Prophylaxis of Supraventricular and Ventricular Arrhythmias After Coronary Artery Bypass Grafting With Low-Dose Sotalol

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1 Prophylaxis of Supraventricular and Ventricular Arrhythmias After Coronary Artery Bypass Grafting With Low-Dose Sotalol Patrick Evrard, MD, Manuel Gonzalez, MD, Jacques Jamart, MD, Brigitte Malhomme, RN, Dominique Blommaert, MD, Philippe Eucher, MD, and Etienne Installé, MD Divisions of Intensive Care Medicine, Biostatistics, Cardiology, and Cardiothoracic Surgery, Mont-Godinne University Hospital, Université Catholique de Louvain, Yvoir, Belgium Background. Supraventricular tachyarrhythmia (SVT) commonly occurs shortly after coronary artery bypass grafting (CABG), but ventricular arrhythmias are less documented. Methods. On the 1st postoperative day, 206 consecutive eligible patients were prospectively randomized to a sotalol group (80 mg b.i.d.; n 103) or a control group without -blockade or antiarrhythmic drugs (n 103). Results. The SVT incidence (predominantly atrial fibrillation) accounted for 16% in the sotalol group versus 48% (p < ). Multivariate analysis showed that sotalol reduced the SVT incidence (p < , odds ratio, 0.20; 95% confidence interval, 0.09 to 0.42), whereas a lower preoperative left ventricular ejection fraction (p 0.019) and older age (p 0.031) were independent risk factors of SVT occurrence. The Holter electrocardiographic analysis (24 hours) demonstrated that sotalol (32 versus 92; p 0.031) decreased the median number of ventricular events, mostly isolated premature ventricular beats. Neither ventricular proarrhythmia effect nor torsades de pointes were detected. Despite strict hemodynamic-based selection, sotalol had to be discontinued in 8 patients (7.8%), for reasons related to asthma in 3 or cardiac reasons in 5. Conclusions. Oral low-dose sotalol provided considerable and reliable protection in selected nondepressed cardiac function patients, reducing the occurrence of both supraventricular and ventricular arrhythmias after CABG. (Ann Thorac Surg 2000;70:151 6) 2000 by The Society of Thoracic Surgeons Supraventricular tachyarrhythmia (SVT), mainly atrial fibrillation, commonly occurs shortly after coronary artery bypass grafting (CABG). This has been reported in up to 40% of patients, depending on the trial (observational or therapeutic) but also on the study site [1 5]. The rate of detection, however, depends on technique and thoroughness of postoperative surveillance, and in studies using continuous electrocardiographic monitoring, almost all patients have experienced episodes of atrial tachyarrhythmia [6]. Such rhythm disturbances are associated with an increased incidence of postoperative stroke, ventricular arrhythmias, and the need for a permanent pacemaker [4]. Consequently hospital charges are also linked to SVT [7]. Except perhaps for the off-pump CABG procedure, technical advances in surgical procedure and anesthesia, as well as in changing the method of myocardial protection, have not reduced the incidence of these arrhythmias [3 5, 7 9]. The evolution of postoperative ECG or Holter monitoring and the increasing age of the patient population Accepted for publication Feb 14, Address reprint requests to Dr. Evrard, Division of Intensive Care Medicine, Mont-Godinne University Hospital, 1 Therasse Ave, 5530 Yvoir, Belgium; patrick.evrard@rean.ucl.ac.be. account for the major factors that have contributed to the consistently higher incidence of SVT in recent years [10]. Determining the risk factors and defining which drug can be administered to the patient at risk are issues to be addressed. Recent studies have reported a significant benefit using -blockers for SVT prevention [2, 5, 6, 11 18]. Ventricular arrhythmias are less frequently documented and require continuous ECG or Holter monitoring. Holter monitoring eliminates the bias of direct observation and the risk of missing events, but it has been used to evaluate the incidence and severity of arrhythmia after open heart surgical procedures in only a few studies [6, 11, 16]. Sotalol, a -blocking agent with additional class III antiarrhythmic properties, appears to be effective in suppressing both supraventricular and ventricular arrhythmias [19]. This study evaluates, in an open randomized way, the efficacy and safety of oral low-dose sotalol in the prophylactic treatment of supraventricular and ventricular arrhythmias after CABG. Independent risk factors for the occurrence of SVT are also identified. Patients and Methods Patients Two hundred six consecutive eligible patients were included into this study from a cohort of 1,204 patients who 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 152 EVRARD ET AL Ann Thorac Surg SOTALOL AND CABG ARRHYTHMIAS 2000;70:151 6 had undergone CABG without cardiac concomitant procedures (valve replacement, aneurysm repair, or others). Ineligible patients were those with a left ventricular ejection fraction (LVEF) less than 35%, a history of obstructive lung disease, or known intolerance to -blocking agents such as conduction disturbances (second or third atrioventricular block or corrected QT interval greater than 0.45 seconds or both). Patients also were excluded if they had a history of recurrent or persistent SVT, ventricular