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FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiolog

FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011 . Giuseppe Di Pasquale Unità Operativa Cardiologia Ospedale Maggiore, Bologna. Disclosures.

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FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiolog

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  1. FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE HSM Genoa Cardiology Meeting Genova, 22 Ottobre 2011 Giuseppe Di Pasquale Unità Operativa Cardiologia Ospedale Maggiore, Bologna

  2. Disclosures • Member of Advisory Board of Dabigatran, Rivaroxaban, Apixaban, Dronedarone • Consulting fees / honoraria • - Boehringer Ingelheim • - Bayer AG • - Sanofi Aventis - BMS

  3. Antithrombotic Therapy for AFibStroke Risk Reduction Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 -64% Antiplatelet drugs vs. Placebo 8 Trials n = 4,876 -19% 50% - 50% 100% 0 Hart RG et al. Ann Intern Med 2007; 146: 857

  4. Limiti della terapia con antagonisti della Vitamina K Risposta non prevedibile Frequentiaggiustamentidella dose La terapia con antagonisti della vitamina K presenta diversi limiti che ne rendono difficoltoso l’impiego nella pratica clinica Finestraditrattamentostretta(INR range 2-3) Numerose interazioni alimentari Monitoraggioroutinariodeifattoridellacoagulazione Numeroseinterazioni con altrifarmaci Resistenza al Warfarin Lente insorgenza/termine d’azione 1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187.

  5. Limiti della Terapia Anticoagulante Orale Conseguenze nella FA • Un significativo numero di pazienti con FA a rischio di stroke non riceve la TAO

  6. Steering Committee Giuseppe Di Pasquale (Chairman ANMCO), Giovanni Mathieu (Chairman FADOI), Francesco Chiarella, Fabrizio Colombo, Michele Gulizia, Gualberto Gussoni, Carlo Nozzoli, Domenico Panuccio, Salvatore Pirelli, Marino Scherillo, Giorgio Vescovo, Massimo Zoni Berisso

  7. Setting of the Study 360 Participating Centers 7148 enrolled patients • 164 • Cardiology Departments • Cardiology ward • Cardiology ward and Cath Lab • Cardiology ward with Cath Lab and CCH • 196 • Internal Medicine Dept. • Hospital without cardiology • Hospital with cardiology ward • Hospital with cardiology ward and Cath Lab (with or without CCH) From each Center: Duration of the enrollment 4 weeks

  8. A T A Antithrombotic Treatments in non valvular AF (4.845 pts) F OAC Other ATT None

  9. Limiti della Terapia Anticoagulante Orale Conseguenze nella FA • Un significativo numero di pazienti con FA a rischio di stroke non riceve la TAO • L’intensità della scoagulazione è spesso al di fuori del range terapeutico (INR 2.0 – 3.0)

  10. Anticoagulation Control in Real Life in Italy % of INR DeterminationsbyRange in VKA TreatedPatients

  11. The Promise of New Anticoagulants

  12. New Anticoagulants • Coagulationcascade • Drug Tissue factor pathway inhibitors:NAPc2 • TF/VIIa • Initiation • X • IX • IXa • VIIa Indirect: fondaparinux, idraparinux Direct Oral: rivaroxaban, apixaban, edoxaban • Propagation • Xa • Va • II • Thrombin activity Direct Parenteral: bivalirudin Direct Oral: ximelagatran, dabigatran, AZD0837 • IIa • Fibrinogen • Fibrin

  13. N Engl J Med 2009;361(12):1139-51

  14. N Engl J Med August 10, 2011

  15. N Engl J Med August 28, 2011

  16. Atrial Fibrillation Phase 3 Study Timelines Edoxaban Rivaroxaban Dabigatran ENGAGE AF TIMI 48 Study ongoing Expected 2012 ROCKET AF Published August 2011 RE-LY Published 2009 2009 2010 2011 2012 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

  17. Atrial Fibrillation Phase 3 Study Timelines Edoxaban Rivaroxaban Dabigatran ENGAGE AF TIMI 48 Study ongoing Expected 2012 ROCKET AF Published August 2011 RE-LY Published 2009 2009 2010 2011 2012 AVERROES Published February 2011 ARISTOTLE Published August 2011 Apixaban

  18. The RE-LY Study:Randomized Evaluation of Long-term anticoagulant therapY Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

  19. Atrial fibrillation with ≥ 1 risk factor Absence of contraindications R Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 Warfarin 1 mg, 3 mg, 5 mg (INR 2.0-3.0) N=6000 RE-LY® – study design • Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin • Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Ezekowitz MD, et al. Am Heart J 2009;157:805-10. Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

  20. TIME TO FIRST STROKE OR SSE Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin RR 0.90 (95% CI: 0.74–1.10) P<0.001 (NI) P=0.30 (Sup) RR 0.65 (95% CI: 0.52–0.81) P<0.001 (NI) P<0.001 (Sup) 0.05 0.04 RRR35% 0.03 Cumulative hazard rates 0.02 0.01 0.0 0 0.5 1.0 1.5 2.0 2.5 3.0 Years RR = relative risk; RRR = relative risk reduction; SSE = systemic embolism. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

  21. MAJOR BLEEDING RATES 5.0 4.0 3.0 3.57 2.87 3.32 2.0 1.0 0 RR 0.93 (95% CI: 0.81–1.07) P=0.32 (superiority) RR 0.80 (95% CI: 0.70–0.93) P=0.003 (superiority) RRR 20% Rate per year (%) D150 mg BID D110 mg BID Warfarin Events/n: 399 / 6,076 342 / 6,015 421 / 6,022 D = dabigatran; RR = relative risk; RRR = relative risk reduction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.

