ARCTIC investigators s

ARCTIC investigators s 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 - NCT 00827411 - COI DISCLOSURE FOR DR. MONTALESCOT: Research Grants to the Institution or Consulting/Lecture Fees from Abbott Vascular, Astra-Zeneca, Bayer, Biotronik, Boehringer-Ingelheim, Boston Scientific, Cleveland Clinic Foundation, Cardiovascular Research Foundation, Cordis, Daiichi-Sankyo, Duke institute, Eli-Lilly, Europa, Fédération Française de Cardiologie, Fondation de France, GSK, ICM, INSERM, Medtronic, Menarini, Nanospheres, Novartis, Pfizer, Sanofi-Aventis Group, Servier, Société Française de Cardiologie, The Medicines Company, TIMI group.

Trial conduct ACTION Study Group (Academic Research Organization, Paris): - Academic Coordinating Center: Institute of Cardiology - Pitié-Salpêtrière, Paris - Academic Sponsor: AP-HP, Paris - Academic Global Trial Operations: URC - Lariboisière, Paris - Funding: ACTION, Fondation de France, Fondation SGAM, Sanofi-Aventis, Cordis, Boston-Scientific, Medtronic - Steering Committee: G. Montalescot, JP Collet, G. Cayla, T. Cuisset, S. Elhadad, G. Rangé, E. Vicaut - Investigation sites : 38 French Intervention Centers

Centers and principal investigators CHU Pitié-Salpêtrière, Paris, Drs Montalescot/Collet Hôpital de la Timone, Marseille, Dr Cuisset CH de Chartres, Dr Rangé CHU Carémeau, Nîmes, Drs Ledermann/Cayla CH de Lagny, Marne-la-Vallée, Drs Elhadad/Cohen Clinique Sainte Clothilde, La Réunion, Dr Pouillot CH Clermont-Ferrand, Dr Motreff Hôpital Lariboisière, Paris, Dr Henry Hôpital de Rangueil, Toulouse, Dr Carrié CH de la Région Annecienne, Annecy, Dr Belle CH de Bastia, Dr Boueri Hôpital Cardiologique Albert Calmette, Lille, Dr Van Belle GH du Centre Alsace, Drs Lhoest/Levai Hôpital Nord Marseille, Dr Paganelli CHU Jean Minjoz, Besançon, Dr Bassand Clinique du Parc, Castelnau-le-Lez, Dr Shadfar Polyclinique de Bordeaux Caudéran, Bordeaux, Dr Casteigt CH Marie Lannelongue, Le Plessis-Robinson, Dr Caussin Hôpital François Mitterrand, Pau, Dr Delarche Hôpital Pasteur, Nice, Dr Ferrari Clinique du Tonkin, Villeurbanne, Dr Champagnac CHU de Poitiers, Dr Christiaens Hôpital Arnaud de Villeneuve, Montpellier, Dr Leclercq Hôpital Cardio-Vasculaire Louis Pradel, Lyon, Dr Finet Hôpital Saint-Joseph, Marseille, Dr D Houdain Clinique de l Europe, Amiens, Dr Py Hôpital privé Beauregard, Marseille, Dr Wittenberg CH de Cannes, Drs Tibi/Zemour CHR Strasbourg, Dr Ohlmann Hôpital Cochin, Paris, Dr Varenne CH d Avignon, Drs Pansieri/Barney Hôpital Cardiologique du Haut Lévêque, Pessac, Dr Coste CH Lens, Dr Pecheux Clinique de l'orangerie, Strasbourg, Dr Aleil Clinique Nantaise, Nantes, Dr Brunel CH de Compiègne, Dr Sayah Hôpital Pontchaillou, Rennes, Dr Le Breton CH Dijon, Dr Cottin

Background 100 Cardiac Death and ST 95 90 85 P <0.001 Clopidogrel Nonresponders Dual Nonresponders 0 30 60 90 120 150 180 Brar S, et al. J Am Coll Cardiol. 2011;58:1945 1954. Time (Days) Gori AM, et al. J Am Coll Cardiol. 2008;52:734-739

GRAVITAS / TRIGGER-PCI designs Coronary angiogram Stent-PCI Screening 24hrs after PCI with VerifyNow P2Y12 High platelet reactivity (PRU 230) Rd Clopi High Dose Clopidogrel / Prasugrel Standard Dose 6-month FU Price MJ et al. JAMA 2011;305:1097 105 Trenk D et al. J Am Coll Cardiol 2012;59:2159 64.

