Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement

Summary

Early studies suggested interactions between statins and clopidogrel. Based on the outcome and platelet data, there is now huge evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with 600-mg loading are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P4503A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63 and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 μM was similar irrespective of statin treatment at baseline (p=0.968). RPA at CA was 46.2 ± 16.8% in patients without statin (n=682), 45.5 ± 17.0% in patients with atorvastatin (n=255), 45.8 ± 16.3% with simvastatin (n=335), 47.3 ± 14.9% with fluvastatin (n=42) and 45.9 ± 16.2% with pravastatin (n=81; p=0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n=553), the one-year incidence of death, myocardial infarction and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p=0.645).Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.

Keywords

Clinical trials - antiplatelet drugs - clopidogrel - statins - drug-drug interaction - percutaneous coronary intervention

• References

• 1 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.
• 2 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
• 3 Neubauer H, Gunesdogan B, Hanefeld C. et al. Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function – a flow cytometry study. Eur Heart J 2003; 24: 1744-1749.
• 4 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.
• 5 Mitsios JV, Papathanasiou AI, Rodis FI. et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004; 109: 1335-1338.
• 6 Müller I, Besta F, Schulz C. et al. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation 2003; 108: 2195-2197.
• 7 Gorchakova O, von Beckerath N, Gawaz M. et al. Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting. Eur Heart J 2004; 25: 1898-1902.
• 8 Serebruany VL, Malinin AI, Callahan KP. et al. Statins do not affect platelet inhibition with clopidogrel during coronary stenting. Atherosclerosis 2001; 159: 239-241.
• 9 Serebruany VL, Midei MG, Malinin AI. et al. Absence of interaction between atorvastatin or other statins and clopidogrel. Arch Intern Med 2004; 164: 2051-2057.
• 10 Vinholt P, Poulsen TS, Korsholm L. et al. The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease. Thromb Haemost 2005; 94: 438-443.
• 11 Saw J, Steinhubl SR, Berger PB. et al. Lack of adverse clopidogrel-atorvastatin clinical interaction from ing dose regimen of clopidogrel. Consistently, our study does not suggest that statins metabolized by CYP3A4 (atorvastatin, simvastatin) curtail the beneficial effects of clopidogrel in PCI. Acknowledgements The EXCELSIOR study was supported by an unrestricted grant from Herz- Zentrum Bad Krozingen. The authors appreciate the invaluable technical assistance of Martina Siefer and Petra Enderle from the Laboratory of the Department of Clinical Pharmacology. secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003; 108: 921-924.
• 12 Mukherjee D, Kline-Rogers E, Fang J. et al. Lack of clopidogrel-CYP3A4 statin interaction in patients with acute coronary syndrome. Heart 2005; 91: 23-26.
• 13 Saw J, Brennan DM, Steinhubl SR. et al. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol 2007; 50: 291-295.
• 14 Wienbergen H, Gitt AK, Schiele R. et al. Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies. Am J Cardiol 2003; 92: 285-288.
• 15 Brophy JM, Babapulle MN, Costa V. et al. A pharmacoepidemiology study of the interaction between atorvastatin and clopidogrel after percutaneous coronary intervention. Am Heart J 2006; 152: 263-269.
• 16 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600 mg loading dose of clopidogrel in a large unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
• 17 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
• 18 Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/ American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J 2000; 21: 1502-1513.
• 19 Labarthe B, Theroux P, Angioi M. et al. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 2005; 46: 638-645.
• 20 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
• 21 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
• 22 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. A patient with stent thrombosis, clopidogrel-resistance and failure to metabolize clopidogrel to its active metabolite. Thromb Haemost 2005; 93: 789-791.
• 23 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004; 25: 1903-1910.
• 24 Bates ER, Lau WC. Controversies in antiplatelet therapy for patients with cardiovascular disease. Circulation 2005; 111: e267-271.
• 25 Kurihara A, Hagihara K, Kazui M. et al. In vitro metabolism of antiplatelet agent clopidogrel: Cytochrome P450 isoforms responsible for two oxidation steps involved in the active metabolite formation. Drug Metab Rev 2005; 37: 99
• 26 Hulot J-S, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006: 2244-2247.
• 27 Trenk D, Hochholzer W, Fromm MF. et al. Cytochrome P450 2C19*2 polymorphism diminishes periinterventional antiplatelet effect of clopidogrel in patients undergoing percutaneous coronary intervention. Eur Heart J 2007; 28 (Abstract Supplement): 14.
• 28 de Morais SM, Wilkinson GR, Blaisdell J. et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994; 269: 15419-15422.
• 29 Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Brit J Clin Pharmacol 2001; 52: 349-355.
• 30 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66. e69–16.