Amiodarone

Purpose: We studied the use of perioperative IV and oral administration of amiodarone for the prevention of postoperative atrial fibrillation in patients undergoing coronary artery bypass graft surgery (CABG).

Background: In the United States, > 500,000 patients undergo CABG each year. Numerous studies to date have suggested that postoperative atrial fibrillation occurs in 30 to 50% of patients, leading to significant morbidity, including hypotension, heart failure, thromhoemholic complications, prolonged hospital stay, and increased hospital costs. The ohjective of this study was to assess the use of IV amiodarone in combination with oral amiodarone to reduce the incidence of postoperative atrial fibrillation.

Method: From January 1999 to October 1999, 51 patients scheduled for CABG were randomly selected for participation in the amiodarone administration trial. IV amiodarone, 0.73 mg/min, was administered on call to the operating room for 48 h, followed by oral amiodarone, 400 mg q12h, for the next 3 days. The amiodarone group was case-control matched to the incidence of postoperative atrial fibrillation in 92 patients undergoing CABG using conventional medical therapy during the same period. The primary end point of this study was the incidence of postoperative atrial fibrillation, length of hospital stay, and hospital costs, compared to the control group undergoing CABG during the same time.

Results: Atrial fibrillation occurred in 3 of 51 patients (5.88%) in the amiodarone group, compared to 24 of 92 patients (26.08%) in the control group. Length of hospital stay in the amiodarone group was less than in the control group (5.3 days vs 6.7 days), with a trend toward decrease in hospital costs.

Conclusion: The administration of IV amiodarone in conjunction with oral amiodarone for a total dose of 4,500 mg over 5 days appears to be a hemodynamically well-tolerated, safe, and effective treatment in decreasing the incidence of postoperative atrial fibrillation, shortening length of slay, and a trend toward lowering hospital costs, even in patients with significantly reduced left ventricular function (< 30%). A large multicenter study using IV and oral amiodarone should be pursued prior to deciding whether its use should become standard therapy in all patients undergoing CABG in order to decrease the incidence of postoperative atrial fibrillation.

Key words: amiodarone prophyhtxis; atrial fibrillation; cardiopulmonary bypass; coronary artery bypass grafting; ejection fraction

Abbreviations: ARCH = Amiodarone Reduction in Coronary Heart; CABG = coronary artery bypass graft surgery; CPR = cardiopulmonary bypass; EF = ejection fraction; LV left ventricular

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In 1999 approximately 553,000 coronary artery bypass graft surgery (CABG) procedures were conducted in the United States. (1) Numerous studis (2-6) have suggested that postoperative atrial fibrillation is the most common arrhythmia, occurring in 30 to 50% of patients, and is a significant cause of increased morbidity and increased length of stay, and significantly increases hospital costs. In the multi-center study of perioperative ischemia, Matthew et ala studied > 2,400 patients undergoing CABG who acquired postoperative atrial fibrillation, and found that patients remained an average of 13 h longer in the ICU and 2 days longer in the ward, compared with patients without atrial fibrillation.

A number of strategies have been attempted in the past to decrease the incidence of postoperative atrial fibrillation, with mixed results. Trials (1,7) using perioperative verapamil and digoxin showed no significant benefits compared to a placebo. Two metaanalyses (8-12) of [beta]-blockers have shown benefits with the use of [beta]-blockers in the prevention of postoperative atrial fibrillation, with a 50% risk reduction at best. Recently, numerous studies using antiarrhythmie therapy have been performed including IV procainamide, (13-14) IV amiodarone, (15-17) as well as oral amiodarone (18-21) and oral sotalol, (22-24) with promising results. We set out to explore the possibility of an additional benefit of IV amiodarone in conjunction with oral amiodarone to further reduce the incidence of postoperative atrial fibrillation, shorten length of stay, and reduce hospital costs.

MATERIALS AND METHODS

Patient Population

>From January 1999 to October 1999, 51 patients scheduled for CABG were randomly selected for participation in the amiodarone administration trial. Parameters monitored included ejection fraction (EF), age, gender, weight, height, left atrial size, bypass time, cross-clamp time, on cardiopulmonary bypass (CPB) or off CPB, length of stay, and treatment with [beta]-blockers, digoxin, and calcium-channel blockers. Cardiac risk factors including hypertension, diabetes, smoking, family history of coronary artery disease, history of previous myocardial infarction, congestive heart failure, COPD, or cerebrovascular accident in the past were also compared (Table 1).

