Usefulness of High Clopidogrel Maintenance Dose According to CYP2C19 Genotypes in Clopidogrel Low Responders Undergoing Coronary Stenting for Non ST Elevation Acute Coronary Syndrome Thomas Cuisset, MD, PhDa,b,c,*, Jacques Quilici, MDa, William Cohen, MDb,c, Laurent Fourcade, MDd, Noémie Saut, PhDb,c, Mathieu Pankert, MDa, Bénédicte Gaborit, MDb,c, Patrizia Carrierie,f, Pierre-Emmanuel Morange, MD, PhDb,c, Jean Louis Bonnet, MDa, and Marie-Christine Alessi, MD, PhDb,c The cytochrome P450 (CYP) 2C19*2 loss-of-function allele has been associated with impaired clopidogrel response and worse prognosis in clopidogrel-treated patients. The benefit of tailored therapy according to platelet function test results remains unclear, and the potential effect of genotypes on this benefit has not been addressed in unstable patients. The present study was designed to evaluate the benefit of tailored therapy with a higher maintenance dose according to CYP2C19 genotypes in patients identified as nonresponders who underwent percutaneous coronary intervention for non–ST-segment elevation acute coronary syndromes. Three hundred forty-six consecutive patients were enrolled and received a loading dose of 600 mg, including 86 *2 carriers (13 homozygotes and 73 heterozygotes) and 260 *2 noncarriers. Clopidogrel response, assessed with platelet reactivity index vasoactive-stimulated phosphoprotein, was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p ! 0.01). Accordingly, the rate of clopidogrel nonresponse was higher in CYP2C19*2 allele carriers (53% vs 41%, p ! 0.04). All clopidogrel nonresponders (n ! 151), including 105 *2 noncarriers and 46 *2 carriers, received high 150-mg clopidogrel maintenance doses at discharge to overcome initial low response. After 1 month, high maintenance doses overcame clopidogrel low response in only 44% of the whole population and significantly less frequently in *2 carriers than in noncarriers (28% vs 50%, p ! 0.01). In conclusion, higher clopidogrel maintenance doses were able to overcome clopidogrel low response in fewer than half of clopidogrel low responders who underwent percutaneous coronary intervention for non-ST–segment elevation acute coronary syndromes. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers. Therefore, these patients might require alternative strategies with new P2Y12 blockers. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:760 –765) Dual-antiplatelet therapy with aspirin and clopidogrel is currently the gold standard for patients who undergo percutaneous coronary interventions (PCI) and/or those with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS).1–3 Several biologic studies have described a broad interindividual variability of biologic response to clopidogrel.4 The clinical relevance of such biologic variability has been demonstrated in different clinical settings for ischemic5–9 and bleeding complications.10,11 Mechanisms underlying this variability of response remain unclear and multifactorial.4 Clopidogrel is a Département de Cardiologie and cLaboratoire d’Hématologie, CHU Timone; bInserm, U626, Faculté de Médecine; dHIA Laveran; eUniversité Aix Marseille, IRD, UMR-S912; and fINSERM, U912 (SE4S), ORS PACA, Observatoire Régional de la Santé Provence Alpes Côte d’Azur, Marseille, France. Manuscript received March 16, 2011; revised manuscript received and accepted May 6, 2011. *Corresponding author: Tel: 33-49185794; fax: 33-491384726. E-mail address: [email protected] (T. Cuisset).

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.05.045

an inactive prodrug that requires several biotransformation steps.12–14 After intestinal absorption, clopidogrel biotransformation into its active metabolite is mainly mediated by the hepatic cytochrome P450 (CYP). Recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in unstable patients15 and an impaired prognosis in clopidogrel-treated patients.16,17 The benefit of tailored antiplatelet therapy based on platelet test results in patients identified as nonresponders is still questionable, and randomized studies are ongoing to evaluate its benefits in different settings.18 Doubling of the clopidogrel maintenance dose may represent an appealing alternative compared to a switch to new P2Y12 blockers in subjects with poor response profiles. Indeed, higher clopidogrel regimens for loading and maintenance doses have been used to overcome variability of response in biologic studies,19 –21 and recently, the clinical benefit of such doses has been suggested in patients who undergo PCI for ACS.22 However, the benefit of tailored therapy www.ajconline.org

