Running title: Montalescot et al.; Landmark analysis of ARCTIC

High-On Treatment Platelet Reactivity as a Risk Factor for Secondary Prevention after Coronary Stent Revascularization: A Landmark Analysis of the ARCTIC Study Running title: Montalescot et al.; Landmark analysis of ARCTIC Gilles Montalescot, MD, PhD 1 ; Grégoire Rangé, MD 2 ; Johanne Silvain, MD, PhD 1 ; Jean-Louis Bonnet, MD 3 ; Ziad Boueri, MD 4 ; Olivier Barthélémy, MD 1 ; Guillaume Cayla, MD, PhD 5 ; Loic Belle, MD 6 ; Eric Van Belle, MD, PhD 7 ; Thomas Cuisset, MD, PhD 3 ; Simon Elhadad, MD 8 ; Christophe Pouillot, MD 9 ; Patrick Henry, MD, PhD 10 ; Pascal Motreff, MD, PhD 11 ; Didier Carrié, MD, PhD 12 ; Hélène Rousseau PhD 13 ; Pierre Aubry, MD 14 ; Jacques Monségu, MD 15 ; Pierre Sabouret, MD 1 ; Stephen A O Connor, MB BCh, MD 1 ; Jérémie Abtan, MD 16 ; Mathieu Kerneis, MD 1 ; Christophe Saint-Etienne, MD 17 ; Farzin Beygui, MD, PhD 18 ; Eric Vicaut MD, PhD 13 ; Jean-Philippe Collet, MD, PhD 1 for the ARCTIC investigators 1 ACTION Study Group, Institut de Cardiologie (AP-HP), INSERM UMR 937, Université Paris 6, ICAN, Paris; 2 Hôpital Louis Pasteur, Le Coudray; 3 Hôpital de la Timone, Marseille; 4 CH de Bastia, Bastia; 5 CHU Carémeau, Nîmes; 6 CH de la Région Annecienne, n ennen Annecy; 7 Hôpital Cardiologique, Lille; le; 8 CH de Lagny, Marne-la-Vallée; a-va 9 Clinique ique Sainte-Clothilde, lde, La Réunion; n; 10 Hôpital Lariboisière, isière, Paris; 11 CHU Clermont-Ferrand, errand nd, Clermont-Ferrand; errand; 12 Hôpital de Rangueil, Toulouse; 13 Unite de Recherche Clinique, Hôpital Lariboisière, ACTION Study Group, Paris; 14 Hôpital Bichat, Paris; 15 HIA du Val-du-Grâce, Paris; 16 Hôpital Bichat, ACTION study group, Paris; 17 Hôpital Trousseau, u, Chambray-lès-Tours, -Tou rs, ACTION study group, Paris; 18 CHU Côte de Nacre, Caen, ACTION Study Group, Caen, France Address for Correspondence: Gilles Montalescot, MD, PhD Institut de Cardiologie, Bureau 2-236 Centre Hospitalier Universitaire Pitié-Salpêtrière 47 Boulevard de l Hôpital 75013 Paris, France Tel: +33 1 42 16 30 06 Fax: +33 1 42 16 29 31 E-mail: gilles.montalescot@psl.aphp.fr Journal Subject Code: Treatment:[118] Cardiovascular pharmacology 1

Abstract Background Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the ARCTIC study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when peri-procedural events have been excluded, is unknown. Methods and Results In ARCTIC, 2,440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow TM P2Y 12 /Aspirin point of care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug and/or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke or urgent revascularization through one year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (HR 1.105; 95% CI [0.835;1.461], p=0.48). Stent thrombosis or urgent revascularization ariz at ion occurred curred in 4.4% and 4.5% in the monitoring and conventional ntional arms, respectively (p=0.99). There was no difference ence for any of the other ischemic c end points. Major bleeding event rates were 1.8% in the monitoring arm versus 2.8% in the conventional arm (p=0.11) 1) while major or minor bleeding event rates were 2.3% and 3.4%, respectively ec (p=0.10). Conclusions Detection ons D ecti tion of platelet et hyper-reactivity r eact ity by platelet et function testing in patients undergoing ng coronary onar stenting ting with further therapeutic eutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyper-reactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization. Clinical Trial Registration Information http://clinicaltrials.gov; Identifier: NCT00827411. Key words: antiplatelet therapy, percutaneous coronary intervention, platelet function testing 2

