Atrial Fibrillation 2009

Transcription

1 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

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3 Rhythm vs rate control PIAF RACE STAF AFFIRM None of the studies reported advantage of rhythm control for survival / stroke risk

4 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 % CI ; p< AFFIRM 2 HR % CI ; p< Reduced mortality risk Hazard Ratio (HR) Increased mortality risk 1. Pedersen OD. et al. Circulation. 2001;104: Corley SD et al. Circulation 2004; 109:

5 AFFIRM effect of SR Better survival (Circ 2004) Less strokes (Arch Int Med 2005) Better NYHA FC (JACC 2005)

6 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

7 Is rhythm control obsolete? The rumors of my death have been greatly exaggerated Mark Twain

8 New Approaches to Rhythm Control Novel medications Ablation procedures Surgery

9 RF catheter ablation for pts with AF 1C flutter ablation: hybrid therapy Pulmonary vein isolation and Left atrial circumferential ablation Ablate and pace approach

10 Atrial flutter - approach

11 Flutter medical therapy 42% at 1 mo Babaev et al. AJC 2003

12 Cava-tricuspid isthmus ablation > 95% technical success < 10% recurrence > 90% long term freedom from recurrence of AFL? % long term recurrence of AF

13 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: % free from AFib during 6-8 months f/u

14 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

15 Focal Trigger within PV

16 Muscular skeleton of PV s- LA junctions Nathan H, and Eliakim M., Circulation, 1966;34:

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18 CARTO LEFT ATRIAL CIRCUMFERENTIAL ABLATION (LACA) NAVEX LSPV LIPV LAA RSPV & RIPV COMMON ORIFICE TVA

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20 Circumferential (linear) PV ablation Freedom from AF Survival % patients dead 5 years AF(+) AF(-) JACC, 2003

21 Wazni, O. M. et al. JAMA 2005.

22 Circulation vs 59 AARx vs RF ablation Pts resistant to > 1 AA medication 63% crossover from medical group 9% crossover from ablation group QOL improved

23 Real World 1 year PAF > 70% success (may require > 1 procedure) Persistent >50 % Long lasting (1 year) < 50%

24 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)

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26 Potential Reasons for ablation QOL! CHF Stroke??? Survival??? Stopping anticoagulation NO! AT THIS TIME PRIMARY JUSTIFICATION PRESENCE OF SYMPTOMATIC AF

27 Rate control Methods -Drugs ( AVN slowing agents) - AVN RF Ablation ( Ablate and Pace ) Efficacy 100%

28 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

29 Ablate and pace approach ADVANTAGES Simple Safe Fast About 100% successful Symptomatic relief Diminish drug burden Meta analysis of 21 studies (1181 pts)

30 Ablate and pace approach DISADVANTAGES PM dependence Chronic AF CHF exacerbation in some cases Pacemaker induced cardiomyopathy

31 PABA CHF (n= 82) Khan NEJM 2008

32 AF Surgery Classical Cox Maze procedure >90% success Mini maze Concomittant surgery Stand alone

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34 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

35 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

36 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, 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/ mg BID vs placebo Morbidity/Mortality in HF

37 Adonis and Euridis Trials: N= 800 vs 400 Increased time to 1 st recurrence Safety = placebo (NEJM 2007)

38 Dronedarone Increased Time to First Recurrence of AF/AFL INTERNAL USE ONLY Placebo Dronedarone x Days x x 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

39 INTERNAL USE ONLY Cumulative Incidence of All-cause Mortality Placebo DR 400mg bid Cumulative Incidence Placebo (n=317) Dronedarone 800mg (n=310) Number of patients who died Relative risk (relative to placebo) % CI [1.071; 4.247] Log rank p value No. at risk: Time (days) Placebo DR 400mg bid Køber L et al. N Engl J Med. 2008;358:

40 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

41 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

42 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 Primary Endpoint Mean follow-up 22 ± 5 months RRR=24.2 % P= Placebo Dronedarone Months

43 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 <0.001 Atrial fibrillation <0.001 Congestive heart failure Acute coronary syndrome Syncope CV death Sudden cardiac death Death from any cause

44 INTERNAL USE ONLY Significant reduction in Stroke Cummulative Incidence (%) HR=0.66 (RRR =34%) p=0.027 Placebo Dronedarone Months Placebo Dronedarone Mean follow-up 21 ± 5 months

45 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%)

46 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

47 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

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