title: Pharmacodynamic effects of adjunctive cilostazol therapy in patients with coronary artery disease on dual antiplatelet therapy: impact of high on-treatment platelet reactivity and diabetes mellitus status.
abstract: BACKGROUND
  In patients on dual antiplatelet therapy with aspirin and clopidogrel, the adjunctive use of cilostazol is associated with enhanced platelet inhibition. However, if cilostazol exerts different pharmacodynamic (PD) effects according to levels of on-treatment platelet reactivity remains unknown. This study aimed to determine the PD effects of cilostazol in patients with and without high on-clopidogrel platelet reactivity (HPR) according to diabetes mellitus (DM) status.
  
  
  METHODS
  This is a post-hoc analysis derived from patients (n = 79) enrolled in a prospective, randomized, double-blind, double-dummy, crossover study comparing cilostazol with placebo in stable coronary artery disease patients on aspirin and clopidogrel therapy. In the present analysis, patients were divided according to the presence or absence of HPR (HPR and non-HPR). HPR was defined as a P2Y12 units (PRU) > 240 as assessed by the VerifyNow P2Y12 assay. The PD effects of cilostazol were evaluated in patients with and without HPR according to DM status.
  
  
  RESULTS
  Significant absolute changes in PRU values were observed after adjunctive cilostazol in both HPR [53.4 (95% CI 24.7-82.1), P = 0.001] and non-HPR [40.8 (95% CI 28.7-52.8), P < 0.0001] patients. This difference was statistically significant in HPR patients with DM (P = 0.001), but not without DM (P = 0.24), and in non-HPR patients with and without DM (P = 0.0001 for both). The greatest mean reduction in PRU was observed in HPR patients with DM (72.9; 95% CI 33.7-112.0). Thrombin generation was not affected by cilostazol, irrespective of HPR status.
  
  
  CONCLUSIONS
  Cilostazol reduces platelet reactivity both in HPR and non-HPR patients, although these PD effects are enhanced in HPR patients with DM. Nevertheless, larger studies are needed to better evaluate possible differential effects of cilostazol on platelet reactivity by diabetes status.
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida 32209, USA.
authors.forename: Piera
authors.initials: P
authors.lastname: Capranzano
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ferreiro
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ueno
authors.forename: Davide
authors.initials: D
authors.lastname: Capodanno
authors.forename: Kodlipet
authors.initials: K
authors.lastname: Dharmashankar
authors.forename: Andrew
authors.initials: A
authors.lastname: Darlington
authors.forename: Bhaloo
authors.initials: B
authors.lastname: Desai
authors.forename: Antonio
authors.initials: A
authors.lastname: Tello-Montoliu
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rollini
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
mesh_terms: D000368:Aged; D001241:Aspirin / Q000008:administration & dosage* / Q000009:adverse effects; D001792:Blood Platelets / Q000187:drug effects*; D000077407:Cilostazol; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality; D018592:Cross-Over Studies; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000401:mortality; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D011446:Prospective Studies; D011859:Radiography; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077144:Clopidogrel; D000077407:Cilostazol; D013988:Ticlopidine; D001241:Aspirin