Introduction Although high on-treatment platelet reactivity in coronary patients is a marker of ischemic risk, and a biological information potentially available to adjust antiplatelet therapy, a few randomized studies have been unable to establish differences in clinical outcomes with platelet function monitoring and treatment adjustment for coronary stenting as compared with standard antiplatelet therapy without monitoring. 1,2,3 The ARCTIC (Assessment by a double Randomization of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and of Treatment Interruption versus Continuation one year after stenting) study was unique in the fact that poor response to both aspirin and clopidogrel was searched and treated, starting before intervention to prevent peri-procedural and long term events. 3 No hint of improvement of ischemic outcomes was observed from randomization performed before the interventional procedure to one year follow-up. As randomization occurred early, most events ents were peri-procedural roce myocardial infarction. io n. We wondered whether her results would differ when considering ing patients ts only after hospital discharge, when patients are on maintenance therapy to prevent new clinical cal ischemic ic events once they have returned home. Whether individualized treatment of platelet hyper-reactivity, considered as a new risk factor, can improve secondary prevention during the first year following hospital discharge after coronary stenting is unknown. The ARCTIC trial gives an opportunity to examine this question. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary composite endpoint of death, myocardial infarction, stent thrombosis, stroke or urgent revascularization over one year, as well as all the other pre-specified secondary endpoints. 3

Methods Study design and population ARCTIC was a randomized study recruiting patients scheduled for planned drug-eluting stent implantation at 38 centers in France. Primary percutaneous coronary intervention for STelevation myocardial infarction, planned use of glycoprotein (GP) IIbIIIa inhibitors, chronic anticoagulation therapy or bleeding diathesis were exclusion criteria. The study protocol was registered at ClinicalTrials.gov under the number NCT00827411 and the main results have been published previously. 3 Written informed consent was obtained from all patients. Eligible patients were centrally randomized, to a strategy of platelet function evaluation with adjustment of antiplatelet drugs and doses in patients with inadequate platelet t inhibitory responsese (monitoring ng arm) or to a conventional strategy of treatment without platelet function assessment (conventional ntio na arm). In the monitoring arm, plateletet function measurements emen ents were performed for both aspirin and P2Y 12 inhibitors. ibit itor The same measurements were repeated eate 2 to 4 weeks after discharge for further adjustment of maintenance nanc nce therapy in case of persistent inadequate ate response to treatment. The treatment tment adjustments in the monitoring ng arm could be performed both ways and antiplatelet therapy could also be reduced in case of hyper-response to treatment. Platelet function monitoring was performed with the VerifyNow TM assay (Accumetrics, San DiegoCA), a point-of-care platelet function test that uses two different cartridges for aspirin and clopidogrel. An algorithm for drug and dose adjustments in the monitoring group was provided to all investigators. The 14-30 day time point measure allowed adjustment of the MD of thienopyridine and/or aspirin. Patients with high on-thienopyridine platelet reactivity were switched either to prasugrel 10mg MD or to a 75mg increase in clopidogrel MD. Patients without high onthienopyridine platelet reactivity remained on the same thienopyridine MD and those with very 4

low on-thienopyridine platelet reactivity, defined as a % inhibition >90%, were switched to clopidogrel 75mg MD if on prasugrel 10mg or clopidogrel 150mg MD. 4 Patients with optimal platelet reactivity after testing were left with the same treatment for the rest of the study. The primary end point was the composite of all-cause death, myocardial infarction, stroke or transient ischemic attack, urgent coronary revascularization, and stent thrombosis. All definitions have been described elsewhere. 3,4 The main secondary efficacy end point was the composite of stent thrombosis (revascularized or not) and urgent revascularization. All the other pre-specified end points of the study protocol were also analyzed. The main safety end point was defined as major bleeding using the percutaneous coronary intervention-specific STEEPLE definitions. 5 All events were adjudicated by an independent Clinical Events Committee tee unaware a of treatment assignments. Statistical tica analysis The analysis alysis was based on all events ents that occurred in the intention-to-treat ntion-to-tre population defined as all randomized patients who signed an informed consent form. In case of patients withdrawing consent during the study, only their data collected lect cted before the day of withdrawal wal were included in the database. The end points were analyzed using a Cox model. We performed an additional analysis adjusting for clinically relevant baseline characteristics (age, sex, weight, diabetes, smoking, prior myocardial infarction) that were included in the Cox regression model. When performing the landmark analyses from discharge to the end of the trial, we ascertained that the number of patients at risk included all patients who were alive with any available information after discharge, regardless of whether a nonfatal event had occurred during the hospital stay. All patients were censored at the date of last available information. The 95% confidence interval of the hazard ratio is presented. For baseline characteristics of patients in the landmark analysis for 5

