title: Cilostazol attenuates on-treatment platelet reactivity in patients with CYP2C19 loss of function alleles receiving dual antiplatelet therapy: a genetic substudy of the CILON-T randomised controlled trial.
abstract: OBJECTIVE
  To evaluate whether the addition of cilostazol to dual antiplatelet therapy (DAT, aspirin plus clopidogrel) can attenuate clopidogrel on-treatment platelet reactivity (OPR) in patients with the CYP2C19 loss-of-function (LOF) allele.
  
  
  METHODS
  In the CILON-T randomised trial, patients were randomly assigned to either DAT or triple antiplatelet therapy (TAT, DAT plus cilostazol). Genotyping of cytochrome P450 CYP2C19 *2, *3 and *17 was performed and OPR was measured using the VerifyNow P2Y12 assay. Carriers were those with at least one CYP2C19 LOF allele.
  
  
  RESULTS
  474 patients were enrolled; 236 received DAT, 238 TAT. Mean OPR was significantly lower in the TAT compared with the DAT group (207 ± 5 vs 236 ± 5, p<0.001, P2Y12 reaction units, PRU). When grouped according to the presence of the CYP2C19 LOF allele, mean OPR was significantly lower in the TAT compared with the DAT group in only carriers of the LOF allele and not non-carriers (213 ± 6 vs 256 ± 7 PRU, p<0.001 in carriers, 196 ± 9 vs 211 ± 8 PRU, p=0.242 in non-carriers for TAT vs DAT, respectively). The proportion of patients with high OPR was highest in carriers receiving DAT (60.8%) compared with the other three groups. On multivariate analysis, carriers on DAT was an independent predictor of high OPR (OR 2.93, 95% CI 1.64 to 5.21) along with female gender and increasing age.
  
  
  CONCLUSIONS
  TAT significantly reduced OPR compared with DAT in carriers of the CYP2C19 LOF allele, but not in non-carriers. These data suggest that the addition of cilostazol to DAT may be a good strategy to attenuate CYP2C19 LOF-related high OPR.
authors.affiliation: Cardiovascular Center, Seoul National University Main and Bundang Hospital, Seoul, Korea.
authors.forename: Kyung Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Park
authors.forename: Seung-Pyo
authors.initials: SP
authors.lastname: Lee
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Oh
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Suh
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.forename: Bon-Kwon
authors.initials: BK
authors.lastname: Koo
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Youn
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Chae
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: Choi
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000368:Aged; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000502:physiology*; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000235:genetics / Q000517:prevention & control*; D000077407:Cilostazol; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004359:Drug Therapy, Combination / Q000379:methods; D054855:Drug-Eluting Stents; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000077407:Cilostazol; D013988:Ticlopidine; D001241:Aspirin