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Single-day loading dose of oral amiodarone for the prevention of new-onset atrial fibrillation after coronary artery bypass surgery
Single-day loading dose of oral amiodarone for the prevention of new-onset atrial fibrillation after coronary artery bypass surgery Dejan Maras˘, MD,a Srdjan D. Bos˘kovic´, MD,b Zoran Popovic´, MD, PhD,b Aleksandar N. Nes˘kovic´, MD, PhD,b Slobodan Kovac˘evic´, MD,a Petar Otas˘evic´, MD,b Jelena Marinkovic´, PhD,b Liljana Vuk, MD,a Milorad Borzanovic´, MD, PhD,a Stevan Nastasic´, MD, PhD,c Tomislav Jovanovic´, MD, PhD,d Milovan Bojic´, MD, PhD,b Rade Babic´, MD, PhD,b and Aleksandar D. Popovic´, MD, PhDb Belgrade, Yugoslavia
Background Various regimens have been proposed for the prevention of postoperative atrial fibrillation, including the use of intravenous and oral amiodarone. The purpose of this study was to determine the effectiveness of a single-day loading dose of oral amiodarone in prophylaxis of atrial fibrillation during the 7 days after coronary artery bypass surgery. Methods We conducted a double-blind, randomized, placebo-controlled study encompassing 315 consecutive patients who underwent coronary artery bypass surgery. They received either amiodarone (159 patients) or placebo (156 patients). Therapy consisted of a single oral loading dose of 1200 mg of amiodarone 1 day before surgery, followed by the maintenance dose of 200 mg daily during the next 7 days. Only episodes of atrial fibrillation lasting more than 1 hour or associated with hemodynamic compromise were taken into consideration.
Results Overall, the incidence of atrial fibrillation was similar in patients who received amiodarone (31/159, 19.5%) and placebo (33/156, 21.2%) (P = .78). However, amiodarone reduced the incidence of atrial fibrillation in elderly patients (age ≥60 years): it occurred in 20 of 75 (26.7%) patients on amiodarone and in 28 of 65 (43.1%) patients in the placebo group (P = .05). There were no differences between the study groups regarding the postoperative intrahospital morbidity and mortality and the duration of hospital stay. Conclusions A single-day loading dose of oral amiodarone (1200 mg) does not prevent postoperative atrial fibrillation in a general population of patients undergoing coronary artery bypass surgery. However, it appears that this regimen reduces the occurrence of postoperative atrial fibrillation in elderly patients. (Am Heart J 2001;141:e8.)
New-onset atrial fibrillation occurs in 20% to 40% of patients undergoing coronary artery bypass surgery.1,2 Among different preoperative and intraoperative factors,3-7 age has been identified as the strongest and most persistent predictor of postoperative atrial fibrillation.4,5,8,9 This observation is important because of the increasing age of the coronary artery bypass surgery patient population.10 Although not associated with an increased long-term mortality and morbidity,2,4 new-onset postoperative atrial fibrillation may be associated with thromboemFrom the aDepartment of Cardiology, the b”Dr Aleksandar D. Popovic´ “Cardiovascular Research Center, the cDepartment of Cardiac Surgery, Dedinje Cardiovascular Institute, and the dInstitute of Physiology, Belgrade University School of Medicine, Belgrade, Yugoslavia. Presented in part at the XXIst Congress of the European Society of Cardiology, Barcelona, Spain, August 1999. Submitted June 27, 2000; accepted January 12, 2001. Reprint requests: Aleksandar N. Nes˘kovic´, MD, “Dr Aleksandar D. Popovic´” Cardiovascular Research Center, Dedinje Cardiovascular Institute, Milana Tepic´a 1, 11040 Belgrade, Yugoslavia. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 1097-6744/2001/$35.00 + 0 4/90/114201 doi:10.1067/mhj.2001.114201
bolic events and hemodynamic compromise that may result in prolonged hospital stay and increased cost.4,5 Various regimens have been proposed for prophylaxis of postoperative atrial fibrillation, including use of different drugs (ie, β-adrenergic blockers, quinidine, calcium channel antagonists, magnesium, etc) and pacing protocols.11-16 Amiodarone, a class III antiarrhythmic agent, has been recently advocated as possible effective therapy for prophylaxis of postoperative atrial fibrillation.17,18 Both intravenous and oral administration of amiodarone have been shown to reduce the incidence of postoperative atrial fibrillation.17-21 Oral amiodarone given preoperatively during 7 days significantly reduces the occurrence of postoperative atrial fibrillation and shortens the duration of the hospital stay.18 On the other hand, smaller studies using different regimens showed no beneficial effect of oral amiodarone on postoperative atrial fibrillation.19 The shortest preoperative loading period and the smallest dose of amiodarone that is effective in suppressing postoperative atrial fibrillation have not been determined yet. This study sought to assess the efficacy of preoperative singleday loading dose of oral amiodarone in pre-
vention of new onset atrial fibrillation during the 7 days after coronary artery bypass surgery.
Methods Patient population From June 1998 to February 1999, all patients admitted to Dedinje Cardiovascular Institute for coronary artery bypass surgery were screened for participation in this study. Inclusion criteria were age >18 years, elective coronary artery bypass surgery, and no history of atrial fibrillation. Patients were excluded if they have used amiodarone or other antiarrhythmic drugs (except β-adrenergic blockers, calcium channel antagonists, or digitalis) within the last 4 months, were allergic to amiodarone, had uncontrolled thyroid dysfunction, had serum aspartate aminotransferase or alanine aminotransferase levels four times higher than upper normal limit, had a resting heart rate on admission of ≤50 beats/min, had valvular heart disease requiring surgery, or had congestive heart failure. Written informed consent was obtained from all patients.
Study design After the initial evaluation, patients were randomly assigned to receive either oral amiodarone or matching placebo in addition to their usual medications. Because it was anticipated before the start of the study that the development of postoperative atrial fibrillation is strongly influenced by patient age,8,9 the randomization was stratified according to whether the patients were younger or older than 60 years. After the randomization, patients received either an initial single loading dose of 1200 mg of amiodarone or placebo 1 day before cardiac surgery. Amiodarone or placebo was continued for the next 7 days, including the operation day, with the maintenance dose of 200 mg daily. If a patient had atrial fibrillation during the follow-up, treatment was directed to heart rate control (digitalis, calcium channel antagonists, and, if necessary, β-adrenergic blockers) and anticoagulation. Administration of other antiarrhythmic drugs or electric cardioversion was restricted only to the patients with severe hemodynamic compromise and congestive heart failure. Immediately after surgery, all patients were monitored for at least 24 hours in the intensive care unit. After that, an electrocardiogram was routinely obtained twice daily at 10 and 17 hours, and heart rate was measured by radial artery palpation 6 times daily: at 6 AM, 10 AM, 2 PM, 6 PM, 10 PM, and midnight. If an irregular pulse was noticed during the heart rate measurement or the patient had tachycardia (defined as heart rate ≥100 beats/min), an electrocardiogram was recorded. An electrocardiogram was also recorded if the patient was hypotensive or had angina, dyspnea, or sweating. Serial electrolyte profiles were performed daily, including serum potassium levels at the detection of atrial fibrillation. All patients were screened for possible amiodarone side effects on a daily basis. Serial electrocardiograms and clinical observations were also used to detect arrhythmias other than atrial fibrillation. The study was conducted during the first 7 postoperative days. If the patient needed to stay in the hospital after the termination of the study, amiodarone was discontinued if the patient did not have other indications for its administration.
End points The primary end point of the study was the occurrence of significant new-onset atrial fibrillation after coronary artery bypass surgery. Significant atrial fibrillation episodes were defined as those lasting more than 1 hour or the episodes associated with hemodynamic compromise. Secondary end points were the duration of atrial fibrillation, the presence of atrial fibrillation–induced tachycardia, and the presence of hemodynamic disturbances caused by atrial fibrillation. Tertiary end points included cumulative 30-day and total intrahospital time mortality and morbidity, as well as the length of hospital stay. The effects of oral amiodarone on these end points were assessed both in all patients and in prespecified strata.
