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.