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Ann Thorac Surg 2004;77:1288-1292
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Indicators of atrial fibrillation risk in cardiac surgery patients on prophylactic amiodarone

^a College of Medicine, University of Connecticut, Hartford, Connecticut, USA
^b College of Pharmacy, University of Connecticut, Hartford, Connecticut, USA
^c Hartford Hospital, Department of Pharmacy, Hartford, Connecticut, USA
^d Hartford Hospital, Department of Cardiothoracic Surgery, Hartford, Connecticut, USA
^e Hartford Hospital, Department of Cardiology, Hartford, Connecticut, USA
^f University of Rhode Island College of Pharmacy and Rhode Island Hospital Department of Pharmacy, Providence, Rhode Island, USA

Accepted for publication September 15, 2003.

^* Address reprint requests to Dr Coleman, Department of Pharmacy Practice, Pharmacoeconomic and Outcomes Studies Group, College of Pharmacy, University of Connecticut, Hartford Hospital—Drug Information Center, 80 Seymour St, Hartford, CT 06102, USA.
e-mail: ccolema{at}harthosp.org

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
BACKGROUND: Atrial fibrillation is a common complication of cardiothoracic surgery (coronary artery bypass graft surgery or cardiac valve repair or replacement). Although predictors of postoperative atrial fibrillation have been explored in patients not receiving prophylactic antiarrhythmic therapy, independent predictors of postoperative atrial fibrillation in patients receiving prophylactic amiodarone have not been elucidated.

METHODS: This was a substudy of a clinical trial evaluating the efficacy of an amiodarone regimen or an atrial-septal pacing strategy on the occurrence of postoperative atrial fibrillation. The association between the occurrence of postoperative atrial fibrillation and preoperative, intraoperative, and postoperative data from the total study population and the amiodarone and placebo subpopulations were explored using multiple logistic regression analysis.

RESULTS: The following clinical factors were independent predictors of postoperative atrial fibrillation in the total population: age (p < 0.001), history of atrial fibrillation (p = 0.021), diabetes mellitus (p = 0.008), and high-dose postoperative nonsteroidal antiinflammatory drug use (p = 0.038). Age (p = 0.016), history of mitral regurgitation (p = 0.029), heart failure (p = 0.010), and postoperative nonsteroidal antiinflammatory drug use (p = 0.038) were independent predictors when amiodarone was used, and age was the only predictor of postoperative atrial fibrillation (p = 0.024) among patients treated with placebo.

CONCLUSIONS: This subanalysis demonstrates some novel predictors of postoperative atrial fibrillation, including diabetes mellitus and postoperative nonsteroidal antiinflammatory drug use. We have also demonstrated that predictors of atrial fibrillation differ when prophylactic amiodarone is used.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication after cardiothoracic surgery (CTS; coronary artery bypass grafting or valve repair or replacement surgery), occurring in up to 50% of patients without prophylaxis [1]. Postoperative atrial fibrillation increases the risk of hemodynamic instability and stroke while lengthening intensive care and total hospitalization time [2]. ß-Blocking agents and amiodarone have been found to be successful strategies for preventing POAF [2]. As such, most hospitals have CTS clinical pathways that use strategies to reduce the incidence of POAF. This carte blanche approach allows all patients without contraindications to be treated with a therapy that will prevent only some patients from experiencing POAF. However, some patients will still experience POAF despite prophylactic therapy and others would never have developed POAF in the first place. These patients are exposed to therapies with potential adverse events and that increase cost of care. Determining predictors of POAF could allow therapy to be targeted to those most likely to experience benefit and minimize exposure among those unlikely to receive benefit.

The published literature contains limited data, which demonstrate that certain preoperative and postoperative clinical factors are multivariate predictors of POAF. Only age has consistently been shown to be a multivariate predictor of POAF, although many other factors have been suggested [3–6]. None of these prospective studies evaluated independent predictors of POAF specifically among patients receiving prophylactic antiarrhythmic therapy.

