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(Chest. 2005;128:3421-3427.)
© 2005 American College of Chest Physicians

Statin Use Is Associated With a Reduction in Atrial Fibrillation After Noncardiac Thoracic Surgery Independent of C-Reactive Protein*

David Amar, MD; Hao Zhang, MD; Paul M. Heerdt, MD, PhD; Bernard Park, MD; Martin Fleisher, PhD and Howard T. Thaler, PhD

* From the Departments of Anesthesiology and Critical Care Medicine (Drs. Amar, Zhang, and Heerdt), Clinical Laboratories (Dr. Fleisher), Surgery (Dr. Park), and Epidemiology and Biostatistics (Dr. Thaler), Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY.

Correspondence to: David Amar, MD, Director of Thoracic Anesthesia, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, M-304, New York, NY 10021; e-mail: amard{at}mskcc.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Study objectives: The level of C-reactive protein (CRP) has been shown to be elevated in patients with atrial fibrillation/flutter (AF) unrelated to surgery, and statins are known to lower the CRP level. To determine whether an elevated CRP level predisposes the patient to postoperative AF and whether statin use is associated with a reduced AF incidence, we studied a consecutive group of patients who were at risk for AF after undergoing thoracic surgery (age, ≥ 60 years).

Design and setting: A prospective study in a tertiary care cancer center of 131 patients (mean [± SD] age, 73 ± 6 years) who had undergone major lung or esophageal resection. High-sensitivity CRP and interleukin (IL)-6 levels were measured before surgery, on arrival at the postanesthesia care unit, and on the first morning after surgery. Continuous telemetry was used for 72 to 96 h to detect AF.

Results: AF occurred in 38 of 131 patients (29%) at a median time after surgery of 3 days. Although CRP and IL-6 levels increased significantly (p < 0.001) in response to surgery, patients with or without AF did not differ in perioperative values. In a stepwise logistic regression, statin use was associated with a threefold decrease in the odds of developing AF (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08 to 0.82; p = 0.022) and a greater PR interval (OR, 1.11 per 5-ms increments; 95% CI, 1.01 to 1.22; p = 0.027) predicted an increase in the risk of AF.

Conclusions: The preoperative use of statins was associated with a protective effect against postoperative AF independent of CRP levels. In contrast to AF in the general population, early markers of inflammation did not predict the postoperative occurrence of AF.

Key Words: arrhythmias • complications • inflammation


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Postoperative atrial arrhythmias, and atrial fibrillation/flutter (AF) specifically, are seen in > 20% of elderly patients undergoing noncardiac thoracic surgery.1 Patients with postoperative AF have an extended hospital stay with accompanying increased costs as well as a greater risk of stroke.12 As in patients with AF that is unrelated to surgery, age ≥ 60 years is consistently the only independent preoperative risk factor that is most strongly associated with postoperative AF.123 It is well-known that aging causes degenerative changes in atrial anatomy that are accompanied by related changes in atrial physiology, atrial stiffening, and splitting of the atrial excitation waveform.45 Beyond older age, however, our ability to further identify those patients who are at the greatest risk for postoperative AF is limited. While several medications have been used for the prophylaxis of postoperative AF without risk discrimination, a better understanding of the mechanisms responsible for postoperative AF could help design novel prophylactic or therapeutic measures targeted only to those who are at the greatest risk.1 Statins have recently been shown to confer a protective role against AF after cardiac surgery as well as against AF that is unrelated to surgery.678 These "antiarrhythmic" effects have been attributed largely to the antiinflammatory actions of statins; however, their antioxidant or cell membrane fatty acid-modulating activities may also be responsible for antiarrhythmic effects by altering transmembrane ion channel properties.678

