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Three Part Question

In [patients undergoing cardiac surgery] is [prophylactic amiodarone] effective in [reducing the post-operative incidence of Atrial Fibrillation]?

Clinical Scenario

You are in the bar with an American Colleague while attending the European Cardiothoracic conference in Monaco, and he is shocked that you do not give all your patients prophylactic Amiodarone to reduce the incidence of Atrial Fibrillation. You find yourself unable to counter his arguments although you suspect that there must be a higher incidence of bradycardia and hypotension in his patients. Thus, as you are due to meet him on the conference golf course tomorrow, you therefore resolve to look up the evidence before teeing off!

Search Strategy

Medline 1966-July 2003 using the OVID interface.
([exp thoracic surgery OR cardiac surgery OR exp Cardiac Surgical Procedures OR exp Coronary Artery Bypass OR exp cardiopulmonary bypass OR CABG.mp OR cardiac surgical procedures.mp] AND [exp amiodarone OR amiodarone.mp] AND [exp atrial fibrillation OR atrial fibrillation.mp]) LIMIT to Human AND English language.

Search Outcome

90 abstracts were found, of which 78 were irrelevant. 11 RCTs and a meta-analysis were found and these are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Dorge et al, 2000, Germany	150 patients undergoing CABG randomised to one of 3 groups: Group I: 300mg iv bolus of Amiodarone then 20mg/kg/day for 3 days, N=50 Group II: 150mg iv bolus of Amiodarone then 10mg/kg/day for 3 days, N=50 Group III: placebo, N=50	PRCT	Atrial fibrillation measured using continuous ECG monitoring for 10 post-operative days	New onset AF: Group I 24%, Group II 28%, Group III 34%, P-value N/S	Student T to compare 2 groups is inappropriate when 3 categories exist. Kruskal-Wallis is the correct test Young age group mean 61-63 years Blinding methods not described. Not double blinded
			Fast AF defined as ventricular response >120bpm	Fast AF: Group I 14%, Group II 24%, Group III 32%, P-value< 0.05 Group I Vs Group III
			Complications from Amiodarone were recorded	TFTs were mildly elevated in 11 patients.Atrial pacing for bradycardia was required in 48% of Group 1 and 28% of group 3
Lee et al, 2000, Taiwan	150 patients undergoing CABG 74 patients received Amiodarone, iv, 150mg loading dose then 0.4mg/kg/hr for 3 preoperative days and 5 postoperative days 76 controls had glucose infusion	Single blind PRCT	Incidence of AF	Amiodarone group 12%, Control group34%, P<0.01
			Maximum rate during AF	Amiodarone group 107, Control group138, P<0.01
			Complications	2 deaths from ventricular arrhythmia in both groups 2 patients had Amiodarone stopped due to bradycardia
Giri et al, 2001, USA	220 patients on B-blockers undergoing open-heart surgery over the age of 60. (mean age 73 ) Slow loading N=120 200mg tds for 5 days, 400mg bd on day of surgery, 400mg bd days 1-4 post-op, or placebo equivalent Rapid load N=100 400mg qds for 1 day, 600mg bd on day of surgery, 400mg bd days 1-4 post-op, or placebo equivalent.	Double-blind PRCT	Atrial Fibrillation of over 5 mins	Amiodarone group 22.5%Control group 38%P=0.01NNT= 6.5	89% of patients received B-blockers pre-op. No cases of pulmonary toxicity but routine CXRs not done Nausea occurred occasionally in the Amiodarone group but no excess bradycardia was found.
			Symptomatic AF defined as hypotension, heart failure, palpitatons, cest pain, SoB, syncope	Amiodarone group 4.2%, Control group18%, P=0.001
			CVA, defined as neurological deficits for more than 24 hrs documented by a neurologist with confirmation on CT or MRI	Amiodarone group 1.7%, Control group 7.0%, P=0.04
Tokmakoglu et al, 2001, Turkey	241 consecutive patients undergoing CABG only. Group I N=77: Metoprolol 100mg/24hr orally pre-op, 2x500mcg Digoxin iv on operating day, and 250mg Digoxin orally and 100mg metoprolol orally from day 1 to discharge. Group II N=72 : 300mg Amiodarone iv over 1 hr and then 900mg over 24 hrs immediately post-op, then 450mg iv the next day then 200mg tds orally until discharge. Group III N=92: control group and given no additional medication.	PRCT	Post operative AF measured by continuous ECG monitoring until discharge	Group I:13/77 (16.8%), Group II:6/72 (8.3%), Group III:31/92 (33.6%) NNT = 4 P value of Group II to Group III is 0.001 Also significantly fewer clinical deteriorations due to AF and ventricular arrhythmias were found compared to controls	No blinding No placebo used 2 patients had Amiodarone stopped due to AV block
