Influence of amlodipine on antiplatelet effect of clopidogrel in patients treated with percutaneous coronary intervention: result of the randomized, prospective, two-period, crossover, ACCEL-CCB trial

초록

Background: Although amlodipine has a potential to reduce clopidogrel bioactivation in vivo through the CYP3A4 enzyme, previous studies have shown the controversial results in terms with this drug-drug interaction. ACCEL-CCB was performed to confirm the influence of amlodipine on antiplatelet effect of clopidogrel in PCI-treated patients.Methods: We recruited PCI-treated patients (n=40) who had been treated for at least 6 months with clopidogrel (75 mg/day), aspirin (100 mg/day) plus rosuvastatin. Patients were randomly assigned to receive either daily 5 mg amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Antiplatelet effect was measured with VerifyNow P2Y12 assay. The primary endpoint was P2Y12 Reaction Units (PRU). Prevalence of high platelet reactivity (HPR: PRU >208) was also evaluated.Results: During the study periods, there were no serious adverse events. Amlodipine maintenance decreased antiplatelet effect of clopidogrel compared with amlodipine discontinuation (176.8±75.4 vs. 150.7±65.5 PRU; Δ mean: 26.1 PRU; Δ 95% CI: 4.5 to 47.7 PRU; p=0.019). In addition, amlodipine maintenance the increased prevalence of HPR (35.0% vs. 12.5%; p=0.003). After amlodipine discontinuation, 27 patients (67.5%) showed the increase in clopidogrel responsiveness (Responder). By the ROC curve analysis, “PRU ≥160” was the optimal cutoff for predicting “Responder” (AUC: 0.760; 95% CI: 0.594 to 0.883; p=0.006). Multivariate analysis indicated that “PRU ≥160” was only independent covariate to determine “Responder” (OR: 62.014; 95% CI: 2.302 to 1670.328; p=0.014).Conclusion: ACCEL-CCB is the confirmative study to demonstrate the pharmacodynamic interaction between clopidogrel and amlodipine. Effect of amlodipine discontinuation on clopidogrel responsiveness was dependent on the level of on-amlodipine platelet reactivity.