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 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
– 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
100
Flecainide 300 mg
Propafenone 600 mg
p<0.001 vs. placebo
SR (%)
p<0.001 vs. placebo
78
80
60
Placebo
72
59
51
39
40
18
20
0
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 + 0.007 mg/kg/min, maintenance
• Oral administration
• Mean efficacy:
flecainide 300 mg
propafenone 600 mg
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
Prior to enrolment
45.6
50
p<0.001
Number per month
Number per month
50
During follow-up
25
25
15
4.9
0
p<0.001
1.6
0
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
Cowan et al
Digoxin IV
Hou et al
Duration
of study
OR of SR with
amiodarone
p
34
24 h
1.11
NS
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
3h
77% amiod./
0% verap
<0.001
McAlister et al
Quinidine
36
8h
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
Magnesium sulfate
42
24 h
0.64
<0.05
Moran et al
Primary
endpoint
Conversion to
sinus rhythm
Connolly SJ Circulation (1999) 100: 2025
Amiodarone for Cardioversion of
Recent-Onset AFib: Meta-analysis
100
Bolus only
Bolus + infusion
95
• Amiodarone IV (3-7 mg/kg ±
infusion 0.9-3.0 g/day)
80
• Amiodarone oral (25-30 mg/kg)
Conversion (%)
69
• Time to conversion > 6-8 h
55
60
• Amiodarone > 1.5 g/day IV >
40
placebo
34
• Amiodarone 25-30 mg/kg oral >
placebo
20
• Amiodarone not > other AADs
0
2-4 h
8h
• Safe in patients with structural
cardiopathies and low LVEF
Khan IA, et al. Int J Cardiol (2003) 89: 239
Amiodarone Single Oral Administration
for Cardioversion of Recent Onset AFib
Placebo
Amiodarone
100
Patients in AFib (%)
80
60
40
20
0
0
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
Amiodarone
Flecainide
Placebo
32
28
Cardioversion (%)
p=0.001
p=0.007
24
20
16
12
8
4
0
0
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
100
Flecainide
Sotalol
* p=0.005
80
69*
60
52*
44
40
31
23
17
20
0
0
Total
<24 hours
<7 days
0
<6 months
Reisinger J, et al. Am J Cardiol (1998) 81: 1450
Amiodarone Cardioversion in
Persistent AFib
67 patients with AFib >48 hours
A
100
B
Amiodarone
Placebo
p<0.001
82
77
Sinus rhythm (%)
80
65
60
48
40
32
31
30
20
0
0
Total
LA (mm)
>45 <45
LVEF (%)
>50 <50
AFib (m)
>1
<1
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
80
Sinus rhythm (%)
Sinus rhythm (%)
80
p<0.0001
60
40
60
40
20
20
0
0
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
70 patients
(57 AFib, 13 AFlutter)
Ibutilide 2 mg
Recovery of SR (%)
80
60
54
39
40
20
0
AFlutter
AFib
Glatter K, et al. Circulation (2001) 103: 253
Electrical Cardioversion
(transthoracic)
Technical Aspects
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: 1282-7
Defibrillation Waves
Monophasic wave
Biphasic wave
30
Ampere
Ampere
10
20
0
10
-10
0
0
4
8
msec
12
0
4
8
12
msec
Mittal S, et al. Circulation (2000) 101: 1282
Cumulative Efficacy of
Cardioversion
Monophasic or biphasic shock
p<0.005
p<0.0001
100
Efficacy of cardioversion (%)
85
91
94
79
80
68
68
60
44
40
21
20
0
100 J
200 J
300 J
Monophasic
360 J
70 J
120 J
150 J
170 J
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: 1956-63
Dermal Injury Dependent on
Waveform
60
Monophasic
Biphasic
50
40
30
20
10
0
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
No conversion
Immediate recurrent AFib
Early recurrent AFib
Late recurrence AFib
90
Sinus rhythm (%)
