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Ann Thorac Surg 2002;73:1665-1669
© 2002 The Society of Thoracic Surgeons
a The Cardiovascular Center of the University of Florida Health Science Center at Jacksonville, Jacksonville, Florida, USA
* Address reprint requests to Dr Haan, The Cardiovascular Center, UFHSC/J, 655 West Eighth St, Jacksonville, FL 32209 USA
e-mail: connie.haan{at}jax.ufl.edu
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Abstract |
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Introduction |
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Atrial fibrillation (AF) after coronary artery bypass grafting (CABG) most often develops between the second and fifth day [1], with a peak incidence in the first 2 to 3 postoperative days [4]. This dysrhythmia can cause significant hemodynamic instability and thromboembolic events with morbid sequelae [2, 3]. Although often transient, self-limited, and benign, AF usually results in the patient requiring additional medical treatment, laboratory tests, nursing time, and a prolonged hospital stay [2] even when uncomplicated. Yilmaz and coworkers [7] looked at long-term prevention of AF after CABG in patients in whom AF had occurred and normal sinus rhythm had been restored, comparing amiodarone with other medications (quinidine and verapamil); they found no difference in maintenance of sinus rhythm after AF postoperatively.
Prophylaxis against AF with standard medications has not reduced its incidence. However, new information on amiodarone suggests the need for critical analysis of the data for the drug’s effectiveness, side effects, and cost compared with those of other available pharmacologic agents.
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Material and methods |
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Articles that focused on ventricular arrhythmias were excluded. A second sorting process excluded articles on the hemodynamic effects of amiodarone during surgery, and on pediatric cases and arrhythmias (eg, junctional ectopic tachycardia). Of the remaining 10 manuscripts, two were review articles that gave broad summary evidence of the possible benefit of amiodarone in preventing postoperative AF [5, 8]. Another article presented a decision analysis model and cost-effectiveness analysis of the use of amiodarone as prophylaxis against AF after coronary bypass surgery [9]. The critical review below concentrates on the seven remaining publications of prospective trials examining amiodarone therapy effect on AF incidence after adult cardiac surgery (Table 1).
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Results |
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Five of the studies looked only at CABG patients. Amiodarone decreased the incidence of postoperative AF in all of the studies, and reached statistical significance (p 
0.05) in two (Fig 2).
As the AF risk is significantly higher for patients undergoing valve procedures [3, 4], perhaps the articles including valve patients in the study groups should be excluded from comparison. However, as amiodarone was shown to be at least as effective in these trials as in the CABG-only studies, inclusion of (higher risk) valve surgery patients in fact strengthens the case for amiodarone use [13, 15].
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In these trials, the reported adverse events were infrequent, averaging 2.8%. Two studies reported no adverse events [11, 15]. The Amiodarone Reduction in Coronary Heart (ARCH) study revealed that 7 of the amiodarone group had drug infusion terminated with the following reasons provided: bradycardia and pacemaker failure (2), ventricular tachycardia (1), hypotension (1), stroke (1), and central line complications (2) [13]. Only a small number of patients (13 of 1,064) required amiodarone discontinuation, 1 for nausea [16] and the rest primarily for bradycardia and QTc prolongation [10, 12–14]. Of note is that QTc prolongation by amiodarone occurs through a unique mechanism, is seen in virtually all patients taking the drug chronically, and is not associated with the proarrhythmia accompanying similar electrocardiographic changes induced by other drugs or electrolyte disorders; hence true amiodarone tolerance is likely to be better than reported.
Hospital length of stay [13] and intensive care unit length of stay [10] were included as outcomes of interest in one study each, and two reports included hospital costs as outcomes [15, 16]. Lee and colleagues [10] showed a shorter average length of ICU stay (132 versus 111 hours, p < 0.01). The ARCH trial showed postoperative amiodarone to be safe and effective but reported only a nonsignificant trend toward decreased hospital length of stay [13]. Two articles looking at oral amiodarone included hospital costs as an outcome [15, 16], but only one, Daoud and associates [16], showed amiodarone to have a significant impact on hospital costs. This finding differed from the stronger, favorable conclusions of the cost-effectiveness article by Reddy and colleagues [9], which described a regimen similar to that of the trial by Redle and coworkers [16].
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Comment |
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Limitations of this review include the small numbers of patients included in each of the studies (total of 1,064 in 7 papers) and the variation in dosing, timing, and route of drug administration among trials. The optimal regimen for amiodarone dosing to prevent postoperative AF remains unclear, as does the influence (if any) of other concurrently administered medications such as digoxin, ß-adrenergic antagonists, calcium channel blockers, and magnesium on amiodarone efficacy and safety. Most of these medications were noted as part of the baseline patient characteristics in the trials reviewed, but their use was not controlled. Although in-hospital AF rate or incidence is admittedly an intermediate outcome, it serves as an objectively measurable proxy for outcomes of real interest: total cost of care (from hospital length of stay, readmissions, and complications—especially stroke and heart failure, anticoagulation, negative dromotropic agents, and cardioversion), quality of life, and mortality.
