Published online before print October 20, 2003, doi: 10.1161/01.CIR.0000099507.32936.C0
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(Circulation. 2003;108:2195.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Effects of Statins on Platelet Inhibition by a High Loading Dose of Clopidogrel
From Medizinische Klinik, Klinikum rechts der Isar und Deutsches Herzzentrum, Technische Universität München, Germany.
Correspondence to Meinrad Gawaz, MD, 1 Medizinische Klinik und Deutsches Herzzentrum, Technische Universität München, Klinikum rechts der Isar, Ismaninger Straße 22, 81675 München, Germany. E-mail meinrad.gawaz{at}med1.med.tu-muenchen.de
Received March 7, 2003; de novo received July 14, 2003; revision received September 16, 2003; accepted September 18, 2003.
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Abstract |
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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 µmol/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.
Key Words: platelets • stents • coronary disease • prevention
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Introduction |
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Rapid and effective antiplatelet medication is a cornerstone of therapy for patients undergoing percutaneous coronary intervention (PCI). Combined antiplatelet treatment with aspirin and an ADP receptor blocker (ticlopidine or clopidogrel) has reduced stent thrombosis significantly in patients undergoing coronary stenting.1–3 Clopidogrel is an inactive prodrug that requires liver metabolism and activation by cytochrome P-450. Patients with symptomatic coronary artery disease who are undergoing coronary stenting are frequently given clopidogrel in conjunction with statins, which are also metabolized by cytochrome P-450. Recently, experimental studies showed that other drugs metabolized by cytochrome P-450 interfere with clopidogrel metabolism.4,5 Other studies have suggested that the antiplatelet activity of clopidogrel is diminished in patients taking the HMG-CoA reductase inhibitor atorvastatin but not by other statins such as pravastatin.6 Thus, potential drug interactions between discrete statins and clopidogrel might occur that could limit the efficacy of antiplatelet treatment and have a significant clinical impact. Usually, clopidogrel therapy is initiated with a loading dose of 300 mg in patients undergoing coronary stenting.7 Previously, our group8,9 and others10 showed that increasing the loading dose of clopidogrel substantially accelerates platelet inhibition and maximizes inhibitory effects within the first 4 hours after administration of 600 mg.9 Thus, an initial clopidogrel dose of 600 mg may circumvent potential interactions with statins in patients undergoing PCI. We prospectively analyzed the consequence of concomitant medication of statins and a high loading dose of clopidogrel on platelet inhibition in patients scheduled for coronary intervention.
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Methods |
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We studied 77 patients with stable coronary artery disease. The Institutional Ethics Committee of the Technische Universität München approved the study, and all patients were given extensive information and provided written consent before enrollment. None of the patients received any statin before the study. All patients received regular aspirin therapy (100 mg/d). Patients were randomized to receive 20 mg/d atorvastatin (n=7), fluvastatin (n=7), lovastatin (n=20), pravastatin (n=20), or simvastatin (n=6) or 0.3 mg/d cerivastatin (n=5) or placebo (n=12) 24 hours before clopidogrel administration. Clopidogrel therapy was initiated with a loading dose of 600 mg followed by 75 mg twice per day before coronary angiography. Venous blood samples for platelet analysis were drawn before and 2 and 4 hours after clopidogrel administration and before coronary angiography. Platelet function was evaluated ex vivo by optical aggregometry as described previously9 with platelet-rich plasma (PRP) using 2 concentrations of ADP (5 and 20 µmol/L). The primary comparison of the study was between 2 chemically different statins: the hydrophilic statin pravastatin, which is not metabolized by cytochrome P-450, and the lipophilic statin lovastatin, which is a substrate of CYP3A4 and thus might interfere with clopidogrel comedication. Analyses of the other statins with the lower sample size were confirmatory.
