverse events and their associations with premature discontinuation of dual antiplatelet therapy (DAPT). We enrolled East Asian patients presented with acute coronary syndrome who took DAPT with 90-mg ticagrelor (n = 270) or 75-mg clopidogrel (n = 674). During 1-month treatment, antiplatelet effect was evaluated with the VerifyNow P2Y12 assay, and the occurrence of Bleeding Academic Research Consortium (BARC) bleeding and modified Medical Research Council (mMRC) dyspnea was assessed with the dedicated questionnaire. During 1-month follow-up, patients on ticagrelor showed the higher risks of bleeding (any BARC type: 45.6% vs. 23.6%; odds ratio [OR], 2.71 and BARC 1 or 2 type: 45.2% vs. 22.1%; OR, 2.90, respectively) and dyspnea (26.3% vs. 13.6%; OR, 2.25) compared with those on clopidogrel. In a receiver-operating characteristics curve analysis to predict bleeding risk, ticagrelor showed a lower cutoff of low platelet reactivity (LPR) (P2Y12 reaction unit [PRU] ≤ 20) than clopidogrel (PRU ≤ 110). Early occurrence of bleeding episode was significantly associated with LPR phenotype (OR, 2.68), not type of P2Y12 inhibitor. In multivariate analysis, type of P2Y12 inhibitor (ticagrelor vs. clopidogrel: OR, 2.19) and bleeding episode (OR, 2.94) were independent predictors for dyspnea occurrence. During 1-year follow-up, DAPT with ticagrelor showed a higher risk of premature discontinuation compared to DAPT with clopidogrel (27.8% vs. 4.7%; adjusted HR, 8.84), which risk appeared frequent during the first month (14.4%) during DAPT with ticagrelor. Early occurrence of bleeding and dyspnea synergistically increased a risk of DAPT non-adherence, irrespective of type of P2Y12 inhibitor. This analysis is the first evidence to show the different cutoff of low platelet reactivity during the reversible (ticagrelor) versus irreversible P2Y12 inhibitor (clopidogrel). Early occurrence of bleeding and dyspnea is very common during standard-dose ticagrelor treatment in East Asian patients, which show a close association with premature DAPT discontinuation. [https://www.clinicaltrials.gov], identifier[NCT046 50529].

EE81 The Budget Impact of Cangrelor for the Treatment of Patients Undergoing Percutaneous Coronary Intervention When Oral P2Y12 Inhibitors Are Not Feasible or Desirable in the UK

Cangrelor is an intravenous, direct-acting, reversible P2Y12 inhibitor indicated for the reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) who have not received an oral P2Y12 inhibitor prior to the PCI procedure, and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. The objective of this analysis is to estimate the UK budget impact of introducing cangrelor, for the ST-elevation myocardial infarction (STEMI) population in whom oral P2Y12 inhibitors are not feasible or desirable.

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

AbstractThe phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.

Safety and Efficacy of Periprocedural Bridging With Cangrelor Versus Eptifibatide.

Patients with percutaneous coronary interventions undergoing procedures often require interruptions in their dual antiplatelet therapy. Periprocedural bridging is considered for patients at high thrombotic risk using intravenous cangrelor, a reversible P2Y12 inhibitor with a short half-life, or eptifibatide, a glycoprotein IIb/IIIa inhibitor, with a slightly longer half-life but less costly alternative. This study aims to assess the safety and efficacy of cangrelor compared with eptifibatide when used in a periprocedural setting. The primary outcome of this retrospective cohort study was the incidence of bleeding events defined by the global use of strategies to open occluded coronary arteries criteria, and the secondary outcomes include the transfusion requirements, inpatient major cardiac adverse events, and cost savings per patient. A total of 75 patients were included who were bridged to procedures (cangrelor, n = 50; eptifibatide, n = 25). There were no significant differences in overall bleeding events defined by global use of strategies to open occluded coronary arteries criteria: mild bleeding [8% (n= 4) vs. 8% (n= 2); P = 0.68], moderate bleeding [28% (n = 14) vs. 48% (n = 12); P = 0.07), and severe bleeding [8% (n = 4) vs. 8% (n = 2); P = 0.25] between cangrelor and eptifibatide. The composite inpatient major cardiac adverse events were also similar between cangrelor and eptifibatide [10% (n = 10) vs. 8% (n = 8); P = 0.78]. The average cost savings per each cangrelor patient on the equivalent duration of eptifibatide was calculated out to be $5824 per patient. Cangrelor and eptifibatide were similar in terms of safety and efficacy when used as a bridge in patients with recent coronary stents, but considerable cost savings could be made if cangrelor was substituted for by eptifibatide in select patients. Further studies are needed to determine its applicability specifically in patients at high thrombotic and hemorrhagic risk.

