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Ann Thorac Surg 2008;85:28-32. doi:10.1016/j.athoracsur.2007.07.060
© 2008 The Society of Thoracic Surgeons
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Original Articles: Cardiovascular

Amiodarone Cost Effectiveness in Preventing Atrial Fibrillation After Coronary Artery Bypass Graft Surgery

Lars R. Zebis, MD, PhDa,*, Thomas D. Christensen, MD, PhDa, Ivar S. Kristiansen, DMScb,c, Vibeke E. Hjortdal, MD, DMSca

a Department of Cardiothoracic and Vascular Surgery, and Institute of Clinical Medicine, Aarhus University Hospital, Skejby, Denmark
b Research Units of General Practice in Denmark, University of Southern Denmark, Odense, Denmark
c Institute of Health Management and Health Economics, University of Oslo, Oslo, Norway

Accepted for publication July 23, 2007.

* Address correspondence to Dr Zebis, Department of Cardiothoracic and Vascular Surgery and Institute of Clinical Medicine, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, Aarhus N, DK-8200, Denmark (Email: lrz{at}post.tele.dk).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The purpose of this study was to estimate the costs and health benefits of routinely administered postoperative amiodarone as prevention of atrial fibrillation for patients undergoing coronary artery bypass grafting (CABG) for stable angina.

Methods: This cost-effectiveness study was based on a randomized, controlled, double-blind trial (the RASCABG study) using avoidance of atrial fibrillation as the measure of benefit at the Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Skejby, Denmark. Two hundred and fifty eligible consecutively enrolled CABG patients were included to receive either 300 mg amiodarone or placebo (5% aqueous dextrose solution) administered intravenously over 20 minutes followed by 600 mg amiodarone/placebo orally twice a day (8 AM and 8 PM) for the first 5 postoperative days.

Results: In the amiodarone group, there were 14 cases of atrial fibrillation compared with 32 in the control group (p < 0.01) whereas there were no differences in the length of stay. The mean total cost per patient was {euro}7,639 in the amiodarone group and {euro}7,814 in the placebo group (p < 0.01).

Conclusions: Routine use of postoperative prophylactic intravenous bolus and subsequent 5 days of oral amiodarone therapy after coronary artery bypass grafting reduces the risk of atrial fibrillation and decreases the total costs of care by {euro}175 per patient.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Postoperative atrial fibrillation (AF) is seen in 5% to 65% [1, 2] of patients undergoing cardiac surgery. Some studies indicate no impact of the occurrence of AF on the hospital length of stay (LOS) [3,4], whereas others show that patients in whom AF develops have longer LOS than those in whom it does not [5–8]. A twofold increase in LOS in the intensive care unit and prolongation of the total hospital stay with increased cost have been reported [7, 9].

Medical therapy to control heart rate and restore sinus rhythm has included various antiarrhythmic drugs, but most of these drugs have adverse effects [10]. Amiodarone is a well-documented drug for the prevention of AF and reduces the risk of AF after coronary artery bypass grafting (CABG) operation [11–14], but may also entail side effects. Several side effects have been reported from the use of amiodarone, but the Reduction of Atrial fibrillation Study for patients undergoing CABG (RASCABG) [14] showed that 5 days of high-dose oral amiodarone after an intravenously administered bolus was a feasible regimen that lowered the risk of postoperative AF without causing side effects. This study showed a 14% absolute reduction in the risk of AF with a number needed to treat of 6.9 patients [14]. In other studies, amiodarone has been administrated intravenously preoperatively or postoperatively, or both [13, 15, 16], or intravenously or orally [11]. These prophylactic regimens all prolonged the in-hospital LOS as a consequence of the length of the prophylactic regimen. A 5-day prophylactic regimen was chosen that in itself did not alter the length of the in-hospital LOS. This design makes it possible to detect whether LOS was influenced by prophylaxis against AF [14].

The hypotheses of this substudy were, first, that a combined intravenous and 5-day oral amiodarone regimen would reduce the LOS in hospital; and, second, that it reduces health care costs. The aim was therefore to find out whether the instituted prophylactic regimen was cost effective.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Of about 1.5 million inhabitants in Western Denmark, approximately 1,100 persons are referred for cardiac surgery at Aarhus University Hospital, Denmark, each year. Informed consent was obtained from eligible patients who were screened and consecutively enrolled for participation in the RASCABG study [14]. Each enrolled patient consented to be in the study. Three patients refused to participate.

