Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients

JACC Cardiovasc Interv. 2014 Apr;7(4):426-34. doi: 10.1016/j.jcin.2013.11.019. Epub 2014 Mar 13.

Abstract

Objectives: The purpose of this study was to assess the in vitro P2Y12 receptor inhibitory effects of cangrelor on platelets from patients on maintenance prasugrel therapy treated with 2 reloading dose regimens.

Background: Despite its more potent and rapid antiplatelet effects compared with clopidogrel, recent studies have shown variability in prasugrel-mediated P2Y12 receptor inhibition, particularly in high-risk settings. Cangrelor is a potent intravenous P2Y12 receptor inhibitor.

Methods: A total of 60 patients with coronary artery disease on maintenance prasugrel (10 mg/day) therapy were randomized to a 30- or 60-mg reload of prasugrel. The platelet reactivity index (PRI), as assessed by whole-blood vasodilator-stimulated phosphoprotein, was measured with and without in vitro incubation of cangrelor (500 nM) at baseline, and at 1 and 4 h after reload.

Results: In the absence of cangrelor, prasugrel reloading reduced PRI (p < 0.001 for both doses), although a 60-mg reload had greater platelet inhibition compared with a 30-mg reload at 4 h (p = 0.001). Cangrelor was associated with a reduction in PRI values during the overall study time course in patients reloaded with 30 mg (p = 0.001) and 60 mg (p < 0.001) of prasugrel. In patients reloaded with 30 mg prasugrel, cangrelor decreased PRI at each time point (baseline, p < 0.001; 1 h, p = 0.013; 4 h, p = 0.001). In patients reloaded with 60 mg prasugrel, cangrelor decreased PRI at baseline (p < 0.001) and 1 h (p = 0.002); levels of platelet reactivity comparable to those achieved with cangrelor were observed only at 4 h (p = 0.325). The intergroup comparisons with cangrelor were not significant at any time point.

Conclusions: 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.

Keywords: cangrelor; platelet reactivity; prasugrel.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / pharmacology
  • Aged
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cell Adhesion Molecules / blood
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / diagnosis
  • Coronary Artery Disease / drug therapy*
  • Drug Administration Schedule
  • Female
  • Florida
  • Humans
  • Male
  • Microfilament Proteins / blood
  • Middle Aged
  • Percutaneous Coronary Intervention
  • Phosphoproteins / blood
  • Phosphorylation
  • Piperazines / administration & dosage*
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Platelet Function Tests
  • Prasugrel Hydrochloride
  • Prospective Studies
  • Purinergic P2Y Receptor Antagonists / administration & dosage*
  • Receptors, Purinergic P2Y12 / blood
  • Receptors, Purinergic P2Y12 / drug effects*
  • Signal Transduction / drug effects*
  • Thiophenes / administration & dosage*
  • Time Factors
  • Vasodilator-Stimulated Phosphoprotein

Substances

  • Cell Adhesion Molecules
  • Microfilament Proteins
  • P2RY12 protein, human
  • Phosphoproteins
  • Piperazines
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y12
  • Thiophenes
  • Vasodilator-Stimulated Phosphoprotein
  • Adenosine Monophosphate
  • cangrelor
  • Prasugrel Hydrochloride