Statistical analysis The sample size was estimated on the basis of the following assumptions: the rate of postoperative new-onset atrial fibrillation in the placebo group would be 30%, the risk would be reduced by 50% in the amiodarone group, and the power (β power) to detect the difference between the treatment groups would be at least 90%. Data were analyzed on the basis of the intention-to-treat principle. Continuous variables were expressed as means ± SD. Baseline characteristics were compared with the t test (continuous variables) or the chi-square test (categorical variables). Kaplan-Meier analysis with the log-rank test was used to determine and compare the proportion of patients free of postoperative atrial fibrillation in the amiodarone and placebo groups during the study period. Correlation of estimates with the 95% confidence interval was used to determine relative risk reduction for analyzed data. All P values were 2 tailed, and those <.05 were considered statistically significant.
Results Patient characteristics and surgical data During the trial period, 315 patients who underwent coronary artery bypass surgery were enrolled in the study. Among them, 159 were assigned to receive amiodarone and 156 to receive placebo. The mean duration of preoperative hospital stay did not differ between groups (3.7 ± 2.7 in the amiodarone group vs 4.2 ± 3.0 days in the placebo group, P = .16). Groups were similar in respect to all preoperative characteristics except the use of β-adrenergic blockers (Table I): patients assigned to the placebo group more often used these drugs before surgery (88/156, 56% vs 70/159, 44%, P = .032). Administration of β-adrenergic blockers was similar in both groups immediately after surgery (61/159, 38% in the amiodarone group vs 69/156, 44% in the placebo group, P = .3). The extent of coronary artery disease and surgical data did not differ between groups (Table II). Groups did not differ in baseline heart rate (71.4 ± 10.1 vs 69.9 ± 9.0 beats/min, P = .25) and systolic (161.2 ± 19.7 vs 164.8 ± 21.4 mm Hg, P = .12) and diastolic (88.9 ± 10.2 vs 90.2 ± 10.4 mm Hg, P = .26) blood pressure before drug administration. However, patients
Figure 1
Table I. Baseline patient characteristics Amiodarone (n = 159) Age (y) Male sex (%) LVEF NYHA functional class History of CHF (%) Previous MI (%) Hypertension (%) Diabetes mellitus (%) Tobacco use (%) Hypercholesterolemia (%) Preoperative drug usage (%) β-Blockers Digoxin Calcium channel blockers
58.3 ± 9.1 128 (80) 42.92 ± 14.2 1.97 ± 0.56 3 (2) 97 (61) 111 (70) 38 (24) 110 (70) 58 (36) 70 (44) 7 (4) 69 (43)
Placebo (n = 156) 57.3 ± 8.4 119 (76) 44.96 ± 13.8 2.02 ± 0.59 5 (3) 82 (53) 106 (68) 32 (21) 114 (73) 65 (41) 88 (56)* 4 (3) 60 (38)
LVEF, Left ventricular ejection fraction; NYHA, New York Heart Association; CHF, congestive heart failure; MI, myocardial infarction. *P = .032, between groups.
who received a loading dose of amiodarone had a slower heart rate (65.9 ± 9.3 vs 84.7 ± 10.4 beats/min, P < .0001) and lower systolic (150.5 ± 23.6 vs 159.5 ± 26.5 mm Hg, P = .01) and diastolic (81.9 ± 11.4 vs 86.2 ± 12.9, P = .02) blood pressure on the day of operation compared with patients who received placebo.
Postoperative atrial fibrillation New-onset atrial fibrillation was detected during the first 7 postoperative days in 31 of 159 (19%) patients in the amiodarone group compared with 33 of 156 (21%) patients in the placebo group (P = .78). The proportion of patients remaining free of postoperative atrial fibrillation in the amiodarone and placebo groups are shown in Figure 1. Atrial fibrillation occurred most frequently during the third postoperative day (15/64, 23%). Time to the first episode of postoperative atrial fibrillation was also similar between groups (3.4 ± 2.0 in the amiodarone vs 3.1 ± 1.4 days in the placebo group (P = .52). Serum potassium levels measured at the detection of atrial fibrillation were similar in both groups (3.77 ± 0.47 in the amiodarone vs 3.85 ± 0.49 mmol/L in the placebo group, P = .52). Also, the mean duration of atrial fibrillation in the amiodarone and placebo groups (28.39 ± 39.94 vs 21.09 ± 29.06 hours, P = .41), as well as the number of episodes of atrial fibrillation (1.86 ± 1.16 vs 2.01 ± 1.78, P = .69), were not different between the groups. Only 3 of 31 (10%) patients in the amiodarone group who had atrial fibrillation had tachycardia at the detection of atrial fibrillation compared with 12 of 33 patients (36%) in the placebo group (P = .017). The ventricular response rate at the detection (102.6 ± 10.3
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in all patients. There was no difference between treatment groups (P = .75 by log-rank test). CAB, Coronary artery bypass.
Table II. Preoperative coronary artery disease and surgical data
Coronary artery disease (%)* Left main LAD LCx RCA Operative data No. of grafts per patient Saphenous vein grafts (No./patient) Internal thoracic artery grafts (%) Aorta cross-clamp time (min) Bypass pump time (min)
Amiodarone (n = 159)
Placebo (n = 156)
18 (11) 152 (96) 78 (49) 114 (72)
12 (8) 149 (95) 86 (55) 114 (73)
2.30 ± 0.70 1.77 ± 0.90
2.41 ± 0.79 1.89 ± 0.95
81 (51) 42.15 ± 15.9 71.51 ± 21.5
76 (49) 42.68 ± 17.8 71.37 ± 24.7
LAD, Left anterior descending coronary artery; LCx, left circumflex coronary artery; RCA, right coronary artery. *Coronary artery disease was defined as ≥50% diameter stenosis of the major epicardial coronary artery.
vs 128.4 ± 16.2 beats/min, P < .001) and during atrial fibrillation (85.3 ± 8.53 vs 94.6 ± 14.4 beats/min, P = .006) was significantly lower in the amiodarone group than in the placebo group. The occurrence of hemodynamic compromise associated with atrial fibrillation was similar in patients who received amiodarone (15/31, 48%) and in those who received placebo (18/33, 54%) (P = .94). Atrial fibrillation developed in 19 of 98 (19%) patients in the amiodarone group who received β-adrenergic blockers postoperatively and in 12 of 61 (20%) patients
Table III. Strata analysis: clinical characteristics Younger stratum
Elderly stratum
Amiodarone (n = 84)
Placebo (n = 91)
Amiodarone (n = 75)
50.8 ± 5.7 69 (82.1) 44.8 ± 12.7 36 (42.9) 11 (13.1)
51.6 ± 5.7 77 (84.6) 47.6 ± 13.0 42 (46.2) 5 (5.5)
66.1 ± 3.9 59 (78.3) 43.3 ± 13.5 25 (33.3) 20 (26.7)
Age (y) Male sex (No. [%]) LVEF (%) β-Blockers (No. [%]) Postoperative atrial fibrillation (No. [%])
Placebo (n = 65) 65.4 ± 3.8 42 (64.6) 44.4 ± 14.1 27 (41.5) 28 (43.1)
LVEF, Left ventricular ejection fraction.
