Section II: Clinical Management of AFib

Section II: Clinical Management of AFib

Section II. Clinical Management of AFib
Clinical Evaluation of AFib Treatment Options for AFib Cardioversion Drugs to prevent AFib Drugs to control ventricular rate Drugs to reduce thromboembolic risk Non-pharmacological options

1. Clinical Evaluation of AFib

Clinical Evaluation Minimum Discretionary
History and Physical examination Electrocardiogram Trans-thoracic echocardiogram Blood tests of thyroid, renal and hepatic function Discretionary Six-minute walk test Exercise testing Holter monitoring or event recording Trans-oesophageal echocardiography Electrophysiological study Chest radiograph ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

Opportunistic Case Finding
In patients presenting with symptoms commonly associated with AFib: breathlessness/dyspnoea palpitations syncope/dizziness chest discomfort Manual pulse palpation should be performed to determine the presence of an irregular pulse that may indicate underlying AFib NICE recommendation: Developed by National Collaborating Centre for Chronic Conditions at the Royal College of Physicians; Atrial fibrillation: full guideline DRAFT (January 2006)

Primary Therapeutic Aims in AFib
Restore and maintain sinus rhythm whenever possible Prevent thromboembolic events In order to: Reduce symptoms and improve QoL Minimize impact of AFib on cardiac performance Reduce risk of stroke Minimize cardiac remodeling ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

2. Treatment Options for AFib

Treatment Options for AFib
Cardioversion Pharmacological Electrical Drugs to prevent AFib Antiarrhythmic drugs Non-antiarrhythmic drugs Drugs to control ventricular rate Drugs to reduce thromboembolic risk Non-pharmacological options Electrical devices (implantable pacemaker and defibrillator) AV node ablation and pacemaker implantation (ablate & pace) Catheter ablation Surgery (Maze, mini-Maze)

Treatment Options for AFib Cardioversion

Cardioversion of AFib Pharmacological Electrical Early onset AFib
Long-standing AFib Electrical Transthoracic

Cardioversion of AFib Prompt treatment essential
Limit duration to minimize cardiac remodelling Avoid anticoagulation therapy (necessary for arrhythmias that last >48 hours) Avoid prolonged hospital recovery Improve quality of life

Pharmacological Cardioversion

Pharmacological Cardioversion
More effective in recent-onset AFib Class IA-IC-III drugs administered IV Class IC favoured in non-cardiopathic patients Class III favoured in cardiopathic patients or those with delays in conduction Oral loading can be performed with class IC drugs Flecainide ( mg) Propafenone ( mg)

Pharmacological Cardioversion Recent onset AFib

Oral Loading with Class IC Drugs for Recent Onset AFib
Flecainide 300 mg Propafenone 600 mg Placebo 100 p<0.001 vs. placebo p<0.001 vs. placebo 80 78 72 59 60 51 SR (%) 39 40 18 20 3 hours 8 hours Capucci A, et al. Am J Cardiol (1994) 74: 503

Cardioversion of Paroxysmal AFib with Class IC Drugs
Paroxysmal AFib (<48h), good LVEF Class IC drugs (propafenone, flecainide) IV 2 mg/kg mg/kg/min, maintenance Oral administration flecainide 300 mg propafenone 600 mg Mean efficacy: 80% Mean time of efficacy: 3h Proarrhythmia: FLA 1:1 ECG monitoring necessary (<0.5%) with patients in resting condition

Risk with Class IC Drugs: Transformation of AFib into Atrial Flutter with 1:1 AV Conduction
Flecainide

Treatment Out-of-Hospital with Class IC Drugs
Symptomatic, rare episodes of AFib Recent onset AFib No structural heart disease Prior hospital experience Good physician-patient relationship Resting conditions for at least 4 hours

Pill-in-the-Pocket In a selected (no or mild HD), risk-stratified patient population with recurrent AFib not currently taking AADs 79% developed ≥ 1 episodes of recurrent AFib during 15 ± 5m follow-up Acute oral flecainide or propafenone successfully terminated 94% of episodes within 113 ± 84 min, with side effects in 7% of patients Alboni P, et al. N Engl J Med (2004) 351: 2384

Pill-in-the-Pocket 45.6 15 4.9 1.6 Number per month Calls to ER
Prior to enrolment During follow-up 50 45.6 50 p<0.001 p<0.001 Number per month 25 Number per month 25 15 4.9 1.6 Calls to ER Hospitalisation Alboni P, et al. N Engl J Med (2004) 351: 2384

Conversion to SR with Amiodarone IV (randomized studies)
Control drug n Primary endpoint Duration of study OR of SR with amiodarone p Cowan et al Digoxin IV 34 Conversion to sinus rhythm 24 h 1.11 NS Hou et al 50 1.30 0.0048 Cotter et al Placebo 80 1.34 0.029 Galve et al 100 1.13 0.532 Donovan et al 64 1.05 Flecainide 66 0.86 Nos et al Verapamil 24 3 h 77% amiod./ 0% verap <0.001 McAlister et al Quinidine 36 8 h 0.64 0.04 Pilati et al 75 1.09 Kerin et al 32 1.07 Di Biasi et al Propafenone 40 1.15 Larbuisson et al 84 1.22 Chapman et al Procainamide 26 12 h 0.99 Moran et al Magnesium sulfate 42 <0.05 Connolly SJ Circulation (1999) 100: 2025

Amiodarone for Cardioversion of Recent-Onset AFib: Meta-analysis
Bolus only 100 Bolus + infusion 95 Amiodarone IV (3-7 mg/kg ± infusion g/day) Amiodarone oral (25-30 mg/kg) Time to conversion > 6-8 h Amiodarone > 1.5 g/day IV > placebo Amiodarone mg/kg oral > placebo Amiodarone not > other AADs Safe in patients with structural cardiopathies and low LVEF 80 69 60 55 Conversion (%) 40 34 20 2-4 h 8 h Khan IA, et al. Int J Cardiol (2003) 89: 239

Time to conversion (hours)
Amiodarone Single Oral Administration for Cardioversion of Recent Onset AFib Amiodarone Placebo 100 80 60 Patients in AFib (%) 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 Time to conversion (hours) Peuhkurinen K, et al. Am J Cardiol (2000) 85: 462

Flecainide IV vs Amiodarone IV for Cardioversion in Recent-Onset AFib
32 Flecainide Placebo 28 p=0.001 p=0.007 24 20 Cardioversion (%) 16 12 8 4 1 2 3 4 5 6 7 8 (hours) Donovan KD, et al. Am J Cardiol (1995) 75: 693

Pharmacological Cardioversion Long-lasting AFib

Effect of Duration on Efficacy of Pharmacological Cardioversion
106 patients with AFib <6 months Flecainide 100 Sotalol * p=0.005 80 69* 60 52* 44 40 31 23 20 17 Total <24 hours <7 days <6 months Reisinger J, et al. Am J Cardiol (1998) 81: 1450

