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Ann Thorac Surg 2004;77:838-843
© 2004 The Society of Thoracic Surgeons
a Division of Coronary Care Unit, Valencia, Spain
b Division of Cardiovascular Surgery, Clinic University Hospital, Valencia, Spain
Accepted for publication May 6, 2003.
* Address reprint requests to Dr Sanjuán, Unitat Coronaria, Hospital Clínic Universitari, Av Blasco Ibáñez 17, 46010, Valencia, Spain.
e-mail: sanjuan_raf{at}gva.es
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Abstract |
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METHODS: A total of 253 consecutive eligible patients (66 ± 8 years; mean ± standard deviation) scheduled to undergo cardiac surgery were enrolled in this study. Patients were randomized in a prospective open manner 1.5:1 to atenolol group (50 mg/daily; 153 patients) or sotalol group (80 mg twice daily; 100 patients).
RESULTS: Atrial fibrillation occurred in 44/253 patients (17.45%). A significant difference was found in the occurrence of atrial fibrillation in the atenolol group (34 patients, 22%) compared with those receiving sotalol (10 patients, 10%; p = 0.013). Therapeutic efficiency and efficacy was 12% and 54%, respectively. Stepwise logistic regression analysis revealed that age more than 68 years old (odds ratio = 2.72; 95% confidence interval [CI] = 1.37–5.41; p = 0.004), the use of ß-adrenergic agents (odds ratio = 2.74; 95% CI = 1.5–5; p = 0.001), and sotalol (odds ratio = 0.46; 95% CI = 0.23–0.95; p = 0.035) were independently associated with development of atrial fibrillation.
CONCLUSIONS: Oral low-dose sotalol provides a considerable reduction in the occurrence of atrial fibrillation. A selective approach based on clinical risk prediction should decrease the occurrence of atrial fibrillation after cardiac surgery.
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Introduction |
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There is no clear strategy for reducing the incidence of postcardiac surgery AF because its pathophysiologic mechanism is unknown. Several antiarrhythmic agents have been used in the treatment and prophylaxis of postoperative AF with varying degrees of success [4–6]. Various studies have reported that ß-blockers (BBs) decrease the incidence of AF in coronary artery bypass grafting (CABG) patients and in those undergoing valve surgery. This benefit is observed when BBs are administered before or immediately after surgery [7].
Sotalol and atenolol have been compared separately with placebos in various open double-blind trials. A significant reduction in postoperative atrial tachyarrhythmias was always observed [8–15]. To date no study has been conducted comparing the two drugs in the prevention of postcardiac surgery AF. Several studies have emphasized the importance of preoperative risk stratification in order to accurately identify those high-risk patients who ought to receive antiarrhythmic therapy for the prevention of atrial tachyarrhythmias [16–18].
The purpose of the present study is to compare the effects of preoperatively administered sotalol and atenolol on the incidence of postcardiac surgery AF, and to find predictor factors for the identification of high-risk patients.
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Material and methods |
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Ventricular function was evaluated in all patients in the 2 months preceding the intervention, by using either echocardiography or left ventricular angiography. Exclusion criteria consisted of the following: (1) a left ventricular ejection fraction (LVEF) less than 35% or a clinical diagnosis of congestive heart failure; (2) any degree of atrioventricular (AV) block; (3) a QTc more than 450 msec; (4) clinical chronic obstructive pulmonary disease or respiratory functional tests compatible with it; and (5) chronic treatment with antiarrhythmic drugs.
Because the majority of the patients in the study population suffered from ischemic heart disease and were being treated with anti-angina agents, they were randomized 1.5:1 to receive atenolol (50 mg/day) or sotalol (80 mg every 12 hours). The randomization was carried out using the Study Design Pack program. One hundred fifty-three patients were assigned to the atenolol group and 100 patients to the sotalol group. In this way a smaller number of unstable patients received sotalol, a ß-blocking agent but with less clinical use for angina.
As soon as informed consent was obtained from the patients, treatment began 24 hours before surgery. All patients were required to have a sinus rhythm rate higher than 60 beats per minute immediately before beginning treatment. All patients were monitored by electrocardiogram (ECG) continuously from the time of surgery and during the coronary care unit (CCU) stay. Subsequently, once the patients were released from the CCU, postoperative care consisted of a daily physical exam by the physician in charge, a 12-lead ECG recording every day, and an additional ECG if there was any hint of atrial tachyarrhythmia.
