title: Cytochrome 2C19 polymorphism and response to adjunctive cilostazol versus high maintenance-dose clopidogrel in patients undergoing percutaneous coronary intervention.
abstract: BACKGROUND
  Among patients treated with clopidogrel, carriers of the cytochrome P450 (CYP) 2C19 loss-of-function allele have shown increased platelet reactivity and higher rates of ischemic events. Although adjunctive cilostazol to dual antiplatelet therapy (or "triple antiplatelet therapy") intensifies platelet inhibition, it remains unknown whether triple antiplatelet therapy after percutaneous coronary intervention can achieve adequate platelet inhibition in patients with the CYP2C19 mutant allele.
  
  
  RESULTS
  CYP2C19 genotyping for *1, *2, and *3 was performed in 134 high-risk patients undergoing elective percutaneous coronary intervention. After measurement of preprocedural platelet reactivity, patients were randomly assigned to receive either adjunctive cilostazol 100 mg twice daily (triple group; n=69) or high maintenance-dose (MD) clopidogrel of 150 mg daily (high-MD group; n=65). Using light transmittance aggregometry and the VerifyNow P2Y(12) assay, platelet reactivity was assessed before the index procedure and at 30-day follow-up. The primary end point was absolute change in maximal platelet aggregation (ΔAgg(max)) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 μmol/L ADP-induced maximal platelet aggregation >50%. In noncarriers of the CYP2C19*2/*3 mutant allele, ΔAgg(max) values after 5 and 20 μmol/L ADP stimuli did not differ significantly between the triple (n=22) versus the high-MD group (n=22) (23.6±21.6% versus 16.6±15.4%, P=0.224 and 26.4±22.2% versus 18.6±14.9%, P=0.174, respectively). Absolute changes in late platelet aggregation and P2Y(12) reaction unit were not different between the groups. The rate of high posttreatment platelet reactivity at 30-day follow-up also was comparable between the triple versus the high-MD group (4.5% versus 13.6%, P=0.607). In carriers of at least 1 CYP2C19*2/*3 mutant allele, the triple group (n=47) showed greater values of ΔAgg(max) after addition of 5 μmol/L (25.8±16.8% versus 11.1±19.8%, P<0.001) and 20 μmol/L ADP (26.3±16.0% versus 11.5±16.3%, P<0.001) compared with the high-MD group (n=43). Likewise, absolute changes in late platelet aggregation and P2Y(12) reaction unit were consistently greater in the triple versus the high-MD group. Fewer patients in the triple group met the criteria of high posttreatment platelet reactivity at 30-day follow-up compared with the high-MD group (6.4% versus 37.2%, P<0.001).
  
  
  CONCLUSIONS
  Among high-risk patients undergoing elective percutaneous coronary intervention, adjunctive cilostazol can achieve consistently intensified platelet inhibition and reduce the risk of high posttreatment platelet reactivity irrespective of CYP2C19 genotyping.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01012193.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Korea.
authors.forename: Seok-Jae
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Jeong
authors.forename: In-Suk
authors.initials: IS
authors.lastname: Kim
authors.forename: Ki-Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Kang
authors.forename: Jin-Sin
authors.initials: JS
authors.lastname: Koh
authors.forename: Jeong Rang
authors.initials: JR
authors.lastname: Park
authors.forename: Yongwhi
authors.initials: Y
authors.lastname: Park
authors.forename: Eun-Ha
authors.initials: EH
authors.lastname: Koh
authors.forename: Choong Hwan
authors.initials: CH
authors.lastname: Kwak
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Hwang
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Kim
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D000077407:Cilostazol; D000077144:Clopidogrel; D018389:Codon, Nonsense / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D004252:DNA Mutational Analysis; D006801:Humans; D007511:Ischemia / Q000209:etiology* / Q000517:prevention & control; D010974:Platelet Aggregation / Q000187:drug effects; D011110:Polymorphism, Genetic; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D018389:Codon, Nonsense; C548576:P2RY12 protein, human; D058925:Receptors, Purinergic P2Y12; D013777:Tetrazoles; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000077407:Cilostazol; D013988:Ticlopidine