This is a planned subanalysis of the second Atrial Fibrillation Suppression Trial (AFIST II) [7]. Our subanalysis objective was to determine multivariate predictors of POAF in our total CTS population, in which more than 80% received postoperative ß-blockers, as well as in subgroups of CTS patients randomized to either amiodarone or placebo prophylaxis.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
The methodology used in the Atrial Fibrillation Suppression Trial II has been presented previously [7]. In brief, patients scheduled to undergo CTS were randomized to either amiodarone (1,050 mg intravenously on the day of surgery, then 400 mg by mouth three times daily on postoperative days 1 to 4; [Cordarone, Upsher-Smith Laboratories, Minneapolis, MN]) or placebo, and then to an atrial septal pacing strategy or no pacing for 4 postoperative days, in a 2 x 2 factorial design. As a standard of care, more than 82% of patients in the Atrial Fibrillation Suppression Trial II received ß-blockers postoperatively regardless of drug randomization. Patients were monitored continuously with telemetry, and episodes of POAF (any POAF lasting 5 minutes) were prospectively recorded over 5 postoperative days. Preoperative, intraoperative, and postoperative data were collected prospectively.

In this analysis, we examined the association between the occurrence of POAF and preoperative, intraoperative, and postoperative data from the study population overall and in the amiodarone and placebo populations separately (univariate analysis). All variables with a p value of less than or equal to 0.2 in the univariate analysis were entered into a multivariate logistic regression model. As with univariate analysis, multivariate regression was performed for the total population and separate amiodarone and placebo subpopulations. Variables that were not identified as univariate predictors of POAF, but which have been previously identified as predictors, were also included into the multivariate model. In the multivariate model, variables were selected by stepwise, backward elimination, and a p value less than 0.05 was considered significant. Odds ratios and 95% confidence intervals were calculated for independent predictors of POAF. All statistics were calculated using SPSS v.11.0 (SPSS Inc, Chicago, IL).

The study was approved by the institutional review board in March 2000, and all enrolled patients provided informed consent before randomization.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
As demonstrated in Table 1, patient (n = 160) demographics and clinical characteristics were similar among the amiodarone and placebo groups [7]. In summary of the main study results, atrial fibrillation occurred in approximately 31% of patients. Amiodarone significantly reduced the occurrence of POAF by approximately 43%, whereas atrial septal pacing had no impact on the rate of POAF. A total of 33 preoperative, intraoperative, and postoperative variables were evaluated by univariate analysis for the total population and the separate amiodarone and placebo groups. These variables are listed in Table 2.

View larger version (27K): [in this window] [in a new window]   Fig 1. Multivariate predictors of postoperative atrial fibrillation. This figure presents the multivariate analyses of the total population, and the amiodarone and placebo subgroups. Confidence intervals (arrows) falling completely to the left of 1 represent factors that decrease the risk of developing postoperative atrial fibrillation. Those falling completely to the right of 1 represent factors that increase the risk of developing postoperative atrial fibrillation. (AF = atrial fibrillation; BBL = ß-blocker; CI = confidence interval; DM = diabetes mellitus; MR = mitral regurgitation; OR = odds ratio; POAF = postoperative atrial fibrillation; NSAID = nonsteroidal antiinflammatory drug.)

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

Age was the only multivariate predictor of POAF present in the total population as well as in the individual amiodarone and placebo groups. Age was actually the only multivariate predictor in the placebo group. Finding that age is an independent predictor of POAF in the total population is consistent with the available literature [3–6].

Among those treated with prophylactic amiodarone after CTS, patients with a history of heart failure, mitral regurgitation, or postoperative NSAID use were still at increased risk of developing POAF despite prophylaxis. All three of these factors can contribute to an increase in atrial pressure either through backward blood flow through the mitral valve or through increased sodium and fluid retention. Elevated atrial pressure in experimental models leads to induction of atrial fibrillation [10], and the severity of heart failure is associated with the incidence of atrial fibrillation in nonoperative situations [11]. The use of high-dose NSAIDs may also be an indirect marker of pericarditis, which has also been shown in nonoperative situations to induce atrial fibrillation [12]. The use of high-dose NSAIDs was an independent predictor of POAF in the total population as well.