one-year discharge, normality of quantitative variables were tested by Shapiro-Wilk test. Since in our study they were found non-gaussian, they were summarized as median (quartiles) and compared by Mann-Whitney test. ²test for frequency comparisons was used. All tests were made at a two-sided 5% significance level with SAS version 9.2 (from SAS Institute). The trial and the statistical analyses were performed by the non-for-profit Academic Research Organization ACTION (Allies in Cardiovascular Trials, Initiatives and Organized Networks), based at Pitié-Salpêtrière Hospital (www.action-coeur.org). Research grants were obtained from Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific and Fondation SGAM which had no involvement in the conduct of the study. Results Patients ts and treatments A total t of 2,440 40 patients were enrolled ed of whom 1,227 were assigned signed to the conventional onal group and 1,213 to the monitoring oring group. Of those 1191 patients of the conventional ntio nal group and 1194 patients of the monitoring ng group were evaluated in the landmark ark analysis alys starting at hospital discharge (Figure 1). Baseline characteristics of the population were well matched in the two study groups, including for the main landmark analysis of the present study related to outcomes after hospital discharge (Table 1). 3 In the monitoring arm, high on-aspirin platelet reactivity and high on-clopidogrel platelet reactivity were detected prior to stent implantation in 7.6% and 34.5% of patients respectively, and led to treatment adjustments in the catheterization laboratory. When on-treatment platelet reactivity measurements were repeated 2-4 weeks after hospital discharge, high on-aspirin platelet reactivity was found in 3.9% of patients and high onclopidogrel platelet reactivity in 15.6% of patients. Treatments were further adjusted according 6

to the pre-specified algorithms and were not controlled again during the year of treatment. After monitoring 2-4 weeks after discharge, 11.2% of patients had their thienopyridine treatment decreased (prasugrel towards clopidogrel or lower dose of clopidogrel) because of low onthienopyridine platelet reactivity and 10.8% of patients had their clopidogrel dose increased or changed towards prasugrel because of high on-thienopyridine platelet reactivity on a treatment that was felt not to be maximal yet. Based on the ARU values obtained at Day 14, the aspirin dose was decreased in 3.4% of patients and increased in 3.1% of patients. Antiplatelet therapy in the control arm was left to the discretion of the investigators and decided upon without platelet function testing being performed. Efficacy end points The event rates from randomization to hospital discharge did not differ significantly between the two groups (Table 2). A non-significant trend was observed for more frequent ent in-hospital death or resuscitated cardiac arrest rest during the hospital period in the monitoring ng arm (p=0.06). 06). The number of events ents for the primary ry endpoint between een hospital discharge and 1-year follow-up ow-u represents 22.9% 2.9% of all the events accumulated ul ated over the period from randomization atio ion to 1-year follow-up. Following discharge, the primary end point occurred in 103/1194 patients in the monitoring arm and 94/1191 in the conventional arm (p=0.48; Table 3, Figure 2). Consistent results were found for the main secondary endpoint and across all secondary end points (Table 3, Figure 3). All the results were also confirmed when the Cox regression model was adjusted with important clinical variables, in the analyses performed both before and after the landmark cut point. The primary endpoint rate in the one year follow-up period increased modestly and not significantly across tertiles of high platelet reactivity measured 2-4 weeks after discharge. The 7

