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Ann Thorac Surg 2009;88:886-895. doi:10.1016/j.athoracsur.2009.04.074
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

A Randomized Trial Evaluating Amiodarone for Prevention of Atrial Fibrillation After Pulmonary Resection

James E. Tisdale, PharmDa,b,*, Heather A. Wroblewski, MSNa, Donna S. Wall, PharmDc, Karen M. Rieger, MDd, Zane T. Hammoud, MDd, Jerry V. Young, MDe, Kenneth A. Kesler, MDd

a Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, Indianapolis, Indiana
b Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
d Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
e Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana
c Department of Pharmacy, Indiana University Hospital of Clarian Health Partners, Indianapolis, Indiana

Accepted for publication April 21, 2009.

* Address correspondence to Dr Tisdale, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, W7555 Myers Bldg, WHS, 1001 W 10th St, Indianapolis, IN 46202 (Email: jtisdale{at}iupui.edu).

Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


CARDIOTHORACIC ANESTHESIOLOGY: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Background: Atrial fibrillation (AF) occurs commonly after anatomic pulmonary resection. In this study, the efficacy of amiodarone for prevention of post–pulmonary resection AF was investigated.

Methods: One hundred thirty patients undergoing lobectomy, bilobectomy, or pneumonectomy were randomly assigned prospectively to receive amiodarone (n = 65) or no prophylaxis (control group, n = 65). The amiodarone group received 1,050 mg by continuous intravenous infusion over 24 hours, initiated at the time of anesthesia induction, followed by 400 mg orally twice daily until hospital discharge or for a maximum of 6 days. The primary endpoint was AF requiring treatment during hospitalization. Secondary endpoints included postoperative length of hospital and intensive care unit stays.

Results: There were no significant differences between the amiodarone and control groups in demographics, comorbid conditions, extent of pulmonary resection, or preoperative or postoperative use of β-blockers or calcium-channel blockers. The incidence of AF was lower in the amiodarone group than in the control group (13.8% versus 32.3%, p = 0.02; relative risk reduction = 57%). There was no difference between the amiodarone and control groups in median length of hospital stay (7 versus 8 days, p = 0.79), but median length of intensive care unit stay was shorter in the amiodarone group (46 versus 84 hours, p = 0.03). There was no significant difference between the amiodarone and control groups in the incidence of pulmonary complications or other adverse effects.

Conclusions: Amiodarone prophylaxis significantly reduces the incidence of AF after anatomic pulmonary resection, and is associated with a significant reduction in length of intensive care unit stay.


Dr Tisdale discloses that he has a financial relationship with Astellis Pharmaceuticals.

 

Thousands of patients undergo anatomic pulmonary resection procedures annually. Atrial fibrillation (AF) is a common complication after pulmonary resection, with a reported incidence ranging from 24% to 67% after pneumonectomy [1–6] and 12% to 30% after lobectomy [3–7]. Although rarely an independent cause of mortality, AF after pulmonary resection may result in a variety of adverse symptoms, hemodynamic instability [8], and occasionally stroke [9]. Post–pulmonary resection AF has been reported to prolong the total length of hospital stay by 2 to 3 days [3, 5, 7, 10] and duration of intensive care unit (ICU) stay as much as fourfold [11], with associated increases in hospital costs [6, 10]. Therefore, strategies for prevention of AF after anatomic lung resection may be beneficial.

Amiodarone is an antiarrhythmic agent that has been shown to be effective for the management of AF unrelated to surgery [12, 13]. In addition, numerous prospective trials have reported that amiodarone is effective for prevention of AF after cardiac surgery [14–23]. On the basis of these studies, amiodarone has been recommended for prevention of AF after coronary artery bypass graft surgery (CABG) by the American Heart Association, American College of Cardiology, and European Society of Cardiology (class IIa, level of evidence A) [24] and by the American College of Chest Physicians [25]. Despite the documented efficacy of amiodarone for prophylaxis of post-CABG AF, no prospective randomized data exist regarding its efficacy for prevention of AF after anatomic pulmonary resection.