Inclusion criteria were as follows: (1) elective coronary artery bypass grafting, (2) age over 18 years, (3) willingness to be randomly assigned, (4) provision of informed consent.

Exclusion criteria were as follows: (1) other types of heart surgery, (2) previous heart surgery performed, (3) resting heart rate below 40 beats a minute, (4) atrioventricular block of any degree, (5) preoperative atrial fibrillation or flutter, (6) previous known atrial fibrillation or flutter lasting more than 1 month, (7) hepatic dysfunction (alanine aminotransferase more than twice the upper normal limit), (8) hyperthyroidism, (9) pregnancy, (10) breastfeeding, and (11) known adverse reactions to amiodarone.

Each enrolled patient was randomly assigned to receive amiodarone or placebo, based on a computerized prospective randomization schedule. Randomization was done in blocks of 4 and was stratified by age (≤65 years and >65 years) and by preoperative use of β-blockers.

Each patient received a randomization number that was recorded and sent by fax to the pharmacy at Aarhus University Hospital, along with the patient’s Civil Registration number. The pharmacy decoded the number, prepared the appropriate infusion and pills, and forwarded them to the Department of Cardiothoracic and Vascular Surgery, along with a sealed opaque envelope containing the randomization assignment. The study was approved by the Institutional Ethics Committee on Human Research.

Study Design
We performed a randomized, controlled, double blinded trial following the Consort Statement [17].

Intervention
The patient received a bolus infusion containing 300 mg amiodarone or placebo (dextrose 5% in water) over 20 minutes at 8 AM the morning after surgery at the intensive care unit together with the first 600 mg dose of oral amiodarone or placebo. The oral administration dose of 600 mg amiodarone/placebo was given twice a day at 8 AM and at 6 PM for 5 days. The patients continued their regular medication until the day of surgery and resumed it at the intensive care unit on the first postoperative day.

Atrial Fibrillation and Surgery
Atrial fibrillation was defined as fast irregular, eddy current activation of the atrium with neutralization of its contractions. Treatment followed normal standard procedures at Aarhus University Hospital, Skejby, Denmark, or after transfer, the guidelines at the department in charge.

All operations were performed with a standard procedure through a median sternotomy using cardiopulmonary bypass following the guidelines of the department [14].

During surgery and until discharge from the intensive care unit, the patients were under continuous telemetry monitoring. The following morning they were transferred to the ward around 10.00 AM, telemetry monitoring was disconnected; the patients’ rhythm was then followed by standard 12-lead electrocardiograms and monitored in a continuous report formula. If clinical suspicion of atrial fibrillation was raised, an electrocardiogram was obtained. If atrial fibrillation was documented, the study drug was discontinued and the department’s relevant treatment was initiated. The patients were transferred to the local hospital on day 5, and discharge summaries from the local hospitals were collected.

On postoperative day 30, the patients were contacted by a study physician and asked whether clinical AF had developed or not. At the same time, they were asked to contact their own physician to obtain an ECG, which was sent to the study group.

Endpoints
The endpoints of this subanalysis were costs; the LOS at Aarhus University Hospital, Skejby; the combined LOS at Aarhus University Hospital, Skejby, and local hospital; the LOS at the intensive care unit and intermediary unit at Aarhus University Hospital, Skejby; and the occurrence of postoperative AF.

Resource Costs and Statistical Analysis
The economic analysis, conducted from the payer perspective, included medical costs associated with CABG and its complications. All cost were measured in 2005 Danish kroner (DKK) and translated into Euros ({euro}1.00 equals approximately 7.8 DKK). Perioperative (defined as from admittance at the specialist department to the day of discharge to the local hospital) costs for each patient was estimated from resource utilization data collected in the RASCABG-1 study. Total costs were a function of resources consumed (routine and intensive care unit length of stay, blood products, utilization acquired, and complications postoperative stroke, postoperative acute myocardial infarction, or in-hospital death). All data on resource use were collected from the patient records. Unit costs were based on market prices and hospital accounts, where upper bound and lower bound were applied with 20% margins (Table 1).


