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(Chest. 2001;120:1936-1941.)
© 2001 American College of Chest Physicians

Prevention of Atrial Fibrillation After Cardiac Surgery*

The Significance of Postoperative Oral Amiodarone

Sotiris C. Stamou, MD, PhD; Peter C. Hill, MD, FCCP; George A. Sample, MD; Elizabeth Snider, MS; Albert J. Pfister, MD; Robert C. Lowery, MD and Paul J. Corso, MD

* From the Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center and MedStar Research Institute, Washington, DC.

Correspondence to: Paul J. Corso, MD, Director of Cardiac Surgery, Washington Hospital Center, 106 Irving Street NW, Suite 316, South Tower, Washington, DC 20010; e-mail: paul.j.corso{at}MedStar.net


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Atrial fibrillation (AF) is a common occurrence after cardiac surgery (10 to 53%) that contributes to increased length of stay and hospital cost. Recent evidence suggests that treatment with amiodarone may provide safe and effective prophylaxis against AF in many patients undergoing cardiac operations. This study sought to investigate whether oral amiodarone administered postoperatively would reduce the incidence of postoperative AF.

Design: Prospective nonrandomized cohort study.

Patients and participants: In this prospective study, 1,196 consecutive patients who underwent various open-heart procedures with cardiopulmonary bypass between July 1999 and February 2000 received oral amiodarone, 400 mg bid, from the transfer to the cardiovascular recovery room until the day of hospital discharge, or up to 7 days postoperatively. The incidence of AF in this group of patients was compared with a group of 1,246 patients who underwent cardiac surgery with cardiopulmonary bypass in the preceding 8-month period (November 1998 to June 1999) at the same institution without receiving amiodarone postoperatively.

Setting: Tertiary health-care center.

Measurement and results: AF developed in 294 patients (25%) in amiodarone-treated group and in 385 patients (31%) in the control group (p = 0.001). In multivariate logistic regression analysis, oral amiodarone treatment emerged as an independent predictor of lower risk of AF (odds ratio, 0.7; 95%; 95% confidence interval, 0.6 to 0.9; p = 0.002) and shorter hospital length of stay (odds ratio, 0.8; 95% confidence interval, 0.5 to 0.9; p = 0.006).

Conclusions: Postoperative oral amiodarone treatment is a safe and effective regimen associated with a reduced incidence of new-onset AF and decreased length of hospital stay. Prospective randomized trials are needed to evaluate the benefits of amiodarone treatment relative to its side effect profiles.

Key Words: administration, oral • atrial fibrillation, prevention and control • comparative study


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Atrial fibrillation (AF) is a frequent adverse event after cardiac surgery, occurring in 10 to 53% of patients.1 2 3 4 5 6 7 Postoperative AF has been associated with increased morbidity and prolonged hospitalization after cardiac surgery.8 Prophylactic strategies to prevent AF after cardiac surgical procedures, most commonly involving verapamil, digoxin,9 10 or ß-adrenergic antagonists, have been evaluated.11 Digoxin and verapamil were not found to be as effective as prophylactic amiodarone in preventing postoperative AF.12 In previous studies,11 13 14 15 prophylactic therapy with ß-adrenergic antagonists has been reported to reduce AF rate, but other studies16 17 18 have failed to confirm this beneficial effect.

In contrast to the ß-adrenergic antagonists, amiodarone, as a class III antiarrhythmic agent, has a direct antifibrillatory effect on the atrium that may reduce postoperative AF.12 19 20 Other investigators have shown7 21 that administration of amiodarone appeared to prevent new-onset AF and decrease hospital length of stay in a group of patients after cardiopulmonary bypass. In this study, we sought to investigate the role of oral amiodarone administered in the early postoperative period in preventing AF and reducing postoperative length of stay in a large patient population after cardiac surgery.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
All patients (n = 3,694) who underwent cardiac surgery at the Washington Hospital Center between November 1998 and February 2000 were identified using the computerized database system of the Section of Cardiac Surgery at the Washington Hospital Center. Patients with preoperative bradycardia (heart rate < 60 beats/min; n = 240) who were dependent on a pacemaker (n = 34), who underwent cardiac transplantation (n = 6), who underwent coronary artery bypass grafting (CABG) without cardiopulmonary bypass (n = 860), or had preoperative AF (n = 112) were excluded from the study. Of the remaining patients (n = 2,442), 1,196 patients had been prospectively entered in a clinical protocol between July 1, 1999, and February 1, 2000, which included postoperative oral administration of amiodarone, 400 mg bid. Baseline characteristics and early in-hospital outcomes were recorded and compared with those of patients who underwent cardiac surgery during the preceding 8-month period from November 1, 1998, to June 30, 1999 (n = 1,246).

Definitions
Preoperative Variables: Diabetes was defined as a history of diabetes mellitus, regardless of duration of the disease or need for oral agents or insulin. COPD was defined as FEV1 < 75% of predicted and/or long-term use of bronchodilators. Chronic renal insufficiency was defined as a serum creatinine value >= 2.0 mg/dL.

