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Three Part Question

In [a patient with atrial fibrillation and left ventricular dysfunction requiring rapid rate control] does [digoxin or amiodarone] lead to [faster and safer rate control]?

Clinical Scenario

An elderly gentleman comes into the emergency department complaining of dizziness, palpitations and shortness of breath for the last 5 hours. An ECG reveals atrial fibrillation with a ventricular rate of 113bpm. On examination he has a raised jugular venous pressure. You remember that digoxin is both negatively chronotropic and positively inotropic but have been advised by a cardiologist that amiodarone may be more suitable.

Search Strategy

Embase 1980 to 2008 Week 24.
Medline 1950 to June Week 1 2008 using ovid interface.

[exp Atrial Fibrillation/ or (atrial adj fibrillation).mp.] AND [rate control.mp. or exp heart rate/ or ventricular rate.mp] AND [exp digoxin/ or digoxin.mp. or exp digitalis/ or digitalis.mp. or exp digitalis glycosides/] AND [exp Amiodarone/ or amiodarone.mp. or cordarone.mp.] LIMIT to humans AND english language.
Medline: LIMIT to “all adult (19 plus years)”
Embase: LIMIT to adult <18 to 64 years> OR to aged <65+ years>

Search Outcome

173 papers found of which 170 were irrelevant to the clinical question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hou ZH et al. 1995 China	50 patients aged 50-82 with persistent AF or flutter with ventricular rates above 130bpm for less than 10 days. Amiodarone (for a 70kg subject: 5mg/min for 1st hour, 3mg/min for next 3h, 1mg/min for 6h, 0.5mg/min for remaining 14h.) Vs. Digoxin (0.013mg/kg IV in 3 divided doses, each dose 2h apart and infused over 30min)	Randomized, open-labelled, digoxin-controlled study	Conversion to sinus rhythm	Significantly more patients in the amiodarone group were converted during the 24h period (p=0.0048)	Open-labelled study, potential for bias No sample size calculation Small sample size of only 50 patients Unclear results section, which was difficult to draw ones own conclusions from Median interval from onset of arrhythmia to initiation of study drug infusion was different for 2 drugs: Digoxin- 4h (range= 0.5-240h) Amiodarone 14h (range= 1-96h)
			Ventricular rates	n digoxin group rates were significantly reduced on and beyond 1st hour after initiation of infusion. The maximum reduction was reached at 8h and was maintained. In amiodarone group the mean heart rate reduced significantly after 20min of infusion. The amplitude of reduction in heart rate of amiodarone group was significantly more than that of the digoxin group at 1h (p<0.01) until 8h (p<0.05) after medication.
			Adverse reactions	No serious complications occurred due to digoxin. In amiodarone group, there were 2 serious complications: 1.Aggravation of heart failure at 1h of infusion, which was then aborted. Pt. stabilized after treatment. 2.Patient with toxic epidermal necrolysis and ARDS, AF was converted by amiodarone after 2h of infusion. Severe bradycardia followed by cardiac arrest developed resulting in death of patient.
Cowan JC et al. 1986 United Kingdom	34 patients admitted to CCU with suspected myocardial infarction, with atrial fibrillation on admission or who soon developed atrial fibrillation Amiodarone 7mg/kg IV over 30 mins via central line (n=18) Vs. Digoxin 0.5 mg Iv over 30 mins via peripheral line (n=16) (If after 30 mins still in AF with HR > 60bpm then amiodarone group given further 1500mg minus initial loading dose over 23h; digoxin group given 0.5mg IV over 30 mins, subsequent digoxin doses were at discretion of physician.) Drud were stopped once sinus rhythm was achieved	Randomized open-label study	Ventricular rate	Fell more rapidly in amiodarone group than digoxin group.	Small study numbers and no power calculation Open label protocol
			Blood pressure	Systolic blood pressure fell in amiodarone group but did not reach statistical significance when compared to digoxin group. In 3 patients on amiodarone, systolic BP fell by >20mmHg. 1 patient on amiodarone suffered profound drop in systolic BP (140mmHg to 80 mmHg) which corrected on termination of infusion.
			Deaths	1 patient died during 24h study period. He had received amiodarone therapy. Cause= left ventricular rupture. 7 other patients died prior to discharge, 3 amiodarone, 4 digoxin.
Hofmann R et al. 2005 Austria	100 consecutive patients with atrial fibrillation with ventricular rate above 135bpm, presenting during daytime working hours to CCU Amiodarone 450mg IV Vs. Digoxin 0.6mg IV (if HR >100 bpm after 30 mins, given another 300mg amiodarone IV or 0.4mg digoxin IV)	Prospective randomized study	Heart rate after 30 and 60 minutes	A statistically significant different reduction in ventricular heart rate (amiodarone> digoxin) could be seen within 5 mins of drug administration that remained consistent throughout the following 60 mins. Baseline: Amiodarone 144.5±19.5 bpm, Digoxin 145.4± 14.8 bpm. 1h after drug admin: Amiodarone 94.2±22 bpm, Digoxin 105.3±22 bpm (P=0.03)	Objectives not clearly stated Study was not blinded
			Conversion to sinus rhythm after 30, 60 minutes and 24 hours	30 mins: 28% amiodarone, 6% digoxin returned to normal sinus rhythm (p=0.003). 60 mins: 42% amiodarone, 18% digoxin in NSR (p=0.012)
			Blood pressure	Baseline systolic: Amiodarone 126 ± 25mmHg, Digoxin 134 ± 19mmHg. 5minutes after drug administration: Amiodarone 114 ± 24mmHg, Digoxin 132 ± 18mmHg. Fluid administration was required in 4 cases receiving amiodarone.
			Safety	No patient developed inadvertent bradycardia, cardiac arrest or ventricular tachyarrhythmia. In amiodarone group, 1 case of superficial phlebitis and 4 cases requiring fluid administration to maintain blood pressure.

Comment(s)

In the study by Cowan JC et al. the more rapid initial fall in ventricular rate in the amiodarone group was in part accounted for by a greater proportion of patients in sinus rhythm. However, analysis of just the patients remaining in atrial fibrillation revealed that amiodarone still caused a significantly slower ventricular rate at 30 mins and 1 hour than digoxin. Amiodarone is toxic to veins and whilst the initial IV bolus can be given peripherally the infusion must be given via a central line. This amongst other adverse affects makes it more dangerous than digoxin. Furthermore, digoxin is positively inotropic and so may be more appropriate in the setting of left ventricular dysfunction, whilst amiodarone is negatively inotropic and frequently causes hypotension as demonstrated in the studies by Hofmann et al. and Cowan et al.

Clinical Bottom Line

Based on the evidence available amiodarone is more effective than digoxin at reducing the ventricular rate in acute onset atrial fibrillation.

References

1. Hou ZH, Chang MS, Chen CY, Tu MS, Lin SL, Chiang HT, Woosley RL. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone: A randomized, digoxin-controlled study. European Heart Journal. 1995; 16: 521-528
2. Cowan JC, Gardiner P, Reid DS, Newell DJ, Campbell WF. A Comparison of Amiodarone and Digoxin in the Treatment of Atrial Fibrillation Complicating Suspected Acute Myocardial Infarction. Journal of Cardiovascular Pharmacology. 1986; 8:252-256.
3. Hofmann R, Steinwender C, Kammler J, Kypta A, Leisch F. Effects of a high dose intravenous bolus amiodarone in patients with atrial fibrillation and a rapid ventricular rate. International Journal of Cardiology. 2006; 110: 27-32.