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Amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation
International Journal of Cardiology 89 (2003) 239–248 www.elsevier.com / locate / ijcard
Amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation a, a b Ijaz A. Khan *, Nirav J. Mehta , Ramesh M. Gowda a
Division of Cardiology, Department of Medicine, Creighton University School of Medicine, 3006 Webster St., Omaha, NE 68131, USA b Division of Cardiology, Department of Medicine, Long Island College Hospital, Brooklyn, NY, USA Received 22 April 2002; received in revised form 15 August 2002; accepted 8 September 2002
Abstract The efficacy and safety of amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation was examined by reviewing the trials on the subject identified through a comprehensive literature search. Amiodarone has been used both intravenously (i.v.) and orally for the pharmacological cardioversion of recent-onset atrial fibrillation. Intravenous amiodarone has been used as a bolus only or as a bolus followed by a continuous i.v. infusion until conversion or up to 24 h. The dose of i.v. bolus given ranged from 3 to 7 mg / kg body weight and that of infusion from 900 to 3000 mg / day. The efficacy reported is 34–69% with the bolus only regimens, and 55–95% with the bolus followed by infusion regimens. Only the higher dose (.1500 mg / day) amiodarone is superior to placebo in converting recent-onset atrial fibrillation to sinus rhythm. The highest 24-h conversion rates have been reported with the i.v. regimen of 125 mg / h until conversion or a maximum of 3 g and the oral regimen of 25–30 mg / kg body weight administered as a single loading-dose (.90% and .85%, respectively). Most of the conversions occur after 6–8 h of the initiation of therapy. Predictors of successful conversion are shorter duration of atrial fibrillation, smaller left atrial size, and higher amiodarone dose. Amiodarone is not superior to the other antiarrhythmic drugs conventionally used for the pharmacological cardioversion of recent-onset atrial fibrillation but is relatively safe in patients with structural heart disease and in those with depressed left ventricle function. Therefore, amiodarone could be used particularly in patients with structural heart disease and in those with left ventricular systolic dysfunction as the use of class IC drugs, propafenone and flecainide, for cardioversion of atrial fibrillation is contraindicated in such patients. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Amiodarone; Pharmacological cardioversion; Chemical cardioversion; Class III antiarrhythmic drugs
1. Introduction Sustained atrial fibrillation results in mechanical dysfunction and electrophysiological remodeling of the atria. The electrophysiological remodeling and the changes in atrial refractoriness start taking place within a few hours of the initiation of atrial fibrillation, thereby, decreasing the chances of successful *Corresponding author. Tel.: 11-402-280-4573; fax: 11-402-2804938. E-mail address: [email protected] (I.A. Khan).
conversion to and maintenance of the sinus rhythm [1]. Both the atrial mechanical dysfunction and the electrophysiological remodeling can be prevented or reversed by an earlier restoration of sinus rhythm. The early restoration of sinus rhythm may also relieve symptoms, prevent tachycardia-related cardiomyopathy, eliminate the need for the long-term use of atrioventricular node blocking drugs, and prevent or decrease the risk of atrial stunning and thromboembolism [2]. Approximately 50% of patients with recent-onset atrial fibrillation convert spontaneously to sinus
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0167-5273(02)00477-1
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rhythm within 24 h and this rate can be increased to about 80–90% by pharmacological or electrical cardioversion [3]. Pharmacological cardioversion appears to be the most effective when carried out within 2 weeks after the onset of atrial fibrillation and has the advantages of being simpler and convenient, free of the need of conscious sedation or anesthesia, and feasible in recent post-prandial state [3]. Class IA (quinidine, procainamide), class IC (propafenone, flecainide), and class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs have been used for the pharmacological cardioversion of atrial fibrillation, and, although the drug of choice is unclear, propafenone, flecainide and amiodarone have been reported as the most effective drugs with acceptable safety profiles [3–5]. Amiodarone, which is generally considered a class III antiarrhythmic drug, possesses electrophysiological characteristics of all four Vaughan Williams classes, and has the advantage of being administered both by parenteral and oral routes.
2. Data collection The efficacy and safety of amiodarone for cardioversion of recent-onset atrial fibrillation was examined by reviewing the trials on the subject identified through a comprehensive search of the PubMed / Medline (National Library of Medicine, Bethesda, MD, USA). The trials were examined if they had evaluated efficacy, safety, or both of amiodarone as the sole drug or in comparison to placebo or with other antiarrhythmic drugs for the pharmacological cardioversion of recent-onset atrial fibrillation. Atrial fibrillation of #2 weeks was considered as recent-onset. The references in the articles were checked for additional relevant studies. The trials on the use of amiodarone for post-operative atrial fibrillation were not included. All trials [6–26] were examined and data were manually extracted and tabulated (Tables 1 and 2). Due to the marked differences in the study enrollment and design, including differences in the dose of amiodarone used and in the way the recentness of atrial fibrillation was defined in various trials, it was not possible to pool the data for meta-analysis. Therefore, a narrative but
succinct overview is provided, and the important studies are highlighted in each group.
3. Efficacy
3.1. Intravenous amiodarone versus placebo Data on the efficacy of amiodarone for the pharmacological cardioversion of recent-onset atrial fibrillation is given in Table 1. In most of the trials amiodarone was used intravenously. The i.v. amiodarone has been used as a bolus only or as a bolus followed by a continuous i.v. infusion [6–24]. The i.v. bolus doses given in various trials ranged from 3 to 7 mg / kg body weight and the doses of infusion ranged from 900 to 3000 mg / day [6–24]. In most of the trials, continuous infusion has been used for 24 h and the efficacy has been evaluated at different time intervals up to 24 h from the initiation of therapy [6–24]. The reported efficacy of i.v. amiodarone for successful cardioversion of recentonset atrial fibrillation ranges from 34 to 69% with the bolus only regimens, and 55–95% with the bolus followed by infusion regimens, depending on the duration of atrial fibrillation, the duration of the follow-up after drug administration, the patient population enrolled, left atrial size, and the dose of amiodarone [6–24]. Most of the patients who successfully converted with the use of i.v. amiodarone did so after 6–8 h of initiation of therapy [6–24]. The dose of amiodarone optimal for cardioversion of recent-onset atrial fibrillation has not been established and various trials have used different dose regimens. When compared with placebo, only higher dose regimens of amiodarone (.1500 mg / 24 h) resulted in significantly higher rates of cardioversion of recent-onset atrial fibrillation, whereas, the conventional dose regimens were not better than placebo [11,13,14,17,20,21,24]. Galve et al. [17] demonstrated that amiodarone administered at a conventional dose of a bolus of 5 mg / kg body weight followed by 1200 mg over 24 h was not significantly superior to placebo for the conversion of recent-onset (,7 days) atrial fibrillation with the 24-h conversion rates being 68 and 60%, respectively (P5NS). On the other hand, conversion rates of over 90% have been reported in trials where the higher dose amiodarone
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241
Table 1 Data on the efficacy of amiodarone for cardioversion of recent-onset atrial fibrillation Trial [Ref.]
