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Ann Thorac Surg 2002;74:69-74
© 2002 The Society of Thoracic Surgeons
a Divisions of Cardiology and Drug Information, Hartford Hospital, Hartford, USA
b University of Connecticut Schools of Pharmacy and Medicine, Storrs and Farmington, Connecticut, USA
Accepted for publication March 11, 2002.
* Address reprint requests to Dr Kluger, Arrhythmia Service, Division of Cardiology, 80 Seymour St, Hartford Hospital, Hartford, CT 06102-5037, USA
e-mail: jkluger{at}harthosp.org
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Abstract |
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Methods. This is a randomized, double-blinded, placebo-controlled trial of 220 patients undergoing OHS. Patients (average age, 73 years) received 7 g of oral amiodarone more than 10 days starting 5 days before OHS (slow load; n = 56), a 6 g oral amiodarone regimen more than 6 days starting 1 day before OHS (fast load; n = 64), or matching placebo in one of the two previously mentioned regimens (n = 100).
Results. Patients receiving the slow load amiodarone regimen had a significant reduction in the risk of AF (48.4%; p = 0.013), AF lasting more than 24 hours (76.5%; p = 0.003), symptomatic AF (90.0%; p = 0.002), and recurrent AF (64.5%; p = 0.025) as compared with the placebo. Patients receiving the fast load amiodarone regimen had significant reductions in the risk of AF lasting more than 24 hours (52.6%; p = 0.038) and symptomatic AF (65.0%; p = 0.024), but the incidence of any AF or any recurrence of AF only showed a trend toward significance (34.0% and 45.5%; p = 0.054 and 0.09, respectively).
Conclusions. Oral amiodarone in a slow loading regimen provides significant suppression of all AF factors and can be used when a patient has started it at least 5 days before OHS. If a patient has less than 5 days before OHS, the fast loading regimen is an efficacious alternative as it provides significant benefits in preventing AF from lasting more than 24 hours and for preventing symptomatic AF. Both regimens were well tolerated and safe in elderly patients receiving ß blockade according to the hospital’s standard protocol.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Previous studies have evaluated several pharmacologic strategies to reduce postoperative OHS AF including, ß blockade, sotalol, and amiodarone [6–15]. These strategies have had variable success but were evaluated among patients with a mean age less than 65 years and the sotalol and amiodarone studies had limited background ß blockade [8–15].
In the Atrial Fibrillation Suppression Trial we evaluated an amiodarone dosing strategy that used one of two amiodarone dosing regimens of different intensities and different durations to placebo therapy in an OHS population receiving standard therapy with ß blockade [16]. Our population’s average age was approximately 73 years and preoperative and postoperative OHS ß blockade was used in almost 90% of patients in both groups. This strategy resulted in significant reductions in the risk of AF by 41%, symptomatic AF by 77%, and the risk of cerebrovascular accidents by approximately 77% [16]. However, the effectiveness, tolerability, and safety of either amiodarone regimen alone have not been reported. Without this knowledge, assumptions about individual regimen superiority or similarity in terms of efficacy or safety might lead to suboptimal choices as to which regimen to use in an individual patient. More specifically, in a patient with 5 days until open heart surgery, should the longer duration and larger dose amiodarone regimen be used over the other potentially more convenient regimen?