The presence of any adverse effects such as bradycardia equal to or less than 50 beats per minute, systolic blood pressure less than 95 mm Hg, clinical signs of lung congestion, or low cardiac output were reasons for withdrawing study medication, resulting in suspension of treatment protocols.
Treatment was considered a failure if an incident of AF occurred lasting 10 minutes or more [18] during the patient's hospital stay. Treatment protocols were reviewed and approved by the Hospital ethics committee.
Operative techniques
Cardiopulmonary bypass with moderate systemic hypothermia (28°C), moderate hemodilution, flow rates of 2.4 L · min-1 · m-2, and mean systemic pressure of 50 to 70 mm Hg were used. All patients underwent single atrial cannulation, and myocardial protection with cold potassium cardioplegic arrest was applied. Standard surgical techniques were used with all distal coronary anastomoses performed during a single period of aortic cross clamping. The left internal thoracic artery served as a bypass conduit in the majority of patients.
Off-pump surgery was performed through a median sternotomy. Octopus II and III (Medtronic, Minneapolis, MN) stabilizers were used in all patients. The target vessel was then exposed and snared with a silicone snugger to prevent coronary injury. The coronary artery was then opened and the anastomoses was performed.
All patients underwent routine intraoperative hemodynamic and continuous ECG monitoring. At the end of surgery, patients were transferred to the intensive care unit. The lungs were ventilated with 50% oxygen using volume-controlled ventilation and a tidal volume of 10 mL/kg with 5 cm H2O of positive end-expiratory pressure. Adjustments in FiO2 and respiratory rate were made according to routine blood gas analysis. Patients were extubated as soon as they met the following criteria: hemodynamic stability, no excessive bleeding (<80 mL/hour), normothermia, and consciousness with pain control. Potassium and magnesium deficiency was promptly treated when necessary to maintain electrolyte balance within the normal range.
Statistical analysis
In order to calculate the sample size, the trial was designed to have 85% statistical power in detecting a 30% reduction in the incidence of AF in the sotalol group, assuming an AF rate of 30% among patients assigned to atenolol, with a two-sided significance level of 0.05. Variables were tested using the 
2, Fischer's exact test, or a t test when appropriate. Continuous variables are expressed as mean ± standard deviation or standard error of mean, and categoric variables as percentages. Receiver-operating characteristic curves were used to obtain the optimum continuous variables cut-off. The Kaplan-Meier product-limit method was used for estimation of cumulative incidence of AF after cardiac surgery in both groups.
We have used the term "therapeutic efficiency" in referring to the relationship between relative risk and absolute event rates. Efficacy was based on the fractional or relative reduction of end-point events in one treatment group compared with the other [19].
A stepwise logistic regression analysis was performed to select the predictors of AF after surgery. The model was built using variables that demonstrated a p value less than or equal to 0.10 in univariate analysis. The significance within the model was evaluated with the Wald statistical test. All tests were two-tailed and performed by SPSS 9.0 statistic software (Chicago, IL).
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Results |
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Figure 1 illustrates the Kaplan-Meier analysis of the percentage of patients free of AF on sotalol compared with the atenolol group (log-rank test = 5.4; p = 0.02). The distribution of AF incident cases is depicted in Figure 2. It reveals that the peak incidence of AF was on the third postoperative day in both groups, and 86% of all AF occurred before the fourth day.
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Predictors of AF
In the univariate analysis, clinical variables associated with the development of postoperative AF were age, inotropic drug administration, elevated blood pressure levels, and postoperative low cardiac output (Table 3).
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In the multivariate analysis it was observed that age and the use of ß-adrenergic drugs for hemodynamic support during the surgical procedure, were the only independent predictive variables of AF (Table 3).
Mortality
Seventeen patients died in the hospital during the study (6.7%). Death was associated with AF in univariate analyses (odds ratio [OR] = 3.31; 95% confidence interval [CI] = 1.33–8.22), with age more than 68 years (OR = 1.5, 95% CI = 1.2–2) and with diabetes mellitus (OR = 1.8, 95% CI = 1.1–2.7). AF occurred in 41% of the patients who died. Nevertheless, in the multivariate analysis only age more than 68 years old had an independent predictive character (OR = 3.9, 95% CI = 1.1–13.8).
