Thrombosis Research 126 (2010) e397–e399 Contents lists available at ScienceDirect is l se written informed consent for participation. Blood samples for testing platelet reactivity were drawn in the catheterization laboratory from a six-French arterial sheath before the atorvastatin or rosuvastatin after coronary stenting for NSTE ACS have similar effects on lipidic and inflammatory parameters and on clopidogrel response. Previous studies have raised the potential of a antiplatelet therapy: aspirin 75 mg and 150 mg clopidogrel daily and randomized 1:1 to atorvastatin 80 mg or rosuvastatin 20 mg by sealed envelopes. Platelet tests were performed one month after hospital discharge at clinical follow-up (T1). The study protocol was approved by the ethics committee of our institution, and patients gave Letter to the Editors-in-Chief Comparison of rosuvastatin and atorvastatin on clopidogrel response and lipidic and inflammatory parameters after coronary stenting for acute coronary syndrome: The prospective, randomized OSCAR study (optimal statin therapy with clopidogrel after coronary revascularisation) Introduction Dual oral antiplatelet therapy is currently the “gold standard” therapy in patients undergoing coronary stenting after Non ST Elevation Acute Coronary Syndrome (NSTE ACS) [1–3]. Several studies have demonstrated a broad variability of biological response to clopidogrel and its clinical relevance [4]. Mechanisms underlying this variability of response remain controversial and multiple factors are involved including metabolic and genetic factors [4]. Clopidogrel is a prodrug, whichmust bemetabolized in the liver to generate an activemetabolite and acquire its antiplatelet properties. Accordingly, clopidogrel re- sponse has been related to the level of activation of the CYP450 [5] and loss of function allele of CYP2C19 has been associated with lower response to clopidogrel in both healthy volunteers and patients [6] and worse clinical outcomes in clopidogrel treated patients [7]. In addition, medicationsmetabolized by CYP450 such as omeprazole or atorvastatin have been shown to influence clopidogrel effect [8,9] potentially negating its antiplatelet properties.Metabolismof rosuvastatin, a recent developed statin does not involve CYP450 pathway [10]. We therefore designed a prospective, randomized study to compare the influence of high doses of a CYP3A4 metabolized statin (atorvastatin) and a non- CYP3A4 metabolized statin (rosuvastatin) on antiplatelet effect of high 150 mg maintenance dose of clopidogrel in patients undergoing coronary stenting for NSTE ACS. Consecutive patients admitted for NSTE ACS in our institution were eligible for this prospective study if they had undergone successful coronary stenting. The design of the study is described in Fig. 1. Patients received oral loading doses of 250 mg aspirin and 600 mg clopidogrel at least 12 hours before stenting. Initial platelet parameters were assessed between 12 and 24 hours after the loading dose (T0). Patients were discharged with the following dual Thrombos j ourna l homepage: www.e coronary angiography and repeated after one month from a venous catheter. - To determine the VAsodilator-Stimulated Phosphoprotein (VASP) phosphorylation state of whole blood, we used a standardized flow cytometric assay [Platelet VASP®; Diagnostica Stago (Biocytex), Asnières, France], which is an adaptation of themethod of Schwarz 0049-3848/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2010.08.005 previously described [11]. A platelet reactivity index (PRI VASP) was calculated from the median fluorescence intensity of samples incubated with Prostaglandin E1 or Prostaglandin E1 and ADP according to the formula: PRI VASP=[(MFI (PGE1)-MFI (PGE1+ADP)/ MFIPGE1]×100. - For assessment of ADP-induced platelet aggregation (ADP-Ag), platelets were stimulated with ADP (10 μmol.L-1) and aggregation was assessed with a PAP4 Aggregometer (Biodata Corporation, Wellcome, Paris, France). Aggregation was expressed as the maximal percentage change in light transmittance from baseline with Platelet Poor Plasma as reference. Here we report data on maximal intensity of ADP-Ag. The primary endpoint of the study was clopidogrel response one month after hospital discharge assessed with the PRI VASP and post-treatment platelet reactivity with ADP-induced platelet aggregation (ADP-Ag). The secondary biological endpoint was efficacy of the statin on lipidic and inflammatory parameters. Clinical follow-up was performed at 1 month by clinical visit to assess occurrence of recurrent ischemic event, bleeding and lipid-lowering therapy tolerance. 