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Methods

Table 1 Baseline characteristics Variable

Age (years) Women Body mass index (kg/m2) Hypertension Diabetes mellitus Smoker Dyslipidemia History of coronary artery disease # blockers Angiotensin-converting enzyme inhibitors Calcium antagonists Proton pump inhibitors Statin therapy Left ventricular function Creatinine ("mol/L)

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Clopidogrel Low responders (VASP &50%) (n " 151)

Clopidogrel p Responders Value (VASP !50%) (n " 195)

64 ' 12 30 (20%) 27.8 ' 6 94 (62%) 43 (28%) 66 (44%) 86 (57%) 36 (24%)

64 ' 12 35 (18%) 26.5 ' 5 115 (59%) 56 (29%) 73 (37%) 106 (54%) 71 (36%)

0.89 0.68 0.02 0.58 1.0 0.27 0.66 0.02

114 (75%) 104 (69%)

150 (77%) 142 (73%)

0.80 0.47

14 (9%) 134 (89%) 141 (93%) 54 ' 8 90 ' 49

18 (9%) 168 (86%) 183 (94%) 55 ' 7 90 ' 28

1.0 0.52 1.0 0.80 0.20

Data are expressed as mean ' SD or as number (percentage).

Figure 1. Clopidogrel response assessed by PRI VASP after 600-mg clopidogrel loading dose (LD) in patients who underwent PCI after NSTE ACS according to CYP2C19 genotype, allowing identification of 151 clopidogrel nonresponders with PRI VASP &50%.

with high maintenance doses in unstable patients and the effect of the CYP2C19*2 loss-of-function allele on this benefit have not been properly addressed. Therefore, we designed the present study to assess the benefit of high maintenance doses in low-response patients and the impact of CYP2C19*2 genotypes on this benefit.

Consecutive patients admitted for NSTE ACS to our institution from July 2008 to January 2010 were eligible for this prospective study if they had undergone successful PCI. NSTE ACS were defined as clinical symptoms compatible with acute myocardial ischemia !12 hours before admission and !1 of the following: a new finding of ST-segment changes in !2 leads, elevated levels of cardiac markers, or coronary artery disease as documented by a history of revascularization or acute myocardial infarction. The exclusion criteria were a history of bleeding diathesis, persistent ST-segment elevation ACS, New York Heart Association class IV, PCI or coronary artery bypass grafting !3 months, contraindications to antiplatelet therapy, platelet count !100 G/L, and creatinine clearance !25 ml/min. Patients received oral loading doses of aspirin 250 mg and clopidogrel 600 mg !12 hours before PCI. Initial platelet parameters were assessed 12 to 24 hours after the loading dose. PCI was performed !24 hours after admission. Anticoagulation was obtained with unfractionated heparin or subcutaneous fondaparinux 2.5 mg/day plus additional unfractionated heparin during PCI. The use of a glycoprotein IIb/IIIa antagonist during PCI was allowed at the operator’s discretion during the procedure. After initial assessment, patients identified as low responders received higher 150-mg maintenance doses of clopidogrel, and platelet tests were repeated 1 month after hospital discharge at clinical follow-up. Verbal compliance was also systematically checked during this consultation. The study protocol was approved by the ethics committee of our institution, and patients gave written informed consent for participation. Blood samples for testing clopidogrel response were drawn !12 hours after the loading dose of clopidogrel and at 1-month follow-up. Blood was sent immediately to the hemostasis laboratory to determine the vasoactive-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 the method of Schwarz et al previously described.23 A platelet reactivity index (PRI) VASP (VASP) was calculated from the median fluorescence intensity (MFI) of samples incubated with prostaglandin E1 (PGE1) or PGE1 and adenosine diphosphate (ADP) according to the formula PRI VASP " (MFIPGE1 # MFIPGE1$ADP/MFIPGE1) % 100. Clopidogrel low response was defined as PRI VASP &50%, as previously proposed.24 Genomic deoxyribonucleic acid was extracted from peripheral blood leukocytes by the salting-out method. CYP2C19*2 (rs4244285) genotyping was done using amplification refractory mutation system polymerase chain reaction. The primers (Invitrogen, Carlsbad, California) were as follows: *2 forward: CAg AgC TTg gCA TAT TgT ATC; *2 reverse: TAT CgC AAg CAg TCA CAT AAC; *2 G specific (sens): ACT ATC ATT gAT TAT TTC CCg; and *2 A specific (antisens): gTA ATT TgT TAT ggg TTC CT. The sizes of the polymerase chain reaction products generated are as follows: CYP2C19 *2 forward/reverse: 373 bp, *2 G (normal allele): 283 bp; and *2 A (mutated) allele: 129 bp. Reactions were made in a final volume of 12.5 "l, using