The purpose of this study was to test the hypotheses that amiodarone is effective and safe for prevention of AF after anatomic pulmonary resection, and that reduction in AF may result in reductions in the duration of postoperative hospital and ICU stays.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Patients
This study was conducted at Indiana University Hospital of Clarian Health Partners, a 270-bed tertiary care hospital, and Wishard Memorial Hospital, a 340-bed acute care hospital, both located in Indianapolis, Indiana. All patients greater than 40 years of age undergoing lobectomy, bilobectomy, or pneumonectomy were evaluated for potential enrollment. Exclusion criteria were as follows: history of AF or atrial flutter; AF or atrial flutter requiring treatment occurring during the surgical procedure; previous severe adverse reaction or contraindication to amiodarone (namely, pulmonary fibrosis, thyroid dysfunction, hepatotoxicity); received a Vaughan Williams class I or III antiarrhythmic drug or other QT-interval–prolonging drug within five half-lives of the administration of amiodarone; pretreatment Bazett's-corrected QT interval greater than 450 ms; and serum alanine transaminase or aspartate transaminase concentrations more than three times the upper limit of normal. This study was approved by the Institutional Review Board at Indiana University-Purdue University-Indianapolis. All patients provided written informed consent before participation.

Study Protocol
This was a prospective, randomized, parallel-group study. A description of patients screened, consenting, randomly assigned, and enrolled in the study is shown in Figure 1. Patients were randomly allocated to receive amiodarone or no amiodarone (control group). The specific randomization sequence was computer-generated. Patients allocated to the amiodarone group received a continuous intravenous infusion of 1,050 mg in 1,000 mL 5% dextrose administered over 24 hours (43.75 mg/hour), which was initiated at anesthesia induction. On postoperative day 1, the amiodarone infusion was discontinued, and oral amiodarone was initiated at a dose of 400 mg orally twice daily for 6 days or until hospital discharge. For patients with a nasogastric tube, a suspension of crushed amiodarone tablets [26] was administered through the tube. Patients assigned to the control group did not receive amiodarone prophylaxis. Postoperative care was per standard protocol, which included limiting total intravenous fluid to 75 mL per hour and analgesia with intravenous and epidural narcotics. Continuous telemetry electrocardiographic monitoring was initiated intraoperatively. After pulmonary resection, patients were admitted either to an ICU or to a non-ICU step-down unit, at the decision of the surgeon according to a standard care plan. Decisions regarding transfer of patients from the ICU to a non-ICU step-down unit and decisions regarding discharge from hospital were made according to standard hospital criteria. Through the hospital course, all study patients underwent continuous telemetry monitoring, which was equipped with a triggered alarm and recording systems for abnormal rhythms. Any patient who had AF, regardless of assignment to receive amiodarone or to the control group, was managed by critical care attending physicians, cardiology consultants, surgical residents, or surgical attending physicians during the course of routine postoperative care with rate control and rhythm conversion strategies as deemed appropriate.


Figure 1
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  		Fig 1. Summary of patients screened, consented, randomized, and included in the study. (AF = atrial fibrillation; bpm = beats per minute; GI = gastrointestinal; LFT = liver function tests; OR = operating room.)

 
Blood for the determination of serum amiodarone and desethylamiodarone (DEA) concentrations was collected in 10-mL nonheparinized evacuated tubes (Vacutainer; Becton Dickinson, Franklin Lakes, NJ) at 9:00 AM on postoperative day 2, before the third oral amiodarone dose. The blood samples were placed on ice, allowed to clot, and then were centrifuged at 2,500 rpm for 25 minutes. Serum was harvested and stored at –70°C until analysis. Serum amiodarone and DEA concentrations were determined using high-performance liquid chromatography (ARUP Laboratories, Salt Lake City, UT) [27]. The lower and upper limits of detection of this assay for amiodarone and DEA were 0.3 µg/mL and 6.0 µg/mL, respectively.

Study Endpoints
The primary endpoint was AF requiring treatment due to a rapid ventricular rate, symptoms such as shortness of breath and fatigue, or hemodynamic compromise [15]. Prespecified secondary endpoints were (1) total postoperative length of hospital stay, (2) length of ICU stay, (3) incidence of adverse effects, and (4) cost of hospitalization from the time of surgery until hospital discharge. An additional post-hoc endpoint was evaluated, which was the incidence of AF (treated or untreated) lasting longer than 30 s [24, 28]. Adverse effects were defined as follows: hypotension (systolic blood pressure < 90 mm Hg); bradycardia (heart rate < 50 beats per minute); and respiratory complications (adult respiratory distress syndrome [ARDS], pneumonia, pulmonary fibrosis, or atelectesis requiring bronchoscopy and/or reintubation). Hospital charges were obtained from the Indiana University Hospital Claims Management Database. Hospital-derived cost-to-charge ratios were applied to convert hospital charges to costs.

