Portal de Periódicos da CAPES

Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?

2003; Lippincott Williams & Wilkins; Volume: 107; Issue: 12 Linguagem: Inglês

10.1161/01.cir.0000065125.50640.70

1524-4539

Victor L. Serebruany, Steven R. Steinhubl, Charles H. Hennekens,

Diabetes Treatment and Management

HomeCirculationVol. 107, No. 12Are Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAre Antiplatelet Effects of Clopidogrel Inhibited by Atorvastatin?A Research Question Formulated but Not Yet Adequately Tested Victor L. Serebruany, MD, PhD, Steven R. Steinhubl, MD and Charles H. Hennekens, MD, DrPH Victor L. SerebruanyVictor L. Serebruany From the Sinai Thrombosis Center, (V.L.S.), Baltimore, Md; the University of North Carolina (S.R.S.), Chapel Hill, NC; and the University of Miami (C.H.H.), Miami, Fla. , Steven R. SteinhublSteven R. Steinhubl From the Sinai Thrombosis Center, (V.L.S.), Baltimore, Md; the University of North Carolina (S.R.S.), Chapel Hill, NC; and the University of Miami (C.H.H.), Miami, Fla. and Charles H. HennekensCharles H. Hennekens From the Sinai Thrombosis Center, (V.L.S.), Baltimore, Md; the University of North Carolina (S.R.S.), Chapel Hill, NC; and the University of Miami (C.H.H.), Miami, Fla. Originally published1 Apr 2003https://doi.org/10.1161/01.CIR.0000065125.50640.70Circulation. 2003;107:1568–1569With respect to antiplatelet therapy, randomized trials and their meta-analyses1 indicate benefits of clopidogrel either as an alternative2 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 Clopidogrel, 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.6In randomized trials of secondary and primary prevention of cardiovascular disease and their meta-analyses,7 statins reduce risks of myocardial infarction, stroke, and cardiovascular death. Recently, in a randomized trial in patients undergoing percutaneous coronary intervention,8 statins have been shown to reduce the incidence of major adverse coronary events, especially among the subgroups of diabetics and those with multivessel disease. In these high-risk patients, the National Cholesterol Education Program III guidelines recommend 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.10Thus, in patients receiving coronary stents, both clopidogrel 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 (n=44), 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 Reduction Of New Thrombus Occurrence (PRONTO) trial compared platelet inhibition with clopidogrel in 100 patients undergoing coronary intervention who also received statins.12 In PRONTO, there was no evidence of any specific deleterious 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 greater relevance to this hypothesis, a similar pattern was observed in 12 of 75 patients who did not receive any statin. In total, about 20% of patients did not achieve profound platelet inhibition with clopidogrel, but this seemed unrelated to treatment with any statins. It is tempting to speculate that in certain patients, the burden of platelet activation is so excessive that usual treatment regimens are not sufficient to achieve even moderate platelet inhibition. Retrospective data from the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and Clopidogrel Unstable angina to prevent Recurrent Events (CURE) trials among subgroups of patients concurrently administered clopidogrel and statins indicated no clinically significant adverse interactions.Further data, especially from prospective studies, are necessary to test the hypothesis of potential interactions between clopidogrel and statins. One such study, INTERACTIONs of atorvastatin and clopidogrel therapy (INTERACT), has been designed to address this issue by serial measurements of various platelet characteristics by conventional as well as whole blood aggregometry, by point of care tests with 2 rapid analyzers, and by assessment of 14 receptors on the platelet surface by whole blood flow cytometry.At present, therefore, the suggested inhibition of antiplatelet effects of clopidogrel by atorvastatin represents a formulated but untested hypothesis awaiting further data, including those from prospective studies such as the ongoing INTERACTION trial. Thus, the hypothesis should remain a research challenge but not a clinical one.13 In the meantime, clinicians should continue using these drugs when indicated, alone and in combination, until a sufficient totality of evidence emerges to support any change in clinical practice.