Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?

Abstract

Ith respect to antiplatelet therapy, randomized trials and their meta-analyses 1 indicate benefits of clopidogrel either as an alternative 2 or an adjunct3 to aspirin in some high-risk patients. Regarding the metabolic pathways of clopidogrel, the active thiol metabolite binds rapidly and irreversibly to platelet adenosine diphosphate (ADP) receptors, thus inhibiting platelet aggregation. 4 Clopi- dogrel, a thienopyridine, is a platelet ADP-receptor blocker that is known to be beneficial during and after coronary stenting.2-5 Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. Results of in vitro studies in human liver microsomes and recombinant cytochromes P450 have shown that several cytochromes are involved in the oxidative metabolism of clopidogrel.6 In randomized trials of secondary and primary prevention of cardiovascular disease and their meta-analyses, 7 statins reduce risks of myocardial infarction, stroke, and cardiovas- cular death. Recently, in a randomized trial in patients undergoing percutaneous coronary intervention,8 statins have been shown to reduce the incidence of major adverse coro- nary events, especially among the subgroups of diabetics and those with multivessel disease. In these high-risk patients, the National Cholesterol Education Program III guidelines rec- ommend statin therapy to achieve low-density lipoprotein (LDL) goals of less than 100 mg/dL.9 Of the 5 marketed statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), four (atorvastatin, fluvastatin, lovastatin, and simvastatin) are also metabolized by the cytochrome P450 pathway.10 Thus, in patients receiving coronary stents, both clopi- dogrel and statin therapy are likely to contribute to beneficial effects on subsequent cardiovascular disease. A recent report has raised the possibility that the ability of clopidogrel to affect platelets is inhibited by atorvastatin. 11 We have a number of concerns about the validity of these findings and therefore believe the totality of evidence to be far from complete and not consistent. In that study, the sample size was small (n44), patient selection was poorly defined, no control for the presence of medications affecting CYP 450 3A4 pathway was performed before initiation, and the data were retrospective and non-randomized. Using a single method to assess platelet function was also unconventional. Furthermore, data from the larger retrospective Plavix Reduc- tion Of New Thrombus Occurrence (PRONTO) trial com- pared platelet inhibition with clopidogrel in 100 patients undergoing coronary intervention who also received statins. 12 In PRONTO, there was no evidence of any specific deleteri- ous interaction between clopidogrel and atorvastatin in terms of platelet activity. The analysis showed that only 4 of 25 patients in the atorvastatin treated group did not exhibit sustained platelet inhibition on days 2 and 5 after treatment with clopidogrel and aspirin. A similar pattern was observed in 2 of 9 patients treated with fluvastatin and 1 of 6 patients treated with pravastatin, neither of which is metabolized by the cytochrome P450 3A4 pathway. Finally, of perhaps even