rates were respectively 7.6%, 8.3% and 9.7% across the three tertiles of PRU (NS), and 6.4%, 8.5% and 10.5% across the three tertiles of ARU (NS). Safety end points Major bleeding did not differ between the two groups neither during the hospital stay nor during the one-year period following hospital discharge (Tables 2 and 3). STEEPLE major bleeding occurred in 33/1191 patients in the control arm and 21/1194 in the monitoring arm after hospital discharge (p=0.11). STEEPLE major or minor bleeding tended also to be less frequent in the monitoring group after hospital discharge (p=0.10).these results were confirmed when the Cox regression model was adjusted with important clinical variables, in the analyses performed both before and after the landmark cut point. The rates of major or minor bleeding in the one year follow-up period increased numerically across tertiles of high platelet reactivity measured 2-4 weeks eks after discharge. The rates were respectively ely 1.5%, 2.0% and 3.3% across the three tertiles es of PRU (NS), and 1.3%, 2.0% and 3.6% across the three tertiles es of ARU (NS). Discussion It has been suggested that high on-treatment platelet reactivity is a risk factor for ischemic events in coronary artery disease, in particular after coronary stenting. 6,7,8,9,10 Measurement of this biological risk factor with point-of-care assays has led to the possibility of treating this risk factor as we are used to with glycemia or LDL-cholesterol for secondary prevention. In the present study, high on-treatment platelet reactivity was identified in patients allocated by randomization to the strategy of platelet function monitoring and treatments were adjusted to control as much as possible this risk factor both before and after hospital discharge. However, 8

this strategy failed to show a benefit on ischemic events that occur during the first year after hospitalization for revascularization with coronary stenting. The present analysis focused on the secondary prevention phase by excluding all in-hospital events and confirms the global results of the study. High on-treatment platelet reactivity is not only a marker of risk but also a risk factor that we can possibly modify with the antiplatelet drugs available. However, our findings suggest that the modifications of treatment do not impact clinical outcome. This has been observed before with other biomarkers such as HDL-cholesterol or triglycerides, that are also modifiable risk factors with, however, no demonstration of a clinical benefit of an intervention on the level of these risk factors. 11,12 The risk benefit ratio of interventions designed to modify risk factors can vary depending on multiple beneficial or harmful effects beyond their effect on the risk factor. Some strategies are known to improve patient outcomes, whereas others affect only riskfactor levels. els. Our data a adds to the evidence that a strategy aiming only at controlling platelet reactivity, considered ed as a risk factor, may not predict its effect ect on patient outcomes. These findings ings however, do not call into question the benefit of dual antiplatelet telet therapy after coronary ry stenting for which there is paramount evidence. ence The present analysis adds considerably to the understanding of the value of a platelet function-guided strategy to improve the clinical response to antiplatelet therapy after drug eluting stent- coronary revascularization. The landmark analyses reported herein provide one additional step in understanding the disconnect between achievement of an optimal on-treatment platelet reactivity and the improvement in clinical outcome. In ARCTIC like in the GRAVITAS, CURRENT, TRILOGY and ACCOAST trials, lower platelet reactivity obtained with stronger P2Y 12 inhibition was not associated with improved ischemic outcomes. 1,13,14,15,16 The benefit of this class of drugs appears to depend not only on the drug and dose effects but also on the 9

clinical situation that includes recent stenting, risk level of the population, time and appropriateness of drug administration. We believe that the design of our study is optimal to answer the question of detection of this new risk factor (on-treatment platelet reactivity) with intensification of platelet inhibition in patients with a poor response to clopidogrel and/or aspirin in order to improve clinical outcome. While a few other studies had different designs, all the conclusions are consistent across the randomized studies. All these studies dealt more or less with stable patients undergoing coronary stenting. We cannot exclude a benefit of platelet function testing to adjust therapy in higher risk patients. The ongoing TRANSLATE-POPS study (NCT01088503) and ANTARCTIC study (NCT01538446) will address the question of platelet function testing to guide antiplatelet tele let therapy in higher risk populations. 17 Our conclusions may not directly apply to other platelet function tests ts or the same test using different cut off values to trigger treatment adjustments although it is unlikely that the conclusions would differ much. 18 Along the same line, our conclusions ons cannot be extended ed to genetic profiling ing and recent studies suggest gest that genetic testing may guide effectively fect ely the choice ce of antiplatelet atel e therapy in patients ts at low or high h risk (NCT01390974). 19,20,21 However a clinical trial comparable to ARCTIC still needs to be performed with genetic testing. h. 18 Our study has a number of limitations including the fact that this analysis was not prespecified but was required at some point to sort out the acute from the chronic effects of the strategy of monitoring with treatment adjustment. It should also be noted that a limitation of landmark analysis is that the original effects of randomization at entry into the trial are no longer present because of deaths or dropouts before the time of the landmark cut point. To alleviate this issue of landmark analysis, we presented the baseline characteristics of the patients which were 10

