Effect of Cangrelor on Infarct Size in ST-Segment-Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial).

BACKGROUND: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention. METHODS: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile-third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P<0.05 was considered statistically significant. RESULTS: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3-22.6] %LVmass versus cangrelor, 16.3 [9.9-24.4] %LVmass; P=0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P=0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60-4.65] %LVmass versus cangrelor, 1.18 [0.53-3.37] %LVmass; P=0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium-defined major bleeding events in either group in the first 48 hours. CONCLUSIONS: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment-elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723.

The Use of Cangrelor in Cardiogenic Shock: Insights from the CAMEO Registry.

INTRODUCTION: Little is known about the use of cangrelor in patients with myocardial infarction (MI) presenting with cardiogenic shock (CS). METHODS: CAMEO (Cangrelor in Acute MI: Effectiveness and Outcomes) is a multicenter observational registry evaluating platelet inhibition in patients with MI. We examined the duration of cangrelor infusion and the amount of time to transition from cangrelor to an oral P2Y12 inhibitor in patients with CS. We also assessed major adverse cardiovascular events (MACEs) and bleeding risks, stratified by dosage duration, time to transition and oral P2Y12 inhibitor potency. RESULTS: Among 2352 cangrelor-treated patients with MI, 249 patients were in CS. Among the patients with CS, 16 (6.4%) received the "bridge" infusion dose, 202 (81.1%) the PCI cangrelor infusion dose, and 30 (12.0%) had a combination of both infusion doses. Patients with CS had a median age of 66 years; 32% were women; 21% were Black patients; 35% had diabetes; 19% received thrombectomy; and 59% received mechanical circulatory support (MCS) (35% intra-aortic balloon pump, 27% Impella). The median duration of infusion was 3.9 (2-21.5 hours) in patients with CS and was 2 (1.6-3.1 hours) for all cangrelor-treated patients. The median duration of transition from cangrelor to oral P2Y12 inhibitor administration was 0.1 (-0.5-21.0 hours) for patients with CS. In multivariable modeling, chronic lung disease and the use of MCS and was associated with longer cangrelor infusions (defined as > 3.9 hours). Among cangrelor-treated patients with CS, 24.1% of these patients had a bleeding event, and 41.8% had a MACE event. After adjustment, a longer cangrelor infusion duration was associated with increased risk of bleeding (P < 0.05). CONCLUSIONS: The median duration of cangrelor infusion was longer for patients presenting with CS. Use of MCS was associated with longer cangrelor infusion durations in patients with CS. Further work is needed to understand the pharmacodynamics of antiplatelet agents in patients with CS.

How selective antagonists and genetic modification have helped characterise the expression and functions of vascular P2Y receptors.

Vascular P2Y receptors mediate many effects, but the role of individual subtypes is often unclear. Here we discuss how subtype-selective antagonists and receptor knockout/knockdown have helped identify these roles in numerous species and vessels. P2Y1 receptor-mediated vasoconstriction and endothelium-dependent vasodilation have been characterised using the selective antagonists, MRS2179 and MRS2216, whilst AR-C118925XX, a P2Y2 receptor antagonist, reduced endothelium-dependent relaxation, and signalling evoked by UTP or fluid shear stress. P2Y2 receptor knockdown reduced endothelial signalling and endothelial P2Y2 receptor knockout produced hypertensive mice and abolished vasodilation elicited by an increase in flow. UTP-evoked vasoconstriction was also blocked by AR-C118925XX, but the effects of P2Y2 receptor knockout were complex. No P2Y4 receptor antagonists are available and P2Y4 knockout did not affect the vascular actions of UTP and UDP. The P2Y6 receptor antagonist, MRS2578, identified endothelial P2Y6 receptors mediating vasodilation, but receptor knockout had complex effects. MRS2578 also inhibited, and P2Y6 knockout abolished, contractions evoked by UDP. P2Y6 receptors contribute to the myogenic tone induced by a stepped increase in vascular perfusion pressure and possibly to the development of atherosclerosis. The P2Y11 receptor antagonists, NF157 and NF340, inhibited ATP-evoked signalling in human endothelial cells. Vasoconstriction mediated by P2Y12/P2Y13 and P2Y14 receptors was characterised using the antagonists, cangrelor, ticagrelor, AR-C67085 and MRS2211 or PPTN respectively. This has yet to be backed up by receptor knockout experiments. Thus, subtype-selective antagonists and receptor knockout/knockdown have helped identify which P2Y subtypes are functionally expressed in vascular smooth muscle and endothelial cells and the effects that they mediate.