80
70
60
50
40
30
20
10
0
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
Patients with AF Recurrence (%)
Treatment Arm
100
Rate control
Rhythm control
80
60
40
Log rank statistic = 58.62
p<0.0001
20
0
0
1
2
4
5
6
10,481 (92)
73,494 (75)
2,484 (95)
18,503 (79)
Time (years)
N, Events (%)
Rate control:
Rhythm control:
3
563,3 (0)
729,2 (0)
167,383 (69)
344,356 (50)
96,440 (80)
250,422 (60)
42,472 (87)
143,470 (69)
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
7 days
Daoud
337
9
5 min
De Simone
107
14
7 days
61
36
5 days
116
7
24 hours
50
26
1 min
Tieleman
Villani
Yu
• 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
Prevalence of IRAF (%)
90
80
70
60
48
50
27
40
30
34
20
45
72
10
0
1
hr
1-24
hrs
1-7
days
7-30
days
31-90
days
36
13
40
91-180 181-365
days
days
>365
days
Duration of AFib
Oral H, et al. J Cardiovasc Electrophysiol (2003) 14: 182
Oral Propafenone Before Electrical
Cardioversion in Persistent AFib
Effect on early recurrence of arrhythmia
100
80
70
60
Propafenone
Placebo
0
10 min
24 min
48 min
Complex atrial arrhythmia (%)
Sinus rhythm (%)
90
50
70
p<0.01
p<0.002
60
52
50
40
30
20
18
10
0
10 minutes
Bianconi L, et al. J Am Coll Cardiol (1996) 28: 700
Effect of Pre-treatment with Oral
Amiodarone
30
Amiodarone
GIK
No treatment
100
p<0.005
p<0.05
80
Conversion (%)
Conversion (%)
24
Amiodarone
GIK
No treatment
18
12
60
40
6
20
0
0
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
30
Short-term Amiodarone
62
32
38
DCCV
100
Placebo
30
Long-term Amiodarone
61
16
Sinus Rhythm
Short-term Amiodarone
48
10
Chemical
26
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
50
in all patients given
ibutilide and in 14/50
patients failing
cardioversion alone
Patients (%)
40
• The mean energy for
30
defibrillation was less
with ibutilide
20
• Sustained polymorphic
tachycardia in 2/64 (3%)
patients treated with
ibutilide within 15 min
of the infusion
10
0
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
60
PFN
PFN + VER
PFN - VER
p=0.04
p=0.02
Recurrence (%)
50
p=0.04
39
p=0.01
40
30
30
20
10
0
15
17
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: 578-80
Effect of Pre-treatment with Verapamil
on Early Recurrence Following ECV
A randomised trial (90 patients with amiodarone)
60
Amio + Ver
Amio
NS
50
Recurrence (%)
NS
40
30
NS
20
10
0
6h
7d
30 d
Follow-up
Bertaglia E, et al. Heart (2001) 85: 578-80
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
Serial ECV
1 ECV, no AADs
Maintenance of SR (%)
90
80
70
60
50
40
30
20
10
0
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: 1522-8
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 (%)
Group AGG
Group CTL
100
90
80
70
60
50
40
30
20
10
0
0
7
30
days
180
365
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
– 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
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
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
Drugs studied
Antiarrhythmic
vs Control
Class IA
Disopyramide
hydrochloride
Quinidine sulfate
All class IA
Class IB
All: aprindine
hydrochloride,
bidisomide
Class IC
Flecainide acetate
Propafenone
hydrochloride
All class IC
Class II
All: metroprolol
tartrate
No. of
Studies
Antiarrhythmic
Peto OR (95% Cl)
Control
p value
0.10
1
10
2
40/75
49/71
0.52 (0.27-1.01)
0.05
7
8
741/1106
781/1118
417/518
449/564
0.51 (0.40-0.65)
0.51 (0.40-0.64)
<0.001
<0.001
2
639/781
