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NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO DELLA FIBRILLAZIONE ATRIALE

NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO DELLA FIBRILLAZIONE ATRIALE. G.L. Botto, MD, FACC, FESC UO Cardiologia, UOS Elettrofisiologia ed Elettrostimolazione Ospedale Sant’Anna, Como. Remodeling. Ventricular dilation. MI. HF. End-stage microvascular heart disease.

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NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO DELLA FIBRILLAZIONE ATRIALE

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  1. NUOVI FARMACI ANTIARITMICI PER IL TRATTAMENTO DELLA FIBRILLAZIONE ATRIALE G.L. Botto, MD, FACC, FESC UO Cardiologia, UOS Elettrofisiologia ed Elettrostimolazione Ospedale Sant’Anna, Como

  2. Remodeling Ventricular dilation MI HF End-stage microvascular heart disease Atherosclerosis and LVH Risk factors (diabetes, hypertension) Death Atrial fibrillation AFIB Within The Cardiovascular Continuum AF is NOT a DISEASE, but rather a manifestation of a number of CLINICAL SYNDROMES, some of which are curable

  3. AF: Introduction of AADChronological Overview 1749 Quinidine 1785 Digitalis 1936 Procainamide 1954 Disopyramide 1962 Beta Blocking agents 1972 Amiodarone 1978 Propafenone 1982 Flecainide 1984 Sotalolo 1995 Ibutilide (i.v. only) 1996 Dofetilide (U.S. only)

  4. 74 Control After 48 h of AF + 4 ms 78 d-Sotalol Loss of Efficacy of IKr Blockers by Electrical Remodeling in the Goat 142 Control Sinus Rhythm + 44 ms 186 d-Sotalol Duytschaever, Blaauw et al.

  5. AF: Investigational Antiarrythmic Agents Dronedarone (IKr; IKs; ICa; Ito; INa; B1) Celivarone SSR 149744 C (similar to dronedarone) ATI-2042 atrial selective (IKr; IKs; B1; ICa; Ito; INa) Piboserod (5-HT4-receptor antagonist) Tedisamil (IV) (IKr; Ito; IKATP; INa; IKur) Vernakalant (RSD1235) (atrial-selective K inhibitor-IKur; Ito; Ina; IKACh) ZP-123 rotigaptide (GAP 486) (facilitates conduction in gap junction) CVT-150 (long-acting IV A-1 adenosine agonist) AVE-0118 (atrial-selective K inhibitor-IKur) NIP-151 (IKACh blocker) GsMtx-4 (blocks stretch activated channels) Cariporide (Na+/H+ exchange inhibitor)

  6. Different Drugs for Remodeled Atria? Control Remodeled Early Class III Drugs? Present Class III Drugs Ito Ito ICa ICa IKur IKur IKr IKs IKr IKs 0 100 200 300 400 ms 0 100 200 300 400 ms

  7. Class III Effect of IKur Blockers NOT Lost by Electrical Remodeling 162 Control Sinus Rhythm + 46 ms 208 AVE 0118 66 Control After 48h of AF + 90 ms 156 AVE 0118 Courtesy of M. Allessie

  8. Contractile and Electrical Remodeling ‘Go Hand in Hand’ Refractory Period (ms) Work Index (mm2Hg) AF Conversion SR 20 140 Refractory Period 15 Work Index 120 10 100 5 80 0 0 1 2 3 4 5 6 7 8 9 10 Time (days) Schotten et al. Circulation 2003

  9. Recent Onset Atrial FibrillationIntravenous Flecainide vs Amiodarone p=NS p=0.007 p=0.001 Conversion to SR (N°) (hours) Donovan K.D. Am J Cardiol 75:693; 1995

  10. Atrial FibrillationArryhthmia Duration and Drugs Efficacy * p=0.005 106 pt, AFIB < 6 months * * Reisinger J. Am J Cardiol 81: 1450; 1998

  11. AIAC Out-of-Hospital Treatment of Paroxismal Atrial Fibrillation With the “Pill-In-the-Pocket” Approach • Long QT or Brugada syndrome • SSS (SR <50 bpm) • 2nd or 3rd degree AV block • Thromboembolic episodes • Prophylactic AADs treatment • Known intolerance to flecainide or propafenone Exclusion Criteria • Previous MI or IHD • Dilated or hypertrophic CMP • History of heart failure • Moderate/Severe Valvular HD • LV dysfunction ( EF < 50%) • Chronic cor pulmonale • Renal or hepatic insufficiency • Hypokaliemia (< 3 mEq/L) Botto GL. G Ital Aritm Cardiostim 2001; 3: 109