Intravenous antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention : A report from the INVEST-STEMI group.

The use of intravenous antiplatelet therapy during primary percutaneous coronary intervention (PPCI) is not fully standardized. The aim is to evaluate the effectiveness and safety of periprocedural intravenous administration of cangrelor or tirofiban in a contemporary ST-segment elevation myocardial infarction (STEMI) population undergoing PPCI. This was a multicenter prospective cohort study including consecutive STEMI patients who received cangrelor or tirofiban during PPCI at seven Italian centers. The primary effectiveness measure was the angiographic evidence of thrombolysis in myocardial infarction (TIMI) flow < 3 after PPCI. The primary safety outcome was the in-hospital occurrence of BARC (Bleeding Academic Research Consortium) 2-5 bleedings. The study included 627 patients (median age 63 years, 79% males): 312 received cangrelor, 315 tirofiban. The percentage of history of bleeding, pulmonary edema and cardiogenic shock at admission was comparable between groups. Patients receiving cangrelor had lower ischemia time compared to tirofiban. TIMI flow before PPCI and TIMI thrombus grade were comparable between groups. At propensity score-weighted regression analysis, the risk of TIMI flow < 3 was significantly lower in patients treated with cangrelor compared to tirofiban (adjusted OR: 0.40; 95% CI: 0.30-0.53). The risk of BARC 2-5 bleeding was comparable between groups (adjusted OR:1.35; 95% CI: 0.92-1.98). These results were consistent across multiple prespecified subgroups, including subjects stratified for different total ischemia time, with no statistical interaction. In this real-world multicenter STEMI population, the use of cangrelor was associated with improved myocardial perfusion assessed by coronary angiography after PPCI without increasing clinically-relevant bleedings compared to tirofiban.

Efficacy of Therapeutic Plasma Exchange or Cangrelor as an Adjunctive Strategy to Facilitate Cardiopulmonary Bypass in Patients with Heparin-Induced Thrombocytopenia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Conduct a systematic review and meta-analysis of the efficacy of therapeutic plasma exchange (TPE) or intravenous cangrelor to prevent thromboembolism in patients with heparin-induced thrombocytopenia (HIT) who undergo cardiopulmonary bypass (CPB) with heparin. DESIGN: Systematic review and meta-analysis. SETTING: N/A. PARTICIPANTS: Adults having cardiac surgery with a history of HIT who received preoperative or intraoperative TPE or intravenous cangrelor as an adjunct to CPB with heparin. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: A systematic review was performed using MEDLINE, PubMed, and Google Scholar. The primary outcome was avoidance of thromboembolism (venous or arterial) during or after CPB. Proportional meta-analysis with a random effects model was used to calculate a weighted-pooled proportion/efficacy for the study's primary outcome. Fifty-seven patients in 17 reports received TPE as an adjunctive treatment to prevent HIT-related thrombosis related to heparinization during CPB and 3 (5.3%) experienced thrombosis. Proportional meta-analysis suggested a weighted-pooled freedom from perioperative thromboembolism rate of 91.0% (95% CI 82.6%-96.9%). Fifteen patients in 6 reports received intravenous cangrelor as an adjunctive treatment to prevent HIT-related thrombosis related to heparinization during CPB and 2 (13.3%) experienced thrombosis. Proportional meta-analysis suggested a weighted-pooled freedom from perioperative thromboembolism rate of 83.0% (95% CI 61.2%- 97.6%). CONCLUSIONS: TPE and cangrelor are feasible strategies to prevent thromboembolism in adults with HIT who require CPB with heparin. Given the relatively small number of cases in the published literature and a high likelihood for publication and detection biases, prudence remains warranted when using these strategies.

