I.V. Enoxaparin or Unfractionated Heparin in Primary PCI: Acute and Long-term results

1. G. Montalescot, M. Cohen, P. Goldstein, K. Huber, C. Pollack, U. Zeymer, E. Vicaut for the ATOLL investigators I.V. Enoxaparin or Unfractionated Heparin in Primary PCI: Acute and Long-term results ATOLL: Acute STEMI Treated with primary PCI and intravenous enoxaparinOr UFH to Lower ischemic and bleeding events at short- and Long-term follow-up (Investigator-driven study) G. Montalescot, disclosure: 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, FédérationFrançaise de Cardiologie, Fondation de France, GSK, ICM, INSERM, Lead-up, Medtronic, Menarini, Nanospheres, Novartis, Pfizer, Sanofi-Aventis Group, Servier, SociétéFrançaise de Cardiologie, The Medicines Company, TIMI group.

2. Intravenousenoxaparinvs. UFH in PCI ? • 57% • Major Bleeding • (p=0.004) • 23% • Death or re-MI • (p<0.001) Montalescot G et al. N Engl J Med 2006;355:1006 –17 Gibson MC et al. J Am Coll Cardiol 2007;49:2238–46

3. ATOLL Trial design Randomization as early as possible (MICU +++) Real life population (shock, cardiacarrestincluded) No anticoagulationand no lyticbeforeRx Similarantiplatelettherapy in both groups STEMI  Primary PCI ENOXAPARIN IV 0.5 mg/kg with or withoutGPIIbIIIa UFH IV 50-70 IU with GP IIbIIIa 70-100IU without GP IIbIIIa (Dose ACT-adjusted) IVRS PrimaryPCI ENOXAPARIN SC UFH IV or SC 30-day and 6-monthresults

4. Trial organization ACTION Study Group (Academic Research Organization, Paris): 1-Coordinating Center: Institute of Cardiology, Pitié-Salpêtrière Hospital, Paris 2-Sponsor:AP-HP (Assistance Publique-Hôpitaux de Paris) 3-Data center, Statistics: Unité Recherche Clinique, Lariboisière Hospital, Paris 4-International CRO: Pierrel-Hyperphar 5-Funding: AP-HP and unrestricted research grant from Sanofi-Aventis Group Steering Committee: G. Montalescot (Chair, France), M. Cohen (USA), P. Goldstein (France), K. Huber (Austria), C. Pollack (USA), E. Vicaut (France), U. Zeymer (Germany) Data Safety Monitoring Board: A. Cohen (Chair, France), M. Cucherat (France), A. Gitt (Germany) Core Laboratory: R. Dumaine, A. Samadi Clinical Event Committee: F. Philippe, P. Sabouret, F. Boccara, A. Bellemain, O. Gournay

5. Main objectives • 1° EP: • All-cause mortality at D30, • Complications of MI at D30 [resuscitated cardiac arrest, recurrent MI/ACS, urgent revascularization, stroke, peripheral or pulmonary embolism], • Procedure failure [definite stent thrombosis; B.O. use of GpIIB/IIIa; Non-TIMI 3 flow after PCI; ST resolution < 50% after PCI], • Non-CABG major bleeding during hospitalization • Main 2° EP: All-cause mortality, Recurrent ACS or Urgent revascularization at D30 • Main safety EP: Non-CABG major bleeding (STEEPLE definition) during hospitalization

6. FINAL 30-DAY RESULTS

7. Selected Baseline Characteristics

8. PrimaryEndpoint Death, Complication of MI, ProcedureFailure or Major Bleeding

9. Main SecondaryEndpoint (ischemic) Death, RecurrentACS or Urgent Revascularization

10. Consistent therapyPre-specifiedanalysis: no protocol violation (88%)

11. Death or Complication of MI Death, resuscitatedcardiacarrest, recurrentACS, UrgRevasc, stroke, peripheral or pulmonaryembolism

12. Deathorresuscitatedcardiacarrest Death (any)

13. SafetyEndpoints NS Protocole definitions (STEEPLE)

14. Death, Complication of MI or Major bleeding Net clinicalbenefit

15. 6-month Follow-up

16. 6-monthresults • Follow-up on mortality • 100% follow-up • Weused a Cox regression model to identifyindependentpredictors of deathat 6 months. Wefirstlyperformedunivariateanalysis and significant variables wereintroducedinto a stepwisecoxregression model

17. 0.10 UFH 0.08 0.06 Death ENOX 0.04 0.02 Log Rank Test: p=0.11 0.00 0 1 2 3 4 5 6 Months Death over 6 months 7.2% 7.0% 6.3% r=2.5% r=2.5% r=2.5% 4.7% 4.5% 3.8%

18. Independentcorrelates of deathat 6 months

19. Conclusions • In this1sthead-to-headcomparisonbetweentwo anticoagulants in primary PCI, i.v. enoxaparin: • Reducedseriousischemicevents, on top of intense antiplatelettherapy • Had a good safety profile, with a superior net clinicalbenefit • Tended to reducemortalityover 6 months

20. SpecialThank to: INVESTIGATORS – Austria: WR. Benzer, K. Huber, F. Leisch, F. Weidinger – France: F. Adnet, M. Angioi, B. Barberon, JF. Benezet, JL. Bonnet, J. Boschat, B. Boulanger, D. Carrie, T. Chouihed, P. Coste, Y. Cottin, H. Courcoux, C. Cuvier, N. Danchin, JL. Ducasse, F. Duclos, P. Ecollan, S. Elhadad, E. Filippi, M. Freysz, F. Funck, S. Gallula, B. Gelée, A. Greffet, P. Henry, A. Jacquemin, T. Joseph, JM. Lablanche, H. Lardoux, H. Le Breton, B. Lederman, A. Margenet, G. Mehu, O. Nallet, F. Paganelli, M. Pansieri, L. Payot, C. Pouges, E. Salengro, C. Spaulding, G. Steg, O. Stibbe, E. Teiger, M. Thicoipe, C. Thuaire, J. Treuil, O. Wittenberg, O. Wolf –Germany: D. Andresen, C. Axthelm, Fischer, E. Girth, E.Hauptmann, U. Zeymer –USA: M.Cohen, F. Shamoon COMMITTEES – A Appaix-Bellemain, F Boccara, A Cohen, M. Cohen, M Cucherat, R Dumaine, A Gitt, P Goldstein, O Gournay, K Huber, F Philippe, C Pollack, P Sabouret, A Samadi, E Vicaut, U Zeymer PIERRELResearch– L. Basso, L. Merlini, M. Mazzoleni ACTION study Group– ME. Assossou, M. Aout, B. Bertin, D. Brugier, JP. Collet, M. Courreges-Viaud, V. Gallois, P. Gallula, V. Jouis, S. Kabla, C. Misse, G. Ngouala, A. Pena, S. Paulsrud, N. Vignolles