Epidemiology of CYP 3A4‐Mediated Clopidogrel Drug–Drug Interactions and Their Clinical Consequences

Summary Aims 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 CYP 3A4 activity. Methods Co‐administrations of clopidogrel together with well‐established CYP 3A4 inhibitors, CYP 3A4 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 CYP 3A4 inhibitors, CYP 3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 ( P  < 0.001) for CYP 3A4 inducer users and 0.74 ( P  = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP 3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P  < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP 3A4 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 CYP 3A4 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. CYP 3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.