In this article we compare the effectiveness, tolerability, and safety of two different oral amiodarone regimens to the placebo among patients receiving standard therapy with ß blockade.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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440 msec. Patients were excluded if they had chronic AF, myocardial infarction (MI) less than 3 weeks before OHS, a heart rate less than 45 per minute, advanced heart block, an implantable defibrillator, a history of amiodarone toxicity or treatment with certain interacting drugs (cimetidine, phenytoin, cholestyramine, cyclosporine, or class I and III antiarrhythmic drugs), untreated thyroid disease, serum transaminases more than four times normal. Overall, 1,430 patients were screened to derive our 220 patient sample. The patients who were ineligible for this study were previously described [16]. Patients scheduled for OHS of more than 5 days in the future (slow load; n = 100) were randomized separately from those scheduled less than 5 days but more than or equivalent to 1 day in the future (rapid load; n = 120). In both the slow and fast loading categories, stratified allocation to amiodarone or placebo therapy was performed for patients with valvular surgery and those without valvular surgery (coronary artery bypass grafting alone) to assure equal distribution. The four randomization tables used in the study (slow load and no valve; slow load and valve; fast load and no valve; fast load and valve) were generated using commercially available statistical software. The hospital pharmacy dispensed all study medication (amiodarone or matching placebo) in 200 mg opaque capsules. The drug regimens are delineated in Figure 1.
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As part of the institution’s OHS critical pathway, the preprinted admission order sheet for OHS patients includes ß blockers. Overall, 91% of patients who received the placebo also received ß blockers compared with 88% of those patients who received amiodarone (p = 0.41). Metoprolol was used in 77% of the patients in the placebo group with an average preoperative dose of 146 ± 22 mg compared with the amiodarone group in which metoprolol was used in 81% of the patients with an average preoperative dose of 137 ± 36 mg (p = 0.07 vs placebo).
Electrocardiographic and plasma concentration monitoring
After surgery, patients were admitted to the cardiothoracic intensive care unit and subsequently transferred to a monitored unit. A certified technician continuously monitored the alarm-triggered, electrocardiogram telemetry equipment (Hewlett-Packard, Waltham, MA) and saved the printouts of abnormal rhythms. A study nurse coordinator reviewed the 24-hour report and stored rhythms with a study physician daily for any episodes of arrhythmia. In addition, a 12-lead electrocardiogram was obtained daily and additionally for symptoms or when an arrhythmia was suspected.
The QTc intervals were determined using Bazett’s formula at base line and on postoperative day 2 or 3 as a measure of Vaughn-Williams Class III antiarrhythmic effect [12, 13]. All patients continued the study protocol regardless of the arrhythmia noted or treatment received, and AF was treated under the direction of the attending cardiologist without unblinding.
Using high-performance liquid chromatography, plasma amiodarone, and desethylamiodarone levels were determined on postoperative days 1 and 5 in 63 patients receiving amiodarone therapy [17].
Study endpoints and definitions
The primary endpoint was the development of AF detected by continuous electrocardiogram monitoring. For the purpose of this study the following definitions were used: (1) postoperative AF: any documented atrial fibrillation of more than 5 minutes in duration, (2) symptomatic AF: associated with hemodynamic compromise (ie, hypotension, heart failure) requiring therapy or feeling of subjective discomfort (ie, palpitations, chest pain, shortness of breath, syncope), or both, (3) recurrent AF: development of AF after being in sinus rhythm for more than 24 hours after the first AF episode, (4) cerebrovascular accident: development of a stroke (ie, documentation by an attending neurologist of a focal neurologic deficit lasting > 24 hours with confirmation or cerebral infarction by brain computed tomography or magnetic resonance imaging) or transient ischemic attack (ie, documentation of a focal neurologic deficit lasting for < 24 hours), and (5) ventricular tachycardia: greater than or equal to 30 seconds or requiring treatment for termination.
Tolerability and safety
We contacted patients on day 2 or 3 of outpatient therapy (slow loading regimen only) to ask about any adverse effects and stress the need for compliance. While receiving inpatient therapy, side effects that were reported to the patient’s nurse, physician, or the study investigator (who met with patients daily to fill out the study forms, obtain blood, electrocardiograms, and other factors) were gathered. We continued to follow patients for their entire hospital stay.
Follow-up
During the routine outpatient visit scheduled 3 to 6 weeks after hospital discharge, vital signs and a 12-lead electrocardiogram were recorded. Patients were also queried about intercurrent hospitalizations or emergency room evaluations. Follow-up telephone surveys were performed 1 month after discharge on all surviving patients; the occurrence of adverse events were probed, and the medical records were reviewed by a study investigator.
