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. Methods and 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 (Delta Agg(max)) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 mu mol/L ADP-induced maximal platelet aggregation > 50%. In noncarriers of the CYP2C19*2/*3 mutant allele, Delta Agg(max) values after 5 and 20 mu mol/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 Delta Agg(max) after addition of 5 mu mol/L (25.8 +/- 16.8% versus 11.1 +/- 19.8%, P=0.001) and 20 mu mol/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 P2Y12 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.