To qualify for participation in the study, the patient had to be > 18 years old, able to give informed consent, be scheduled for CABG only, have had normal sinus rhythm at the time of enrollment, and have no history of atrial fibrillation. Both groups were similar in baseline characteristics including age, gender, and EF, as well as use of [beta]-blockers. Patients were excluded if they had been receiving amiodarone in the past year or had allergic or toxic reactions to the drug. Other exclusion criteria were use of antiarrhythmic agents other than 13-blockers, calcium-channel blockers, or digitalis, patients with thyroid disease, abnormal liver function test results, pregnancy, resting sinus bradyeardia in the absence of medical therapy, or uncontrolled heart failure.

Study Protocol

The Investigative and Research Board approved the study protocol at Maimonides Medical Center. All patients in the study were evaluated for left ventricular (LV) function (either using echocardiography, multiple gated acquisition scan, or coronary angiography). All patients gave consent 1 to 2 days prior to surgery. Baseline thyroid traction tests and liver function tests were performed on all patients. Pulmonary function tests including diffusion and lung capacity were performed as clinically warranted. IV amiodarone was started on call to the operating room at a constant infusion rate of 0.73 mg/min without any loading dose or bolus and continued over the next 48 b. This was followed by oral administration of amiodarone, 400 mg q12h, over the next 3 days. Alder surgery the patients were transferred to the cardiothoracic ICU and subsequently to a telemetry step-down unit. -Patients were continuously monitored with ECG telemetry equipment until the rime of discharge. Patients were evaluated on a daily basis until discharge by one of the investigators, and the telemetry record was reviewed daily. An episode of atrial fibrillation was considered to have occurred if the arrhythmia persisted for at least 30 min, or < 30 min if it led to hemodynainic instability requiring intervention. Management of the arrhythmia was left to the discretion of the cardiac surgery team. All patients were followed up from the time of surgery to the time of discharge. 13-blockers were continued during the perioperative period in all patients unless a contraindication developed or the private physician discontinued it. The option to perform surgery on or off CPB was left to the discretion of the surgeon.

Study End Point

The primary study end point was onset of atrial fibrillation lasting > 30 min or earlier warranting symptomatic treatment; secondary end points were surgery on or off CBP, length of hospital stay, and cost of hospitalization.

Statistical Analysis

Differences in parametric measures between the groups were assessed using t tests; frequency data were analyzed with the Xz statistics. An a of 0.05 was established as the level of sigmificance. Statistical analyses were conducted using SPSS (Version 10.0; SPSS; Chicago, IL).

RESULTS

Table 1 summarizes the characteristics of patients overall, as well as pump status for each group. Of the 51 patients enrolled in the amiodarone study, 37 were male, 14 were female, and the mean age was 69 years. Ninety-two patients were in the case-control group (56 were male, 36 were female, and mean age was 68 years). Both groups were similar in baseline characteristics, including age, gender, and EF, as well as use of 13-blockers.

Of the 51 patients who consented to enroll in the amiodarone study, only 3 patients acquired postoperative atrial fibrillation (5.9%; 95% confidence interval, 5.87 to 12.36%) [Fig 1]. One of these patients was a 67-year old man with an EF of 35% who was operated on with CPB. The other two were operated on without CPB: an 83-year-old woman with an EF of 55%, and a 66-year-old man with an EF of 35%. The control group had 24 patients (24 of 92 patients; 26.09%; 95% confidence interval, 17.12 to 35.06%) who acquired postoperative atrial fibrillation: 7 patients (29%) without CPB, and 17 patients (71%) with CPB. The mean EF was 39% in the amiodarone group and 41% in the control group.

[FIGURE 1 OMITTED]

Hospital Course

The dose of IV amiodarone used in the study was 2,100 mg over 2 days. The dose of oral amiodarone was 2,400 mg over the next 3 days, for a total of 4,500 mg over 5 days. Except for one patient for whom the medication was discontinued because of extreme bradycardia, all others tolerated the medication without clinically adverse events. [beta]-blockers were resumed in all patients in the control group as a protocol unless a contraindication developed, or if their private physicians chose not to continue the drug. One patient had a prolonged hospital stay secondary to sternal wound infection and renal failure unrelated to the study drug. Another patient had to be excluded as a result of nonadherence to the study protocol since the medication was stopped prematurely. No other clinically significant drug-related side effects were observed.

