Atrial Fibrillation 2009 Michael Glikson, MD Director of Pacing & Electrophysiology Leviev Heart Center Sheba medical Center Sheba Medical Center Tel Hashomer The Leviev Heart Center
Rhythm vs rate control PIAF RACE STAF AFFIRM None of the studies reported advantage of rhythm control for survival / stroke risk
Patients who Maintained Sinus Rhythm in Outcome Studies had Better Prognoses INTERNAL USE ONLY Patients in sinus rhythm, independent of the treatment group DIAMOND 1 HR 0.44 95% CI 0.30-0.64; p<0.0001 AFFIRM 2 HR 0.53 99% CI 0.39-0.72; p<0.0001 0 0.5 1 1.5 2 2.5 Reduced mortality risk Hazard Ratio (HR) Increased mortality risk 1. Pedersen OD. et al. Circulation. 2001;104:292-296 2. Corley SD et al. Circulation 2004; 109:1509-13.
AFFIRM effect of SR Better survival (Circ 2004) Less strokes (Arch Int Med 2005) Better NYHA FC (JACC 2005)
Rhythm Control The beneficial effect of maintaining sinus rhythm is offset by the adverse effects of medications We should aim at alternative methods of maintaining sinus rhythm
Is rhythm control obsolete? The rumors of my death have been greatly exaggerated Mark Twain
New Approaches to Rhythm Control Novel medications Ablation procedures Surgery
RF catheter ablation for pts with AF 1C flutter ablation: hybrid therapy Pulmonary vein isolation and Left atrial circumferential ablation Ablate and pace approach
Atrial flutter - approach
Flutter medical therapy 42% at 1 mo Babaev et al. AJC 2003
Cava-tricuspid isthmus ablation > 95% technical success < 10% recurrence > 90% long term freedom from recurrence of AFL? % long term recurrence of AF
Class 1C atrial flutter ablation Sequence: Paroxysmal AFib Drug for arrhythmia prevention (1C or Amiodarone) Arrhythmia recurrence as typical Atrial Flutter Flutter ablation (TVA-IVC line) Results: 70-80 % free from AFib during 6-8 months f/u
Focal atrial fibrillation Concept Single very fast firing focus initiates chaotic activation of atria Proximal pulmonary veins musculature harbor arrhythmogenic foci in the vast majority of cases Elimination or isolation of pulmonary vein focus by ablation can cure AF
Focal Trigger within PV
Muscular skeleton of PV s- LA junctions Nathan H, and Eliakim M., Circulation, 1966;34:412-422
CARTO LEFT ATRIAL CIRCUMFERENTIAL ABLATION (LACA) NAVEX LSPV LIPV LAA RSPV & RIPV COMMON ORIFICE TVA
Circumferential (linear) PV ablation Freedom from AF Survival % patients dead 5 years AF(+) AF(-) JACC, 2003
Wazni, O. M. et al. JAMA 2005.