Comparison of Outcomes in Patients Requiring Mechanical Circulatory Support Who Received Cangrelor in Addition to Anticoagulation Versus Anticoagulation Alone.

OBJECTIVES: To evaluate the safety of cangrelor administered concurrently with heparin or bivalirudin in patients on mechanical circulatory support. DESIGN: A single-center, retrospective cohort study of adult patients consecutively admitted between January 2016 and October 2020. SETTING: A tertiary medical center. PARTICIPANTS: Adult patients admitted to the cardiovascular intensive care unit put on mechanical circulatory support for acute myocardial infarction (AMI) or non-AMI indications. Patients who received cangrelor underwent percutaneous coronary intervention with stenting during the index event or within the last year. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of major bleeding, defined by the Extracorporeal Life Support Organization criteria, in patients with mechanical circulatory support receiving cangrelor plus anticoagulation with heparin or bivalirudin with or without aspirin versus patients who did not receive cangrelor. Sixty-eight patients were included in the study. Twenty-nine patients received cangrelor, and 39 did not. Cangrelor was not associated with an increase in major bleeding; however, the CI was wide (adjusted hazard ratio 1.93, 95% CI 0.61-6.11; p = 0.262). CONCLUSIONS: Patients receiving cangrelor did not appear to be at higher risk of major bleeding compared to patients not receiving cangrelor. Larger trials should be conducted to better evaluate the safety of cangrelor in patients with mechanical circulatory support.

Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y12 Antagonists and Interference with Inflammation and NLRP3 Assembly.

Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.

Comparison of clinical outcomes with cangrelor plus aspirin versus oral dual antiplatelet therapy in patients supported with venoarterial extracorporeal membrane oxygenation.

BACKGROUND: Patients with refractory cardiogenic shock from an acute myocardial infarction may receive percutaneous coronary intervention (PCI) and require the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO). The purpose of this study was to compare bleeding and thrombotic events in patients treated with cangrelor plus aspirin versus oral dual antiplatelet therapy (DAPT) while supported with VA-ECMO. METHODS: We conducted a retrospective review of patients who received PCI, were supported with VA-ECMO, and were treated with either cangrelor plus aspirin or oral DAPT from February 2016 through May 2021 at Allegheny General Hospital. The primary objective was the incidence of major bleeding, defined as Bleeding Academic Research Consortium (BARC) type 3 or greater. The incidence of thrombotic events was a secondary objective. RESULTS: Thirty-seven patients were included, 19 in the cangrelor plus aspirin group, and 18 in the oral DAPT group. All the patients in the cangrelor group received a dose of 0.75 mcg/kg/min. Major bleeding occurred in 7 patients (36.8%) in the cangrelor group compared to 7 patients (38.9%) in the oral DAPT group (p = 0.90). No patient developed stent thrombosis. Two patients (10.5%) in the cangrelor group had a thrombotic event versus 3 patients (16.7%) in the oral DAPT group (p = 0.66). CONCLUSIONS: Bleeding and thrombotic events were comparable between patients receiving cangrelor plus aspirin versus oral DAPT while on VA-ECMO.

Evaluation of Cangrelor Use After Percutaneous Coronary Intervention in Patients With Mechanical Circulatory Support.

