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Section II:Clinical Management of AFib
Section II. Clinical Management of AFib
1. Clinical Evaluation of AFib
2. 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– 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 FibrillationJ 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)
• 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
Primary Therapeutic Aims in AFib
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial FibrillationJ 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
– 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 (200-300 mg)
– Propafenone (450-600 mg)
Pharmacological Cardioversion
Recent onset AFib
Oral Loading with Class IC Drugs for Recent Onset AFib
Capucci A, et al. Am J Cardiol (1994) 74: 503
100
60
80
40
20
SR
(%
)
Propafenone 600 mgFlecainide 300 mg Placebo
3 hours 8 hours0
p<0.001 vs. placebo p<0.001 vs. placebo
59
51
18
7872
39
Cardioversion of Paroxysmal AFib with Class IC Drugs
Paroxysmal AFib (<48h), good LVEF
• IV 2 mg/kg + 0.007 mg/kg/min, maintenance
• Oral administration flecainide 300 mgpropafenone 600 mg
• Mean efficacy: 80%
• Mean time of efficacy: 3h
• Proarrhythmia: FLA 1:1 ECG monitoring necessary (<0.5%) with patients in resting
condition
Class IC drugs (propafenone, flecainide)
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
0
50
Nu
mb
er
per
mon
th
25
Prior to enrolment During follow-up
Hospitalisation
p<0.001
0
50
25
Calls to ER
45.6
4.9
15
1.6N
um
ber
per
month
p<0.001
Alboni P, et al. N Engl J Med (2004) 351: 2384
Connolly SJ Circulation (1999) 100: 2025
Controldrug n
Primary endpoint
Durationof 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 Digoxin IV 50 24 h 1.30 0.0048
Cotter et al Placebo 80 24 h 1.34 0.029
Galve et al Placebo 100 24 h 1.13 0.532
Donovan et al Placebo 64 24 h 1.05 NS
Donovan et al Flecainide 66 24 h 0.86 NS
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 Quinidine 75 24 h 1.09 NS
Kerin et al Quinidine 32 24 h 1.07 NS
Di Biasi et al Propafenone 40 24 h 1.15 NS
Larbuisson et al Propafenone 84 24 h 1.22 NS
Chapman et al Procainamide 26 12 h 0.99 NS
Moran et al Magnesium sulfate 42 24 h 0.64 <0.05
Conversion to SR with AmiodaroneIV (randomized studies)
Amiodarone for Cardioversion of Recent-Onset AFib: Meta-analysis
Khan IA, et al. Int J Cardiol (2003) 89: 239
• Amiodarone IV (3-7 mg/kg ± infusion 0.9-3.0 g/day)
• Amiodarone oral (25-30 mg/kg)
• Time to conversion > 6-8 h
• Amiodarone > 1.5 g/day IV > placebo
• Amiodarone 25-30 mg/kg oral > placebo
• Amiodarone not > other AADs
• Safe in patients with structural cardiopathies and low LVEF
100
80
60
40
20
Con
vers
ion
(%
)
Bolus + infusionBolus only
2-4 h 8 h0
34
55
69
95
Amiodarone Single Oral Administration for Cardioversion of Recent Onset AFib
Peuhkurinen K, et al. Am J Cardiol (2000) 85: 462
100
60
80
40
20
Pati
en
ts in
AFib
(%
)
AmiodaronePlacebo
00
2 4 6 8 10 12 14 16 18 20 22 26
Time to conversion (hours)
24
Flecainide IV vs Amiodarone IV for Cardioversion in Recent-Onset AFib
Donovan KD, et al. Am J Cardiol (1995) 75: 693
32
24
28
16
8
Card
iovers
ion
(%
)
00
1 2 3 4 5 6 7 8
(hours)
20
12
4
p=0.007p=0.001
AmiodaroneFlecainidePlacebo
Pharmacological Cardioversion
Long-lasting AFib
Effect of Duration on Efficacy of Pharmacological Cardioversion
Reisinger J, et al. Am J Cardiol (1998) 81: 1450
106 patients with AFib <6 months
100
60
80
40
20
SotalolFlecainide
* p=0.005
Total
52*
23
<24 hours
69*
31
<7 days
44
17
<6 months
0 00
Amiodarone Cardioversion in Persistent AFib
Kochiadakis GE, et al. Am J Cardiol (1999) 83: 61
67 patients with AFib >48 hours
100
60
80
40
20
PlaceboAmiodarone
p<0.001
Total
48
0
LA (mm) >45 <45
32
82
LVEF (%)>50 <50
31
65
AFib (m)>1 <1
30
77
0
A B
Sin
us r
hyth
m (
%)
Conversion of Atrial Flutter or AFib with Ibutilide IV
Stambler BS, et al. Circulation (1996) 94: 1613
100
60
80
40
20
Sin
us r
hyth
m (
%)
p<0.0001
Ibutilide0
Placebo
100
60
80
40
20S
inu
s r
hyth
m (
%)
p<0.0001
AFlutter0
AFib
266 patients
Adverse effects: 8.3% polymorphic ventricular tachycardia
Conversion of Atrial Flutter or AFib with Ibutilide IV
Glatter K, et al. Circulation (2001) 103: 253
Effect “on top” of long-term amiodarone
80
60
40
20
Recovery
of
SR
(%
)
AFlutter0
AFib
70 patients(57 AFib, 13 AFlutter)
Ibutilide 2 mg
39
54
Electrical Cardioversion(transthoracic)
Technical Aspects