Sample Size Determination and Data Analysis
The a priori sample size calculation was based on an expected incidence of AF of 32% in the control group [6]. A sample size of 65 patients per group allows detection of an absolute difference in incidence of AF of 17% (corresponding to a relative risk reduction of 47%) at a power = 0.80 and {alpha} = 0.05. Statistical analyses were performed using the statistical software SPSS 16 (SPSS, Chicago, IL). Analyses were based on the intention-to-treat principle. Normality of continuous data was determined using the Kolmogorov-Smirnov test. Continuous data that were normally distributed were analyzed using Student's unpaired t test. Continuous data that were not normally distributed were analyzed using the nonparametric Wilcoxon rank sum test. Noncontinuous data were analyzed using the {chi}2 test or Fisher's exact test as appropriate. For all analyses, a p value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
Study Population
Between September 2004 and April 2008, 130 patients were enrolled in the study; 65 patients were randomly assigned to each arm (Fig 1). There were no significant differences between the two study groups with respect to demographic characteristics, comorbid conditions, and preoperative or postoperative medications, including β-blockers and calcium-channel blockers (Table 1). The indication for surgery was nonsmall-cell lung cancer in 51 patients (78.5%) and 50 patients (76.9%) in the amiodarone and control groups, respectively (p = 0.76). Other indications for surgery included metastatic or other primary lung neoplasms (amiodarone group, n = 12 [18.5%], control group, n = 11 [16.9%], p > 0.99), and benign pathology (amiodarone group, n = 2 [3.5%], control group, n = 4 [6.2%], p = 0.68). Two patients in the amiodarone group received the 24-hour intravenous infusion, but did not receive any oral amiodarone, because of lack of gastrointestinal access. These patients are included in the intention-to-treat analysis.


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  		Table 1 Characteristics of Patients Enrolled
 
Incidence of AF Requiring Treatment
Overall, 30 patients (23.1%) had AF requiring treatment. The incidence of postoperative AF requiring treatment was significantly lower in the amiodarone group (9 of 65 [13.8%]) than in the control group (21 of 65 [32.3%]; relative risk 0.43; 95% confidence interval [CI]: 0.14 to 0.81; p = 0.02; Fig 2), which corresponds to a 57% reduction in relative risk. Based on an 18.5% reduction in the absolute incidence of AF, the number of patients needed to be treated with prophylactic amiodarone to prevent one episode of AF is 5.4 (95% CI: 2.6 to 18.1). Mean maximum recorded heart rate in the patients who had AF in the amiodarone and control groups was 143 ± 24 versus 154 ± 21 beats per minute, respectively (p = 0.21). The mean time from surgery to the onset of electrocardiographically-documented AF in patients with AF requiring treatment was longer in the amiodarone group than in the control group (87.1 ± 28.8 versus 60.6 ± 37.5 hours), but the difference did not reach statistical significance (p = 0.07). Of the 9 patients in the amiodarone group who had AF, 1 (11.1%) was discharged from the hospital in AF, compared with 4 of 21 patients (19.0%) in the control group (p > 0.99).


Figure 2
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  		Fig 2. Kaplan-Meier cumulative incidence of atrial fibrillation. Log rank p = 0.009.

 
Incidence of AF Lasting Longer Than 30 Seconds
Overall, 31 patients (23.8%) had AF lasting longer than 30 s. The incidence of postoperative AF lasting longer than 30 s was significantly lower in the amiodarone group (9 of 65 [13.8%]) than in the control group (22 of 65 [33.8%]; relative risk 0.41; 95% CI: 0.20 to 0.82; p = 0.001), which corresponds to a 59% reduction in relative risk. Based on a 20% reduction in the absolute incidence of AF lasting longer than 30 s, the number of patients needed to be treated with prophylactic amiodarone to prevent one episode of AF is 5.0 (95% CI: 2.9 to 17.4). Mean maximum recorded heart rate in the patients who had AF lasting longer than 30 s in the amiodarone and control groups was 143 ± 24 versus 155 ± 22 beats per minute, respectively (p = 0.19). The mean time from surgery to the onset of electrocardiographically-documented AF in patients with AF lasting longer than 30 s was longer in the amiodarone group than in the control group (87.1 ± 28.8 versus 62.2 ± 37.4 hours), but the difference did not reach statistical significance (p = 0.08).