  12. Atrial FibrillationPharmacologic Conversion • Low-Risk Patients • Recent-onset AFIB • Monitored setting • Caution with some drugs in women (i.e., greater risk of torsade de pointes) When & How to Use

  13. Ibutilide in Atrial Fibrillation M.F. 56 y.o. Male Valvular HD LVEF 46%

  14. The Concept of Atrial Selective Compounds

  15. VernakalantAtrial Selective Effect

  16. Rate-Dependent Sodium Current Blockade by VernakalantBased on in vitro Data From Human Embryonic Kidney Cells INa IC = 9 µM at -80 mV, 20 Hz 50 INa IC = 43 µM at -80 mV, 1 Hz 50 0.8 0.6 1 Hz Fractional current 0.4 20 Hz Range of plasma levels in patients 0.2 0.0 1 10 100 1000 Vernakalant concentration (µM) Fedida D. Expert Opin Investig Drugs 2007;16:519–532 Fedida D et al. J Cardiovasc Electrophysiol. 2005;16:1227–1238.

  17. Vernakalant in Patients With AFIB Dobrev D., Nattel S. Lancet 2010; 375: 1212-23

  18. AVRO TrialBaseline Characteristics Camm AJ. JACC 2011; 57: 313-21

  19. AVRO: Study Design Continuous Heart Rhythm Monitoring Day 30 FU Call Continuous Holter Monitoring Day 7 Randomization Hour 4 Visit Dischargec Screening Primary End PointEfficacy Period Time - 1 h 0 10 25 35 60 90 min 2 h 4 h 6 h/Discharge 7 d±2 d 30 d±3 d VernakalantN=116 3 mg/kg 2 mg/kga Electrical cardioversion or rate control permitted AmiodaroneN=116 5 mg/kgb 50 mgb aInfusion only given if patient in atrial fibrillation. bInfusion stopped upon conversion to sinus rhythm. cPatient discharge was at the discretion of the investigator, but patients remained in the clinic at least 6 hours after randomization. Camm A.J. et al. JACC Vol.57, No 3,2011; Jan18, 2011:313-21

  20. 90 min 240 min AVRO TrialTime to Treatment-Induced Cardioversion 254 AF pts (3 to 48 h duration) VER 3 mg/Kg in 10 min + 2 mg/Kg in 10 min AMI 5 mg/Kg in 60 min + 50 mg infusion VER Median time to conversion = 11 min Higher rate of symptoms relief @ 90 min VER 53,4% vs AMI 32,8 % p=0.0012 SAE or AE leading to discontinuation uncommon

  21. Vernakalant Added to 2010 ESC Guidelines: Drugs for Pharmacologic Cardioversion of Recent-Onset AF • Vernakalant therapeutic indications: • For non-surgery patients: AF ≤7 days duration • For post-cardiac surgery patients: AF ≤3 days duration The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369–2429.

  22. Atrial FibrillationEffect on Mortality of Rate vs Rhythm Control Pts with Thromboembolic Risk Factors Pts with Heart Failure AFFIRM Trial N Engl J Med 2002; 347: 1825 AF-CHF Trial N Engl J Med 2008; 358: 2667

  23. Amiodarone in 5060 AF Patients Meta-analysis Conversion/maintenance of SR is NOT associated with a reduction of all-cause death or all-cause hospitalisation 8 studies compared A with a rate control drug, either beta-blocker or digoxin 4 trials compared A with placebo. Doyle JFD. Mayo Clin Proc. 2009; 84: 234-242.

  24. AFFIRM“On-Treatment” AnalysisNormal Sinus Rhythm is Associate with Better Survival 0.54 (0.42 – 0.70; p<0.001) 0.47 (0.36 – 0.61; p<0.001) 1.50 (1.18 – 1.89; p<0.001) 1.41 (1.10 – 1.83; p<0.0005) Other significant factors: age, CAD, CHF, smoking, stroke/TIA, N-LVEF, MR Corley SD. Circulation 2004; 109: 1509-1513

  25. AFFIRM“On-Treatment” AnalysisThe Hope of Newer Antiarrhythmic Drugs 0.54 (0.42 – 0.70; p<0.001) 0.47 (0.36 – 0.61; p<0.001) 1.50 (1.18 – 1.89; p<0.001) 0 (xxx-yyy; p<0.000n) Other significant factors: age, CAD, CHF, smoking, stroke/TIA, N-LVEF, MR