• Impedence
•Position of paddles
•Pressure applied to paddles
•Waveform
The efficacy of electrical cardioversion depends on the density of current delivered to the atrial myocardium, which is dependent on:
•Transthoracic Cardioversion of Atrial FibrillationComparison 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: 1282-7
Defibrillation Waves
Mittal S, et al. Circulation (2000) 101: 1282
Monophasic wave Biphasic wave
Am
pere
0
20
10
0
4 8 12
msec
Am
pere
0
10
0
-10
4 8 12
msec
30
Cumulative Efficacy of Cardioversion
Mittal S, et al. Circulation (2000) 101: 1282
Monophasic or biphasic shock
100
60
80
40
20
Effi
cacy o
f card
iovers
ion
(%
)
p<0.0001
100 J
21
70 J
68
200 J
44
120 J
85
300 J
68
150 J
91
360 J
79
170 J
94
0
p<0.005
Monophasic Biphasic
•Biphasic vs Monophasic Shock Waveform for Conversion of Atrial FibrillationThe 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: 1956-63
Dermal Injury Dependent on Waveform
Page RL, et al. J Am Coll Cardiol (2002) 39: 1956
60
40
50
30
20
10
BiphasicMonophasic
None(no erythema)
Mild(no tenderness)
Moderate(tenderness)
Severe(blistering)
0
Success of Monophasic (MP) and Biphasic (BP) Waveforms at Cumulative EnergyLevels
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
Van Gelder IC, et al. Am J Cardiol (1999) 84: 147R
100
60
80
40
20
Sin
us r
hyth
m (
%)
02 min
90
50
70
30
10
Immediate recurrent AFibNo conversion
Early recurrent AFibLate recurrence AFib
2 weeks 1 year
cardioversion
Recurrence Following Cardioversion: AFFIRM Study
Raitt MN, et al. Am Heart J (2006) 151: 390
AFFIRM:most recurrences occur within 2 monthsof cardioversion
Time (years)
Pati
en
ts w
ith
AF R
ecu
rren
ce (
%)
0
20
40
60
80
100
0 1 2 3 4 5 6
Log rank statistic = 58.62p<0.0001
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)
N, Events (%)
Rate control
Rhythm control
Treatment Arm
Immediate Recurrence of AFib Following Successful Electrical Cardioversion
Authors n ERAF (%) Timing
Bertaglia 90 28 7 days
Bianconi 96 18 24 hours
Botto 156 61 7 days
Daoud 337 9 5 min
De Simone 107 14 7 days
Tieleman 61 36 5 days
Villani 116 7 24 hours
Yu 50 26 1 min
Immediate/Early Recurrence of AFib After Electrical Cardioversion
•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
Oral H, et al. J Cardiovasc Electrophysiol (2003) 14: 182
100
70
90
60
40
30
80
50
20
10
1hr
1-24hrs
1-7days
7-30days
31-90days
91-180days
181-365days
>365days
Duration of AFib
48
27
34 45
7236 40
13
0
Pre
vale
nce o
f IR
AF
(%
)
Oral Propafenone Before Electrical Cardioversion in Persistent AFib
Bianconi L, et al. J Am Coll Cardiol (1996) 28: 700
Effect on early recurrence of arrhythmia
70
60
50
40
30
20
10
100
80
90
70
60
Sin
us r
hyth
m (
%)
p<0.01
0
Com
ple
x a
tria
l arr
hyth
mia
(%
)
p<0.002
10 minutes50
10 min 24 min 48 min0
PlaceboPropafenone
18
52
Effect of Pre-treatment with Oral Amiodarone
Capucci A, et al. Eur Heart J (2000) 21: 66
30
18
24
12
6
Con
vers
ion
(%
)
p<0.005
SR before ECV0
GIKAmiodarone
No treatment
100
60
80
40
20C
on
vers
ion
(%
)
p<0.05
SR with cardioversion0
GIKAmiodarone
No treatment
No differences in energy for cardioversion
Chenner KS, et al. Eur Heart J (2004) 25: 144
Stable anticoagulation for 2 weeks
Short-term Amiodarone20 (32%)
Placebo2 (5%)
Long-term Amiodarone30 (49%)
Short-term Amiodarone29 (47%)
Placebo6 (16%)
Long-term Amiodarone34 (56%)
Sinus Rhythm at 52 weeks
Sinus Rhythm at 8 weeks
Short-term Amiodarone48
Placebo30
Long-term Amiodarone48
Sinus Rhythm
Short- and Long-term Treatment with Amiodarone after Cardioversion Reduces Recurrence
DCCV100
Chemical26
Short-term Amiodarone62
Placebo38
Long-term Amiodarone61
30 32 38 16 10
Protocol violation = 4; Withdrew consent = 7
Randomization172
Effect of Pre-treatment with Ibutilide IV
Oral H, et al. N Engl J Med (1999) 340: 1849
• 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 minof the infusion
50
30
40
20
10
Pati
en
ts (
%)
0
SR after ECV
SR before ECV
AFib
IBU No IBU
•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
De Simone A, et al. J Am Coll Cardiol (1999) 34: 810
60
30
50
20
40
10
1 week
30
0
Recu
rren
ce (
%)
3 months
610
39
1517
PFN + VERPFN
PFN - VER
p=0.01
p=0.04
p=0.02
p=0.04
•Effects of Pre-treatmentwith Verapamil on Early Recurrences after Electrical Cardioversionof Persistent Atrial FibrillationA Randomised Study
E Bertaglia, D D’Este, A Zanocco, F Zerbo, P Pascotto.