tachycardia or fibrillation, postoperative intraaortic balloon pumping, renal failure (serum creatinine 2 mg/dl), digoxin or other antiarrhythmic drug administration between operation and randomization. Possible loss of magnesium was also covered intravenously (8.2 mmol/day of magnesium sulfate) for 48 hours to all patients. The final inclusion occurred on the 1st postoperative morning provided that the patient was in sinus rhythm more than 60 beats/min, had a potassium ion concentration between 3.5 and 5.0 mmol/l, and reached the hemodynamic criteria (systolic blood pressure 100 mm Hg, pulmonary capillary wedge pressure 15 mm Hg, cardiac index [CI] 2.5 L min 1 m 2, and calculated left ventricular stroke work index [LVSWI] 35 g.m/m 2 ) without inotropic support other than dopamine less than 3 g kg 1 min 1. Approval by the institutional review board was obtained and all patients gave their informed consent before entering the study. Drug Administration Patients were randomized by block in a prospective open manner to a sotalol treatment group or a control group that did not receive any -blocking agent or antiarrhythmic drugs. The initiation of sotalol (80 mg) immediately followed randomization at noon on the 1st postoperative day. The drug was given thereafter at 10 pm and onward twice daily. Operative Techniques Cardiopulmonary bypass with moderate systemic hypothermia (28 C), moderate hemodilution (hematocrit 0.20 to 0.25), flow rates of 2.4 L min 1 m 2, and mean systemic pressure of 50 to 70 mm Hg was used. All patients underwent single atrial cannulation and myocardial protection with cold potassium cardioplegic arrest was applied. This included crystalloid or blood cardioplegia and delivery of cardioplegia through the antegrade or the antegrade/retrograde routes. 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. All patients underwent routine intraoperative and postoperative hemodynamic monitoring including measurements of cardiac output by thermodilution. Data Collection All patients were observed during at least 48 hours by continuous ECG monitoring and a 12-lead ECG recording daily in the intensive care unit (ICU). Subsequently, the postoperative follow-up consisted of daily examination by the physician in charge, a 12-lead ECG recording every 2 days until hospital discharge, and additional recordings upon suspicion or signs of sustained arrhythmia (patient s complaint of palpitation, irregular pulse, or pulse rate exceeding the range from 50 to 100 beats/min or both). A 24-hour Holter ECG monitoring was also recorded on postoperative day 5 2 in patients remaining in the study at this period. They were automatically analyzed and medically controlled independently from study medical staff. End Points of Study Therapy was considered a failure if sustained SVT (atrial fibrillation or flutter, atrial or sinus tachycardia) occurred. Sustained SVT was defined as any symptomatic atrial arrhythmia or an episode of arrhythmia lasting more than 15 minutes, or both, or persistent sinus tachycardia as a heart rate more than 120 beats/min necessitating treatment with -blockers. In patients with sustained SVT, trial medication was stopped and patients were treated according to the physician in charge by amiodarone or digitalization, or both, -blockers, sotalol, or increased dose of sotalol. The occurrence of severe adverse effects was also a reason for discontinuing the study: mean heart rate less than 50 beats/min, systolic blood pressure less than 100 mm Hg, CI less than 2.2 L min 1 m 2, or evidence of respiratory distress (heart failure or airway obstructive disease). Statistical Analysis Numerical variables are expressed, unless otherwise noted, as mean standard deviation. Chi-square or Fisher s exact test when appropriate, Student s t test, and Wilcoxon rank-sum test were used for respectively comparing categorical, continuous, or ordinal variables. A multivariate analysis of factors influencing the occurrence of SVT was performed by logistic regression with backward selection of variables by Wald test for all variables that showed a value of less than 0.10 at univariate analysis. All tests were two-tailed and performed by SPSS statistical software (SPSS Inc, Chicago, IL). Results During the trial period, 103 patients were randomized in each group. About 45% of the 1,204 CABG patients did not reach the hemodynamic inclusion criteria, mainly a CI more than 2.5 L min 1 m 2 and an LVSWI greater than 35 g.m/m 2. Preoperative and postoperative characteristics of the 2 groups were fully comparable (Table 1). Until discharge from the hospital, there was 1 death in each group, 1 of ischemic event in the sotalol group and 1 of pulmonary infection in the control group. No perioperative new Q-wave myocardial infarctions were reported. Treatment failure occurred in 16% (16 of 103) of patients who received sotalol and in 48% (50 of 103) of patients in the control group (p ); the crude