Postoperative Variables: Low-output syndrome was defined as the postoperative use of inotropic support for > 48 h for the purpose of generating an adequate cardiac output. Prolonged ventilatory support was defined as pulmonary insufficiency requiring ventilatory support for > 48 h. Stroke was defined as any new major (type II) neurologic deficit presenting in the hospital and persisting > 72 h.22 Transient ischemic attacks were not included in this analysis. Postoperative AF was defined as new-onset AF detected by telemetry analysis and requiring treatment. Patients with AF that did not resolve during their hospital stay were considered to have persistent AF.

Treatment of AF
Treatment of AF was based on duration of new-onset AF for >= 20 min or > 60 min in a 24-h period and included heart rate control, chemical cardioversion, and/or electrical cardioversion. For rate heart control, 5 mg of IV metoprolol was infused over a 1-min period every 5 min until the patient’s heart rate was < 110 beats/min or until a maximum dose of 15 mg was administered. After heart rate control was accomplished, oral metoprolol, 25 to 100 mg bid, was administered. In patients contraindicated to receive ß-adrenergic antagonists, IV diltiazem (15 to 25 mg over 2 min until the heart rate was controlled and then 30 to 60 mg tid) or oral digoxin (loading dose of 1 mg and then 0.125 to 0.25 mg qd) were administered. When heart rate control was achieved, chemical conversion of AF was accomplished with oral procainamide (loading dose of 1 g followed by 750 mg qid, adjusted for body weight) or increase in oral amiodarone to 600 mg bid. Electrical cardioversion (transthoracic synchronous discharge of 50 to 200 J) was administered when drug cardioversion failed to convert AF to sinus rhythm within 24 h. Patients who did not convert to sinus rhythm within 48 h, despite the aforementioned protocol, received anticoagulation with IV heparin and were discharged receiving oral warfarin.

Statistical Analysis
Primary comparisons were made between patients with vs without postoperative oral intake of amiodarone. All statistical analyses were two tailed. Categorical variables were compared using Fisher’s Exact {chi}2 test for proportions with appropriate degrees of freedom. In the analysis of continuous variables, the Student’s unpaired t test was used for variables with normal distributions and the Mann-Whitney U test was used for variables with nonnormal distributions. A stepwise logistic regression analysis was conducted to determine the independent predictors of postoperative AF (dependent variable), including all variables with p < 0.20 in the univariate analysis as independent variables. Following the same methodology, we also investigated the independent predictors of prolonged hospital stay (> 7 days; 75th percentile of postoperative stay). All p values < 0.05 were considered statistically significant. Statistical analysis was performed using statistical software (Statistical Package for the Social Sciences for Windows 95, Version 9.0; SPSS; Chicago, IL).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline clinical and demographic characteristics are summarized in Table 1 . The incidence of congestive heart failure was lower in patients who received postoperative amiodarone (3% in the amiodarone-treated group vs 5% in the control group; p = 0.006). Congestive heart failure was added to the logistic regression model in order to adjust for this obvious imbalance between the patients of the two groups. Preoperative administration of ß-blockers was similar between patients of the two groups. Treatment with ß-blockers was continued in all patients during the postoperative period.


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  		Table 1.. Baseline and Demographic Patient Characteristics (Univariate Analysis)*

 
The patients of the two groups were similar with respect to the types of operative procedures and complications (Table 2 ). Only postoperative length of stay was significantly different (lower) in patients who received amiodarone than in patients in the control group (p = 0.01). During the study period, AF developed in 25% of patients in the amiodarone-treated group vs 31% in the control group (p < 0.001; Table 3 ). Other arrhythmic complications were similar between patients of the two groups (Table 3) .


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  		Table 2.. Operative and Postoperative Patient Characteristics (Univariate Analysis)*

 

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  		Table 3.. Arrhythmic Complications (Univariate Analysis)*

 
Predictors of New-Onset AF
In multivariate logistic regression analysis, the following variables emerged as independent predictors of AF: age > 75 years, hypertension, CABG with valve replacement, ARDS, and prolonged ventilation. Postoperative administration of amiodarone was associated with a lower incidence of postoperative AF (Table 4 ), even after adjusting for congestive heart failure as well as variables with p < 0.20 in the univariate analysis comparing the two groups.


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  		Table 4.. Predictors of New-Onset AF (Multivariate Analysis)*

 
Predictors of Prolonged Hospital Stay
Patients in whom AF developed had a prolonged postoperative length of stay (mean ± SD, 8 ± 4 days for AF vs 6 ± 3 days for no AF; p = 0.01). In the multivariate logistic regression analysis, ejection fraction < 35%, age > 75 years, CABG with valve replacement, prolonged ventilation, postoperative stroke, ARDS, low cardiac output, and new-onset AF were found to prolong postoperative length of stay (> 7 days), whereas postoperative administration of amiodarone correlated with an abbreviated postoperative stay (Table 5 ).


