PREOPERATIVE AMIODARONE AS PROPHYLAXIS
AGAINST ATRIAL FIBRILLATION AFTER CARDIAC
VALVE SURGERY AMONG RHEUMATIC HEART
DISEASE PATIENTS: A Meta-analysis
Ian Lusoc, MD
Flordeliz Lontok, MD
The Heart Institute, St. Luke’s Medical Center
Quezon City
Introduction
• Atrial fibrillation (AF) is common among
patients with valvular heart disease and is a
frequent rhythm disorder after cardiac
surgery1
• It occurs in up to 60% of patients who
undergo any cardiac surgery and those who
undergo valve procedure2,3,4
1. Maesen B, Nijs J, Maessen J, Allesie M, Schotten U. Post-operative atrial fibrillation: a maze of mechanisms. Europace 2012;14:159-74.
2. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061-73.
3. Mitchell LB, et al. Prophylactic oral amiodarone for the prevention of arrhythmias that begin early after revascularization, valve replacement, or
repair. PAPABEAR: A randomized controlled trial. JAMA 2005; 294:3093-3100.
4. Daoud EG, Strickberger SA, Man KC, Goyal R, Deeb M, Bolling S, Pagani F, Bitar C, Meissner M, Morady F. Preoperative amiodarone as prophylaxis
against atrial fibrillation after heart surgery. N Engl J Med 1997; 337: 1786-91.
Introduction
 In developing countries like the Philippines,
valvular heart disease of rheumatic origin is
the most frequent etiology of this disorder1
 Once present, it poses risks such as
hemodynamic instability, thromboembolism,
necessity for anticoagulation, and prolonged
hospital stay.
1. ABC of Atrial Fibrillation: History, Epidemiology, and Importance of Atrial Fibrillation. Gregory Y H Lip, et al. BMJ
1995;1311:1361.
STUDY
Wyse, 2002
(AFFIRM)
TITLE
A Comparison of Rate
Control and Rhythm
Control in Patients with
AF
POPULATION /
INTERVENTION
Patients with
nonrheumatic AF
were given either
antiarrhythmic
drug or drug for
rate control
OUTCOME
Rhythm-control
strategy offers no
survival advantage
over the ratecontrol strategy in
AF
STUDY
TITLE
POPULATION /
INTERVENTION
OUTCOME
Wyse, 2002
(AFFIRM)
A Comparison of Rate
Control and Rhythm
Control in Patients with
AF
Patients with
nonrheumatic AF
were given either
antiarrhythmic
drug or drug for
rate control
Rhythm-control
strategy offers no
survival advantage
over the ratecontrol strategy in
AF
Raine, 2004
Effect of Mitral Valve
Repair/Replacement
Surgery on
Atrial Arrhythmia
Behavior
Mitral valve surgery Mitral valve surgery
in patients with
alone restored
chronic AF
sinus
rhythm in only
8.5%
STUDY
TITLE
POPULATION /
INTERVENTION
OUTCOME
Wyse, 2002
(AFFIRM)
A Comparison of Rate
Control and Rhythm
Control in Patients with
AF
Patients with
nonrheumatic AF
were given either
antiarrhythmic
drug or drug for
rate control
Rhythm-control
strategy offers no
survival advantage
over the ratecontrol strategy in
AF
Raine, 2004
Effect of Mitral Valve
Repair/Replacement
Surgery on
Atrial Arrhythmia
Behavior
Mitral valve surgery Mitral valve surgery
in patients with
alone restored
chronic AF
sinus
rhythm in only
8.5%
Vora, 2004
Control of Rate vs
Rhythm in Rheumatic AF
Oral amiodarone (
DC cardioversion)
given to RHD
patients
undergoing mitral
valve surgery
Maintenance of
sinus rhythm
superior to
ventricular rate
control in patients
with rheumatic
atrial fibrillation
Introduction
 Role of IV amiodarone in restoring sinus
rhythm after valve surgery in RHD patients
with or without chronic AF.
Research Question
• Among rheumatic heart disease patients
undergoing cardiac valve surgery, how
effective is IV amiodarone in reducing the
incidence of post-operative atrial fibrillation?