Evidence for an inflammatory contribution to AF after cardiac surgery was initially suggested in a very small study9 showing an elevation in levels of C-reactive protein (CRP)-complement complexes that was greater in patients who developed AF. Unrelated to surgery, single measurements of elevated CRP levels were shown in patients with AF and were thought to represent chronic pathologic changes that are associated with AF such as atrial myocyte loss and eventual fibrosis that are seen with aging.1011 In a small retrospective study,12 we demonstrated that patients who developed AF after major thoracic surgery had a nearly twofold increase in postoperative CRP levels in comparison to control subjects. Therapy with statins was shown to lower CRP levels and to attenuate the duration of AF induced in an experimental model of sterile pericarditis, as well as to decrease interleukin (IL)-6 levels after cardiac surgery.1314 The ability of statins to lower CRP levels has been reported15 following as little as 4 days of therapy. Therefore, this prospective study was designed to extend our initial observations and to test the hypothesis that elevated CRP or IL-6 levels predispose older patients to the risk of postoperative AF after undergoing major thoracic surgery, and that the preoperative use of statins mitigates these inflammatory changes and is accompanied by a reduced incidence of AF.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
From April 2002 until April 2003, all patients who were at high risk for postoperative AF (age, ≥ 60 years), had been scheduled for major thoracic surgery, and met the inclusion criteria were approached to enroll in this study, subject to the availability of research staff. With Institutional Review Board approval and written informed consent, 131 patients who had undergone pulmonary lobectomy (n = 117), pneumonectomy (n = 5), or esophagectomy (n = 9) were studied. Excluded from the study were patients who were not in sinus rhythm prior to surgery, and those receiving therapy with antiarrhythmic class I or III drugs, or systemic corticosteroids. Also excluded from this study were patients who had consented prior to surgery but had undergone an exploratory thoracotomy only (n = 8) or patients who had undergone a minor wedge or segment resection (n = 31) and therefore were at very low risk for AF.3 Statin use prior to the diagnosis and evaluation of a pulmonary neoplasm was recorded. No prophylactic doses of diltiazem or other drugs to prevent postoperative AF were administered. A history of smoking, hypertension, coronary artery disease, diabetes mellitus, and preoperative chemotherapy exposure was recorded. The preoperative therapy with ß-blockers was continued postoperatively to avoid withdrawal. Patients who were receiving calcium channel blockers for hypertension or coronary artery disease resumed therapy with these medications on the first postoperative day. P-wave duration (lead II), PR interval, and heart rate were derived from the preoperative standard 12-lead ECG. Ten-second samples of all 12 leads, simultaneously acquired, were analyzed using software (General Electric Medical Systems; Milwaukee, WI) that measured the mean PR interval and the maximum P-wave duration in lead II. The primary end point of the study was the new onset of AF for > 5 min after being detected by continuous telemetry (ApexPro 7-lead system; General Electric Medical Systems) for 72 to 96 h after surgery or AF episodes requiring intervention because of symptoms or hemodynamic compromise. AF was defined by an irregularly atrial rhythm without clear P waves that was confirmed by a 12-lead ECG. Blood specimens for the measurement of high-sensitivity CRP and IL-6 levels were obtained before surgery, on arrival to the postanesthesia care unit (PACU), and on the first morning after surgery. Serum was separated by centrifugation and stored at –70°C until analysis. IL-6 quantitation was performed on an analyzer (Immulite 1000; Diagnostic Products Corporation; Los Angeles, CA) using sequential immunometric chemiluminescent analysis. The IL-6 assay was calibrated using the first International Standard 89/548 (in international units per milliliter, where 1 IU/mL = 0.07 pg/mL). The analytical characteristics of the assay demonstrate an analytical low-end sensitivity at 5 pg/mL and linearity to 1,220 pg/mL. Within an assay precision of < 5%, the coefficient of variation was obtained at a concentration of 400 pg/mL. The CRP level was measured on an immunochemistry analyzer (Immage; Beckman Coulter; Fullerton, CA) using rate nephelometry. The CRP assay was standardized to the International Federation of Clinical Chemistry Reference Preparation for Plasma Proteins lot CRM470 which was certified by the Bureau of Reference of the European Community. The analytical range is acceptable at 0.02 to 144 mg/dL. Assay precision at all levels of quality control concentration during routine analysis was < 5.2% the coefficient of variation.

Standard anesthesia induction regimens consisting of propofol, 1 to 3 mg/kg, fentanyl, 1 to 4 µg/kg, vecuronium for muscle relaxation, and maintenance of anesthesia consisting of fentanyl and isoflurane in oxygen were used for all patients. The operations were performed using standard thoracotomy approaches that were designed to completely remove all neoplastic disease along with an ipsilateral mediastinal lymph node dissection. Based on surgeon preference, postoperative pain relief was provided to all patients by the continuous administration of either epidural opioid (usually fentanyl with bupivacaine 0.05%) administration (n = 109) or IV opioid (usually morphine) patient-controlled analgesia (n = 22). After an overnight stay in the PACU, patients were transferred to the thoracic surgical floor on the first postoperative day. Major postoperative cardiac or pulmonary complications were recorded throughout the hospital stay. A research assistant monitored patients for major cardiovascular complications (eg, arrhythmia, myocardial infarction, congestive heart failure, or stroke) or pulmonary complications (eg, pneumonia or respiratory failure) as outpatients for 30 days by reviewing computerized physician records or hospital records for intercurrent readmission to our hospital or any other hospital. An investigator reviewed these medical records.