Abstract 1122‐000210: Cangrelor to Prevent Intraluminal Thrombosis in Endovascular Therapy for Acute Stroke: Single Center Case Series

Introduction : Intraluminal thrombosis after endovascular therapy (EVT) is a peri‐procedural complication that carries a high burden of morbidity and mortality. The use of anti‐thrombotic therapies during EVT remains an evolving field. Recent surveys suggest the glycoprotein IIb/IIIa inhibitor, tirofiban, is often used during EVT. However, the increased intracranial hemorrhage risk and the medication’s long half‐life pose significant challenges to management. Cangrelor, an intravenous and reversible P2Y12 inhibitor, was first approved by FDA in 2015 for use in patients with coronary artery disease undergoing percutaneous intervention. Its rapid onset and offset are beneficial as an anti‐thrombotic during EVT. Our case series aim to characterize the safety and efficacy of cangrelor use in our institution and contribute towards its growing body of data. Methods : Chart review was conducted for patients that required endovascular therapy for acute stroke and received intravenous cangrelor at our center between January 2019 to December 2020. We included patients that underwent both extracranial and intracranial stent placement, as well as patients who suffered from intraluminal thromboses intra‐procedurally. Variables of interest included lesion pathophysiology, peri‐procedural complications including intraluminal re‐occlusion and intracranial hemorrhage, TICI score post‐procedurally, vessel patency and MRS on post‐hospitalization followup. Results : Nine patients received intravenous cangrelor during endovascular therapy. Mean age was 50 (range 41–67 years old), 3/9 patients were male. Seven patients (77.8%) had ischemic stroke, of whom five exhibited tandem intracranial occlusions and three required intraprocedural stent deployment. 3/7 patients received IV TPA prior to EVT. Interestingly, one patient had a previously placed Precise stent for acute internal carotid thrombus, briefly placed on eptifibatide (180mcg/kg), suffered from stent re‐occlusion on POD1 and required repeat thrombectomy with cangrelor intra‐procedurally; stent patency was maintained for the rest of her hospital course. One patient received balloon angioplasty of supraclinoid internal carotid artery. The remaining two patients required cangrelor for visualized intraluminal platelet aggregates during the EVT. Two patients presented with aneurysmal subarachnoid hemorrhage, one treated with flow diversion stent and the other requiring stenting for prolapsed aneurysm coiling. Dosing of cangrelor bolus and infusion varied. Six patients were bolused with 15 mcg/kg, while three patients received 7.5 mcg/kg. Infusion rates range from 0.5 to 4 mcg/kg/minute with all nine patients reaching therapeutic range P2Y12 levels on post‐procedural testing. Cangrelor infusion was transitioned to oral antiplatelet on post‐operative day 4 on average. In all nine patients, vessel and stent patency was maintained intra‐procedurally with cangrelor. Subsequent vascular imaging during hospitalization demonstrated no intraluminal thrombosis. One patient experienced intracranial hemorrhage, however they received intraprocedural eptifibatide (180mcg/kg) and cangrelor infusion (15 mcg/kg bolus, 2 mcg/kg/min) for their extensive clot burden and triple stent placement. Five patients attended three‐month post‐hospitalization followups. Their median MRS was 2 and all followup vessel imaging demonstrated patent vessels. Conclusions : Our case series demonstrate the promising efficacy of cangrelor in patients undergoing emergent endovascular therapy to prevent intraluminal thrombosis. Further studies with larger sample sizes can elucidate the optimal dose of cangrelor, length of treatment before oral transition, and compare its efficacy to eptifibatide.