453/540
0.84 (0.63-1.13)
0.26
3
31/71
56/78
0.31 (0.16-0.60)
<0.001
5
376/720
276/378
0.37 (0.28-0.48)
<0.001
9
443/843
342/466
0.36 (0.28-0.45)
<0.001
1
127/197
140/197
0.74 (0.49-1.13)
0.16
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
15
1484/2401
1148/1433
0.37 (0.32-0.43)
<0.001
Class III
All class III
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
Proportion without Recurrence (%)
70
60
50
40
30
20
10
0
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
Odds Ratio
5
4
3
2
1
0
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
Patients without AFib (%)
p<0.001
80
60
40
Sotalol
20
0
0
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 AntiArrhythmic Drug
AFFIRM Study
222 pts
256 pts
Percent without recurrence
100
p=0.011
100
62%
60%
80
80
60
60
Amiodarone
40
Amiodarone
40
23%
38%
Class I Drugs
20
0
p<0.001
0
1
2
3
Years
Sotalol
20
4
5
0
0
1
2
3
4
5
Years
AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20
Amiodarone and Solatolol Equivalent in
Patients with Ischaemic Heart Disease
SAFE-T Investigators
All patients
Patients with IHD
1.0
0.8
Amiodarone
0.6
Sotalol
0.4
Placebo
0.2
0
0
200
400
600
800 1000
Probability of remaining in SR
Probability of remaining in SR
1.0
0.8
0.6
Amiodarone
0.4
Sotalol
0.2
Placebo
0
0
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
2.4%
Amiodarone Trials Meta-analysis Investigators Lancet (1997) 350: 1417
Amiodarone Discontinuations
Associated with Major Adverse Events
• Gastrointestinal events
• Pulmonary events
4.0%
2.6%
• Ocular events
0.6%
• Other
7.1%
AFFIRM Investigators J Am Coll Cardiol (2003) 42: 20
Major Adverse Experiences Associated
with Early Drug Discontinuation
• Amiodarone meta-analysis
• CTAF
41% at 2y
18% at 16m
• PIAF
25% at 1y
• AFFIRM
12.3% at 1y
Major Adverse Experiences
Associated with AADs
Drugs studied
No. of
Studies
Withdrawals
Peto OR (95% Cl)
Antiarrhythmic vs Control
Class IA
0.10
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
All class IA
Class IB
All: aprindine hydrochloride
Class IC
Flecainide acetate
Propafenone hydrochloride
All class IC
Class II
All: metoprolol tartrate
7
8
1.90 (0.90-4.02)
2.02 (1.00-4.10)
1
0.66 (0.11-3.95)
3
5
9
9.14 (1.94-42.90)
1.69 (1.09-2.62)
1.93 (1.27-2.93)
1
3.16 (1.43-6.99)
Amiodarone
3,4
5.55 (2.24-13.70)
Dofetilide
1,2
1.61 (0.41-6.23)
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)
2
2.46 (1.51-4.01)
14,16
1.63 (1.29-2.07)
1
10
Class III
Sotalol hydrochloride: PAFAC, SOPAT
Azimilide dihydrochloride + Dronedarone
All class III
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
Proarrhythmia Associated with AADs
Drugs studied
No. of
Studies
Proarrhythmia
Peto OR (95% Cl)
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
All class IA
Class IB
All: aprindine hydrochloride
Class IC
Flecainide acetate
Propafenone hydrochloride
All class IC
Class II
All: metoprolol tartrate
7
8
2.10 (1.02-4.33)
2.06 (1.00-4.26)
1
No Events
3
5
9
5.97 (1.67-21.30)
1.52 (0.33-7.02)
3.41 (1.28-9.09)
1
7.96 (2.84-22.30)
Amiodarone
3, 4
2.65 (0.88-8.00)
Dofetilide
1, 2
3.77 (1.31-10.80)
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)
2
3.30 (1.01-10.80)
14, 16
2.20 (1.31-3.69)
0.10
1
10
Class III
Sotalol hydrochloride: PAFAC, SOPAT
Azimilide dihydrochloride + dronedarone
All class III
Lafuente-Lafuente C, et al. Arch Intern Med (2006) 166: 719
Proarrhythmic Profile of AADs
Torsade
