ARCTIC investigators s ARCTIC : A ssessment by a double R - PowerPoint PPT Presentation

ARCTIC investigators s ARCTIC : A ssessment by a double R andomization of a C onventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of T reatment I nterruption versus C ontinuation one year after stenting - NCT 00827411 - COI D ISCLOSURE FOR D R . M ONTALESCOT : 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. Embargoed for 3:52pm PT, Sunday, Nov. 4 LBCT01-G. Montalescot - ARCTIC

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

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

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

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

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

Adjustment rules DES-PCI ARU>550 (Aspirin) %inh<15% and/or PRU>235 (P2Y 12 ) 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% if clopidogrel 150mg � ↘ 75mg Doubling the aspirin dose ↗ Clopidogrel dose by at least 75 if prasugrel � clopidogrel 75mg mg or switch to prasugrel 10mg*

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

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

Day-14 monitoring and adjustment Cath lab Day 14 High on-clopidogrel High on-aspirin reactivity reactivity 43% 43% % had % ha ad ad d d their d th h he ei eir cl e r clopidogrel c opi dogre el MD el e M MD D D increased D in cr c ed 46% % had ad d their ei r aspirin in n MD D increased ed 17% % were % re re e put on n prasugrel e el MD el D

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% 200 0 100 300

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% 4.6% 200 0 100 300

Pre-specified subgroups Primary Endpoint 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 3.3 2.3 Major bleeding - % 0.70 [0.43; 1.14] 0.15 1.7 1.0 Minor bleeding - % 0.12 0.57 [0.28; 1.16] 4.5 3.1 Major or minor bleeding - % 0.08 0.69 [0.46; 1.05] 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