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PREOPERATIVE AMIODARONE AS PROPHYLAXIS AGAINST ATRIAL FIBRILLATION AFTER CARDIAC VALVE SURGERY AMONG RHEUMATIC HEART
DISEASE PATIENTS: A Meta-analysis
Ian Lusoc, MDFlordeliz Lontok, MD
The Heart Institute, St. Luke’s Medical CenterQuezon 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 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 advantageover the rate-control 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 advantageover the rate-control strategy in AF
Raine, 2004 Effect of Mitral Valve Repair/Replacement Surgery onAtrial Arrhythmia Behavior
Mitral valve surgery in patients with chronic AF
Mitral valve surgery alone restored sinusrhythm 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 advantageover the rate-control strategy in AF
Raine, 2004 Effect of Mitral Valve Repair/Replacement Surgery onAtrial Arrhythmia Behavior
Mitral valve surgery in patients with chronic AF
Mitral valve surgery alone restored sinusrhythm 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 patientswith 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 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 Reports included (n = 2)
Trials of amiodarone vs placebo in RHD patients undergoing cardiac valve surgery
Study Design CharacteristicsSelvaraj,1 2009 Kar,2 2011
Trial design RCT RCT
Sample size, total 82 56
Amiodarone 42 28
Control (placebo) 40 28
Type of Surgery MVR or AVR, or both MVR or AVR, or both
Timing of amiodarone administration
Perioperative (after anesthesia induction, before CPB)
Perioperative (after anesthesia induction, before CPB)
Total dose of amiodarone
3 mg/kg IV infusion over 30 min
3 mg/kg IV infusion over 20 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 CharacteristicsSelvaraj, 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 CharacteristicsSelvaraj et al, 2009 Kar et al, 2011
Amiodarone(n = 42)
Placebo(n = 40)
Amiodarone(n = 28)
Placebo(n = 28)
Age, years SD 33.48 ± 14.11 35.55 ± 11.65 36 ± 89 35.25 ± 8.4Male:female 23:19 17:23 16:12 14:14Body weight (kg) 52.24 ± 13.78 55.45 ± 13.76 51 ± 11.35 50.53 ± 6.77Height (cm) 160.76 ± 8.85 163.13 ± 7.73Number of patients in AF (preinduction)
42 40 12 12
NYHA class Class II 21 19 28 28 Class III 21 21 0 0Severity of mitral stenosis Mild 6 4 4 3 Moderate 11 9 3 1 Severe 22 27 0 0Severity of mitral regurgitation Mild 7 8 5 0 Moderate 18 15 22 27 Severe 14 17 0 0
Baseline CharacteristicsSelvaraj et al, 2009 Kar et al, 2011
Amiodarone(n = 42)
Placebo(n = 40)
Amiodarone(n = 28)
Placebo(n = 28)
LV function
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
Type of heart surgery
MVR 35 35 26 24
AVR 3 0 0 0
DVR 4 5 2 4
Pre-op LA size (mm) 49.14 ± 11.29 47.98 ± 8.7
LA size (mm)
< 45 14 12 0 13
45 – 59 21 25 28 15
≥ 60 7 3 0 0
Incidence of AF
After Aortic Cross-clamping
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.24, df = 1 (P = 0.62); I² = 0%Test for overall effect: Z = 2.93 (P = 0.003)
Events
26
8
Total
2842
70
Events
815
23
Total
2840
68
Weight
34.2%65.8%
100.0%
M-H, Fixed, 95% CI
0.25 [0.06, 1.07]0.38 [0.16, 0.88]
0.34 [0.16, 0.70]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours Amiodarone Favours Placebo
Incidence of AF
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.40, df = 1 (P = 0.53); I² = 0%Test for overall effect: Z = 2.82 (P = 0.005)
Events
04
4
Total
2842
70
Events
413
17
Total
2840
68
Weight
25.3%74.7%
100.0%
M-H, Fixed, 95% CI
0.11 [0.01, 1.97]0.29 [0.10, 0.82]
0.25 [0.09, 0.65]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours Amiodarone Favours Placebo
At the End of Surgery
Incidence of AF
Post-op in ICU within 24 hours
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.28, df = 1 (P = 0.60); I² = 0%Test for overall effect: Z = 2.09 (P = 0.04)
Events
45
9
Total
2839
67
Events
79
16
Total
2827
55
Weight
39.7%60.3%
100.0%
M-H, Fixed, 95% CI
0.57 [0.19, 1.74]0.38 [0.14, 1.02]
0.46 [0.22, 0.95]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours Amiodarone Favours Placebo
Incidence of AF
First Post-op Day
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.00, df = 1 (P = 0.96); I² = 0%Test for overall effect: Z = 3.66 (P = 0.0002)
Events
69
15
Total
2842
70
Events
1522
37
Total
2840
68
Weight
40.0%60.0%
100.0%
M-H, Fixed, 95% CI
0.40 [0.18, 0.88]0.39 [0.20, 0.74]
0.39 [0.24, 0.65]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours Amiodarone Favours Placebo
Adverse Events
Hypotension
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.19, df = 1 (P = 0.67); I² = 0%Test for overall effect: Z = 1.16 (P = 0.25)
Events
15
6
Total
2842
70
Events
19
10
Total
2840
68
Weight
9.8%90.2%
100.0%
M-H, Fixed, 95% CI
1.00 [0.07, 15.21]0.53 [0.19, 1.44]
0.58 [0.23, 1.47]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours Amiodarone Favours Placebo
Adverse Events
Bradycardia
Study or Subgroup
Kar, 2011Selvaraj, 2009
Total (95% CI)
Total eventsHeterogeneity: Chi² = 0.41, df = 1 (P = 0.52); I² = 0%Test for overall effect: Z = 2.10 (P = 0.04)
Events
116
17
Total
2842
70
Events
16
7
Total
2840
68
Weight
14.0%86.0%
100.0%
M-H, Fixed, 95% CI
1.00 [0.07, 15.21]2.54 [1.10, 5.84]
2.32 [1.06, 5.12]
Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI
0.01 0.1 1 10 100Favours 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
ValidityCRITERIA Selvaraj 2009 Kar 2011Randomization Yes YesAllocation Concealment Yes Yes
Baseline Characteristics Yes Yes
Blinding of Patients Yes Yes
Blinding of Caregivers Yes Yes
Blinding of Assessors Yes Yes
Intention to treat Yes YesAdequacy of Follow-up Yes Yes
References1. Maesen B, Nijs J, Maessen J, Allesie M, Schotten U. Post-operative atrial fibrillation: a maze of mechanisms. Europace
2012;14:159-74.2. 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.