Heart (2001) 85: 578-80
Effect of Pre-treatment with Verapamilon Early Recurrence Following ECV
Bertaglia E, et al. Heart (2001) 85: 578-80
A randomised trial (90 patients with amiodarone)60
30
50
20
40
10
0
Recu
rren
ce (
%)
Amio + VerAmio
6 h
NS
7 d
NS
30 d
NS
Follow-up
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
Van Gelder IC, et al. Arch Int Med (1996) 156: 2585
100
60
80
40
20
Main
ten
an
ce o
f S
R (
%)
01
90
50
70
30
10
1 ECV, no AADsSerial ECV
Months post-cardioversion
2 3 4 5 6 7 8 9 10 11 12
•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: 1522-8
Serial Electrical Cardioversion
90 patients with persistent AFib who hadpreviously undergone at least one successfulelectrical cardioversion
RandomizationCardioversion repeated up to 2 timesin 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 RhythmDuring Long-term Follow-up
0102030405060708090
100
0 7 30 180 365
Group AGG Group CTL
Aggressive repeated ECV beneficial in highly recurrent persistent AFib
days
Bertaglia E, et al. Eur Heart J (2002) 23: 1522
Sin
us r
hyth
m (
%)
2.Treatment Options for AFib
Drugs to Prevent AFib
Drugs to Prevent AFib
• 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
•Disopyramide 400-750 mg
•Procainamide 1000-4000 mg
•Quinidine 600-1500 mg
•Flecainide 200-300 mg
•Propafenone 450-900 mg
•Amiodarone 100-400 mg
•Dofetilide 500-1000 mcg
•Sotalol 240-320 mg
Drugs to Maintain SR in Patients with AFib – Recommended Daily Doses
•Even with the most effective AAD, such as amiodarone, long-term efficacy is low
~50% or less at 1 year
Effectiveness of Current AADs
Prevention of Recurrencewith AADs
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
No. of Events/Total Peto OR (95% Cl)
Drugs studiedNo. of
Studies Antiarrhythmic Control p value
Antiarrhythmicvs ControlClass IADisopyramide hydrochloride 2 40/75 49/71 0.52 (0.27-1.01) 0.05
Quinidine sulfate 7 741/1106 417/518 0.51 (0.40-0.65) <0.001
All class IA 8 781/1118 449/564 0.51 (0.40-0.64) <0.001
Class IBAll: aprindine hydrochloride, bidisomide
2 639/781 453/540 0.84 (0.63-1.13) 0.26
Class IC
Flecainide acetate 3 31/71 56/78 0.31 (0.16-0.60) <0.001Propafenone hydrochloride 5 376/720 276/378 0.37 (0.28-0.48) <0.001
All class IC 9 443/843 342/466 0.36 (0.28-0.45) <0.001
Class IIAll: metroprolol tartrate 1 127/197 140/197 0.74 (0.49-1.13) 0.16
Class III
Amiodarone 4 200/428 209/245 0.19 (0.14-0.27) <0.001
Dofetilide 2 252/431 274/325 0.28 (0.20-0.38) <0.001
Sotalol hydrochloride 9 916/1391 622/815 0.53 (0.44-0.65) <0.001
Dronedarone 1 116/151 43/48 0.45 (0.20-1.02) 0.06
All class III 15 1484/2401 1148/1433 0.37 (0.32-0.43) <0.001
0.10 1 10
Prevention of recurrence in studies comparing AADs with placebo or no treatment
70
40
60
30
10
50
20
Quinidine
Pro
port
ion
wit
hou
t R
ecu
rren
ce (
%)
DisopyramidePropafenone Flecainide Amiodarone Sotalol0
Prevention of Recurrence with AADs
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
Antiarrhythmic Drugs for Maintenance of Sinus Rhythm
Tamariz L, et al. J Am Coll Cardiol 2003: 536A
Meta-analysis of 18 randomized, controlled trials
7
4
6
3
1
5
2
Quinidine
Od
ds R
ati
o
Disopyramide Propafenone Flecainide Amiodarone Sotalol0
Amiodarone > risk of non-cardiac adverse effects
Pati
en
ts w
ith
ou
t A
Fib
(%
)
Roy D, et al. N Engl J Med (2000) 342: 913
Amiodarone to Prevent Recurrence of AFib
Follow-up (days)
0 100 200 300 400 500 600
p<0.001
Sotalol
Propafenone
Amiodarone
0
20
40
60
80
100
CTAF Study: mean follow-up 16 months
AFFIRM Substudy of First Anti-Arrhythmic Drug
AFFIRM Study
AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20
Perc
en
t w
ith
ou
t re
cu
rren
ce
Years
100
0 1 2 3 4 5
Class I Drugs
Amiodarone
0
20
40
60
80
0 1 2 3 4 50
20
40
60
80
100
Amiodarone
Sotalol
Years
222 pts 256 pts
62%
23%
60%
38%
p<0.001p=0.011
Pro
bab
ilit
y o
f re
main
ing
in
SR
Follow-up (days)
1.0
0 200 400 600 800 1000
Sotalol
Placebo
Amiodarone
0
0.2
0.4
0.6
0.8
SAFE-T Investigators
0 200 400 600 800 10000
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f re
main
ing
in
SR
All patients Patients with IHD
Amiodarone
Sotalol
Placebo
Singh BN, et al. N Engl J Med (2005) 352: 1861
Amiodarone and Solatolol Equivalent in Patients with Ischaemic Heart Disease
