En Que Pacientes Elijo Dronedarona? Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor Department of Medicine Director Arrhythmia & Pacing Service Director Syncope & Autonomic Disorder Unit Director Hamilton Atrial Fibrillation Referral Centre McMaster University, Hamilton Health Sciences Principal Investigator Arrhythmia & Global Health Population Health Research Institute Hamilton, Ontario, Canada * * * 1 Conflicts of Interest Research Grants: Biosense Webster, Boston Scientific, Medtronic, St. Jude Medical, Transoma, Juan Valdez Café de Colombia, Other Undisclosed Colombian Pharmaceutical Companies! Honorarium: Biosense Webster, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Transoma, Astra Zeneca, Boeringher Ingelheim, Procaps, Sanofi-Aventis, Merck, Servier. Advisory Boards: Medtronic, Biosense Webster, Boston Scientific, Biotronik, Transoma, Schering Plough, Boeringher Ingelheim, Sanofi Aventis, Procaps, Biocaps, Servier I have no stock options under my name… all under Dr. Stuart Connolly’s & Salim Yusuf’s names! (AIG, Merryll Lynch) I have received Pens, Bags, Memory sticks, tickets to ball games, hockey games, soccer games, invitations for dinner, drinks and other undisclosed entertainment. Nonetheless… I do have my own unbiased opinions! Recent Developments New Oral Anticoagulants New AF Mechanisms New Antiarrhythmic Drugs New Ablation Therapy New Device Brinavess Therapy for Prevention of Thromboembolism Caso Paciente con Episodios de Presyncope precedidos por palpitaciones durante su ejercicio diario que consiste en 3 km de caminata rapida. Medalla de Oro Juegos Pnamericanos y Bronze Olimpicos Examen Fisico Normal: Dismunucion Agudeza visual. No recibe medicaciones fuera de ASA. Antiarrhythmic medical therapies Class Ia: Disopyramide, Quinidine and Procainamide Amiodarone Propafenone Class Beta-Blockers Class III Antiarrhythmic Agents Ic Sotalol New and Old Flecainide Nexterone Upstream and New Ryanodine Budio- Class III Agents Novel Drugs Receptor therapies Modulator darone SAC RotigaptideConnexin Blockers DangaptideModulator For VT only Na+/H+ N/ADofetilide ex USA Azimilide RanolazineLate Na blockers Inhibitor IKACh Abandoned Na+/Ca2+ NTC-801 Tedisamil Dronedarone Inhibitor Blocker Multi- IK1 IKur channel Vernakalant Celivarone Chloroquine Xen 0103 blockers Blockers Blockers Adapted from Savelieva I, et al. Europace. 2008:10:647-65 Dronedarone O C4H9 CH3SO2NH O (CH2)3 N C4H9 O C4H9 Amiodarone-like compound lacking iodine Similar electrophysiological properties No evidence of thyroid or pulmonary toxicity 24-hour half-life Food effect (2–3 x increase in plasma levels) Extensive 1st pass metabolism (CYP450 3A4) 15% bioavailability Dronedarone is a multichannel blocker • Dronedarone Possesses Electrophysiologic Characteristics of all Four Vaughan Williams Classes1 – Outward currents 50 Ito • Ikr: rapidly activating delayed rectifier IKur (atrial) potassium current ICa 0 • Iks: slowly activating delayed rectifier IKr potassium current I V [mV] Na IKs • Ik1: inward rectifier potassium current • Ito: transient outward current -50 • Ik(Ach): muscarinic receptor-operated K+ current (atria) IK1 IAch (atrial) – Inward currents 0 100 200 300 400 • Fast sodium currents Time [ms] • Calcium channel antagonist • Dronedarone has anti-fibrillatory effects in the ventricles and atria in animals2 1.Gautier P, et al. J Cardiovasc Pharmacol. 