Recently, practitioners may have begun receiving phone calls from pharmacies regarding a drug interaction between atorvastatin (Lipitor) and clopidogrel (Plavix). Is there a concern and what are the data? In a study published in Circulation in January 2003, Lau et al suggest, because of the inhibitory effects of atorvastatin on the cytochrome (CYP) 450 3A4 metabolic pathway, that clopidogrel, a pro-drug, is not converted to its active form. This small study was a non-randomized, observation of 44 patients with no mention of the presence of medications affecting CYP 450 pathways. They concluded that the use of a HMG CoA reductase inhibitor not metabolized by CYP 450 3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel. In a follow-up analysis, 19 volunteers who were randomized to receive either erythromycin or rifampin, two agents known to inhibit and induce CYP 450 3A4, respectively, showed no changes in platelet aggregation.
Of the 5 currently marketed HMG CoA reductase inhibitors, atorvastatin, fluvastatin, lovastatin and simvastatin are significantly metabolized through the CYP 450 pathways. Pravastatin undergoes significant first-pass effect without further significant effects on CYP 450. The clinical significance of this remains to be determined.
Numerous studies evaluating the efficacy of clopidogrel have not demonstrated any deleterious effects of co-administered statins. The PRONTO trial retrospectively evaluated 100 patients undergoing percutaneous coronary intervention (PCI). The outcome was to determine the ability of clopidogrel to prevent new thrombosis. These patients were also receiving statins. Analysis showed that only 4 of 25 patients in the atorvastatin did not maintain platelet inhibition on days 2 and 5 after treatment with clopidogrel and aspirin. These findings were similar to those with patients in groups receiving other statins. Data from the CAPRIE and CURE trials did not indicate any clinically significant adverse reactions among the subgroup populations either. CAPRIE compared clopidogrel to aspirin in patients at risk for ischemic events. Subgroup analysis of patients receiving statin therapy did not reveal any differences either. CURE evaluated the efficacy of clopidogrel in unstable angina. There were no differences between groups of patients receiving statins and those that were not.
Although the basic science seems interesting, clinical relevance remains to be elucidated. A current study, Interactions of Atorvastatin and Clopidogrel Therapy (INTERACT), may be able to hopefully shed light on this hypothesis. This study has been designed to address this issue by serial measurements of various platelet characteristics by conventional as well as whole blood aggregometry, by point of care tests with 2 rapid analyzers, and by assessment of 14 receptors on the platelet surface by whole blood flow cytometry. At present, therefore, the suggested inhibition of antiplatelet effects of clopidogrel by atorvastatin represents a formulated but untested hypothesis awaiting an answer. The positive benefits of statins have been proven time and again and to restrict this therapy without equally opposing data is not warranted.
References:
1. Lau WC, Waskell LA, Watkins PB et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32-37.
2. Gurbel PA, Cummings CC, Bell CR et al. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective stenting: The Plavix Reduction of New Thrombus Occurrence (PRONTO) trial. Am Heart J 2003; 145: 239-47.
3. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-1339.
4. The CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med 2001; 345: 494-502.