Abstract 2125: Cytochrome P450 Polymorphisms and Response to Adjunct Cilostazol versus High Maintenance-dose Clopidogrel
Background: Carriers of the loss-of-function-CYP2C19 mutant allelles have significantly diminished platelet inhibition and a higher rate of ischemic events. We have demonstrated that adjunct cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) intensifies platelet inhibition as compared to high maintenance-dose (MD) clopidogrel of 150mg/day. Whether triple antiplatelet therapy can overcome the loss-of-function in patients with this genetic variant is unknown. The purpose of this study was to assess the impact of adjunct cilostazol on platelet inhibition according to CYP2C19 polymorphism.
Methods: Genotyping for CYP2C19 variant was performed after coronary stenting (n=107). Patients on clopidogrel were assigned to receive either adjunct cilostazol 100mg twice daily (triple group; n=55) or high MD clopidogrel (high-MD group; n=52). Platelet function was assessed immediately before procedure and after 30-day therapy by conventional aggregometry and VerifyNow. Primary end point was absolute change of ADP-induced maximal aggregation (Aggmax). High post-clopidogrel platelet reactivity (HPPR) was defined as Aggmax >50% with 5uM ADP.
Results: In non-carriers of CYP2C19 mutant allelle, the triple group (n=17) showed similar reductions of platelet reactivity as compared to the high-MD group (n=17). After 30-day therapy, the rate of HPPR also did not differ between the two groups (0% vs. 5.9%, P=0.317). In carriers of at least one CYP2C19 mutant allele, the triple (n=38) vs. high-MD group (n=35) achieved significantly higher changes of 5 or 20 uM ADP-induced Aggmax (25.7±14.7% vs. 14.8±14.9%, P=0.002; 26.2±13.1% vs. 13.9±12.0%, P<<med>0.001, respectively). Likewise, absolute changes of ADP-induced late aggregation were consistently greater in the triple vs. high-MD group. Change of P2Y12 reaction unit in the triple group showed more enhanced platelet inhibition compared to the high-MD group (114±78 vs. 69±63, P=0.019). After 30-day therapy, significantly fewer patients in the triple group had HPPR compared to the high-MD group (5.3% vs. 28.6%, P=0.010).
Conclusions: Contrary to high-MD clopidogrel of 150mg/day, adjunct cilostazol may overcome the loss-of-function effect of CYP2C19 mutant allele.