In the atenolol group, 9 patients died (5.8%) compared with 8 patients (8%) in the sotalol group (without significant differences). The causes of death were as follows: 2 patients died in the operating room, never having come off the pump (sotalol group); 4 patients developed cardiogenic shock through acute myocardial infarction during their stay in the CCU (3 patients in the atenolol group and 1 patient in the sotalol group); in 8 patients death was preceded by bronchopneumonia with a septic process resistant to antibiotic therapy, mechanical ventilation, and multiple organ failure (4 patients in each group); in 3 patients death was sudden and unexpected (1 patient in the sotalol group and 2 patients in the atenolol group) while in the cardiology ward, and not under continuous ECG monitoring.
Side effects of therapy
The QT interval was measured before the administration of sotalol and 2 ± 1 days after cardiac surgery to determine any type III effects of sotalol. The QTc interval was slightly prolonged on sotalol compared to before its administration (401 ± 25 msec vs 422 ± 35 msec; p = 0.02). There was no significant difference in the QTc in the atenolol group, presurgery and postsurgery (418 ± 33 msec vs 410 ± 25 msec; p = 0.1). No patient on sotalol had Torsade de Pointes or ventricular tachycardia.
Bradycardia in 2 patients, and postoperative low cardiac output in 10 patients, were considered adverse effects possibly related to the treatment, requiring discontinuation of Atenolol. In the sotalol group 8 patients (8%) needed to discontinue the medication, because of bradycardia in 1 patient, and congestive heart failure (CHF) in 7 patients. In 2 patients from the sotalol group, the drug was reduced due to QTc more than 480 msec.
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Comment |
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Various studies, including two meta-analyses, have reported that BBs reduce the incidence of AF in patients undergoing CABG from 40% to 20% and from 60% to 30% after valve surgery [4–8]. This beneficial effect, seen when BBs are administered before or immediately after surgery, is independent of the dose and type of ß-blocker used. However, the results of these studies are difficult to compare due to the diversity of the study protocols.
This study was designed to evaluate the effect of sotalol and a selective ß-blocking agent (atenolol) in the prevention of postcardiac surgery AF, in order to try to distinguish between the effects attributable to the antiarrhythmic class III action of sotalol, and those of the ß-adrenergic blocker only. Atenolol was selected for its long half-life, which permits a single daily administration, and also because it is commonly used in patients with ischemic cardiopathy in this context. Initially both drugs could have been randomized 1:1 but the instability of some patients, in spite of triple antiangina therapy before surgery, caused us to choose to "reduce" the number of patients who would need to have the ß-blocker withdrawn, and to administer sotalol in a randomized fashion. For this reason, we decided to calculate the sample size at a ratio of 1.5:1, given the characteristics of the study population.
Previously, two prospective randomized studies were published that demonstrate the efficacy of atenolol (administered before or after surgery) in reducing the incidence of supraventricular tachyarrhythmias following elective myocardial revascularization, in patients with good left ventricular function [8, 20]. Sotalol, which in its dl-racemic form has both ß-blocking and type III antiarrhythmic activity, is also effective for prophylaxis against postoperative AF [10–15].
Suttorp and coworkers [10], in a study in which 300 patients were randomized to sotalol (40 mg every 6 hours) or placebo, beginning 4 hours before surgery and continuing for 6 days, observed that postoperative supraventricular tachyarrhythmias were significantly lower with sotalol (16% vs 33%). Gomes and colleagues [12] observed in a study with fewer patients, that sotalol was also effective when begun 24 to 48 hours before surgery. Parikkath and associates [11], in a randomized study comparing the administration of sotalol (160 mg) with metoprolol (75 mg per day), postsurgery, observed that the incidence of arrhythmias was lower with sotalol (16% vs 32%). Evrard and coworkers [14] conclude that low-dose oral sotalol (administered on the first postoperative day) provides very reliable protection in selected patients with nondepressed cardiac function. In another study Nystrom and colleagues [15] observed, in 101 patients undergoing CABG, that sotalol was more effective than the "regular treatment" in the reduction of postsurgery AF.
