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a Department of Cardiothoracic Surgery, St. George's Hospital, London, United Kingdom
b Department of Cardiac and Vascular Sciences, St. George's University of London, London, United Kingdom
Accepted for publication January 11, 2008.
* Address correspondence to Prof Jahangiri, Department of Cardiac Surgery, St. George's Hospital, Blackshaw Rd, London, SW17 0QT, United Kingdom (Email: marjan.jahangiri{at}stgeorges.nhs.uk).
| Adult cardiac surgery:
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| Abstract |
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Methods: A retrospective study of 680 consecutive patients undergoing coronary bypass graft surgery and/or aortic valve replacement was done. Excluded were 57 patients (8.4%) with history of AF, permanent pacemakers, and those receiving antiarrhythmic medication. Preoperative statin treatment and occurrence of postoperative AF were examined using propensity score matching to adjust for differences in patient characteristics between the statin and no-statin groups.
Results: The cohort comprised 623 patients. The statin group had a 27.1% incidence of postoperative AF vs 38.3% in the no-statin group (adjusted odds ratio [OR], 2.00; 95% confidence interval, 1.24 to 3.24; p = 0.004). Simvastatin (40 mg) and atorvastatin (40 mg) demonstrated the greatest effect on postoperative AF at 15.6% and 21.2%, respectively, vs no statins (respective adjusted ORs, 3.89 [p < 0.0001] and 2.76 [p = 0.012]). Intermediate-dose (20 mg) statins were also effective against AF, at 24.4% for simvastatin (adjusted OR, 2.32; p = 0.004) and 26.4% for atorvastatin (adjusted OR, 1.99, p = 0.047). Low-dose statins, simvastatin or atorvastatin (10 mg), did not influence postoperative AF.
Conclusions: Statin treatment may reduce the incidence of AF after cardiac surgery. Higher-dose statins have the greatest preventative effect, whereas low-dose statins do not influence postoperative AF.
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. The incidence of AF has been reported to be 19.2/1000 patient-years in men aged older than 65 [1]. Patients undergoing cardiac operations are more likely to develop AF during their postoperative period, with an incidence ranging from 11% to more than 50% in some series [2]. Moreover, postoperative AF is associated with increased morbidity and prolonged hospitalization [3].
Although the exact cause of AF remains unknown, several theories have been suggested. Atrial fibrosis, electrophysiologic remodeling, and inflammation are some of the factors that have been proposed to initiate and possibly precipitate AF [4, 5]. Specifically to postoperative AF, the metabolic and autonomic response to trauma, transient cardiac ischemia, and the inflammatory response associated with cardiopulmonary bypass are possible contributing factors [6].
The possible role of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in the prevention of postoperative AF has recently been suggested. In a prospective nonrandomized study, preoperative statin treatment significantly reduced the incidence of AF after coronary artery bypass graft (CABG) operations [7]. However, the statin type, dose, and duration of treatment varied between patients. In a recent randomized controlled trial, patients who received 40 mg of atorvastatin 7 days before CABG had a lower incidence of AF compared with placebo (35% vs 57%, p = 0.003) [8].
The aim of this study was to identify the effect of varying doses of statins in the occurrence of AF after cardiac procedures and raise the importance of high-dose statin therapy as a possible preventative measure against postoperative AF.
| Material and Methods |
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From the 623 patients included, demographic characteristics, medical history, and drug therapy were evaluated. Preoperative cardiac investigations and clinical findings were also recorded. Operative variables and postoperative events were evaluated with emphasis on the occurrence of AF and hospital length of stay. A detailed assessment of medical records, daily electrocardiograms (ECGs), and drug charts was combined with data obtained from the audit database for outcomes in cardiac surgery at St George's Hospital. All patients included in the statin group received statins for a minimum of 2 months before operation.
Routine postoperative heart rhythm assessment was achieved with continuous telemonitoring for the first 72 hours after the operation and with 4-hourly clinical examinations thereafter. Twelve-lead ECGs were also obtained and assessed daily.
The primary end point was the development of postoperative AF during the hospital stay. We compared the incidence of postoperative AF in patients taking statins with patients not taking statins. The incidence of postoperative AF was then assessed in patients receiving different treatment doses of atorvastatin and simvastatin compared with patients not receiving statins. Six additional patients were further excluded because they received an unusual statin dose (simvastatin, 30 mg, 1; atorvastatin, 30 mg, 2; simvastatin, 80 mg, 3). Patients taking other statin types (pravastatin, 16; rosuvastatin, 9) accounted for only 4.6% of the total statin population and these subgroups were not analyzed; however, these statin subgroups were included in the statin vs no-statin analysis.
Statistical Analysis
Univariate analysis was performed to examine differences in variables between patients on statins and patients not on statins. Variables with a significance level of less than 0.2 were entered into a multivariable regression model and predictors of statin group membership were identified. Logistic regression with forward elimination determined the most important denominators (CABG, AVR, and β-blocker use) for receiving statin treatment or not. A propensity model was then constructed based on these variables and was used to calculate the propensity score, which reflects the probability of a patient's assignment to statin treatment.