well balanced between the two groups at the time of the landmark cut point. Moreover, we adjusted for important characteristics that were included in the Cox regression model and we confirmed the non-adjusted results. There is a precedent for landmark analyses in cardiology, 22,23 but because of the observational nature of landmark methodology, the findings should be interpreted in the context of cumulative survival analyses from randomization to the end of the study. The cut point of the landmark analysis was taken arbitrarily as it corresponds well to the period of maintenance therapy and secondary prevention. We performed sensitivity analyses (data not shown) with a different cut point (Day 30) which all confirmed the results currently presented in the manuscript. Finally, this study like previous studies may lack power to draw definite conclusions but the consistency of the results across the randomized studies suggests gest sts that our conclusions are valid. 2,3,8 In conclusion, our data do not suggest searching for high on-treatment tment t platelet reactivity in patients undergoing ng stent revascularization arization to further adjust antiplatelet atel et treatment, as this strategy tegy did not reduce ischemic ic recurrences r es in the first year after the intervention. ntion. Subsequently, entl high on-treatment tmen t platelet reactivity it cannot be considered ed as a risk factor requiring ing incremental antiplatelet treatment for secondary prevention after percutaneous coronary revascularization. Conflict of Interest Disclosures: G Montalescot reports research grants to the institution or consulting/lecture fees from Bayer, BMS, Boehringer-Ingelheim, Duke Institute, Europa, GSK, Iroko, Lead-Up, Novartis, Springer, TIMI group, WebMD, Wolters, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Roche, Sanofi-Aventis, Pfizer, Accumetrics, Abbott Vascular, Daiichi-Sankyo, Eli Lilly, Fédération Française de Cardiologie, Fondation de France, INSERM, Institut de France, Nanosphere, Stentys, Société Française de Cardiologie. JP Collet has received research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Federation Française de Cardiologie, and Société Française de Cardiologie; 11

consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly. J. Silvain reports receiving research grants from Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie and Société Française de Cardiologie; consulting fees from Daiichi-Sankyo, Eli Lilly and speaker honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Iroko Cardio and Servier. SA O Connor has received grants from A Menarini and the European Society of Cardiology. J Abtan has received research grants from FERCM. M Kerneis has received research grants from Fédération Française de Cardiologie. G. Cayla reports receiving a research grant from la Fédération Française de Cardiologie; consultant fees from Abbott Vascular, AstraZeneca, CLS Behring, Daiichi Sankyo, Eli Lilly; lecture fees from Abbott Vascular, AstraZeneca, Biotronik, CLS Behring, Daiichi Sankyo, Eli Lilly and Iroko Cardio. E. Vicaut reports receiving consulting fees and lecture fees from Abbott, Amgen, Eli Lilly, Pfizer, Sanofi-Aventis, Servier F. Beygui has received speaker honoraria from Pfizer, Astellas, Sanofi-Aventis, and Roche. References: 1. Price MJ, Berger PB, Teirstein ein PS, Tanguay JF, Angiolillo illolo DJ, Spriggs gs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari ari DE, Stinis is CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ; GRAVITAS AS Investigators. Standard- vs high- dose clopidogrel based on platelet et function testing after percutaneous coronary ry intervention: ntion: the GRAVITAS AS randomized d trial. JAMA. 2011;305:1097-1105. 1;30 1 105. 2. Trenk D, Stone GW, Gawaz M, Kastrati ati A, Angiolillo llo DJ, Müller U, Richardt G, Jakubowski ki JA, Neumann FJ. A Randomized Trial of Prasugrel Versus Clopidogrel in Patients With High Platelet Reactivity on Clopidogrel After Elective Percutaneous Coronary Intervention With Implantation of Drug-Eluting Stents: Results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) Study. J Am Coll Cardiol. 2012;59:2159-2164. 3. Collet JP, Cuisset T, Rangé G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrié D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monségu J, Sabouret P, O'Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthélémy O, Beygui F, Silvain J, Vicaut E, Montalescot G; ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367:2100-2109. 4. 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 12

interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J. 2011;161:5-12.e5. 5. Montalescot G, Gallo R, White HD, Cohen M, Steg PG, Aylward PE, Bode C, Chiariello M, King SB 3rd, Harrington RA, Desmet WJ, Macaya C, Steinhubl SR; STEEPLE Investigators. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. New Engl J Med. 2006; 355:1006-1017. 6. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, Deneer VH, Harmsze AM, van der Heyden JA, Rensing BJ, Suttorp MJ, Hackeng CM, ten Berg JM. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation (POPular Study). JAMA. 2010;303:754-762. 7. 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. 8. Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance of post-clopidogrel platelet reactivity ity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008;29:992-1000. 29:9929 13. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG, Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE, White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S; CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high- 9. Brar SS, ten Berg J, Marcucci ci R, Price MJ, Valgimigli igli M, Kim HS, Patti G, Breet et NJ, DiSciascio G, Cuisset T, Dangas G. Impact of platelet reactivity ity on clinical cal outcomes omes after percutaneous us coronary intervention.a ention.a collaborative meta-analysis analysis of individual dual participant pant data. J Am Coll Cardiol. 2011;58:1945-1954. 1;58 5-19 1954. 10. Stone GW, Witzenbichler B, Weisz G, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri afer ri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013;382:614-623. 11. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356:1304-1316. 12. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes- Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267. 13

dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376:1233-1243. 14. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cintez M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367:1297-1309. 15. Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M, Goodman SG, Huber K, Chan MY, Cornel JH, Brown E, Zhou C, Jakubowski JA, White HD, Fox KA, Prabhakaran D, Armstrong PW, Tantry US, Roe MT; for the TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA. 2012;308:1785-1794. 16. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, ten Berg JM, Miller DL, Costigan TM, Goedicke J, Silvain J, Angioli P, Legutko J, Niethammer M, Motovska Z, Jakubowski JA, Cayla G, Visconti LO, Vicaut E, Widimsky P; ACCOAST Investigators. Pretreatment reat with prasugrel in non-st-segment elevation acute coronary onar syndromes. N Engl J Med. 2013;369:999-1010. 369:999-1010 10. 17. Chin CT, Wang TY, Anstrom KJ, Zhu B, Maa JF, Messenger senger JC, Ryan KA, Davidson-Ray L, Zettler tl er M, Effron fron MB, Mark DB, Peterson ED. Treatment with adenosine diphosphate phat receptor inhibitors-longitudinal n itud assessment ent of treatment patterns tern and events after acute coronary onary syndrome (TRANSLATE-ACS) ATE-AC ACS) study design: expanding ng the paradigm adig of longitudinal na l observational research. Am Heart J. 2011;162:844-851. 1;162: 2:84 851 18. Montalescot G, Vicaut E, Collet JP. Bedside monitoring of antiplatelet therapy for coronary stenting. N Engl J Med. 2013;368:871-872. 19. Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O'Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proofof-concept trial. Lancet. 2012;379:1705-1711. 20. Chevalier B, Montalescot G, Hulot JS, on behalf of the GIANT investigators. CYP2C19 genetic profiling for thienopyridine management after primary percutaneous coronary intervention: Results of the GIANT study. TCT meeting. LBCT Abstract. San Francisco, USA, November 2013. 21. Cayla G, Hulot JS, O'Connor SA, Pathak A, Scott SA, Gruel Y, Silvain J, Vignalou JB, Huerre Y, de la Briolle A, Allanic F, Beygui F, Barthélémy O, Montalescot G, Collet JP. 14

Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011;306:1765-1774. 22. Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159-168. 23. Antman EM, Wiviott SD, Murphy SA, Voitk J, Hasin Y, Widimsky P, Chandna H, Macias W, McCabe CH, Braunwald E. Early and Late Benefits of Prasugrel in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention - A TRITON TIMI 38 Analysis. J Am Coll Cardiol. 2008;51:2028-2033 15