Length of Total Hospital Stay, Length of ICU Stay, and Cost of Hospitalization
The mean duration of postoperative hospital stay and ICU stay in the overall study population was 9.8 ± 7.5 days (median 8) and 120.3 ± 185.1 hours (median 68), respectively. Considering all enrolled patients, there was a significant difference in median total duration of hospital stay in patients who had AF requiring treatment as compared with patients who did not (10 versus 7 days, p = 0.03). Median duration of postoperative hospital stay was significantly longer for patients with AF requiring treatment and postoperative respiratory complications (16 days, n = 15) than for patients with AF and no postoperative respiratory complications (9 days, n = 15) or for those who did not have AF requiring treatment (7 days, n = 100, p = 0.002). Median duration of ICU stay was significantly longer for patients who had AF requiring treatment (137 hours) compared with patients who did not (51 hours, p = 0.001).

Using the definition of AF lasting longer than 30 s, median total duration of hospital stay was longer in patients who had AF (10 days) compared with patients who did not (7 days, p = 0.04). There was a significant difference in median duration of ICU stay in patients who had AF lasting longer than 30 s compared with patients who did not (130 versus 52 hours, p = 0.001).

Median total length of postoperative hospital stay in the amiodarone and control groups was similar (7 versus 8 days, respectively; p = 0.79). However, median length of ICU stay was significantly shorter for amiodarone-treated patients (46 versus 84 hours for control group, p = 0.03), translating to a 45% relative reduction in length of ICU stay. Total mean cost of hospitalization in the amiodarone group was $13,453 ± 6,303 compared with $14,445 ± 7,623 in the control group (p = 0.46).

Postoperative Adverse Events/Morbidity/Mortality
Adverse events in the two groups are presented in Table 2. There was no significant difference between amiodarone and control groups with respect to the incidence of hypotension, respiratory complications, or gastrointestinal adverse effects. There was a trend toward a higher incidence of bradycardia associated with amiodarone (4 patients in the amiodarone group versus 1 patient in the control group). Amiodarone therapy was discontinued in 3 patients (4.6%) owing to adverse drug effects: sinus bradycardia in 2 patients (3.1%) and prolongation of the corrected QT (QTc) interval in 1 patient. One of the 2 patients in the amiodarone group for whom the drug was discontinued secondary to bradycardia was also receiving a β-blocker.


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  		Table 2 Postoperative Adverse Events/Morbidity/Mortality
 
There were 3 total operative deaths, 2 in the amiodarone group and 1 in the control group. All deaths were after pneumonectomy secondary to multisystem organ failure. Of the 2 deaths in the amiodarone group, 1 patient died on the ninth postoperative day after hypotension secondary to bleeding that required return to the operating room on the first postoperative day, and the other patient died on the 66th postoperative day after undergoing emergency colectomy on the 11th postoperative day for an ischemic perforation. The patient in the control group who died developed a contralateral pneumonia and ultimately died on the 28th postoperative day.

Serum Amiodarone and DEA Concentrations
Mean serum amiodarone and DEA concentrations in the treatment group on postoperative day 2 were 0.91 ± 0.45 µg/mL and 0.014 ± 0.079 µg/mL, respectively. The mean amiodarone serum concentration was approximately 40% higher in patients who did not have AF, although this difference did not reach statistical significance (0.95 ± 0.47 versus 0.68 ± 0.24 µg/mL, p = 0.10). There was no significant difference in mean serum DEA concentration in patients who did not have postoperative AF (0.016 ± 0.085 µg/mL) compared with patients who did experience postoperative AF (0.00 ± 0.000 µg/mL, p = 0.57).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Atrial fibrillation is a common complication after anatomic pulmonary resection. Mechanisms of AF after pulmonary resection have not been established. Evidence suggests that AF occurring after CABG surgery may be a result of enhanced activity of the sympathetic nervous system, [29] the renin-angiotensin-aldosterone system [30], or postsurgical inflammation [31–33]. Conflicting data exist regarding the influence of inflammation on the occurrence of AF after pulmonary resection. Preoperative and postoperative plasma concentrations of the inflammatory markers interleukin-6 and high-sensitivity C-reactive protein have not been shown to be significantly different in patients who had AF after pulmonary resection compared with patients who did not [34]. However, statin drugs, which have anti-inflammatory properties, have been shown to be associated with a reduction in the incidence of post-pulmonary resection AF [33]. Increased tricuspid regurgitation jet velocity has been shown to be an independent risk factor for AF after noncardiac thoracic surgery, suggesting that elevated right-side heart pressure may have a significant role in the development of AF [35].