de Pointe
Dysopiramide
Quinidine
Procainamide
Lidocaina
Mexiletine
Morizicine
Propafenone
Flecainide
Amiodarone
Ibutilide
Sotalol
1-2%
2%
1-2%
Rare
Rare
Rare
<1%
4-5%
2-5%
Atrial
Flutter 1:1 Bradyarrhythmia
VF
VT *
++
++
++
Rare
Rare
+
+
+
+
+
+
+
Rare
Rare
++
++
++
+
+
+
+
++
++
+
Rare
++
+++
+++
+
+
+
+
+
Rare
Rare
+
++
++
+++
Rare
+++
* 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
Drugs studied
Antiarrhythmic
vs Control
Class IA
Disopyramide
phosphate
Quinidine sulfate
All class IA
Class IB
All: aprindine
hydrochloride,
bidisomide
Class IC
Flecainide acetate
Propafenone
hydrochloride
All class IC
Class II
All: metroprolol
tartrate
No. of
Studies
No. of Events/Total
Antiarrhythmic
Peto OR (95% Cl)
Control
p value
0.10
1
10
2
2/75
0/71
7.56 (0.47-1.22)
0.16
7
8
21/1128
23/1203
4/548
4/594
2.26 (0.93-5.45)
2.39 (1.03-5.59)
0.07
0.04
2
9/781
3/540
1.89 (0.59-6.03)
0.28
3
0/71
0/78
Not estimable
NA
5
0/720
2/378
0.05 (0.00-1.02)
0.05
9
1/843
2/466
0.14 (0.00-1.88)
0.14
1
3/197
0/197
7.47 (0.77-72.20)
0.08
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)
0.06
Azimilide
dihydrochloride +
dronedarone
2
10/1042
4/537
1.31 (0.43-3.97)
0.63
16
136/3292
95/1922
1.19 (0.88-1.61)
0.27
Class III
All class III
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
100
80
Quinidine
Placebo
p<0.001
p<0.001
p<0.001
p<0.05
69
58
(%)
60
50
45
40
33
25
20
# of patients
17
3
0
3 month
6 month
12 month
Mortality
Coplen SE, et al. Circulation (1990) 82: 1106
Physician Visits Associated
with AAD Use Over Time
7
Visits on medication (%)
6
Quinidine
Class IC
Amiodarone Hydrochloride
5
4
3
2
1
0
1991-1992
1993-1994
1995-1996
1997-1998
1999-2000
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
Rhythm vs Rate Trials
Trial
n
Age, y
AFFIRM
Rate control
Rhythm control
2027
2033
70
70
256
266
68
68
100
100
65
66
85
70
6
7.5
21
24
10
39
96-99
86-99
5.5
7.9
17
13
0
NR
NR
NR
0.6
3.1
5
2.5
10
56
100
100
NR
NR
1.6
1.6
NR
63.5
74
NR
1
2.9
1
2.9
12m
125
127
61
60
Hot Cafe
Rate control
Rhythm control
35
63
22m
PIAF
Rate control
Rhythm control
Mortality
%
27m
STAF
Rate control
Rhythm control
Thromboembolic
complications
%
42m
RACE
Rate control
Rhythm control
Mean
Follow-up
Sinus
rhythm Warfarin
(%)
(%)
20m
101
104
61
60
Falk, RH. Circulation (2005) 111: 3141
AFib Follow-up Investigation of Rhythm
Management (AFFIRM)
No survival advantage of rhythm over rate (n=4060)
Cumulative mortality (%)
30
p=0.08
25
Rhythm control
20
15
Rate control
10
5
0
No. of
deaths
0
1
2
3
4
5
Years
Rhythm control
0
80 (4)
175 (9)
357 (13)
314 (18)
352 (24)
Rate control
0
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)
Weight
(%)
OR (95% CI
Random)
Van Den Berg
388/2027
438/2033
89.86
0.86 (0.74, 1.00)
SOLVD
1/101
6/104
0.46
0.16 (0.02, 1.38)
TRACE
2/125
4/127
0.72
0.50 (0.09, 2.78)
Ueng
24/256
32/266
6.72
0.76 (0.43, 1.32)
CAPP
97100
9/100
2.24
1.00 (0.38, 2.63)
2609
2630
100.0
0.85 (0.73, 0.98)
Total (95% CI)
OR
(95% CI Random)
0.1
0.2
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
0.5
Rate
control better
1
2
5
10
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
Covariate
HR: 99% CL
Lower
Upper
p
HR
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
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
0.0005
1.41
1.10
1.83
First episode of AFib
Rhythm-control drug use
* 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
Drug
No.