Diabetes mellitus has not been previously identified as a predictor of POAF but was a predictor in our overall population. Diabetes mellitus has been described as an independent predictor of atrial fibrillation among nonoperative patients in the Framingham Heart Study [13]. One explanation for atrial fibrillation in diabetic patients could be related to autonomic neuropathy. Autonomic neuropathy blunts parasympathetic activity, allowing for a state of relative sympathetic excess [14]. Removal of the parasympathetically innervated aortic fat pad during CTS greatly increased the risk of POAF in one study as compared with patients in whom the fat pad was left intact [15]. This surgical parasympathetic withdrawal could induce POAF similarly to autonomic dysfunction in diabetic patients. Interestingly, diabetes mellitus was not an independent predictor of POAF among patients treated with prophylactic amiodarone. This could be expected as amiodarone has antiadrenergic properties, which could help to rebalance myocardial sympathetic and parasympathetic tone.

The finding that history of angina or preoperative ß-blocker use are negative risk factors could relate to the fact that patients possessing these characteristics might be more likely in the postoperative period to receive adequate doses of ß-blockers. The finding that risk of POAF is decreased with increasing number of grafts anastamosed is opposite to what one might expect [9]. We do not have a solid explanation for this finding. However, it may be possible that history of angina, use of preoperative ß-blockers, and larger number of grafts represent the population not undergoing valve surgery. This would make sense because valvular surgery is associated with greater POAF incidence in several studies.

Identification of patient factors associated with the occurrence of POAF may be important because prophylactic strategies targeted to these patients would have a better risk-benefit profile. Our study has determined that even with standard-of-care ß-blocker prophylaxis there are still potent independent predictors for POAF. The patients receiving the addition of amiodarone to standard-of-care therapy also have several independent predictors of POAF remaining. These patients may be good future targets for additional drug, device, or other prophylactic strategy. Unfortunately, our present study does not determine whether or not amiodarone therapy per se is especially beneficial in higher risk patients or not beneficial with the exclusion of the higher risk patients.

The typical limitations of logistic regression analysis apply to our study. First, the results of a logistic regression analysis are partially dependent on the patient variables that were entered into the model. As such, collection and inclusion of different patient data could have changed the findings of our analysis. However, we used accepted methodology and a reputable statistical software package to analyze our data. Another limitation is that logistic regression only demonstrates an association between the dependent and independent variables and does not demonstrate causality. Therefore, these results should be interpreted cautiously. Although this was a prespecified subanalysis of a larger clinical trial, the primary purpose of our design was not to evaluate indicators of POAF. Therefore, results may have been different if the study had been designed specifically for this purpose. Finally, our sample size was relatively small, which could explain some of the unexpected findings in our analysis.

This multivariate analysis of a large prospective study provides insight into the variables that may predict POAF both in the general CTS population and in those receiving a postoperative amiodarone prophylaxis strategy. Age and disorders or drugs that increase atrial pressures are independent predictors of POAF among patients receiving amiodarone prophylaxis.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
This study was funded in part by The Hartford Hospital Research Foundation. Oral amiodarone and placebo tablets were provided by Upsher-Smith Laboratories (Minneapolis, MN), and pacemakers were provided by Medtronic, Inc (Minneapolis, MN). James S. Kalus, PharmD, is funded in part by the American College of Clinical Pharmacy/Merck Cardiovascular Therapeutics Fellowship Award.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hiroyoshi Takata Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalus, J. S. Articles by Kluger, J. Search for Related Content PubMed PubMed Citation Articles by Kalus, J. S. Articles by Kluger, J. Related Collections Electrophysiology - arrhythmias