Amar and colleagues [9] investigated the efficacy of prophylactic intravenous diltiazem in a randomized double-blind placebo-controlled study conducted in 330 patients undergoing pulmonary resection. Patients randomly assigned to receive diltiazem were administered an intravenous loading dose of 0.25 mg/kg over 30 minutes, followed by 0.1 mg/kg per hour for 18 to 24 hours, initiated upon admission to the postanesthesia care unit. The incidence of postsurgical supraventricular arrhythmias in the diltiazem group was significantly lower (15%) compared with that in the placebo group (25%). There was no significant difference between diltiazem and placebo in total duration of hospital stay or cost of hospitalization. In addition, there was no significant difference between the groups in the incidence of adverse effects, although 3.5% of diltiazem-treated patients required temporary discontinuation of the drug owing to hypotension.

In another prospective, randomized, controlled study, Van Mieghem and colleagues [36] investigated the efficacy of verapamil in 199 patients undergoing pulmonary resection. In this study, verapamil was not significantly more effective than placebo in reducing the incidence of AF. Although β-blockers have been shown to be effective for prevention of AF after CABG surgery [25,37], there are few data regarding the efficacy of β-blockers for prophylaxis of AF after pulmonary resection. Bayliff and colleagues [38] conducted a randomized, placebo-controlled evaluation of oral propranolol for prevention of arrhythmias in 99 patients undergoing lobectomy, pneumonectomy, or esophagectomy. The incidence of postoperative tachyarrhythmias (including AF, atrial flutter, sinus tachycardia, supraventricular tachycardia, and ventricular tachycardia) requiring treatment was 6% in the propranolol group, compared with 20% in the placebo group (p = 0.071). However, the incidence of hypotension and bradycardia was significantly higher among propranolol-treated patients.

Amiodarone is an antiarrhythmic agent that has been shown to be effective for the management of AF not related to surgery [12, 13]. Amiodarone inhibits sodium, potassium, and calcium conductance and possesses noncompetitive {alpha}- and β-blocking activity [13]. The drug's antiarrhythmic effects have been primarily attributed to inhibition of sodium and potassium channels, prolonging atrial repolarization and action potential duration. Although amiodarone has been widely studied for the prevention of AF after cardiac surgery [14–23], the efficacy of amiodarone for prevention of AF after noncardiac thoracic surgery has not widely studied. Lanza and colleagues [6] performed a retrospective analysis of 31 patients who received amiodarone prophylaxis after pulmonary resection, and compared this population to a matched group of 52 patients who did not receive preoperative amiodarone. In this study, amiodarone-treated patients received 200 mg orally every 8 hours, initiated when oral intake was resumed, and continued until hospital discharge. The incidence of AF in the amiodarone group was 9.7%, compared with 33% in the control group, corresponding to an odds ratio of 0.22 (95% CI: 0.059 to 0.829, p = 0.0253).

Van Mieghem and colleagues [39] initiated a prospective randomized investigation of the efficacy of intravenous amiodarone, verapamil, or placebo for prevention of AF after pulmonary resection. However, the investigators terminated the study prematurely, as a result of a high incidence of pulmonary adverse effects associated with amiodarone. The incidence of AF was 4.8% (1 of 21) in the amiodarone group, compared with 0% in the verapamil group (n = 21) and 27.3% (6 of 22) in the placebo group. The results of our prospective, randomized study indicate that intravenous perioperative followed by oral postoperative administration of amiodarone is associated with a 57% reduction in the relative risk of AF after anatomic pulmonary resection. Furthermore, the reduction in AF was associated with a significant reduction in median length of ICU stay; however, it was not associated with a significant reduction in the total length of hospital stay or a corresponding decrease in cost of hospitalization. In our study, the median duration of postoperative hospital stay was significantly longer for patients who had AF as compared with those who did not have AF, independent of group assignment. Although the duration of hospital stay in patients who had AF is influenced by the incidence of associated pulmonary complications, it seems plausible that a reduction in the incidence of AF alone may result in significant decrease in duration of hospital stay and in corresponding costs with a larger sample size or utilizing postoperative care strategies of "fast tracking" for early hospital discharge.

Blood for determination of serum amiodarone and DEA concentrations was obtained on postoperative day 2, which is the average time at which postoperative AF has been reported to occur [23]. Although there was no significant difference in mean serum amiodarone concentrations between patients who had AF and patients who did not, the mean serum amiodarone concentration was approximately 40% higher in patients who did not have AF, a difference that trended toward significance. Further study is required to determine whether a "threshold" serum amiodarone concentration exists for optimal prevention of AF after pulmonary resection, and whether a higher dose of amiodarone may be more effective.