OBJECTIVES: To describe cangrelor use in patients on concurrent mechanical circulatory support who underwent postpercutaneous coronary intervention. DESIGN: A single-center, retrospective, cohort study. SETTING: At a quaternary teaching hospital. PARTICIPANTS: Included patients were ≥18 years old, admitted to the intensive care unit, underwent percutaneous coronary intervention with stent placement, initiated on mechanical circulatory support, and received cangrelor in the postpercutaneous coronary intervention period. INTERVENTIONS: Retrospectively analyzed cangrelor use in patients on mechanical circulatory support. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of thrombosis and bleeding events during cangrelor administration. Additional outcomes included initial cangrelor dose, number of cangrelor dose adjustments per patient, survival from mechanical circulatory support, and mortality within 30 days. Overall, 19 patients were included in this study. In total, 14 patients (74%) experienced a bleeding event; however, 93% were classified as a minor bleed. There was 1 major bleeding event. There were no thrombotic events observed during cangrelor administration. The median initial cangrelor dose was 0.5 µg/kg/min. There were 10 patients who underwent dose adjustment, with the majority being dose reductions based on antiplatelet monitoring (VerifyNow assay). Survival from mechanical circulatory support occurred in 17 patients (89%), and 30-day mortality occurred in 8 patients (42%). CONCLUSIONS: For patients receiving cangrelor as a bridge to oral P2Y12 inhibitor therapy on mechanical circulatory support, the authors observed a low rate of major bleeding and no episodes of thrombosis. Lower starting doses appear feasible with no observed increased risk of thrombotic complications. Future studies are needed to confirm these observations.

Advanced pharmacodynamics of cangrelor in healthy volunteers: a dose-finding, open-label, pilot trial.

BACKGROUND: High on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers. METHODS: We conducted a dose-finding, open-label, pilot trial including 12 healthy volunteers and tested three ascending bolus infusions of cangrelor (5 mg, 10 mg and 20 mg) and a bolus infusion followed by a continuous infusion via an intravenous (IV) flow regulator. Platelet function was assessed using multiple electrode aggregometry (MEA), vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P) and the platelet function analyzer. In an ex vivo experiment, epinephrine was used to counteract the antiplatelet effect of cangrelor. RESULTS: All cangrelor bolus infusions resulted in immediate and pronounced platelet inhibition. Bolus infusions of cangrelor 20 mg resulted in sufficient platelet inhibition assessed by MEA for 20 min in 90% of subjects. Infusion of cangrelor via the IV flow regulator resulted in sufficient platelet inhibition throughout the course of administration. Ex vivo epinephrine, in concentrations of 200 and 500 ng/mL was able to partially reverse the antiplatelet effect of cangrelor in a dose-dependent manner. CONCLUSIONS: Weight-adapted bolus infusions followed by a continuous infusion of cangrelor via IV flow regulator result in immediate and pronounced platelet inhibition in healthy subjects. Cangrelor given as weight-adapted bolus infusion followed by a continuous infusion using an IV flow regulator may be a viable treatment approach for effective and well controllable prehospital platelet inhibition. TRIAL REGISTRATION: EC (Medical University of Vienna) 1835/2019 and EudraCT 2019-002792-34 .

"Tailored" antiplatelet bridging therapy with cangrelor: moving toward personalized medicine.

In the setting of patients with indication to receive dual antiplatelet therapy undergoing surgery or invasive procedures, the risk of perioperative cardiac ischemic events, particularly stent thrombosis, is high, because surgery has a prothrombotic effect and antiplatelet therapy is withdrawn in order to avoid bleeding complications. Cangrelor, an intravenous P2Y12 receptor antagonist, has been tested in a randomized trial as a "bridge" to cardiac surgery from discontinuation of oral P2Y12 receptor antagonists. Thus, a consensus document extended its off-label use in this setting and before non-cardiac surgery. Currently, despite the implementation of a standardized bridging protocol with cangrelor, a residual risk of adverse outcome mainly due to bleeding events, still persist during the perioperative phase.Accordingly, a personalized management driven by platelet reactivity serial measurements and careful assessment of ischemic and bleeding risks has potential to optimize outcomes and costs as compared to a standardized bridging protocol, based on average pharmacodynamic data of oral P2Y12 inhibitors.While specific indications for bridging have been extensively addressed in the aforementioned consensus statement, the aim of the present document is the proposal of a "tailored" clinical decision-making algorithm inspired to the principle of personalized medicine dealing with complex clinical scenarios.

Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial.

BACKGROUND: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention. METHODS: The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 µmol/L adenosine diphosphate. RESULTS: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016). CONCLUSIONS: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.

Cangrelor vs. glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention.

BACKGROUND: To date, there are no real-world studies comparing cangrelor to glycoprotein IIb/IIIa inhibitors (GPI) during percutaneous coronary intervention (PCI). Thus, we performed this study to evaluate the safety and effectiveness of cangrelor compared to GPI during PCI. METHODS: We identified patients who underwent PCI at our institution who received either cangrelor or GPI during PCI. Patients already on GPI or cangrelor prior to PCI or who received both cangrelor and GPI were excluded. Baseline demographics and clinical outcomes were extracted. Major bleeding is defined as a composite of major hematoma >4 cm, hematocrit drop >15, and gastrointestinal bleeding. RESULTS: A total of 2072 patients received adjunctive antiplatelet therapy during PCI (cangrelor [n=478]; GPI [n=1594]). Patients' mean age was 61±12 years. Most (66%) presented with acute coronary syndrome. Patients who received cangrelor were older and had a higher percentage of acute coronary syndrome and lower baseline hematocrit in comparison with patients who received GPI. Procedural success was achieved in 94% of patients, with no difference between groups. Major bleeding events (1.7% vs. 5.1%, P=.001), any vascular complication rates, and hospital length of stay were significantly lower in the cangrelor group. In-hospital ischemic events did not differ between groups. On regression analysis, patients on cangrelor were noted to have significantly lower major bleeding events (OR 0.23; 95% CI, 0.09-0.59). CONCLUSIONS: Balancing ischemic and bleeding risks with adjunctive antiplatelet drugs is of prime importance during PCI. Our real-world analysis shows that cangrelor is safe and effective when compared to GPI during PCI.

Clinical Use of Cangrelor After Percutaneous Coronary Intervention in Patients Requiring Mechanical Circulatory Support.

BACKGROUND: Patients with cardiogenic shock after percutaneous coronary intervention (PCI) may require mechanical circulatory support (MCS). The combination of dual antiplatelet therapy with cangrelor and continuous anticoagulation required for MCS may increase the risk of bleeding. OBJECTIVE: The objective of the study is to describe the complications and outcomes of patients who received cangrelor during MCS following PCI. METHODS: This is a single-center, retrospective, observational case series of 17 patients who received cangrelor while on MCS from June 2017 to September 2019. RESULTS: In a case series of 17 patients, 8 patients (47%) were supported with an Impella device and 4 patients (24%) with venoarterial (VA) extracorporeal membrane oxygenation (ECMO); 5 required (29%) concomitant VA ECMO and Impella support in the setting of cardiogenic shock. All patients received triple antithrombotic therapy with aspirin, heparin, and cangrelor. Cangrelor was commonly initiated at a median dose of 0.75 (range 0.5-4) µg/kg/min. Cangrelor dose adjustments included changes in increments up to 0.25 µg/kg/min with review of P2Y12 levels. A total of 10 patients (59%) experienced a bleeding event, most commonly located at the peripheral cannulation site (40%) and in the gastrointestinal tract (30%). Seven (70%) and 3 (30%) of the bleeding complications were classified as major and minor, respectively. No patient developed in-stent thrombosis during the hospitalization; 14 (82%) patients survived their MCS course. CONCLUSION AND RELEVANCE: This case series suggests that cangrelor doses less than 0.75 µg/kg/min may be beneficial. Larger studies should evaluate alternative dosing regimens.

