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Ann Thorac Surg 2006;82:1332-1337
© 2006 The Society of Thoracic Surgeons
a Department of Pharmacy Practice, School of Pharmacy, The University of Kansas Medical Center, Kansas City, Kansas
b Mid America Thoracic and Cardiovascular Surgery, Inc, The University of Kansas Hospital, Kansas City, Kansas
Accepted for publication April 24, 2006.
* Address correspondence to Dr Barnes, Pharmacy Practice, The University of Kansas Medical Center, Mail Stop 4047, 3901 Rainbow Blvd, Kansas City, KS 66160-7231 (Email: bbarnes{at}kumc.edu).
| Adult cardiac surgery:
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.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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METHODS: A retrospective, observational analysis of 509 patients who underwent cardiac surgery in 2003 was performed. Data sources included The Society of Thoracic Surgeons national database; medical and medication administration records; and the activity-based cost data from our institution. Risk stratification for POAF was determined using a validated risk index. Cost-effectiveness was determined from the hospital's perspective.
RESULTS: The mean patient age was 63 years, 27% were female, 80% underwent coronary artery bypass grafting, and 29% underwent valve surgery. When a risk-stratified evaluation was made, 50% of patients were at an elevated risk for having POAF develop. When compared with nonprophylaxed patients, those receiving AMP (59%) experienced less POAF (31% vs 22%; p = 0.027) and shorter durations of POAF (4.7 vs 2.7 days; p = 0.025). In the elevated-risk group, AMP clinically (but not significantly) reduced length of stay in the intensive care unit (101 vs 68 hours; p > 0.05) and post-procedural hospital length of stay (9.7 vs. 7.9 days, p > 0.05). In the elevated-risk group, AMP was robustly cost-effective in reducing POAF.
CONCLUSIONS: Amiodarone prophylaxis reduced the prevalence and duration of POAF. Baseline risk for POAF was a major determinant of the overall cost-effectiveness of AMP. The greatest cost savings with AMP was seen in patients at an elevated risk for POAF. These findings suggest the need for risk stratification when prescribing AMP.
Atrial fibrillation is the most common cardiac arrhythmia occurring after cardiothoracic surgery. Thirty-two percent of patients will experience postoperative atrial fibrillation (POAF), most frequently on the second and third postoperative days [1]. Postoperative atrial fibrillation has been associated with an increase in neurological, renal, and infectious complications, as well as an increase in mortality, hospital length of stay (LOS), and overall hospital costs [1–3].
Among the possible preventive strategies, the use of prophylactic amiodarone has demonstrated the most promise. To date, 19 prospective, controlled-clinical trials have documented the efficacy of amiodarone prophylaxis (AMP) for the prevention of POAF [2–20]. A pooled analysis found that AMP reduced the relative risk of POAF by 38% [21]. However, the safety and effectiveness of AMP in patients at low risk of having POAF develop has been questioned. Of increasing concern is the association of amiodarone with potentially fatal organ derangements [22–25]. The risk-benefit ratio of short-term AMP in cardiac surgery patients has not been adequately evaluated. Moreover, the impact of baseline risk for POAF has only been evaluated by one pharmacoeconomic study [26].
This study investigated the use of AMP in a patient cohort stratified for risk of having POAF develop after cardiac surgery. Specifically, we assessed the impact of AMP on the prevalence of POAF, the intensive care unit (ICU) and hospital LOS, and its cost-effectiveness.
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Patients and Methods |
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18 years of age) without chronic atrial fibrillation were included in the study. Subjects with incomplete medical information were excluded. Patients undergoing cardiac surgery were prescribed AMP at their surgeon's discretion. Study groups were categorized by the administration of AMP and the development of POAF.
Risk Stratification for POAF
Using a previously validated model, we stratified patients into 3 risk groups: (1) low, (2) moderate, and (3) high risk [1]. Model variables that increased the risk of having POAF develop included: advancing age, a history of atrial fibrillation or chronic obstructive pulmonary disease, patients undergoing heart valve surgery, or patients whose beta-blockers or angiotensin converting enzyme inhibitors are withdrawn after surgery. Variables that decrease the risk of having POAF develop include the use of postoperative beta-blocker alone, both preoperative and postoperative beta-blockade or angiotensin converting enzyme inhibition, postoperative nonsteroidal anti-inflammatory drugs, or postoperative potassium supplementation. Each of these variables possess their own contribution weights. When the weights are totaled, patients are classified as low risk (< 14 points), moderate risk (14 to 31 points), or high risk (> 31 points). We combined patients in the moderate-risk and high-risk groups into a single elevated-risk group.
