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Ann Thorac Surg 2007;84:1158-1164
© 2007 The Society of Thoracic Surgeons
a Department of Surgical Sciences, Cardiac Surgery Unit, Varese University Hospital, University of Insubria, Varese, Italy
b Cardiac Surgery Unit, Civic Hospital, Brescia, Italy
c Service of Biometry and Clinical Epidemiology, Scientific Direction, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
d Department of Surgical Sciences, Vascular Surgery Unit, Varese University Hospital, University of Insubria, Varese, Italy
Accepted for publication May 7, 2007.
* Address correspondence to Dr Mariscalco, Department of Surgical Sciences, Cardiac Surgery Division, Varese University Hospital, Varese, I-21100, Italy (Email: giovannimariscalco{at}yahoo.it).
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Abstract |
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Methods: Over a two-year period, 405 consecutive patients underwent isolated CABG procedures. Univariate analysis was performed exploring the relationship regarding statin use and AF development. A propensity score for treatment with statins was obtained from core patient characteristics. The role of statin therapy on postoperative AF was assessed by means of a conditional logistic model, while stratifying on the quintiles of the propensity score. All analysis was performed retrospectively.
Results: Postoperative AF occurred in 29.5% of the patients with preoperative statin therapy compared with 40.9% of those patients without it (p = 0.021). No statistical differences among development of AF and type, dose, or duration of preoperative statin therapy were observed. Preoperative statins were associated with a 42% reduction in risk of AF development after CABG surgery (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37 to 0.91, p = 0.017, while stratifying on the propensity score). No different effect of statins on AF was observed with respect to age groups (
70 and >70 years) (interaction p = 0.711).
Conclusions: Preoperative statins may reduce postoperative AF after CABG. Patients undergoing elective revascularization may benefit from a preventive statin approach.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Therefore, the purpose of the present study was to evaluate the influence of preoperative statin therapy on AF development after coronary artery bypass grafting (CABG). The identification of further operative and postoperative determinants of AF was evaluated as a secondary endpoint.
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Patients and Methods |
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Data Definitions
All variables analyzed in the study are listed in the Appendix. Preoperative patient characteristics were evaluated after current guidelines. In particular, hypertension was considered according to the Joint National Committee VI, diabetes mellitus according to the American Diabetes Association, and dyslipidemia according to the National Cholesterol Education Program–Adult Treatment Panel II criteria [9–11]. Angina was defined by the Canadian Cardiovascular Society Classification [12]. Chronic obstructive pulmonary disease (COPD), peripheral vascular disease, and renal failure were defined according to the European system for cardiac operative risk evaluation [13]. The latest was also considered to quantify the preoperative surgical risk [13].
The study was approved by our Institutional Review Board (protocol nr.117) and, because of its retrospective nature, individual patient consent was waived. The study was also not supported by any external source of funding.
Clinical Management and AF Definition
All patients were subjected to preoperative coronary angiography, transthoracic echocardiography, and color-Doppler ultrasound of epiaortic vessels. Preoperative medications, including ß-blockers, diuretics, antihypertensives, statins, and calcium-channel blockers, were routinely omitted on the day of the operation and restarted after the operation, unless clinically contraindicated. Commercially available statins screened for in this study were atorvastatin, pravastatin, simvastatin, lovastatin, rosuvastatin, and fluvastatin.
All patients were daily monitored until discharge with continuous electrocardiographic telemetry, as well as standard 12-lead electrocardiography. Additional recordings were collected at clinical suspicion of AF. Only AF episodes lasting longer than 15 minutes were considered [14]. Atrial flutter or tachycardia were disregarded because of their different mechanisms [15]. Amiodarone, either oral or intravenously administered, constituted the standard pharmacologic treatment of AF. Patients without successful rhythm cardioversion and with persistent AF were given warfarin and were discharged to the referring hospital, with a planned electric cardioversion within thirty days.