Statistical analysis
Data were analyzed using the intention to treat principle. Slow loading and fast loading amiodarone groups were compared with the placebo group separately using 1-sided Fisher’s exact test for categorical data and 2-tailed t test for continuous data. Slow loading and fast loading amiodarone groups were also compared with each other using the same statistical tests. Statistical analyses were performed using the SPSS 9.0 statistical software (SPSS Inc, Chicago, IL).
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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The ventricular response rate during AF was significantly lower in both amiodarone groups versus the placebo group (23.2% and 21.8% lower; p < 0.001 for both). Similarly, both active treatment groups had a reduced need for additional rate control or cardioversion when AF occurred as compared with the placebo group. When the active treatment groups were compared directly, the slow load group had less need for additional rate control or cardioversion with chemical or electrical modalities (p = 0.034). The reduced need for cardioversion was the primary contributor to this factor (0% vs 9.4%; p = 0.042) (Table 2).
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Thirty-four patients receiving amiodarone in the rapid loading regimen and 24 amiodarone patients receiving the slow loading regimen had plasma sampled for amiodarone and desethylamiodarone concentrations. Patients receiving rapid loading achieved similar plasma amiodarone and desethylamiodarone levels on postoperative day 1 (0.114 ± 0.108 g/dL vs 0.165 ± 0.105 g/dL; p = 0.67) and (0.078 ± 0.085 g/dL vs 0.089 ± 0.082 g/dL; p = 0.82) and postoperative day 5 (0.359 ± 0.125 g/dL vs 0.367 ± 0.047 g/dL; p = 0.71) and (0.213 ± 0.108 g/dL vs 0.213 ± 0.080 g/dL; p = 0.98) when compared with the slow loading group, respectively.
There was a 38% reduction in the need for defibrillation to initiate the heartbeat in the operating room among those subjects receiving the slow load amiodarone regimen versus the placebo (p = 0.024).
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Logistically, providing the slow load patients their drug during preadmission testing was more difficult than the fast loading regimen because the slow load strategy relies on patients to take the drug on their own for 5 preoperative days. In addition, the fast load regimen could have beenused by all patients in our institution regardless of their time before surgery, which could allow easier implementation of this program system-wide.
We found that the slow loading group achieved superior results to the placebo for several AF factors, including any occurrence of AF, the occurrence of symptomatic AF, and the recurrence of AF. Although the fast loading group achieved superior results to the placebo group for many AF factors, such as symptomatic AF, this group did not have significantly lower incidences of any AF episode and recurrent AF. In addition, the slow loading group demonstrated qualitatively better effects than the fast loading group for every AF factor evaluated. Patients in the slow loading amiodarone group did not need cardioversion by chemical or electrical means, and that was significantly lower than what was seen in the fast loading amiodarone group.
The reasons for qualitative AF incidence differences between amiodarone groups in our study are not entirely clear. In our study, 7 g of amiodarone begun 5 days before OHS and continuing until postoperative day 4 reduced the AF incidence by 48.4%, whereas 6 g of amiodarone begun 1 day before OHS and continued until postoperative day 4 reduced AF by 34.0%. The differences could be related to the total dose delivered, the duration of therapy, or just by chance (given our lack of adequate power for this type of analysis).