Data Sources
Data sources included institutional specific data located in the national database of The Society of Thoracic Surgeons, medical charts, medication administration records, and activity-based cost data from our institution. Study data included 184 different variables for each patient. All data was maintained using Microsoft Excel, version 2003 (Microsoft Corp, Redmond, WA).
End Points and Definitions
To evaluate the impact of AMP on POAF in the entire and risk-stratified cohorts we determined the occurrence of POAF by reviewing ICU and ward flow sheets for each patient day. Throughout hospitalization, patients were monitored by continuous telemetry. Trained nurses recorded each patient's cardiac rhythm no less than every 4 hours. Postoperative atrial fibrillation was documented as having occurred if greater than 4 hours of new onset atrial fibrillation was recorded on the flow sheet. The number of days that POAF was experienced and its recurrence were also recorded. Variables regarding amiodarone and other drug therapy (including dose, route, frequency, duration, and dates and times of administration) were collected from medication administration records. Drug administration to the patient was verified by reviewing Pyxis MedStation 2000 (Cardinal Health, San Diego, CA) dispensing records. Amiodarone prophylaxis was defined as documented administration of greater than or equal to 1 day of either intravenous or oral amiodarone, or a combination of both routes, between postoperative days 0 to 4, prior to the onset of any POAF. Timing of amiodarone administration was compared with the onset of POAF to verify patients had received amiodarone as prophylactic therapy. To assess what influence AMP and POAF had on duration of hospitalization, we analyzed LOS for the ICU (in hours) and hospital (in days). To determine the cost-effectiveness of AMP we obtained activity-based cost data from the Charge Description Master database (Chargemaster Suite, Nampa, ID 83687) maintained by the Department of Product Line Management at our institution.
Statistical and Power Analysis
All statistical analyses were performed using SPSS, version 13.0 (SPSS, Inc, Chicago, IL). We established an a priori 
level of 0.05 to indicate statistical significance. Chi-squared tests were used to evaluate the impact of AMP on the prevalence of POAF (and other categorical data). This outcome had a power of 70% and 80% in the entire cohort and elevated-risk groups, respectively, but was underpowered in the low-risk group, given the small effect size (6% difference between groups). Odds ratios with 95% confidence intervals and relative-risk reductions were also calculated. Two-tailed t tests were used to determine what influence AMP and POAF had on ICU and hospital LOS (and other continuous variables). Cost-effectiveness, threshold, and sensitivity analyses were conducted from our hospital's perspective using DATA Pro, release 11 (TreeAge Software, Inc, Williamstown, MA). The effectiveness variable was defined as the percentage of patients who did not develop POAF. For the sensitivity and threshold analyses, we varied the probability of POAF by 20% and hospital costs using the terminal ends of the 95% confidence interval.
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Results |
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Prevalence and Impact of POAF
Development of POAF significantly increased morbidity and costs in our entire cohort. Postoperative atrial fibrillation was significantly associated with advancing age, preoperative atrial fibrillation or lung disease, the presence of preoperative digoxin and diuretic use, and the absence of AMP or nonsteroidal anti-inflammatory drug use. Patients who had POAF develop also experienced more postoperative reintubation and ventilation greater than 24 hours. Overall hospital costs were increased by $9,029 per patient ($25,850 vs $34,879; p < 0.001) when POAF occurred.
Impact of AMP on POAF
In the entire cohort, POAF occurred in 31% of patients (64 of 207) who did not receive AMP, and 22% of patients (67 of 302) who received AMP (odds ratio, 0.64; 95% confidence interval, 0.43–0.95; relative-risk reductions, 28%; p = 0.027). In the low-risk cohort, POAF occurred in 21% of patients (23 of 112) who did not receive AMP, and in 15% of patients (22 of 143) who received AMP (odds ratio, 0.70; 95% confidence interval, 0.37–1.33; relative risk reduction, 25%; p = 0.284). In the elevated-risk cohort, POAF occurred in 43% of patients (41 of 95) who did not receive AMP, and in 28% of patients (45 of 159) who received AMP (odds ratio, 0.52; 95% confidence interval, 0.31–0.88; RR, 34%; p = 0.015). When POAF developed, patients treated with AMP experienced shorter durations of POAF (2.7 ± 2.6 days vs 4.7 ± 6.5 days; p = 0.025) and less recurrence of POAF (36% vs 48%; p = 0.144) when compared with those patients who did not receive AMP.
Impact of AMP and POAF on LOS
Table 2
illustrates the influence of AMP on ICU and hospital LOS. The AMP did not result in statistically significant reductions in either length of ICU or hospital stay. However, in the elevated-risk group, clinically significant reductions in LOS (defined as ICU or hospital discharge occurring at least 24 hours earlier) were noted in patients receiving AMP. Elevated-risk patients receiving AMP spent 32 hours less in the ICU and were discharged 1.8 days earlier after surgery. Development of POAF significantly increased both hospital and ICU LOS. Postoperative atrial fibrillation increased total hospitalization by 4.8 days, postprocedural LOS by 4.5 days, the initial time spent in the ICU by 46 hours, and the total time spent in the ICU by 59 hours (all p < 0.05).