From our results and those of previous studies it may be deduced that the administration of sotalol should be protocolized in all patients with good ventricular function who are undergoing cardiac surgery. Nevertheless, some authors have emphasized that there are patients with these clinical characteristics who do not need any prophylaxis at all [16] given their low risk of presenting atrial tacyarryhthmias. This makes evident the importance of patient stratification in order to limit the administration of preventive antiarrhythmic treatment to high-risk patients.
A number of studies indicate conflicting results concerning clinical conditions that may predict postoperative AF [17]. In our study variables such as advanced age and the use of ß-adrenergic agents during surgery have been identified as strong predictors of postoperative AF.
Advanced age presupposes an increased risk of AF in the general population [21]. It is well known that dilatation and fibrosis of the atria increase with age due to a loss of side-to-side electrical coupling between the groups of atrial muscle fibers. Consequent slowing of electrical conduction within the atria provides a substrate for arrhythmogenesis. It has been postulated [22, 23] that the increase in atrial connective tissue with age, and the resulting nonuniform anisotropic conduction could be maximal by the eighth decade of life. Although the number of patients within this age group was relatively small, the finding is important, given that the average age of patients undergoing CABG continues to increase. This may serve as an anatomical substrate on which various intraoperative and postoperative factors act to trigger AF after cardiac surgery [24].
Atrial fibrillation and postoperative norepinephrine levels are significantly higher in patients with abrupt preoperative withdrawal of ß-adrenoceptor antagonist therapy [25, 26]. In keeping with the findings of Kalman and coworkers [25] and Aranki and colleagues [27], the univariate analysis of the present study reveals that the need for postoperative inotropic support is associated with the development of AF during postoperative care. We also observed in our study that the administration of vasoactive drugs (dopamine, dobutamine) before or during surgical procedures, was an independent predictive variable, in a multivariate analysis, for the appearance of AF. This data suggests that sympathetic activation may play a significant role in the pathogenesis of AF after surgery.
Patients who develop AF have prolonged postoperative hospital stays compared with patients who remain in sinus rhythm; this finding has been confirmed in previous studies [2, 3]. Recent evidence shows that prolonged hospitalization is attributable to an arrhythmia per se rather than any other specific clinical characteristics of the patients [27, 28]. Postoperative atrial fibrillation therefore is a significant consumer of hospital resources, contributing significantly to high health costs associated with CABG surgery.
One unexpected finding was the elevated mortality of our patients who were considered a priori low risk. The following facts could explain such results: 47% of the patients died with a septic process originating in the lungs (this could be related to the presence of diabetes mellitus or the advanced age of the patients); even though in our statistical analysis we have not observed a relationship between mortality and atenolol or sotalol, that possibility cannot be ignored in patients with low cardiac output, the minor effect of ß-adrenergic drugs; and in spite of the pro-arrhythmogenic action of sotalol associated with prolonged QT intervals [29, 30], we did not encounter a pro-arrhythmogenic action in this drug. In fact, of the sudden deaths in the hospital, only 1 patient was receiving low doses of sotalol. The possibility of the presence of malignant ventricular tacyarryhthmias cannot be ignored.
One of the most significant limitations of the present study is the absence of continuous electrocardiographic monitoring during the length of the hospital stay because hemodynamically well tolerated nonsustained episodes of AF might be missed, especially once the patient has left the CCU. Given that this limitation was present in both treatment groups it is unlikely that it affects the results of our study as a confounding variable. Another limitation that could have influenced the results of this study is the method of administering the drugs and the length of time for the ß-blocker to take effect; the half-life of atenolol usually varies between 16 and 18 hours and was administered only in a single dose. In spite of this, low doses were called for with both drugs in order to reduce side effects.
The results of this study lead us to conclude that sotalol is more effective than atenolol in preventing AF with an acceptable safety profile; that age and the use of ß-adrenergic inotropic drugs were independent predictors of peri/postoperative AF; and in clinical practice, we recommend prophylactic use of sotalol in high-risk patients who have good ventricular function.
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  R. Shrivastava, B. Smith, D. Caskey, and P. Reddy Atrial Fibrillation After Cardiac Surgery: Does Prophylactic Therapy Decrease Adverse Outcomes Associated With Atrial Fibrillation J Intensive Care Med, January 1, 2009; 24(1): 18 - 25. [Abstract] [PDF]
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= sotalol.