Circulation 2008 53 vs 59 AARx vs RF ablation Pts resistant to > 1 AA medication 63% crossover from medical group 9% crossover from ablation group QOL improved
Real World Results @ 1 year PAF > 70% success (may require > 1 procedure) Persistent >50 % Long lasting (1 year) < 50%
Complications of AF ablation Tamponade 1-2 % PV stenosis / occlusion (technique dependent) 1-2% Atrio Esophageal fistula very rare, often fatal Phrenic injury rare CVA < 1 % (few TIAs) Post ablation exacerbation of arrhythmias (usually transient)
Potential Reasons for ablation QOL! CHF Stroke??? Survival??? Stopping anticoagulation NO! AT THIS TIME PRIMARY JUSTIFICATION PRESENCE OF SYMPTOMATIC AF
Rate control Methods -Drugs ( AVN slowing agents) - AVN RF Ablation ( Ablate and Pace ) Efficacy 100%
Ozcan, NEGM 2001 Survival after AV node ablation Mayo Clinic experience 350 pts 229 controls on drugs 36 ± 26 mo f/u None of 26 pts with lone AF die
Ablate and pace approach ADVANTAGES Simple Safe Fast About 100% successful Symptomatic relief Diminish drug burden Meta analysis of 21 studies (1181 pts)
Ablate and pace approach DISADVANTAGES PM dependence Chronic AF CHF exacerbation in some cases Pacemaker induced cardiomyopathy
PABA CHF (n= 82) Khan NEJM 2008
AF Surgery Classical Cox Maze procedure >90% success Mini maze Concomittant surgery Stand alone
INTERNAL USE ONLY Dronedarone has Key Structural Differences to Amiodarone Dronedarone O (CH 2 ) 3 CH 3 CH 3 SO 2 HN O(CH 2 ) 3 N (CH 2 ) 3 CH 3 O (CH 2 ) 3 CH 3 Amiodarone O (CH 2 ) 3 CH 3 I O(CH 2 ) 2 N CH 2 CH 3 O I CH 2 CH 3
INTERNAL USE ONLY Dronedarone Displays Important Differences to Amiodarone Blocks Multiple K + Channels Na + Channel Blockade Sympathetic Blockade Ca 2+ Channel Blockade Overall Effects Slows heart rate Slows ventricular rate in atrial fibrillation Prolongs APD and QT/QTc Similar electrophysiological and antifibrillatory effects in ventricles and atria Reduces effect of EDA in M-cells and PF Reduces intrinsic and drug-induced heterogeneity of myocardial refractoriness Negligible proarrhythmia and may be anti-torsadogenic potential Elimination half-life 1-2 days Anti-ischemic and Antifibrillatory LVEF: Not Much Influence Pulmonary Fibrosis Unusually Long Plasma Half-life Shared Properties Non shared properties Thyroid Hormone Effects
INTERNAL USE ONLY Overview of Key Clinical Trials EURIDIS N=615 (Europe) 400 mg BID vs placebo Atrial Fibrillation/Atrial Flutter Maintenance Atrial Fibrillation/ Atrial Flutter DAFNE N=270 (Europe) 400, 600, 800 mg BID vs placebo Atrial Fibrillation/Atrial Flutter Conversion + Maintenance ADONIS N=629 (US, CN, AU, AG, SA) 400 mg BID vs placebo Atrial Fibrillation/Atrial Flutter Maintenance ERATO N=160 (Europe) 400 mg BID vs placebo Rate Control ATHENA N=4,628 400 mg BID vs placebo Morbidity/Mortality in Atrial Fibrillation + High CV Risk Left Ventricular Dysfunction ACT2401 N=124 (US) 400, 800, 1,200 mg vs placebo Safety in HF ANDROMEDA N=627/1000 400 mg BID vs placebo Morbidity/Mortality in HF
Adonis and Euridis Trials: N= 800 vs 400 Increased time to 1 st recurrence Safety = placebo (NEJM 2007)
Dronedarone Increased Time to First Recurrence of AF/AFL INTERNAL USE ONLY Placebo Dronedarone 180 160 x 2.67 158 140 Days 120 100 80 60 40 59 x 2.34 41 96 x 2.19 53 116 20 0 n=146 n=246 n=155 n=272 ADONIS EURIDIS n=155 n=272 Combined Singh BN et al. N Engl J Med 2007;357:987 99
