title: Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial.
abstract: BACKGROUND
  The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied.
  
  
  OBJECTIVE
  In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid.
  
  
  METHODS
  A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed.
  
  
  RESULTS
  Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose.
  
  
  CONCLUSIONS
  Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.
authors.affiliation: Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. Electronic address: r.f.storey@sheffield.ac.uk.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Thomas
authors.affiliation: Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Judge
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rollini
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Francesco
authors.initials: F
authors.lastname: Franchi
authors.affiliation: Trent Cardiac Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors.forename: Arif J
authors.initials: AJ
authors.lastname: Ahsan
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Kuder
authors.affiliation: INSERM-Unité 1148, Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, and Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France.
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark, New Jersey.
authors.forename: Marc
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Department of Cardiology, Rotherham NHS Foundation Trust, Rotherham, United Kingdom.
authors.forename: Rangasamy
authors.initials: R
authors.lastname: Muthusamy
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001792:Blood Platelets / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy*; D010974:Platelet Aggregation / Q000187:drug effects*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077486:Ticagrelor; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine
keywords: P2Y(12) receptor; aspirin; coronary artery disease