Table IV. Subgroup data analyses All patients (n = 315) Amiodarone Placebo (n = 159) (n = 156) All patients LVEF ≥40% <40% Previous MI Present Absent Hypertension Present Absent RCA stenosis Present Absent
Relative risk (95% CI)
Elderly strata (n = 140) Amiodarone Placebo (n = 75) (n = 65)
Relative risk (95% CI)
Younger strata (n = 175) Amiodarone Placebo (n = 84) (n = 91)
Relative risk (95% CI)
31/159
33/156
0.92 (0.60-1.43)
20/75
28/65 0.62 (0.39-0.99)†
11/84
5/91
2.38 (0.86-6.57)
17/105 14/54
24/112 9/44
0.76 (0.43-1.32) 1.27 (0.61-2.65)
12/48 8/27
20/45 0.56 (0.31-1.01) 8/20 0.74 (0.34-1.63)
5/57 6/27
4/67 1/24
1.47 (0.41-5.21) 5.33 (0.69-41.2)
17/97 14/62
14/82 19/74
1.03 (0.54-1.95) 0.88 (0.48-1.61)
11/47 9/28
12/36 0.70 (0.35-1.40) 16/29 0.58 (0.31-1.09)
6/50 5/34
2/46 3/45
2.76 (0.59-13.0) 2.21 (0.57-8.60)
23/111 8/48
26/106 7/50
0.84 (0.52-1.38) 1.19 (0.47-3.03)
16/59 4/16
23/51 0.60 (0.36-1.01) 5/14 0.70 (0.23-2.11)
7/52 4/32
3/55 2/36
2.47 (0.67-9.04) 2.25 (0.44-11.5)
25/116 6/43
29/113 4/43
0.84 (0.53-1.34) 1.50 (0.46-4.94)
16/59 4/16
25/52 0.56 (0.34-0.93)* 3/13 1.08 (0.29-4.00)
9/57 2/27
4/61 1/30
2.41 (0.78-7.39) 2.22 (0.21-23.2)
CI, Confidence interval; LVEF, left ventricular ejection fraction; MI, myocardial infarction; RCA, right coronary artery. *P = .03 between groups. †P = .05 between groups.
in the amiodarone group who were not using these drugs (P = .87). Patients assigned to placebo who received β-blockers postoperatively had a lower incidence of postoperative atrial fibrillation (8/69, 12%) than patients who did not receive these drugs and who were in the same study group (25/87, 29%) (P = .01).
Strata analysis Major clinical characteristics of the younger and older strata are presented in Table III. The development of atrial fibrillation was highly associated with age. Postoperative atrial fibrillation was detected more frequently in the elderly strata than in the younger strata: 48 of 140 patients (34%) versus 16 of 175 patients (9%) (P < .0001). In the elderly strata, atrial fibrillation occurred in 20 of 75 (27%) patients who received amiodarone and in 28 of 65 patients (43%) assigned to placebo group (P = .05). Relative risk for the occurrence of the atrial fibrillation in patients who received amiodarone
in this strata was 0.62 (95% confidence interval 0.390.99). The proportion of patients remaining free of postoperative atrial fibrillation and receiving amiodarone or placebo in the elderly strata is shown in Figure 2. The occurrence of atrial fibrillation in patients who received amiodarone (11/84 patients, 13.1%) or placebo (5/91 patients, 5.6%) in the younger strata was similar (P = .11) (Figure 3).
Subgroup analysis The effect of treatment on the development of postoperative atrial fibrillation was also analyzed in subgroups defined on the basis of pretreatment characteristics (left ventricular ejection fraction, previous myocardial infarction, history of hypertension, and significant stenosis of the right coronary artery). Analyses were performed for all patients, as well as for both predetermined strata (Table IV). Amiodarone was associ-
Figure 2
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in the elderly strata. Compared with the placebo group, a larger proportion of patients receiving amiodarone remained free of atrial fibrillation during the study period (P = .046 by log-rank test). CAB, Coronary artery bypass.
Figure 3
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in the younger strata. There was no difference between study groups (P = .073 by log-rank test). CAB, Coronary artery bypass.
Table V. Postoperative morbidity and mortality
ated with a reduced incidence of postoperative atrial fibrillation in elderly patients with significant right coronary artery disease (P = .03) compared with those without significant right coronary artery disease. The relative risk for development of atrial fibrillation in this subgroup of patients was 0.56 (95% confidence interval 0.34-0.93).
Intrahospital morbidity and mortality and the length of hospital stay Major causes of postoperative morbidity are shown in Table V. Postoperative thromboembolic episodes occurred in 6 of 159 (4%) patients treated with amiodarone and in 12 of 156 (8%) patients receiving placebo (P = .152). There was a trend toward a lower incidence of stroke in the amiodarone group (4/159 vs 11/156, P = .068). Atrial fibrillation was detected in 8 of 15 patients with stroke and in 56 of 300 patients without stroke (P = .038). In 3 of 8 patients with both atrial fibrillation and stroke, stroke occurred before the onset of atrial fibrillation, which makes a nonsignificant 1.7-fold increase in the risk of stroke in patients with preceding atrial fibrillation (P = .49). Death occurred in 9 of 159 (6%) patients receiving amiodarone and in 7 of 156 (5%) receiving placebo (P = .84). Interestingly, 6 of 7 (86%) patients from the placebo group who died had atrial fibrillation during the postoperative course. These patients had atrial fibrillation more frequently than did patients from the amiodarone group who died (1/9 patients, 11%) (P = .09). Amiodarone did not reduce the duration of the post-
Major morbidity (%) Postoperative MI Thomboembolism Stroke Respiratory failure Infection Mortality (No. [%]) Total Cardiac causes Noncardiac causes
Amiodarone (n = 159)
Placebo (n = 156)
10 (6) 6 (4) 4 (2) 19 (12) 7 (4)
4 (3) 12 (8) 11 (7)* 24 (15) 5 (3)
9 (6) 5 (3) 4 (2)
7 (4) 4 (3) 3 (2)
MI, Myocardial infarction. *P = .068 between groups.
operative hospital stay (10.3 ± 6.2 in the amiodarone vs 10.4 ± 5.0 days in the placebo group, P = .90). Also, the length of stay in the intensive care unit was similar for both groups (3.2 ± 5.1 in the amiodarone vs 2.2 ± 8.7 days in the placebo group, P = .21). Patients who had postoperative atrial fibrillation had a prolonged postoperative hospital stay compared with those who remained in sinus rhythm (13.1 ± 9.3 vs 9.7 ± 4.1 days, P < .0001).
Safety and adverse reactions The single-day loading dose of oral amiodarone (1200 mg) did not result in any side effect directly related to amiodarone therapy. None of the patients in either group had to discontinue amiodarone or placebo therapy because of side effects. The incidence of postoper-
ative respiratory failure was similar in both treatment groups (Table V). Significant bradycardia (defined as a heart rate ≤50 beats/min) was present in 10 of 159 (6%) patients receiving amiodarone and in 7 of 156 (4%) patients in the placebo group (P = .67). Also, the incidence of second- and third-degree atrioventricular block was similar in both groups (3/159 patients in the amiodarone group vs 2/156 patients in the placebo group, P = .97). Ventricular tachycardia occurred in 6 of 159 patients who received placebo and in 2 of 156 patients on amiodarone (P = .28). Episodes of “torsade de pointes” ventricular tachycardia were not detected.
Discussion Although numerous predictors of atrial fibrillation after coronary artery bypass surgery have been identified, including age as the strongest among them,4-7 its pathogenesis still remains uncertain. A possible mechanism is the presence of pre-existing arrhythmogenic substrate for atrial fibrillation, which could induce atrial fibrillation if properly triggered by different factors including postoperative autonomic imbalance, inadequate atrial protection during surgery, and local ischemia and inflammation caused by pericardial effusion.22-24 Without definitive knowledge of the pathogenesis, a specific pathophysiology-based approach for prophylaxis and treatment of postoperative atrial fibrillation cannot be applied. Therefore there is a persistent need for a prophylactic regimen that could reduce the incidence of postoperative atrial fibrillation, being at the same time safe, inexpensive, and applicable to all patients, especially to the high-risk ones.
Main findings To our knowledge, the current study is the largest double-blind, randomized, placebo-controlled study of prophylactic usage of oral amiodarone for postoperative atrial fibrillation. This study is the first to assess the prophylactic regimen with a single-day loading dose of oral amiodarone given 1 day before cardiac surgery. Furthermore, this trial analyzed the efficacy of this prophylactic regimen in a specific strata of patients with different risks for development of postoperative atrial fibrillation. Our study showed that oral amiodarone, when given at the lowest loading dose (1200 mg) and over the shortest loading period (1 day), does not reduce the overall incidence of postoperative atrial fibrillation. However, according to prespecified strata and subgroup analyses, it appears that this regimen reduces the incidence of atrial fibrillation in elderly patients, leading to a relative risk reduction of postoperative atrial fibrillation of 38%. In addition, the relative risk reduction in elderly patients with significant right coronary artery stenosis was 44%. Also, a single-day loading dose of oral
amiodarone reduces the ventricular response rate at the detection and during the episode of atrial fibrillation in the overall study population.