Randomized
Mean
Follow-Up
Mean
LVEF
HTN
(%)
Rate of AF
in Control
Group (%)
AF, CHF
Lisinopril
30
84 days
n/a
n/a
64
AF
Enalapril
145
270 days
(61-575)
51
32
43
LVD, CHF,
NSR
Enalapril
374
3.3 yrs
27
20
24
Post-MI, NSR
Lisinopril
17,711
42 days
n/a
30
8
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
CHF, NSR
Candesartan
5,518
3.2 yrs
39
55
8
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
Author/Study, Date
Patient
Group
ACE-I trials
Van Den Burg, 1995
Ueng, 2003
Vermes (SOLVD), 2003
Pizetti (GISSI), 2001
Pedersen (TRACE),
1999
ARB trials
CHARM, 2003*
Madrid, 2002
*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
Treatment
(n/N)
Control
(n/N)
2/7
SOLVD
TRACE
RR
(95% CI Random)
Weight
(%)
RR (95% CI
Random)
7/11
1.7
0.45 (0.13, 1.57)
10/186
45/188
4.8
0.22 (0.12, 0.43)
22/790
42/787
6.6
0.52 (0.31, 0.87)
Ueng
18/70
32/75
7.0
0.60 (0.37, 0.97)
CAPP
117/5492
135/5493
11.4
0.87 (0.68, 1.11)
STOP-H2
200/2205
357/4409
13.0
1.12 (0.95, 1.32)
GISSI
665/8855
721/8846
14.0
0.92 (0.83, 1.02)
1034/17615
1339/19809
58.7
0.72 (0.56, 0.93)
Study
ACE inhibitor
Van Den Berg
Sutotal (95% CI)
28%
p=0.01
Test for heterogeneity chi-square=32.58; df=6; p<0.00001
Test for overall effect z=-2.53; p=0.01
1
2
0
5
10
Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832
Effect of Treatment Based on Class
of Drug: ARBs
Treatment
(n/N)
Control
(n/N)
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
Study
RR
(95% CI Random)
Weight
(%)
RR (95% CI
Random)
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)
ARB
Madrid
29%
p=0.00002
Test for heterogeneity chi-square=5.25; df=3; p=0.15
Test for overall effect z=-4.12; p=0.00004
1
2
0
5
10
Healey JS, et al. J Am Coll Cardiol (2005) 45: 1832
Effect of ACE Inhibitors or ARB Based
on Indication
RR (95% CI Random)
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
Test for heterogeneity chi-square=15.01; df=3; p<0.0018
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
Test for heterogeneity chi-square=13.34; df=2; p=0.0013
Test for overall effect z=-0.82; p=0.4
1
2
0
Weight (%) RR (95% CI Random)
44%
1.7
4.8
11.8
12.5
30.9
0.45
0.22
0.67
0.62
0.56
(0.13,
(0.12,
(0.53,
(0.66,
(0.37,
1.57)
0.43)
0.84)
1.00)
0.85)
12%
11.4
12.6
13.0
37.1
0.87
0.71
1.12
0.88
(0.69,
(0.59,
(0.95,
(0.65,
1.11)
0.85)
1.32)
1.19)
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)
RR (95% CI Random)
Control (n/N)
Atrial Fibrillation
Madrid
9/79
22/75
Ueng
15/70
32/75
Sutotal (95% CI)
27/149
54/150
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
Test for heterogeneity chi-square=4.64; df=1; p=0.031
Test for overall effect z=-1.12; p=0.3
1
2
0
Weight (%) RR (95% CI Random)
48%
4.3
7.0
11.4
0.39 (0.19, 0.79)
0.60 (0.37, 0.97)
0.52 (0.35, 0.79)
27%
6.6
14.0
20.7
0.52 (0.31, 0.87)
0.92 (0.83, 1.02)
0.73 (0.43, 1.26)
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
Statin drugs
in protecting
against AFib
Retrospective
analysis of
prospective study
database
Medication
and subjects
OR
Comments
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 Retrospective
recurrence after
analysis of
cardioversion
patients referred
for cardioversion
Statin users vs
nonusers in a
population with
persistent lone
AFib (n=62)
0.31 (CI 0.10-0.90)
Prevastatin to
prevent recurrent
AFib after
electrical
cardioversion
Pravastatin
1.08 (CI not
40 mg/day vs
available)
no drug 3 weeks
prior and 6 weeks
cardioversion
(n=114)
Prospective,
open-label,
controlled
multicenter study
52%
69%
8%
Patients on statins had
higher cholesterol and
were older than
nonusers.