Amiodarone Cardioversion in Persistent AFib
67 patients with AFib >48 hours A B Amiodarone 100 Placebo p<0.001 82 80 AFib (m) >1 <1 30 77 65 60 Sinus rhythm (%) Total 48 40 32 31 20 LA (mm) >45 <45 LVEF (%) >50 <50 Kochiadakis GE, et al. Am J Cardiol (1999) 83: 61

Conversion of Atrial Flutter or AFib with Ibutilide IV
266 patients 100 100 p<0.0001 p<0.0001 80 80 60 60 Sinus rhythm (%) Sinus rhythm (%) 40 40 20 20 Ibutilide Placebo AFlutter AFib Adverse effects: 8.3% polymorphic ventricular tachycardia Stambler BS, et al. Circulation (1996) 94: 1613

Conversion of Atrial Flutter or AFib with Ibutilide IV
Effect “on top” of long-term amiodarone 80 60 54 70 patients (57 AFib, 13 AFlutter) Ibutilide 2 mg 39 Recovery of SR (%) 40 20 AFlutter AFib Glatter K, et al. Circulation (2001) 103: 253

Electrical Cardioversion (transthoracic)

Technical Aspects Impedence Position of paddles
The efficacy of electrical cardioversion depends on the density of current delivered to the atrial myocardium, which is dependent on: Impedence Position of paddles Pressure applied to paddles Waveform

Transthoracic Cardioversion of Atrial Fibrillation Comparison of Rectilinear Biphasic vs Damped Sine Wave Monophasic Shocks Suneet Mittal, Shervin Ayati, Kenneth M. Stein, David Schwartzman, Doris Cavlovich, Patrick J. Tchou, Steven M. Markowitz, David J. Slotwiner, Marc A. Scheiner, Bruce B. Lerman. Circulation 2000; 101:

Defibrillation Waves msec msec Monophasic wave Biphasic wave 4 8 12 4
30 10 20 Ampere Ampere 10 -10 4 8 12 4 8 12 msec msec Mittal S, et al. Circulation (2000) 101: 1282

Cumulative Efficacy of Cardioversion
Monophasic or biphasic shock p<0.005 p<0.0001 100 94 91 85 79 80 68 68 60 Efficacy of cardioversion (%) 44 40 21 20 100 J 200 J 300 J 360 J 70 J 120 J 150 J 170 J Monophasic Biphasic Mittal S, et al. Circulation (2000) 101: 1282

Biphasic vs Monophasic Shock Waveform for Conversion of Atrial Fibrillation The Results of an International Randomized, Double-Blind Multicenter Trial RL Page, RE Kerber, JK Russel, T Trouton, J Waktare, D Gallik, JE Olgin, P Ricard, GW Dalzell, R Reddy, R Lazzara, K Lee, M Carlson, B Halperin, GH Bardy, for the BiCard Investigators. JACC (2002) 39:

Dermal Injury Dependent on Waveform
60 Monophasic Biphasic 50 40 30 20 10 None (no erythema) Mild (no tenderness) Moderate (tenderness) Severe (blistering) Page RL, et al. J Am Coll Cardiol (2002) 39: 1956

Success of Monophasic (MP) and Biphasic (BP) Waveforms at Cumulative Energy
Levels Adgey AA & Walsh SJ Heart (2004) 90: 1493

Success of Cumulative Shocks for Different Biphasic Devices
Adgey AA & Walsh SJ Heart (2004) 90: 1493

Electrical Cardioversion Pharmacological pretreatment and management of recurrence

Failure of Electrical Cardioversion
100 Immediate recurrent AFib No conversion Early recurrent AFib Late recurrence AFib 90 80 70 60 Sinus rhythm (%) 50 40 30 20 10 2 min 2 weeks 1 year cardioversion Van Gelder IC, et al. Am J Cardiol (1999) 84: 147R

Recurrence Following Cardioversion: AFFIRM Study
AFFIRM:most recurrences occur within 2 months of cardioversion Rate control Rhythm control Treatment Arm 100 80 60 Patients with AF Recurrence (%) 40 Log rank statistic = 58.62 p<0.0001 20 1 2 3 4 5 6 Time (years) N, Events (%) Rate control: 563,3 (0) 167,383 (69) 96,440 (80) 42,472 (87) 10,481 (92) 2,484 (95) Rhythm control: 729,2 (0) 344,356 (50) 250,422 (60) 143,470 (69) 73,494 (75) 18,503 (79) Raitt MN, et al. Am Heart J (2006) 151: 390

Immediate Recurrence of AFib Following Successful Electrical Cardioversion

Immediate/Early Recurrence of AFib After Electrical Cardioversion
Authors n ERAF (%) Timing Bertaglia 90 28 7 days Bianconi 96 18 24 hours Botto 156 61 Daoud 337 9 5 min De Simone 107 14 Tieleman 36 5 days Villani 116 7 Yu 50 26 1 min

Effect of Atrial Fibrillation Duration on Probability of Immediate Recurrence after Transthoracic Cardioversion H Oral, M Ozadyn, C Sticherling, H Tada, C Scharf, A Chugh, SWK Lai, F Pelosi, BP Knight, SA Strickeberger, F Morady. JCE 2003; 14: 182-5

Immediate Recurrence of AFib (IRAF) According to the Duration of Arrhythmia
100 90 80 70 60 48 Prevalence of IRAF (%) 50 40 27 30 20 34 45 13 36 40 10 72 £1 hr 1-24 hrs 1-7 days 7-30 days 31-90 days days days >365 days Duration of AFib Oral H, et al. J Cardiovasc Electrophysiol (2003) 14: 182

Authors Bertaglia Bianconi Botto Daoud De Simone Tieleman Villani Yu
Immediate and Early Recurrence Following Cardioversion Authors Bertaglia Bianconi Botto Daoud De Simone Tieleman Villani Yu Pts (n) 90 96 156 337 107 61 116 50 ERAF (%) 28 18 61 9 14 36 7 26 Timing 7 days 24 hours 5 min 5 days 1 min

Oral Propafenone Before Electrical Cardioversion in Persistent AFib
Effect on early recurrence of arrhythmia 100 70 p<0.01 p<0.002 60 90 52 50 80 40 Sinus rhythm (%) Complex atrial arrhythmia (%) 30 70 18 20 60 Placebo Propafenone 10 50 10 min 24 min 48 min 10 minutes Bianconi L, et al. J Am Coll Cardiol (1996) 28: 700

