Clinical Analysis of the Pharmacological Interactions of Clopidogrel and Gender Differences: A Case-Control Study

Background: Clopidogrel is a prodrug metabolized by cytochrome P450-2C19. Drugs inhibiting this enzyme might reduce its antiplatelet activity. In order to reduce gastrointestinal bleedings, proton-pump inhibitors are usually prescribed in association with clopidogrel. The study aims at assessing the clinical importance of interactions between clopidogrel and inhibitors of CYP2C19. It also aims to evaluate any possible factors that may reduce the therapeutic efficacy of the drug. Particular attention was devoted to possible gender differences in responsiveness to treatment with clopidogrel or clopidogrel plus proton-pump inhibitors. This analysis is a retrospective case-control observational study carried out by the University Hospital of Ferrara. Methods: Subjects were patients who had received clopidogrel from 01-01-2008 to 31-12-2008. For them, we analysed hospital admissions and data of drug prescriptions relative to dispensing of drugs cytochrome P-450-2C19 inhibitors. Patients were subdivided into case and control groups based on the occurrence or not of cardiovascular or cerebrovascular secondary events during therapy with clopidogrel. Results: The study focused on 781 patients, 20.1% of which (n.157) experienced secondary effects. The mean age is 70 years old. Men (67% of the analyzed population) experienced secondary events more than women (OR 1.54; CI 95% 1.04 - 2.28; p < 0.03). 70% of patients took PPIs and we noticed that the risk of secondary events increased by 2.2% with respect to the remaining patients (20.77% vs 18.57%; OR 1.15; CI 0.78 - 1.70; p = NS). Among PPIs, lansoprazole is the most used. For this subgroup the risk is 5.2% higher (risk in those exposed of 23.75% vs 18.57% in those not exposed; or 1.37, 95% CI 0.92 - 2.03; p = NS). The interaction with PPIs is particularly interesting only among women, with a risk 6.3% higher (17.46% exposed, 11.11% non exposed). The risk remains the same among men. Conclusions: Analyzed data show an increase in cardiovascular or cerebral secondary events for patients exposed to PPIs. It also demonstrated the existence of differrent gender in therapeutic response to clopidogrel.