Objectives
1. To determine the efficacy of IV amiodarone
in comparison with placebo in reducing the
incidence of post-operative AF
2. To determine the safety of amiodarone in
terms of occurrence of adverse events.
Inclusion Criteria
• Randomized controlled trials comparing IV
amiodarone vs. placebo among patients with
RHD in preventing the occurrence of AF,
and/or converting AF to NSR after a cardiac
valve surgery.
Trial Selection
Potentially eligible reports
identified and retrieved
(n = 339)
Reports included (n = 2)
Trials of amiodarone vs placebo
in RHD patients undergoing
cardiac valve surgery
Reports excluded (n = 337)
Observational studies
Case reports
Animal studies
Reviews
Not amiodarone as intervention
Not amiodarone vs placebo
Not cardiac surgery
Not cardiac valve surgery
Not RHD patients
Not AF
Study Design Characteristics
Selvaraj,1 2009
Kar,2 2011
RCT
RCT
82
56
Amiodarone
42
28
Control (placebo)
40
28
Trial design
Sample size, total
Type of Surgery
MVR or AVR, or both
MVR or AVR, or both
Timing of amiodarone Perioperative (after
administration
anesthesia induction,
before CPB)
Perioperative (after
anesthesia induction,
before CPB)
Total dose of
amiodarone
3 mg/kg IV infusion
over 20 min
3 mg/kg IV infusion
over 30 min
1. Selvaraj T, Kiran U, Das S, Chauhan S, Sahu B, Gharde P. Effect of single intraoperative dose of amiodarone in patients with
rheumatic valvular heart disease and atrial fibrillation undergoing valve replacement surgery. Ann Card Anaesthesia
2009;12:10-6.
2. Kar SK, Dasgupta CS, Goswami A. Effect of prophylactic amiodarone in patients with rheumatic valve disease undergoing
valve replacement surgery. Ann Card Anaesthesia 2011;14:176-82
Study Design Characteristics
Selvaraj, 2009
Kar, 2011
Arrhythmia
AF
AF
Period when AF was
observed to occur
At aortic cross-clamp
release, at end of
surgery, within 24 hours
post-operatively, and
before hospital
discharge
At aortic cross-clamp
release, at end of
surgery, and within 24
hours post-operatively
RESULTS
Baseline Characteristics
Age, years  SD
Male:female
Body weight (kg)
Height (cm)
Number of patients in AF
(preinduction)
NYHA class
Class II
Class III
Severity of mitral
stenosis
Mild
Moderate
Severe
Severity of mitral
regurgitation
Mild
Moderate
Severe
Selvaraj et al, 2009
Amiodarone
Placebo
(n = 42)
(n = 40)
33.48 ± 14.11
35.55 ± 11.65
23:19
17:23
52.24 ± 13.78
55.45 ± 13.76
160.76 ± 8.85
163.13 ± 7.73
42
40
Kar et al, 2011
Amiodarone
Placebo
(n = 28)
(n = 28)
36 ± 89
35.25 ± 8.4
16:12
14:14
51 ± 11.35
50.53 ± 6.77
12
12
21
21
19
21
28
0
28
0
6
11
22
4
9
27
4
3
0
3
1
0
7
18
14
8
15
17
5
22
0
0
27
0
Baseline Characteristics
Selvaraj et al, 2009
Kar et al, 2011
Amiodarone
(n = 42)
Placebo
(n = 40)
Amiodarone
(n = 28)
Placebo
(n = 28)
Normal
33
29
13
12
Mild dysfunction
9
11
15
16
Severe dysfunction
0
0
0
0
Digoxin
42
40
Betablocker
14
15
Calcium channel blocker
5
5
MVR
35
35
26
24
AVR
3
0
0
0
DVR
4
5
2
4
49.14 ± 11.29
47.98 ± 8.7
< 45
14
12
0
13
45 – 59
21
25
28
15
≥ 60
7
3
0
0
LV function
Type of heart surgery
Pre-op LA size (mm)