INTERNAL USE ONLY Cumulative Incidence of All-cause Mortality 0.8 0.7 Placebo DR 400mg bid Cumulative Incidence 0.6 0.5 0.4 0.3 0.2 0.1 Placebo (n=317) Dronedarone 800mg (n=310) Number of patients who died 12 25 Relative risk (relative to placebo) 2.3 95% CI [1.071; 4.247] Log rank p value 0.02717 No. at risk: 0.0 0 30 60 90 120 150 180 210 Time (days) Placebo 317 256 181 103 50 18 6 1 DR 400mg bid 310 257 174 104 59 22 5 1 Køber L et al. N Engl J Med. 2008;358:2678-87
A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patients with Atrial fibrillation/atrial flutter (AF/AFL) INTERNAL USE ONLY
INTERNAL USE ONLY Objective Evaluate the efficacy and safety of dronedarone 400 mg bid vs placebo in the prevention of CV hospitalisation or death from any cause over a minimum treatment and follow-up duration of 12 months in patients with paroxysmal or persistent AF/AFL Study design : Prospective multicenter trial (551 centers in 37 countries) with 4,628 AF patients already receiving standard therapy including rate control and antithrombotics Inclusion criteria High-risk patients with a history of paroxysmal or persistent AF/AFL Aged 75 years with or without additional risk factors Aged 70 years and 1 risk factor (hypertension; diabetes; prior stroke/tia; LA 50 mm; LVEF < 0.40) Hohnloser SH et al. J Cardiovasc Electrophysiol 2008;19:69-73
ATHENA shows for the 1st time an antiarrhythmic drug reduces CV hospitalizations or deaths INTERNAL USE ONLY 13 Cummulative Incidence (%) Patients at risk Placebo Dronedarone 50 40 30 20 10 Primary Endpoint 0 0 6 12 18 24 30 2327 2301 1858 1963 Mean follow-up 22 ± 5 months RRR=24.2 % P=0.00000002 1625 1776 1072 1177 385 403 3 2 Placebo Dronedarone Months
ATHENA : Reduction in CV Hospitalizations and CV deaths INTERNAL USE ONLY Outcome Placebo (N=2327) Dronedarone (N=2301) RRR (%) P-value First hospitalization for Cardiovascular reasons 859 675 25 <0.001 Atrial fibrillation 510 335 37 <0.001 Congestive heart failure 132 112 14 0.221 Acute coronary syndrome 89 62 30 0.030 Syncope 32 27 15 0.542 CV death 94 65 30 0.025 Sudden cardiac death 35 14 60 0.003 Death from any cause 139 116 16 0.176 18
INTERNAL USE ONLY Significant reduction in Stroke Cummulative Incidence (%) 5 4 3 2 1 HR=0.66 (RRR =34%) p=0.027 Placebo Dronedarone 0 0 6 12 18 24 30 Months 2327 2301 2275 2266 2220 2223 1598 1572 618 608 6 4 Placebo Dronedarone Mean follow-up 21 ± 5 months
Adverse events in randomized and treated patients Placebo (N=2313) Dronedarone (N=2291) INTERNAL USE ONLY Patients with any TEAE 1603 (69%) 1649 (72%) Gastro-intestinal 508 (22%) 600 (26%) Respiratory 337 (15%) 332 (15%) Skin 176 (8%) 237 (10%) Creatinine increase 31 (1%) 108 (4.7%) Patients with any serious TEAE 489 (21%) 456 (20%) Gastro-intestinal 68 (3%) 81 (4%) Respiratory 45 (2%) 41 (2%) Skin 6 (0.3%) 7 (0.3%) Creatinine increase 1 (<0.1%) 5 (0.2%) Patients permanently discontinued study drug for any TEAE 187 (8%) 290 (13%)
INTERNAL USE ONLY Trial Summary - ATHENA What did the trial investigate? Effect of dronedarone on CV outcomes, specifically on the prevention of CV hospitalisation or death from any cause What were the main results? Dronedarone significantly reduced hospitalisation/death Dronedarone reduced the risk of stroke (post hoc analysis) What are the implications for Dronedarone communication? Dronedarone is the first and only AAD to demonstrate outcomes benefits in AF patients, in the largest AAD trial
Athena - conclusions In patients with PAF and embolic risk factors: Dronedarone significantly reduced hospitalization/death Dronedarone reduced the risk of stroke (post hoc analysis) Dronedarone is the first and only AAD to demonstrate outcomes benefits in AF patients, in the largest AAD trial Sheba Medical Center Tel Hashomer The Leviev Heart Center