A power analysis was performed to evaluate the ability of preoperative CRP level to distinguish patients who develop postoperative AF. Based on pilot CRP data in similar patients and assuming a 20 to 30% AF rate, it was estimated that a sample size of 130 to 150 patients (30 AF patients) would be required to detect similar differences in CRP level with 90% power at a significance level of 0.05.112 To determine the difference in patient and operative characteristics between patients with and without AF, all variables were examined by univariate analysis (Student t test and Fisher exact test). Due to the nonnormal distribution, CRP and IL-6 data were log-transformed prior to analysis. Receiver operating characteristic (ROC) analysis for AF and CRP or IL-6 levels was performed. Four preoperative variables (baseline CRP level, age, PR interval, and statin use) showing a univariate association (p < 0.2) with AF occurrence were considered in a stepwise logistic regression model. The criterion for entry into the logistic regression equation was p < 0.05. The data are presented as the mean value ± SD, unless otherwise indicated, and p < 0.05 was considered to be significant. Statistical analysis was performed with statistical software packages (SPSS, version 10.0; SPSS; Chicago, IL; and SAS, version 9.0; SAS Institute; Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
Patient characteristics and surgical data based on AF occurrence are presented in Table 1 . AF occurred in 38 of 131 patients (29%; 95% confidence interval [CI], ± 8%) patients, at a median time of 70 h (range, 6 to 164 h) after undergoing surgery. The occurrence of AF in patients using statins before surgery was significantly lower than that in patients who were not (4 of 38 patients [11%] vs 27 of 93 patients [29%], respectively; p = 0.025). Among the patients receiving statins, 15 (48%) received atorvastatin, 10 to 20 mg/d, 13 (42%) received simvastatin, 10 to 40 mg/d, and 3 (10%) received pravastatin, 20 to 40 mg/d. The reasons for receiving statins were hyperlipidemia in 26 of 31 patients (86%) and atherosclerotic cardiovascular disease in 5 of 31 patients (14%). Patients receiving statins had a greater incidence of hypertension (p = 0.03) and coronary artery disease (p < 0.0001), had greater use of ß-blockers (p = 0.04) and nonsteroidal antiinflammatory drugs (p = 0.02), and had a lower PR interval (p = 0.007) [Table 2 ].


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  		Table 1.. Patient Characteristics*

 

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  		Table 2.. Patient Characteristics and Statin Therapy

 
There was a trend for AF patients to be older (73 ± 7 vs 70 ± 6 years of age, respectively; p = 0.07). AF patients had a significantly greater PR interval when compared to patients without AF (170 ± 23 vs 161 ± 22 ms, respectively; p = 0.04). The incidence of postoperative AF did not differ significantly between patients who did or did not have epidural analgesia (34 of 109 patients [31%] vs 4 of 22 patients [18%], respectively; p = 0.30). CRP levels in both groups increased significantly on the first postoperative day in comparison to preoperative values (p < 0.0001) [Table 3 ]. IL-6 levels in both groups were greater when measured in the PACU as well as on the first postoperative day when compared to preoperative values (p < 0.0001) [Table 3]. After correction for multiple comparisons, patients with or without AF, however, did not differ in CRP or IL-6 values at all three study points (Table 3). AF occurrence could not be predicted by increased CRP level (Fig 1 ) or IL-6 level (Fig 2 ) with area under the ROC curves of ≤ 0.5 for both variables at each of the three measurement points. The change in CRP level from baseline also did not differ between patients who did or did not develop AF. CRP and IL-6 levels in patients who received statins did not differ significantly during the study and are shown in Table 4 . Among the patients who did not receive statins, those who experienced AF had lower, rather than higher, CRP levels at baseline (geometric mean, 0.22 mg/dL [95% CI, 0.14 to 0.35 mg/dL] vs 0.44 mg/dL [95% CI, 0.33 to 0.59 mg/dL], respectively; p = 0.011 [unadjusted for multiple post hoc subgroup comparisons]). After stepwise logistic regression, statin use was associated with a threefold decrease in the odds of developing AF (odds ratio [OR], 0.26; 95% CI, 0.08 to 0.82; p = 0.022), and a greater PR interval (OR, 1.11 per 5-ms increments; 95% CI, 1.01 to 1.22; p = 0.027) predicted increased AF risk.


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  		Table 3.. Perioperative Changes in CRP and IL-6 Levels*

 


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  		Figure 1.. ROC curves of CRP levels measured at the three study time points and the risk of atrial fibrillation. AUC = area under the curve.

