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.

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.

CONCLUSION: 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.