Amiodarone prophylaxis was associated with a relatively low incidence of adverse effects in our study. There were no significant differences between the amiodarone and control groups in the incidence of hypotension, gastrointestinal adverse effects, QTc-interval prolongation, or in-hospital mortality. There was a higher incidence of bradycardia in the amiodarone group. While this difference was not statistically significant, the incidence of bradycardia in the amiodarone group was approximately fourfold higher than that in the control group. In trials of amiodarone for prophylaxis of AF after CABG surgery, the incidence of bradycardia has ranged from 2.7% to 11.7% [17, 18, 21, 24]. Based on the results of this current study, amiodarone-induced bradycardia is a potential complication of AF prophylaxis in post–pulmonary resection patients, although the incidence was relatively low. Electrocardiographic monitoring of patients receiving amiodarone seems prudent until risk factors for bradycardia associated with the drug can be more accurately defined.

Amiodarone therapy has been associated with pulmonary toxicity. Pulmonary fibrosis has been reported in association with oral amiodarone therapy, with an overall incidence of less than 3% [13]. However, pulmonary fibrosis occurs in association with long-term oral therapy, and is most likely related to large cumulative doses [13]. Pulmonary fibrosis has not been reported in association with short-term oral administration. Data have suggested that intravenous amiodarone may be associated with an increased incidence of ARDS in patients undergoing lung surgery. In the study by Van Mieghem and coworkers [39], amiodarone treatment was discontinued as a result of ARDS in 3 of 32 amiodarone-treated patients (9.4%). However, a cumulative intravenous amiodarone dose of 3,750 mg was administered over 3 days in this study. Of note, ARDS is known to occur after pulmonary resection in non–amiodarone-treated patients, with an estimated incidence of 2.45% [40]. A more recent study reported that ARDS developed in none of 43 patients who received lower doses of intravenous amiodarone after pulmonary resection [8]. These data and the results of our present study suggest that lower doses of intravenous amiodarone are safe for patients undergoing lung resection.

The definition of AF used in this study was AF requiring treatment because of a rapid ventricular rate, symptoms such as shortness of breath and fatigue, or hemodynamic compromise [15]. We chose this definition because we wanted the study to reflect clinically important AF; we did not want to consider brief runs of AF that were asymptomatic and did not require treatment, because in practice those would not be of great clinical importance. However, in view of the unblinded nature of the study, we also performed a post-hoc analysis defining AF as any AF that lasted longer than 30 s [24, 28]. When applying this more stringent definition of AF, the results of the study were essentially the same. Therefore, regardless of which AF definition was used, amiodarone significantly reduced the incidence of AF and corresponding length of ICU stay in patients undergoing pulmonary resection in this study.

The 18.5% absolute reduction in the incidence of AF resulting from amiodarone prophylaxis in this study corresponds to a number needed to treat of 5.4. Therefore, to prevent postoperative AF in 1 patient, approximately 5 patients have to be exposed to the potential adverse effects of amiodarone, 4 of whom will not receive benefit from the drug. While amiodarone administration was found to be relatively safe in this study, it is reasonable to question whether the risk of exposing 5 patients to the potential for sinus bradycardia associated with amiodarone is worth prevention of AF in 1 of those patients. Ideally, amiodarone prophylaxis would be administered only to patients in whom AF is most likely to develop, thus avoiding amiodarone exposure for lower-risk patients. However, while risk factors for AF after pulmonary resection have been identified [4], studies of the effectiveness of using risk factor stratification for selecting higher-risk patients for amiodarone prophylaxis have not yet been performed. Further study to determine the utility of risk factor stratification for assigning patients to undergo pharmacologic postsurgical AF prophylaxis is warranted.

Limitations of this investigation include the lack of a double-blind, placebo-control design. We believe, however, that because the treatment of AF was left to the discretion of a physician within a standard institutional care plan, the threshold for treatment of symptoms and hemodynamic instability was similar between the two study groups. Additionally, although our study was adequately powered to identify significant differences in the incidence of AF in an amiodarone-treated group versus a control group, larger studies are necessary to accurately determine differences in postoperative length of hospital stay and cost of hospitalization. Larger studies may also help to identify infrequently occurring adverse effects associated with amiodarone therapy. The findings of this study provide support for a larger multicenter, double-blind, placebo-controlled trial.