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Comment |
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Although more than 19 randomized controlled trials have evaluated AMP for POAF, only 1 prior study has included over 500 patients. The Prophylactic Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization, Valvular Repair, or Replacement (PAPABEAR) study is the largest prospective, randomized, controlled investigation of oral AMP to date [9]. In that study, 601 patients were randomized to receive either oral AMP (10 mg/kg/day) or a placebo for 6 preoperative days, on the day of surgery, and for 6 postoperative days. With the AMP, the POAF decreased from 29.5% to 16.1%; p < 0.001. The impact of AMP was maintained regardless of age (older or younger than age 65), in patients undergoing isolated coronary artery bypass grafting, in patients undergoing valve surgery with or without coronary artery bypass grafting, or in patients who also received preoperative beta-blocker therapy.
Although the efficacy of AMP has been documented by this and numerous other studies, no trial has investigated the effectiveness of AMP among risk-stratified cohorts. Our study determined that nearly 50% of patients were at elevated risk of having POAF develop, and the impact of AMP was most significant among these high-risk patients. In this study, POAF occurred in 31% of patents not receiving AMP, which is very similar with the prevalence of POAF reported (32.3%) in a large study of 4,657 cardiac surgery patients [1]. Our study also determined that when POAF developed, patients receiving AMP spent 43% less time in atrial fibrillation when compared with those not receiving prophylaxis.
Preoperative and postoperative use of beta-blocking agents is recommended after cardiac surgery to prevent POAF [27]. Furthermore, the addition of AMP to beta blockade has demonstrated large reductions in POAF [5]. In this study, beta blockers were prescribed in 68% of patients preoperatively and 77% of patients postoperatively. Given that POAF occurs most frequently within the first 5 postoperative days, this study defined the use of beta blockade as drug given for greater than or equal to 1 day between postoperative days 0 to 4. Using this definition, 66% of patients were administered postoperative beta-blocker therapy.
Only 3 prospective trials have demonstrated the ability of AMP to significantly decrease LOS [2, 12, 15]. In our study, statistically significant reductions in LOS were not observed. It is notable that clinically significant reductions in LOS were observed in only our patients with elevated baseline risk for POAF.
With varying levels of methodologic sophistication, 12 studies have evaluated the financial impact of AMP on POAF [2, 3, 5, 11, 12, 16, 19, 26, 28–31]. Only one study has investigated the impact of baseline risk on the financial impact of AMP [26]. In this study, Mahoney and colleagues [26] concluded that older patients and those at increased risk of POAF are the most appropriate candidate for AMP. Similarly, we found that AMP was robustly cost-effective in those patients at elevated-risk of having POAF develop.
Limitations of this study include its retrospective design, which could have introduced treatment biases. In addition we were unable to determine if patients had received preoperative outpatient antiarrhythmic therapy. Overall, the baseline demographics were similar between those receiving AMP and those not prescribed prophylaxis. Although documented by trained nurses, the development of POAF was not confirmed by cardiologists.
Documented concerns regarding the safety of amiodarone during long-term therapy have raised questions regarding the safety and tolerability of short-term AMP. Although clinical trials have reported that AMP was well tolerated, and none have suggested significant toxicity, this concern has not been adequately addressed, and further research is needed. Prescribers should be cognizant of both the acute and chronic toxicities of amiodarone and should actively screen for these adverse events.
The findings from this observational study suggest that AMP should be selectively prescribed to patients at elevated risk of having POAF develop. Although our data imply that patients at low risk do not benefit clinically or economically from AMP, the analyses in this group were statistically underpowered. It is possible that this lack of difference is the result of a type II statistical error.
In summary, those patients with advanced age, a history of atrial fibrillation, chronic obstructive pulmonary disease, or valvular heart disease requiring surgery, or a combination of these are often at elevated risk of having POAF develop. The use of AMP should be strongly considered in patients with these medical conditions. To reduce the risk of POAF after cardiac surgery, preoperative and postoperative beta blockers and angiotensin converting enzyme inhibitors should also be prescribed. Our study suggests that in addition to the previously described therapies, AMP significantly decreases the risk and duration of POAF, with the greatest benefits seen in patients with elevated baseline risk for POAF. In these higher-risk patients, AMP was shown to be robustly cost-effective. Similar benefits were not observed with AMP in patients at low risk of developing POAF.
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Acknowledgments |
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