Statistical Analysis
Sample size calculation was based on the primary end point being compared by a 2-sided Wilcoxon test. Pilot studies showed changes in aggregation within 4 hours (from before to after ADP) of 55%. For the statin group, a corresponding aggregation of 29% was assumed because this is a common lower borderline for aggregation. This resulted in a difference of 26% to be detected. A common SD of 22% was assumed. To achieve a power of 90% and a significance level of 5%, a sample size of 20 per group was required. Sample size calculation was performed with nquery for Windows (version 5.0). Continuous variables are reported as mean±SEM. Values of platelet aggregation are demonstrated as percentage of maximal possible aggregation. Continuous variables were tested for interindividual differences by Mann-Whitney U test or Kruskal-Wallis H test. Categorical variables were compared with 
2 tests. A value of P<0.05 was regarded as significant.
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Results |
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There were no differences in age, gender, cardiovascular risk factors, or medication that might have interfered with platelet function or with cytochrome P-450 metabolism (Table). Inhibition of 5 µmol/L (Figure) or 20 µmol/L (data not shown) ADP-induced platelet aggregation by 600 mg of clopidogrel was similar in patients receiving statins and those not receiving concomitant statin therapy. The degree of platelet inhibition 2 and 4 hours after 600 mg clopidogrel administration was not significantly altered by any of the tested statins (Figure).
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and 2 (
) and 4 (•) hours after 600-mg clopidogrel administration in patients receiving various statins or placebo. Any statin represents mean value of all tested statins. |
Discussion |
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The present study demonstrates that coadministration of HMG-CoA reductase inhibitors with clopidogrel does not influence platelet inhibition in patients with stable coronary artery disease scheduled for elective PCI, provided that a high loading dose of clopidogrel is applied. Recently, it has been reported that clopidogrel given in a loading dose of 300 mg is less effective in inhibiting platelet aggregation when administered with atorvastatin, another substrate of cytochrome P-450-3A4 (CYP3A4).6 CYP3A4 might also activate clopidogrel, which suggests that the lipophilic substance atorvastatin decreases the metabolic conversion of clopidogrel to its active metabolite and thus reduces the degree of platelet inhibition.6 In contrast, the hydrophilic pravastatin did not alter the degree of platelet inhibition after clopidogrel administration.6 Previously, we8,9 and others10 showed that increasing the loading dose of clopidogrel to 600 mg accelerates platelet inhibition, with a maximal suppression of ADP-induced platelet aggregation within 4 hours. A potential interference of statins with clopidogrel that affects platelet inhibition in patients undergoing PCI or in those with acute coronary syndrome may have a substantial clinical impact. Thus, we tested whether statins also attenuate platelet aggregation when a high (600 mg) loading dose of clopidogrel is applied. The present results show that platelet inhibition by 600 mg of clopidogrel was not modified by concomitant statin treatment, regardless of the type of statin used. We did not find any significant influence of either lipophilic or hydrophilic statins on platelet inhibition by clopidogrel, which is consistent with a previous report in which a loading dose of 300 mg of clopidogrel was administered.11 The present study cannot rule out the possibility that long-term administration of statins may interfere with clopidogrel. However, recent data from the Interaction of Atorvastatin and Clopidogrel Trial12 show that atorvastatin does not affect the antiplatelet properties of clopidogrel in patients treated with statins for 30 days. Furthermore, on the basis of the present data, we cannot exclude the possibility that increasing the dosage of distinct statins may have an impact on clopidogrel-dependent platelet inhibition. Nevertheless, a high loading dose of clopidogrel may circumvent any potential interference of drugs metabolized by CYP3A4 for the benefit of patients undergoing PCI as a result of an optimized platelet inhibition therapy.13
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Acknowledgments |
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Supported by a grant from the Deutsche Forschungsgemeinschaft (Ga 381/4-1) and by the Graduate Program 438 Vascular Biology in Medicine. The authors are indebted to Sandra Kerstan, Laura Weninger, and Kirsten Langenbrink for expert technical assistance.
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References |
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1. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001; 103: 1967–1971.
2. Schömig A, Neumann FJ, Kastrati A, et al. A randomised comparison of antiplatelet and anticoagulant therapy after the placement of coronary artery stents. N Engl J Med. 1996; 334: 1084–1089.
3. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol. 2002; 39: 9–14.
4. Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome p450 3A and is inhibited by atorvastatin. Drug Metab Dispos. 2003; 31: 53–59.
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