Length of Stay

The mean length of stay for the amiodarone group was 5.3 days (SD, 2.76) and 6.7 days for the control group (SD, 8.40) [Fig 2]. The median length of stay for both groups was 5 days (amiodarone group range, 3 to i4; and control group range, 3 to 76). Although the length of hospital stay in the amiodarone group was less than the control group, the difference did not reach statistical significance (t = 1.12, degrees of freedom = 141). Furthermore, the control group was marked by two patients with very long stays (31 days and 76 days, respectively); the longest stay in the amiodarone group was 14 days. Due to these extreme values, a Mann-Whitney test of ranks was used to analyze the stay times; the Mann-Whitney U of 1,964 was also not statistically significant. However, due to the different shapes of the distributions (Fig 3), results of a two-sample Kolmogorov-Smirnov test of whether the distributions came from one common distribution were statistically significant (Z = 1.42, p < 0.05), rejecting the hypothesis of a common distribution. It was not possible to obtain the actual cost of the patient stays; thus, charges must be based on length of stay. Consequently, the difference in costs due to the treatments was also not statistically significant by the t test and the Mann-Whitney U, but the extremes noted in Figure 3 and the significant Kolmogorov-Smirnov test indicate a significantly higher cost for the control group.

[FIGURES 2-3 OMITTED]

Hospital Charges

The mean length of stay in the amiodarone group was 5.3 days vs the control Group 6.7 days for a difference of 1.4 days (Fig 2, 4; Table 2). Following are the charges associated with the stay at our hospital: average daily charges of hospital stay on telemetry unit, $3,750; increase in charges per patient due to prolonged stay of 1.4 days, $5,250; total number of CABGs done in 1999 in our hospital, 927; incidence of atrial fibrillation in control group, 26.09% (242 patients expected to acquire atrial fibrillation in all CABG patients in 1999); charge for IV amiodarone therapy, $980; and charge for oral amiodarone therapy for 3 days, $14.88.

[FIGURE 4 OMITTED]

A comprehensive comparison of charges for the amiodarone group with the control group is provided in Table 2, which compares the amiodarone group with the control group by whether or not patients acquired postoperative atrial fibrillation. For patients with no atrial fibrillation, the difference in the mean length of stay was 0.38 days favoring the amiodarone group, with a mean savings of $430.12 per patient in charges. For patients acquiring postoperative atrial fibrillation, the per-patient, per-stay difference favoring the amiodarone group was $11,350.12, but this was primarily due to the control patient with a 76-day length of stay. If the patient is removed from the analysis, the difference is $527.62. Extrapolating these charges nationally is difficult due to the lack of national data on the exact incidence of atrial fibrillation following CABG. However, if a conservative estimate of $500 is used, the savings for 553,000 patients per year is > $277 million, amounting to a savings that are quite substantial. When one takes into account the potential savings (on a national level) as well as the possible reduction in morbidity and mortality associated with postoperative atrial fibrillation, one must give serious thought to the use of amiodarone for patients undergoing CABG.

DISCUSSION

Atrial fibrillation in patients after CABG remains the most common complication, occurring in 30 to

50% of patients. This leads to a significant increase in morbidity as well as delay in discharging patients, and a substantial increase in hospital costs. (1-6) The mechanism of postoperative atrial fibrillation remains unclear. (3,25) Mathew et al (3) suggested that independent predictors of postoperative atrial fibrillation include advanced age (1.24 per 5-year increase), male gender, past history of atrial fibrillation, congestive heart failure, and precardiopulmonary bypass heart rate of > 100 beats/min. Surgical practices such as pulmonary vein venting, bicaval venons cannulation, postoperative atrial pacing, and longer cross-clamp time also were identified as independent predictors of postoperative atrial fibrillation. Patients with postoperative atrial fibrillation remained an average of i3 h longer in the ICU and 2 days longer in the ward when compared with patients without atrial fibrillation. Numerous studies have been done using digoxin, (1) verapamil, (7) and [beta]-blockers (8-12) to decrease the incidence of postoperative atrial fibrillation. The results have been quite disappointing. [beta]-blockers, which were initially studied in early 1990, have shown beneficial effects in reducing postoperative atrial fibrillation, and have recently been incorporated as standard therapy perioperatively. However, the risk reduction is only 50%. This has led to a search for a better and improved therapy to further reduce the incidence of postoperative atrial fibrillation. Numerous antiarrthythmics have been tried, including IV procainamide, (13,14) IV amiodarone, (15-17) as well as oral amiodarone (18-21) and IV sotalol. (22-24) The small pilot trial done by Lanb et al (14) using IV procainamide followed by oral procainamide administered postoperatively was shown to have reduced the incidence of postoperative atrial fibrillation. However, the study was relatively small (22 patients), and the discontinuation rate was high (68%). Two trials using quinidine (26) and propafenone (8) have not shown significant beneficial effects. A recent article by Gomes et al (22) suggested that the use of sotalol in the perioperative period appeared promising. However, due to the fact that torsades de pointes is a potential side effect of sotalol and its use is limited in patients with asthma or renal insufficiency, we believe that its use as standard therapy in CABG patients is limited.

