Platelet Inhibition With Cangrelor and Crushed Ticagrelor in STEMI (CANTIC)

Platelet Inhibition With CANgrelor and Crushed TICagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention: The CANTIC Study

In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel. The PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.

In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor, which require more than 2 hours to exert their full antiplatelet effects, and thus exposing these high-risk patients to an increased risk of early thrombotic complications. The mechanism of this delayed onset of antiplatelet effect is likely multifactorial due to the presence in the setting of STEMI of specific conditions that translate into delayed drug absorption which in turn affect the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oral P2Y12 receptor inhibitors. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel and the clinical profile of cangrelor among patients treated with prasugrel or ticagrelor is currently unknown. This is noteworthy because ACS patients, in particular STEMI undergoing PPCI, are commonly treated with either prasugrel or ticagrelor. PD investigations conducted in vitro or ex vivo in stable patients have shown cangrelor to be associated with enhanced platelet inhibition compared with that induced by prasugrel and ticagrelor. However, the PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.

Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h.

Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h.

Platelet reactivity at 30 minutes after starting cangrelor or placebo assessed by VerifyNow PRU and reported as P2Y12 Reaction Units (PRU)

Platelet reactivity at 30 minutes after starting cangrelor or placebo measured by VASP and reported as platelet reactivity index (PRI%). Higher PRI% means higher platelet reactivity.

Inclusion criteria: Patients with STEMI undergoing primary PPCI Age > 18 years old Exclusion criteria: Inability to provide written informed consent Known history of prior intracranial bleeding On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in the prior 10 days Known allergies to aspirin, ticagrelor or cangrelor On treatment with oral anticoagulant Treatment with glycoprotein IIb/IIIa inhibitors Fibrinolytics within 24 hours Active bleeding High risk of bleeding Known platelet count <80x106/mL Known hemoglobin <10 g/dL Intubated patients (prior to randomization) Known creatinine clearance <30 mL/minute or on hemodialysis. Known severe hepatic dysfunction Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. Pregnant or lactating females.

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