Low-dose oral amiodarone, atrial fibrillation, and maintenance of sinus rhythm It has been shown that low-dose oral amiodarone is highly effective both in cardioversion of paroxysmal atrial fibrillation and in the maintenance of sinus rhythm after successful cardioversion for chronic atrial fibrillation.25-27 Furthermore, a study by Andrivet et al28 revealed that a single-day loading dose of oral amiodarone (25.7 ± 0.9 mg/kg) compared with intravenous amiodarone is equally successful in cardioversion of recent-onset atrial tachyarrhythmias of different origin. According to these findings and the fact that the α- and β-receptor blocking effect of amiodarone becomes apparent quickly after the initiation of therapy,29 it seemed appropriate to use the single-day oral loading dose of amiodarone followed by the low maintenance dose for the prevention of postoperative atrial fibrillation.
Prophylaxis of postoperative atrial fibrillation Various drug regimens have been proposed for the prevention of atrial fibrillation after coronary artery bypass surgery.11-15 Two meta-analyses of previous studies found that β-blockers have the most persistent protective effect.30,31 Similarly, our patients assigned to the placebo group and receiving β-blockers postoperatively also had a lower incidence of atrial fibrillation compared with those patients in the placebo group who were not receiving these drugs. On the other hand, β-blockers did not show any effects in patients receiving amiodarone. However, despite their beneficial effect, the use of β-blockers is usually limited to those patients who do not have ventricular dysfunction, chronic obstructive lung disease, or diabetes.14,15
Amiodarone and postoperative atrial fibrillation Both intravenous and oral amiodarone have been introduced for the prevention of atrial fibrillation after coronary artery bypass surgery.17-21 The Amiodarone Reduces CABG Hospitalization (ARCH) trial, which used low-dose intravenous amiodarone (1 g/d for the first 2 postoperative days) showed a relative risk reduction of postoperative atrial fibrillation of 26% in patients receiving amiodarone, a finding that has also been noted in smaller studies using intravenous amiodarone.21 The side effects of intravenous amiodarone, such as hypotension or bradycardia, present in the 4.4% of patients in the ARCH study were even more pronounced in other studies using an intravenous regimen.17,20 In the study of Butler et al20 bradycardia developed in 78% of treated patients compared with 48% of patients receiving placebo. Data regarding the prophylactic use of oral amio-
darone for the prevention of postoperative atrial fibrillation are controversial. In the study of Daoud et al,18 oral amiodarone was given in a dose of 600 mg daily 7 days before surgery on an outpatient basis, followed by 200 mg daily after surgery until discharge. These authors showed that oral amiodarone reduces the incidence of postoperative atrial fibrillation by 50%. In contrast to this, Redle et al,19 using a similar total loading dose of oral amiodarone with a shorter loading period, did not show a beneficial effect. Although Daoud et al18 showed the most pronounced beneficial effect of preoperative administration of oral amiodarone, their study was not conducted in a uniform cohort of the patient population. More than one half of enrolled patients had valvular surgery. It is not clear whether those results would be similar in patients undergoing coronary artery bypass surgery only. Moreover, in this study outpatient premedication before surgery was associated with high compliance. Whether this high compliance could be achieved in everyday practice remains uncertain.
Safety, intrahospital complications, and length of hospital stay In our study, the single-day loading dose of oral amiodarone was well tolerated and did not induce any related side effect. Particularly, there was no evidence of amiodarone-related proarrhythmic effects or clinically relevant pulmonary or thyroid abnormalities. These findings are in concordance with previous studies of oral amiodarone.18,19,21 Amiodarone was well tolerated even in patients with impaired left ventricular function. This finding is supported by the reported safety of amiodarone in patients with left ventricular dysfunction and congestive heart failure.32,33 The incidence of intrahospital postoperative complications in our study was similar in the both study groups. Interestingly, there was a trend toward a lower incidence of stroke in patients treated with amiodarone (2.52% in the amiodarone vs 7.05% in the placebo group). Although our data and that of previous studies have demonstrated an association between stroke and postoperative atrial fibrillation,2,4,5 the reduction of the incidence of stroke as a result of lower incidence of atrial fibrillation has not been shown. Data regarding the duration of the postoperative hospital stay and the prophylactic use of amiodarone for postoperative atrial fibrillation are controversial.18-20 Some trials showed significant shortening of hospital stay in patients receiving amiodarone, but whether this is related only to a reduced incidence of postoperative atrial fibrillation remains unknown.18 However, our study showed that patients receiving amiodarone had a similar duration of postoperative hospital stay compared with the placebo group.
Limitations of the study Because continuous electrocardiographic monitoring was not available, except for the first day after surgery, it is possible that some minor episodes of atrial fibrillation were undetected and that the duration of individual atrial fibrillation episodes was underestimated. However, because our primary end point was the appearance of significant atrial fibrillation episodes, it is unlikely that by the applied protocol any of them was missed. Our study was restricted only to the first 7 days after coronary artery bypass surgery. Although amiodarone therapy was discontinued after this period, some distinctive trends between the study groups might have been more pronounced if the patients were followed up for a longer period of time. Finally, some concerns may be raised regarding the low dose of amiodarone used in this study. However, we believe that this dose was justified by the observed significant hemodynamic, electrophysiologic, and clinical effects.
Clinical implications The current study sought to investigate possible beneficial effects of a single-day loading dose of oral amiodarone in the predetermined strata and subgroups. A positive prophylactic impact of amiodarone found in the elderly patients and a low incidence of atrial fibrillation in the younger ones emphasize the need for preoperative risk stratification according to age. Whether this prophylactic regimen is effective in patients with multiple risk factors for the development of atrial fibrillation after coronary artery bypass surgery remains unknown and requires confirmation in further trials.
References 1. Ommen SR, Odel JA, Stenton MS. Atrial arrhythmias after cardiothoracic surgery. N Engl J Med 1997;336:1429-33. 2. Lauer MS, Eagle KA, Buckley MJ, et al. Atrial fibrillation following coronary artery bypass surgery. Prog Cardiovasc Dis 1989;31: 367-78. 3. Crosby LH, Pifalo WB, Woll KR, et al. Risk factors for atrial fibrillation after coronary artery bypass surgery. Am J Cardiol 1990;66: 1520-2. 4. Mathew JP, Parks R, Savino JS, et al. Atrial fibrillation following coronary artery bypass surgery: predictors, outcomes and resource utilization. JAMA 1996;276:300-6. 5. Aranki SF, Shaw DP, Adams DH, et al. Predictors of atrial fibrillation after coronary artery surgery: current trends and impact on hospital resources. Circulation 1996;94:390-7. 6. Frost L, Molgaard H, Christiansen EH, et al. Atrial fibrillation and flutter after coronary artery bypass surgery: epidemiology, risk factors and preventive trials. Int J Cardiol 1992;36:253-61. 7. Mendes LA, Connely GP, Mckenney PA, et al. Right coronary artery stenosis: an independent predictor of atrial fibrillation after coronary artery bypass surgery. J Am Coll Cardiol 1995;25:198-202. 8. Leitch JW, Thomson D, Baird DK, et al. The importance of age as a predictor of atrial fibrillation and flutter after coronary artery bypass grafting. J Thorac Cardiovasc Surg 1990;100:338-42.