Effect of Pre-treatment with Oral Amiodarone
GIK Amiodarone No treatment GIK Amiodarone No treatment 30 100 p<0.005 p<0.05 24 80 18 60 Conversion (%) Conversion (%) 12 40 6 20 SR before ECV SR with cardioversion No differences in energy for cardioversion Capucci A, et al. Eur Heart J (2000) 21: 66

Short- and Long-term Treatment with Amiodarone after Cardioversion Reduces Recurrence
Stable anticoagulation for 2 weeks Randomization 172 Protocol violation = 4; Withdrew consent = 7 Placebo 38 Short-term Amiodarone 62 Long-term Amiodarone 61 30 32 38 16 10 DCCV 100 Sinus Rhythm Chemical 26 Placebo 30 Short-term Amiodarone 48 Long-term Amiodarone 48 Sinus Rhythm at 8 weeks Placebo 6 (16%) Short-term Amiodarone 29 (47%) Long-term Amiodarone 34 (56%) Sinus Rhythm at 52 weeks Placebo 2 (5%) Short-term Amiodarone 20 (32%) Long-term Amiodarone 30 (49%) Chenner KS, et al. Eur Heart J (2004) 25: 144

Effect of Pre-treatment with Ibutilide IV
SR before ECV SR after ECV AFib Successful cardioversion in all patients given ibutilide and in 14/50 patients failing cardioversion alone The mean energy for defibrillation was less with ibutilide Sustained polymorphic tachycardia in 2/64 (3%) patients treated with ibutilide within 15 min of the infusion 50 40 30 Patients (%) 20 10 IBU No IBU Oral H, et al. N Engl J Med (1999) 340: 1849

Pre-treatment with Verapamil in Patients with Persistent or Chronic Atrial Fibrillation Who Underwent Electrical Cardioversion A De Simone, G Stabile, DF Vitale, P Turco, M Di Stasio, F Petrazzuoli, M Gasparini, C De Matteis, R Rotunno, T Di Napoli. J Am Coll Cardiol (1999) 34: 810-4

Pre-treatment with Verapamil for Reducing Recurrence post-ECV
PFN 60 PFN + VER PFN - VER p=0.04 50 p=0.02 p=0.04 39 p=0.01 40 30 Recurrence (%) 30 20 17 15 10 10 6 1 week 3 months De Simone A, et al. J Am Coll Cardiol (1999) 34: 810

Effects of Pre-treatment with Verapamil on Early Recurrences after Electrical Cardioversion of Persistent Atrial Fibrillation A Randomised Study E Bertaglia, D D’Este, A Zanocco, F Zerbo, P Pascotto. Heart (2001) 85:

Effect of Pre-treatment with Verapamil on Early Recurrence Following ECV
A randomised trial (90 patients with amiodarone) 60 Amio + Ver Amio NS 50 NS 40 Recurrence (%) 30 NS 20 10 6 h 7 d 30 d Follow-up Bertaglia E, et al. Heart (2001) 85:

Effect of Verapamil on Immediate and Early Recurrence after Cardioversion of AFib
Effectiveness demonstrated A De Simone et al (JACC 1999) E Daoud et al (JCE 2000) GQ Villani et al (AHJ 2002) A De Simone et al (AJC 2002) GL Botto et al (JACC 2002) Not efficacious E Bertaglia et al (Heart 2001) T Van Noord et al (JCE 2001) H Ramanna et al (JACC 2001)

Cardioversion of AFib and Maintenance of SR
100 1 ECV, no AADs Serial ECV 90 80 70 60 Maintenance of SR (%) 50 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 Months post-cardioversion Van Gelder IC, et al. Arch Int Med (1996) 156: 2585

Success of Serial External Electrical Cardioversion of Persistent Atrial Fibrillation in Maintaining Sinus Rhythm E Bertaglia, D D’Este, F Zerbo, F Zoppo, P Delise, P Pascotto. European Heart Journal (2002) 23:

Serial Electrical Cardioversion
90 patients with persistent AFib who had previously undergone at least one successful electrical cardioversion Randomization Cardioversion repeated up to 2 times in case of recurrent AFib within 1 month of the preceding electrical cardioversion (Group AGG) or Recurrences were left untreated (Group CTL) Bertaglia E, et al. Eur Heart J (2002) 23: 1522

Persistence of Sinus Rhythm During Long-term Follow-up
Aggressive repeated ECV beneficial in highly recurrent persistent AFib Sinus rhythm (%) days Bertaglia E, et al. Eur Heart J (2002) 23: 1522

2.Treatment Options for AFib Drugs to Prevent AFib

Drugs to Prevent AFib Antiarrhythmic drugs Non-antiarrhythmic drugs
Class I-III antiarrhythmics Non-antiarrhythmic drugs ACE-I, ARBs Statins PUFA

Rationale for Drug Treatment to Prevent Recurrence
Suppression of symptoms Avoidance of tachycardia-induced cardiomyopathy Reduction of thromboembolism Prevention of heart failure? Decrease of mortality?

Drugs to Prevent AFib Antiarrhythmics

Vaughan Williams Classification
Type lA Disopyramide Procainamide Quinidine Type IB Lidocaine Mexiletine Type IC Flecainide Moricizine Propafenone Type II Beta-blockers Type III Amiodarone Bretylium Dofetilide Ibutilide Sotalol Type IV Calcium antagonists

Drugs to Maintain SR in Patients with AFib – Recommended Daily Doses
Disopyramide mg Procainamide mg Quinidine mg Flecainide mg Propafenone mg Amiodarone mg Dofetilide mcg Sotalol mg

Effectiveness of Current AADs
Even with the most effective AAD, such as amiodarone, long-term efficacy is low ~50% or less at 1 year

Prevention of Recurrence with AADs
No. of Events/Total Peto OR (95% Cl) Drugs studied No. of Studies Antiarrhythmic Control p value Antiarrhythmic vs Control Class IA Disopyramide hydrochloride 2 40/75 49/71 0.52 ( ) 0.05 Quinidine sulfate 7 741/1106 417/518 0.51 ( ) <0.001 All class IA 8 781/1118 449/564 0.51 ( ) Class IB All: aprindine hydrochloride, bidisomide 639/781 453/540 0.84 ( ) 0.26 Class IC Flecainide acetate 3 31/71 56/78 0.31 ( ) Propafenone hydrochloride 5 376/720 276/378 0.37 ( ) All class IC 9 443/843 342/466 0.36 ( ) Class II All: metroprolol tartrate 1 127/197 140/197 0.74 ( ) 0.16 Class III Amiodarone 4 200/428 209/245 0.19 ( ) Dofetilide 252/431 274/325 0.28 ( ) Sotalol hydrochloride 916/1391 622/815 0.53 ( ) Dronedarone 116/151 43/48 0.45 ( ) 0.06 All class III 15 1484/2401 1148/1433 0.37 ( ) 0.10 1 10 Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