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Figure 2. Clopidogrel response assessed by PRI VASP in clopidogrel low responders (CYP2C19*2 carriers and noncarriers) after 600-mg loading dose and after tailored therapy with 150-mg maintenance dose.

Figure 3. Incidence of clopidogrel low response (CLR), defined as PRI VASP &50%, after 150-mg maintenance dose in CYP2C19*2 carriers and noncarriers.

200 nmol/L of primer except for *2 A primer (300 nmol/L), 0.15 U of Taq deoxyribonucleic acid polymerase (Qbiotaq; MP Biomedicals, Solon, Ohio) in its accompanying buffer,

200 "mol/L of accompanying deoxynucleotide triphosphates, and 25 ng of genomic deoxyribonucleic acid. The sequence variation c.681G&A in the CYP2C19 gene was screened to determine the presence of the wild-type allele or 2*. Base numbering and allele definitions followed the nomenclature of the Human Cytochrome P450 Allele Nomenclature Committee (http://www.cypalleles.ki.se) according to the recommendations of den Dunnen (http://www. hgvs.org/mutnomen/). The end points of the present study were (1) the effect of the CYP2C19*2 allele on clopidogrel response after a 600-mg loading dose in patients with NSTE ACS, (2) the benefit of a high 150-mg maintenance dose in clopidogrel low responders after PCI for NSTE ACS, and (3) the effect of CYP2C19*2 genotypes on the benefit of a high maintenance dose in low responders. Statistical analysis was performed using the GraphPad Prism version 4.00 (GraphPad Software, San Diego, California). Continuous variables were analyzed for a normal distribution using the Shapiro-Wilk test and are expressed as mean ' SD. One-way analysis of variance was used for comparisons across genotypes and to generate p values for