Duration
Route and dose of amiodarone (n5number of patients)
Comparison with (n5number of patients)
Conversion rate (amiodarone vs. the drug compared)
Absolute benefit (%) of amiodarone
Pvalue
Strasberg et al. [6]
15 min to 48 h
i.v. 5 mg/kg over 3–5 min (26)
None
In ,30 min: 46% (12/26) At 8 h: 73% (18/26)
Cowan et al. [7]
New onset
i.v. 7 mg/kg loading over 30 min followed by 1500 mg in 23 h (18)
i.v. digoxin 0.5 mg infusion over 30 min, repeated if ventricular rate.60/min (16)
At 4 h: 72% (11/15) versus 31% (4/14)
41
,0.1
Noc et al. [8]
20 min to 48 h
i.v. 5 mg/kg over 3 min (13)
i.v. verapamil 0.075 mg/kg over 1 min (11)
At 3 h: 77% (10/13) versus 0% (0/11)
77
,0.001
Negrini et al. [9]
,3 weeks
i.v. 5 mg/kg bolus over 20 min, 15 mg/kg infusion for 24 h then 400 mg oral Q 6 h (33)
Oral quinidine 0.2 g Q 6 h 1st day, 0.4 g Q 6 h 2nd day and 0.6 g Q 6 h 3rd day (29)
At 24 h: 70% (23/33) versus 62% (18/29) At 3 days: 94% (31/33) versus 93% (27/29)
8
NS
1
NS
8
NS
NS
Pilati et al. [10]
,72 h
i.v. 300 mg over 30 min followed by i.v. infusion of 300 mg Q 8 h (37)
Oral quinidine 150 mg orally Q 3 h for first 24 h and then 300 mg Q 8 h plus digoxin (38)
At 48 h: 100% (37/37) versus 92% (35/38)
Vietti-Ramus et al. [11]
,24 h
i.v. 2 mg/kg per h up to maximum dose of 2400 mg/24 h (44)
None
At 24 h: 89% (39/44)
Andrivet et al. [12]
.3 h
i.v. 3–5 mg/kg bolus then infusion of 10–15 mg/kg per 24 h (27)
Oral amiodarone 25.760.9 mg/kg as single loading dose (45)
At 24 h: 67% (18/27) versus 64% (29/45)
3
Hou et al. [13]
,10 days
i.v. 5 mg/kg for 1 h, 3 mg/min for 3 h, 1 mg/kg for 6 h and 0.5 mg/kg for next 14 h (26)
i.v. digoxin 0.013 mg/kg in three divided doses 2 h apart (24)
At 24 h: 92% (24/26) versus 71% (17/24)
21
Donovan et al. [14]
.30 min ,72 h
i.v. 7 mg/kg (32)
i.v. flecainide 2 mg/kg maximum 150 mg (34)
At 2 h: 34% (11/32) versus 59% (20/34) At 8 h: 59% (19/32) versus 68% (23/34)
225
NS
29
NS
235
Moran et al. [15]
.1 h
i.v. 5 mg/kg loading over 15–20 min followed by infusion of 10 mg/kg per 24 h (16)
i.v. magnesium sulfate 0.037 g/kg over 5 min then 0.025 g/kg/h (18)
At 24 h: 43% (7/16) versus 78% (14/18)
Kumar [16]
.30 min
i.v. 300 mg over 1 h (8)
None
At 1 h: 88% (7/8)
Galve et al. [17]
,1 week
i.v. 5 mg/kg over 30 min followed by 1200 mg/24 h (50)
Placebo (50)
At 24 h: 68% (34/50) versus 60% (30/34)
Cybulski et al. [18]
,24 h
i.v. 150 mg over 10 min, repeated after 30-35 min if arrhythmia persisted (142)
None
At 12 h: 64% (91/142)
8
0.005
0.08 a
NS
I. A. Khan et al. / International Journal of Cardiology 89 (2003) 239–248
242 Table 1. Continued Trial [Ref.]
Duration
Route and dose of amiodarone (n5number of patients)
Comparison with (n5number of patients)
Conversion rate (amiodarone vs. the drug compared)
Absolute benefit (%) of amiodarone
Boriani et al. [19]
,7 days
i.v. 5 mg/kg bolus followed by 1.8 g/24 h (51)
i.v. propafenone 2 mg/kg bolus followed by 0.0078 mg/kg per min (57)
At 8 h: 57% (29/51) versus 75% (43/57)
218
0.04 a
Oral propafenone 600 mg single dose (119)
At 8 h: 57% (29/51) versus 76% (91/119)
219
0.01 a
Oral flecainide 300 mg single dose (69)
At 8 h: 57% (29/51) versus 75% (52/69)
218
0.03 a
Placebo (121)
At 8 h: 57% (29/51) versus 37% (45/121)
20
0.02 a
i.v. propafenone 2 mg/kg over 15 min followed by 10 mg/kg over next 24 h (46)
At 24 h: 83% (40/48) versus 78% (36/46)
5
Placebo (49)
At 24 h: 83% (40/48) versus 55% (27/49)
28
28
Kochiadakis et al. [20]
,48 h
i.v. 300 mg over 1 h followed by 20 mg/kg over next 24 h plus 1800 mg/day in three divided doses (48)
Cotter et al. [21]
,48 h
i.v. 125 mg/h till conversion or for 24 h (50)
Placebo (50)
At 24 h: 92% (46/50) versus 64% (32/50)
Kreiss et al. [22]
,48 h
i.v. 1200 mg/24 h followed by oral 1200 mg/day for 3 days, 800 mg/day for 3 days, 400 mg/day for 3 days and maintenance dose of 200 mg/day (20)
None
At 48 h: 55% (11/20)
Martinez-Marcos et al. [23]
,48 h
i.v. 5 mg/kg bolus followed by 50 mg/h infusion (50)
i.v. flecainide 2 mg/kg bolus followed by second bolus dose of 1 mg/kg if conversion is not achieved after 8 h (50)
At 12 h: 64% (32/50) versus 90% (45/50)
226
i.v. propafenone 2 mg/kg bolus followed by second bolus dose of 1 mg/kg if conversion is not achieved after 8 h (50)
At 12 h: 64% (32/50) versus 72% (36/50)
8
Joseph et al. [24]
,24 h
i.v. 5 mg/kg over 30 min then 400 mg Q 8 h for six doses (39)
i.v. sotalol 1.5 mg/kg then 80 mg Q 8 h for six doses oral (40) i.v. digoxin 500 mg followed by 250 mg orally Q 6 hourly for four doses then 250 mg/day (36)
At 48 h: 77% (30/39) versus 88% (35/40)
Pvalue
NS
,0.02
0.0017
0.002
NS
211
0.05
19
0.05
At 48 h: 77% (30/39) versus 58% (21/36)
Blanc et al. [25]
,2 weeks
Oral 30 mg/kg for 24 h (43)
Oral propafenone 600 mg (43)
At 24 h: 47% (20/43) versus 56% (24/43)
–9
NS
Peuhkurinen et al. [26]
,48 h
Oral single dose of 30 mg/kg (31)
Placebo (31)
At 8 h: 50% versus 20% At 24 h: 87% (27/31) versus 35% (11/31)
30 52
,0.001 ,0.001
i.v., intravenous; NS, not significant. a P-value calculated by authors from data given in the trial.
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243
Table 2 Data on the safety of amiodarone for cardioversion of recent-onset atrial fibrillation Trial [Ref.] a
Amiodarone route and comparison (n5patient)
Side effects in amiodarone group (n5patients with side effects)
Strasberg et al. [6]
i.v. amiodarone only (26)
Mild flushing (7)
Cowan et al. [7]
i.v. amiodarone (18) versus i.v. digoxin (16)
Transient hypotension (1)
Transient bradycardia and hypotension (1)
Noc et al. [8]
i.v. amiodarone (13) versus i.v. verapamil (11)
Transient hypotension (1)
None
Negrini et al. [9]
i.v. amiodarone (33) versus oral quinidine (29)
Transient first degree AV block (1)
Gastrointestinal disturbances (3) ventricular arrhythmias (2) marked QTc prolongation (1)
Pilati et al. [10]
i.v. amiodarone (37) versus oral quinidine (38)
Phlebitis (4)
Gastrointestinal disturbances (2) Atrial tachycardia (2) Atrial flutter (1)
Vietti -Ramus et al. [11]
i.v. amiodarone alone (44)
Phlebitis (9) Transient hypotension (5)
Andrivet et al. [12] Hou et al. [13]
i.v. amiodarone (27) versus oral amiodarone (45) i.v. amiodarone (26) versus i.v. digoxin (24)
First degree AV block (6) Transient junctional escape (1) Phlebitis (1) Aggravation of heart failure (1) Cardiac arrest (1)
First degree AV block (1) Sinus bradycardia (1) NR
Donovan et al. [14]
i.v. amiodarone (32) versus i.v. flecainide (34) and placebo (32)
Nausea (2) Headache (1) Hypotension (5) Wenckebach phenomenon (1)
Flecainide: Hypotension (8) Blurred vision (1)
NR
Moran et al. [15]
i.v. amiodarone (21) versus i.v. magnesium (21)
NR
Kumar [16]
i.v. amiodarone alone (8)
No side effects
Galve et al. [17]
i.v. amiodarone (50) versus placebo (50)
Phlebitis (1) Nonsustained ventricular tachycardia (1) Transient hypotension (4)
Cybulski et al. [18]
i.v. amiodarone alone (142)
First degree AV block (2)
Boriani et al. [19]
i.v. amiodarone (51) versus i.v. propafenone (57) versus oral propafenone (119) versus oral flecainide (69) versus placebo (121)
None reported
i.v. amiodarone (48) versus i.v. propafenone (46) versus placebo (49)
Allergic reaction leading to discontinuation (1)
Kochiadakis et al. [20]
Side effects in the compared with group (n5patients with side effects)
Placebo: Hypotension (8) Ventricular tachycardia (1)
Transient hypotension (4) Vomiting (2) Atrial flutter (1) Transient junctional rhythm (1)
Propafenone: Hypotension and pulmonary edema (1) Flecainide: Atrial flutter with 1:1 conduction (2) Left ventricular decompensation (2) Placebo: Transient hypotension and bradycardia (10) Atrial flutter with 1:1 conduction leading to collapse (1) Propafenone: Excessive QRS widening (1)
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Table 2. Continued Trial [Ref.] a
Amiodarone route and comparison (n5patient)
Side effects in amiodarone group (n5patients with side effects)
Side effects in the compared with group (n5patients with side effects)
Cotter et al. [21]
i.v. amiodarone (50) versus placebo (50)
Phlebitis (8) Asymptomatic bradycardia (5)
Phlebitis (3) Asymptomatic bradycardia (2)
Kreiss et al. [22]
i.v. amiodarone alone (20)
Phlebitis (5) Transient hypotension (1)
Martinez-Marcos et al. [23]
i.v. amiodarone (50) versus i.v. flecainide (50) versus i.v. propafenone (50)
Transient atrial tachycardia (1) Symptomatic hypotension (1) Urticarial rash (1)
Flecainide: Atrial flutter with 1:1 conduction (1) Transient junctional rhythm (2) Symptomatic hypotension (1) Paresthesia (2) Propafenone: Aggravation of heart failure (1) Transient junctional rhythm (3) Transient atrial tachycardia (2) Symptomatic hypotension (1)
Joseph et al. [24]
i.v. amiodarone (39) versus i.v. sotalol (40) versus i.v. digoxin (36)
Bradycardia (1) Left ventricular failure (2) QTc .500 ms (2) Phlebitis (1) Temporary pacemaker (1)
Sotalol: Hypotension (2) QTc .500 ms (5) Digoxin: Bradycardia (1) Temporary pacemaker (1)
Blanc et al. [25]
Oral amiodarone (43) versus oral propafenone (43)
Gastrointestinal disturbances (4) Supraventricular tachycardia (1) Nonsustained ventricular tachycardia (1)
Gastrointestinal disturbances (4) Atrial flutter (1) Nonsustained ventricular tachycardia (1)
Peuhkurinen et al. [26]
Oral amiodarone (31) versus placebo (31)
Gastrointestinal disturbances (4) Symptomatic bradycardia and hypotension with syncope (1)
Gastrointestinal disturbances (2) Headache (2) Sinus arrest with collapse (1)
P5NS where comparison possible. The P-values were not reported in any of the trials but were calculated by authors from data given in the trials. AV, atrioventricular; i.v., intravenous; NR, not reported. a Please refer to Table 1 for the doses of amiodarone and other drugs.