138 consecutive patients were prospectively included and random- ized to rosuvastatin 20 mg (n=69) or atorvastatin 80 mg (n=69). Baseline characteristics were similar between both groups. Baseline levels of ADP-Ag and PRI VASP (T0) were not significantly different between patients randomized to rosuvastatin or atorvastatin. After one month of statin therapy (T1), patients receiving rosuvastatin and atorvastatin had no difference for platelet response to clopidogrel as assessed with the PRI VASP: 44.6±2.5% vs 46±2.3 % respectively, p=0.66 and ADP-Ag: 53.3±1.7% vs 50±2.1% respectively , p=0.23 (Fig. 2A and B). On lipidic parameters, the effect of rosuvastatin and atorvastatin were not significantly different for LDL cholesterol (2.2± 0.14 mmol/L and 2.1±0.08 mmol/L respectively, p=0.22), HDL cho- lesterol (1.1±0.05 mmol/L and 1±0.03 mmol/L respectively, p=0.20) (Fig. 3A and B). The number of patients reaching the target LDL cholesterol of less than 2.59 mmol/L was similar in both groups: 74% (n=51) with rosuvastatin and 71% (n=49) with atorvastatin. P=0.85. For inflammatory parameter such as us CRPwe did not observe any significant difference between patients randomized to rosuvastatin or atorvastatin: 3.3±0.6 mg/L and 3.8±0.6 mg/L respectively, p=0.56. The clinical follow-up was performed in all patients. We did not observe any significant difference between both groups neither for ischemic or bleeding events, nor for side effects related to statin therapy. The present study suggests that high dose maintenance of Research v ie r.com/ locate / th romres drug-drug interaction between clopidogrel and CYP3A4 metabolized statin, primarily atorvastatin, in reducing the antiplatelet activity of clopidogrel [9]. Controversy, our present study did not suggest any impaired clopidogrel response in patients treated with atorvastatin. These differences might be explained by the high clopidogrel mainte- nance dose used in our study, which probably reduces the interaction between drugs increasing active metabolite production. We used this maintenance dose according to the recently presented results of the CURRENT OASIS 7 trial, suggesting benefit of higher 150 mg of clopidogrel after PCI for NSTE ACS [12]. In agreement with our results, Patients undergoing coronary stenting for non ST elevation acute coronary syndrome Aspirin 250 mg + 600 mg Clopidogrel T0: ADP-induced aggregation Platelet Reactivity Index VASP Aspirin 75 mg + 150 mg Clopidogrel Daily Randomization Rosuvastatin 20 mg Atorvastatin 80 mg One month Follow up T1 ADP-induced aggregation Platelet Reactivity Index VASP Fig. 1. Design of the study. p=0.23 100 A p=0.22 6 8 A te ro l (m mo l/L ) e398 Letter to the Editors-in-Chief 75 g (% ) Rosuvastatin Atorvastatin Rosuvastatin Atorvastatin 0 25 50 B A DP - A p=0.66 0 20 40 60 80 PR IV AS P (% ) Fig. 2. A and B Clopidogrel response assessed with ADP-induced platelet aggregation (ADP-Ag) and PRI VASP according to statin therapy. Rosuvastatin Atorvastatin Rosuvastatin Atorvastatin 0 2 4 B LD L Ch ol es p=0.20 0.0 0.5 1.0 1.5 2.0 2.5 HD L Ch o le st er ol (m m ol /L ) Fig. 3. A and B LDL cholesterol and HDL cholesterol onemonth after NSTE ACS according to statin therapy (mmol/L). e399Editors-in-Chief several studies using varying methods to measure platelet inhibition with clopidogrel have demonstrated no significant decrease in the antiplatelet efficacy of clopidogrel when coadministered with statins, including atorvastatin [13–15]. Moreover, data from a post hoc analysis of the CREDO trial and CHARISMA study suggested no adverse effect for clinical outcome in patients with clopidogrel and atorvastatin coad- ministration [16,17]. Few data are available about the effects of rosuvastatin on platelet inhibition by clopidogrel: in healthy volunteers, no effect on clopidogrel potency as assessed by ADP-Ag could be observed [18]. In another study [19], Riondino et al. found no difference in ADP induced platelet aggregation after PCI in patients taking rosuvastatin or atorvastatin,while treatedbyclopidogrel.More recently, a small study by Malmström et al. [20] suggested no attenuation of clopidogrel effect with atorvastatin in comparison with rosuvastatin. However, in these studies, doses of statins and clopidogrel were lower, respectively rosuvastatin 10 mg, atorvastatin 20 mg and clopidogrel 75 mg and did not include high risk patients such as NSTE ACS patients. Moreover, in these studies, the authors did not use the PRI VASP, which is the most specific test for assessment of clopidogrel response. Using this test, our present study suggested that inhigh riskpatients, highdose of atorvastatin has no negative effect on high maintenance dose of clopidogrel, while providing same benefit on cholesterol lowering. However, the sample size of this present biological study is relatively small anddoesnot allow for definitive conclusionsabout the interaction. Therefore, larger randomized clinical studies are required. Conflict of interest None. Financial disclosure None. References [1] Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators FT. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–9. [2] Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST- segment elevation. N Engl J Med 2001;345:494–502. [3] Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. [4] Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in Individual Responsiveness to Clopidogrel Clinical Implications, Management, and Future Perspectives. J Am Coll Cardiol 2007;49:1505–16. [5] LauWC, Gurbel PA,Watkins PB, Neer CJ, Hopp AS, Carville DG, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004;109(2):166–71. [6] Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006;108(7):2244–7. [7] Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373(9660):309–17. [8] Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51(3):256–60. [9] Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003;107(1):32–7. [10] White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol 2002;42(9):963–70. [11] Schwarz UR, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets-definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 1999;82:1145–52. [12] Mehta S. Organisation to Assess Strategies for Ischemic Syndromes (OASIS)-7 Results, Oral Communication. Barcelona: ESC Congress; 2009. [13] Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5weeks in patients with acute coronary syndromes. Circulation 2004(109):1335–8. [14] Gorchakova O, von Beckerath N, Gawaz M, Mocz A, Joost A, Schömig A, 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;25:1898–902. [15] Serebruany VL, Midei MG, Malinin AI, Oshrine BR, Lowry DR, Sane DC, et al. Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study. Arch Intern Med 2004;164:2051–7. [16] Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, et al. Clopidogrel for theReduction of Events DuringObservation Investigators. Circulation 2003;108:921–4. [17] Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K, et al. CHARISMA Investigators. J Am Coll Cardiol 2007;50:291–5. [18] Mach F, Senouf D, Fontana P, Boehlen F, Reber G, Daali Y, et al. Not all statins interfere with clopidogrel during antiplatelet therapy. Eur J Clin Invest 2005;35(8):476–81. [19] Riondino S, Petrini N, Donato L, Torromeo C, Tanzilli G, Pulcinelli FM, et al. Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients. J Thromb Thrombolysis 2009;28(2):151–5. http://www.ncbi.nlm.nih.gov/pubmed/18636229. [20] Malmström RE, Ostergren J, Jørgensen L, Hjemdahl P. for the CASTOR investigators. Influence of statin treatment on platelet inhibition by clopidogrel - a randomized comparison of rosuvastatin, atorvastatin and simvastatin co-treatment. J InternMed 2009 Nov;266(5):457–66. Raphaël Poyet Département de Cardiologie, CHU Timone, Marseille, F-13385 France Thomas Cuisset Département de Cardiologie, CHU Timone, Marseille, F-13385 France Inserm, U626, Marseille, F-13385 France Faculté de Médecine, Marseille, F-13385 France Corresponding author. Département de Cardiologie, CHU Timone, Marseille, F-13385 France. Tel.: +33 49185794; fax: +33 491254336. E-mail address:
[email protected]. Corinne Frere Inserm, U626, Marseille, F-13385 France Laboratoire d'Hématologie, CHU Timone, Marseille, F-13385 France Faculté de Médecine, Marseille, F-13385 France Jacques Quilici Département de Cardiologie, CHU Timone, Marseille, F-13385 France Bénédicte Gaborit Inserm, U626, Marseille, F-13385 France Laboratoire d'Hématologie, CHU Timone, Marseille, F-13385 France Faculté de Médecine, Marseille, F-13385 France Pierre-Julien Moro Département de Cardiologie, CHU Timone, Marseille, F-13385 France Laurence Camoin Laboratoire d'Hématologie, CHU Conception, Marseille, F-13385 France Pierre-Emmanuel Morange Inserm, U626, Marseille, F-13385 France Laboratoire d'Hématologie, CHU Timone, Marseille, F-13385 France Faculté de Médecine, Marseille, F-13385 France Marie-Christine Alessi Inserm, U626, Marseille, F-13385 France Laboratoire d'Hématologie, CHU Timone, Marseille, F-13385 France Faculté de Médecine, Marseille, F-13385 France Jean-Louis Bonnet Département de Cardiologie, CHU Timone, Marseille, F-13385 France 25 June 2010 Letter to the Comparison of rosuvastatin and atorvastatin on clopidogrel response and lipidic and inflammatory parameters after coronary stenting for acute coronary syndrome: The prospective, randomized OSCAR study (optimal statin therapy with clopidogrel after coronary revascularisation) Introduction Conflict of interest Financial disclosure References