Perioperative and postoperative administration of amiodarone reduces the incidence of AF after anatomic pulmonary resection, and is associated with a decrease in duration of ICU stay. Amiodarone prophylaxis of AF should be considered in patients undergoing anatomic pulmonary resection. Further study is required to determine subsets of high-risk patients who would most benefit from amiodarone prophylaxis.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR ARA VAPORCIYAN (Houston, TX): Doctor Tisdale and his group should be congratulated on the presentation of a well-designed and well-executed randomized control trial that demonstrated a significant reduction in postoperative atrial fibrillation in patients undergoing pulmonary resection after receiving a prophylactic dose of amiodarone. Personally, I would also like to thank the authors for providing the manuscript well in advance, which was, like their presentation, clearly written and clearly presented.

Their hypothesis, that amiodarone would reduce the incidence of postoperative atrial fibrillation after pulmonary resection, was based on prior publications by others using this agent in postcardiotomy patients. While it is true that amiodarone has not been studied extensively in patients undergoing pulmonary resection, the excellent Cochrane database review published in 2005 by Sedrakyan and associates in the Journal of Thoracic and Cardiovascular Surgery presented 11 randomized control trials published between 1980 and 2003 addressing this issue. Most of the studies included in that review used digitalis, diltiazem, or β-blockade. While the results of prophylaxis with digitalis was actually counterproductive, excellent results were seen with diltiazem and β-blockade.

Interestingly, they also presented a single randomized control trial examining the efficacy of amiodarone, and that was included in their review. This small trial of 62 patients randomized patients to amiodarone or placebo and was led by Dr Van Mieghem and published in Chest in 1994. In that study, the amiodarone group had an incidence of atrial fibrillation of 3.1% versus nearly 22% in the control group. Unfortunately, their trial failed to reach significance, with a p value of only 0.06. With regard to the present study, the protection from atrial fibrillation was significant, and the number needed to treat with an absolute reduction of approximately 17% was 6. Interestingly, the study by Van Mieghem and associates, if significant, would have led to a similar number needed to treat of only 6 patients. While the current study was unable to demonstrate a reduction in hospital cost or hospital stay, it is not surprising as the majority of other positive studies presented in the Sedrakyan paper also failed to show a significant reduction in hospital stay.

I have three questions for the authors. First, neither in the presentation nor in the manuscript is the frequency of video-assisted thoracoscopic (VATS) resections in the two experimental arms reported. There have been some publications suggesting that a video-assisted technique for lobectomy or bilobectomy may be associated with a reduction in the development of postoperative atrial fibrillation. Clearly, if the frequency of video-assisted techniques were not similar between the two groups, this might be a potential confounding factor. Was the incidence of VATS resection similar in the two groups?

Second, the choice of a randomized control trial is an appropriate experimental design, but why was the decision for the endpoint based on a clinician-dependent variable such as the decision to treat atrial fibrillation? The relevance of this question stems from the fact that if a clinician was so inclined, he or she might subconsciously elect to watch a patient briefly to see if they will spontaneously convert back to a normal sinus rhythm. In fact, the data presented in the paper confirmed that the amiodarone group experienced their atrial fibrillation nearly 27 hours later than the control arm group. While the delay may reflect an impact of the drug on the development of the endpoint, it may also reflect the fact that the patients did not receive treatment.

Last question. You reported that atrial fibrillation developed in 14 patients but they were excluded because the atrial fibrillation developed during the procedure. This is a bit of an outlier since most of our patients develop atrial fibrillation approximately 48 to 72 hours after the procedure. Could you explain that?

DR TISDALE: Thank you very much, Dr Vaporciyan, for your excellent review and those insightful questions. With respect to the first question, the frequency of video-assisted resection: during the time frame in which we conducted the study, we were not performing very many video-assisted resections at our institution. Consequently, there was only 1 patient of 130 in our study who underwent a VATS procedure. Therefore, the frequency of VATS procedures in the two groups was not different, and was not a confounding factor in the study. The fact that only 1 patient in our study underwent a VATS procedure could potentially affect the external validity of the study if VATS procedures are being performed with increased frequency, and we are performing more of them now at our institution. I know that the data regarding the incidence of atrial fibrillation associated with the VATS compared with open thoracotomy are conflicting, but I am aware of a study a couple of years ago by Dr Amar and his group in New York who found an equally high incidence of atrial fibrillation after video-assisted thoracotomy as with open thoracotomy.