Reversible P2Y12 inhibitor versus irreversible P2Y12 inhibitor in ACS patients undergoing PCI (the acute coronary syndrome israeli survey (ACSIS)

Abstract Introduction Based on data from randomized controlled trials, both American and European guidelines recommend treating acute coronary syndrome (ACS) patients with second generation P2Y12 inhibitors.1,2 Direct head-to-head comparison of these agents was scarce until the recent publication of the ISAR-REACT-5 study which demonstrated the superiority of the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) over the reversible P2Y12 inhibitor in terms of 1-year composite of death, myocardial infarction (MI), and stroke.3,4,5 Given the unexpected outcomes of this trial, we sought to perform a comparison of ticagrelor and prasugrel in real-life ACS patients. Purpose To compare the outcomes of ACS (acute coronary syndrome) patients undergoing in-hospital PCI (percutaneous coronary intervention) treated with the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) versus the reversible P2Y12 inhibitor. Methods ACSIS (Acute Coronary Syndrome in Israel) is a national ACS snapshot survey conducted in all 25 cardiology departments in Israel since 2000 over a two-month period, every two to three years. Both the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) and the reversible P2Y12 inhibitor were commercially introduced in Israel in 2010. We therefore considered patients enrolled in ACSIS surveys 2010–2018 for the present analysis. Results Among 7,233 patients enrolled to the ACSIS (Acute Coronary Syndrome in Israel) registry between 2010 and 2018, we identified 1133 eligible patients treated with the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) and 825 with the reversible P2Y12 inhibitor. In hospital complication rates, including rates of stent thrombosis, were roughly similar between groups. Compared to the reversible P2Y12 inhibitor, the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) was associated with lower 1-year death in ST-elevation myocardial infarction (STEMI) patient compared to non-ST-elevation ACS (NSTE-ACS) patients (p for interaction 0.03). In propensity score matched STEMI patients (502 receiving the Irreversible thienopyridine type P2Y12 inhibitor (prodrug), 251 the reversible P2Y12 inhibitor) 30-day re-hospitalization rate (p<0.05), 30-day MACE (the composite of death, MI, stroke, urgent revascularization; p=0.006), and 1-year mortality rates (p=0.08) were higher in the the reversible P2Y12 inhibitor group compared to the the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) group; In NSTE-ACS patients, outcomes were not impacted by drug choice. Conclusion The Irreversible thienopyridine type P2Y12 inhibitor (prodrug) was more effective than the reversible P2Y12 inhibitor in STEMI patients, but not in NSTE-ACS patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): the Israeli working group on acute cardiac care of the Israel heart society

Perioperative dual antiplatelet therapy for patients undergoing spine surgery soon after drug eluting stent placement.

Background: Performing emergent spinal surgery within 6 months of percutaneous placement of drug-eluting coronary stent (DES) is complex. The risks of spinal bleeding in a “closed space” must be compared with the risks of stent thrombosis or major cardiac event from dual antiplatelet therapy (DAPT) interruption.Methods: Eighty relevant English language papers published in PubMed were reviewed in detail.Results: Variables considered regarding surgery in patients on DAPT for DES included: (1) surgical indications, (2) percutaneous cardiac intervention (PCI) type (balloon angioplasty vs. stenting), (3) stent type (drug-eluting vs. balloon mechanical stent), and (4) PCI to noncardiac surgery interval. The highest complication rate was observed within 6 weeks of stent placement, this corresponds to the endothelialization phase. Few studies document how to manage patients with critical spinal disease warranting operative intervention within 6 months of their PCI for DES placement.Conclusion: The treatment of patients requiring urgent or emergent spinal surgery within 6 months of undergoing a PCI for DES placement is challenging. As early interruption of DAPT may have catastrophic consequences, we hereby proposed a novel protocol involving stopping clopidogrel 5 days before and aspirin 3 days before spinal surgery, and bridging the interval with a reversible P2Y12 inhibitor until surgery. Moreover, postoperatively, aspirin could be started on postoperative day 1 and clopidogrel on day 2. Nevertheless, this treatment strategy may not be appropriate for all patients, and multidisciplinary approval of perioperative antiplatelet therapy management protocols is essential.

Analysis of the Financial Impact of Using Cangrelor on the Safety and Efficacy Outcomes in Patients Undergoing Percutaneous Coronary Intervention in Whom Oral Therapy with P2Y12 Inhibitors is Not Feasible or Desirable, in Spain.

