1. 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

2. Introduction Atrial fibrillation (AF) is common among patients with valvular heart disease and is a frequent rhythm disorder after cardiac surgery 1 It occurs in up to 60% of patients who undergo any cardiac surgery and those who undergo valve procedure 2,3,4 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.

3. Introduction  In developing countries like the Philippines, valvular heart disease of rheumatic origin is the most frequent etiology of this disorder 1  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.

4. STUDYTITLEPOPULATION / 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 rate- control strategy in AF

5. STUDYTITLEPOPULATION / 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 rate- control strategy in AF Raine, 2004Effect of Mitral Valve Repair/Replacement Surgery on Atrial Arrhythmia Behavior Mitral valve surgery in patients with chronic AF Mitral valve surgery alone restored sinus rhythm in only 8.5%

6. STUDYTITLEPOPULATION / 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 rate- control strategy in AF Raine, 2004Effect of Mitral Valve Repair/Replacement Surgery on Atrial Arrhythmia Behavior Mitral valve surgery in patients with chronic AF Mitral valve surgery alone restored sinus rhythm in only 8.5% Vora, 2004Control 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

7. Introduction  Role of IV amiodarone in restoring sinus rhythm after valve surgery in RHD patients with or without chronic AF.

8. 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?

9. 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.

10. 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.

11. 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

12. Study Design Characteristics Selvaraj, 1 2009Kar, 2 2011 Trial designRCT Sample size, total8256 Amiodarone4228 Control (placebo)4028 Type of SurgeryMVR or AVR, or both Timing of amiodarone administration 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

13. Study Design Characteristics Selvaraj, 2009Kar, 2011 ArrhythmiaAF 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

14. RESULTS

15. Baseline Characteristics Selvaraj et al, 2009Kar et al, 2011 Amiodarone (n = 42) Placebo (n = 40) Amiodarone (n = 28) Placebo (n = 28) Age, years  SD 33.48  14.1135.55  11.6536  89 35.25  Male:female23:1917:2316:1214:14 Body weight (kg)52.24  13.7855.45  13.7651  11.3550.53  6.77 Height (cm)160.76  8.85163.13  7.73 Number of patients in AF (preinduction) 424012 NYHA class Class II211928 Class III21 00 Severity of mitral stenosis Mild6443 Moderate11931 Severe222700 Severity of mitral regurgitation Mild7850 Moderate18152227 Severe141700

16. Baseline Characteristics Selvaraj et al, 2009Kar et al, 2011 Amiodarone (n = 42) Placebo (n = 40) Amiodarone (n = 28) Placebo (n = 28) LV function Normal33291312 Mild dysfunction9111516 Severe dysfunction0000 Digoxin4240 Betablocker1415 Calcium channel blocker55 Type of heart surgery MVR35 2624 AVR3000 DVR4524 Pre-op LA size (mm)49.14  11.2947.98  8.7 LA size (mm) < 451412013 45 – 5921252815 ≥ 607300

17. Incidence of AF After Aortic Cross-clamping

18. Incidence of AF At the End of Surgery

19. Incidence of AF Post-op in ICU within 24 hours

20. Incidence of AF First Post-op Day

21. Adverse Events Hypotension

22. Adverse Events Bradycardia

23. 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.

24. 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.

25. Recommendation Larger RCTs with similar protocols Follow up cardiac rhythm of patients after hospital discharge.

26. THANK YOU

27. Validity CRITERIASelvaraj 2009Kar 2011 RandomizationYes Allocation ConcealmentYes Baseline CharacteristicsYes Blinding of PatientsYes Blinding of CaregiversYes Blinding of AssessorsYes Intention to treatYes Adequacy of Follow-upYes

29. References 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. 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.i 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.

30. 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.

31. 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.

32. 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.i