AFib diagnosed by ECG
at routine follow-up
visits.
Open-label design, small
study, conventional
antiarrhythmics also
used.
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
Freedom from recurrence
1.0
Atorvastatin
0.9
0.8
p=0.01
0.7
control
0.6
0.5
0
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
Control Group
Patients free of AFib (%)
90
80
70
60
Log-rank p=0.009
50
40
30
20
10
0
0
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
Survival free of AFib
p<0.0001
(log-rank test for equality
of survivor functions)
0.9
5+/wk
0.8
1-4/wk
1-3/mo
0.7
<1/mo
0.6
0
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
Survival free of AFib
p=0.0001
(log-rank test for equality
of survivor functions)
0.9
0.8
<1/mo
1-3/mo
1+/wk
0.7
0.6
0
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 60 - 80 bpm
At rest
 VR 90 - 115 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
51%
• Beta-blockers
49%
• Calcium antagonists
41%
• AV node ablation
5%
Digoxin in Permanent AFib
• Heart rate during physical exercise and at various
plasma concentrations
190
191
SR
Low
Nil
High
182
171
170
p<0.05
150
bpm
164
161
140
130
118
108
110
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
*°
bpm
150
* p<0.05 vs DG+DL
* p<0.05 vs DL 360
° p<0.05 vs DG 240
130
110
90
70
50
142
132
128
*
101
136
106
88
86
*
154
79
67
Rest
Submax Exercise
Max Exercise
Roth A, et al. Circulation 73: 316
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
0.8 – 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
GLL
VRP
167
149
150
°
* p<0.001
o p<0.01 vs DGX
*
137
*
bpm
125
142
100
90
91
82
80
75
59
50
Median VR
63
59
59
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
175
DGX
NDL
p<0.01
150
bpm
125
100
75
50
25
0
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
500
DGX
24
DLT
p<0.01
22
kg/min
Sec
CLP
p<0.01
450
400
350
300
DGX
20
18
Exercise time
DiBianco R, et al. Am Heart J (1984) 108: 1121
16
O2 Consumption
Atwood JE, et al. J Am Coll Cardiol (1987) 10: 314
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
DGX
320
DLT
MTP
185
300
175
170
*
165
o
160
Metres walked
Max heart rate
180
280
*
*o
*
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
100
90
Placebo
Amiodarone (400 mg/d)
NS
p=0.001
p=0.001
p=0.006
Baseline
2w
6m
12 m
80
70
bpm
60
50
40
30
20
10
0
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
1330
420
378
Warfarin
ASA
(INR 2-4.5) 325 mg
Warfarin
(PT 1.2-1.5x
Control)
Warfarin
(INR 2-3)
Number of Patients
Drug Used
AFASAK
SPINAF
1007
571
Warfarin
ASA
Warfarin
(INR 2.8-4.2) 75 mg (INR 1.2-1.5)
Embolic Rate (%)
Treatment
Control
Risk Reduction (%)
(95% confidence)
2,3
7,4
3,6
6,3
0,41
2,98
3,5
5,2
1,5
6,2
6,0
6,2
4,3
0,9
67
42
86
45
53
—
79
1.5
1.6
1.4
1.9
0.9
0.5
2.5
0.5
6.3
0.0
0.6
0.0
1.5
0.9
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
108
3691
All
100%
50%
Warfarin better
0%
-50%
-100%
Warfarin worse
Reduction in Stroke Risk – Metaanalysis of 5 Trials
Annual risk of stroke (%)
5
4.5%
4
Reduction in risk = 68%
3
2
1.4%
1
0
Control
Warfarin
Atrial Fibrillation Investigators Arch Intern Med (1994) 154: 1449