9. Fuller JA, Adams GG, Buxton B. Atrial fibrillation after coronary artery bypass grafting: is it a disorder of the elderly? J Thorac Cardiovasc Surg 1989;97:821-5. 10. Jones EL, Weintraub WS, Craver JM, et al. Coronary artery bypass surgery: is the operation different today? J Thorac Cardiovasc Surg 1991;101:108-15. 11. Roffman JA, Fieldman A. Digoxin and propranolol in the prophylaxis of supraventricular tachyarrhythmias after coronary artery bypass surgery. Ann Thorac Surg 1981;31:496-501. 12. Davidson R, Hartz R, Kaplan K, et al. Prophylaxis of supraventricular tachyarrhythmias after coronary artery bypass surgery with oral verapamil: a randomized, double-blind trial. Ann Thorac Surg 1985;39:336-9. 13. Fanning WJ, Thomas CS, Roach A, et al. Prophylaxis of atrial fibrillation with magnesium sulfate after coronary artery bypass grafting. Ann Thorac Surg 1991;52:529-33. 14. Suttorp MJ, Kingma JH, Gin MTJ, et al. Efficacy and safety of lowand high-dose sotalol versus propranolol in the prevention of supraventricular tachyarrhythmias early after coronary artery bypass operation. J Thorac Cardiovasc Surg 1990;100:921-6. 15. Gomes AJ, Ip J, Santoni-Rugiu F, et al. Oral d,l sotalol reduces the incidence of postoperative atrial fibrillation in coronary artery bypass surgery patients: a randomized, double-blind placebocontrolled study. J Am Coll Cardiol 1999;34:334-9. 16. Gerstenfield EP, Hill MRS, French SN, et al. Evaluation of right atrial and biatrial temporary pacing for the prevention of atrial fibrillation after coronary artery bypass surgery. J Am Coll Cardiol 1999;33: 1981-8. 17. Hohnloser SH, Meinertz T, Dammbacher T, et al. Electrocardiographic and antiarrhythmic effects of intravenous amiodarone: results of a prospective, placebo-controlled study. Am Heart J 1991;121:89-95. 18. Daoud EG, Strickberger SA, Man KC, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997;337:1785-91. 19. Redle JD, Khurana S, Marzan R, et al. Prophylactic oral amiodarone compared with placebo for prevention of atrial fibrillation after coronary artery bypass surgery. Am Heart J 1999;138:14450.
20. Butler J, Harriss DR, Sinclair M, et al. Amiodarone prophylaxis for tachycardias after coronary artery surgery: a randomized double blind, placebo controlled trial. Br Heart J 1993;70:56-60. 21. Guarnieri T, Nolan S, Gottlieb SO, et al. 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;34:343-7. 22. Cox JL. A perspective of postoperative atrial fibrillation in cardiac operations. Ann Thorac Surg 1993;56:405-9. 23. Frost L, Molgaard H, Christiansen EH, et al. Atrial ectopic activity and atrial fibrillation/flutter after coronary artery bypass surgery. Int J Cardiol 1995;50:153-62. 24. Kalman JM, Munawar M, Howes LG, et al. Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation. Ann Thorac Surg 1995;60:1709-15. 25. Gosselink ATM, Crijns HJGM, Van Gelder IC, et al. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation and flutter. JAMA 1992;267:3289-93. 26. Middlekauff HR, Wiener I, Stevenson WG. Low-dose amiodarone for atrial fibrillation. Am J Cardiol 1993;72:75-81F. 27. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913-20. 28. Andrivet P, Boubakri E, Dove PJ, et al. A clinical study of amiodarone as a single oral dose in patients with recent-onset atrial tachyarrhythmia. Eur Heart J 1994;15:1396-402. 29. Mason JW. Amiodarone. N Engl J Med 1978;316:455-66. 30. Andrews TC, Reimold SC, Berlin JA, et al. Prevention of supraventricular arrhythmias after coronary artery bypass surgery: a metaanalysis of randomized controlled trials. Circulation 1991;84(3 Suppl):III-236-44. 31. Kowey PR, Taylor JE, Rials SJ, et al. Meta-analysis of the effectiveness of prophylactic drug therapy in preventing supraventricular arrhythmia early after coronary artery bypass grafting. Am J Cardiol 1992;69:963-5. 32. Doval HC, Hul DR, Grancelli HO, et al. Randomized trial of lowdose amiodarone in severe heart failure. Lancet 1994;344:493-8. 33. Hamer AWF, Arkles LB, Johns JA. Beneficial effects of low dose amiodarone in patients with congestive heart failure: a placebocontrolled trial. J Am Coll Cardiol 1989;14:1768-74.
Background Various regimens have been proposed for the prevention of postoperative atrial fibrillation, including the use of intravenous and oral amiodarone. The purpose of this study was to determine the effectiveness of a single-day loading dose of oral amiodarone in prophylaxis of atrial fibrillation during the 7 days after coronary artery bypass surgery. Methods We conducted a double-blind, randomized, placebo-controlled study encompassing 315 consecutive patients who underwent coronary artery bypass surgery. They received either amiodarone (159 patients) or placebo (156 patients). Therapy consisted of a single oral loading dose of 1200 mg of amiodarone 1 day before surgery, followed by the maintenance dose of 200 mg daily during the next 7 days. Only episodes of atrial fibrillation lasting more than 1 hour or associated with hemodynamic compromise were taken into consideration.
Results Overall, the incidence of atrial fibrillation was similar in patients who received amiodarone (31/159, 19.5%) and placebo (33/156, 21.2%) (P = .78). However, amiodarone reduced the incidence of atrial fibrillation in elderly patients (age ≥60 years): it occurred in 20 of 75 (26.7%) patients on amiodarone and in 28 of 65 (43.1%) patients in the placebo group (P = .05). There were no differences between the study groups regarding the postoperative intrahospital morbidity and mortality and the duration of hospital stay. Conclusions A single-day loading dose of oral amiodarone (1200 mg) does not prevent postoperative atrial fibrillation in a general population of patients undergoing coronary artery bypass surgery. However, it appears that this regimen reduces the occurrence of postoperative atrial fibrillation in elderly patients. (Am Heart J 2001;141:e8.)
New-onset atrial fibrillation occurs in 20% to 40% of patients undergoing coronary artery bypass surgery.1,2 Among different preoperative and intraoperative factors,3-7 age has been identified as the strongest and most persistent predictor of postoperative atrial fibrillation.4,5,8,9 This observation is important because of the increasing age of the coronary artery bypass surgery patient population.10 Although not associated with an increased long-term mortality and morbidity,2,4 new-onset postoperative atrial fibrillation may be associated with thromboemFrom the aDepartment of Cardiology, the b”Dr Aleksandar D. Popovic´ “Cardiovascular Research Center, the cDepartment of Cardiac Surgery, Dedinje Cardiovascular Institute, and the dInstitute of Physiology, Belgrade University School of Medicine, Belgrade, Yugoslavia. Presented in part at the XXIst Congress of the European Society of Cardiology, Barcelona, Spain, August 1999. Submitted June 27, 2000; accepted January 12, 2001. Reprint requests: Aleksandar N. Nes˘kovic´, MD, “Dr Aleksandar D. Popovic´” Cardiovascular Research Center, Dedinje Cardiovascular Institute, Milana Tepic´a 1, 11040 Belgrade, Yugoslavia. E-mail: [email protected] Copyright © 2001 by Mosby, Inc. 1097-6744/2001/$35.00 + 0 4/90/114201 doi:10.1067/mhj.2001.114201
bolic events and hemodynamic compromise that may result in prolonged hospital stay and increased cost.4,5 Various regimens have been proposed for prophylaxis of postoperative atrial fibrillation, including use of different drugs (ie, β-adrenergic blockers, quinidine, calcium channel antagonists, magnesium, etc) and pacing protocols.11-16 Amiodarone, a class III antiarrhythmic agent, has been recently advocated as possible effective therapy for prophylaxis of postoperative atrial fibrillation.17,18 Both intravenous and oral administration of amiodarone have been shown to reduce the incidence of postoperative atrial fibrillation.17-21 Oral amiodarone given preoperatively during 7 days significantly reduces the occurrence of postoperative atrial fibrillation and shortens the duration of the hospital stay.18 On the other hand, smaller studies using different regimens showed no beneficial effect of oral amiodarone on postoperative atrial fibrillation.19 The shortest preoperative loading period and the smallest dose of amiodarone that is effective in suppressing postoperative atrial fibrillation have not been determined yet. This study sought to assess the efficacy of preoperative singleday loading dose of oral amiodarone in pre-
vention of new onset atrial fibrillation during the 7 days after coronary artery bypass surgery.
Methods Patient population From June 1998 to February 1999, all patients admitted to Dedinje Cardiovascular Institute for coronary artery bypass surgery were screened for participation in this study. Inclusion criteria were age >18 years, elective coronary artery bypass surgery, and no history of atrial fibrillation. Patients were excluded if they have used amiodarone or other antiarrhythmic drugs (except β-adrenergic blockers, calcium channel antagonists, or digitalis) within the last 4 months, were allergic to amiodarone, had uncontrolled thyroid dysfunction, had serum aspartate aminotransferase or alanine aminotransferase levels four times higher than upper normal limit, had a resting heart rate on admission of ≤50 beats/min, had valvular heart disease requiring surgery, or had congestive heart failure. Written informed consent was obtained from all patients.