PurposeCangrelor is an intravenous, direct-acting, reversible P2Y12 inhibitor indicated for the reduction of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) in whom oral P2Y12 inhibitors are not feasible or desirable. The objective was to assess the financial impact of introducing cangrelor into the hospital formulary in Spain.Patients and MethodsA budget impact model was developed to calculate the cost difference between two scenarios (without and with cangrelor) to treat CAD patients undergoing PCI in whom oral P2Y12 inhibitors are not feasible or desirable, over 3 years. Intravenous P2Y12 inhibitor (cangrelor), oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor), and glycoprotein IIb-IIIa inhibitors (GPIs) for bail-out use were considered. Epidemiological, efficacy (thrombotic events including cardiac death), safety (bleeding events), and costs (€, 2019) data were based on Spanish registries, clinical trials, and meta-analyses. One-way sensitivity analysis established the effect of uncertainty on results.ResultsFor years 1, 2, and 3, the target population to receive cangrelor was 607, 1,822, and 3,340 patients, and cangrelor uptake was 23.70%, 58.30%, and 51.30%, respectively. The 3-year budget impact was 1,021,717€ varying from 50,245€ in year 1 to 599,272€ in year 3. The results were sensitive to the number of patients treated with GPIs in Spanish hospitals.ConclusionBased on our results, the financial effort needed to introduce the use of cangrelor in patients undergoing PCI in whom antiplatelet therapy with oral P2Y12 inhibitors is not feasible or desirable barely exceeds one million € over three years, in Spain.

Cangrelor PK/PD analysis in post‐operative neonatal cardiac patients at risk for thrombosis

Unlabelled Box AbstractBackgroundSystemic‐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 P2Y12 inhibitor, may fill this unmet need. ObjectivesTo evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of cangrelor in neonates undergoing stage 1 palliation. MethodsThis 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. ResultsTwenty‐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. ConclusionsFavorable PK/PD properties of cangrelor 0.5 µg/kg/min dosing and safety profile warrant further evaluation in neonates following palliative cardiac procedures.

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro

Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y12 inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering anti-apoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hCPCs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hCPCs.

Rationale and design of PREvalence of DyspneA in patients treated with TicagrelOR (PREDATOR) program

Background: Ticagrelor, a reversible P2Y12 inhibitor, is a mainstay of antiplatelet strategy in patients with acute coronary syndrome (ACS). However, a large number of ticagrelor-induced dyspnea decrease patients’ adherence and reduce an overall efficacy of the therapy. Design: The PREDATOR program consists of phase III and IV, multicenter, randomized, double-blind, placebo-controlled clinical trials and preceding pilot studies that assesses the prevalence and treatment of ticagrelor-induced dyspnea in coronary artery disease (CAD) and ACS patients. The PREDATOR LD is designed to evaluate the occurrence of dyspnea after 180 mg ticagrelor loading dose, and relief of dyspnea by theophylline administration in low-to-high risk acute coronary syndromes without ST-segment elevation (NSTE-ACS) and stable CAD designated to undergo invasive treatment. The PREDATOR MD is a cross-over trial in stable CAD patients 1 year after percutaneous coronary intervention for ACS. Enrolled patients will be randomized to one of four antiplatelet treatment regimens (ticagrelor 2x90 mg, ticagrelor 2x60 mg, ticagrelor 2x45 mg or clopidogrel 75 mg [morning]+placebo [evening]) or placebo and will be assessed for dyspnea at the day 7, then undergo a switch of treatment and reassessment at day 14. The sample size will be estimated based on preceding pilot studies. Discussion: The PREDATOR LD is expected to prospectively assess dyspnea rate with a loading dose of ticagrelor, and analyze a potential of theophylline to elevate symptoms of ticagrelor-induced dyspnea, while the PREDATOR MD will prospectively assess dyspnea and adverse events rate with a maintenance dose of P2Y12 inhibitors prospectively assess. All evaluations will be conducted using standardized metrics for dyspnea quantification.

TCT-569 Lower mortality after clinically significant bleeding in patients treated with reversible P2Y12 agent Ticagrelor: A comparative, all-comers, prospective, 2-year follow up study in patients treated with invasive strategy after acute coronary syndrome

Reversible P2Y12 inhibitor Ticagrelor have theoritical advantage of improved outcomes after bleeding episodes compared to irreversible P2Y12 inhibitors namely prasugrel and clopidogrel after acute coronary syndrome (ACS). Data on combined net adverse events (NAE) of mortality after bleeding and

Prolonging Ticagrelor Beyond a Year of Acute Coronary Syndrome: Worth or Harmful?

Platelet activation plays a central role in triggering and complicating acute coronary syndromes, especially in case of stent thrombosis and myocardial infarction. On top of aspirin, P2Y12- inhibitors are successfully used to treat and prevent these events for a duration of one year after an acute coronary episode or 6 months after drug-eluting stent implantation. However, patients with acute coronary syndromes remain at heightened risk for recurrent ischemic events after the recommended durations of P2Y12-inhibitors and therefore, prolonging treatment is often considered in clinical practice. However, the higher risk for bleeding limits the utility of such approach to a restricted group who is still poorly defined by available measures. This review aims to discuss potential benefits and highlight important pitfalls of prolonged treatment with P2Y12-inhibitors, with a focus on ticagrelor, an attractive reversible P2Y12-inhibitor in patients after myocardial infarction.