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  		Table 1 Unit Costs
 
Comparison of the endpoints in the two groups was performed using intention-to-treat analyses. The data were analyzed using the Stata package (Stata Corp, College Station, Texas). Differences in costs and LOS were analyzed with t tests as the data were normally distributed.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
The demographics of the patients in each group is shown in Table 2. There were no significant differences among the two prophylactic groups other than the number of grafted right coronary arteries, which was highest in the amiodarone group (p = 0.02). The length of stay was almost the same in the two treatment arms with respect to intensive care and usual ward at Aarhus University Hospital, Skejby, and subsequent stay in local hospitals (Table 3), but the occurrence of atrial fibrillation was lower in the amiodarone group (11% versus 26%, p < 0.01). All patients left Aarhus University Hospital, Skejby, with sinus rhythm. The nurse and doctor time spent on a patient with AF (p < 0.01) was approximately 20 minutes. Because fewer patients in the amiodarone group had AF, the cost per patient was lower in the amiodarone group. Total cost for atrial fibrillation treatment was also less in the amiodarone group (p < 0.01). There were no significant differences between the groups with respect to intensive care treatment (p = 0.21), intermediate care treatment (p = 0.06), treatment at the ward at Aarhus University Hospital, Skejby (p = 0.10), and at the local hospitals (p = 0.54; Table 4).


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  		Table 2 Demographics Characteristics
 

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  		Table 3 Average Length of Hospital Stay and Occurrence of Atrial Fibrillation According to Type of Treatment With 95% Confidence Intervals (CI)
 

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  		Table 4 Average Cost ({euro}) per Patient According to Treatment Arm With 95% Confidence Intervals (CI)
 
Based on the unit costs and the observed use of health care (Table 4), the mean total costs were {euro}7,639 in the amiodarone group and {euro}7,814 in the control group, representing a saving of {euro}175 per patient (p < 0.01) in the amiodarone group. The lower cost of the prophylactic amiodarone treatment stemmed from less use of laboratory tests, doctor and nurse time, radiology examinations, intensive care treatment, and less use of medication for converting atrial fibrillation.

In one-way sensitivity analyses, we tested whether changes in the input cost data could change the results of the study. These analyses demonstrate that the amiodarone regimen entails lower cost under a wide range of cost assumptions.

Two patients died during the trial, 1 after an acute myocardial infarction and 1 of complex cancer. Two patients had transient stroke. The distribution among the treatment arms was equal, as 1 died and 1 had transient stroke in both groups.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
In this randomized, placebo-controlled trial, we found a significant reduction in the occurrence of AF and a significant reduction in total cost from the use of prophylactic amiodarone treatment. If potentially high risk patients could be selected, this regimen could be even more economically beneficial, as it has proved to minimize the risk for AF and especially symptomatic AF, which is more economical demanding. Several attempts were made to identify high-risk patients by perioperative transesophageal echocardiography and by analyzing demographic data and relevant literature. Only age was found to be a consistent prognostic factor. This study therefore indicates that patients, doctors, nurses, and administration all have benefit from the introduction of the proposed prophylactic regimen. Patients avoid episodes of AF, blood sampling, and insecurity. Doctor, nurses, and bioanalytics avoid allocating additional time to the patients. The hospital saves money and resources. This regimen is therefore a good, feasible, economical, and practical way of reducing the risk of postoperative atrial fibrillation after coronary artery bypass grafting surgery.

Meta-analyses [13, 18, 19] regarding amiodarone prophylaxis of atrial fibrillation after coronary artery bypass grafting show that amiodarone reduces the risk of atrial fibrillation, ventricular tachyarrhythmias, and strokes, and in addition, the hospital stay is reduced. These findings are based upon different trials [5, 20–23] showing reduced hospital cost, whereas other studies [3, 6, 24–26] did not indicate cost savings.

The strength of our study is that it is a blinded, randomized, controlled trial, carried out without changing the normal routines at the ward. It is a potential problem in the study, however, that we focused on clinically important AF. We have no documentation of subclinical atrial fibrillation and the possible impact it may have had on LOS, and that could have skewed the data. Moreover, data on resource use were collected retrospectively from the patient records, and imprecision in the hospital accounts may bias the unit cost estimates.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Ina Hoegh, the project nurse, participated in enrolling and randomizing patients and in conducting follow-up. The study was funded by the following private sources: Statens Sundhedsvidenskabelige Forskningsfond, Skejby Fonden, Elin Holms Forskningsfond, Lily Benthine Lunds Fond, Lykfeldts Legat, Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Fond, and Kirsten Anthonius Mindelegat.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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