•Hypothyroidism 7.0%
•Hyperthyroidism 1.4%
•Peripheral Neuropathy 0.5%
•Lung Infiltrates 1.6%
•Liver Dysfunction 1.0%
•Bradycardia 2.4%
Major Adverse Experiences Associated with Early Drug Discontinuation
Amiodarone Trials Meta-analysis Investigators Lancet (1997) 350: 1417
•Gastrointestinal events 4.0%
•Pulmonary events 2.6%
•Ocular events 0.6%
•Other 7.1%
Amiodarone Discontinuations Associated with Major Adverse Events
AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20
•Amiodarone meta-analysis 41% at 2y
•CTAF 18% at 16m
•PIAF 25% at 1y
•AFFIRM 12.3% at 1y
Major Adverse Experiences Associated with Early Drug Discontinuation
Major Adverse Experiences Associated with AADs
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
No. ofStudies
WithdrawalsPeto OR (95% Cl)
Drugs studied
Antiarrhythmic vs Control
Class IA
Disopyramide hydrochioride 2 3.85 (1.13-13.20)
Quinidine sulfate: higher dose 5 3.58 (2.01-6.40)
Quinidine: lower dose 2 0.81 (0.59-1.10)
Quinidine: all studies 7 1.90 (0.90-4.02)
All class IA 8 2.02 (1.00-4.10)
Class IB
All: aprindine hydrochloride 1 0.66 (0.11-3.95)
Class IC
Flecainide acetate 3 9.14 (1.94-42.90)
Propafenone hydrochloride 5 1.69 (1.09-2.62)
All class IC 9 1.93 (1.27-2.93)
Class II
All: metoprolol tartrate 1 3.16 (1.43-6.99)
Class III
Amiodarone 3,4 5.55 (2.24-13.70)
Dofetilide 1,2 1.61 (0.41-6.23)
Sotalol hydrochloride: PAFAC, SOPAT 2 0.95 (0.68-1.33)
Sotalol: rest of studies 6,7 3.02 (1.65-5.53)
Sotalol: all studies 8,9 1.47 (0.84-2.60)
Azimilide dihydrochloride + Dronedarone 2 2.46 (1.51-4.01)
All class III 14,16 1.63 (1.29-2.07)
0.10 1 10
Proarrhythmia Associated with AADs
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
No. ofStudies
ProarrhythmiaPeto OR (95% Cl)
Drugs studied
Antiarrhythmic vs Control
Class IA
Disopyramide hydrochloride 2 No Events
Quinidine sulfate: higher dose 5 4.56 (1.20-17.30)
Quinidine: lower dose 2 1.53 (0.64-3.60)
Quinidine: all studies 7 2.10 (1.02-4.33)
All class IA 8 2.06 (1.00-4.26)
Class IB
All: aprindine hydrochloride 1 No Events
Class IC
Flecainide acetate 3 5.97 (1.67-21.30)
Propafenone hydrochloride 5 1.52 (0.33-7.02)
All class IC 9 3.41 (1.28-9.09)
Class II
All: metoprolol tartrate 1 7.96 (2.84-22.30)
Class III
Amiodarone 3, 4 2.65 (0.88-8.00)
Dofetilide 1, 2 3.77 (1.31-10.80)
Sotalol hydrochloride: PAFAC, SOPAT 2 1.42 (0.56-3.60)
Sotalol: rest of studies 6, 7 2.67 (1.44-4.98)
Sotalol: all studies 8, 9 2.20 (1.31-3.69)
Azimilide dihydrochloride + dronedarone 2 3.30 (1.01-10.80)
All class III 14, 16 2.20 (1.31-3.69)
0.10 1 10
Proarrhythmic Profile of AADs
Dysopiramide 1-2% ++ + ++ +Quinidine 2% ++ + ++ +Procainamide 1-2% + + + + +Lidocaina Rare Rare Rare RareMexiletine Rare Rare RareMorizicine Rare + ++ ++ +Propafenone Rare + ++ +++ ++Flecainide Rare + ++ +++ ++Amiodarone <1% + + + +++Ibutilide 4-5% + RareSotalol 2-5% + + + +++
Torsade Atrialde Pointe VF VT * Flutter 1:1 Bradyarrhythmia
* 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
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
No. ofStudies
No. of Events/Total Peto OR (95% Cl)
p valueDrugs studied Antiarrhythmic Control
Antiarrhythmicvs ControlClass IADisopyramide phosphate 2 2/75 0/71 7.56 (0.47-1.22) 0.16
Quinidine sulfate 7 21/1128 4/548 2.26 (0.93-5.45) 0.07
All class IA 8 23/1203 4/594 2.39 (1.03-5.59) 0.04
Class IBAll: aprindine hydrochloride, bidisomide
2 9/781 3/540 1.89 (0.59-6.03) 0.28
Class IC
Flecainide acetate 3 0/71 0/78 Not estimable NAPropafenone hydrochloride 5 0/720 2/378 0.05 (0.00-1.02) 0.05
All class IC 9 1/843 2/466 0.14 (0.00-1.88) 0.14
Class IIAll: metroprolol tartrate 1 3/197 0/197 7.47 (0.77-72.20) 0.08
Class III
Amiodarone 4 13/428 3/245 1.96 (0.68-5.67) 0.21
Dofetilide 2 83/431 83/325 0.97 (0.67-1.40) 0.88
Sotalol hydrochloride 9 30/1391 5/815 2.09 (0.97-4.49) 0.06Azimilide dihydrochloride + dronedarone
2 10/1042 4/537 1.31 (0.43-3.97) 0.63
All class III 16 136/3292 95/1922 1.19 (0.88-1.61) 0.27
0.10 1 10
Coplen SE, et al. Circulation (1990) 82: 1106
100
40
80
20
60
0
(%)
PlaceboQuinidine
3 month
p<0.001
69
45
6 month
p<0.001
58
33
12 month
p<0.001
50
25
Mortality
p<0.05
17
3
# of patients
Mortality Associated with Class 1A Drugs