Prevention of Recurrence with AADs
Prevention of recurrence in studies comparing AADs with placebo or no treatment 70 60 50 40 Proportion without Recurrence (%) 30 20 10 Quinidine Disopyramide Propafenone Flecainide Amiodarone Sotalol Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

Antiarrhythmic Drugs for Maintenance of Sinus Rhythm
Meta-analysis of 18 randomized, controlled trials 7 6 5 4 Odds Ratio 3 2 1 Quinidine Disopyramide Propafenone Flecainide Amiodarone Sotalol Amiodarone > risk of non-cardiac adverse effects Tamariz L, et al. J Am Coll Cardiol 2003: 536A

Amiodarone to Prevent Recurrence of AFib
CTAF Study: mean follow-up 16 months 100 p<0.001 80 60 Patients without AFib (%) 40 Sotalol 20 Propafenone Amiodarone 100 200 300 400 500 600 Follow-up (days) Roy D, et al. N Engl J Med (2000) 342: 913

AFFIRM Substudy of First Anti-Arrhythmic Drug
AFFIRM Study 222 pts 256 pts 100 100 p=0.011 p<0.001 62% 60% 80 80 60 60 Amiodarone Amiodarone Percent without recurrence 40 40 23% 38% Class I Drugs Sotalol 20 20 1 2 3 4 5 1 2 3 4 5 Years Years AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20

Probability of remaining in SR Probability of remaining in SR
Amiodarone and Solatolol Equivalent in Patients with Ischaemic Heart Disease SAFE-T Investigators All patients Patients with IHD 1.0 1.0 0.8 0.8 Amiodarone 0.6 0.6 Probability of remaining in SR Probability of remaining in SR Amiodarone 0.4 Sotalol 0.4 Sotalol Placebo 0.2 0.2 Placebo 200 400 600 800 1000 200 400 600 800 1000 Follow-up (days) Singh BN, et al. N Engl J Med (2005) 352: 1861

Major Adverse Experiences Associated with Early Drug Discontinuation
Hypothyroidism 7.0% Hyperthyroidism 1.4% Peripheral Neuropathy 0.5% Lung Infiltrates 1.6% Liver Dysfunction 1.0% Bradycardia % Amiodarone Trials Meta-analysis Investigators Lancet (1997) 350: 1417

Amiodarone Discontinuations Associated with Major Adverse Events
Gastrointestinal events 4.0% Pulmonary events 2.6% Ocular events % Other % AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20

Major Adverse Experiences Associated with Early Drug Discontinuation
Amiodarone meta-analysis 41% at 2y CTAF % at 16m PIAF % at 1y AFFIRM % at 1y

Major Adverse Experiences Associated with AADs
No. of Studies Withdrawals Peto OR (95% Cl) Drugs studied Antiarrhythmic vs Control Class IA Disopyramide hydrochioride 2 3.85 ( ) Quinidine sulfate: higher dose 5 3.58 ( ) Quinidine: lower dose 0.81 ( ) Quinidine: all studies 7 1.90 ( ) All class IA 8 2.02 ( ) Class IB All: aprindine hydrochloride 1 0.66 ( ) Class IC Flecainide acetate 3 9.14 ( ) Propafenone hydrochloride 1.69 ( ) All class IC 9 1.93 ( ) Class II All: metoprolol tartrate 3.16 ( ) Class III Amiodarone 3,4 5.55 ( ) Dofetilide 1,2 1.61 ( ) Sotalol hydrochloride: PAFAC, SOPAT 0.95 ( ) Sotalol: rest of studies 6,7 3.02 ( ) Sotalol: all studies 8,9 1.47 ( ) Azimilide dihydrochloride + Dronedarone 2.46 ( ) All class III 14,16 1.63 ( ) 0.10 1 10 Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

Proarrhythmia Associated with AADs
No. of Studies Proarrhythmia Peto OR (95% Cl) Drugs studied Antiarrhythmic vs Control Class IA Disopyramide hydrochloride 2 No Events Quinidine sulfate: higher dose 5 4.56 ( ) Quinidine: lower dose 1.53 ( ) Quinidine: all studies 7 2.10 ( ) All class IA 8 2.06 ( ) Class IB All: aprindine hydrochloride 1 Class IC Flecainide acetate 3 5.97 ( ) Propafenone hydrochloride 1.52 ( ) All class IC 9 3.41 ( ) Class II All: metoprolol tartrate 7.96 ( ) Class III Amiodarone 3, 4 2.65 ( ) Dofetilide 1, 2 3.77 ( ) Sotalol hydrochloride: PAFAC, SOPAT 1.42 ( ) Sotalol: rest of studies 6, 7 2.67 ( ) Sotalol: all studies 8, 9 2.20 ( ) Azimilide dihydrochloride + dronedarone 3.30 ( ) All class III 14, 16 0.10 1 10 Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

Proarrhythmic Profile of AADs
Torsade Atrial de Pointe VF VT * Flutter 1:1 Bradyarrhythmia Dysopiramide 1-2% Quinidine 2% Procainamide 1-2% Lidocaina Rare Rare Rare Rare Mexiletine Rare Rare Rare Morizicine Rare Propafenone Rare Flecainide Rare Amiodarone <1% Ibutilide 4-5% + Rare Sotalol 2-5% More frequent in pts with structural HD or history of ventricular arrhythmias Friedman P, et al. Am J Cardiol (1998) 82: 50N

Overall Mortality Associated with AADs
No. of Studies No. of Events/Total Peto OR (95% Cl) p value Drugs studied Antiarrhythmic Control Antiarrhythmic vs Control Class IA Disopyramide phosphate 2 2/75 0/71 7.56 ( ) 0.16 Quinidine sulfate 7 21/1128 4/548 2.26 ( ) 0.07 All class IA 8 23/1203 4/594 2.39 ( ) 0.04 Class IB All: aprindine hydrochloride, bidisomide 9/781 3/540 1.89 ( ) 0.28 Class IC Flecainide acetate 3 0/78 Not estimable NA Propafenone hydrochloride 5 0/720 2/378 0.05 ( ) 0.05 All class IC 9 1/843 2/466 0.14 ( ) 0.14 Class II All: metroprolol tartrate 1 3/197 0/197 7.47 ( ) 0.08 Class III Amiodarone 4 13/428 3/245 1.96 ( ) 0.21 Dofetilide 83/431 83/325 0.97 ( ) 0.88 Sotalol hydrochloride 30/1391 5/815 2.09 ( ) 0.06 Azimilide dihydrochloride + dronedarone 10/1042 4/537 1.31 ( ) 0.63 All class III 16 136/3292 95/1922 1.19 ( ) 0.27 0.10 1 10 Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719