Secondary Prevention
Study
Range INR
Average
EAFT
2.5 – 4.0
Stroke risk reduction
- 68%
- 62%
vs placebo
1007 patients > 70 with previous TIA or minor stroke
European Atrial Fibrillation Trial Lancet (1993) 342: 1255
Aspirin vs Placebo
Study
ASA dose
Stroke risk reduction
Primary prevention
AFASAK
SPAF
75 mg
325 mg
- 18% (ns)
- 44% (p<0.02)
Secondary prevention
EAFT
300 mg
- 14% (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 I (1)
SPAF I (3)
AFASAK II (2)
EAFT (9)
EAFT (9)
ESPS II (14)
PATAF (15)
LASAF (13)
SPAF II (4)
UK-TIA (16)
All trials (n=5)
All trials (n=6)
100
50
0
-50
-100
Warfarin better
Warfarin worse
(%)
(%)
100
50
Aspirin better
(%)
0
-50
-100
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. Lowintensity, 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)
SPAF III – Stroke Rate
20
18
16
14
Combination therapy
12
10
8
6
Adjusted-dose warfarin
4
2
0
365
0
730
Days from randomization
Number at Risk
Combination therapy
521
378
265
166
61
Warfarin therapy
523
397
273
173
65
SPAF Investigators Lancet (1996) 348: 633
SPAF III – Relative Risk
Primary events
Disabling
ischaemic stroke
All disabling
strokes
Vascular
death
Stroke, MI,
Vascular death
Major
haemorrhage
0
0-5
Adjusted dose warfarin better
1
1-5
2
Combination therapy better
SPAF Investigators Lancet (1996) 348: 633
AFASAK 2 - Copenhagen
Investigators
677 patients with
permanent AFib
Warfarin
fixed-dose
1.25 mg
5.8 %
Warfarin
fixed-dose
1.25 mg +
ASA 300 mg
7.2 %
ASA 300 mg
3.6 %
Warfarin
dose variable
(INR 2.03.0)
2.8 %
Cumulative incidence of primary events – 12m follow-up
Primary Prevention Trials –
Anticoagulation Ranges
Warfarin – INR range
AFASAK
2.8-4.2
SPAF I + II
2.0-4.5
BAATAF
1.5-2.7
2.0-3.0
CAFA
SPINAF
1.4-2.8
2.5-4.0
EAFT
SPAF III
1.2-1.5
(fixed)
SPAF III
2.0-3.0
(adjusted)
1.0
1.5
2.0
2.5
3.0
3.5
4.0
INR range (2.0-3.0) recommended by 4th ACCP Consensus on Antithrombotic Therapy
4.5
Optimal Anticoagulation Ranges
Therapeutic window
Clinical events
Thromboembolic
2
INR
3
Haemorrhagic
Intracranial haemorrhage (%/y)
Intracranial Haemorrhage in Trials
– Influence of Age
2
Oral
anticoagulant
SPAF II (>75)
Aspirin
CAFA
SPAF I
SPINAF
1
BAATAF
SPINAF
(>70)
4 trials
(>75)
SPAF II
(<75)
60
EAFT
65
70
AFASAK
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 > 75
Previous stroke or systemic embolism
History of arterial hypertension
Cardiac insufficiency o ventricular dysfunction
Mitral valve disease
Prosthetic valve replacement
Minor Risk Factors
Age 65 - 75
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
No risk factors
One moderate-risk factor
Any high-risk factor or more
than 1 moderate-risk factor
Less validated or weaker
Risk factors
Recommended therapy
Aspirin, 81 to 325 mg daily
Aspirin, 81 to 325 mg daily, or warfarin (INR
2.0 to 3.0, target 2.5)
Warfarin (INR 2.0 to 3.0, target 2.5)*
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 2.0-3.0)
3-4 weeks
+
Cardioversion
Warfarin
3-4 weeks
Positive
Negative
Heparin + warfarin
24 h
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