 


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  		Figure 2.. ROC curves of IL-6 levels measured at the three study time points and the risk of atrial fibrillation. See the legend of Figure 1 for abbreviation not used in the text.

 

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  		Table 4.. Statin Use and Perioperative Changes in CRP and IL-6 Levels

 
The incidence of postoperative complications such as pneumonia and acute respiratory failure did not differ between patients who developed postoperative AF when compared to those without AF (Table 1). The length of hospital stay was significantly greater for patients with AF compared to those without AF (9 ± 4 vs 7 ± 4 d, respectively; p = 0.01).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
The main finding of this study was that preoperative statin use is associated with more than a threefold reduction in the incidence of AF after major thoracic surgery, independent of CRP or IL-6 levels. As would be expected in patients receiving statins primarily for the treatment of hyperlipidemia, the incidence of hypertension and coronary artery disease, and use of ß-blockers was greater than in those patients not receiving statins. Although atorvastatin and simvastatin (received by 90% of the patients in this study) have the potential to lower CRP levels, in the subset of patients who received statins before surgery we were unable to detect differences in CRP or IL-6 levels, perhaps due to the varying doses used and study sample size. Patients with AF had a statistically greater PR interval than those without AF, whereas patients receiving statins had a lower PR interval than those that did not. While a greater PR interval may reflect prolonged interatrial conduction as well as intraatrial activity, in this and other studies of patients undergoing thoracic surgery we were unable to show that the preoperative presence of a prolonged P-wave duration, as an indicator of intraatrial conduction delay, identified those patients who are likely to develop postoperative AF.316 Thus, the clinical usefulness of the PR interval in predicting the risk of postoperative AF needs to be elucidated. Older age is a known risk factor for postoperative AF,123 and the finding that the greater age of AF patients did not reach statistical significance may be explained by our study design of restricting study entry to only those patients ≥ 60 years of age. Consistent with the results of prior studies,1 the overall length of hospitalization was longer in patients who developed postoperative AF.

Statins have been shown78 to reduce the AF risk in nonsurgical patients with coronary artery disease as well as to significantly reduce the recurrence of AF after successful cardioversion of the arrhythmia. The use of statins has been associated with lower CRP levels and a significant reduction in the duration of AF induced in an experimental model of sterile pericarditis.13 Brull et al14 demonstrated that the normal rise in IL-6 levels in response to surgical stress was blunted in patients who received therapy with statins prior to undergoing cardiac surgery. These investigators did not measure CRP levels, however, nor did they comment on clinical outcomes. Dotani et al6 were the first to report an association between precardiac surgery statin use and reduced postoperative arrhythmias including AF. In that retrospective study, CRP levels were also not measured. While we found that statin use was associated with a threefold to fourfold reduction in AF risk, this occurred independently of increases in the levels of established markers of inflammation. These findings may not be surprising since statins can lower CRP levels independently of cholesterol levels, and their beneficial role in reducing AF levels may be via their antioxidant activity or cell membrane ion channel stabilization.17 This latter effect was demonstrated with the use of ascorbate as an antioxidant administered before and after cardiac surgery, which was associated with a reduced incidence of postoperative AF.18 We acknowledge that while we have made comparisons in our discussion between patients undergoing cardiac surgery and those undergoing noncardiac thoracic surgery due to the similarly high incidence of postoperative AF common to both populations, the two groups of patients differ in many aspects, including the severity of coronary or valvular disease, exposure to cardiopulmonary bypass, and the need for therapy with postoperative vasoactive agents. Nevertheless, we consider our findings to be both exciting and preliminary, requiring confirmation in a larger, randomized study of patients undergoing noncardiac thoracic surgery.

The role of inflammation in the pathogenesis of AF unrelated to surgery has received much attention over the past few years.1011 In a population-based study of 5,491 elderly subjects,11 those without AF at baseline were more likely to develop AF in the future if their baseline CRP level was elevated. It is important to realize that in these studies small differences in CRP levels were detected, most likely due to the relatively large sample size of their populations. These investigators speculated that the known pathologic changes associated with AF such as normal atrial myocyte loss and eventual fibrosis that are seen with aging may be contributing to this low-level inflammatory response.1011 However, a more recent study of patients with chronic AF19 suggested that increased CRP and IL-6 levels are related to indexes of a prothrombotic state, and may be related to the clinical variables of the patient’s comorbidities rather than to AF itself. In contrast, early after cardiac or thoracic surgery the presence of an intense inflammatory process has been suggested by the activation of the complement system and the release of proinflammatory cytokines.91220 Bruins et al9 originally reported that IL-6 levels peak 6 h after cardiac surgery, and a second phase then occurs with an increase in levels of CRP and complement-CRP complexes, which peaks on postoperative day 2, coinciding with the peak incidence of atrial arrhythmias in 7 of 19 patients. The shortcomings of that report are the small sample size and the small number of patients who developed supraventricular arrhythmias not limited to AF.9 Goette et al21 did not measure IL-6 levels but found no difference in CRP levels obtained before cardiac surgery or on postoperative day 2 between patients who did develop AF (n = 52) and those who did not (n = 207). The role of inflammation and a genetic predisposition to postoperative atrial arrhythmias has been proposed by the assessment of the IL-6 promoter gene variant in a relatively small study of patients undergoing cardiac surgery.22 In the current study of patients undergoing thoracic surgery, we also found an early rise in IL-6 levels and a later increase in CRP levels, but without a difference in whether patients developed AF.