Previous evaluations of oral amiodarone in OHS patients do not help to determine the answers; moreover the study with the highest dose delivered was also the one with the longer duration of loading. Daoud and colleagues [8] used a 13-day preoperative loading period with therapy continuing to hospital discharge. An average dose of 4.8 g of amiodarone was delivered. A 53% reduction in AF incidence was found; ß blocker usage was 41% in the amiodarone group, and the average age was 57 years in the amiodarone group. In a study by Redle and colleagues [9], a dose of 2 g was administered to OHS patients (average age 63 years, beginning 1 to 4 days preoperatively). These authors only showed a nonsignificant 25% reduction in the risk of AF even though the use of ß blockade was low (59%). However, a study by Hohnloser and colleagues [10] used 4.5 g of intravenous amiodarone over 4 days and did not start therapy until after the OHS. Because oral amiodarone has a bioavailability of approximately 50%, this dose is the equivalent of 9 g of the oral drug. The incidence of AF was reduced by 76% in this study. The average age in the amiodarone group was 59 years and the use of ß blockade was not specified. This study shows that an extended preoperative loading time before OHS is not a requirement for efficacy, but it does not identify whether a longer loading time has intrinsic value in suppressing AF.
When we evaluated the concentrations of amiodarone and its active metabolite, desethylamiodarone, on postoperative days 1 and 5, no differences were noted. However, the QTc interval, a surrogate for the degree of Class III antiarrhythmic effect, showed a trend toward being higher in the slow load amiodarone group compared with the fast load group. Hence the concentrations in the plasma may not fully represent the myocardial tissue concentrations of amiodarone and desethylamiodarone. Previous studies have shown a disconnection between the plasma concentrations of amiodarone and the electrophysiologic effects caused by amiodarone therapy [18, 19]. Unfortunately it is not known whether the increased QTc effects are caused by the higher dose given in the slow loading group, the extended duration of therapy, or both.
The slow loading amiodarone group exhibited significant reductions in needing postoperative OHS defibrillation to initiate the heartbeat as compared with the placebo group, whereas the fast load group did not. Reductions in cerebrovascular accidents and ventricular tachycardia were noted in both amiodarone groups versus the placebo group, but with the small number of events overall, these did not achieve significance. The similar qualitative reductions in cerebrovascular accidents between the two amiodarone groups may be explained by the reductions in the duration of AF in both groups (AF lasting > 24 hours) and the similar reductions in the ventricular response rate when AF occurred [16]. These were both found to be predictors for cerebrovascular accidents in the analysis of our total Atrial Fibrillation Suppression Trial population and were previously reported [16]. Our 7% incidence of cerebrovascular accidents in an elderly population who could receive coronary artery bypass operations, valvular operations, or both, is not out of line with previous studies. Of the 67,764 patients undergoing surgery at 22 centers in the United States, the rate of postoperative neurologic events (stroke, transient ischemic attack, coma) was 10.2% among elderly patients [20].
No qualitative differences were noted between the two amiodarone groups and the placebo group in terms of intensive care unit length of stay or hospital length of stay. However, this is not surprising since AF was usually initiated on postoperative day 2 to 4, and the average hospital stay was more than 9 days in the study for all groups.
Both amiodarone therapies were well tolerated. The fast loading amiodarone group had more nausea than placebo, whereas the slow load group did not. This may be related to the high dose of amiodarone given orally on the day before surgery and the day of surgery in comparison with the slow load group. However, the slow loading group showed a trend toward a greater need for ventricular pacing as compared with the fast loading group. Neither adverse effect has important clinical relevance though as the nausea did not result in therapy discontinuation to a greater extent than the placebo, and pacemaker wires are placed prophylactically in all patients anyway.
Because the slow loading amiodarone group showed qualitatively better results in several AF indicators and was the only regimen to reduce the incidence of any AF and recurrent AF, the clinical implications to continue using this regimen when a patient has 5 preoperative days before surgery makes sense. Our study shows that both amiodarone loading regimens are effective at preventing symptomatic AF, reducing the need for additional rate control or cardioversion when AF occurs, and slowing the ventricular response rate of AF, which suggests that the fast loading regimen is warranted when a patient does not have 5 preoperative days before surgery. Both therapies can be used safely in an OHS population.