  26. Dronedarone Dronedarone O (CH2)3CH3 CH3SO2HN (CH2)3CH3 O(CH2)3N (CH2)3CH3 O O (CH2)3CH3 I CH2CH3 O(CH2)2N CH2CH3 O Amiodarone I Kathofer F. Cardiovasc Drug Rev. 2005; 23: 217-30

  27. Dronedarone was Less Effective on Maintaining SR but with more Favorable Safety ProfileResults From The Dyonisos Study Loading regimen of amiodarone resulted in a lower incidence of AF recurrences at the cost of a less favourable safety profile

  28. DRONEDARONE STARTS HERE 20-Oct-2011

  29. EURIDIS & ADONISPooled Tolerability and Safety Data • No evidence of proarrhythmia, in particular, no case of torsade de pointes reported during 12-month follow-up. • No detection of thyroid disorders (systematic hormonal monitoring) or pulmonary or hepatic toxicity Singh BN, et al. N Engl J Med. 2007; 357:1039-41

  30. Placebo Donedarone 400mg BID Dronedarone AF/AFL Pool:Time to First Serious Hepatic Adverse Events* 0.10 HR=0.875 [0.542 – 1.414] p=0.9811 0. 5 Cumulative Incidence Months 0 0 6 12 18 24 Number at risk: *ALT≥5ULN or hepatic adverse events from SOC “Hepatobiliary disorders” and the SMQ “Liver related investigation signs and symptoms”; All randomized and treated patients in DRI3550/DAFNE, EFC3153/EURIDIS, EFC4788/ADONIS, EFC4508/ERATO, EFC5555/ATHENA Data on file, sanofi-aventis

  31. ATHENA Trial Design • Prospective double-blind trial to assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in AF/AFL patients with and additional risk factors* Age ≥75 y or ≤75 y with Hypertension Diabetes Prior Stroke/TIA LAD >50 mm or LVEF ≤0.40 Dronedarone 400 mg BID (n=2301) AF/AFL patients with additional risk factors* Double-blind R Placebo (n=2327) 12 – 30 Months

  32. ATHENA TrialCardiovascular Hospitalization or Death A B a Efficacy population bRandomized and treated patients C D bRandomized and treated patients bRandomized and treated patients Hohnloser S. N Engl J Med. 2009: 360: 668-78

  33. ATHENA Post-Hoc AnalysisEffect on Non-AF Related CV Hospitalizations by 14% HR=0.86 p=0.016 0 6 12 18 24 30 30 Placebo 25 Dronedarone 20 Cumulative incidence (%) 15 10 5 0 Months Patients at risk: Mean follow-up 21 ± 5 months - on Study Torp-Petersen C et al. Circulation. 2008;118:S_828 (presented at scientific sessins AHA 2008)

  34. ATHENA Post-Hoc AnalysisReduction in CV Hospitalization or Death in Permanent AF 26% reductionin relativerisk Cumulative incidence (%) 0 6 12 18 24 30 50 Placebo on top of standard therapy Dronedarone 400 mg b.i.d. on top of standard therapy 40 HR = 0.74 30 p=0.096 20 10 Mean follow-up 21 ± 5 months Months 0 Patients at risk 37 Page RL et al. Circulation. 2008;118:S_827. (presented at scientific sessions AHA 2008)

  35. HR=0.66 p=0.027 Dronedarone and Risk of StrokeATHENA Subanalysis Mean follow-up 21 ± 5 months Connolly SJ. Circulation 2009; 120: 1174-80

  36. Algorithm For The Management of AF2010 ESC Guidelines

  37. Algorithm For The Management of AF2011 ACCF/AHA/HRS Updated Guidelines

  38. Summary • AF is a chronic, CV disease with increasing socioeconomic impact • Prevalence of AF is projected to be 5.6 million by 2050 • AF is associated with increased risk of mortality, risk of stroke, and compromised QoL • Hospitalizations for AF have increased 2- to 3-fold and are projected to continue rising • Early restoration and maintenance of SR has an integral role in overall AF treatment strategy • AF causes several types of remodeling over time that have adverse physiologic consequences • Sustaining SR may be associated with decreased mortality • Decreasing AF burden offers potential to successfully treat pts • Successful management of AF includes the reduction of symptoms during episodes • A measure of success can be defined by decreased mortality, decreased hospitalizations, and increased QoL

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