Mortality Associated with Class 1A Drugs
Prophylaxis of AFib with quinidine: Meta-analysis of 6 randomized trials Quinidine 100 Placebo p<0.001 p<0.001 p<0.001 p<0.05 80 69 58 60 50 (%) 45 40 33 25 # of patients 20 17 3 3 month 6 month 12 month Mortality Coplen SE, et al. Circulation (1990) 82: 1106

Physician Visits Associated with AAD Use Over Time
Quinidine 7 Class IC Amiodarone Hydrochloride 6 5 4 Visits on medication (%) 3 2 1 Visit (years) Fang FC et al. Arch Intern Med 2004; 164: 55-60

Rhythm and Rate Control Studies
PIAF, Lancet 2000 RACE, NEJM 2002 AFFIRM, NEJM 2002 PAF-2, Eur Heart J 2002 STAF, JACC 2003 HOT-CAFÉ, Chest 2004

Thrombo-embolic complications
Rhythm vs Rate Trials Thrombo-embolic complications % Mortality % Trial Mean Follow-up n Age, y Sinus rhythm (%) Warfarin (%) AFFIRM 42m Rate control Rhythm control 2027 2033 70 35 63 85 6 7.5 21 24 RACE 27m 256 266 68 10 39 96-99 86-99 5.5 7.9 17 13 STAF 22m 100 65 66 NR 0.6 3.1 5 2.5 PIAF 12m 125 127 61 60 56 1.6 Hot Cafe 20m 101 104 63.5 74 1 2.9 Falk, RH. Circulation (2005) 111: 3141

AFib Follow-up Investigation of Rhythm Management (AFFIRM)
No survival advantage of rhythm over rate (n=4060) 30 p=0.08 25 Rhythm control 20 Cumulative mortality (%) 15 Rate control 10 5 1 2 3 4 5 No. of deaths Years Rhythm control 80 (4) 175 (9) 357 (13) 314 (18) 352 (24) Rate control 78 (4) 148 (7) 210 (11) 275 (16) 306 (21) AFFIRM Investigators N Engl J Med (2002) 347: 1825

Meta-Analysis of Rhythm Control versus Rate Control Studies
Odds Ratio for Combined Endpoint (All-cause Death + Thromboembolic Stroke) Study or sub-category Rate control (n/N) Rhythm control (n/N) Van Den Berg 388/2027 438/2033 SOLVD 1/101 6/104 TRACE 2/125 4/127 Ueng 24/256 32/266 CAPP 97100 9/100 Total (95% CI) 2609 2630 Weight (%) OR (95% CI Random) 89.86 0.86 (0.74, 1.00) 0.46 0.16 (0.02, 1.38) 0.72 0.50 (0.09, 2.78) 6.72 0.76 (0.43, 1.32) 2.24 1.00 (0.38, 2.63) 100.0 0.85 (0.73, 0.98) OR (95% CI Random) 0.1 0.2 0.5 1 2 5 10 Total events: 424 (Rate control). 489 (Rhythm control) Test for heterogeneity chi-square=2.97; df=4; p=0.56; I2=0% Test for overall effect z=2.24; p=0.03 Rate control better Rhythm control better Testa L, et al. Eur Heart J (2005) 26: 2000

AFFIRM On-Treatment Analysis: SR but not AAD Use Associates with Improved Survival
HR: 99% CL Covariate p HR Lower Upper Age at enrollment* <0.0001 1.06 1.04 1.08 Coronary artery disease 1.65 1.31 2.07 Congestive heart failure 1.83 1.45 2.32 Diabetes 1.56 1.22 2.00 Stroke or transient ischemic attack 1.54 1.17 2.05 Smoking 1.75 1.29 2.39 First episode of AFib 0.0067 1.27 1.01 1.58 Sinus rhythm 0.54 0.42 0.70 Warfarin use 0.47 0.36 0.61 Digoxin use 1.50 1.18 1.89 Rhythm-control drug use 0.0005 1.41 1.10 * per year of age AFFIRM Investigators Circulation (2004) 109: 1509

AFFIRM On-Treatment Analysis: SR Associates with Survival
Implications In patients with AFib such as those enrolled in the AFFIRM study, warfarin improves survival. The presence of SR but not AAD use is associated with a lower risk of death. These results suggest that if an effective method for maintaining SR with fewer side effects were available, it might improve survival AFFIRM Investigators Circulation (2004) 109: 1509

Drugs to Prevent AFib Non-antiarrhythmic drugs

Non-antiarrhythmic Drugs to Prevent AFib
ACE Inhibitors and Angiotensin Receptor Blockers Statins Polyunsaturated fatty acids (omega-3)

Non-antiarrhythmic drugs ACE Inhibitors and Angiotensin Receptor Blockers

Characteristics of ARB and ACE-I Studies in AFib
Author/Study, Date Patient Group Drug No. Randomized Mean Follow-Up Mean LVEF HTN (%) Rate of AF in Control Group (%) ACE-I trials Van Den Burg, 1995 AF, CHF Lisinopril 30 84 days n/a 64 Ueng, 2003 AF Enalapril 145 270 days (61-575) 51 32 43 Vermes (SOLVD), 2003 LVD, CHF, NSR 374 3.3 yrs 27 20 24 Pizetti (GISSI), 2001 Post-MI, NSR 17,711 42 days 8 Pedersen (TRACE), 1999 Post-MI, LVD, NSR Trandolapril 1,577 2-4 yrs 33 22 5 STOP-H2, 1999 HTN 10,985 5.0 yrs 100 CAPP, 1999 Captopril 6,614 6.1 yrs 2 ARB trials CHARM, 2003* CHF, NSR Candesartan 5,518 3.2 yrs 39 55 Madrid, 2002 Irbesartan 154 254 days (60-710) 42 29 ValHeFT, 2003* Valsartan 4,409 2 yrs 28 7 Wachtell, (LIFE), 2003* HTN, LVH, NSR Losartan 9,193 4.9 yrs 6 Abstract only. ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; CHF = congestive heart failure; HTN = hypertension; LVD = left ventricular dysfunction; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NSR = sinus rhythm; Post-MI = post-myocardial infarction Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

Effect of Treatment Based on Class of Drug: ACE Inhibitors
Study Treatment (n/N) Control (n/N) ACE inhibitor Van Den Berg 2/7 7/11 SOLVD 10/186 45/188 TRACE 22/790 42/787 Ueng 18/70 32/75 CAPP 117/5492 135/5493 STOP-H2 200/2205 357/4409 GISSI 665/8855 721/8846 Sutotal (95% CI) 1034/17615 1339/19809 RR (95% CI Random) Weight (%) RR (95% CI Random) 1.7 0.45 (0.13, 1.57) 4.8 0.22 (0.12, 0.43) 6.6 0.52 (0.31, 0.87) 7.0 0.60 (0.37, 0.97) 11.4 0.87 (0.68, 1.11) 13.0 1.12 (0.95, 1.32) 14.0 0.92 (0.83, 1.02) 58.7 0.72 (0.56, 0.93) 28% p=0.01 Test for heterogeneity chi-square=32.58; df=6; p< Test for overall effect z=-2.53; p=0.01 1 2 5 10 Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