Table 1. Baseline characteristics for patients included in the landmark analysis starting at the time of hospital discharge Treatment group Conventional Monitoring P-value (n=1191) (n=1194) Age, median (Q1;Q3) 63 (56;72) 63 (56;72) 0.6657 Age (>75) 184 (15.4%) 188 (15.7%) 0.8420 Sex (Female) 240 (20.2%) 220 (18.4%) 0.2855 Body weight index (kg/m 2 ), median (Q1;Q3) 27 (24.5;29.7) 26.55 (24.2;29.65) 0.1594 Medical history and risk factors Prior cancer 72 (6%) 77 (6.4%) 0.6839 Diabetes 433 (36.4%) 434 (36.3%) 0.9969 Dyslipidemia 816 (68.5%) 807 (67.6%) 0.6278 Hypertension 725 (60.9%) 768 (64.3%) 0.0818 Current smoking 283 (23.8%) 304 (25.5%) 0.3355 Prior stroke 57 (4.8%) 52 (4.4%) 0.6145 Prior cardiovascular events Prior heart failure 39 (3.3%) 43 (3.6%) 0.6614 Prior myocardial infarction 373 (31.3%) 346 (29%) 0.2131 Prior percutaneous coronary intervention 533 (44.8%) 501 (42%) 0.1688 Prior coronary ry artery bypass graft 83 (7%) 73 (6.1%) 0.3984 Concomitant o medications Angiotensin converting enzyme inhibitors 641 (53.8%) 668 (55.9%) 0.2968 Beta blockers 715 (60%) 675 (56.5%) 5%) 0.08300830 Statins 814 (68.3%) 810 (67.8%) 0.7907 07 Proton on pump inhibitors 380 (31.9%) 388 (32.5%) 0.7579 79 Aldosterone inhibitors 22 (1.8%) 27 (2.3%) 0.4759 Calcium channel blockers 243 (20.4%) 267 (22.4%) 0.2434 Coronary intervention Stent implanted 1171 (98.3%) 1175 (98.4%) 0.8655 Drug-eluting stent implanted 1157 (97.1%) 1165 (97.6%) 0.5166 16

Table 2. Ischemic and bleeding endpoints from randomization to hospital discharge Conventional treatment (n=1227) Monitoring Treatment (n=1213) HR[95%CI] P-value Any death, Myocardial infarction, stent thrombosis, stroke or 322 (26.2%) 341 (28.1%) 1.086 [0.932;1.264] 0.2911 TIA, urgent revascularization (primary endpoint) Stent thrombosis (revascularized or not) or any urgent 5 (0.4%) 7 (0.6%) 1.378[0.436;4.353] 0.5853 revascularization (main secondary) Any death, recurrent ACS, stroke or TIA 13 (1.1%) 20(1.6%) 1.549[0.769;3.120] 0.2205 Death or resuscitated cardiac arrest 3 (0.2%) 10 (0.8%) 3.381[0.930;12.296] 381[ 0;12.2.296 96] 0.0644 Death or Myocardial Infarction 321(26.2%) 339 (27.9%) 1.082[0.929;1.261].929 29;1.261 0.3114 Any death, Myocardial infarction, Stent thrombosis 325 (26.5%) 341 (28.1%) 1.076[0.924;1.253] 0 1 253] 0.3448 revascularized or not), Stroke or TIA, Urgent revascularization, TIMI Major bleed (Net clinical benefit) ) Any death 1 (0.1%) 6 (0.5%) 6.230[0.750;51.792] 0.0904 Myocardial al infarction ion 321 (26.2%) 2%) 335 (27.6%) 1.069[0.917;1.246] 0.3925 Stent thrombosis osis 3 (0.2%) 2 (0.2%) 0.675[0.113;4.048].113 13;4.048 48] 0.6673 Stroke or TIA 2 (0.2%) 2 (0.2%) 1.009[0.142;7.167] 0 0.1 7 0.9925 Urgent revascularization 3 (0.2%) 5 (0.4%) 1.609[0.382; 0.3 6.758] 0.5161 Bleeding STEEPLE Major Bleeding 7 (0.6%) 7 (0.6%) 1.017[0.356;2.905] 1.3.905] 0.9743 STEEPLE Minor Bleeding 10 (0.8%) 4 (0.3%) 0.386[0.121;1.232] 1;1.23 232] 2] 0.1079 STEEPLE Major Or Minor Bleeding edin 16 (1.3%) 11 (0.9%) 0.679[0.315;1.464] 0.3235 TIMI Major Bleeding 1 (0.1%) 2 (0.2%) 1.933[0.175;21.344] 0.5906 TIMI Minor Bleeding 5 (0.4%) 3 (0.2%) 0.599[0.143;2.515] 0.4841 TIMI Major Or Minor Bleeding 6 (0.5%) 5 (0.4%) 0.824[0.251;2.707] 0.7500 17