regimens were used [11,13,21]. Hou et al. [13] demonstrated that a higher dose regimen of amiodarone (1620 mg / 24 h) increased the 24-h conversion rate of recent-onset (,10 days) atrial fibrillation from 72% (placebo arm) to 92% (P50.004). In another randomized, placebo-controlled, crossover trial on 100 patients with atrial fibrillation (duration,48 h), Cotter et al. [21] compared the effects of high-dose i.v. amiodarone (125 mg / h until conversion, or a total of 3 g) versus placebo. The patients in the placebo group who did not convert to sinus rhythm within 24 h were crossed over to i.v. amiodarone. Patients who had severe bradyarrhythmia, sinoatrial and atrioventricular node disease, symptomatic hypotension, ischemia, congestive heart failure, chronic lung disease, hepatic failure, active
hepatitis, myocardial infarction in the prior 1 week, or recent treatment with amiodarone, class I or III antiarrhythmic drugs or digoxin were excluded. The conversion rates within the first 24 h were 92% versus 64% in the amiodarone and placebo groups, respectively (P50.001). Among the 18 patients in the placebo group who did not convert spontaneously within 24 h, 15 (85%) converted after being crossed over to the amiodarone therapy. However, it cannot be predicted how many of those would have been converted spontaneously beyond 24 h.
3.2. Oral loading amiodarone versus placebo Another method of amiodarone administration tested for the cardioversion of recent-onset atrial fibrillation is of single dose oral loading. Oral loading
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of 25–30 mg / kg body weight of amiodarone as a single dose has been found to be an effective, simple and well-tolerated therapy for the pharmacological cardioversion of recent-onset atrial fibrillation [12,25,26]. The efficacy of this regimen was evaluated in a randomized, placebo-controlled trial on 72 patients with recent-onset (,48 h) atrial fibrillation [26]. Patients with thyroid disease, acute myocardial infarction, acute pulmonary edema, sick sinus syndrome, high-degree atrioventricular block, anemia, hypovolemia, stroke, sepsis, renal disease, or hepatic disease, and women of child bearing potential were excluded. All medications affecting cardiac rhythm or conduction were discontinued before randomization and the patients taking class III antiarrhythmic drugs were excluded from the trial. The single oral loading dose of amiodarone used was of 30 mg / kg body weight. Conversion to sinus rhythm was significantly better in the amiodarone-treated patients with 8- and 24-h conversion rates of 50 and 87%, respectively, in the amiodarone-treated group and 20 and 35%, respectively, in the placebo group (P,0.0001 for both time points). However, the median time for conversion (8.7 h for amiodarone vs. 7.9 h for placebo) was not significantly different in both groups.
3.3. Oral versus i.v. amiodarone The efficacies of the single dose oral loading regimen and an i.v. regimen of amiodarone administration were examined and compared in a randomized, open-labeled trial [12]. Andrivet et al. [12] compared single oral loading dose (n545 patients, 30 mg / kg) with an i.v. regimen of amiodarone (n527 patients, 3–5 mg / kg over 30 min bolus followed by a continuous infusion of 10–15 mg / kg for 24 h) in recent-onset atrial tachyarrhythmias, of which atrial fibrillation was the most frequent arrhythmia (n550 patients). The proportion of patients with atrial fibrillation in oral and i.v. groups was 73 and 63%, respectively. The overall efficacy within the first 24 h after the single dose oral loading was 64% and that after the i.v. regimen was 68% (P5NS). The patients who failed to convert to sinus rhythm more frequently had congestive heart failure, pulmonary edema, lower fractional shortening, or larger cardiac diameters.