ARCTIC trial design Coronary angiogram Rd VerifyNow P2Y12 + ASA Drug (ASA, clopidogrel, prasugrel, GP2b3a I.) and Dose adjustments if high platelet reactivity Stent-PCI Drug (ASA, clopidogrel, prasugrel) and Dose adjustments at day 14 Standard of care Stent-PCI Standard of care Primary endpoint at 12 months: Death, MI, stroke, stent thrombosis, urgent revascularization Statistical considerations: Assuming an annual risk of 9% and a 33% relative risk reduction (α risk at 5% and error β at 80%, bilateral test), 2,466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment 12-month FU ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12

Inclusion / Exclusion Patients scheduled for planned PCI DES implantation Consent and Rx before start of PCI Primary PCI for STEMI Any PCI with planned use of GPIIbIIa BMS or oral anticoagulation requirement Short life expectancy Bleeding diathesis

Adjustment rules DES-PCI ARU>550 (Aspirin) %inh<15% and/or PRU>235 (P2Y12) GPIIb/IIIa + clopidogrel (re)ld (>600 mg) or prasugrel LD 60 mg then, MD clopidogrel 150 mg or prasugrel 10mg

Adjustment rules VerifyNow @ day 14-30 ARU>550 %inh<15% and/or PRU>235 %inh>90% Doubling the aspirin dose Clopidogrel dose by at least 75 mg or switch to prasugrel 10mg* if clopidogrel 150mg 75mg if prasugrel clopidogrel 75mg

Baseline characteristics Conventional (n=1227) Monitoring (n=1213) Age - median 63 63 Diabetes - % 37 36 Prior MI - % 31 29 Prior PCI - % 44 42 Prior CABG - % 7 6 Beta blockers -% 60 56 Proton pump inhibitors - % 32 33 Stent implanted - % 98 98 Drug-eluting stent implanted - % 97 97

In-Lab monitoring and adjustment Conventional (n=1227) Monitoring (n=1213) Aspirin poor responders - % NA 7.6 On-table aspirin loading in poor responders - % NA 85 Thienopyridine poor responders - % NA 35 On-table clopi. loading in poor responders - % NA 80 On-table prasu. loading in poor responders - % NA 3.3 On-table GP IIbIIIa loading in poor responders - % NA 80

Day-14 monitoring and adjustment Cath lab Day 14 High on-clopidogrel reactivity High on-aspirin reactivity 43% had their clopidogrel MD increased ed 17% were e put on prasugrel MD 46% had their aspirinin MD increaseded

Primary Endpoint to 1 year Death, MI, stroke, stent thrombosis, urgent revascularization Monitoring Conventional HR = 1.13 [0.98-1.29] p= 0. 096 34.6% 31.1% 0 100 200 300

Main Secondary Endpoint to 1 year Stent thrombosis or urgent revascularization Monitoring Conventional HR = 1.06 [0.74-1.52] p= 0. 77 4.9% 0 100 200 300 4.6%

Primary Endpoint Pre-specified subgroups Main Secondary Endpoint

Other Ischemic Endpoints Conventional Monitoring HR [95%CI] P Death or myocardial Infarction - % 28.8 31.7 1.11 [0.96; 1.29] 0.15 Any death - % 1.6 2.3 1.41 [0.79; 2.50] 0.24 Myocardial infarction - % 28.4 30.3 1.08 [0.93; 1.25] 0.32 Stent thrombosis - % 0.7 1 1.34 [0.56; 3.18] 0.51 Stroke or TIA- % 0.6 0.7 1.15 [0.42; 3.18] 0.78 Urgent revascularization - % 4.2 4.5 1.06 [0.73; 1.55] 0.76

Key Safety Outcomes Conventional Monitoring HR [95%CI] P Major bleeding - % 3.3 2.3 0.70 [0.43; 1.14] 0.15 Minor bleeding - % 1.7 1.0 0.57 [0.28; 1.16] 0.12 Major or minor bleeding - % 4.5 3.1 0.69 [0.46; 1.05] 0.08 STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006 17

1. PFT + antiplatelet therapy adjustment before and after stenting does not improve clinical outcome as compared with standard treatment without PFT. 2. Our data do not support routine use of PFT in patients undergoing stenting. 3. ARCTIC-2 continues: 2 nd randomization for continuation vs. interruption of clopidogrel at 1 year follow-up. 4. ANTARCTIC (NCT01538446) evaluates the value of PFT in the elderly population with a paradigm shift towards safety. PFT: Platelet Function Testing