Study design After the initial evaluation, patients were randomly assigned to receive either oral amiodarone or matching placebo in addition to their usual medications. Because it was anticipated before the start of the study that the development of postoperative atrial fibrillation is strongly influenced by patient age,8,9 the randomization was stratified according to whether the patients were younger or older than 60 years. After the randomization, patients received either an initial single loading dose of 1200 mg of amiodarone or placebo 1 day before cardiac surgery. Amiodarone or placebo was continued for the next 7 days, including the operation day, with the maintenance dose of 200 mg daily. If a patient had atrial fibrillation during the follow-up, treatment was directed to heart rate control (digitalis, calcium channel antagonists, and, if necessary, β-adrenergic blockers) and anticoagulation. Administration of other antiarrhythmic drugs or electric cardioversion was restricted only to the patients with severe hemodynamic compromise and congestive heart failure. Immediately after surgery, all patients were monitored for at least 24 hours in the intensive care unit. After that, an electrocardiogram was routinely obtained twice daily at 10 and 17 hours, and heart rate was measured by radial artery palpation 6 times daily: at 6 AM, 10 AM, 2 PM, 6 PM, 10 PM, and midnight. If an irregular pulse was noticed during the heart rate measurement or the patient had tachycardia (defined as heart rate ≥100 beats/min), an electrocardiogram was recorded. An electrocardiogram was also recorded if the patient was hypotensive or had angina, dyspnea, or sweating. Serial electrolyte profiles were performed daily, including serum potassium levels at the detection of atrial fibrillation. All patients were screened for possible amiodarone side effects on a daily basis. Serial electrocardiograms and clinical observations were also used to detect arrhythmias other than atrial fibrillation. The study was conducted during the first 7 postoperative days. If the patient needed to stay in the hospital after the termination of the study, amiodarone was discontinued if the patient did not have other indications for its administration.
End points The primary end point of the study was the occurrence of significant new-onset atrial fibrillation after coronary artery bypass surgery. Significant atrial fibrillation episodes were defined as those lasting more than 1 hour or the episodes associated with hemodynamic compromise. Secondary end points were the duration of atrial fibrillation, the presence of atrial fibrillation–induced tachycardia, and the presence of hemodynamic disturbances caused by atrial fibrillation. Tertiary end points included cumulative 30-day and total intrahospital time mortality and morbidity, as well as the length of hospital stay. The effects of oral amiodarone on these end points were assessed both in all patients and in prespecified strata.
Statistical analysis The sample size was estimated on the basis of the following assumptions: the rate of postoperative new-onset atrial fibrillation in the placebo group would be 30%, the risk would be reduced by 50% in the amiodarone group, and the power (β power) to detect the difference between the treatment groups would be at least 90%. Data were analyzed on the basis of the intention-to-treat principle. Continuous variables were expressed as means ± SD. Baseline characteristics were compared with the t test (continuous variables) or the chi-square test (categorical variables). Kaplan-Meier analysis with the log-rank test was used to determine and compare the proportion of patients free of postoperative atrial fibrillation in the amiodarone and placebo groups during the study period. Correlation of estimates with the 95% confidence interval was used to determine relative risk reduction for analyzed data. All P values were 2 tailed, and those <.05 were considered statistically significant.
Results Patient characteristics and surgical data During the trial period, 315 patients who underwent coronary artery bypass surgery were enrolled in the study. Among them, 159 were assigned to receive amiodarone and 156 to receive placebo. The mean duration of preoperative hospital stay did not differ between groups (3.7 ± 2.7 in the amiodarone group vs 4.2 ± 3.0 days in the placebo group, P = .16). Groups were similar in respect to all preoperative characteristics except the use of β-adrenergic blockers (Table I): patients assigned to the placebo group more often used these drugs before surgery (88/156, 56% vs 70/159, 44%, P = .032). Administration of β-adrenergic blockers was similar in both groups immediately after surgery (61/159, 38% in the amiodarone group vs 69/156, 44% in the placebo group, P = .3). The extent of coronary artery disease and surgical data did not differ between groups (Table II). Groups did not differ in baseline heart rate (71.4 ± 10.1 vs 69.9 ± 9.0 beats/min, P = .25) and systolic (161.2 ± 19.7 vs 164.8 ± 21.4 mm Hg, P = .12) and diastolic (88.9 ± 10.2 vs 90.2 ± 10.4 mm Hg, P = .26) blood pressure before drug administration. However, patients
Figure 1
Table I. Baseline patient characteristics Amiodarone (n = 159) Age (y) Male sex (%) LVEF NYHA functional class History of CHF (%) Previous MI (%) Hypertension (%) Diabetes mellitus (%) Tobacco use (%) Hypercholesterolemia (%) Preoperative drug usage (%) β-Blockers Digoxin Calcium channel blockers
58.3 ± 9.1 128 (80) 42.92 ± 14.2 1.97 ± 0.56 3 (2) 97 (61) 111 (70) 38 (24) 110 (70) 58 (36) 70 (44) 7 (4) 69 (43)
Placebo (n = 156) 57.3 ± 8.4 119 (76) 44.96 ± 13.8 2.02 ± 0.59 5 (3) 82 (53) 106 (68) 32 (21) 114 (73) 65 (41) 88 (56)* 4 (3) 60 (38)
LVEF, Left ventricular ejection fraction; NYHA, New York Heart Association; CHF, congestive heart failure; MI, myocardial infarction. *P = .032, between groups.
who received a loading dose of amiodarone had a slower heart rate (65.9 ± 9.3 vs 84.7 ± 10.4 beats/min, P < .0001) and lower systolic (150.5 ± 23.6 vs 159.5 ± 26.5 mm Hg, P = .01) and diastolic (81.9 ± 11.4 vs 86.2 ± 12.9, P = .02) blood pressure on the day of operation compared with patients who received placebo.
Postoperative atrial fibrillation New-onset atrial fibrillation was detected during the first 7 postoperative days in 31 of 159 (19%) patients in the amiodarone group compared with 33 of 156 (21%) patients in the placebo group (P = .78). The proportion of patients remaining free of postoperative atrial fibrillation in the amiodarone and placebo groups are shown in Figure 1. Atrial fibrillation occurred most frequently during the third postoperative day (15/64, 23%). Time to the first episode of postoperative atrial fibrillation was also similar between groups (3.4 ± 2.0 in the amiodarone vs 3.1 ± 1.4 days in the placebo group (P = .52). Serum potassium levels measured at the detection of atrial fibrillation were similar in both groups (3.77 ± 0.47 in the amiodarone vs 3.85 ± 0.49 mmol/L in the placebo group, P = .52). Also, the mean duration of atrial fibrillation in the amiodarone and placebo groups (28.39 ± 39.94 vs 21.09 ± 29.06 hours, P = .41), as well as the number of episodes of atrial fibrillation (1.86 ± 1.16 vs 2.01 ± 1.78, P = .69), were not different between the groups. Only 3 of 31 (10%) patients in the amiodarone group who had atrial fibrillation had tachycardia at the detection of atrial fibrillation compared with 12 of 33 patients (36%) in the placebo group (P = .017). The ventricular response rate at the detection (102.6 ± 10.3
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in all patients. There was no difference between treatment groups (P = .75 by log-rank test). CAB, Coronary artery bypass.