The use of cangrelor in neurovascular interventions: a multicenter experience.

PURPOSE: Thromboembolic events represent the most common procedure-related complication associated with neurointerventions. Cangrelor is a potent, intravenous (IV), P2Y12-receptor antagonist with a rapid onset and offset presented as an alternative antiplatelet agent. We aim to evaluate the safety and effectiveness of IV cangrelor in neurovascular intervention. METHODS: This is a retrospective analysis of data from four cerebrovascular interventional centers. We identified patients who underwent acute neurovascular intervention and received cangrelor as part of their optimum care. Patients were divided into 2 groups: ischemic and aneurysm. Periprocedural thromboembolic events, hemorrhagic complications, and outcomes were analyzed. RESULTS: Sixty-six patients were included, 42 allocated into the ischemic group (IG), and 24 into aneurysm group (AG). The IG periprocedural symptomatic complication rate was 9.5%, represented by 3 postoperative intracranial hemorrhages and 1 retroperitoneal hematoma. At discharge, 47.6% had a favorable outcome and the mortality rate was 2.4%, related to clinical deterioration of a large infarct. In the AG, 4.2% had a periprocedural complication during or after cangrelor infusion, represented by an intracranial hemorrhage in an initially ruptured aneurysm. Favorable clinical outcome was seen in 56.2% and 87.7% of ruptured and unruptured aneurysms, respectively, upon discharge. CONCLUSIONS: Cangrelor may be a feasible alternative for patients requiring immediate intervention with the use of endoluminal devices. It allows the possibility for a secure transition to long-term ticagrelor and progression to surgery in the setting of unexpected complications.

Feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing percutaneous coronary intervention: rationale of the Dutch Cangrelor Registry.

BACKGROUND: Despite the advances of potent oral P2Y12 inhibitors, their onset of action is delayed, which might have a negative impact on clinical outcome in patients undergoing percutaneous coronary intervention (PCI). Trials conducted in the United States of America have identified cangrelor as a potent and rapid-acting intravenous P2Y12 inhibitor, which has the potential of reducing ischemic events in these patients without an increase in the bleeding. As cangrelor is rarely used in The Netherlands, we conducted a nationwide registry to provide an insight into the use of cangrelor in the management of patients with suboptimal platelet inhibition undergoing (primary) PCI (the Dutch Cangrelor Registry). STUDY DESIGN: The Cangrelor Registry is a prospective, observational, multicenter, single-arm registry with cangrelor administered pre-PCI in: (1) P2Y12 naive patients with ad-hoc PCI, (2) patients with STEMI/NSTEMI with suboptimal P2Y12 inhibition including (3) stable resuscitated/defibrillated patients with out-of-hospital cardiac arrest (OHCA) due to acute ischemia and (4) STEMI/NSTEMI patients with a high thrombotic burden. Primary endpoint is 48 h Net Adverse Clinical Events (NACE), which is a composite endpoint of all-cause death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), stroke, stent thrombosis (ST) and BARC 2-3-5 bleeding. The Dutch Cangrelor Registry will assess the feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing (primary) PCI in the setting of acute coronary syndrome (ACS) and stable coronary artery disease (CAD) in the Netherlands.

Cangrelor in addition to standard therapy reduces cardiac damage and inflammatory markers in patients with ST-segment elevation myocardial infarction.