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Victor L. Serebruany, MD, Sinai Center for Thrombosis Research, Johns Hopkins University, Sinai Hospital, 2401 West Belvedere Ave, Research Building 209, Baltimore, MD 21215. E-mail [email protected] References 1 Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.CrossrefMedlineGoogle Scholar2 CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet. 1996; 348: 1329–1339.CrossrefMedlineGoogle Scholar3 CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med. 2001; 345: 494–502.CrossrefMedlineGoogle Scholar4 Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Disp. 2002; 30: 1288–1295.CrossrefMedlineGoogle Scholar5 Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. JAMA. 2002; 288: 2411–2420.CrossrefMedlineGoogle Scholar6 Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000; 84: 891–896.CrossrefMedlineGoogle Scholar7 Hebert PR, Gaziano JM, Chan KS, et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997; 278: 1660–1661.MedlineGoogle Scholar8 Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 287: 3215–3222.CrossrefMedlineGoogle Scholar9 Eidelman RS, Lamas GA, Hennekens CH. The new national cholesterol education program guidelines: clinical challenges for more widespread therapy of lipids to treat and prevent coronary heart disease. Arch Int Med. 2002; 162: 2033–2036.CrossrefMedlineGoogle Scholar10 Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Eur J Clin Pharm. 2001; 57: 357–364.CrossrefMedlineGoogle Scholar11 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.LinkGoogle Scholar12 Serebruany VL, Malinin AI, Kallahan KP, et al. Statins do not affect platelet inhibition with clopidogrel during coronary stenting. Atherosclerosis. 2001; 239: 259–261.Google Scholar13 Hennekens CH. Increasing global burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation. 1998: 97: 1095–1102.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By (2016) HMG coenzyme-A reductase inhibitors Meyler's Side Effects of Drugs, 10.1016/B978-0-444-53717-1.00850-7, (763-780), . Verstuyft C, Simon T and Kim R (2009) Personalized medicine and antiplatelet therapy: ready for prime time?, European Heart Journal, 10.1093/eurheartj/ehp295, 30:16, (1943-1963), Online publication date: 2-Aug-2009. Kim K, Park P and Park J (2008) Effect of CYP3A5*3 genotype on the pharmacokinetics and antiplatelet effect of clopidogrel in healthy subjects, European Journal of Clinical Pharmacology, 10.1007/s00228-008-0471-0, 64:6, (589-597), Online publication date: 1-Jun-2008. Feher G, Koltai K, Alkonyi B, Papp E, Keszthelyi Z, Kesmarky G and Toth K (2007) Clopidogrel resistance: Role of body mass and concomitant medications, International Journal of Cardiology, 10.1016/j.ijcard.2006.09.014, 120:2, (188-192), Online publication date: 1-Aug-2007. Plosker G and Lyseng-Williamson K (2007) Clopidogrel, Drugs, 10.2165/00003495-200767040-00013, 67:4, (613-646), . Meco J and Pintó X (2006) Controversia terapéutica: clopidogrel y estatinas, Clínica e Investigación en Arteriosclerosis, 10.1016/S0214-9168(06)73705-6, 18, (34-48), Online publication date: 1-Jun-2006. Walsh S, McClelland A and Adgey J (2006) Clopidogrel in the treatment of ischaemic heart disease, Expert Opinion on Pharmacotherapy, 10.1517/14656566.7.9.1109, 7:9, (1109-1120), Online publication date: 1-Jun-2006. Smit J, Ernst N, Slingerland