245
3.4. Amiodarone versus other antiarrhythmic drugs Several trials have compared amiodarone with the other antiarrhythmic drugs, which have been used conventionally for the pharmacological cardioversion of recent-onset atrial fibrillation, including quinidine, propafenone, flecainide, and sotalol [9,10,14,19,20,23–25]. Amiodarone has not been found to be superior to these drugs. In a randomized open-label study by Negrini et al. [9], efficacy of amiodarone was compared to that of quinidine in cardioversion of recent-onset atrial fibrillation. Sixtyeight patients were randomly assigned to receive either amiodarone (5 mg / kg i.v. bolus followed by a 15 mg / kg infusion for 24 h, then 400 mg orally every 6 h until conversion or for a maximum of 3 days) or quinidine sulfate (200, 400, and 600 mg every 6 h on days one, two and three, respectively, until conversion or for a maximum of 3 days). Patients who received quinidine also received digitalis to control the ventricular rate. In the first 24 h, the conversion rates in the amiodarone and quinidine groups were 70 and 62% (P5NS), respectively. The conversion rates at the period of 3 days were 94 and 93% (P5NS), with the mean conversion times of 19616 h versus 23622 h (P5NS), respectively, in the amiodarone and quinidine-treated groups. Patients with NYHA class III or IV heart failure, acute myocardial infarction, unstable angina, sick sinus syndrome, WolffParkinson-White syndrome, conduction abnormalities, or thyroid dysfunction and those on concomitant antiarrhythmic drugs were excluded from the study. In another placebo-controlled trial by Kochiadakis et al. [20], 143 patients with recent-onset (,48 h) atrial fibrillation were randomized to receive either i.v. amiodarone (300 mg over 1 h, followed by 20 mg / kg over the next 24 h, plus simultaneously 1800 mg / day orally in three divided doses), i.v. propafenone (2 mg / kg over 15 min, 10 mg / kg over the next 24 h), or placebo. During 24 h, the conversion to sinus rhythm occurred in 83, 78 and 55% of patients in amiodarone, propafenone and placebo groups, respectively (P5NS for amiodarone vs. propafenone: P,0.02 for drug vs. placebo). The mean time to conversion was 765 h for amiodarone and 263 h for propafenone (P,0.05). The atrial diameter size was smaller in patients who converted versus who did not
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(42.765 vs. 47.267 mm, P,0.001). The study concluded that both high-dose amiodarone and propafenone were equally effective for the conversion of recent-onset atrial fibrillation. Martinez-Marcos et al. [23] reported a prospective, single blind trial in which 150 patients with atrial fibrillation of ,48 h were randomized to receive i.v. amiodarone (5 mg / kg bolus in 20 min, followed by continuous infusion of 50 mg / h for 12 h), i.v. propafenone (2 mg / kg bolus, followed by a second bolus of 1 mg / kg if conversion was not achieved within 8 h), or i.v. flecainide (2 mg / kg bolus, followed by a second bolus of 1 mg / kg if conversion was not achieved within 8 h). The primary end-point was 12-h conversion rate, which was 64, 72 and 90% in the amiodarone, propafenone, and flecainide groups, respectively (P5NS for amiodarone vs. propafenone: P50.002 for flecainide vs. amiodarone). Median time to conversion was longer in the amiodarone group than that in the propafenone (333 vs. 30 min, P,0.001) and the flecainide (333 vs. 25 min, P,0.001) groups. Blanc et al. [25] compared the efficacy of oral amiodarone with that of oral propafenone for conversion of recent-onset (,2 weeks) atrial fibrillation. In this randomized trial (n586 patients), the patients in the amiodarone group received a single oral loading dose of 30 mg / kg body weight amiodarone and, if necessary, a repeat dose of 15 mg / kg body weight after 24 h, and the patients in the propafenone group received a single oral loading dose of 600 mg propafenone and, if necessary, a repeat dose of 300 mg after 24 h. The 24-h conversion rates were 47% versus 56% (P5NS) in the amiodarone and the propafenone-treated groups. The median conversion time with propafenone was significantly shorter than that with amiodarone (2.4 vs. 6.9 h, P50.05). In a subgroup analysis based on the duration of atrial fibrillation, 84% of all the patients with atrial fibrillation of ,2 days duration converted to sinus rhythm compared to 45% of those with atrial fibrillation of $2 days (P50.001). In another randomized, digoxin-controlled trial, Joseph and Ward [24] compared the efficacy of amiodarone and sotalol for cardioversion of recentonset (,24 h) atrial fibrillation. The primary endpoint was set at 48 h. One-hundred twenty patients with recent-onset atrial fibrillation were randomly
assigned to amiodarone (5 mg / kg i.v. over 30 min, then 400 mg orally every 8 h for six doses), sotalol (1.5 mg / kg i.v. over 30 min, then 80 mg orally every 8 h for six doses), and digoxin (500 mg i.v. over 30 min, followed by 250 mg orally every 6 h for four doses, and then 250 mg daily) regimens. The conversion rates were not significantly different between amiodarone and sotalol groups at 24 (69 vs. 80%, P5NS) and 48 h (77 vs. 88%, P5NS). The time to conversion was 18.162.9 h in amiodarone-treated patients and 13.062.5 h in the sotalol-treated group (P5NS).
4. Safety Data on the safety of amiodarone for the pharmacological cardioversion of recent-onset atrial fibrillation is given in Table 2. None of the major proarrhythmic events, such as sustained ventricular tachycardia, ventricular fibrillation or torsade de pointes have been reported with the use of amiodarone for the cardioversion of recent-onset atrial fibrillation. The minor cardiac effects reported were first-degree atrioventricular block, self-limited sinus bradycardia, hypotension, and nonsustained ventricular tachycardia [8,9,12,17,23]. These adverse effects were more common with the i.v. treatment than the oral use of the drug [12,17]. Asymptomatic sinus bradycardia has been reported in up to 10% of patients and hypotension in up to 18% of patients who received i.v. amiodarone [12,14,21]. All the episodes of hypotension were transient and responded to saline volume expansion or inotropic support. Hypotension with i.v. use of amiodarone is due to the vehicle and not the drug itself. An improved i.v. preparation of amiodarone is under investigation. Phlebitis over the amiodarone infusion site has been noted in up to 16% of patients [17,21]. Other rare side effects were nausea, diarrhea, blurred vision, and allergic reactions [20,23,26]. The gastrointestinal side effects were reported predominantly with the oral administration of the drug. Amiodarone appears to be relatively safe in patients with structural heart disease and in those with systolic dysfunction, but the occasional occurrence of the worsening of heart failure has been reported [16,27]. One death was reported in the trial by Hou et
I. A. Khan et al. / International Journal of Cardiology 89 (2003) 239–248
al. [13], where one patient, while receiving i.v. amiodarone, developed severe bradycardia and cardiac arrest, and died despite an aggressive resuscitation attempt. This patient, in addition to atrial fibrillation, was also suffering toxic epidermal necrolysis and adult respiratory distress syndrome. The absence of major side effects at a large scale even at higher i.v. doses was probably due to a relatively short duration of the drug administration required for the cardioversion of recent-onset atrial fibrillation.
5. Conclusions Conversion rates of recent-onset atrial fibrillation with the use of amiodarone range from 34 to 95% depending on the amiodarone dose used, the duration of atrial fibrillation, the left atrial size, and the duration of follow-up after administration of the drug. Amiodarone is superior to placebo in converting recent-onset atrial fibrillation to sinus rhythm only if used in higher doses (.1500 mg / day), intravenously or orally. In most of the i.v. trials, amiodarone has been given until conversion to sinus rhythm or for a maximum of 24 h. The i.v. regimen of 125 mg / h until conversion or a maximum of 3 g and the oral regimen of 25–30 mg / kg body weight administered as a single loading dose have the highest 24-h conversion rates. Hypotension, if developed with the use of higher doses of amiodarone intravenously, usually responds well to i.v. saline administration. Amiodarone has not been found superior to the other antiarrhythmic drugs conventionally used for the pharmacological cardioversion of recent-onset atrial fibrillation. Conversion time is significantly longer with amiodarone, and most of the conversions occur after 6–8 h of the initiation of amiodarone therapy. The amiodarone use for the cardioversion of recentonset atrial fibrillation appears to be relatively safe, even in patients with structural heart disease and in those with left ventricular systolic dysfunction. Therefore, amiodarone could be used particularly in patients with structural heart disease and in those with left ventricular systolic dysfunction as the use of class IC drugs, propafenone and flecainide, for cardioversion of atrial fibrillation is contraindicated in such patients.
247
Acknowledgements No financial support was received for this paper.
References [1] Daoud EG, Marcovitz P, Knight BP et al. Short-term effects of atrial fibrillation on atrial contractile function in humans. Circulation 1999;99:3024–7. [2] Khan IA. Transient atrial mechanical dysfunction (atrial stunning) after cardioversion of atrial fibrillation and flutter. Am Heart J 2002;144:11–22. [3] Gallik D, Altamirano J, Singh BN. Restoring sinus rhythm in patients with atrial flutter and fibrillation: pharmacologic or electrical cardioversion. J Cardiovasc Pharmacol Ther 1997;2:135–44. [4] Khan IA. Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation. J Am Coll Cardiol 2001;37:542–7. [5] Khan I A. Oral loading single dose flecainide for pharmacological cardioversion of recent-onset atrial fibrillation. Int J Cardiol 2003;87:121–8. [6] Strasberg B, Arditti A, Sclarovsky S, Lewin RF. Efficacy of intravenous amiodarone in the management of paroxysmal or new atrial fibrillation with fast ventricular response. Int J Cardiol 1985;7:47–55. [7] 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. J Cardiovasc Pharmacol 1986;8:252–6. [8] Noc M, Stajer D, Horvat M. Intravenous amiodarone versus verapamil for acute conversion of paroxysmal atrial fibrillation to sinus rhythm. Am J Cardiol 1990;65:679–80. [9] Negrini M, Gibelli G, De Ponti C. Amiodarone versus quinidine for the conversion of recent onset atrial fibrillation to sinus rhythm. G Ital Cardiol 1990;20:207–14. [10] Pilati G, Lenzi T, Trisolino G. Amiodarone versus quinidine for conversion of recent onset atrial fibrillation to sinus rhythm. Curr Ther Res 1991;46:140–6. [11] Vietti-Ramus G, Veglio F, Marchisio U, Burzio P, Latini R. Efficacy and safety of short intravenous amiodarone in supraventricular tachyarrhythmias. Int J Cardiol 1992;35:77–85. [12] Andrivet P, Boubakri E, Dove PJ, Mach V, Vu Ngoc C. A clinical study of amiodarone as a single oral dose in patients with recentonset atrial tachyarrhythmia. Eur Heart J 1994;15:1396–402. [13] Hou ZY, Chang MS, Chen CY et al. Acute treatment of recent-onset atrial fibrillation and flutter with a tailored dosing regimen of intravenous amiodarone. Eur Heart J 1995;16:521–8. [14] Donovan KD, Power BM, Hockings BEF, Dobb GJ, Lee KY. Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation. Am J Cardiol 1995;75:693–7. [15] Moran JL, Gallagher J, Peake SL, Cunningham DN, Salagaras M, Leppard P. Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study. Crit Care Med 1995;23:1816–24. [16] Kumar A. Intravenous amiodarone for therapy of atrial fibrillation and flutter in critically ill patients with severely depressed left ventricular function. South Med J 1996;89:779–85. [17] Galve E, Rius T, Ballester R et al. Intravenous amiodarone in treatment of recent-onset atrial fibrillation. Results of a randomized controlled study. J Am Coll Cardiol 1996;27:1079–82.