Prophylaxis of AFib with quinidine: Meta-analysis of 6 randomized trials
Physician Visits Associatedwith AAD Use Over Time
Fang FC et al. Arch Intern Med 2004; 164: 55-60
Vis
its o
n m
ed
icati
on
(%
)
Visit (years)
1991-1992 1993-1994 1995-1996 1997-1998 1999-2000
Quinidine
Class IC
Amiodarone Hydrochloride
0
2
3
4
5
7
6
1
Rhythm and RateControl Studies
• PIAF, Lancet 2000
• RACE, NEJM 2002
• AFFIRM, NEJM 2002
• PAF-2, Eur Heart J 2002
• STAF, JACC 2003
• HOT-CAFÉ, Chest 2004
TrialAge, y
MeanFollow-up
Thrombo-embolic
complications%
Mortality%
Falk, RH. Circulation (2005) 111: 3141
Rhythm vs Rate Trials
n
AFFIRM 42m
Rate control Rhythm control
20272033
7070
3563
8570
67.5
2124
RACE 27m
Rate control Rhythm control
256266
6868
1039
96-9986-99
5.57.9
1713
STAF 22m
Rate control Rhythm control
100100
6566
0NR
NRNR
0.63.1
52.5
PIAF 12m
Rate control Rhythm control
125127
6160
1056
100100
NRNR
1.61.6
Hot Cafe 20m
Rate control Rhythm control
101104
6160
NR63.5
74NR
12.9
12.9
Sinus rhythm
(%)Warfarin
(%)
Cu
mu
lati
ve m
ort
ality
(%
)
Rhythm control
Rate control
No. ofdeaths
0
30
25
20
15
5
Rhythm control
Rate control10
Years
357 (13)80 (4) 352 (24)0 175 (9) 314 (18)
210 (11)78 (4) 306 (21)0 148 (7) 275 (16)
0 54321
p=0.08
AFFIRM Investigators N Engl J Med (2002) 347: 1825
AFib Follow-up Investigation of Rhythm Management (AFFIRM)No survival advantage of rhythm over rate (n=4060)
Testa L, et al. Eur Heart J (2005) 26: 2000
Study orsub-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)
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
OR(95% CI Random)
10510.1 0.2 0.5 2
Ratecontrol better
Rhythmcontrol better
Odds Ratio for Combined Endpoint (All-cause Death + Thromboembolic Stroke)
Meta-Analysis of Rhythm Control versus Rate Control Studies
Age at enrollment* <0.0001 1.06 1.04 1.08
Coronary artery disease <0.0001 1.65 1.31 2.07
Congestive heart failure <0.0001 1.83 1.45 2.32
Diabetes <0.0001 1.56 1.22 2.00
Stroke or transient ischemic attack <0.0001 1.54 1.17 2.05
Smoking <0.0001 1.75 1.29 2.39
First episode of AFib 0.0067 1.27 1.01 1.58
Sinus rhythm <0.0001 0.54 0.42 0.70
Warfarin use <0.0001 0.47 0.36 0.61
Digoxin use <0.0001 1.50 1.18 1.89
Rhythm-control drug use 0.0005 1.41 1.10 1.83
UpperCovariate Lowerp HRHR: 99% CL
* per year of age
AFFIRM Investigators Circulation (2004) 109: 1509
AFFIRM On-Treatment Analysis: SR but not AAD Use Associates with Improved Survival
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
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
Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832
*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
Author/Study, DatePatient Group Drug
No. Randomized
MeanFollow-Up
MeanLVEF HTN (%)
Rate of AFin Control Group (%)
ACE-I trials
Van Den Burg, 1995 AF, CHF Lisinopril 30 84 days n/a n/a 64
Ueng, 2003 AF Enalapril 145 270 days(61-575) 51 32 43
Vermes (SOLVD), 2003 LVD, CHF, NSR Enalapril 374 3.3 yrs 27 20 24
Pizetti (GISSI), 2001 Post-MI, NSR Lisinopril 17,711 42 days n/a 30 8
Pedersen (TRACE), 1999
Post-MI, LVD, NSR Trandolapril 1,577 2-4 yrs 33 22 5
STOP-H2, 1999 HTN Enalapril 10,985 5.0 yrs n/a 100 8
CAPP, 1999 HTN Captopril 6,614 6.1 yrs n/a 100 2
ARB trials
CHARM, 2003* CHF, NSR Candesartan 5,518 3.2 yrs 39 55 8
Madrid, 2002 AF Irbesartan 154 254 days(60-710) 64 42 29
ValHeFT, 2003* CHF, NSR Valsartan 4,409 2 yrs 28 7 8
Wachtell, (LIFE), 2003* HTN, LVH, NSR Losartan 9,193 4.9 yrs n/a 100 6
Characteristics of ARB and ACE-I Studies in AFib
StudyTreatment
(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
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)
Test for heterogeneity chi-square=32.58; df=6; p<0.00001Test for overall effect z=-2.53; p=0.01
Effect of Treatment Based on Class of Drug: ACE Inhibitors
28%p=0.01
0 10521
RR(95% CI Random)
Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832
StudyTreatment
(n/N)Control(n/N)
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)
Test for heterogeneity chi-square=5.25; df=3; p=0.15Test for overall effect z=-4.12; p=0.00004
Effect of Treatment Based on Class of Drug: ARBs
29%p=0.00002
0 10521
RR(95% CI Random)