The triad of preexisting atrial pathology (mostly due to aging),14521 intraoperative aggravating factors (unavoidable and variable extent of autonomic denervation due to surgery),12324 and arrhythmia triggers (autonomic imbalance and premature atrial contractions)2526 best explains the multifactorial nature of why postoperative AF develops in some patients but not in other patients who undergo the exact same operation. This theory is supported by the findings of Goette et al21 in 259 patients who had right atrial appendage specimens obtained during cardiac surgery to determine the relationship of the degree of atrial fibrosis and the incidence of postoperative AF. This study showed that the combination of older age, greater P-wave duration from the standard ECG, and the degree of atrial fibrosis were jointly associated with the occurrence of postoperative AF. The amount of atrial fibrosis in patients with and without postoperative AF, however, overlapped markedly.21 Using analyses of heart rate variability 2 h prior to the onset of AF, we have demonstrated26 significant increases in time-domain and frequency-domain parameters during a time when heart rate also increased, implying that vagal resurgence competing in the setting of sympathetic predominance serves as the trigger for postoperative AF in this patient population. Taken together, these data support an important role for adrenergic but not proinflammatory mechanisms contributing to the postoperative risk for AF.

Limitations
Our study sample size was derived using pilot data from our institution.12 Although it is possible that we could have detected smaller differences in CRP levels with a larger group of patients, our results are consistent with those of others212227 showing an inability for CRP level to predict the postoperative occurrence of AF. One may argue that additional postoperative CRP measurements would also help to differentiate AF risk. Our rationale for stopping at postoperative day 1 was based on our intention to use CRP level as a predictor before most of the AF episodes would likely occur and by the lack of evidence that measurements on postoperative day 2 or 3 help to differentiate patients with AF.2122 Furthermore, data in the general population linking elevated CRP levels with chronic AF was made with single measurements. We made serial measurements of CRP and IL-6 levels before and after surgery, and failed to show a clear association between AF occurrence and elevated levels of CRP or IL-6.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Postoperative AF is a frequent complication in elderly patients undergoing thoracic surgery that is associated with increased length of hospital stay. Preoperative statin use is associated with more than a threefold reduction in the incidence of AF after major thoracic surgery independent of CRP or IL-6 levels. Perioperative levels of early markers of inflammation did not predict postoperative AF occurrence. The presence of systemic inflammation alone is unlikely to be important in the pathogenesis of postoperative AF; its role in the maintenance of postoperative AF is controversial. In contrast to patients with AF unrelated to surgery who show evidence of low-grade chronic inflammation, thoracic surgical patients with similar elevations in CRP levels do not demonstrate a similar risk for acute postoperative AF. Our finding that statin use is associated with a significant reduction in AF occurrence is exciting and will require confirmation in a randomized study.


   Footnotes
 
Abbreviations: AF = atrial fibrillation/flutter; CI = confidence interval; CRP = C-reactive protein; IL = interleukin; OR = odds ratio; PACU = postanesthesia care unit; ROC = receiver operating characteristic

Presented in part at the Annual Meeting of the American Society of Anesthesiologists, October 11–15, 2003, San Francisco, CA.

This research was supported by individual departments at Memorial Sloan-Kettering Cancer Center.

Received for publication May 25, 2005. Accepted for publication July 9, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

  1. Amar, D (2002) Perioperative atrial tachyarrhythmias. Anesthesiology 97,1618-1623[CrossRef][ISI][Medline]
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  13. Kumagai, K, Nakashima, H, Saku, K The HMG CoA-reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model. Cardiovasc Res 2004;62,105-111[Abstract/Free Full Text]
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Statin use and reduced post-surgery atrial fibrillation. Which are their underlying mechanisms?
Miguel Ahumada, et al.
Chest Online, 28 Jan 2006 [Full text]
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