LA size (mm)
Incidence of AF
After Aortic Cross-clamping
Experimental
Study or Subgroup
Events
Control
Risk Ratio
Risk Ratio
Total Events Total Weight M-H, Fixed, 95% CI
Kar, 2011
2
28
8
28 34.2%
0.25 [0.06, 1.07]
Selvaraj, 2009
6
42
15
40 65.8%
0.38 [0.16, 0.88]
68 100.0%
0.34 [0.16, 0.70]
Total (95% CI)
Total events
70
8
23
Heterogeneity: Chi² = 0.24, df = 1 (P = 0.62); I² = 0%
Test for overall effect: Z = 2.93 (P = 0.003)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Incidence of AF
At the End of Surgery
Experimental
Study or Subgroup
Events
Control
Risk Ratio
Risk Ratio
Total Events Total Weight M-H, Fixed, 95% CI
Kar, 2011
0
28
4
28 25.3%
0.11 [0.01, 1.97]
Selvaraj, 2009
4
42
13
40 74.7%
0.29 [0.10, 0.82]
68 100.0%
0.25 [0.09, 0.65]
Total (95% CI)
Total events
70
4
17
Heterogeneity: Chi² = 0.40, df = 1 (P = 0.53); I² = 0%
Test for overall effect: Z = 2.82 (P = 0.005)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Incidence of AF
Post-op in ICU within 24 hours
Experimental
Study or Subgroup
Control
Risk Ratio
Risk Ratio
Events Total Events Total Weight M-H, Fixed, 95% CI
Kar, 2011
4
28
7
28 39.7%
0.57 [0.19, 1.74]
Selvaraj, 2009
5
39
9
27 60.3%
0.38 [0.14, 1.02]
55 100.0%
0.46 [0.22, 0.95]
Total (95% CI)
Total events
67
9
16
Heterogeneity: Chi² = 0.28, df = 1 (P = 0.60); I² = 0%
Test for overall effect: Z = 2.09 (P = 0.04)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Incidence of AF
First Post-op Day
Experimental
Study or Subgroup
Control
Risk Ratio
Risk Ratio
Events Total Events Total Weight M-H, Fixed, 95% CI
Kar, 2011
6
28
15
28 40.0%
0.40 [0.18, 0.88]
Selvaraj, 2009
9
42
22
40 60.0%
0.39 [0.20, 0.74]
68 100.0%
0.39 [0.24, 0.65]
Total (95% CI)
Total events
70
15
37
Heterogeneity: Chi² = 0.00, df = 1 (P = 0.96); I² = 0%
Test for overall effect: Z = 3.66 (P = 0.0002)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Adverse Events
Hypotension
Experimental
Study or Subgroup
Control
Risk Ratio
Risk Ratio
Events Total Events Total Weight M-H, Fixed, 95% CI
Kar, 2011
1
28
1
28
9.8%
1.00 [0.07, 15.21]
Selvaraj, 2009
5
42
9
40 90.2%
0.53 [0.19, 1.44]
68 100.0%
0.58 [0.23, 1.47]
Total (95% CI)
Total events
70
6
10
Heterogeneity: Chi² = 0.19, df = 1 (P = 0.67); I² = 0%
Test for overall effect: Z = 1.16 (P = 0.25)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Adverse Events
Bradycardia
Experimental
Study or Subgroup
Kar, 2011
Selvaraj, 2009
Risk Ratio
Risk Ratio
Events Total Events Total Weight M-H, Fixed, 95% CI
1
28
1
28 14.0%
1.00 [0.07, 15.21]
16
42
6
40 86.0%
2.54 [1.10, 5.84]
68 100.0%
2.32 [1.06, 5.12]
Total (95% CI)
Total events
Control
70
17
7
Heterogeneity: Chi² = 0.41, df = 1 (P = 0.52); I² = 0%
Test for overall effect: Z = 2.10 (P = 0.04)
M-H, Fixed, 95% CI
0.01
0.1
1
10
100
Favours Amiodarone Favours Placebo
Conclusion
• Among RHD patients with or without chronic
AF undergoing cardiac valve surgery, IV
amiodarone appears to decrease the
incidence of atrial fibrillation after surgery
• The incidence of adverse event (bradycardia)
appears to be higher in the amiodarone
group.