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 FailureVan Den Berg 2/7 7/11SOLVD 10/186 45/188ValHeFT 116/2209 173/2300Charm 179/2769 216/2749Sutotal (95% CI) 307/5171 441/5148
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)
Test for heterogeneity chi-square=15.01; df=3; p<0.0018Test for overall effect z=-2.72; p=0.007
44%
HypertensionCAPP 117/5492 135/5493LIFE 178/4417 252/4387STOP-H2 200/2205 357/4409Sutotal (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)
Test for heterogeneity chi-square=13.34; df=2; p=0.0013Test for overall effect z=-0.82; p=0.4
12%
0 10521
RR (95% CI Random)
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) Weight (%) RR (95% CI Random)
Atrial FibrillationMadrid 9/79 22/75Ueng 15/70 32/75Sutotal (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)Test for heterogeneity chi-square=1.33; df=1; p=0.31Test for overall effect z=-3.13; p=0.002
48%
Post-Myocardial InfarctionTRACE 22/790 42/787GISSI 665/8865 721/6646Sutotal (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)
Test for heterogeneity chi-square=4.64; df=1; p=0.031Test for overall effect z=-1.12; p=0.3
27%
0 10521
RR (95% CI Random)
Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832
Non-antiarrhythmic drugs
Statins
Lozano HF, et al. Heart Rhythm (2005) 2: 1000
Study DesignMedicationand subjects OR Comments
Statin drugsin protecting against AFib
Retrospective analysis of prospective study database
Statin users vs nonusers in a population of chronic CAD (n=449)
0.48 (CI 0.28-0.83) 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 0.10-0.90) 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
Pravastatin40 mg/day vsno 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%
Studies of Statins to Prevent AFib
Effect of Atorvastatin on Reducing AFib Recurrence Post-ECV
Ozaydin M, et al. Am J Cardiol (2006) 297: 1490
Fre
ed
om
fro
m r
ecu
rren
ce
Follow-up (days)
0 30 60 90
Atorvastatin
control
0.5
0.6
0.7
0.8
0.9
1.0
48 patients with AFib lasting >48h and followed for 3m
p=0.01
Non-antiarrhythmic drugs
Polyunsaturated fatty acids(omega-3)
Polyunsaturated Fatty Acids in Preventing AFib
Calò L, et al. J Am Coll Cardiol (2005) 45: 1723
100
60
80
40
20Pati
en
ts f
ree o
f A
Fib
(%
)
00
90
50
70
30
10
Control GroupPUFAs Group
Days after surgery
2 3 4 5 6 7 8 9 10 11 12 181 1716151413
Log-rank p=0.009
Mozzafarian D, et al. Circulation (2004) 110: 3683
AFib-Free Survival According to Fish ConsumptionTuna or other broiled/baked fish
1.0
0.8
Su
rviv
al fr
ee o
f A
Fib
0.60
0.9
0.7
p<0.0001(log-rank test for equalityof survivor functions)
5+/wk
Years
2 4 121086
1-4/wk
1-3/mo
<1/mo
AFib-Free Survival According to Fish ConsumptionFried fish or fish sandwich
1.0
0.8
Su
rviv
al fr
ee o
f A
Fib
0.60
0.9
0.7
p=0.0001(log-rank test for equalityof survivor functions)
<1/mo
Years
2 4 121086
1-3/mo
1+/wk
Mozzafarian D, et al. Circulation (2004) 110: 3683
n-3 Fatty Acid Intake from Fish and Incidence of AFib
Brouwer IA, et al. Am Heart J (2006) 151: 857
• 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
Rotterdam study
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
Clinical symptoms
ECG Criteria
Hemodynamic data
VR 60 - 80 bpm
At rest
VR 90 - 115 bpm
During moderate exercise
Definitions and Criteria for Rate Control
•Digoxin
•Calcium Antagonists
•Beta-Blockers
•Antiarrhythmic Drugs
Drugs Used for Rate Control
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial FibrillationJ Am Coll Cardiol (2006) 48: 854
Rate Control Drugs in AFFIRM
•Digoxin 51%
•Beta-blockers 49%
•Calcium antagonists 41%
•AV node ablation 5%
Beasley R, et al. Br Med J (1985) 290: 9
Digoxin in Permanent AFibb
pm
Rest Moderate50
110
170
190
130
90
Strenuous
p<0.05
105
171
161
140150
70
• Heart rate during physical exercise and at various plasma concentrations
72
108
93
83
118
191182
164
SR
Nil
Low
High
Roth A, et al. Circulation 73: 316
Digoxin plus Diltiazemin Permanent AFib
bp
m
Rest Submax Exercise50
110
170
190
130
90
Max Exercise
* p<0.05 vs DG+DL * p<0.05 vs DL 360° p<0.05 vs DG 240
142
101
128
106
170
132
154
136150
70
• Medium and high doses alone or in combinationwith digoxin
86
67
8879
*°
*
*
DG
DG+DL 240
DL 240
DL 360
• Gallopamil 100 mg b.i.d.
• Diltiazem 120 mg b.i.d.