Surgical Techniques and Operative Management
All procedures were performed through a median sternotomy approach, using either an on-pump or off-pump technique. The anesthetic management followed identical routine methods. Cardiopulmonary bypass was of standardized fashion, with ascending aortic cannulation and two-stage venous cannulation of the right atrium. The CPB was conducted using a membrane oxygenator with hemodilution and mild systemic hypothermia. Myocardial protection was afforded by intermittent cardioplegia (crystalloid or blood, antegrade or retrograde routes).
Off-pump procedures were conducted using the CTS stabilization system (Guidant, Santa Clara, CA) at near normothermia. Intracoronary shunts were used whenever possible.
To reduce blood loss, blood was recollected with a suction cardiotomy reservoir in the CPB group, whereas a cell saver was used in the off-pump group. All procedures had the left internal mammary artery supplying the left anterior descending artery. Other conduits included the right internal mammary artery, radial artery, and saphenous vein, as found appropriate. Proximal anastomoses were performed using a side-biting clamp.
After surgery, patients were transferred to a dedicated cardiovascular intensive care unit (ICU). Heart rate, electrocardiogram, central venous and arterial pressures, and acid-base and blood gases were continuously monitored during the ICU stay. Inotropic support was provided if the ventricular contractility was considered frankly impaired in order to achieve stable hemodynamic conditions. Perioperative need for blood products was determined on an individual, patient-by-patient basis; in general, blood transfusions were administered when hemoglobin was less than 9 g/dL. Fluid intake and output were monitored hourly throughout the hospital stay.
Statistics
Clinical data were prospectively recorded and tabulated with Microsoft Excel (Microsoft Corp, Redmond, WA). Continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test and compared between groups with the unpaired Student ttest for normally distributed values; otherwise the Mann-Whitney Utest was employed. In case of dichotomous variables, group differences were examined by 
2 or Fisher exact tests as appropriate.
The likelihood of receiving a preoperative treatment with statins was taken into account by computing a propensity score (by means of a logistic model) based on the preoperative characteristics listed in Table 1. The role of statin therapy on postoperative AF occurrence (primary endpoint) was assessed by means of a conditional logistic model, while stratifying on the quintiles of the propensity score [16]. Further, the modifying effect of age (70 and >70 years) was assessed by including an interaction term in the model. As a secondary endpoint, potential operative and postoperative determinants of AF were also fitted in the model to assess their prognostic role. These included noncollinear clinically relevant variables, with a pvalue less than 0.15 at the univariate analysis. Kaplan-Meier cumulative AF-free survival was computed according to statin treatment and plotted. Results are expressed as mean ± SD for continuous variables and frequencies for the categoric ones.
A two-sided pvalue less than 0.05 was considered statistically significant. Statistical analysis was performed with Stata 9.2 (StataCorp, College Station, TX) and with SPSS, release 13.0 for Windows (SPSS Inc, Chicago, IL).
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Results |
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The use of calcium-channel blockers, of angiotensin-converting enzyme-inhibitors, and of ß-blockers did not influence the AF development (Table 1). In detail, patients with preoperative ß-blocker therapy compared with patients without it demonstrated similar AF rates (33.1% vs 37.5%, p = 0.420). However, withdrawal from preoperative ß-blocker therapy was significantly associated with a new-onset of AF (45.1% vs 31.6%, p = 0.027). No surgical variables, with the exception of postoperative intraaortic balloon pump (IABP) requirement, were found associated with postoperative AF (Table 2). Also, no differences were evident concerning the modality of revascularization. Postoperative AF occurred in 111 (34.7%) of 320 patients operated on CPB versus 30 (35.3%) of 85 patients subjected to off-pump revascularization (p = 0.999).
No differences were observed between patients with preoperative statins and patients without them, with the exception of patients affected by dyslipidemia and previous myocardial infarction (p = 0.023 and p = 0.025, respectively). In particular, the time of AF occurrence, AF recurrence, and the persistence of the arrhythmia at discharge were not influenced by statin use (Table 3). Withdrawal from preoperative statin therapy occurred in 51 patients (21.6%) essentially because of transitory transaminase increase (62.7%). However, statin withdrawal was not associated with postoperative AF development, AF recurrence, or persistent AF at discharge (p = 0.840, p = 0.573, and p = 0.874, respectively; data not shown).There were also no statistical differences between development of AF and type, dose, or duration of preoperative statin therapy (Table 4). Preoperative statin use was associated with less AF in the on-pump group (p < 0.001) compared with the off-pump group (p = 0.060).
