Pharmacodynamic Effects of Cangrelor on Platelet P2Y12 Receptor–Mediated Signaling in Prasugrel-Treated Patients

Rollini, Fabiana; Franchi, Francesco; Tello‐Montoliu, Antonio; Patel, Raj; Darlington, Andrew; Ferreiro, José Luis; Cho, Jung Rae; Muñiz–Lozano, Ana; Desai, Bhaloo; Zenni, Martin M.; Guzmán, Luis A.; Bass, Theodore A.; Angiolillo, Dominick J.

doi:10.1016/j.jcin.2013.11.019

Cited by 30 publications

(9 citation statements)

References 39 publications

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“…Overall, our results from the in vitro and clinical studies are conceptually well in agreement with the data published for cangrelor and the transition to reversible and irreversible P2Y 12 receptor antagonists and vice versa. 31,32 Cangrelor prevented the binding of C-AM and P-AM to the P2Y 12 receptor in vitro in a concentration-dependent manner. 33 It was also shown clinically that the IPA mediated by clopidogrel or prasugrel when administered during an infusion of cangrelor was diminished.…”

Section: Discussionmentioning

confidence: 90%

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

Schilling

Dingemanse

Dobrow³

et al. 2021

Thromb Haemost

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Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

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Section: Discussionmentioning

confidence: 90%

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

Schilling

Dingemanse

Dobrow³

et al. 2021

Thromb Haemost

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“…The use of potent intravenous antiplatelet agents, prolonging bivalirudin infusion and crushing of oral antiplatelet tablets to facilitate gastrointestinal absorption may help overcome this issue (7,(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Franchi

Rollini

Cho

et al. 2015

JACC: Cardiovascular Interventions

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ST-segment elevation myocardial infarction patients undergoing PPCI frequently exhibit impaired response to ticagrelor in the early hours after drug administration, which cannot be overcome by increasing LD regimens. These PD findings are largely attributed to an impaired PK profile, indicating a delay in drug absorption compared with that reported in stable clinical settings. (High Ticagrelor Loading Dose in STEMI; NCT01898442).

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“…51 In patients on prasugrel maintenance therapy, in vitro incubation with cangrelor provided more rapid than prasugrel reloading platelet inhibition. 52 Furthermore, maintenance treatment with ticagrelor for 5 days did not affect the inhibitory effects of cangrelor. 49 Nevertheless, the use of cangrelor in oral agent-receiving patients and aiming for further platelet inhibition is currently “off-label” and of unclear clinical significance.…”

Section: Unsettled Issuesmentioning

confidence: 90%

Cangrelor in Percutaneous Coronary Intervention: Current Status and Perspectives

Alexopoulos

Pappas

Sfantou

et al. 2017

J Cardiovasc Pharmacol Ther

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Cangrelor is an intravenously administered P2Y receptor antagonist with very fast, potent, and quickly reversible action. In the CHAMPION PHOENIX trial, cangrelor provided an improved anti-ischemic protection compared with clopidogrel, without increasing the risk of severe bleeding. Cangrelor is currently approved by drug regulating authorities for patients undergoing percutaneous coronary intervention (PCI) without prior treatment with a P2Y receptor antagonist and not receiving a glycoprotein IIb/IIIa inhibitor, while its use is endorsed with a class IIb recommendation by the European Society of Cardiology guidelines. Several subanalyses of CHAMPION PHOENIX trial have tried to elucidate the role of cangrelor in PCI, including its usefulness during a 2-hour landmark analysis, impact on intraprocedural stent thrombosis, and reduction in myocardial infarction (MI) rate. The influence of gender, geographic region, access site, and bivalirudin use on cangrelor's effects has also been reported. In patients with ST elevation MI and in clinical scenarios of disturbed absorption of oral antiplatelet agents or in need of an intravenous agent, cangrelor may surpass oral agents' drawbacks. Transitioning to an oral agent is mandatory following cangrelor infusion discontinuation, although ticagrelor may be administered earlier without any pharmacodynamic interaction. Nevertheless, the clinical role of cangrelor in conjunction with administration of prasugrel or ticagrelor remains unclear. Accruing real-life experience is expected to improve our understanding of cangrelor's role in everyday clinical practice.

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Pharmacodynamic Effects of Cangrelor on Platelet P2Y12 Receptor–Mediated Signaling in Prasugrel-Treated Patients

Abstract: 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.

Cited by 30 publications

References 39 publications

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Cangrelor in Percutaneous Coronary Intervention: Current Status and Perspectives

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