Table II. Preoperative coronary artery disease and surgical data
Coronary artery disease (%)* Left main LAD LCx RCA Operative data No. of grafts per patient Saphenous vein grafts (No./patient) Internal thoracic artery grafts (%) Aorta cross-clamp time (min) Bypass pump time (min)
Amiodarone (n = 159)
Placebo (n = 156)
18 (11) 152 (96) 78 (49) 114 (72)
12 (8) 149 (95) 86 (55) 114 (73)
2.30 ± 0.70 1.77 ± 0.90
2.41 ± 0.79 1.89 ± 0.95
81 (51) 42.15 ± 15.9 71.51 ± 21.5
76 (49) 42.68 ± 17.8 71.37 ± 24.7
LAD, Left anterior descending coronary artery; LCx, left circumflex coronary artery; RCA, right coronary artery. *Coronary artery disease was defined as ≥50% diameter stenosis of the major epicardial coronary artery.
vs 128.4 ± 16.2 beats/min, P < .001) and during atrial fibrillation (85.3 ± 8.53 vs 94.6 ± 14.4 beats/min, P = .006) was significantly lower in the amiodarone group than in the placebo group. The occurrence of hemodynamic compromise associated with atrial fibrillation was similar in patients who received amiodarone (15/31, 48%) and in those who received placebo (18/33, 54%) (P = .94). Atrial fibrillation developed in 19 of 98 (19%) patients in the amiodarone group who received β-adrenergic blockers postoperatively and in 12 of 61 (20%) patients
Table III. Strata analysis: clinical characteristics Younger stratum
Elderly stratum
Amiodarone (n = 84)
Placebo (n = 91)
Amiodarone (n = 75)
50.8 ± 5.7 69 (82.1) 44.8 ± 12.7 36 (42.9) 11 (13.1)
51.6 ± 5.7 77 (84.6) 47.6 ± 13.0 42 (46.2) 5 (5.5)
66.1 ± 3.9 59 (78.3) 43.3 ± 13.5 25 (33.3) 20 (26.7)
Age (y) Male sex (No. [%]) LVEF (%) β-Blockers (No. [%]) Postoperative atrial fibrillation (No. [%])
Placebo (n = 65) 65.4 ± 3.8 42 (64.6) 44.4 ± 14.1 27 (41.5) 28 (43.1)
LVEF, Left ventricular ejection fraction.
Table IV. Subgroup data analyses All patients (n = 315) Amiodarone Placebo (n = 159) (n = 156) All patients LVEF ≥40% <40% Previous MI Present Absent Hypertension Present Absent RCA stenosis Present Absent
Relative risk (95% CI)
Elderly strata (n = 140) Amiodarone Placebo (n = 75) (n = 65)
Relative risk (95% CI)
Younger strata (n = 175) Amiodarone Placebo (n = 84) (n = 91)
Relative risk (95% CI)
31/159
33/156
0.92 (0.60-1.43)
20/75
28/65 0.62 (0.39-0.99)†
11/84
5/91
2.38 (0.86-6.57)
17/105 14/54
24/112 9/44
0.76 (0.43-1.32) 1.27 (0.61-2.65)
12/48 8/27
20/45 0.56 (0.31-1.01) 8/20 0.74 (0.34-1.63)
5/57 6/27
4/67 1/24
1.47 (0.41-5.21) 5.33 (0.69-41.2)
17/97 14/62
14/82 19/74
1.03 (0.54-1.95) 0.88 (0.48-1.61)
11/47 9/28
12/36 0.70 (0.35-1.40) 16/29 0.58 (0.31-1.09)
6/50 5/34
2/46 3/45
2.76 (0.59-13.0) 2.21 (0.57-8.60)
23/111 8/48
26/106 7/50
0.84 (0.52-1.38) 1.19 (0.47-3.03)
16/59 4/16
23/51 0.60 (0.36-1.01) 5/14 0.70 (0.23-2.11)
7/52 4/32
3/55 2/36
2.47 (0.67-9.04) 2.25 (0.44-11.5)
25/116 6/43
29/113 4/43
0.84 (0.53-1.34) 1.50 (0.46-4.94)
16/59 4/16
25/52 0.56 (0.34-0.93)* 3/13 1.08 (0.29-4.00)
9/57 2/27
4/61 1/30
2.41 (0.78-7.39) 2.22 (0.21-23.2)
CI, Confidence interval; LVEF, left ventricular ejection fraction; MI, myocardial infarction; RCA, right coronary artery. *P = .03 between groups. †P = .05 between groups.
in the amiodarone group who were not using these drugs (P = .87). Patients assigned to placebo who received β-blockers postoperatively had a lower incidence of postoperative atrial fibrillation (8/69, 12%) than patients who did not receive these drugs and who were in the same study group (25/87, 29%) (P = .01).
Strata analysis Major clinical characteristics of the younger and older strata are presented in Table III. The development of atrial fibrillation was highly associated with age. Postoperative atrial fibrillation was detected more frequently in the elderly strata than in the younger strata: 48 of 140 patients (34%) versus 16 of 175 patients (9%) (P < .0001). In the elderly strata, atrial fibrillation occurred in 20 of 75 (27%) patients who received amiodarone and in 28 of 65 patients (43%) assigned to placebo group (P = .05). Relative risk for the occurrence of the atrial fibrillation in patients who received amiodarone
in this strata was 0.62 (95% confidence interval 0.390.99). The proportion of patients remaining free of postoperative atrial fibrillation and receiving amiodarone or placebo in the elderly strata is shown in Figure 2. The occurrence of atrial fibrillation in patients who received amiodarone (11/84 patients, 13.1%) or placebo (5/91 patients, 5.6%) in the younger strata was similar (P = .11) (Figure 3).
Subgroup analysis The effect of treatment on the development of postoperative atrial fibrillation was also analyzed in subgroups defined on the basis of pretreatment characteristics (left ventricular ejection fraction, previous myocardial infarction, history of hypertension, and significant stenosis of the right coronary artery). Analyses were performed for all patients, as well as for both predetermined strata (Table IV). Amiodarone was associ-
Figure 2
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in the elderly strata. Compared with the placebo group, a larger proportion of patients receiving amiodarone remained free of atrial fibrillation during the study period (P = .046 by log-rank test). CAB, Coronary artery bypass.
Figure 3
Kaplan-Meier plot of the time to the first episode of postoperative atrial fibrillation in the younger strata. There was no difference between study groups (P = .073 by log-rank test). CAB, Coronary artery bypass.
Table V. Postoperative morbidity and mortality
ated with a reduced incidence of postoperative atrial fibrillation in elderly patients with significant right coronary artery disease (P = .03) compared with those without significant right coronary artery disease. The relative risk for development of atrial fibrillation in this subgroup of patients was 0.56 (95% confidence interval 0.34-0.93).
Intrahospital morbidity and mortality and the length of hospital stay Major causes of postoperative morbidity are shown in Table V. Postoperative thromboembolic episodes occurred in 6 of 159 (4%) patients treated with amiodarone and in 12 of 156 (8%) patients receiving placebo (P = .152). There was a trend toward a lower incidence of stroke in the amiodarone group (4/159 vs 11/156, P = .068). Atrial fibrillation was detected in 8 of 15 patients with stroke and in 56 of 300 patients without stroke (P = .038). In 3 of 8 patients with both atrial fibrillation and stroke, stroke occurred before the onset of atrial fibrillation, which makes a nonsignificant 1.7-fold increase in the risk of stroke in patients with preceding atrial fibrillation (P = .49). Death occurred in 9 of 159 (6%) patients receiving amiodarone and in 7 of 156 (5%) receiving placebo (P = .84). Interestingly, 6 of 7 (86%) patients from the placebo group who died had atrial fibrillation during the postoperative course. These patients had atrial fibrillation more frequently than did patients from the amiodarone group who died (1/9 patients, 11%) (P = .09). Amiodarone did not reduce the duration of the post-
Major morbidity (%) Postoperative MI Thomboembolism Stroke Respiratory failure Infection Mortality (No. [%]) Total Cardiac causes Noncardiac causes
Amiodarone (n = 159)
Placebo (n = 156)
10 (6) 6 (4) 4 (2) 19 (12) 7 (4)
4 (3) 12 (8) 11 (7)* 24 (15) 5 (3)
9 (6) 5 (3) 4 (2)
7 (4) 4 (3) 3 (2)
MI, Myocardial infarction. *P = .068 between groups.
operative hospital stay (10.3 ± 6.2 in the amiodarone vs 10.4 ± 5.0 days in the placebo group, P = .90). Also, the length of stay in the intensive care unit was similar for both groups (3.2 ± 5.1 in the amiodarone vs 2.2 ± 8.7 days in the placebo group, P = .21). Patients who had postoperative atrial fibrillation had a prolonged postoperative hospital stay compared with those who remained in sinus rhythm (13.1 ± 9.3 vs 9.7 ± 4.1 days, P < .0001).