Having calculated the propensity score for each patient, we then adjusted the variables of interest and compared surgical outcomes. Furthermore, a univariate analysis of the study population was done by the development (or not) of postoperative AF. Variables that were found to have a value of p < 0.2 in the univariate analysis were examined by multivariate logistic regression to identify independent predictors of postoperative AF and correlate with the outcomes of the propensity score matching. Categoric and dichotomous data were examined with
2 and Fisher exact tests where appropriate. The Mann-Whitney U test was used for continuous variables with nonparametric distribution. Values of p < 0.05 were considered statistically significant. Statistical analysis was performed with SPSS 14.0 software (SPSS Inc, Chicago, IL)
| Results |
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Further univariate analysis of the same patient variables by the development (or not) of postoperative AF (Table 3) demonstrated no significant difference in most preoperative variables between patients who developed postoperative AF compared with those who did not; the only exceptions were age, type of operation, and statin use. More specifically, mean age was significantly higher in the AF group (70.5 ± 8.7 vs 64.7 ± 9.9, p < 0.001) as was the proportion of patients who received CABG with or without AVR (p = 0.002). Statin use was significantly higher in the group that remained in sinus rhythm postoperatively (p = 0.038). Multivariate logistic regression analysis demonstrated that increasing age and no use of statins were the only independent risk factors for postoperative AF (Table 4). This finding is in line with the outcome of the propensity score matching, which identified a significant reduction in postoperative AF in patients on statins.
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| Comment |
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The aim of our study was to assess the effect of varying doses of statins on AF after CABG, AVR, and CABG and AVR. We have shown that preoperative statin treatment is significantly and independently associated with reduced AF; however, further analysis demonstrates that this effect is primarily attributed to higher doses of statin. The low-dose statin regimens that are commonly used in clinical practice for lipid control do not seem to be effective in reducing postoperative AF.
Perioperative β-blocker therapy is known to exhibit a protective effect against AF [12]. In our study, preoperative β-blocker treatment did not influence postoperative AF. However, β-blockers commenced in the early postoperative period significantly reduced new-onset AF (p < 0.001). Angiotensin enzyme-converting inhibitors have also been suggested to exhibit a possible protective effect on postoperative AF [13], but this was not observed in our study.
Others have shown an association between statin therapy and postoperative AF. Marin and colleagues [7] demonstrated a significant reduction in postoperative AF (p = 0.038) associated with previous statin use in a prospective nonrandomized study of 234 patients undergoing CABG; however, the statin type and dose were not uniform in all patients. A recent observational study of 362 patients showed a significant reduction in AF after CABG (p = 0.03) and decreased duration of AF in patients taking statins [14].
The third study, Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery (ARMYDA-3) [8], is the only randomized double-blind trial to demonstrate a reduction in AF and hospital stay after cardiac surgery in patients who received atorvastatin (40 mg) 7 days before operation compared with placebo. The incidence of AF was 35% in the statin group vs 57% in the placebo group (p = 0.003). This rate of postoperative AF is higher than expected in the current literature, as most other studies have shown AF rates of 20% to 40% in their control groups [15–17]. The same trial correlated high postoperative C-reactive protein (CRP) levels with an increased risk of AF, a finding that was not confirmed in a recent cohort study [17]. Finally, statin use was associated with a decreased occurrence of AF after thoracic operations (pulmonary lobectomy, esophagectomy) compared with patients not using statins (11% vs 29%, p = 0.025) [18].
Statins demonstrate a pleiotropic effect compared with other lipid-lowering agents [19]. The antiinflammatory properties of statins have been suggested as one of the mechanisms by which they exhibit their protective role in atherogenesis [20] and possibly in the development of AF. Two independent clinical trials that appeared almost simultaneously were the first to report an association between CRP and AF in non-postoperative patients. The first was a case-control study [21] that included 131 patients with atrial arrhythmias. The concentration of CRP was significantly elevated in patients with AF and was greatest with persistent AF. In the second study [22], 50 patients with paroxysmal AF who underwent pharmacological cardioversion were compared with age and sex-matched controls. Levels of CRP were higher in patients with AF and significantly associated with unsuccessful cardioversion to sinus rhythm. These findings have also been confirmed by others [23].
The concept of an association between AF and inflammation has also been supported by population-based studies, where CRP levels were associated with the development of AF and predicted patients at risk for future AF [24]. The antiinflammatory role of statins as a regulatory mechanism for AF has been suggested in two studies. Kumagai and colleagues [25] evaluated the effect of atorvastatin in AF in a canine sterile pericarditis model. The atorvastatin group had lower CRP levels, less pronounced fibrosis in the atrial myocardium, and a shorter duration of AF compared with the control group. This study deserves attention as the first one to emphasize the role of inflammation on atrial electrophysiologic as well as on atrial structural changes. These findings were supported by another study on mongrel dogs that underwent atrial tachypacing and simvastatin treatment [26]. Atrial tachypacing-induced AF was virtually abolished and effective refractory period shortening was significantly suppressed in the simvastatin treated dogs.
Emerging data suggest that statin treatment is a safe preventative measure for postoperative AF. This study shows that high-dose statin therapy is more effective in reducing AF than low-dose statins. The mechanisms by which statins exhibit this beneficial effect are currently unknown. Further research into the structural changes of the heart and the inflammatory response associated with AF may provide more information on its pathogenesis and guide future treatment strategies.
One study limitation is that postoperative assessment of heart rhythm was performed with telemonitoring for 72 hours and with daily ECGs and clinical examination thereafter. Self-terminating episodes of AF or other arrhythmias may have occurred and not been recorded during these intervals.
This study is also subject to limitations inherent to any retrospective analysis. The indications for preoperative statin therapy were not uniform in our study group and not always recorded in the hospital notes. The duration of preoperative treatment was variable between patients. Despite using a well-established balancing score to adjust for patient characteristics between the statin and no-statin groups, selection bias may not have been completely eliminated. The observed reduction in postoperative AF with increasing statin dose can only suggest a dose-related effect. Despite having used a validated balancing score to adjust for possible covariates, a direct etiologic association cannot be confirmed and is beyond the scope of this study.
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