Effect of Treatment Based on Class of Drug: ARBs
Study Treatment (n/N) Control (n/N) RR (95% CI Random) Weight (%) RR (95% CI Random) ARB Madrid 9/79 22/75 ValHeFT 116/2209 173/2200 Charm 179/2769 216/2749 LIFE 179/4417 252/4387 Sutotal (95% CI) 483/9474 663/9411 43 0.39 (0.19, 0.79) 11.8 0.67 (0.53, 0.84) 12.5 0.82 (0.68, 1.00) 12.6 0.71 (0.59, 0.85) 41.3 0.71 (0.60, 0.84) 29% p= Test for heterogeneity chi-square=5.25; df=3; p=0.15 Test for overall effect z=-4.12; p= 1 2 5 10 Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

Effect of ACE Inhibitors or ARB Based on Indication
Study Treatment (n/N) Control (n/N) Heart Failure Van Den Berg 2/7 7/11 SOLVD 10/186 45/188 ValHeFT 116/2209 173/2300 Charm 179/2769 216/2749 Sutotal (95% CI) 307/5171 441/5148 RR (95% CI Random) Weight (%) RR (95% CI Random) 1.7 0.45 (0.13, 1.57) 4.8 0.22 (0.12, 0.43) 11.8 0.67 (0.53, 0.84) 12.5 0.62 (0.66, 1.00) 30.9 0.56 (0.37, 0.85) 44% Test for heterogeneity chi-square=15.01; df=3; p< Test for overall effect z=-2.72; p=0.007 Hypertension CAPP 117/5492 135/5493 LIFE 178/4417 252/4387 STOP-H2 200/2205 357/4409 Sutotal (95% CI) 496/12114 744/14/283 11.4 0.87 (0.69, 1.11) 12.6 0.71 (0.59, 0.85) 13.0 1.12 (0.95, 1.32) 37.1 0.88 (0.65, 1.19) 12% Test for heterogeneity chi-square=13.34; df=2; p= Test for overall effect z=-0.82; p=0.4 1 2 5 10 Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

Effect of ACE Inhibitors or ARB Based on Indication
Study Treatment (n/N) Control (n/N) RR (95% CI Random) Weight (%) RR (95% CI Random) Atrial Fibrillation Madrid 9/79 22/75 Ueng 15/70 32/75 Sutotal (95% CI) 27/149 54/150 4.3 0.39 (0.19, 0.79) 7.0 0.60 (0.37, 0.97) 11.4 0.52 (0.35, 0.79) 48% Test for heterogeneity chi-square=1.33; df=1; p=0.31 Test for overall effect z=-3.13; p=0.002 Post-Myocardial Infarction TRACE 22/790 42/787 GISSI 665/8865 721/6646 Sutotal (95% CI) 27/149 54/150 6.6 0.52 (0.31, 0.87) 14.0 0.92 (0.83, 1.02) 20.7 0.73 (0.43, 1.26) 27% Test for heterogeneity chi-square=4.64; df=1; p=0.031 Test for overall effect z=-1.12; p=0.3 1 2 5 10 Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832

Non-antiarrhythmic drugs Statins

Studies of Statins to Prevent AFib
Study Design Medication and subjects OR Comments Statin drugs in protecting against AFib Retrospective analysis of prospective study database Statin users vs nonusers in a population of chronic CAD (n=449) 0.48 (CI ) Effect of statins was independent of changes in serum cholesterol. AFib diagnosed by ECG at routine follow-up visits or with new symptoms onset. Prevention of AFib recurrence after cardioversion Retrospective analysis of patients referred for cardioversion Statin users vs nonusers in a population with persistent lone AFib (n=62) 0.31 (CI ) Patients on statins had higher cholesterol and were older than nonusers. AFib diagnosed by ECG at routine follow-up visits. Prevastatin to prevent recurrent AFib after electrical cardioversion Prospective, open-label, controlled multicenter study Pravastatin 40 mg/day vs no drug 3 weeks prior and 6 weeks cardioversion (n=114) 1.08 (CI not available) Open-label design, small study, conventional antiarrhythmics also used. 52% 69% 8% Lozano HF, et al. Heart Rhythm (2005) 2: 1000

Effect of Atorvastatin on Reducing AFib Recurrence Post-ECV
48 patients with AFib lasting >48h and followed for 3m 1.0 Atorvastatin 0.9 0.8 Freedom from recurrence p=0.01 0.7 0.6 control 0.5 30 60 90 Follow-up (days) Ozaydin M, et al. Am J Cardiol (2006) 297: 1490

Non-antiarrhythmic drugs Polyunsaturated fatty acids (omega-3)

Polyunsaturated Fatty Acids in Preventing AFib
100 PUFAs Group 90 Control Group 80 70 60 Log-rank p=0.009 Patients free of AFib (%) 50 40 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Days after surgery Calò L, et al. J Am Coll Cardiol (2005) 45: 1723

AFib-Free Survival According to Fish Consumption
Tuna or other broiled/baked fish 1.0 p< (log-rank test for equality of survivor functions) 0.9 Survival free of AFib 0.8 5+/wk 1-4/wk 1-3/mo 0.7 <1/mo 0.6 2 4 6 8 10 12 Years Mozzafarian D, et al. Circulation (2004) 110: 3683

AFib-Free Survival According to Fish Consumption
Fried fish or fish sandwich 1.0 p= (log-rank test for equality of survivor functions) 0.9 Survival free of AFib 0.8 <1/mo 1-3/mo 1+/wk 0.7 0.6 2 4 6 8 10 12 Years Mozzafarian D, et al. Circulation (2004) 110: 3683

n-3 Fatty Acid Intake from Fish and Incidence of AFib
Rotterdam study European population-based prospective cohort study among subjects aged 55 years and above (n=6808) Dietary intake data available from 5184 subjects without AFib In the subsequent 6.4y follow-up period, 312 subjects developed AFib Incidence of AFib was not significantly associated with either long-chain fatty acid consumption or fish consumption Brouwer IA, et al. Am Heart J (2006) 151: 857

Treatment Options for AFib Drugs to Control Ventricular Rate

Permanent AFib and Ventricular Rate Control
Indications for control of ventricular rate: Failure of antiarrhythmic therapy for preventing recurrence Alternative treatment to maintain sinus rhythm

Definitions and Criteria for Rate Control
Clinical symptoms ECG Criteria Hemodynamic data VR bpm At rest VR bpm During moderate exercise

Drugs Used for Rate Control
Digoxin Calcium Antagonists Beta-Blockers Antiarrhythmic Drugs ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