Although P2Y12 receptor blockers have become a standard, adjunctive therapy in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), the optimal regimen has not been established. We performed a prospective, open-label, randomized study to investigate the effect of cangrelor administration on platelet function and inflammation in patients with primary PCI (PPCI). Twenty-two patients were randomized to receive either cangrelor and ticagrelor or ticagrelor alone (standard group) before PPCI. Platelet reactivity was evaluated at baseline (before PCI), 10 min and the end of the procedure. At baseline, there was no significant difference in platelet reactivity between both groups, whereas platelets were significantly inhibited at 10 min after initiating cangrelor vs. standard (adenosine-diphosphate-induced aggregation 102.2 ± 24.88 vs. 333.4 ± 63.3, P < 0.05 and thrombin-receptor-activating-peptide-induced aggregation 285.8 ± 86.1 vs. 624.8 ± 106.0, P < 0.05). Lower platelet aggregation in the cangrelor group persisted but the difference was reduced by the end of the procedure. Circulating inflammatory cells, pro-inflammatory cytokines, total elastase, and surrogates of neutrophil extracellular traps (total elastase-myeloperoxidase complexes) were significantly lower in the cangrelor compared to the standard therapy group at 6 h after randomization. There was a trend towards reduction in cardiac damage in the cangrelor group as reflected by the changes in late gadolinium enhancement between 48 h and 3 months after STEMI. Early administration of cangrelor in STEMI patients was associated with more effective platelet inhibition during PPCI and significantly dampened the deleterious inflammatory response compared to standard therapy (NCT03043274).

Novel use of cangrelor in pediatrics: A pilot cohort study demonstrating use in ventricular assist devices.

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end-stage heart failure and VAD circulation. Additionally, 20%-40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short-acting, reversible, intravenous P2Y12 platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single-center review of patients admitted to a tertiary medical center with end-stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y12 < 180 platelet reaction units (PRU), was measured with serial point-of-care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5-103). The median duration on cangrelor was 43 days (IQR 8-70). The median cangrelor dose to reach the therapeutic threshold was 0.75 µg/kg/min with the mean P2Y12 , while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long-term use of cangrelor in pediatric patients. The reversibility and short half-life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.

The Use of Cangrelor Infusions After Endovascular Aortic Repair With Prophylactic Lumbar Drain Placement.

Perioperative lumbar drains commonly are placed for spinal cord protection in patients undergoing endovascular aortic repair. However, the logistics of postoperative neuraxial drain removal is challenging in the presence of systemic antithrombotic therapy. This retrospective case series describes the novel use of cangrelor infusions in this high-risk setting. All lumbar drains were placed preoperatively, and descriptive data were collected including cangrelor infusion duration, time to lumbar drain removal after the infusion discontinuation, clinical course, and overall patient outcomes. There were no neurologic complications associated with lumbar drain insertion or removal, and median time to lumbar drain removal was 150 minutes after cangrelor infusion discontinuation. While further study is needed to validate its efficacy and safety, this case series highlights the promise of cangrelor infusions for systemic antithrombotic therapy in the cardiovascular/surgical intensive care unit.

Identification of African Swine Fever Virus Inhibitors through High Performance Virtual Screening Using Machine Learning.

African swine fever virus (ASFV) is a highly contagious virus that causes severe hemorrhagic viral disease resulting in high mortality in domestic and wild pigs, until few antiviral agents can inhibit ASFV infections. Thus, new anti-ASFV drugs need to be urgently identified. Recently, we identified pentagastrin as a potential antiviral drug against ASFVs using molecular docking and machine learning models. However, the scoring functions are easily influenced by properties of protein pockets, resulting in a scoring bias. Here, we employed the 5'-P binding pocket of AsfvPolX as a potential binding site to identify antiviral drugs and classified 13 AsfvPolX structures into three classes based on pocket parameters calculated by the SiteMap module. We then applied principal component analysis to eliminate this scoring bias, which was effective in making the SP Glide score more balanced between 13 AsfvPolX structures in the dataset. As a result, we identified cangrelor and fostamatinib as potential antiviral drugs against ASFVs. Furthermore, the classification of the pocket properties of AsfvPolX protein can provide an alternative approach to identify novel antiviral drugs by optimizing the scoring function of the docking programs. Here, we report a machine learning-based novel approach to generate high binding affinity compounds that are individually matched to the available classification of the pocket properties of AsfvPolX protein.