Limitation
• Small population size
• It is not clear whether an anti-arrhythmic
surgery was done to the study population
which can significantly influence outcome
• Recurrence of AF during entire hospitalization
and beyond was not investigated.
Recommendation
• Larger RCTs with similar protocols
• Follow up cardiac rhythm of patients after
hospital discharge.
THANK YOU
Validity
CRITERIA
Randomization
Allocation Concealment
Selvaraj 2009
Yes
Yes
Kar 2011
Yes
Yes
Baseline Characteristics
Yes
Yes
Blinding of Patients
Yes
Yes
Blinding of Caregivers
Yes
Yes
Blinding of Assessors
Yes
Yes
Intention to treat
Adequacy of Follow-up
Yes
Yes
Yes
Yes
References
1. Maesen B, Nijs J, Maessen J, Allesie M, Schotten U. Post-operative atrial fibrillation: a maze of mechanisms. Europace 2012;14:15974.
2. ABC of Atrial Fibrillation: History, Epidemiology, and Importance of Atrial Fibrillation. Gregory Y H Lip, et al. BMJ 1995;1311:1361.
3. Raine D, Dark J, Bourke JP. Effect of mitral valve repair/replacement surgery on atrial arrhythmia behavior. J Heart Valve Dis 2004;
13:615-21.
4. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061-73.
5. Mitchell LB, et al. Prophylactic oral amiodarone for the prevention of arrhythmias that begin early after revascularization, valve
replacement, or repair. PAPABEAR: A randomized controlled trial. JAMA 2005; 294:3093-3100.
6. Daoud EG, Strickberger SA, Man KC, Goyal R, Deeb M, Bolling S, Pagani F, Bitar C, Meissner M, Morady F. Preoperative amiodarone
as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997; 337: 1786-91.
7. Bealieu Y, Denault AY, Couture P, et al. Perioperative IV amiodarone does not reduce the burden of AF in patients undergoing
cardiac valvular surgery. Anesthesiology 2010; 112:128-37.
8. Aasbo JD, et al. Amiodarone prophylaxis reduces major cardiovascular morbidity and length of stay after cardiac surgery: A
metaanalysis. Ann Intern Med 2005; 143:327-336.
9. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. Atrial fibrillation follow-up investigation of rhythm
management (AFFIRM) investigators: a comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J
Med 2002; 1825-33.
10. Vora A, Kamad D, Goyal V, Naik A, Gupta A, Lokhandwala Y, Kulkami H, Singh B.Control of rate versus rhythm in
rheumatic atrial fibrillation: a randomized study.Indian Heart J. 2004 Mar-Apr;56(2):110-6.
11. Selvaraj T, Kiran U, Das S, Chauhan S, Sahu B, Gharde P. Effect of single intraoperative dose of amiodarone in patients with
rheumatic valvular heart disease and atrial fibrillation undergoing valve replacement surgery. Ann Card Anaesthesia
2009;12:10-6.
12. Kar SK, Dasgupta CS, Goswami A. Effect of prophylactic amiodarone in patients with rheumatic valve disease undergoing valve
replacement surgery. Ann Card Anaesthesia 2011;14:176-82
13. Raanani E, Albage A, David TE, Yau TM, Armstrong S. The efficacy of the Cox/maze procedure combined with mitral valve surgery:
A matched control study. Eur J Cardiothorac Surg 2001;19:438-443.
AFFIRM Trial
Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. Atrial fibrillation follow-up
investigation of rhythm management (AFFIRM) investigators: a comparison of rate control and rhythm control in
patients with atrial fibrillation. N Engl J Med 2002; 1825-33.
Raine D, Dark J, Bourke JP. Effect of mitral valve repair/replacement surgery on atrial arrhythmia behavior. J Heart Valve
Dis 2004; 13:615-21.
Vora A, Kamad D, Goyal V, Naik A, Gupta A, Lokhandwala Y, Kulkami H, Singh B.Control of rate versus rhythm in rheumatic
atrial fibrillation: a randomized study.Indian Heart J. 2004 Mar-Apr;56(2):110-6.