Coronary Artery Disease/High Clopidogrel Dosing in Non Responders

trend tests. The Kruskal-Wallis test was used for comparisons across groups and to generate p values for trend tests of variables not normally distributed. Categorical variables are expressed as frequencies and percentages. Comparisons between groups were made using chi-square or Fisher’s exact tests for categorical variables and nonparametric statistical testing or paired Student’s t tests for continuous variables. A p value !0.05 was considered statistically significant. Results Among 382 patients screened, 346 unrelated participants were included in our study. Baseline characteristics of the population are included in Table 1 according to clopidogrel response. Genetic distributions of the CYP2C19*2 polymorphisms were as follows: 4% *2/*2 (AA) homozygotes (n " 13), 21% *2/wild-type heterozygotes (AG) (n " 73), and 75% wild-type/wild-type homozygotes (GG) (n " 260). The genotype frequencies were consistent with HardyWeinberg predictions. Clopidogrel response was assessed with PRI VASP, and we observed a high rate of low response in the whole population, with 41% of clopidogrel low responders after 600 mg (n " 151). Clopidogrel response was significantly affected by genotype, with lower clopidogrel response in CYP2C19*2 allele carriers (p " 0.01; Figure 1). Accordingly, the rate of clopidogrel low response was higher in CYP2C19*2 allele carriers: 53% (n " 46 of 86) compared to 41% (n " 105 of 260) (p " 0.04). Among *2/*2 homozygotes (n " 13), 77% (n " 10) were nonresponders after 600-mg loading doses (Figure 1). The mean response to clopidogrel in patients identified as low responders was not different between CYP2C19*2 allele carriers and noncarriers (66 ' 10% vs 67 ' 11%, p " 0.58; Figure 2). All clopidogrel low responders (n " 151), including 105 *2 noncarriers and 46 *2 carriers, received tailored therapy with high 150-mg clopidogrel maintenance at discharge, aiming to overcome initial low response. After 1 month, in the whole population of clopidogrel low responders, tailored therapy with a high 150-mg maintenance dose was able to overcome clopidogrel low response in only 44% of the patients (n " 66 of 151). The benefit of tailored therapy was significantly affected by CYP2C19 genotypes. Indeed, mean clopidogrel response after 1 month of tailored therapy was significantly lower in *2 carriers than in *2 noncarriers (57 ' 14% vs 50 ' 16%, p " 0.01; Figure 2). The mean variation of PRI VASP from the in-hospital phase to 1-month follow-up was significantly lower in CYP2C19*2 carriers (9.5% vs 15.7% of PRI VASP reduction, p !0.01; Figure 3). In addition, initial low response was overcome by tailored therapy significantly less frequently in *2 carriers than in noncarriers (28% [n " 13 of 46] vs 50% [n " 53 of 105], p " 0.003; Figure 3). Among initial *2/*2 homozygotes with low response (n " 10), only 1 patient was a responder at 1 month, with 90% of patients (n " 9) still low responders. Discussion In the present study, a higher clopidogrel maintenance dose was able to overcome initial clopidogrel low response

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in fewer than half of clopidogrel low responders who underwent PCI for NSTE ACS. The benefit of this tailored therapy was significantly reduced in CYP2C19*2 carriers, with only 28% of carriers becoming responders with a high maintenance dose. Clopidogrel is a prodrug that undergoes a series of transformations to yield an active metabolite, inhibiting P2Y12 receptor. Clopidogrel undergoes a 2-step oxidation by a series of hepatic CYPs to generate the active metabolite. Among the hepatic enzymes involved in this metabolic process, a key enzyme, CYP2C19, has been shown to have many isoforms, producing large variability in its catalytic activity and conversion of clopidogrel into its active compound. A loss-of-function allele (CYP2C19*2) can attenuate the pharmacodynamic effect of the drug,15 and more important, the “‘genetic resistance’” induced by the carriage of !1 CYP2C19*2 allele translates into a significantly increased risk for recurrent cardiovascular events after PCI.16,17 Variability of clopidogrel response and its clinical relevance have emerged from numerous trials over the past decade.4 –9 These recent findings clearly support the need for optimization of antiplatelet therapy and/or platelet function tests to identify low responder candidates for treatment adaptation. Several strategies of tailored therapy have been proposed. The first solution to overcome variability of clopidogrel response with conventional doses (300 mg/75 mg) is to increase doses in every patient, to provide a higher degree of platelet inhibition and a lower rate of low response.19 –21 In terms of evidence-based medicine and clinical efficiency, the results of the randomized Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events– Optimal Antiplatelet Strategy for Interventions (CURRENTOASIS 7) trial showed a nonsignificant benefit in the whole population.22 However, subgroup analysis suggested benefit of increased loading doses of clopidogrel in patients with ACS treated with PCI.22 The second solution is to provide a tailored therapy on the basis of platelet function test results. Small randomized studies have already suggested the benefit of tailored therapy in the setting of PCI in clopidogrel low responders, with either repeated loading doses of clopidogrel 600 mg25 or the use of glycoprotein IIb/IIIa antagonists.26,27 However, the benefit of individualized therapy based on platelet function test results will have to be confirmed in larger clinical trials such as the ongoing Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy (ARCTIC) study and the Gauging Responsiveness With a VerifyNow Assay—Impact on Thrombosis and Safety (GRAVITAS) study. The results of the GRAVITAS study have been published recently.28 This study tested the benefit of tailored therapy with higher clopidogrel doses in low responders, with randomization after PCI. The primary end point was not reached in this study, with no benefit from tailored therapy compared to standard therapy. Several factors might partially explain these results, such as a low risk profile of patients and randomization after PCI, missing the effect of tailored therapy on periprocedural events. However, these “disappointing” results also suggest that increasing the dose