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[18] Cybulski J, Kulakowski P, Makowska E, Czepiel A, Sikora-Frac M, Ceremuzynski L. Intravenous amiodarone is safe and seems to be effective in termination of paroxysmal supraventricular tachyarrhythmias. Clin Cardiol 1996;19:563–6. [19] Boriani G, Biffi M, Capucci A et al. Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols. Pacing Clin Electrophysiol 1998;21:2470–4. [20] Kochiadakis GE, Igoumenidis NE, Simantirakis EN et al. Intravenous propafenone versus intravenous amiodarone in the management of atrial fibrillation of recent onset. A placebo-controlled study. PACE 1998;21:2475–9. [21] Cotter G, Blatt A, Kaluski E et al. Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm: the effect of no treatment and high dose amiodarone. Eur Heart J 1999;20:1833– 42. [22] Kreiss Y, Sidi Y, Gur H. Efficacy and safety of intravenous amiodarone in recent-onset atrial fibrillation: experience in patients admitted to a general internal medicine department. Postgrad Med J 1999;75:278–81.
[23] Martinez-Marcos FJ, Garcia-Garmendia JL, Ortega-Carpio A, Fernandez-Gomez JM, Santos JM, Camacho C. Comparison of intravenous flecainide, propafenone, and amiodarone for conversion of acute atrial fibrillation to sinus rhythm. Am J Cardiol 2000;86:950– 3. [24] Joseph AP, Ward MR. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Ann Emerg Med 2000;36:1–9. [25] Blanc JJ, Voinov C, Maarek M. Comparison of oral loading dose of propafenone and amiodarone for converting recent-onset atrial fibrillation. Am J Cardiol 1999;84:1029–32. [26] Peuhkurinen K, Niemela M, Ylitalo A, Linnaluoto M, Lilja M, Juvonen J. Effectiveness of amiodarone as a single oral dose for recent-onset atrial fibrillation. Am J Cardiol 2000;85:462–5. [27] Holt AW. Hemodynamic responses to amiodarone in critically ill patients receiving catecholamine infusions. Crit Care Med 1989;17:1270–6.
Amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation a, a b Ijaz A. Khan *, Nirav J. Mehta , Ramesh M. Gowda a
Division of Cardiology, Department of Medicine, Creighton University School of Medicine, 3006 Webster St., Omaha, NE 68131, USA b Division of Cardiology, Department of Medicine, Long Island College Hospital, Brooklyn, NY, USA Received 22 April 2002; received in revised form 15 August 2002; accepted 8 September 2002
Abstract The efficacy and safety of amiodarone for pharmacological cardioversion of recent-onset atrial fibrillation was examined by reviewing the trials on the subject identified through a comprehensive literature search. Amiodarone has been used both intravenously (i.v.) and orally for the pharmacological cardioversion of recent-onset atrial fibrillation. Intravenous amiodarone has been used as a bolus only or as a bolus followed by a continuous i.v. infusion until conversion or up to 24 h. The dose of i.v. bolus given ranged from 3 to 7 mg / kg body weight and that of infusion from 900 to 3000 mg / day. The efficacy reported is 34–69% with the bolus only regimens, and 55–95% with the bolus followed by infusion regimens. Only the higher dose (.1500 mg / day) amiodarone is superior to placebo in converting recent-onset atrial fibrillation to sinus rhythm. The highest 24-h conversion rates have been reported with the i.v. regimen of 125 mg / h until conversion or a maximum of 3 g and the oral regimen of 25–30 mg / kg body weight administered as a single loading-dose (.90% and .85%, respectively). Most of the conversions occur after 6–8 h of the initiation of therapy. Predictors of successful conversion are shorter duration of atrial fibrillation, smaller left atrial size, and higher amiodarone dose. Amiodarone is not superior to the other antiarrhythmic drugs conventionally used for the pharmacological cardioversion of recent-onset atrial fibrillation but is relatively safe in patients with structural heart disease and in those with depressed left ventricle function. Therefore, amiodarone could be used particularly in patients with structural heart disease and in those with left ventricular systolic dysfunction as the use of class IC drugs, propafenone and flecainide, for cardioversion of atrial fibrillation is contraindicated in such patients. 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Amiodarone; Pharmacological cardioversion; Chemical cardioversion; Class III antiarrhythmic drugs
1. Introduction Sustained atrial fibrillation results in mechanical dysfunction and electrophysiological remodeling of the atria. The electrophysiological remodeling and the changes in atrial refractoriness start taking place within a few hours of the initiation of atrial fibrillation, thereby, decreasing the chances of successful *Corresponding author. Tel.: 11-402-280-4573; fax: 11-402-2804938. E-mail address: [email protected] (I.A. Khan).
conversion to and maintenance of the sinus rhythm [1]. Both the atrial mechanical dysfunction and the electrophysiological remodeling can be prevented or reversed by an earlier restoration of sinus rhythm. The early restoration of sinus rhythm may also relieve symptoms, prevent tachycardia-related cardiomyopathy, eliminate the need for the long-term use of atrioventricular node blocking drugs, and prevent or decrease the risk of atrial stunning and thromboembolism [2]. Approximately 50% of patients with recent-onset atrial fibrillation convert spontaneously to sinus
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0167-5273(02)00477-1
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rhythm within 24 h and this rate can be increased to about 80–90% by pharmacological or electrical cardioversion [3]. Pharmacological cardioversion appears to be the most effective when carried out within 2 weeks after the onset of atrial fibrillation and has the advantages of being simpler and convenient, free of the need of conscious sedation or anesthesia, and feasible in recent post-prandial state [3]. Class IA (quinidine, procainamide), class IC (propafenone, flecainide), and class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic drugs have been used for the pharmacological cardioversion of atrial fibrillation, and, although the drug of choice is unclear, propafenone, flecainide and amiodarone have been reported as the most effective drugs with acceptable safety profiles [3–5]. Amiodarone, which is generally considered a class III antiarrhythmic drug, possesses electrophysiological characteristics of all four Vaughan Williams classes, and has the advantage of being administered both by parenteral and oral routes.
2. Data collection The efficacy and safety of amiodarone for cardioversion of recent-onset atrial fibrillation was examined by reviewing the trials on the subject identified through a comprehensive search of the PubMed / Medline (National Library of Medicine, Bethesda, MD, USA). The trials were examined if they had evaluated efficacy, safety, or both of amiodarone as the sole drug or in comparison to placebo or with other antiarrhythmic drugs for the pharmacological cardioversion of recent-onset atrial fibrillation. Atrial fibrillation of #2 weeks was considered as recent-onset. The references in the articles were checked for additional relevant studies. The trials on the use of amiodarone for post-operative atrial fibrillation were not included. All trials [6–26] were examined and data were manually extracted and tabulated (Tables 1 and 2). Due to the marked differences in the study enrollment and design, including differences in the dose of amiodarone used and in the way the recentness of atrial fibrillation was defined in various trials, it was not possible to pool the data for meta-analysis. Therefore, a narrative but
succinct overview is provided, and the important studies are highlighted in each group.