• Verapamil 120 mg b.i.d.
• Digoxin 0.8 – 1.4 µg/ml
Botto GL, et al. Clin Cardiol 21: 837
Study protocol
(7 day administration of slow release formulation)
Calcium Antagonists in Permanent AFib
Calcium Antagonistsin Permanent AFib
bp
m
Median VR Minimum VR50
100
150
175
125
75
Maximum VR
* p<0.001o p<0.01 vs DGX
Holter and walking test
90 91
82 80
5963
59 59
167
149142
137°*
*
DGX
GLL
DLT
VRP
Botto GL, et al. Clin Cardiol 21: 837
DiBianco R, et al. Am Heart J (1984) 108: 1121
Nadolol for Controlof Ventricular Rate
• Effect on heart rate in patients on digoxinb
pm
Resting Low Average
p<0.01
0
50
100
150
200
175
125
75
25
3’ Exercise Max Exercise
Nadolol median dose 87 mg
DGX
NDL
Atwood JE, et al. J Am Coll Cardiol (1987) 10: 314
Beta-blockers for Controlof Ventricular Rate
kg
/min
16
18
24
22
20
• Effect of nadolol on physical exercise capacityS
ec
300
500
450
400
350
Exercise time O2 Consumption
p<0.01 p<0.01
DGX
CLP
DGX
DLT
DiBianco R, et al. Am Heart J (1984) 108: 1121
• Metoprolol 200 mg/d
• Diltiazem 300 mg/d
• Digoxin 0.8 – 1.4 µg/ml
• Placebo
Botto GL, et al. PACE (2000) 23: 649
Randomized, cross-over study with administration for 7-10 days
Randomized, cross-over study with administration for 7-10 days
Modulation of Ventricular Rate
Study protocol
Modulation of Ventricular Rate
Metr
es w
alk
ed
240
260
320
300
280
• Walking test resultsM
ax h
eart
rate
150
155
190
*
185
180
175
170
165
160
o
* p<0.05 vs PLA e DGXo p<.,01 vs PLA e DGX
* p<0.005 vs DGXo p<0.05 vs MTP
**o
*
DGXPlacebo DLT
MTP
Botto GL, et al. PACE (2000) 23: 649
Antiarrhythmic Drugs for Control of Ventricular Rate
•Amiodarone
•Solatolol
CHF-STAT Study: Amiodaronein Permanent AFib
Deedwania PC, et al. Circulation (1998) 98: 2574
bp
m
Baseline 2 w 6 m0
50
100
90
80
70
60
40
30
20
10
12 m
NS p=0.001 p=0.001 p=0.006
Amiodarone (400 mg/d)Placebo
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-rheumaticAtrial Fibrillation
1 Lancet (1989) 1: 1752 N Engl J Med (1990) 323: 1505
3 J Am Coll Cardiol (1991) 18: 349
4 Circulation (1991) 84: 5275 N Eng J Med (1992) 327: 1406
SPAF BAATAF CAFA AFASAK SPINAF
Number of Patients 1330 420 378 1007 571
Drug Used Warfarin ASA Warfarin Warfarin Warfarin ASA Warfarin(INR 2-4.5) 325 mg (PT 1.2-1.5x (INR 2-3) (INR 2.8-4.2) 75 mg (INR 1.2-1.5)
Control)
Embolic Rate (%)
Treatment 2,3 3,6 0,41 3,5 1,5 6,0 4,3Control 7,4 6,3 2,98 5,2 6,2 6,2 0,9
Risk Reduction (%)(95% confidence) 67 42 86 45 53 — 79
Major Bleeding Complications (%)
Treatment 1.5 1.4 0.9 2.5 6.3 0.6 1.5Control 1.6 1.9 0.5 0.5 0.0 0.0 0.9
Major Clinical Trials of Primary Prevention in Non-Valvular AFib
100% 50% 0% -100%-50%
All
Risk reduction
Warfarin betterWarfarin better Warfarin worseWarfarin worse
SPINAF
SPAF
CAFA
BAATAF
AFASAK
Events Pts/y
108
29
23
14
15
27
3691
972
508
478
922
811
Adjusted Dose Warfarin vs Placebo
Atrial Fibrillation Investigators Arch Intern Med (1994) 154: 1449
5
3
2
1
0Control Warfarin
An
nu
al r
isk
of
stro
ke (
%)
1.4%
4
4.5%
Reduction in risk = 68%Reduction in risk = 68%
Reduction in Stroke Risk – Meta-analysis of 5 Trials
Average - 68%
Study Range INR Stroke risk reduction
EAFT 2.5 – 4.0 - 62%
1007 patients > 70 with previous TIA or minor stroke
European Atrial Fibrillation Trial Lancet (1993) 342: 1255
vs placebovs placebo
Secondary Prevention
Primary prevention
AFASAK 75 mg - 18% (ns)
SPAF 325 mg - 44% (p<0.02)
Secondary prevention
EAFT 300 mg - 14% (ns)
Global reduction in risk = 25%(range 14-44%)
Aspirin vs Placebo
Study ASA dose Stroke risk reduction
Warfarin Superior to Aspirin
AFASAK I (1)
AFASAK II (2)
EAFT (9)
PATAF (15)
SPAF II (4)
All trials (n=5)
Relative RiskReduction (95% CI)
100 -1000Warfarin better
(%)Warfarin worse
(%)
Warfarin comparedwith aspirin
-5050
AFASAK I (1)
SPAF I (3)
EAFT (9)
ESPS II (14)
LASAF (13)
UK-TIA (16)
All trials (n=6)
Relative RiskReduction (95% CI)
100 -1000Aspirin better
(%)Aspirin worse
(%)
Aspirin comparedwith placebo
-5050
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial FibrillationJ Am Coll Cardiol (2006) 48: 854
SPAF Investigators Lancet (1994) 343: 634
Discontinued = 31Lost to follow-up = 0
Primary events = 11Deaths = 34
Completed without primary event = 478
1044 eligible patients randomised
