Relationship Between Statin Type and Responsiveness to Clopidogrel in Patients Treated with Percutaneous Coronary Intervention: A Subgroup Analysis of the CILON-T Trial

Abstract

Aim:To compare the responsiveness to clopidogrel in patients who were prescribed two different types of statins, atorvastatin vs. rosuvastatin, following percutaneous coronary intervention. Methods: A total of 915 patients were randomized according to the antiplatelet therapy strategy in the CILON-T trial. In this subgroup analysis, we included patients who took atorvastatin (20 mg/day, n = 295) or rosuvastatin (10 mg/day, n = 261) during the entire study period and underwent measurement of the P2Y12 reaction unit (PRU) values at both discharge and six months. We compared the P2Y12 reaction unit (PRU) values at six months and investigated the relationship between the genotypes of cytochrome P450 (CYP) 3A4, 3A5 and 2C19 with the PRU values at six months in both groups. Results: The baseline characteristics did not differ between the groups. There were no significant differences in the PRU values at discharge (atorvastatin 221.0±87.3 vs. rosuvastatin 217.1±84.7, p=0.59). However, the rosuvastatin group had higher PRU values than the atorvastatin group at six months (atorvastatin 226.4±79.3 vs. rosuvastatin 241.5±88.2, p = 0.033). In the genotype analysis, the number of CYP2C19 loss-of-function (LOF) alleles ( ＊ 2 or ＊ 3) was positively associated with a higher PRU value in both statin groups, and there were no significant interactions regarding the PRU values between the number of CYP 2C19 LOF alleles and the type of statin (p for interaction = 0.56). In the multivariate analysis, the use of rosuvastatin was a significant predictor of a PRU value of ＞273 (the highest tertile) (OR 1.67, 95% confidence interval 1.05-2.65, p= 0.031). Conclusions: Rosuvastatin is associated with high on-treatment platelet reactivity compared with atorvastatin following the coadministration of clopidogrel for six months. Further studies are therefore warranted to clarify the mechanism underlying this relationship.

Statins significantly reduce mortality in patients receiving clopidogrel without affecting platelet activation and aggregation: a systematic review and meta-analysis

“…We also detected the interaction between statin and clopidogrel on the aspect of lipid levels, and no statistic influence on lipids level was observed, except for TG level. Four randomized and placebo-controlled trials [20, 25, 38, 39] compared lipid variables in LDL-C and HDL-C between atorvastatin and rosuvastatin and no differences were found. Serebruany et al general described that TC levels were lower in patients treated with a statin than in those receiving no statin [10].…”

Influence of genetic co-factors on the population pharmacokinetic model for clopidogrel and its active thiol metabolite

“…Also, lower exposure to the active metabolite is observed when CYP2C19-metabolized PPIs, most notably omeprazole and esomeprazole, are co-administered with clopidogrel [ 18 ]. Other drugs, such as rosuvastatin, might have an influence on the higher on-treatment platelet reactivity [ 19 ].…”

Effectiveness and Safety of Clopidogrel Co‐administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study

“…Since then, a few observational studies found that clopidogrel increased adverse cardiac events in patients with a coronary artery stent and coadministered atorvastatin or simvastatin compared with rosuvastatin or pravastatin . However, in other clinical studies, there was a nonsignificant interaction between atorvastatin or simvastatin and clopidogrel, and evidence was not consistent that coadministering CYP3A4‐metabolized statins with clopidogrel increased the frequency of adverse events . Wang et al .…”

“…Thus, the possibility of drug–drug interactions (DDIs) between clopidogrel and these drugs has attracted increasing interest. However, these early studies were followed by many other clinical trials and observational studies showing conflicting results …”