3. Efficacy
3.1. Intravenous amiodarone versus placebo Data on the efficacy of amiodarone for the pharmacological cardioversion of recent-onset atrial fibrillation is given in Table 1. In most of the trials amiodarone was used intravenously. The i.v. amiodarone has been used as a bolus only or as a bolus followed by a continuous i.v. infusion [6–24]. The i.v. bolus doses given in various trials ranged from 3 to 7 mg / kg body weight and the doses of infusion ranged from 900 to 3000 mg / day [6–24]. In most of the trials, continuous infusion has been used for 24 h and the efficacy has been evaluated at different time intervals up to 24 h from the initiation of therapy [6–24]. The reported efficacy of i.v. amiodarone for successful cardioversion of recentonset atrial fibrillation ranges from 34 to 69% with the bolus only regimens, and 55–95% with the bolus followed by infusion regimens, depending on the duration of atrial fibrillation, the duration of the follow-up after drug administration, the patient population enrolled, left atrial size, and the dose of amiodarone [6–24]. Most of the patients who successfully converted with the use of i.v. amiodarone did so after 6–8 h of initiation of therapy [6–24]. The dose of amiodarone optimal for cardioversion of recent-onset atrial fibrillation has not been established and various trials have used different dose regimens. When compared with placebo, only higher dose regimens of amiodarone (.1500 mg / 24 h) resulted in significantly higher rates of cardioversion of recent-onset atrial fibrillation, whereas, the conventional dose regimens were not better than placebo [11,13,14,17,20,21,24]. Galve et al. [17] demonstrated that amiodarone administered at a conventional dose of a bolus of 5 mg / kg body weight followed by 1200 mg over 24 h was not significantly superior to placebo for the conversion of recent-onset (,7 days) atrial fibrillation with the 24-h conversion rates being 68 and 60%, respectively (P5NS). On the other hand, conversion rates of over 90% have been reported in trials where the higher dose amiodarone
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241
Table 1 Data on the efficacy of amiodarone for cardioversion of recent-onset atrial fibrillation Trial [Ref.]
Duration
Route and dose of amiodarone (n5number of patients)
Comparison with (n5number of patients)
Conversion rate (amiodarone vs. the drug compared)
Absolute benefit (%) of amiodarone
Pvalue
Strasberg et al. [6]
15 min to 48 h
i.v. 5 mg/kg over 3–5 min (26)
None
In ,30 min: 46% (12/26) At 8 h: 73% (18/26)
Cowan et al. [7]
New onset
i.v. 7 mg/kg loading over 30 min followed by 1500 mg in 23 h (18)
i.v. digoxin 0.5 mg infusion over 30 min, repeated if ventricular rate.60/min (16)
At 4 h: 72% (11/15) versus 31% (4/14)
41
,0.1
Noc et al. [8]
20 min to 48 h
i.v. 5 mg/kg over 3 min (13)
i.v. verapamil 0.075 mg/kg over 1 min (11)
At 3 h: 77% (10/13) versus 0% (0/11)
77
,0.001
Negrini et al. [9]
,3 weeks
i.v. 5 mg/kg bolus over 20 min, 15 mg/kg infusion for 24 h then 400 mg oral Q 6 h (33)
Oral quinidine 0.2 g Q 6 h 1st day, 0.4 g Q 6 h 2nd day and 0.6 g Q 6 h 3rd day (29)
At 24 h: 70% (23/33) versus 62% (18/29) At 3 days: 94% (31/33) versus 93% (27/29)
8
NS
1
NS
8
NS
NS
Pilati et al. [10]
,72 h
i.v. 300 mg over 30 min followed by i.v. infusion of 300 mg Q 8 h (37)
Oral quinidine 150 mg orally Q 3 h for first 24 h and then 300 mg Q 8 h plus digoxin (38)
At 48 h: 100% (37/37) versus 92% (35/38)
Vietti-Ramus et al. [11]
,24 h
i.v. 2 mg/kg per h up to maximum dose of 2400 mg/24 h (44)
None
At 24 h: 89% (39/44)
Andrivet et al. [12]
.3 h
i.v. 3–5 mg/kg bolus then infusion of 10–15 mg/kg per 24 h (27)
Oral amiodarone 25.760.9 mg/kg as single loading dose (45)
At 24 h: 67% (18/27) versus 64% (29/45)
3
Hou et al. [13]
,10 days
i.v. 5 mg/kg for 1 h, 3 mg/min for 3 h, 1 mg/kg for 6 h and 0.5 mg/kg for next 14 h (26)
i.v. digoxin 0.013 mg/kg in three divided doses 2 h apart (24)
At 24 h: 92% (24/26) versus 71% (17/24)
21
Donovan et al. [14]
.30 min ,72 h
i.v. 7 mg/kg (32)
i.v. flecainide 2 mg/kg maximum 150 mg (34)
At 2 h: 34% (11/32) versus 59% (20/34) At 8 h: 59% (19/32) versus 68% (23/34)
225
NS
29
NS
235
Moran et al. [15]
.1 h
i.v. 5 mg/kg loading over 15–20 min followed by infusion of 10 mg/kg per 24 h (16)
i.v. magnesium sulfate 0.037 g/kg over 5 min then 0.025 g/kg/h (18)
At 24 h: 43% (7/16) versus 78% (14/18)
Kumar [16]
.30 min
i.v. 300 mg over 1 h (8)
None
At 1 h: 88% (7/8)
Galve et al. [17]
,1 week
i.v. 5 mg/kg over 30 min followed by 1200 mg/24 h (50)
Placebo (50)
At 24 h: 68% (34/50) versus 60% (30/34)
Cybulski et al. [18]
,24 h
i.v. 150 mg over 10 min, repeated after 30-35 min if arrhythmia persisted (142)
None
At 12 h: 64% (91/142)
8
0.005
0.08 a
NS
I. A. Khan et al. / International Journal of Cardiology 89 (2003) 239–248
242 Table 1. Continued Trial [Ref.]
Duration
Route and dose of amiodarone (n5number of patients)
Comparison with (n5number of patients)
Conversion rate (amiodarone vs. the drug compared)
Absolute benefit (%) of amiodarone
Boriani et al. [19]
,7 days
i.v. 5 mg/kg bolus followed by 1.8 g/24 h (51)
i.v. propafenone 2 mg/kg bolus followed by 0.0078 mg/kg per min (57)
At 8 h: 57% (29/51) versus 75% (43/57)
218
0.04 a
Oral propafenone 600 mg single dose (119)
At 8 h: 57% (29/51) versus 76% (91/119)
219
0.01 a
Oral flecainide 300 mg single dose (69)
At 8 h: 57% (29/51) versus 75% (52/69)
218
0.03 a
Placebo (121)
At 8 h: 57% (29/51) versus 37% (45/121)
20
0.02 a
i.v. propafenone 2 mg/kg over 15 min followed by 10 mg/kg over next 24 h (46)
At 24 h: 83% (40/48) versus 78% (36/46)
5
Placebo (49)
At 24 h: 83% (40/48) versus 55% (27/49)
28
28
Kochiadakis et al. [20]
,48 h
i.v. 300 mg over 1 h followed by 20 mg/kg over next 24 h plus 1800 mg/day in three divided doses (48)
Cotter et al. [21]
,48 h
i.v. 125 mg/h till conversion or for 24 h (50)
Placebo (50)
At 24 h: 92% (46/50) versus 64% (32/50)
Kreiss et al. [22]
,48 h
i.v. 1200 mg/24 h followed by oral 1200 mg/day for 3 days, 800 mg/day for 3 days, 400 mg/day for 3 days and maintenance dose of 200 mg/day (20)
None
At 48 h: 55% (11/20)
Martinez-Marcos et al. [23]
,48 h
i.v. 5 mg/kg bolus followed by 50 mg/h infusion (50)
i.v. flecainide 2 mg/kg bolus followed by second bolus dose of 1 mg/kg if conversion is not achieved after 8 h (50)
At 12 h: 64% (32/50) versus 90% (45/50)
226
i.v. propafenone 2 mg/kg bolus followed by second bolus dose of 1 mg/kg if conversion is not achieved after 8 h (50)
At 12 h: 64% (32/50) versus 72% (36/50)
8
Joseph et al. [24]
,24 h
i.v. 5 mg/kg over 30 min then 400 mg Q 8 h for six doses (39)
i.v. sotalol 1.5 mg/kg then 80 mg Q 8 h for six doses oral (40) i.v. digoxin 500 mg followed by 250 mg orally Q 6 hourly for four doses then 250 mg/day (36)
At 48 h: 77% (30/39) versus 88% (35/40)
Pvalue
NS
,0.02
0.0017
0.002
NS
211
0.05
19
0.05
At 48 h: 77% (30/39) versus 58% (21/36)
Blanc et al. [25]
,2 weeks
Oral 30 mg/kg for 24 h (43)
Oral propafenone 600 mg (43)
At 24 h: 47% (20/43) versus 56% (24/43)
–9
NS
Peuhkurinen et al. [26]
,48 h
Oral single dose of 30 mg/kg (31)
Placebo (31)
At 8 h: 50% versus 20% At 24 h: 87% (27/31) versus 35% (11/31)
30 52
,0.001 ,0.001
i.v., intravenous; NS, not significant. a P-value calculated by authors from data given in the trial.