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70 and >70 years) (interaction p = 0.711). In addition, at the analysis of the secondary endpoints, patients with withdrawal from preoperative ß-blocker therapy and patients with postoperative need of IABP both appeared to be at higher risk of AF development, although statistical significance was not reached (OR 1.64, 95% CI 0.97 to 2.72, p = 0.062 and OR 2.29, 95% CI 0.65 to 8.06, p = 0.198, respectively).
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Comment |
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The beneficial statin effect on AF has been described in different reports. Statins have been demonstrated protective against AF in patients with stable coronary disease [19]. They also decreased the AF recurrence after external cardioversion and the incidences of death, unstable angina, and cardiac arrhythmias [20, 21]. Two recent studies observed a significant reduction in AF risk after cardiac surgery in patients with preoperative statin use [6, 7]. Similar results with a threefold decrease in the odds of AF have been confirmed after noncardiac thoracic surgery [22]. The atorvastatin for reduction of myocardial dysrhythmia after cardiac surgery study (ARMYDA-3) is the only randomized, controlled trial of pretreatment with statins in elective cardiac surgery patients [8]. In this study, Patti and colleagues [8] randomized 200 patients to preoperative atorvastatin (40 mg/day) or placebo starting seven days before operation, observing a significant decrease in postoperative AF in the atorvastatin-treated group (35% vs 57%, p = 0.003), with a 61% reduction in AF risk at the multivariate level.
However, the protective mechanisms exerted by statins remain unclear. The benefit of preoperative statins may reflect their antiinflammatory effects and the role of inflammation in the pathophysiology of postoperative AF has been widely demonstrated [1, 3, 4]. As a matter of fact, inflammatory markers as cytokine or circulating adhesion molecules are attenuated in patients receiving statins after cardiac operations [5, 23]. Antioxidant effect, direct antiarrhythmic effects by cell membrane ion channel stabilization or direct protection of the ischemic myocardium, and modulation of extracellular matrix are also reported properties [24, 25]. Moreover, the beneficial effects of statin therapy are not limited to patients with dyslipidemia, but the incidence of adverse cardiovascular outcomes and the need for coronary revascularization are reduced even in patients with normal cholesterol levels [26].
The protective effects of statins on postoperative AF are valuable because this arrhythmia is the most frequent complication after cardiac surgery and it is associated with increased mortality and expenditure [1, 2]. In light of the importance of postoperative AF to patient outcome, there has been a great deal of interest in preventing this complication pharmacologically. Amiodarone, ß-blocker agents, and sotalol have been found to reduce but not abolish this postoperative arrhythmia [18]. Several patients still experience AF despite prophylactic therapy, and a large number of the remaining patients are unnecessarily exposed to such drugs with potential adverse events [18]. Moreover, patients with deteriorated left ventricular function (LVF), COPD, and renal failure are frequently excluded from a prophylactic approach with part of the drugs; nevertheless, these patients are the ones most affected by AF, as demonstrated in several studies, and would benefit the most from a preventive treatment [18]. Statin therapy has a low cost, is a low risk preventive AF strategy, and all cardiac surgery patients may benefit from such prophylactic regimen.
In our study, however, no AF effects were observed in LOS in the entire population study nor in patients with preoperative statins. This discrepancy, compared with the ARMYDA-3 study could be justified by the inclusion criteria [8]. In our study, emergency operations were included. As a matter of fact, without considering unstable cases (23.5%), patients affected by postoperative AF experienced a significantly longer hospital stay (7.9 ± 2.7 vs 7.2 ± 2.1 days, p = 0.025). Patients with statin therapy also revealed a shorter, but not significant LOS compared with patients without it (7.3 ± 2.2 vs 7.6 ± 2.6 days).