Fixed, low dose warfarin plus aspirin (n = 521)
INR assessed at 1m and 2m then every 3m
Discontinued = 41Lost to follow-up = 0
Primary events = 44Deaths = 35
Completed without primary event = 442
Adjusted dose warfarin (n = 523)
Weekly INR control until stable, then monthly
SPAF III - Adjusted-dose vs. Low-intensity, Fixed-dose warfarin + ASA
SPAF Investigators Lancet (1996) 348: 633
Combination therapy
Adjusted-dose warfarin
Cu
mu
lati
ve
ev
en
t ra
te (
% p
er
ye
ar)
20
18
16
14
12
10
8
6
4
2
0
0 365 730
Days from randomization
521
523
378
397
265
273
166
173
61
65
Combination therapy
Warfarin therapy
Number at Risk
SPAF III – Stroke Rate
0 0-5 1 21-5
Major haemorrhage
Adjusted dose warfarin better
Stroke, MI,Vascular death
Vascular death
All disabling strokes
Disabling ischaemic stroke
Primary events
Combination therapy better
SPAF Investigators Lancet (1996) 348: 633
SPAF III – Relative Risk
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 2.0-3.0)
Cumulative incidence of primary events – 12m follow-up 5.8 % 7.2 % 3.6 % 2.8 %
1.0 1.5 2.0 4.52.5
SPAF III(adjusted)
INR range (2.0-3.0) recommended by 4th ACCP Consensus on Antithrombotic Therapy
EAFT
SPINAF
CAFA
BAATAF
AFASAK
Warfarin – INR range
3.0 3.5 4.0
SPAF I + II
SPAF III(fixed)
2.8-4.2
2.0-4.5
1.5-2.7
2.0-3.0
1.4-2.8
2.5-4.0
1.2-1.5
2.0-3.0
Primary Prevention Trials – Anticoagulation Ranges
2 INR 3
Cli
nic
al e
ven
ts
Thromboembolic HaemorrhagicTherapeutic window
Optimal Anticoagulation Ranges
Connolly SJ, et al. J Am Coll Cardiol (1991) 18: 349Ezekowitz MD, et al. N Engl J Med (1992) 327: 1406
SPAF II Lancet (1994) 343: 687Connolly SJ, et al. Lancet (1994) 343: 1509
Petersen P, et al. Lancet (1989) 171SPAF Circulation (1991) 84: 527
BAATAF N Engl J Med (1990) 323: 1505EAFT Lancet (1993) 342: 1255
60 65 70 8575Median age (y)
2
1
Intr
acra
nia
l hae
mo
rrh
age
(%
/y)
80
Oral anticoagulant
AspirinSPAF II (>75)
SPINAF(>70)
4 trials(>75)
AFASAKEAFT
BAATAF
SPINAF
CAFASPAF I
SPAF II(<75)
Intracranial Haemorrhage in Trials – Influence of Age
Treatment Options for AFib
Drugs to Reduce Thromboembolic Risk
Risk stratification
Clinical risk factors
Echocardiographic risk factors
Thromboembolic Risk Stratification
Advanced age (> women)
Hypertension
Cardiac insufficiency
Previous TIA
(Diabetes)
Clinical Risk Factors
Left atrial dilatation
Left ventricular systolic dysfunction
Transthoracic 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
Trans Esophageal Echocardiographic Risk Factors
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 FactorsAge > 75 Previous stroke or systemic embolismHistory of arterial hypertensionCardiac insufficiency o ventricular dysfunctionMitral valve diseaseProsthetic valve replacement
Minor Risk FactorsAge 65 - 75 Diabetes mellitusIschaemic cardiopathy with normal ventricular function sinistra
adapted from the 6th ACCP Consensus Conference on Antithrombotic Therapy, Chest (2001) 119 (Suppl): 194S
Risk Stratification in Patients with AFib
Antithrombotic Therapy Recommendations
Female gender Age greater thanor 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*
ThyrotoxicosisLV ejection fraction
35% or lessDiabetes mellitus
Moderate-risk factorsLess validated or weakerRisk factors
*If mechanical valve, target international normalized ratio (INR) greater than 2.5. INR = international normalized ratio; LV = left ventricular; TIA = transient ischemic attack
High-risk factors
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 morethan 1 moderate-risk factor Warfarin (INR 2.0 to 3.0, target 2.5)*
Risk category Recommended therapy
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
Naccarelli GV, et al. Am J Cardiol (2000) 85: 36D
Cardioversion
Heparin + warfarin 24 h
Warfarin(INR 2.0-3.0)
3-4 weeks+
Cardioversion
NegativePositive
Warfarin3-4 weeks
TEE
AFib > 48 hours
Treatment Options for AFib
Non-Pharmacologic Treatment Options
SurgeryElectrophysiologicalDevices
Pacemaker(single or dual chamber)
Internal atrialdefibrillators
Catheter ablation
AV node ablation
Non-Pharmacological Treatment Options for AFib
Maze procedure
Modified Maze
(mini-Maze)
ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial FibrillationJ 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