Redle et al 1999 USA	143 patients undergoing CABG 73 patients given 2g of Amiodarone in divided doses 1-4 days pre-op and 400mg od for 7 days post-op 70 patients given placebo	Double blind PRCT	Post-operative AF	Amiodarone group 24.7%. Placebo group 32.8% P=0.30	Duration of AF, incidence of AF in those receiving B-blockers and Amiodarone, and hospital costs were also not different in the 2 groups
			Rate of fast AF at onset	Amiodarone group 133 bpm. Placebo group 153 bpm P=0.04
Hohnloser et al 1991 Germany	77 patients after CABG Amiodarone group received 300mg iv for 2 hours, then 1200mg every 24 hours for 2 days and 900mg every 24 hours for 2 days	PRCT	Incidence of AF	Amiodarone group 5%. Control group 21% P<0.05	ECG monitoring only performed for 48 hours postoperatively
			Nonsustained VT	Amiodarone group 3%. Control group 16% P<0.05
			Complications	Amiodarone stopped in 18% of their patients Due to QT prolongation
Butler et al 1993 UK	120 patients after CABG 60 patients received 15mg/kg/day by continuous iv infusion after X-clamp removal, and 200mg od for 5 days 60 patients had placebo	Double blind PRCT	Incidence of arrhythmias	Amiodarone group 10%.Control group 23% P=0.05	Incidence of SVT and asymptomatic AF was not significantly different
			Episodes of VT	Amiodarone group 15%. Control group 33% P=0.02
			Complications	Bradycardia: amiodarone 78% vs 48% controls Pauses: 7% Amiodarone vs 0% controls
Guarnieri et al 1999 USA	300 patients undergoing open heart surgery Amiodarone group received 1g/day iv for 2 days post-operatively	Double blind PRCT	Incidence of AF	Amiodarone group 35%. Control group47% P=0.01
			Length of hospital stay	Amiodarone group 7.6. Control group 8.2 P=0.34
Daoud et al 1997 USA	124 patients undergoing elective cardiac surgery (CABG 52, Valve 41, CABG+valve 22, other 9) 64 patients received 600mg per day for 7 days preoperatively, then 200mg od until discharge 60 patients received placebo	Double blind PRCT	Post-operative AF of >5 mins on ECG monitoring for 7 days.	Amiodarone group 16 of 64 (25%). Control group 32 of 60 (53%) P=0.03	High rate of AF in control group Perhaps due to high rate of valve surgery in this study (50%) Mean age is only 59 in this study Cofounding factor is B-blocker use in amoidarone group 40% Vs control group 30%
			No of days in hospital	Amiodarone group 6.5+/-2.6 days. Control group 7.9+/-4.3 days P=0.04
White et al 2002 USA	220 patients undergoing open heart surgery, over 60 years of age and all received preoperative Metoprolol Slow loading group: N=56, 200mg of oral Amiodarone tds for 5 days. 400mg bd on day of surgery, 400mg bd post-op days 1 to 4 Fast loading group (non-randomised): N=64, 400mg of Amiodarone qds for 1 to 4 days pre-op. . 600mg bd on day of surgery, 400mg bd post-op days 1 to 4 Placebo N=100	Double blind PRCT	Rate of documented AF of more than 5 min duration	Slow loading group 11/56 (19.6). Fast loading group 16/64 (25%) placebo 38/100 (38%) p=0.013 slow Vs placebo P=0.059 fast Vs Placebo NNT= 5.6	This is the same study group of patients as used by the AFIST group in the Lancet.
			Symptomatic AF	Slow loading group 1/56 (1.8). Fast loading group 4/64 (6.3%) placebo 18/100 (18%) p<0.001 slow Vs placebo P=0.023 fast Vs Placebo
			Complications	No differences between QT intervals (p=0.073). No difference between groups of death ICU length of stay or CVA. Increased rate of nausea in fast loading group compared to placeo
Yagdi et al 2003 Turkey	157 patients undergoing elective CABG with B-blockers continued in all patients Amiodarone group: 10 mg/kg per day for 48h started 2h after return to ICU. Then 600 mg/day for 5 days, 400 mg/day for 5 days and 200 mg/day for 20 days Placebo group: 5% glucose infusion followed by placebo	Double-blind PRCT (level 1b)	Post-operative AF of more than 5 min	Amiodarone group 8/77 patients (10%)	Randomization technique not stated
			Maximum vantricular rate in patients with AF	Amiodarone group: 105.9 +/- 19.1bpm Placebo group 126.0 +/-18.5bpm P=0.03
Crystal E et al 2002 New Zealand	Systematic review of Medline, Embase, Cinahl, hand searching and scientific meetings up to April 2001 52 RCTs on prophylactic regimes for AF found of which 9 used amiodarone	Meta-analysis (level 1a)	Post-operative amiodarone	Amiodarone groups 37% Control groups 22.5% (OR 0.48; CI 0.37-0.61)	Regimes of each study not examined Does not include the study by Yagdi et al
			Length of stay	Amiodaroine reduced LOS by 0.91 (0.24-1.59) days