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of clopidogrel in nonresponders might not be an effective approach. Our present results showed that such strategy was able to overcome nonresponse in fewer than half of the patients. Therefore, these patients might benefit from alternative drugs, such as new P2Y12 blockers. These new drugs are more potent and have less interindividual variability, such as new thienopyridines (prasugrel) or nonthienopyridine P2Y12 inhibitors (ticagrelor) compared to high doses of clopidogrel.29 They demonstrated better efficacy in 2 large, randomized trials (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38 [TRITONTIMI 38] and A Study of Platelet Inhibition and Patient Outcomes [PLATO]) compared to classic dual-antiplatelet therapy with aspirin and clopidogrel.30,31 The benefit of tailored antiplatelet therapy according to CYP2C19 genotype remains unknown in unstable clinical settings. Bonello et al32 demonstrated that adjusted therapy with additional loading of 600-mg doses was effective to overcome initial low response in CYP2C19*2 allele carriers. This study was focused on the acute phase, and our present data suggest that the overcoming observed in the latter study32 might be reversed within the next days on maintenance therapy, suggesting that after “acute” tailoring, discharge therapy should also be further improved with a switch to new P2Y12 blockers. Indeed, similar results have been recently reported in the GRAVITAS gene study, showing that CYP2C19*2 carriers do not respond to high-dose clopidogrel.33 However, the clinical relevance of platelet function testing and/or genotyping for tailoring antiplatelet therapy will have to be confirmed in further studies. Acknowledgment: We thank our nurses’ team and technicians in executing this study and the hematology laboratory at Conception Hospital for VASP analysis. 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 – 629. 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, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; 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; 358:527–533. 4. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007;49:1505–1516. 5. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–3175.

6. Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse T, Bonnet JL, Alessi MC. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006;4:542–549. 7. Geisler T, Langer H, Wydymus M, Göhring K, Zürn C, Bigalke B, Stellos K, May AE, Gawaz M. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27:2420 –2425. 8. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, Gick M, Caputo A, Büttner HJ, Neumann FJ. 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. 9. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, Moschi G, Gori AM, Abbate R, Antoniucci D. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007;49:2312–2317. 10. Cuisset T, Cayla G, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Morange PE, Alessi MC, Bonnet JL. Predictive value of post-treatment platelet reactivity for occurrence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? Eurointervention 2009;5:325– 329. 11. Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Schömig A, von Beckerath N, Kastrati A. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010;8:250 –256. 12. Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, Defreyn G, Maffrand JP. Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 1992;44:527–532. 13. Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, Herbert JM. The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost 1994;72:313–317. 14. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001;409:202–207. 15. Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N, Faille D, Lambert M, Juhan-Vague I, Bonnet JL, Alessi MC. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008;101: 1088 –1093. 16. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373:309 –317. 17. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthélémy O, Cayla G, Beygui F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010;56:134 –143. 18. Collet JP, Cayla G, Cuisset T, Elhadad S, Rangé G, Vicaut E, Montalescot G. Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the Assessment With a Double Randomization of (1) a Fixed Dose Versus a Monitoring-Guided Dose of Aspirin and Clopidogrel After DES Implantation, and (2) Treatment Interruption Versus Continuation, 1 Year After Stenting (ARCTIC) study. Am Heart J 2011;161: 5–12. 19. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, Beygui F, Drouet L; ALBION Trial Investigators. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48: 931–938. 20. Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, Lehmann A, Lambert M, Bonnet JL, Alessi MC. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes

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