R, Kolkman J, Suryapranata H, Hoorntje J, Dambrink J, Ottervanger J, Gosselink A, de Boer M and van't Hof A (2006) Platelet microaggregation inhibition in patients with acute myocardial infarction pretreated with tirofiban and relationship with angiographic and clinical outcome, American Heart Journal, 10.1016/j.ahj.2005.05.025, 151:5, (1102-1107), Online publication date: 1-May-2006. van Werkum J, Heestermans A, Deneer V, Hackeng C and ten Berg J (2006) Clopidogrel resistance: fact and fiction, Future Cardiology, 10.2217/14796678.2.2.215, 2:2, (215-228), Online publication date: 1-Mar-2006. Weinberger J (2005) Adverse Effects and Drug Interactions of Antithrombotic Agents Used in Prevention of Ischaemic Stroke, Drugs, 10.2165/00003495-200565040-00003, 65:4, (461-471), . Bezerra D and Bogousslavky J (2005) Clopidogrel: cardiologists' panacea or neurologists' headache?, Future Cardiology, 10.2217/14796678.1.5.579, 1:5, (579-590), Online publication date: 1-Sep-2005. Aursnes I (2005) Drugs that affect lipid metabolism Side Effects of Drugs Annual 28, 10.1016/S0378-6080(05)80466-0, (534-537), . Elkind M (2004) Secondary stroke prevention: Review of clinical trials, Clinical Cardiology, 10.1002/clc.4960271405, 27:S2, (25-35), Online publication date: 1-May-2004. Nawarskas J (2004) Clopidogrel-Statin Interaction, Cardiology in Review, 10.1097/01.crd.0000131190.50041.07, 12:5, (236-239), Online publication date: 1-Sep-2004. Xiao Z and Théroux P (2004) Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome, Journal of the American College of Cardiology, 10.1016/j.jacc.2003.10.071, 43:11, (1982-1988), Online publication date: 1-Jun-2004. Lappegard K, Hvassing T and Mollnes T (2004) Statin Drugs Do Not Affect Serum Complement Activation In Vitro, Scandinavian Journal of Immunology, 10.1111/j.0300-9475.2004.01439.x, 60:1-2, (178-183), Online publication date: 1-Aug-2004. Mobley J, Bresee S, Wortham D, Craft R, Snider C and Carroll R (2004) Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization, The American Journal of Cardiology, 10.1016/j.amjcard.2003.10.042, 93:4, (456-458), Online publication date: 1-Feb-2004. Damkier P (2003) Atorvastatin and Clopidogrel, Circulation, 108:13, (e96-e96), Online publication date: 30-Sep-2003. Steinhubl S and Rodgers J (2014) Clopidogrel's role in the management of atherosclerotic disease: a focus on acute coronary syndromes, Expert Review of Cardiovascular Therapy, 10.1586/14779072.1.4.507, 1:4, (507-522), Online publication date: 1-Nov-2003. Jneid H and Bhatt D (2005) Advances in antiplatelet therapy, Expert Opinion on Emerging Drugs, 10.1517/14728214.8.2.349, 8:2, (349-363), Online publication date: 1-Nov-2003. Wodlinger A and Pieper J (2003) The role of clopidogrel in the management of acute coronary syndromes, Clinical Therapeutics, 10.1016/S0149-2918(03)80211-4, 25:8, (2155-2181), Online publication date: 1-Aug-2003. Lévesque H (2003) Atorvastatine et clopidogrel. Une interaction médicamenteuse potentielle aux conséquences cliniques encore inconnues, La Revue de Médecine Interne, 10.1016/S0248-8663(03)00154-1, 24:8, (498-500), Online publication date: 1-Aug-2003. Tendera M and Wojakowski W (2003) Role of antiplatelet drugs in the prevention of cardiovascular events, Thrombosis Research, 10.1016/j.thromres.2003.08.003, 110:5-6, (355-359), Online publication date: 1-Jun-2003. &NA; (2003) Does atorvastatin inhibit the antiplatelet activity of clopidogrel?, Reactions Weekly, 10.2165/00128415-200309520-00007, &NA;:952, (3), Online publication date: 1-May-2003. &NA; (2003) Does atorvastatin inhibit the antiplatelet activity of clopidogrel?, Inpharma Weekly, 10.2165/00128413-200313880-00049, &NA;:1388, (21), Online publication date: 1-May-2003. April 1, 2003Vol 107, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000065125.50640.70PMID: 12668486 Originally publishedApril 1, 2003 KeywordsdrugsEditorialsplateletsstatinsPDF download Advertisement