Epidemiology of CYP3A4‐Mediated Clopidogrel Drug–Drug Interactions and Their Clinical Consequences

Abstract

SUMMARYAims: Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity. Methods: Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding. Results: In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group. Conclusions: No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

“…In addition, sex, age, smoking, drinking or other biomedical indexes were not associated with CR in ischemic stroke patients. Concomitant use of lipophilic statins (atorvastatin, simvastatin) and calcium-channel blockers were suspected to be associated with a diminished antiplatelet response, which is likely due to a shared metabolic pathway via the CYP2C19 or CYP3A4 isoenzymes [41,42] . Therefore, we evaluated the association between CR and the co-administration of statins, anti-hypertensive drugs and other co-administered drugs that might affect the efficacy of clopidogrel according to previous reports [43,44] .…”

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

“…Atorvastatin inhibits CYP3A4‐mediated activation of clopidogrel but there is no consistent evidence of harm for patients with cardiovascular disease using the combination of atorvastatin and clopidogrel (reviewed by Bates et al ). However, in a population‐based pharmacoepidemiological study with patients on clopidogrel treatment, thrombosis complications leading to hospitalizations were more prevalent and the hospitalizations due to bleedings less prevalent in the atorvastatin group when compared with the control group . Our results strengthen the conclusion that CYP3A4 is inhibited by atorvastatin treatment, potentially leading to drug–drug interactions.…”

Prevention of gastric mucosal injury induced by anti‐platelet drugs by famotidine

“…Therefore, CYP3A isozymes also play an important role in the activation of clopidogrel. In fact, clinical consequences of potential drug–drug interactions of clopidogrel with drugs affecting CYP3A isozymes activity was shown in patients receiving concomitant CYP3A isozymes inhibitor, such as atorvastatin, and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality …”

“…The conversion of clopidogrel to the active metabolite is required to be a two‐step, CYP‐dependent process. In these steps, CYP2C19, 1A2, 2B6, 2C9, and 3A4/5 may be involved in the activation of clopidogrel . Of CYP enzymes, recently, the antiplatelet activity of clopidogrel was reported to depend on CYP2C19 genotypes, as well as other CYP enzymes .…”

“…In these steps, CYP2C19, 1A2, 2B6, 2C9, and 3A4/5 may be involved in the activation of clopidogrel . Of CYP enzymes, recently, the antiplatelet activity of clopidogrel was reported to depend on CYP2C19 genotypes, as well as other CYP enzymes . On the other hand, famotidine does not attenuate the active metabolism of clopidogrel because famotidine does not influence the activity of CYP2C19 21 .…”