Comment(s)

Nine of the 11 papers show a significant reduction in the incidence of atrial fibrillation with prophylactic amiodarone. The remaining 2 showed a non-significant trend to lower AF. Included in these papers are 2 very well conducted studies reported in the New England Journal of Medicine and the Lancet. Giri et al reported a 'number needed to treat' of only 6.5 to prevent an occurrence of AF. Complications were low in all studies except in that of Butler et al, who found a significantly higher rate of bradycardia and pauses in the Amiodarone group, and Hohnloser who had to stop Amiodarone in 18% of his patients due to QT prolongation. Significant Bradycardia was investigated in all other studies but found to be non-significant. The results of most of these studies have been summarized in a meta-analysis by Crystal et al. He combined the data from nine of these studies and found a rate of AF in 37% in all control groups. This gives a NNT of 6.9. He did not however summarise the data on the rates of complications. Thus although it is clear that amiodaroine significantly reduces the incidence of AF, the optimal amiodarone regime that should be employed remains unclear as these ranged from oral Amiodarone being started up to 7 days preoperatively to I.V. Amiodarone 2 h after return to ICU.

Clinical Bottom Line

There is strong evidence that both oral and intravenous Amiodarone given prophylactically reduces the incidence of post-operative AF, with a NNT of only 7 to prevent an episode of AF.

References

1. Dorge H, Schoendube FA, Schoberer M, et al. Intraoperative amiodarone as prophylaxis against atrial fibrillation after coronary operations. Ann Thorac Surg 2000;69(5):1358-62.
2. Lee SH, Chang CM, Lu MJ, et al. Intravenous amiodarone for prevention of atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2000;70(1):157-61.
3. Giri S, White CM, Dunn AB, et al. Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial. Lancet 2001;357(9259):830-6.
4. Tokmakoglu H, Kandemir O, Gunaydin S, et al. Amiodarone versus digoxin and metoprolol combination for the prevention of postcoronary bypass atrial fibrillation. Eur J Cardiothorac Surg 2002;21(3):401-5.
5. Redle JD, Khurana S, Marzan R, McCullough PA, Stewart JR, Westveer DC et al. Prophylactic oral amiodarone compared with placebo for prevention of atrial fibrillation after coronary artery bypass surgery. Am Heart J 1999;138(1 pt 1):144-50.
6. Hohnloser SH, Meinertz T, Dammbacher T, Steiert K, Jahnchen E, Zehender M et al. Electrocardiographic and antiarrhythmic effects of intravenous amiodarone: results of a prospective, placebo-controlled study. Am Heart J 1991;121(1 pt 1):89-95.
7. Butler J, Harriss DR, Sinclair M, Westaby S. Amiodarone prophylaxis for tachycardias after coronary artery surgery: a randomised, double blind, placebo controlled trial. Br Heart J 1993;70(1):56-60.
8. Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR. Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial. J Am Coll Cardiol 1999;34(2):343-7.
9. Daoud EG, Strickberger SA, Man KC, Goyal R, Deeb GM, Bolling SF et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Eng J Med 1997;337(25):1785-91.
10. White, C. M, Giri, S, Tsikouris, J. P, Dunn, A, Felton, K, Reddy, P, and Kluger, J. A comparison of two individual amiodarone regimens to placebo in open heart surgery patients. Ann Thorac Surg 2002;74(1):69-74.
11. Yagdi T, Nalbantgil S, Ayik F, Apaydin A, Islamoglu F, Posacioglu H, Calkavur T, Atay Y, Buket S. Amiodarone reduces the incidence of atrial fibrillation after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125(6):1420-5.
12. Crystal E, Connolly SJ, Sleik K, Ginger TJ, Yusuf S. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002;106(1):75-80.