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Acknowledgments |
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References |
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80 years: results from the national cardiovascular network. J Am Coll Cardiol 2000;35:731-738.This article has been cited by other articles:
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  A. Sezai, M. Hata, T. Niino, Y. Kasamaki, T. Nakai, A. Hirayama, and K. Minami Study of the factors related to atrial fibrillation after coronary artery bypass grafting: A search for a marker to predict the occurrence of atrial fibrillation before surgical intervention J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 895 - 900. [Abstract] [Full Text] [PDF]
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 B. J. Barnes, E. A. Kirkland, P. A. Howard, D. W. Grauer, M. E. Gorton, J. B. Kramer, G. F. Muehlebach, and W. A. Reed Risk-stratified evaluation of amiodarone to prevent atrial fibrillation after cardiac surgery. Ann. Thorac. Surg., October 1, 2006; 82(4): 1332 - 1337. [Abstract] [Full Text] [PDF]
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 J. Dunning and P. McKeown Are the american college of chest physicians guidelines for the prevention and management of atrial fibrillation after cardiac surgery already obsolete? Chest, April 1, 2006; 129(4): 1112 - 1113. [Full Text] [PDF]
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 M. E. Craycraft Amiodarone prophylaxis. Ann Intern Med, February 21, 2006; 144(4): 303 - 303. [Full Text] [PDF]
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J. D. Aasbo and R. G. Trohman Amiodarone Prophylaxis Ann Intern Med, February 21, 2006; 144(4): 303 - 303. [Full Text] [PDF]
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 L. B. Mitchell, D. V. Exner, D. G. Wyse, C. J. Connolly, G. D. Prystai, A. J. Bayes, W. T. Kidd, T. Kieser, J. J. Burgess, A. Ferland, et al. Prophylactic Oral Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization, Valve Replacement, or Repair: PAPABEAR: A Randomized Controlled Trial JAMA, December 28, 2005; 294(24): 3093 - 3100. [Abstract] [Full Text] [PDF]
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J. D. Aasbo, A. T. Lawrence, K. Krishnan, M. H. Kim, and R. G. Trohman Amiodarone Prophylaxis Reduces Major Cardiovascular Morbidity and Length of Stay after Cardiac Surgery: A Meta-Analysis Ann Intern Med, September 6, 2005; 143(5): 327 - 336. [Abstract] [Full Text] [PDF]
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R. J. DiDomenico and M. G. Massad Pharmacologic Strategies for Prevention of Atrial Fibrillation After Open Heart Surgery Ann. Thorac. Surg., February 1, 2005; 79(2): 728 - 740. [Abstract] [Full Text] [PDF]
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 J. Dunning, P. Botha, and M. Amanullah Prophylactic Amiodarone effectively prevents post-operative atrial fibrillation Interactive CardioVascular and Thoracic Surgery, September 1, 2004; 3(3): 510 - 515. [Abstract] [Full Text] [PDF]
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 C. M. White, M. F. Caron, J. S. Kalus, H. Rose, J. Song, P. Reddy, R. Gallagher, and J. Kluger Intravenous Plus Oral Amiodarone, Atrial Septal Pacing, or Both Strategies to Prevent Post-Cardiothoracic Surgery Atrial Fibrillation: The Atrial Fibrillation Suppression Trial II (AFIST II) Circulation, September 9, 2003; 108(90101): II-200 - 206. [Abstract] [Full Text] [PDF]
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T. Yagdi, S. Nalbantgil, F. Ayik, A. Apaydin, F. Islamoglu, H. Posacioglu, T. Calkavur, Y. Atay, and S. Buket Amiodarone reduces the incidence of atrial fibrillation after coronary artery bypass grafting J. Thorac. Cardiovasc. Surg., June 1, 2003; 125(6): 1420 - 1425. [Abstract] [Full Text] [PDF]
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M. H. Drucker and I. Smith A simplified amiodarone regimen to prevent postoperative atrial fibrillation Ann. Thorac. Surg., June 1, 2003; 75(6): 2008 - 2008. [Full Text] [PDF]
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