2003;41(2):191-202. 7 2.Doggrell SA, Hancox JC, Expert Opin Investig Drugs 2004;13:415-426. Dronedarone: Array of pharmacological effects and possible links with clinical benefits I , b- Reduction in CaL Rate adrenergic symptoms of control inhibition AF / AFL Prevention of I , I , I , Atrial rhythm KAch Kr Na cerebrovascular I inhibition control Kur events I , b- CaL Ventricular Reduced risk adrenergic, I , Kr rhythm control of sudden death INa inhibition Reduced risk of b-adrenergic Anti-adrenergic acute coronary inhibition effects syndromes Systemic and Reduced risk I inhibition Lowering of CaL coronary of stroke and NO liberation blood pressure vasodilation heart failure sanofi-aventis. US FDA Cardiovascular & Renal Drugs Advisory 8 Committee: Available from URL: http://www.fda.gov Dronedarone Clinical Overview One of the Largest Clinical Trial Programs Ever Done in AF/AFL ADONIS n=625 Sinus Rhythm maintenance Efficacy EURIDIS n=612 ERATO Rate n=174 Control DAFNE ATHENA n=270 n=3,700 Morbidity/ Safety Mortality ANDROMEDA n=626/1,000 AF/AFl Severe CHF Range of Sinus Rhythm Maintenance Relative to Comparator Drugs Amiodarone1,2 10%a 55%b Avs. propafenone Bvs. quinidine Sotalol3,4 10%a 28%c Cvs. placebo Dvs. sotalol 5,6 Flecainide 49%c 70.5%b Dronedarone 22%c 55%c Propafenone7,8 7%d 65%c 0 10 20 30 40 50 60 Risk reduction (%) 1. Kochiadakis GE, et al. Chest 2004;125:377–383. 2. Kerin NZ, et al. Arch Intern Med 1996;156:49–53. 3. European Heart Journal 2004;25:1385–1394. 4. Gosselink AT, et al. JAMA 1992;267:3289–3293. 5. Naccarelli GV, et al. Am J Cardiol 1996;77: 53A–9A. 6. Van Gelder IC, et al. Am J Cardiol 1989;64:1317–1321. 7. Reimold SC, et al. Am J Cardiol 1993;71:558–563. 8. Pritchett E, et al. Am J Cardiol 2003;92:94–946. EURIDIS and ADONIS: Dronedarone Reduces Significantly and Consistently Ventricular Rate at First AF/AFL Recurrence Placebo Dronedarone 120 117.5 116.6 P<0.001 P<0.0001 115 110 104.6 105 102.3 100 Mean Ventricular Rate (TTEM) Rate Ventricular Mean 95 n=102 n=188 n=117 n=199 90 ADONIS EURIDIS Dronedarone reduces ventricular rate across the spectrum of AF patients Paroxysmal Permanent and persistent AF patients2 AF patients1 0 -13.7* -11.7 -4 bpm bpm p<0.001 p<0.0001 -8 EURIDIS/ ERATO ADONIS Primary endpoint Secondary -12 endpoint -16 Reduction in ventricular rate (bpm) vs. vs. placebo (bpm) rate ventricular in Reduction * MULTAQTM : 103.4 bmp vs. Placebo: 117.1 bmp Primary endpoint EURIDIS/ADONIS : time to first AF/AFL 1. Singh BN et al. N Engl J Med 2007;357:987–99. recurrence 2. Davy et al. Am Heart J 2008;156:527.e1-527.e9. 