  22. MAJOR BLEEDING AND COMPONENTS D = dabigatran; W = warfarin. Data represent %/year. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

  23. Hemorrhagic stroke RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 0.38% RRR 74% RRR 69% 30 20 14 10 12 0.12% 0.10% 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

  24. Mortalità per qualsiasi causa

  25. Mortalitàvascolare

  26. RE-LY Subgroup Analyses

  27. RE-LY Subgroup Analysis: Prior TIA or Stroke

  28. Lancet Neurology 2010; 9: 1157-63

  29. Prior stroke/TIA: time to primary outcome 0.08 # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 1195 1160 1132 908 573 289 D150 1233 1201 1164 938 617 321 Warfarin W 1195 1160 1126 895 565 262 0.06 Dabigatran 110 mg Cumulative Hazard Rates 0.04 Dabigatran 150 mg 0.02 0.0 0 0.5 1.0 1.5 2.0 2.5 Years of follow-up

  30. Intra-cranial bleeding rates in patients with prior stroke or TIA RR 0.20 (95% CI: 0.08–0.47) p<0.001 RR 0.41 (95% CI: 0.21–0.79) P=0.007 Number of events RRR 59% RRR 80% 1195 1233 1195

  31. RE-LY Subgroup Analysis: Age & Renal Function

  32. Circulation 2011;123:2363-72

  33. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS:STROKE AND NON-CNS EMBOLISM D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.76 P=0.072 P=0.58 P=0.036 0.5 1.0 1.5 0.5 1.0 1.5 2.0 2.0 0 0 Warfarin better Warfarin better Dabigatran better Dabigatran better BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

  34. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.0003 P=0.0001 P=0.1 P=0.091 0.5 1.0 1.5 0.5 1.0 1.5 2.0 2.0 0 0 Warfarin better Warfarin better Dabigatran better Dabigatran better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

  35. AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: HAEMORRHAGIC STROKE D 110 mg BID vs. warfarin D 150 mg BID vs. warfarin P=0.51 P=0.75 P=0.67 P=0.4 0.5 1.0 1.5 0.5 1.0 1.5 2.0 2.0 0 0 Warfarin better Warfarin better Dabigatran better Dabigatran better BID = twice daily; D = dabigatran; P values for interaction. Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Healey JS, et al. ACC 2010; abstr 1078-120.

  36. EMA approves PRADAXA with the flexibility of two dosing regimensOverall the 150 mg bid dose is recommended; the 110 mg bid dose is indicated for elderly patients aged 80 years at higher risk of bleeding and for those taking verapamil4 August 2011

  37. ANTITHROMBOTIC PROPHYLAXIS IN AF NEW PERSPECTIVES • New oral direct thrombin inhibitors (other than ximelagatran) • Oral Factor Xa inhibitors

  38. New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

  39. New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

  40. N Engl J Med August 10, 2011

  41. ROCKET AF – study design Randomized, double-blind, double-dummy, event-driven • Non-valvular AF • History of stroke, TIA or non-CNS SE • OR • ≥2* of the following: • CHF • Hypertension • Age ≥75 years • Diabetes Rivaroxaban 20 mg once daily# N=14,264 R 30-day follow-up End of study Warfarin target INR 2–3 ~14 – 40 months‡ *Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven. Patel MR et al, 2011 42

  42. ROCKET AF – primary efficacy endpoint on and off treatment Hazard ratio and 95% CIs Primary efficacy endpoint: stroke or systemic embolism ITT on- and off-treatment: post hoc analyses 2 1 0.5 Favours warfarin Favours rivaroxaban Patel MR et al, 2011. 44

  43. ROCKET AF – bleeding analysis 0.2 0.5 1 2 5 Hazard ratio and 95% CIs Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* Favours rivaroxaban Favours warfarin Safety population – on-treatment analysis; *Statistically significant Patel MR et al, 2011. 45

  44. New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation Rivaroxaban Bayer Phase III Apixaban BMS / Pfizer Phase III Edoxaban Daiichi Sankyo Phase III Betrixaban Portola / Merck Phase II Darexaban Astellas Pharma Phase II LY 517717 Lilly Planned TAK – 442 Takeda Planned

  45. N Engl J Med 2011;364(9): 806-17

  46. APIXABAN Phase 3 Clinical Trial vs Aspirin to Prevent Stroke or Embolism in AF Pts AVERROES ≈ 1.6 years Patient characteristics Randomization Apixaban 2.5 mg bid or 5 mg bid • Aged 50 years • Atrial fibrillation • 1 additional risk factor for stroke • Not suitable for vitamin K antagonist N=5600 Aspirin 81-324 mg qd • Primary outcome measures: • Time to composite outcome of stroke or systemic embolism • Time to major bleeding N Engl J Med 2011;364(9): 806-17

  47. AVERROES - Primary Efficacy Outcome N Engl J Med 2011;364(9): 806-17

  48. AVERROES - Primary Safety Outcome N Engl J Med 2011;364(9): 806-17

  49. N Engl J Med August 28, 2011

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