P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

Kaza, Elisabeth; Egalka, Matthew C.; Zhou, Hairu; Chen, Shiguo; Evans, Denise; Prats, Jayne; Li, Ruizhi; Diamond, Scott L.; Vincent, Julie A.; Bacha, Emile A.; Diacovo, Thomas G.

doi:10.1016/j.jacbts.2017.04.002

Cited by 10 publications

(10 citation statements)

References 37 publications

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“…Adequate platelet inhibition, as demonstrated by a P2Y 12 level <180 PRU, was achieved quickly with a much lower dose of cangrelor than previously reported by the manufacturer (1.5 μg/kg/min vs. 4 μg/kg/min) 20 . This may be specific to our population, but a lower dosing regimen approximates a previous study in healthy adult volunteers 39 .…”

Section: Discussionsupporting

confidence: 70%

“…Antagonism of the P2Y 12 receptor with agents such as clopidogrel, ticlopidine or cangrelor is clinically effective in the prevention and/or propagation of thrombosis 18‐21 . Clopidogrel is a prodrug requiring oxidation by hepatic cytochrome P450 to generate an active metabolite that competitively and irreversibly inhibits the P2Y 12 receptor 22 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Subsequent clot buildup relies on the endogenous release of ADP from platelets resulting in P2Y 12 ‐mediated aggregation 29 . Consequently, ~70% of platelet accrual in this system is amenable to P2Y 12 inhibition 22 . With <1 mL of blood, a minimum of eight separate platelet aggregation events were imaged at 1‐minute intervals for each treated participant before, during, and after cangrelor administration at either 0.5 or 0.25 µg/kg/min (Figure 3A, B, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…This is due in part to the limited therapeutic options that exist to prevent shunt thrombosis, especially in the immediate postoperative period where a delicate balance must be struck between providing adequate hemostasis and preventing pathological clot formation. The current clinical trial addresses a major unmet need for an effective and safe thromboprophylactic agent and was predicated on our previous preclinical study demonstrating that platelets isolated from neonatal patients with complex CHD have a robust response to ADP and are amenable to P2Y 12 receptor inhibition with cangrelor 22 …”

Section: Discussionmentioning

confidence: 99%

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

Vargas

Zhou

Xiang

et al. 2021

Journal of Thrombosis and Haemostasis

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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 BackgroundSystemic‐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.

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“…This agent also targets the P2Y12 platelet receptor similar to clopidogrel; however, it binds in a reversible manner. A continuous infusion at 4 µg/kg/min was initiated and titrated to a dose of 2 µg/kg/min based on the VerifyNow test . There was immediate clinical improvement with no further formation of white clots or thrombus deposition in the connector sites, thus avoiding the need for any further circuit modifications for 53 days.…”

Section: Case Reportmentioning

confidence: 99%

Use of a novel antiplatelet agent cangrelor in an infant supported with a ventricular assist device

et al. 2020

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P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

Cited by 10 publications

References 37 publications

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

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

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

Use of a novel antiplatelet agent cangrelor in an infant supported with a ventricular assist device

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