Amiodarone is a class Ill drug, but it also has class I, class II, and antiadrenergie effects. It blocks potassium channels and prolongs repolarization. Amiodarone is a peripheral and coronary vasodilator. When administered IV in doses of 2.5 to 10 mg/kg, ainiodarone can decrease heart rate, systemic vascular resistance, and LV contractile force. Oral doses of amiodarone are sufficient to control cardiac arrhythmias and do not depress LV EF even in patients with reduced EF. (27,28)

Oral amiodarone is slowly and incompletely absorbed, with systemic bioviability of 35 to 65%. Oral concentrations peak 37 h after a single dose. The myocardium develops a concentration of 10 to 15 times more than found in plasma. Plasma clearance in amiodarone is low and renal excretion negligible; therefore, amiodarone does not need to be reduced in patients with renal disease. It has been used for a wide spectrum of supraventricular and ventricular arrhythmias. Onset of action after IV administration is after several hours. The significant side effects of amiodarone are bradycardia, heart block, ventricular arrhythmia, interstitial pneumonitis, and hepatic toxicity. Due to clear evidence of a strong snpraventricular antiarrhythmic potential, there have been numerous studies attempting to use short-term amiodarone (without its potential side effects) to suppress postoperative atrial fibrillation. (18-21) The precise mechanism of the effect of amiodarone on postoperative atrial fibrillation is not clear, but it is possibly related to a combination of its antiadrenergic effect, and class I and class II effects.

In the largest study to date using oral amiodarone, Daoud et al (18) noted that when using oral amiodarone for 1 week preoperatively, there was a 50% reduction in the incidence of postoperative atrial fibrillation. Additionally, a reduction in hospital stay and hospital costs was also noted. Due to the fact that most patients require CABG on an urgent basis, as well as a suggestion of possible pulmonary complications related to preoperative amiodarone, (29) it makes it difficult for this regimen to be used in all patients scheduled for CABG.

IV amiodarone has been used in three studies for the prevention of atrial fibrillation after CABG. Hohnloser et al (17) performed a placebo-controlled study of the use of IV amiodarone prophylaxis for the prevention of atrial fibrillation after CABG in 77 patients. The total IV dose of 4.5 g was similar to the total amiodarone dose used in our study. Amiodarone infusion began after the completion of the surgical procedure, and significantly reduced the incidence of atrial fibrillation from 2i to 5%. However, ECG monitoring was performed only during the first 48 h after surgery, and amiodarone was discontinued in a high percentage of patients (18%). In the second study done by Butler et al, (15) 60 patients received IV amiodarone, 15 mg/kg, followed by 200 mg orally compared to placebo, showing a reduction from 20 to 8%. In the most recent study, the Amiodarone Reduction in Coronary Heart (ARCH) trial, Guarnieri et al (16) randomized 300 patients to receive low-dose IV amiodarone vs placebo. Two grams of amiodarone were administered starting slowly after completion of cardiac surgery. The study confirmed the significant reduction of postoperative atrial fibrillation in the amiodarone-treated group but surprisingly did not reduce length of stay.