Our study was an observational investigation based on prospectively collected data, and a selection bias may have been presented because there was no homogenous indication for the use, type of lipid-lowering agents, and duration of preoperative statin therapy. Indication and type of statins were decided by the referring physicians. However, our analysis accounted for this by assessing the role of statins while stratifying on the propensity score. Moreover, the two groups of patients, statin and no statin use, were comparable in preoperative and operative characteristics. The two groups were also reasonably balanced in the absolute number of cases. Furthermore, our aim was to explore only the statin effects on postoperative AF, without modify at all preoperative drug regimens. Our peripheral cardiac surgery department does not permit a preventive elective AF prophylactic strategy as reported by Patti and colleagues [8], with no possibilities to hospitalize patients several days before the operation (seven days as in the ARMYDA-3 study; our hospitalization before the operation was 2.4 ± 1.2 days). But more importantly, emergent cases (23.5% of our patients) are inevitably excluded from such therapy. The latest are most often older patients, suffering from deteriorated LVF and requiring inotropic drugs with prolonged hospital stay; both AF risk factors as demonstrated in several studies [1, 2, 14, 27]. Moreover, in all studies regarding the statin effect on postoperative AF, patients with a preoperative history of AF were excluded [6, 8]. As largely demonstrated, these patients most often are at higher risk of developing postoperative AF [1, 2, 4]. In our study we did not introduce any exclusion criteria as we aimed to observe the highest possible proportion of patients admitted for CABG. As a matter of fact, only 9% of the subjects were not included in the final analysis, reflecting the complete CABG patient population. On the contrary, in the ARMYDA study about 40% (123 of 323) of hospitalized patients were excluded [8]. Finally, we believe that observational studies like ours are still needed after the publication of controlled clinical trials. Indeed, results of controlled clinical trials may differ from results obtained in clinical practice. Generally, randomized trials involve selected centers only and frequently include younger, selected elective patients, with a lower incidence of comorbidities. Discrepancies between controlled trials and clinical practice may be more pronounced when invasive procedures are involved. An operator’s technical skill and careful patient follow-up may enhance the benefits of the procedure in the context of the clinical trial. Therefore, confirmation of the trial results by observational studies is eagerly needed. This study, conducted in an unselected population, aimed at that purpose. A further limitation of this study is the lack of the baseline assessment of inflammatory markers, which have been associated with postoperative AF [1, 3, 23].
In conclusion, preoperative statins seem to reduce postoperative AF development after CABG and constitute a useful preventive pharmacologic approach in patients undergoing elective revascularization.
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Appendix |
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Preoperative (29): age, sex, BMI (body mass index), BSA (body surface area), preoperative cardiac rhythm, CCS angina classification, angina presentation (stable or unstable), IABP (intraaortic balloon pump), previous AMI (acute myocardial infarction), previous PCI (percutaneous coronary intervention), left main stem stenosis, right coronary artery stenosis; left ventricular function, left atrial antero-posterior diameter; hypertension, diabetes mellitus, hypercholesterolemia, BPCO (chronic obstructive pulmonary disease), peripheral vascular disease, cerebrovascular accident, renal failure, hemoglobin (g/dL), EuroSCORE; ß-blocker agents; calcium-channel blockers, ACE (angiotensin-converting enzyme)-inhibitors; type of statins, dose of statins, duration of preoperative statin therapy.
Operative (11): CPB (cardiopulmonary bypass) use, cardioplegia-route (antegrade, antegrade and retrograde), cardioplegia-type (crystalloid or blood), cardioplegia-temperature (warm, cold), CPB time, ACC (aortic cross-clamp) time, CPB temperature, number of grafts, postoperative IABP, cardiac rhythm at the end operation, inotropic support.
Postoperative (19): time on ventilator, ICU (intensive care unit) time, mediastinal bleeding, fluid balance, MB peak; respiratory failure, surgical revision for bleeding, perioperative AMI, hemotransfusion; atrial fibrillation (AF) occurrence, AF occurrence day, cardiac rhythm at discharge; LOS (length of hospital stay), hospital mortality, one-year mortality; postoperative: ß-blocker agents, calcium-channel blockers, ACE-inhibitors, statins.
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References |
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