Table 3. Ischemic and bleeding endpoints from hospital discharge to end of follow-up (percentages are Kaplan-Meier estimates) Conventional treatment (n=1191) Monitoring Treatment (n=1194) HR[95%CI] P-value Any death, Myocardial infarction, stent thrombosis, stroke or 8.2% 9.1% 1.105[0.835;1.461] 0.4848 TIA, urgent revascularization (primary endpoint) Stent thrombosis (revascularized or not) or any urgent 4.7% 4.7% 1.002[0.685; 1.467] 0.9906 revascularization (main secondary) Any death, recurrent ACS, stroke or TIA 6.8% 7.2% 1.057[0.773;1.443] 0.7296 Death or resuscitated cardiac arrest 1.7% 2.1% 1.220[0.665; 20[0.665; 2.241] 241] 0.5204 Death or Myocardial Infarction 4.8% 5.4% 1.117 11 [0.776;1.608] 76;1.608 08] 0.5530 Any death, Myocardial infarction, Stent thrombosis 9.8% 10.2% 1.043 [0.804;1.352] 0.7523 revascularized or not), Stroke or TIA, Urgent revascularization, STEEPLEMajor bleed (Net clinical benefit) ) Any Death 1.7% 2% 1.167[0.632; 2.156] 0.6225 Myocardial al infarction ion 3.6% 4% 1.105[0.723;1.686] 0.6452 Stent thrombosis osis 0.5% 0.9% 1.678[0.610;4.617].610 10;4.617 17] 0.3162 Stroke or TIA 0.4% 0.5% 1.211[0.370;3.968] 1 3 0.7519 Urgent revascularization 4.4% 4% 4.5% 1.002[0.677;1.483] 0 0 1.4 0.9926 Bleeding STEEPLE Major Bleeding 2.9% 1.9% 0.638[0.369;1.103].369.103 03] 0.1078 STEEPLE MinorBleeding edin ing 1% 0.7% 0.731[0.294;1.818] 8] 0.5009 STEEPLE Major Or Minor Bleeding edin 3.6% 2.4% 0.661[0.407;1.075] 61.407;1.075] 0.0954 TIMI Major Bleeding 0.6% 0.3% 0.575[0.168;1.966] 0.3780 TIMI MinorBleeding 1.1% 0.7% 0.621 [0.257;1.498] 0.2892 TIMI Major Or Minor Bleeding 1.8% 1.1% 0.605 [0.296;1.237] 0.1687 18

Figure Legends: Figure 1. CONSORT flow diagram Figure 2. Kaplan-Meier curve of proportion of patients with primary outcome events (any death, myocardial infarction, stent thrombosis, stroke or TIA, urgent revascularization) after discharge up to one year follow-up Figure 3. Kaplan-Meier curve of proportion of patients with secondary outcome events (stent thrombosis or any urgent revascularization) after discharge up to one year follow-up. 19

2440 Patients in ARCTIC Study 1227 in conventional therapy arm at J0 therapy arm at 1213in monitoring therapy arm at J0 therapy arm at 1 death 2 withdrew consent 33 with no data after after discharge 6 deaths 4 withdrew consent 8with no data after discharge after discharge 1 investigator s decision 1191 were included in the after discharge analysis 1194 were included in the after discharge analysis Figure 1

Figure 2

Figure 3

High-On Treatment Platelet Reactivity as a Risk Factor for Secondary Prevention after Coronary Stent Revascularization: A Landmark Analysis of the ARCTIC Study Gilles Montalescot, Grégoire Rangé, Johanne Silvain, Jean-Louis Bonnet, Ziad Boueri, Olivier Barthélémy, Guillaume Cayla, Loïc Belle, Eric Van Belle, Thomas Cuisset, Simon Elhadad, Christophe Pouillot, Patrick Henry, Pascal Motreff, Didier Carrié, Hélène Rousseau, Pierre Aubry, Jacques Monségu, Pierre Sabouret, Stephen A. O'Connor, Jérémie Abtan, Mathieu Kerneis, Christophe Saint-Etienne, Farzin Beygui, Eric Vicaut and Jean-Philippe Collet for the ARCTIC investigators Circulation. published online April 9, 2014; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2014/04/09/circulationaha.113.007524 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/