Safety and adverse reactions The single-day loading dose of oral amiodarone (1200 mg) did not result in any side effect directly related to amiodarone therapy. None of the patients in either group had to discontinue amiodarone or placebo therapy because of side effects. The incidence of postoper-
ative respiratory failure was similar in both treatment groups (Table V). Significant bradycardia (defined as a heart rate ≤50 beats/min) was present in 10 of 159 (6%) patients receiving amiodarone and in 7 of 156 (4%) patients in the placebo group (P = .67). Also, the incidence of second- and third-degree atrioventricular block was similar in both groups (3/159 patients in the amiodarone group vs 2/156 patients in the placebo group, P = .97). Ventricular tachycardia occurred in 6 of 159 patients who received placebo and in 2 of 156 patients on amiodarone (P = .28). Episodes of “torsade de pointes” ventricular tachycardia were not detected.
Discussion Although numerous predictors of atrial fibrillation after coronary artery bypass surgery have been identified, including age as the strongest among them,4-7 its pathogenesis still remains uncertain. A possible mechanism is the presence of pre-existing arrhythmogenic substrate for atrial fibrillation, which could induce atrial fibrillation if properly triggered by different factors including postoperative autonomic imbalance, inadequate atrial protection during surgery, and local ischemia and inflammation caused by pericardial effusion.22-24 Without definitive knowledge of the pathogenesis, a specific pathophysiology-based approach for prophylaxis and treatment of postoperative atrial fibrillation cannot be applied. Therefore there is a persistent need for a prophylactic regimen that could reduce the incidence of postoperative atrial fibrillation, being at the same time safe, inexpensive, and applicable to all patients, especially to the high-risk ones.
Main findings To our knowledge, the current study is the largest double-blind, randomized, placebo-controlled study of prophylactic usage of oral amiodarone for postoperative atrial fibrillation. This study is the first to assess the prophylactic regimen with a single-day loading dose of oral amiodarone given 1 day before cardiac surgery. Furthermore, this trial analyzed the efficacy of this prophylactic regimen in a specific strata of patients with different risks for development of postoperative atrial fibrillation. Our study showed that oral amiodarone, when given at the lowest loading dose (1200 mg) and over the shortest loading period (1 day), does not reduce the overall incidence of postoperative atrial fibrillation. However, according to prespecified strata and subgroup analyses, it appears that this regimen reduces the incidence of atrial fibrillation in elderly patients, leading to a relative risk reduction of postoperative atrial fibrillation of 38%. In addition, the relative risk reduction in elderly patients with significant right coronary artery stenosis was 44%. Also, a single-day loading dose of oral
amiodarone reduces the ventricular response rate at the detection and during the episode of atrial fibrillation in the overall study population.
Low-dose oral amiodarone, atrial fibrillation, and maintenance of sinus rhythm It has been shown that low-dose oral amiodarone is highly effective both in cardioversion of paroxysmal atrial fibrillation and in the maintenance of sinus rhythm after successful cardioversion for chronic atrial fibrillation.25-27 Furthermore, a study by Andrivet et al28 revealed that a single-day loading dose of oral amiodarone (25.7 ± 0.9 mg/kg) compared with intravenous amiodarone is equally successful in cardioversion of recent-onset atrial tachyarrhythmias of different origin. According to these findings and the fact that the α- and β-receptor blocking effect of amiodarone becomes apparent quickly after the initiation of therapy,29 it seemed appropriate to use the single-day oral loading dose of amiodarone followed by the low maintenance dose for the prevention of postoperative atrial fibrillation.
Prophylaxis of postoperative atrial fibrillation Various drug regimens have been proposed for the prevention of atrial fibrillation after coronary artery bypass surgery.11-15 Two meta-analyses of previous studies found that β-blockers have the most persistent protective effect.30,31 Similarly, our patients assigned to the placebo group and receiving β-blockers postoperatively also had a lower incidence of atrial fibrillation compared with those patients in the placebo group who were not receiving these drugs. On the other hand, β-blockers did not show any effects in patients receiving amiodarone. However, despite their beneficial effect, the use of β-blockers is usually limited to those patients who do not have ventricular dysfunction, chronic obstructive lung disease, or diabetes.14,15
Amiodarone and postoperative atrial fibrillation Both intravenous and oral amiodarone have been introduced for the prevention of atrial fibrillation after coronary artery bypass surgery.17-21 The Amiodarone Reduces CABG Hospitalization (ARCH) trial, which used low-dose intravenous amiodarone (1 g/d for the first 2 postoperative days) showed a relative risk reduction of postoperative atrial fibrillation of 26% in patients receiving amiodarone, a finding that has also been noted in smaller studies using intravenous amiodarone.21 The side effects of intravenous amiodarone, such as hypotension or bradycardia, present in the 4.4% of patients in the ARCH study were even more pronounced in other studies using an intravenous regimen.17,20 In the study of Butler et al20 bradycardia developed in 78% of treated patients compared with 48% of patients receiving placebo. Data regarding the prophylactic use of oral amio-
darone for the prevention of postoperative atrial fibrillation are controversial. In the study of Daoud et al,18 oral amiodarone was given in a dose of 600 mg daily 7 days before surgery on an outpatient basis, followed by 200 mg daily after surgery until discharge. These authors showed that oral amiodarone reduces the incidence of postoperative atrial fibrillation by 50%. In contrast to this, Redle et al,19 using a similar total loading dose of oral amiodarone with a shorter loading period, did not show a beneficial effect. Although Daoud et al18 showed the most pronounced beneficial effect of preoperative administration of oral amiodarone, their study was not conducted in a uniform cohort of the patient population. More than one half of enrolled patients had valvular surgery. It is not clear whether those results would be similar in patients undergoing coronary artery bypass surgery only. Moreover, in this study outpatient premedication before surgery was associated with high compliance. Whether this high compliance could be achieved in everyday practice remains uncertain.
Safety, intrahospital complications, and length of hospital stay In our study, the single-day loading dose of oral amiodarone was well tolerated and did not induce any related side effect. Particularly, there was no evidence of amiodarone-related proarrhythmic effects or clinically relevant pulmonary or thyroid abnormalities. These findings are in concordance with previous studies of oral amiodarone.18,19,21 Amiodarone was well tolerated even in patients with impaired left ventricular function. This finding is supported by the reported safety of amiodarone in patients with left ventricular dysfunction and congestive heart failure.32,33 The incidence of intrahospital postoperative complications in our study was similar in the both study groups. Interestingly, there was a trend toward a lower incidence of stroke in patients treated with amiodarone (2.52% in the amiodarone vs 7.05% in the placebo group). Although our data and that of previous studies have demonstrated an association between stroke and postoperative atrial fibrillation,2,4,5 the reduction of the incidence of stroke as a result of lower incidence of atrial fibrillation has not been shown. Data regarding the duration of the postoperative hospital stay and the prophylactic use of amiodarone for postoperative atrial fibrillation are controversial.18-20 Some trials showed significant shortening of hospital stay in patients receiving amiodarone, but whether this is related only to a reduced incidence of postoperative atrial fibrillation remains unknown.18 However, our study showed that patients receiving amiodarone had a similar duration of postoperative hospital stay compared with the placebo group.
Limitations of the study Because continuous electrocardiographic monitoring was not available, except for the first day after surgery, it is possible that some minor episodes of atrial fibrillation were undetected and that the duration of individual atrial fibrillation episodes was underestimated. However, because our primary end point was the appearance of significant atrial fibrillation episodes, it is unlikely that by the applied protocol any of them was missed. Our study was restricted only to the first 7 days after coronary artery bypass surgery. Although amiodarone therapy was discontinued after this period, some distinctive trends between the study groups might have been more pronounced if the patients were followed up for a longer period of time. Finally, some concerns may be raised regarding the low dose of amiodarone used in this study. However, we believe that this dose was justified by the observed significant hemodynamic, electrophysiologic, and clinical effects.
Clinical implications The current study sought to investigate possible beneficial effects of a single-day loading dose of oral amiodarone in the predetermined strata and subgroups. A positive prophylactic impact of amiodarone found in the elderly patients and a low incidence of atrial fibrillation in the younger ones emphasize the need for preoperative risk stratification according to age. Whether this prophylactic regimen is effective in patients with multiple risk factors for the development of atrial fibrillation after coronary artery bypass surgery remains unknown and requires confirmation in further trials.
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