Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials

Abstract

Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12receptorsin vitro

“…Of note, in the CHAMPION platelet substudy [19] there was no apparent significant pharmacodynamic interaction when clopidogrel was administered at the end of the cangrelor infusion in a group of patients undergoing PCI.…”

“…Since both cangrelor and ticagrelor rely on sustained plasma levels for their inhibitory effects, one might not expect to find a negative pharmacodynamic interaction [19,21].…”

Antiplatelet Therapy in Patients With Diabetes Mellitus and Acute Coronary Syndrome

“…65 A recent study evaluated the pharmacodynamic effects of cangrelor in diabetic and nondiabetic, clopidogrel-naïve patients with coronary artery disease on aspirin therapy; 66 cangrelor provided potent, dose-dependent blockade of platelet P2Y12 receptors by both vasodilator-stimulated phosphoprotein (VASP) assay and multiple electrode aggregometry, without differential effects according to diabetic status. A patient-level pooled analysis from the 3 randomized CHAMPION trials recently compared cangrelor with control (clopidogrel or placebo) in PCI patients; 67 cangrelor significantly reduced the odds of ischemic cardiac events at 48 h (19% reduction), at the expense of increased incidence of GUSTO mild bleeding events.…”

Ticagrelor and Eptifibatide Bolus Versus Ticagrelor and Eptifibatide Bolus With 2‐Hour Infusion in High‐Risk Acute Coronary Syndromes Patients Undergoing Early Percutaneous Coronary Intervention

“…In this respect, a randomized trial is warranted to investigate outcomes of high‐risk patients with NSTE‐ACS undergoing early PCI. Furthermore, randomized trials are warranted to investigate the safety and costs of ticagrelor and eptifibatide bolus versus cangrelor21 (a fast‐acting intravenous P2Y 12 inhibitor) and ticagrelor in high‐risk NSTE‐ACS patients undergoing early PCI.…”