22%/27% reduction in relative risk (p=0.01/p=0.002) 12 Dronedarone EURIDIS & ADONIS Singh BN et al. NEJM 2007;357:987-999. Dyonisios: Primary Endpoint: More AF Events But Less Early Discontinuation With Dronedarone 1.0 0.8 184 (73.9%) 43 endpoints 0.6 42 endpoints 141 (55.3%) 0.4 0.2 RRR (95%CI) = 1.589 (1.275;1.98) p-value <0.001 Cumulative incidenceCumulative 0.0 0 3 6 9 12 15 Months Dronedarone Patients at risk Amiodarone 249 99 84 40 12 0 255 146 126 61 13 0 Dronedarone Amiodarone (n=249) (n=255) Number of patients with endpoint 184 (73.9%) 141 (55.3%) ECG documented AF endpoint 158 (63.5%) 107 (42.0%) Documented AF after conversion 91 (36.5%) 62 (24.3%) Unsucessful electrical cardioversion 29 (11.6%) 16 (6.3%) No spontaneous conversion and no electrical 38 (15.3%) 29 (11.4%) cardioversion on day 10 to day 28 Premature study drug discontinuation 26 (10.4%) 34 (13.3%) Lack of efficacy 1 (0.4%) 0 Intolerance 25 (10.0%) 34 (13.3%) ANDROMEDA – inclusion criteria • Consecutive hospitalized patients 18 years • New/worsening HF with at least another episode of decompensation corresponding to NYHA class III–IV within the last month, and treated with a diuretic • WMI < 1.2 ~ LVEF < 0.35 Randomized < 7days after hospital admission ANDROMEDA: all-cause mortality Placebo Dronedarone 400 mg bid 0.8 Placebo Dronedarone 800 mg 0.7 (n=317) (n=310) 0.6 Number of patients who died 12 25 Relative risk (relative to placebo) 2.3 0.5 95% CI [1.07; 4.25] 0.4 Log rank p value 0.03 0.3 Cumulative Incidence Cumulative 0.2 0.1 0.0 Time (days) 0 30 60 90 120 150 180 210 240 ANDROMEDA study. NEJM 2008. ANDROMEDA: cause of death Increased in patients with very low EF (WMI < 1) ATHENA:Patient Characteristics Placebo Dronedarone All patients (N=2327) (N=2301) (N=4628) Age (mean; SD, years) 72 ± 9.0 72 ± 8.9 72 ± 9.0 Female gender 1038 (45%) 1131 (49%) 2169 (47%) AF/AFI at baseline 586 (25%) 569 (25%) 1155 (25%) Structural heart disease 1402 (61%) 1330 (58%) 2732 (60%) Hypertension 1996 (86%) 1999 (87%) 3995 (86%) Coronary heart disease 737 (32%) 668 (29%) 1405 (30%) Valvular heart disease 380 (16%) 379 (17%) 759 (16%) Non-ischemic 131 (6%) 123 (5%) 254 (6%) cardiomyopathy History of CHF NYHA 515 (22%) 464 (20%) 979 (21%) II/III LVEF< 0.45 285/2281 (13%) 255/2263 (11%) 540/4544 (12%) LVEF< 0.35 87/2281 (4%) 92/2263 (4%) 179/4544 (4%) Lone atrial fibrillation 139 (6%) 140 (6%) 279 (6%) Pacemaker 243 (10%) 214 (9%) 457 (10%) Hohnloser SH, et al. NEJM 2009;360:668-78. ATHENA: Primary Outcome: Risk of unplanned CV hospitalisation or death from any cause 50 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 24% 40 reduction in relative risk 30 HR=0.76 p<0.001 20 The number needed to treat (NNT) to prevent one first CV 10 hospitalisation or death is 13 Cumulative (%) Cumulative Incidence 0 Months Patients at risk: 0 6 12 18 24 30 Placebo 2327 1858 1625 1072 385 3 DR 400mg bid 2301 1963 1776 1177 403 2 Hohnloser SH, et al. NEJM 2009;360:668-78. 19 ATHENA: Dronedarone significantly reduced the relative risk of stroke by 34% 5 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 4 34% reduction in relative 3 risk 2 HR=0.66 1 p=0.027 Cumulative (%) Cumulative Incidence 0 Months 0 6 12 18 24 30 Patients at risk: Placebo 2327 2275 2220 1598 618 6 DR 400mg bid 2301 2266 2223 1572 608 4 Mean follow-up 21 ±5 months. Connolly et al; Circulation. 2009;120:1174-1180. ATHENA: Incidence of Stroke CHADS2 score ≤1 Post Hoc Analysis ≥2 CHF Cumulative incidence of stroke, % No 5 Yes HR = 0.66 Hypertension 4 P = 0.027 No Yes 3 Age in years <75 2 ≥75 Diabetes mellitus 1 Placebo Dronedarone No 0 Yes 0 6 12 18 24 30 Stroke/TIA Months No Yes 0.1 1.0 10.0 Connolly SJ, et al.