Rate Control Drugs in AFFIRM
Digoxin % Beta-blockers 49% Calcium antagonists 41% AV node ablation 5%

Digoxin in Permanent AFib
Heart rate during physical exercise and at various plasma concentrations 191 190 SR Low 182 Nil High 171 170 164 161 p<0.05 150 140 130 bpm 118 110 108 105 93 90 83 72 70 50 Rest Moderate Strenuous Beasley R, et al. Br Med J (1985) 290: 9

Digoxin plus Diltiazem in Permanent AFib
Medium and high doses alone or in combination with digoxin 190 DG DL 240 DG+DL 240 DL 360 170 170 *° 154 150 * p<0.05 vs DG+DL * p<0.05 vs DL 360 ° p<0.05 vs DG 240 142 136 132 * 128 130 bpm 110 106 101 86 88 90 79 * 70 67 50 Rest Submax Exercise Max Exercise Roth A, et al. Circulation 73: 316

(7 day administration of slow release formulation)
Calcium Antagonists in Permanent AFib Study protocol Gallopamil 100 mg b.i.d. Diltiazem 120 mg b.i.d. Verapamil 120 mg b.i.d. Digoxin – 1.4 µg/ml (7 day administration of slow release formulation) Botto GL, et al. Clin Cardiol 21: 837

Calcium Antagonists in Permanent AFib
Holter and walking test 175 DGX DLT 167 GLL VRP 149 150 142 * p<0.001 o p<0.01 vs DGX 137 * * 125 bpm 100 90 91 82 80 75 63 59 59 59 50 Median VR Minimum VR Maximum VR Botto GL, et al. Clin Cardiol 21: 837

Nadolol for Control of Ventricular Rate
Effect on heart rate in patients on digoxin 200 DGX NDL 175 p<0.01 150 125 bpm 100 75 50 25 Resting Low Average 3’ Exercise Max Exercise Nadolol median dose 87 mg DiBianco R, et al. Am Heart J (1984) 108: 1121

Beta-blockers for Control of Ventricular Rate
Effect of nadolol on physical exercise capacity DGX DGX 500 24 DLT CLP p<0.01 p<0.01 450 22 Sec 400 kg/min 20 350 18 300 16 Exercise time O2 Consumption DiBianco R, et al. Am Heart J (1984) 108: 1121 Atwood JE, et al. J Am Coll Cardiol (1987) 10: 314

Randomized, cross-over study with administration for 7-10 days
Modulation of Ventricular Rate Study protocol Metoprolol 200 mg/d Diltiazem 300 mg/d Digoxin 0.8 – 1.4 µg/ml Placebo Randomized, cross-over study with administration for 7-10 days Botto GL, et al. PACE (2000) 23: 649

Modulation of Ventricular Rate
Walking test results 190 Placebo DLT 320 DGX MTP 185 180 300 175 * *o Max heart rate 170 Metres walked 280 * * 165 o 160 260 155 150 240 * p<0.05 vs PLA e DGX o p<.,01 vs PLA e DGX * p<0.005 vs DGX o p<0.05 vs MTP Botto GL, et al. PACE (2000) 23: 649

Antiarrhythmic Drugs for Control of Ventricular Rate
Amiodarone Solatolol

CHF-STAT Study: Amiodarone in Permanent AFib
Placebo 100 Amiodarone (400 mg/d) 90 NS p=0.001 p=0.001 p=0.006 80 70 60 bpm 50 40 30 20 10 Baseline 2 w 6 m 12 m Deedwania PC, et al. Circulation (1998) 98: 2574

Treatment Options for AFib Drugs to Reduce Thromboembolic Risk

Atrial Fibrillation and Stroke
Anticoagulant therapy is clearly indicated and beneficial in valvular atrial fibrillation. In non-valvular atrial fibrillation, major randomized trials have provided useful guidelines for identifying and treating patients at risk.

Major Clinical Trials of Primary Prevention in Non-Valvular AFib
SPAF1 Stroke Prevention in Atrial Fibrillation BAATAF2 Boston Area Anticoagulation Trial for Atrial Fibrillation CAFA3 Canadian Atrial Fibrillation Anticoagulation AFASAK4 Copenhagen Investigators SPINAF5 Stroke Prevention in Non-rheumatic Atrial Fibrillation 1 Lancet (1989) 1: 175 2 N Engl J Med (1990) 323: 1505 3 J Am Coll Cardiol (1991) 18: 349 4 Circulation (1991) 84: 527 5 N Eng J Med (1992) 327: 1406

Major Clinical Trials of Primary Prevention in Non-Valvular AFib
SPAF BAATAF CAFA AFASAK SPINAF Number of Patients Drug Used Warfarin ASA Warfarin Warfarin Warfarin ASA Warfarin (INR 2-4.5) 325 mg (PT x (INR 2-3) (INR ) 75 mg (INR ) Control) Embolic Rate (%) Treatment 2,3 3,6 0,41 3,5 1,5 6,0 4,3 Control 7,4 6,3 2,98 5,2 6,2 6,2 0,9 Risk Reduction (%) (95% confidence) — 79 Major Bleeding Complications (%) Treatment Control

Adjusted Dose Warfarin vs Placebo
Risk reduction Events Pts/y AFASAK 27 811 BAATAF 15 922 CAFA 14 478 SPAF 23 508 SPINAF 29 972 All 108 3691 100% 50% 0% -50% -100% Warfarin better Warfarin worse

Annual risk of stroke (%)
Reduction in Stroke Risk – Meta-analysis of 5 Trials 5 4.5% 4 Reduction in risk = 68% 3 Annual risk of stroke (%) 2 1.4% 1 Control Warfarin Atrial Fibrillation Investigators Arch Intern Med (1994) 154: 1449

Secondary Prevention EAFT 2.5 – 4.0 - 62%
Study Range INR Stroke risk reduction Average % EAFT – % vs placebo 1007 patients > 70 with previous TIA or minor stroke European Atrial Fibrillation Trial Lancet (1993) 342: 1255

Global reduction in risk = 25%
Aspirin vs Placebo Study ASA dose Stroke risk reduction Primary prevention AFASAK mg % (ns) SPAF mg % (p<0.02) Secondary prevention EAFT mg % (ns) Global reduction in risk = 25% (range 14-44%)

Warfarin Superior to Aspirin
Warfarin compared with aspirin Aspirin compared with placebo Relative Risk Reduction (95% CI) Relative Risk Reduction (95% CI) AFASAK I (1) AFASAK II (2) EAFT (9) PATAF (15) SPAF II (4) All trials (n=5) AFASAK I (1) SPAF I (3) EAFT (9) ESPS II (14) LASAF (13) UK-TIA (16) All trials (n=6) 100 50 -50 -100 100 50 -50 -100 Warfarin better (%) Warfarin worse (%) Aspirin better (%) Aspirin worse (%) ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