With respect to your second question, certainly the ideal study design would be double-blind placebo controlled, and we talked about that as a design for our study. There really were two reasons we didn't use a double-blind placebo-controlled study design. One was that, based on the study you cited, the previous amiodarone study by Van Mieghem and colleagues, we had some concerns about the potential for pulmonary adverse effects in our patients, and our surgeon investigators were a little concerned about the logistics of rapidly unblinding patients in case pulmonary adverse effects developed. Therefore, we decided that for the initial study we would use an unblinded study design. Secondly, we had funding for the study, but we didn't really have enough funding to incorporate the additional cost of a double-blind placebo-controlled design. And so those were the reasons that we didn't use that design.

But with respect to how the unblinded design might affect assignment of patients to amiodarone versus control and the determination that a patient had atrial fibrillation: as you mentioned, and I didn't report this in my presentation, in the amiodarone group, the time to onset of atrial fibrillation was 87 hours compared with 61 hours in the control group. But, this was time to actual onset of electrocardiographically-verified atrial fibrillation, not time to onset of the treatment of atrial fibrillation. And so from that standpoint, I don't think that the unblinded design was biased with respect to assessment of the time of onset of atrial fibrillation, and we don't believe that the unblinded design led to bias in the determination as to whether a patient had atrial fibrillation that required treatment. I certainly can't claim there is not any bias in the study based on the design; all studies, whether double-blind or not, are associated with some biases.

The last question, with respect to the patients who had atrial fibrillation, particularly patients who had atrial fibrillation intraoperatively: all of the patients who we report developing atrial fibrillation as our primary endpoint had postoperative atrial fibrillation. None of the patients included in our primary endpoint assessment had intraoperative atrial fibrillation. One of the a priori exclusion criteria for the study was intraoperative atrial fibrillation. We excluded those patients for a number of reasons. One reason is that intraoperative atrial fibrillation may be different mechanistically than postoperative atrial fibrillation, and we wanted the endpoint of our study to be postoperative atrial fibrillation, rather than a mix of postoperative and intraoperative atrial fibrillation. Also, patients randomized to the amiodarone group, at the time that their intraoperative atrial fibrillation developed, would have received intravenous amiodarone for only an hour or two, and so it really wouldn't be a fair assessment of the efficacy of intravenous amiodarone for prevention of intraoperative atrial fibrillation. And thirdly, the patients in our study who had intraoperative atrial fibrillation were almost immediately treated, which would have confounded the assessment of amiodarone for postoperative atrial fibrillation, and so we excluded those patients for that reason as well. But, among all randomized patients in the study, there was no significant difference in the incidence of intraoperative atrial fibrillation between the two groups.

DR DOUGLAS E. WOOD (Seattle, WA): Doctor Tisdale, since ICU stay was your major significant clinical outcome difference, if a program did not use ICU as a routine part of their posttreatment algorithm, how would that impact the results? And then secondly, what are the implications of the two thirds of patients who get treated and never would have had atrial fibrillation? So what is the impact of treating a large cohort of patients who are not going to get the complication.

DR TISDALE: So your first question is related to, if patients are in a fast tracking sort of situation, what are the implications?

DR WOOD: Well, not even a fast tracking, just if the ICU is not a part of your institution's management of routine lung resections.

DR TISDALE: I think the fact that we didn't show a significant reduction in total duration of hospital stay or cost of hospitalization may cause some institutions to decide not to implement prophylaxis, while other institutions may determine that reducing symptoms and hemodynamic instability may be sufficient reasons to administer prophylaxis. Whether or not to implement atrial fibrillation prophylaxis is probably going to be determined on an individual institution basis. We are considering implementing a prophylaxis protocol for our higher-risk patients at our institution, and so one consideration an institution may think about is targeting high-risk patients.

Could you please repeat your second question? I am sorry.

DR WOOD: The unintended consequence of treating two thirds of patients who are never going to receive the complication.

DR TISDALE: Yes, that is one of the reasons that we would like to try to establish whether risk factors can be used to determine which patients should receive prophylaxis. Perhaps we can use risk factors to assign patients or selectively target them to receive amiodarone for prophylaxis, so that we don't expose 100% of the population to the potential adverse effects of the drug to prevent atrial fibrillation in approximately one third of the patients. The drug was relatively safe in our population, but, still, I agree it may be better to target a higher-risk population than expose all of the patients to amiodarone when only about one third will have atrial fibrillation.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
Supported by a grant from the Gustavus and Louise Pfeiffer Foundation. The authors acknowledge the assistance of Katy Trinkley, Tippu Khan, and Neena Phadke with data collection and obtaining and processing of blood samples.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

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