Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation

Abstract

Background-We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results-Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34Ϯ23, 58Ϯ15 (Pϭ0.027), 74Ϯ10 (Pϭ0.002), and 89Ϯ7 (Pϭ0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55Ϯ12 versus 42Ϯ12% platelet aggregation; Pϭ0.002), as did troleandomycin (78Ϯ18 versus 45Ϯ18% platelet aggregation; PϽ0.0003), whereas rifampin enhanced platelet aggregation inhibition (33Ϯ18 versus 56Ϯ20% platelet aggregation, Pϭ0.001). Conclusions-CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel. (Circulation. 2003;107:32-37.)Key Words: drugs Ⅲ pharmacology Ⅲ platelets Ⅲ statins C lopidogrel inhibits platelet aggregation. 1 It decreases the incidence of coronary artery stent thrombosis and is approved for reduction of myocardial infarction, stroke, and vascular death in patients with atherosclerotic vascular disease. [2][3][4] Clopidogrel is an inactive thienopyridine prodrug that requires in vivo conversion in the liver to an active metabolite that exerts its antiplatelet effect by forming an inactivating disulfide bond with the platelet P2Yac (P2Y12) adenosine diphosphate (ADP) receptor. [5][6][7][8] The P2Yac ADP receptor is a guanosine triphosphate (GTP)-coupled 7 transmembrane protein that mediates platelet aggregation by inhibiting adenyl cyclase. 8 In rats, it has been suggested that clopidogrel is activated by cytochrome P450 1A2, 6 whereas an analogue of clopidogrel, CS-747, is speculated to be activated by human cytochrome P450 3A4 (CYP3A4). 9 In humans, it is not known how clopidogrel is activated.Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor widely used to treat hypercholesteremia. It is metabolized by CYP3A4, 10 the most abundant cytochrome P450 in human liver. Patients with atherosclerotic disease are frequently treated for hypercholesteremia with both clopidogrel and atorvastatin or another statin.During the course of evaluating the effect of clopidogrel on platelet function using a novel bedside platelet aggregometer, it was noted that the antiplatelet activity of clopidogrel...

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…26,27 Lau and colleagues sought to determine whether variations in CYP3A4 activity contribute to clopidogrel variability in platelet inhibition by measuring platelet aggregation in 32 patients undergoing PCI with stenting and 35 healthy volunteers. 28 According to the degree of ADPinduced platelet aggregation, 22% and 16% were classified as clopidogrel nonresponders, 32% and 12% as low responders, and 47% and 72% as responders among patients and healthy volunteers, respectively; an inverse correlation was found between platelet activation and CYP3A4 activity (p = 0.003).…”

Comparison of Antiplatelet Effect and Tolerability of Clopidogrel Resinate With Clopidogrel Bisulfate in Patients With Coronary Heart Disease (CHD) or CHD-Equivalent Risks: A Phase IV, Prospective, Double-Dummy, Parallel-Group, 4-Week Noninferiority Trial

“…In subgroup analysis of patients using atorvastatin, which is lipophilic and is reportedly competes with clopidogrel for the cytochrome P450 system, 19,20 groups B and C showed superior P2Y 12 inhibition to group A. The difference in P2Y 12 inhibition between groups B and C did not exceed the predetermined limit of noninferiority ( Figure 6).…”

“…Some investigators have reported that differences in lipophilicity of statins may influence the antiplatelet action of clopidogrel. 19,20 We therefore decided to control the statin used to avoid potential controversy in interpretation of data.…”

Antiplatelet Agents for Stroke Prevention

“…Agents that inhibit the CYP3A4 and CYP2C19 enzyme systems can counter the action of clopidogrel by preventing its conversion to active metabolites from a pro-drug state. Atorvastatin has been demonstrated to attenuate the antiplatelet activity of clopidogrel in a dose-dependent manner [44]. However, this has not been shown to affect clinical events in the post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial [45].…”