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  		Table 5.. Independent Correlates of Prolonged (> 7 d) Hospital Stay After CABG (Multivariate Analysis)*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
AF is one of the most common adverse events after cardiac surgery, occurring in up to 53% of patients after cardiac surgery,21 and has been associated with increased morbidity and prolonged hospitalization.8 Several clinical factors have been associated with AF after cardiac surgical procedures,13 23 24 such as advanced age, depressed ejection fraction, and preexisting AF. Different mechanisms have been proposed to explain the high incidence of AF after cardiac surgery, including withdrawal of ß-blockers administered preoperatively25 ; structural changes of the heart, such as those related to age, effects of cardiopulmonary bypass, and cardioplegia; as well as the effects of postoperative hypoxia, hypovolemia, and electrolyte imbalance.1 Clinical factors that predispose individuals to AF may act through a common denominator, "the dispersion of refractoriness," a term used to describe the heterogeneity of local atrial refractory periods.5 26

Oral amiodarone has been increasingly used as an antiarrhythmic agent to prevent the occurrence of AF after cardiac surgery.21 Amiodarone seems to act through a prolongation of atrial refractoriness. However, the precise mechanism of action is not well understood because amiodarone does not predictably lengthen atrial repolarization acutely.27 28 It has been hypothesized that its effect may stem from its nonspecific antiadrenergic effect, its class I actions, or other actions not yet identified.27 Moreover, amiodarone has coronary vasodilatory effects29 that may benefit cardiac surgical patients.

In our study, the two groups were comparable with respect to baseline characteristics, besides a higher rate of congestive heart failure in patients in the control group. Postoperative complications were similar in both groups. Previous authors30 have related amiodarone administration to a high rate of ARDS, which is estimated to occur in up to 10% of treated patients. In our series, ARDS incidence was equally low in both groups and there were no other pulmonary complications attributable to amiodarone. Similarly, GI complications were not different between patients of the two groups. Severe complications warranting discontinuation of the medication (eg, bradycardia) occurred in 1% of patients (n = 13) who received amiodarone.

Amiodarone, AF, and Postoperative Stay
Operative techniques and standards of care did not change significantly during the course of this study, and all procedures were performed by the same group of heart surgeons. Preoperative (ejection fraction <= 35%, advanced age), operative (CABG with valve replacement) and postoperative variables (prolonged ventilation, stroke, ARDS, low-output syndrome, new-onset AF) were found to independently predict prolonged hospital stay. Amiodarone treatment emerged as an independent predictor of shorter postoperative stay in patients undergoing cardiac surgery, confirming the findings of previous studies.7 21 In the current era of reduced health-care funds, shortened hospital stay may favorably affect the relative risk/benefit ratio for cardiac operations, reduce the use of hospital resources, and therefore lower the cost of care.

Clinical Implications
Postoperative treatment with oral amiodarone was well tolerated and resulted in a decreased prevalence of AF in patients undergoing heart surgery. After adjusting for age and other correlates, postoperative treatment with amiodarone was independently associated with a decrease in postoperative length of stay. Although previous reports have emphasized the requirement of a loading regimen of amiodarone 3 to 7 days before surgery,21 in the present study, initiation of amiodarone treatment at the early postoperative period without a preloading phase resulted in a significant decrease in AF rate. This therapeutic protocol eliminates the need of preoperative monitoring of potential complications of the treatment and patient’s compliance (if therapy is started at home). Moreover, it reduces length of stay since patients may be admitted to the hospital on the day of surgery and not before that. Future prospective studies, despite their limitations, may be needed to confirm these results, investigate the long-term contribution of AF to morbidity and mortality in patients undergoing cardiac surgery, and explore the potential advantage of oral amiodarone therapy with respect to postoperative AF. Moreover, different approaches, such as magnesium infusion, may decrease the incidence of postoperative AF after CABG.31

Limitations of the Study
Limitations of our study include limitations inherent in any retrospective analysis. However, all data elements were prospectively entered according to prespecified definitions.

The main limitation of our study was the nonrandomized single-institution methodology that could not establish direct causal relationships with certainty. However, retrospective studies with a large-enough sample along with multivariate models, such as those developed in the study, may be used to more accurately determine the significance of amiodarone in preventing postoperative AF after cardiac surgery. Prospective randomized studies, although of invaluable scientific merit, are limited by the small sample size (type II statistical error) and significant cost.

Furthermore, it was not possible to determine from our data exactly when and for how long postoperative AF occurred. This prevented estimation of the time frame for the increased risk of AF and subsequent employment of prophylactic measures. Moreover, the true incidence of AF may be underdiagnosed in our study by limiting the definition of AF to episodes requiring treatment.


   Acknowledgements
 
We thank Ellen Shair, MA, for her editorial contribution. We also thank Sherryl A. Orwig, PA-C, and Carol A. Wegman, PA-C, for their contributions to the completion of the study.


   Footnotes
 
Abbreviations: AF = atrial fibrillation; CABG = coronary artery bypass grafting

Received for publication November 8, 2000. Accepted for publication May 4, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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