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243
Table 2 Data on the safety of amiodarone for cardioversion of recent-onset atrial fibrillation Trial [Ref.] a
Amiodarone route and comparison (n5patient)
Side effects in amiodarone group (n5patients with side effects)
Strasberg et al. [6]
i.v. amiodarone only (26)
Mild flushing (7)
Cowan et al. [7]
i.v. amiodarone (18) versus i.v. digoxin (16)
Transient hypotension (1)
Transient bradycardia and hypotension (1)
Noc et al. [8]
i.v. amiodarone (13) versus i.v. verapamil (11)
Transient hypotension (1)
None
Negrini et al. [9]
i.v. amiodarone (33) versus oral quinidine (29)
Transient first degree AV block (1)
Gastrointestinal disturbances (3) ventricular arrhythmias (2) marked QTc prolongation (1)
Pilati et al. [10]
i.v. amiodarone (37) versus oral quinidine (38)
Phlebitis (4)
Gastrointestinal disturbances (2) Atrial tachycardia (2) Atrial flutter (1)
Vietti -Ramus et al. [11]
i.v. amiodarone alone (44)
Phlebitis (9) Transient hypotension (5)
Andrivet et al. [12] Hou et al. [13]
i.v. amiodarone (27) versus oral amiodarone (45) i.v. amiodarone (26) versus i.v. digoxin (24)
First degree AV block (6) Transient junctional escape (1) Phlebitis (1) Aggravation of heart failure (1) Cardiac arrest (1)
First degree AV block (1) Sinus bradycardia (1) NR
Donovan et al. [14]
i.v. amiodarone (32) versus i.v. flecainide (34) and placebo (32)
Nausea (2) Headache (1) Hypotension (5) Wenckebach phenomenon (1)
Flecainide: Hypotension (8) Blurred vision (1)
NR
Moran et al. [15]
i.v. amiodarone (21) versus i.v. magnesium (21)
NR
Kumar [16]
i.v. amiodarone alone (8)
No side effects
Galve et al. [17]
i.v. amiodarone (50) versus placebo (50)
Phlebitis (1) Nonsustained ventricular tachycardia (1) Transient hypotension (4)
Cybulski et al. [18]
i.v. amiodarone alone (142)
First degree AV block (2)
Boriani et al. [19]
i.v. amiodarone (51) versus i.v. propafenone (57) versus oral propafenone (119) versus oral flecainide (69) versus placebo (121)
None reported
i.v. amiodarone (48) versus i.v. propafenone (46) versus placebo (49)
Allergic reaction leading to discontinuation (1)
Kochiadakis et al. [20]
Side effects in the compared with group (n5patients with side effects)
Placebo: Hypotension (8) Ventricular tachycardia (1)
Transient hypotension (4) Vomiting (2) Atrial flutter (1) Transient junctional rhythm (1)
Propafenone: Hypotension and pulmonary edema (1) Flecainide: Atrial flutter with 1:1 conduction (2) Left ventricular decompensation (2) Placebo: Transient hypotension and bradycardia (10) Atrial flutter with 1:1 conduction leading to collapse (1) Propafenone: Excessive QRS widening (1)
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Table 2. Continued Trial [Ref.] a
Amiodarone route and comparison (n5patient)
Side effects in amiodarone group (n5patients with side effects)
Side effects in the compared with group (n5patients with side effects)
Cotter et al. [21]
i.v. amiodarone (50) versus placebo (50)
Phlebitis (8) Asymptomatic bradycardia (5)
Phlebitis (3) Asymptomatic bradycardia (2)
Kreiss et al. [22]
i.v. amiodarone alone (20)
Phlebitis (5) Transient hypotension (1)
Martinez-Marcos et al. [23]
i.v. amiodarone (50) versus i.v. flecainide (50) versus i.v. propafenone (50)
Transient atrial tachycardia (1) Symptomatic hypotension (1) Urticarial rash (1)
Flecainide: Atrial flutter with 1:1 conduction (1) Transient junctional rhythm (2) Symptomatic hypotension (1) Paresthesia (2) Propafenone: Aggravation of heart failure (1) Transient junctional rhythm (3) Transient atrial tachycardia (2) Symptomatic hypotension (1)
Joseph et al. [24]
i.v. amiodarone (39) versus i.v. sotalol (40) versus i.v. digoxin (36)
Bradycardia (1) Left ventricular failure (2) QTc .500 ms (2) Phlebitis (1) Temporary pacemaker (1)
Sotalol: Hypotension (2) QTc .500 ms (5) Digoxin: Bradycardia (1) Temporary pacemaker (1)
Blanc et al. [25]
Oral amiodarone (43) versus oral propafenone (43)
Gastrointestinal disturbances (4) Supraventricular tachycardia (1) Nonsustained ventricular tachycardia (1)
Gastrointestinal disturbances (4) Atrial flutter (1) Nonsustained ventricular tachycardia (1)
Peuhkurinen et al. [26]
Oral amiodarone (31) versus placebo (31)
Gastrointestinal disturbances (4) Symptomatic bradycardia and hypotension with syncope (1)
Gastrointestinal disturbances (2) Headache (2) Sinus arrest with collapse (1)
P5NS where comparison possible. The P-values were not reported in any of the trials but were calculated by authors from data given in the trials. AV, atrioventricular; i.v., intravenous; NR, not reported. a Please refer to Table 1 for the doses of amiodarone and other drugs.
regimens were used [11,13,21]. Hou et al. [13] demonstrated that a higher dose regimen of amiodarone (1620 mg / 24 h) increased the 24-h conversion rate of recent-onset (,10 days) atrial fibrillation from 72% (placebo arm) to 92% (P50.004). In another randomized, placebo-controlled, crossover trial on 100 patients with atrial fibrillation (duration,48 h), Cotter et al. [21] compared the effects of high-dose i.v. amiodarone (125 mg / h until conversion, or a total of 3 g) versus placebo. The patients in the placebo group who did not convert to sinus rhythm within 24 h were crossed over to i.v. amiodarone. Patients who had severe bradyarrhythmia, sinoatrial and atrioventricular node disease, symptomatic hypotension, ischemia, congestive heart failure, chronic lung disease, hepatic failure, active
hepatitis, myocardial infarction in the prior 1 week, or recent treatment with amiodarone, class I or III antiarrhythmic drugs or digoxin were excluded. The conversion rates within the first 24 h were 92% versus 64% in the amiodarone and placebo groups, respectively (P50.001). Among the 18 patients in the placebo group who did not convert spontaneously within 24 h, 15 (85%) converted after being crossed over to the amiodarone therapy. However, it cannot be predicted how many of those would have been converted spontaneously beyond 24 h.
3.2. Oral loading amiodarone versus placebo Another method of amiodarone administration tested for the cardioversion of recent-onset atrial fibrillation is of single dose oral loading. Oral loading
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of 25–30 mg / kg body weight of amiodarone as a single dose has been found to be an effective, simple and well-tolerated therapy for the pharmacological cardioversion of recent-onset atrial fibrillation [12,25,26]. The efficacy of this regimen was evaluated in a randomized, placebo-controlled trial on 72 patients with recent-onset (,48 h) atrial fibrillation [26]. Patients with thyroid disease, acute myocardial infarction, acute pulmonary edema, sick sinus syndrome, high-degree atrioventricular block, anemia, hypovolemia, stroke, sepsis, renal disease, or hepatic disease, and women of child bearing potential were excluded. All medications affecting cardiac rhythm or conduction were discontinued before randomization and the patients taking class III antiarrhythmic drugs were excluded from the trial. The single oral loading dose of amiodarone used was of 30 mg / kg body weight. Conversion to sinus rhythm was significantly better in the amiodarone-treated patients with 8- and 24-h conversion rates of 50 and 87%, respectively, in the amiodarone-treated group and 20 and 35%, respectively, in the placebo group (P,0.0001 for both time points). However, the median time for conversion (8.7 h for amiodarone vs. 7.9 h for placebo) was not significantly different in both groups.
3.3. Oral versus i.v. amiodarone The efficacies of the single dose oral loading regimen and an i.v. regimen of amiodarone administration were examined and compared in a randomized, open-labeled trial [12]. Andrivet et al. [12] compared single oral loading dose (n545 patients, 30 mg / kg) with an i.v. regimen of amiodarone (n527 patients, 3–5 mg / kg over 30 min bolus followed by a continuous infusion of 10–15 mg / kg for 24 h) in recent-onset atrial tachyarrhythmias, of which atrial fibrillation was the most frequent arrhythmia (n550 patients). The proportion of patients with atrial fibrillation in oral and i.v. groups was 73 and 63%, respectively. The overall efficacy within the first 24 h after the single dose oral loading was 64% and that after the i.v. regimen was 68% (P5NS). The patients who failed to convert to sinus rhythm more frequently had congestive heart failure, pulmonary edema, lower fractional shortening, or larger cardiac diameters.