SPAF III - Adjusted-dose vs. Low-intensity, Fixed-dose warfarin + ASA
1044 eligible patients randomised Adjusted dose warfarin (n = 523) Fixed, low dose warfarin plus aspirin (n = 521) Weekly INR control until stable, then monthly INR assessed at 1m and 2m then every 3m Discontinued = 31 Lost to follow-up = 0 Discontinued = 41 Lost to follow-up = 0 Primary events = 11 Deaths = 34 Completed without primary event = 478 Primary events = 44 Deaths = 35 Completed without primary event = 442 SPAF Investigators Lancet (1994) 343: 634

Cumulative event rate (% per year) Days from randomization
SPAF III – Stroke Rate 20 18 16 14 Combination therapy 12 10 Cumulative event rate (% per year) 8 6 Adjusted-dose warfarin 4 2 365 730 Days from randomization Number at Risk Combination therapy Warfarin therapy 521 523 378 397 265 273 166 173 61 65 SPAF Investigators Lancet (1996) 348: 633

Adjusted dose warfarin better Combination therapy better
SPAF III – Relative Risk Primary events Disabling ischaemic stroke All disabling strokes Vascular death Stroke, MI, Vascular death Major haemorrhage 0-5 1 1-5 2 Adjusted dose warfarin better Combination therapy better SPAF Investigators Lancet (1996) 348: 633

677 patients with permanent AFib
AFASAK 2 - Copenhagen Investigators 677 patients with permanent AFib Warfarin fixed-dose 1.25 mg Warfarin fixed-dose 1.25 mg + ASA 300 mg ASA 300 mg Warfarin dose variable (INR ) Cumulative incidence of primary events – 12m follow-up 5.8 % % % %

Primary Prevention Trials – Anticoagulation Ranges
Warfarin – INR range AFASAK SPAF I + II BAATAF CAFA SPINAF EAFT SPAF III (fixed) SPAF III (adjusted) 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 INR range ( ) recommended by 4th ACCP Consensus on Antithrombotic Therapy

Optimal Anticoagulation Ranges
Thromboembolic Therapeutic window Haemorrhagic Clinical events 2 INR 3

Intracranial haemorrhage (%/y)
Intracranial Haemorrhage in Trials – Influence of Age 2 Oral anticoagulant SPAF II (>75) Aspirin CAFA Intracranial haemorrhage (%/y) SPAF I 1 SPINAF BAATAF SPINAF (>70) 4 trials (>75) SPAF II (<75) EAFT AFASAK 60 65 70 75 80 85 Median age (y) Petersen P, et al. Lancet (1989) 171 SPAF Circulation (1991) 84: 527 BAATAF N Engl J Med (1990) 323: 1505 EAFT Lancet (1993) 342: 1255 Connolly SJ, et al. J Am Coll Cardiol (1991) 18: 349 Ezekowitz MD, et al. N Engl J Med (1992) 327: 1406 SPAF II Lancet (1994) 343: 687 Connolly SJ, et al. Lancet (1994) 343: 1509

Treatment Options for AFib Drugs to Reduce Thromboembolic Risk Risk stratification

Thromboembolic Risk Stratification
Clinical risk factors Echocardiographic risk factors

Clinical Risk Factors Advanced age (> women) Hypertension
Cardiac insufficiency Previous TIA (Diabetes)

Transthoracic Echocardiographic Risk Factors
Left atrial dilatation Left ventricular systolic dysfunction

Trans Esophageal Echocardiographic Risk Factors
Thrombus – atrium and/or left atrial appendage Dense spontaneous echo contrast Reduced blood flow in left atrial appendage Dilatation of left atrial appendage Septal aneurysm Complex aortic plaque

Risk Stratification in Patients with AFib
HIGH RISK MODERATE RISK LOW RISK 1 major risk factor NO major risk factor No major or > 1 moderate risk factor 1 moderate risk factor minor risk factors Major Risk Factors Age > Previous stroke or systemic embolism History of arterial hypertension Cardiac insufficiency o ventricular dysfunction Mitral valve disease Prosthetic valve replacement Minor Risk Factors Age Diabetes mellitus Ischaemic cardiopathy with normal ventricular function sinistra adapted from the 6th ACCP Consensus Conference on Antithrombotic Therapy, Chest (2001) 119 (Suppl): 194S

Antithrombotic Therapy Recommendations
Risk category Recommended therapy No risk factors Aspirin, 81 to 325 mg daily One moderate-risk factor Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5) Any high-risk factor or more than 1 moderate-risk factor Warfarin (INR 2.0 to 3.0, target 2.5)* Less validated or weaker Risk factors Moderate-risk factors High-risk factors Female gender Age greater than or equal to 75 y Previous stroke, TIA or embolism Age 65 to 74 y Hypertension Mitral stenosis Coronary artery disease Heart failure Prosthetic heart valve* Thyrotoxicosis LV ejection fraction 35% or less Diabetes mellitus *If mechanical valve, target international normalized ratio (INR) greater than 2.5. INR = international normalized ratio; LV = left ventricular; TIA = transient ischemic attack

Contraindications of Oral Anticoagulants
GI haemorrhage Uncontrolled arterial hypertension Pregnancy Alcoholism Severe hepatic insufficiency Vascular malformations that can lead to risk of haemorrhage Coagulopathies Recent surgical interventions – eyes or CNS Previous severe haemorrhage during anticoagulation therapy Severe neoplastic disease

Cardioversion and Anticoagulation Recommendations
AFib > 48 hours TEE Warfarin (INR ) 3-4 weeks + Cardioversion Positive Negative Heparin + warfarin h Warfarin 3-4 weeks Cardioversion Naccarelli GV, et al. Am J Cardiol (2000) 85: 36D

Treatment Options for AFib Non-Pharmacologic Treatment Options

Non-Pharmacological Treatment Options for AFib
Devices Electrophysiological Surgery Pacemaker (single or dual chamber) Internal atrial defibrillators Catheter ablation AV node ablation Maze procedure Modified Maze (mini-Maze) ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

Management of AFib - Summary
Maintenance of sinus rhythm should be the primary objective of treatment whenever possible sinus rhythm correlates with improved survival Current antiarrhythmic drug therapies, however, are not highly effective in maintaining SR and generally have poor outcomes high recurrence rates adverse effects and high discontinuation rate A potentially curative therapy for AFib is desirable

Section II: Clinical Management of AFib

Similar presentations

Presentation on theme: "Section II: Clinical Management of AFib"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Section II: Clinical Management of AFib

Similar presentations

Presentation on theme: "Section II: Clinical Management of AFib"— Presentation transcript:

Similar presentations

About project

Feedback