Another limitation, hindering strong conclusions and guidance to evidence-based practice, is the significant variability between the available studies. One method to achieve some understanding of the potential role for amiodarone in this setting is to conduct a formal meta-analysis of the studies done to date. These studies are, however, sufficiently dissimilar in dose, route and timing of amiodarone administration as to make them noncomparable, precluding meta-analysis. The studies as presented, however, provide orientation and direction for future trials.
Further study is also required to determine the optimal dosing regimen. To be applicable to the largest target patient population, future trials should compare regimens of no more than a single intravenous preoperative dose plus postoperative dosing schedules that switch to oral administration (or terminate treatment) in a time frame consistent with predictable intensive care unit and hospital discharge. To reduce the incidence of the most frequently cited reason for drug discontinuation, use of nonessential negative chronotropic drugs (digoxin, diltiazem, verapamil, and central 
2-adrenergic agonists such as clonidine) should be restricted whenever possible, substituting chronotropically-neutral antihypertensive and antianginal medications during the study period. Study subjects should be limited to coronary bypass patients until the optimal dosing regimen is better defined, thus limiting the confounding introduced by combined and valve-only procedures. Use of magnesium supplementation perioperatively should be controlled for as well. The study samples of future studies should include a greater proportion of women and compare responses by gender. It will be of value to look also at response to treatment stratified by age categories. That would be particularly useful in light of the bradycardic effects seen in the studies reviewed, so that we can learn more about the potential impact on conduction in older patients—especially if controlling for negative chronotropic drugs as suggested above. Endpoints for future studies should include AF incidence and duration, hospital length of stay, hospital readmissions (timing and admission diagnosis), and incidence of dysrhythmic and hemodynamic complications of prophylaxis. Any measures to better understand the cost of prophylaxis versus complications, both in terms of cost of care and in deterioration of the patient’s quality of life, are important to include wherever possible.
Alternatively, as amiodarone has been compared with placebo in these trials, it may be helpful to study its safety and efficacy versus sotalol, another medication reported in the review articles to also decrease the incidence of postoperative AF. However, with the higher risk of proarrhythmia (especially torsade de points), sinus bradycardia, and atrioventricular block, it seems unlikely that sotalol will match the safety profile thus far seen with amiodarone.
In conclusion, evidence strongly suggests that perioperative amiodarone treatment of cardiac surgical patients is well tolerated and significantly reduces the incidence of AF in a cost-effective manner for both patient and hospital. Much remains to be learned about postoperative AF, but amiodarone prophylaxis appears to be a promising option deserving further study.
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This article has been cited by other articles:
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  S. M. Bagshaw, P. D. Galbraith, L. B. Mitchell, R. Sauve, D. V. Exner, and W. A. Ghali Prophylactic Amiodarone for Prevention of Atrial Fibrillation After Cardiac Surgery: A Meta-Analysis Ann. Thorac. Surg., November 1, 2006; 82(5): 1927 - 1937. [Abstract] [Full Text] [PDF]
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 M. Budeus, M. Hennersdorf, S. Perings, S. Rohlen, S. Schnitzler, O. Felix, K. Reimert, P. Feindt, E. Gams, N. Lehmann, et al. Amiodarone prophylaxis for atrial fibrillation of high-risk patients after coronary bypass grafting: a prospective, double-blinded, placebo-controlled, randomized study Eur. Heart J., July 1, 2006; 27(13): 1584 - 1591. [Abstract] [Full Text] [PDF]
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 L. Brantman and J. Howie Use of Amiodarone to Prevent Atrial Fibrillation After Cardiac Surgery Crit. Care Nurse, February 1, 2006; 26(1): 48 - 58. [Full Text] [PDF]
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 D. Mikroulis, V. Didilis, F. Konstantinou, K. Tsakiridis, G. Vretzakis, and G. Bougioukas Diltiazem versus Amiodarone to Prevent Atrial Fibrillation in Coronary Surgery Asian Cardiovasc Thorac Ann, March 1, 2005; 13(1): 47 - 52. [Abstract] [Full Text] [PDF]
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 W. L. Holman Amiodarone in cardiothoracic surgery patients: What is a surgeon to do? J. Thorac. Cardiovasc. Surg., March 1, 2003; 125(3): 463 - 464. [Full Text] [PDF]
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 J.-F. Legare, K. J. Buth, R. C. Arora, D. A. Murphy, J. A. Sullivan, and G. M. Hirsch The dome of the left atrium: an alternative approach for mitral valve repair Eur J Cardiothorac Surg, March 1, 2003; 23(3): 272 - 276. [Abstract] [Full Text] [PDF]
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