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3.4. Amiodarone versus other antiarrhythmic drugs Several trials have compared amiodarone with the other antiarrhythmic drugs, which have been used conventionally for the pharmacological cardioversion of recent-onset atrial fibrillation, including quinidine, propafenone, flecainide, and sotalol [9,10,14,19,20,23–25]. Amiodarone has not been found to be superior to these drugs. In a randomized open-label study by Negrini et al. [9], efficacy of amiodarone was compared to that of quinidine in cardioversion of recent-onset atrial fibrillation. Sixtyeight patients were randomly assigned to receive either amiodarone (5 mg / kg i.v. bolus followed by a 15 mg / kg infusion for 24 h, then 400 mg orally every 6 h until conversion or for a maximum of 3 days) or quinidine sulfate (200, 400, and 600 mg every 6 h on days one, two and three, respectively, until conversion or for a maximum of 3 days). Patients who received quinidine also received digitalis to control the ventricular rate. In the first 24 h, the conversion rates in the amiodarone and quinidine groups were 70 and 62% (P5NS), respectively. The conversion rates at the period of 3 days were 94 and 93% (P5NS), with the mean conversion times of 19616 h versus 23622 h (P5NS), respectively, in the amiodarone and quinidine-treated groups. Patients with NYHA class III or IV heart failure, acute myocardial infarction, unstable angina, sick sinus syndrome, WolffParkinson-White syndrome, conduction abnormalities, or thyroid dysfunction and those on concomitant antiarrhythmic drugs were excluded from the study. In another placebo-controlled trial by Kochiadakis et al. [20], 143 patients with recent-onset (,48 h) atrial fibrillation were randomized to receive either i.v. amiodarone (300 mg over 1 h, followed by 20 mg / kg over the next 24 h, plus simultaneously 1800 mg / day orally in three divided doses), i.v. propafenone (2 mg / kg over 15 min, 10 mg / kg over the next 24 h), or placebo. During 24 h, the conversion to sinus rhythm occurred in 83, 78 and 55% of patients in amiodarone, propafenone and placebo groups, respectively (P5NS for amiodarone vs. propafenone: P,0.02 for drug vs. placebo). The mean time to conversion was 765 h for amiodarone and 263 h for propafenone (P,0.05). The atrial diameter size was smaller in patients who converted versus who did not
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(42.765 vs. 47.267 mm, P,0.001). The study concluded that both high-dose amiodarone and propafenone were equally effective for the conversion of recent-onset atrial fibrillation. Martinez-Marcos et al. [23] reported a prospective, single blind trial in which 150 patients with atrial fibrillation of ,48 h were randomized to receive i.v. amiodarone (5 mg / kg bolus in 20 min, followed by continuous infusion of 50 mg / h for 12 h), i.v. propafenone (2 mg / kg bolus, followed by a second bolus of 1 mg / kg if conversion was not achieved within 8 h), or i.v. flecainide (2 mg / kg bolus, followed by a second bolus of 1 mg / kg if conversion was not achieved within 8 h). The primary end-point was 12-h conversion rate, which was 64, 72 and 90% in the amiodarone, propafenone, and flecainide groups, respectively (P5NS for amiodarone vs. propafenone: P50.002 for flecainide vs. amiodarone). Median time to conversion was longer in the amiodarone group than that in the propafenone (333 vs. 30 min, P,0.001) and the flecainide (333 vs. 25 min, P,0.001) groups. Blanc et al. [25] compared the efficacy of oral amiodarone with that of oral propafenone for conversion of recent-onset (,2 weeks) atrial fibrillation. In this randomized trial (n586 patients), the patients in the amiodarone group received a single oral loading dose of 30 mg / kg body weight amiodarone and, if necessary, a repeat dose of 15 mg / kg body weight after 24 h, and the patients in the propafenone group received a single oral loading dose of 600 mg propafenone and, if necessary, a repeat dose of 300 mg after 24 h. The 24-h conversion rates were 47% versus 56% (P5NS) in the amiodarone and the propafenone-treated groups. The median conversion time with propafenone was significantly shorter than that with amiodarone (2.4 vs. 6.9 h, P50.05). In a subgroup analysis based on the duration of atrial fibrillation, 84% of all the patients with atrial fibrillation of ,2 days duration converted to sinus rhythm compared to 45% of those with atrial fibrillation of $2 days (P50.001). In another randomized, digoxin-controlled trial, Joseph and Ward [24] compared the efficacy of amiodarone and sotalol for cardioversion of recentonset (,24 h) atrial fibrillation. The primary endpoint was set at 48 h. One-hundred twenty patients with recent-onset atrial fibrillation were randomly
assigned to amiodarone (5 mg / kg i.v. over 30 min, then 400 mg orally every 8 h for six doses), sotalol (1.5 mg / kg i.v. over 30 min, then 80 mg orally every 8 h for six doses), and digoxin (500 mg i.v. over 30 min, followed by 250 mg orally every 6 h for four doses, and then 250 mg daily) regimens. The conversion rates were not significantly different between amiodarone and sotalol groups at 24 (69 vs. 80%, P5NS) and 48 h (77 vs. 88%, P5NS). The time to conversion was 18.162.9 h in amiodarone-treated patients and 13.062.5 h in the sotalol-treated group (P5NS).
4. Safety Data on the safety of amiodarone for the pharmacological cardioversion of recent-onset atrial fibrillation is given in Table 2. None of the major proarrhythmic events, such as sustained ventricular tachycardia, ventricular fibrillation or torsade de pointes have been reported with the use of amiodarone for the cardioversion of recent-onset atrial fibrillation. The minor cardiac effects reported were first-degree atrioventricular block, self-limited sinus bradycardia, hypotension, and nonsustained ventricular tachycardia [8,9,12,17,23]. These adverse effects were more common with the i.v. treatment than the oral use of the drug [12,17]. Asymptomatic sinus bradycardia has been reported in up to 10% of patients and hypotension in up to 18% of patients who received i.v. amiodarone [12,14,21]. All the episodes of hypotension were transient and responded to saline volume expansion or inotropic support. Hypotension with i.v. use of amiodarone is due to the vehicle and not the drug itself. An improved i.v. preparation of amiodarone is under investigation. Phlebitis over the amiodarone infusion site has been noted in up to 16% of patients [17,21]. Other rare side effects were nausea, diarrhea, blurred vision, and allergic reactions [20,23,26]. The gastrointestinal side effects were reported predominantly with the oral administration of the drug. Amiodarone appears to be relatively safe in patients with structural heart disease and in those with systolic dysfunction, but the occasional occurrence of the worsening of heart failure has been reported [16,27]. One death was reported in the trial by Hou et
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al. [13], where one patient, while receiving i.v. amiodarone, developed severe bradycardia and cardiac arrest, and died despite an aggressive resuscitation attempt. This patient, in addition to atrial fibrillation, was also suffering toxic epidermal necrolysis and adult respiratory distress syndrome. The absence of major side effects at a large scale even at higher i.v. doses was probably due to a relatively short duration of the drug administration required for the cardioversion of recent-onset atrial fibrillation.
5. Conclusions Conversion rates of recent-onset atrial fibrillation with the use of amiodarone range from 34 to 95% depending on the amiodarone dose used, the duration of atrial fibrillation, the left atrial size, and the duration of follow-up after administration of the drug. Amiodarone is superior to placebo in converting recent-onset atrial fibrillation to sinus rhythm only if used in higher doses (.1500 mg / day), intravenously or orally. In most of the i.v. trials, amiodarone has been given until conversion to sinus rhythm or for a maximum of 24 h. The i.v. regimen of 125 mg / h until conversion or a maximum of 3 g and the oral regimen of 25–30 mg / kg body weight administered as a single loading dose have the highest 24-h conversion rates. Hypotension, if developed with the use of higher doses of amiodarone intravenously, usually responds well to i.v. saline administration. Amiodarone has not been found superior to the other antiarrhythmic drugs conventionally used for the pharmacological cardioversion of recent-onset atrial fibrillation. Conversion time is significantly longer with amiodarone, and most of the conversions occur after 6–8 h of the initiation of amiodarone therapy. The amiodarone use for the cardioversion of recentonset atrial fibrillation appears to be relatively safe, even in patients with structural heart disease and in those with left ventricular systolic dysfunction. Therefore, amiodarone could be used particularly in patients with structural heart disease and in those with left ventricular systolic dysfunction as the use of class IC drugs, propafenone and flecainide, for cardioversion of atrial fibrillation is contraindicated in such patients.
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Acknowledgements No financial support was received for this paper.
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