In comparison to the ARCH trial, numerous possible mechanisms may explain the significantly lower incidence of postoperative atrial fibrillation in our study: (1) the use of a higher total dose of amiodarone; (2) the increased duration of therapy; (3) the combined use of IV amiodarone and oral amiodarone may further suppress the incidence of postoperative atrial fibrillation in comparison to IV amiodarone alone; and (4) a retrospective analysis of our data revealed much higher percentage of patients done in the amiodarone group were done without CPB (41 of 51 patients; 80.39%), compared to 25 of 92 patients (27.17%) in the control group were done without CPB. In a study by Abren et al, (30) who compared the frequencies of atrial fibrillation after CABG with or without use of CPB, revealed that only three small studies were published looking at the incidence of postoperative atrial fibrillation off CPB with conflicting results. Chauhan et al (31) revealed a significant decrease from 32 to 12%, while Tamis et al (32) showed no significant difference from 33 to 26%, and Abreu et al (30) showed a decrease of 26 to 11%. In our study, looking at the control group alone, there appears to be no benefit of patients being done without CPB. Seventeen of 67 patients (25.37%) with CPB acquired atrial fibrillation, compared to 7 of 25 patients (28%) done without CPB, suggesting a higher incidence of atrial fibrillation in the off-pump group than with CPB (Fig 5). However, in the amiodarone group, due to the low incidence of atrial fibrillation in this group, with only 2 of 41 patients acquiring atrial fibrillation without CPB and 1 of 10 patients acquiring atrial fibrillation with CPB, it is difficult to assess whether amiodarone alone reduced the incidence of atrial fibrillation or due to the high incidence of patients in this group done without CPB was there a possible synergistic benefit of amiodarone and off CPB. Other possible mechanisms that may explain the significantly lower incidence of postoperative atrial fibrillation are as follows: (5) we excluded patients undergoing valvular surgery, most likely causing a lower incidence of atrial fibrillation compared to the ARCH trial; in an article by Daoud et al, (18) the incidence of atrial fibrillation was significantly higher among patients who had valvular surgery (46%) than among patients who underwent CABG alone (29%); and (6) due to the high use of [beta]-blockers in our study (Fig 6) [80% in the amiodarone study arm and 97.8% in the control group], compared to 50% in the ARCH trial can explain the lower incidence of atrial fibrillation; however, 13-blockers did not appear to be an independent variable for reducing the incidence of atrial fibrillation.

[FIGURES 5-6 OMITTED]

Limitations of the Study

Follow-up of the arrhythmias was limited to inpatient monitoring. After discharge, no Holter monitoring was done. We believe that the clinically asymptomatic episodes of arrhythmias after discharge was not a cost-effective proposition to pursue in our study. We also limited our acceptance of an episode of atrial fibrillation to at least 30 min, or < 30 min if there was evidence of hemodynamic compromise. We believe that beyond this point the arrhythmia would be more likely to predispose to a clinical and hemodynamic adverse clinical outcome.

It is not clear whether the low incidence of atrial fibrillation in this study was purely related to the use of IV and oral amiodarone, or if there was a significant synergistic effect in the amiodarone group due to the high percentage of patients done without CPB. In addition, due to the low number of patients in our study and due to the fact that the length-of-stay parameter did not reach statistical significance between the two groups, it makes it difficult to give a definitive statement about charges. However, through the charge analysis (using Table 2), we show the potential for significant savings that may occur due to the significant reduction of postoperative atrial fibrillation that occurred in the amiodarone group. We look forward to the conclusion of the second perioperative amiodarone administration trial to clarify this very vital point.

CONCLUSION

A combination of oral and IV amiodarone in patients undergoing CABG is safe, well tolerated, and reduced the incidence of postoperative atrial fibrillation, thereby decreasing postoperative morbidity. Length of stay and hospital costs had a trend toward reduction but did not achieve statistical significance.

Furthermore, as compared to other antiarrhythmic agents, amiodarone was not associated with an increase risk of adverse events, particularly ventricular proarrhythmia. We believe that a large, multicenter, double-blinded randomized trial should be performed using file combination of IV and oral amiodarone to further elucidate whether this should become standard therapy in all patients undergoing CABG.

ACKNOWLEDGMENT: We thank Dr. Moshe Kerstein and Mr. Asher Rudowsky, for assistance in completing this project; Dr. D. Yens, for the statistical angle of the study; the cardiac surgeons at Maimonides Medical Center, Dr. Joseph Cunningham, Dr. Zvi Zisbrod, and Dr. Israel Jacobowitz; Judy Kerstein, my wife, for helping me complete this work; and Mrs. Erica Sosa and Mrs. Kristina Hecker-Cudjoe, for typing assistance.

* From the Division of Cardiology/, Department of internal Medicine (Drs. Kerstein, Soodan, Qamar, Majid, Lichstein, Hollander, and Shani), Maimonides Medical Center, Brooklyn, NY.

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Manuscript received April 29, 2002; revision accepted April 16, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Joshua Kerstein, MD, Associate Director of Clinical Cardiology, Maimonides Medical Center, 953 49th St, Brooklyn, NY 11219

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