Ticagrelor inhibits platelet-tumor cell interactions and metastasis in human and murine breast cancer.

Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell-platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10mg/kg), but not clopidogrel (10mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell-platelet aggregates in the lungs at 10, 30 and 60min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.

Cangrelor: A New Route for P2Y12 Inhibition.

Antiplatelet therapy with a P2Y12 inhibitor is a key component of treatment for patients with acute coronary syndromes undergoing percutaneous coronary intervention. Before the development of cangrelor (Kengreal, The Medicines Company, Parsippany, NJ), only oral P2Y12 inhibitors were available. Cangrelor is a reversible P2Y12 inhibitor that is administered as an intravenous infusion, and its quick onset and offset make it an appealing option for antiplatelet therapy, particularly for patients who are unable to take oral medications. Although cangrelor struggled to show benefit in early trials, the positive results of the CHAMPION PHOENIX trial led to its approval for use as an adjunct to percutaneous coronary intervention to reduce the risk of periprocedural myocardial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with another P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. Cangrelor has also been evaluated as an option for bridging therapy in patients who must discontinue their oral P2Y12 inhibitor before coronary artery bypass grafting. This review of cangrelor will discuss its mechanism of action, its pharmacodynamics and pharmacokinetics, the clinical trial experience, and its potential place in therapy.

Why we need intravenous antiplatelet agents.

Oral ADP-receptor antagonists combined with aspirin are the standard for dual antiplatelet therapy (DAPT) during percutaneous coronary intervention (PCI). However, the oral route of administration of ADP-receptor antagonists leaves them vulnerable to unpredictable and often inadequate platelet inhibition at the time of PCI, while their prolonged effects often lead to the decision not to load them prior to PCI. Intravenous antiplatelet agents, including glycoprotein IIb/IIIa inhibitors (GPI) and cangrelor, a reversible P2Y12 inhibitor, address these shortcomings. In June 2015, the US FDA approved cangrelor for the prevention of thrombotic events associated with coronary stenting. This review examines the current state of peri-PCI DAPT and demonstrates that the selective use of GPIs and intravenous ADP-antagonist agents reduces the risk of periprocedural thrombosis.

Will cangrelor become the favored agent for acute coronary syndrome treatment?

Clopidogrel has been widely investigated, even if resistance limits its efficacy. Prasugrel and ticagrelor obtain a greater and homogeneous inhibition of platelet aggregation, but a delay onset of action in patients with stent thrombosis elevation myocardial infarction and an increased bleeding risk in case of surgical revascularization have been reported. Cangrelor is an intravenous reversible P2Y12 inhibitor with an immediate onset and a quick offset of action. Based on its pharmacokinetic and pharmacodynamic profile, and on clinical data, cangrelor could become the antiplatelet of choice in case of elective percutaneous coronary intervention without clopidogrel pretreatment and in acute coronary syndrome requiring urgent coronary angiography. However, in acute setting, data of comparison with prasugrel and ticagrelor are needed.

The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer.

Tumor cells use activated platelets to promote their proliferation and metastatic potential. Because platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets, we investigated the potential of the reversible P2Y12 inhibitor ticagrelor, a clinical agent used in the prevention of cardiovascular and cerebrovascular events, to inhibit tumor adhesion and metastasis. In B16-F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline-treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment. In vitro, B16-F10 cells exhibited decreased interaction with platelets from ticagrelor-treated mice compared to saline-treated mice, an effect similar to that observed with blockade of glycoprotein IIbIIIa. Similarly, B16-F10 cells co-incubated with platelets from ticagrelor-treated mice exhibited reduced adhesion to endothelial monolayers compared to those co-incubated with platelets from saline-treated animals, an effect also observed in vivo. Interestingly, pretreatment of endothelial monolayers with ticagrelor did not result in reduced tumor cell adhesion. These findings support a role for P2Y12-mediated platelet activation in promoting metastases, and provide proof-of-concept for the clinical use of ticagrelor in the prevention of tumor metastasis.

Circulation: Cardiovascular Interventions Editors’ Picks

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Circulation: Cardiovascular Interventions Editors’ Picks

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks