Effects of Statins on Platelet Inhibition by a High Loading Dose of Clopidogrel

Abstract

Background-Recent studies suggested that some HMG-CoA reductase blockers might inhibit the antiplatelet activity of clopidogrel. Therefore, we analyzed how various statins together with a high loading dose of clopidogrel (600 mg) affect platelet aggregation. Methods and Results-Seventy-seven patients with stable angina scheduled for elective coronary stenting were studied.Patients were randomized to receive atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin (each 20 mg), cerivastatin (0.3 mg), or placebo, plus a high loading dose of 600 mg of clopidogrel. ADP-induced platelet aggregation (5 and 20 mol/L) was determined before and 2 and 4 hours after first clopidogrel administration. All patients were taking aspirin (100 mg/d) regularly. We found that none of the statins significantly influenced inhibition of platelet aggregation by clopidogrel. Conclusions-Concomitant use of statins with clopidogrel does not significantly inhibit antiplatelet activity, at least when clopidogrel is administered at a high loading dose of 600 mg.

Carboxylesterase 1-Mediated Drug–Drug Interactions between Clopidogrel and Simvastatin

“…Therefore, there has been considerable speculation and concern that potentially significant drug-drug interactions may occur when these two medications are co-administered. [2][3][4][5] A number of in vitro and in vivo studies have been conducted to determine the potential for the interactions with the primary focus upon the effect of simvastatin-mediated CYP3A inhibition on the activation of clopidogrel. 7,9,10) However, these studies have often led to inconsistent conclusions.…”

“…Moreover, the active metabolite simvastatin acid is further metabolized by CYP3A4, with less contribution from CYP3A5, CYP2C8 and uridine 5′-diphosphate (UDP) glucuronosyltransferase. 5) It has been suspected that the activation and antiplatelet effect of clopidogrel could be attenuated under conditions of co-administration with certain statins, such as simvastatin, since CYP3A4 is involved in the metabolism of both compounds and simvastatin is a potent CYP3A4 inhibitor. 5,6) Some in vitro and ex vivo studies showed that simvastatin significantly impaired the biotransformation and antiplatelet activity of clopidogrel via inhibition of CYP3A4 7,8) (Fig.…”

Existence of a Clinically Relevant Interaction between Clopidogrel and HMG‐CoA Reductase Inhibitors? Re‐evaluating the Evidence

“…Secondly, 5 studies (Serebruany et al 2001;Müller et al 2003;Saw et al 2003;Wienbergen et al 2003;Mitsios et al 2004) were not able to demonstrate any interaction between clopidogrel and statins. However, in 2 (Serebruany et al 2001;Wienbergen et al 2003) of those 5 studies, the patients were not categorized in ''patients recieving CYP3A4 metabolized statins'' versus ''patients receiving other statins''.…”

“…First of all, only Müller et al (2003) based their sample size on a power calculation. Consequently, an insufficient sample size could easily be an important issue affecting the results obtained in the remaining trials.…”

“…The clinical relevance of a potential drug-drug interaction between clopidogrel and statins, primarily atorvastatin, has recently been subject to much controversy and discussion (Lau et al 2000(Lau et al & 2003Serebruany et al 2001;Clarke & Waskell 2003;Müller et al 2003;Neubauer et al 2003;Saw et al 2003;Wienbergen et al 2003;Mitsios et al 2004). Clopidogrel is an antiplatelet agent that has a proven efficacy in decreasing the incidence of myocardial infarction, stroke, vascular death and coronary artery stent thrombosis in patients with cardiovascular atherosclerotic disease (CA-PRIE Steering Committee 1996; Bertrand et al 2000;The CURE trial Investigators 2001).…”