A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary...

After percutaneous coronary intervention (PCI), the antiplatelet drug clopidogrel is frequently used to prevent stent thrombosis. A concern has been raised that atorvastatin may competitively inhibit the metabolism of the prodrug clopidogrel to its active metabolites by the cytochrome P450 3A4 (CYP3A4) enzyme, thereby potentially negating its antiplatelet effect. The 30-day rates of adverse cardiovascular events (composite of death, myocardial infarction, 11 unstable angina, stroke or transient ischemic attack, and repeat revascularization procedures) in unselected 12 patients prescribed clopidogrel after PCI as a function of their exposure to CYP3A4 inhibitors has not been fully resolved.

Using the administrative databases from the Province of Québec, we identified all patients in 1999 and 2000 who received an outpatient prescription for clopidogrel within 5 days of PCI with stenting. Using multiple logistic regression, we compared the odds ratios (OR) of the composite cardiovascular outcome within 30 days of the index PCI between patients prescribed drugs inhibiting CYP3A4 activity and those who were not. Event rates were adjusted for demographic variables, disease severity, associated comorbidities, and other medications.

The 2927 patients who were prescribed clopidogrel after PCI were included in our cohort. Of these, 727 were prescribed atorvastatin and 2200 were not. There were 33 (4.54%) adverse events in the group prescribed atorvastatin and 68 (3.09%) in the group not prescribed atorvastatin. The adjusted 30-day OR of the composite outcome was 1.65 (95% CI 1.07-2.54) in patients prescribed atorvastatin with clopidogrel compared to those not prescribed atorvastatin. Other drugs that are substrates for CYP3A4 (OR 1.56, 95% CI 1.02-2.37) and a delay in filling the clopidogrel prescription (OR 1.77, 95% CI 1.16-2.70) were also associated with a higher risk. Sex, previous hospitalizations for unstable angina or myocardial infarction, aspirin use, or a history of revascularization (PCI or coronary artery bypass graft) in the 6 months before the index procedure was not statistically associated with adverse outcomes.

After coronary stenting, a delay in filling the prescription for clopidogrel as well as prescriptions for drugs inhibiting CYP3A4 enzyme activity was associated with adverse cardiovascular events. However, because of the limitations of observational study designs, the clinical significance of these putative drug interactions remains uncertain but merits further investigation.