3 Ann Thorac Surg EVRARD ET AL 2000;70:151 6 SOTALOL AND CABG ARRHYTHMIAS 153 Table 1. Patients Characteristics Characteristic Sotalol Control No. of patients Age (y) 61 9 a 61 9 Men (%) Prior myocardial infarct (%) Preoperative medication (%) Beta-blocker Calcium-blocker Digoxin 3 2 LVEF (%) Bypass time (min) Aortic cross-clamp time (min) No. of grafts Heart rate b (beats/min) Cardiac index b (L min 1 m 2 ) LVSWI b (g.m/m 2 ) CK (IU/L) 1, , CK-MB (IU/L) RBBB (%) a Results are expressed as mean standard deviation. b Heart rate, cardiac index, and LVSWI represent baseline values before randomization. CK peak serum creatine kinase; CK-MB peak serum creatine kinase isoenzyme; LVEF preoperative left ventricular ejection fraction; LVSWI left ventricular stroke work index; RBBB new right bundle-branch block. relative risk was 0.32 (95% confidence interval, 0.21 to 0.50) (Table 2). Sustained atrial fibrillation was the tachyarrhythmia most frequently seen in both groups. Atrial fibrillation was the only rhythm disturbance in patients receiving sotalol. Of the 50 patients with SVT in the control group, 44 (88%) had atrial fibrillation, 3 (6%) had atrial flutter, and 3 (6%) had sustained sinus tachycardia ( 120 beats/min). The time of occurrence of SVT was clustered around the first 3 postoperative days with 71% of the patients developing SVT during these days. The peak incidence on the 2nd postoperative day was not statistically different in both groups: 6 of 16 patients (38%) in the sotalol group versus 20 of 50 (40%) control patients (Fig. 1). Baseline postoperative heart rates did not differ among Table 2. Relative Risk of Supraventricular Tachyarrhythmia With Sotalol Risk 95% Confidence Interval Crude (table 2 2) RR OR Corrected for LVEF and age (logistic regression) OR LVEF preoperative left ventricular ejection fraction; ratio; RR relative risk. OR odds patients treated or not with sotalol (83 12 versus beats/min), but heart rates remained lower on the morning of the 2nd postoperative day in the sotalol group (81 16 versus beats/min) ( p 0.001). Adverse effects possibly related to the treatment drug and necessitating discontinuation of sotalol were observed in 8 patients (7.8%) and were related to asthma in 3, mild heart failure in 1, bradycardia in 1, and reduction in the CI ( 2.2 L min 1 m 2 ) in 3 ICU patients. In the control group, 15 patients (14.6%) needed -blocking therapy for different reasons (sinus tachycardia between 100 and 120 beats/min in 9, moderate hypertension in 4, and premature ventricular beats in 2). According to the univariate analysis of factors listed in Table 1, older age, lower preoperative LVEF, and new right bundle-branch block were noted in patients with postoperative SVT. Multivariate analysis revealed three independent variables to be predictive for the occurrence of SVT after CABG (Table 3). A lower LVEF and older age significantly increased the risk of SVT, whereas prophylactic use of sotalol (odds ratio, 0.20; 95% confidence interval, 0.09 to 0.42) protected patients from the development of these SVT. Holter ECG recorded in 122 patients without previous SVT was also analyzed, 75 in the sotalol group and 47 in the control group. The characteristics of the patients were similar and the median postoperative day of Holter commencement was the 4th in both groups. SVT (only atrial fibrillation) was detected in 2 sotalol-treated pa- Fig 1. Time of occurrence of supraventricular tachyarrhythmias (SVT) after coronary artery bypass grafting. The peak incidence of SVT was on the 2nd postoperative day in both groups and 71% of all SVT occurred by the 3rd postoperative day.

4 154 EVRARD ET AL Ann Thorac Surg SOTALOL AND CABG ARRHYTHMIAS 2000;70:151 6 Table 3. Predictive Factors of Supraventricular Tachyarrhythmia (SVT) Factor SVT (n 66) No SVT (n 140) Univariate p Multivariate p Age (y) LVEF (%) RBBB (%) NS Sotalol (%) LVEF preoperative left ventricular ejection fraction; NS not significant; RBBB postoperative right bundle-branch block. tients versus 9 in the control group, but was not sustained enough for clinical detection. Except for 2 patients in the control group, all SVT reoccurred, reached the clinical definition, and were treated. Therefore, the total number of patients presenting SVT became 52 (50%) in the control group versus 16 (16%) in the sotalol group ( p ). The average Holter heart rate was lower with sotalol (78 11 versus 93 12; p ) and -blocking properties also remained effective in reducing the minimum and maximum heart rates (Table 4). The evaluation of supraventricular events (SVE) showed a slight but not significant reduction in isolated atrial premature contraction by sotalol (20 versus 59 [median]; p 0.064). Otherwise, the number of patients presenting couplets or runs of SVE was insignificantly lower in the sotalol group. Regarding the protection of sotalol against ventricular arrhythmias, the number of ventricular events was reduced in the sotalol-treated patients (32 versus 92 [median]; p 0.031). Except for a slight but insignificant reduction in the number of patients presenting paired premature ventricular beats (31% versus 47%; p 0.072), there was no difference regarding bigeminism, triplets of premature ventricular beats, runs of accelerated idioventricular rhythm, or runs of ventricular tachycardia (Table 4). Moreover, torsades de pointes were not detected in either group. Despite the preventive effect of sotalol, the average hospital stay corresponding to the observation period was 10 days in both groups. Table 4. Results of Holter Monitoring Characteristic Sotalol (n 75) Control (n 47) p Heart rate (beats/min) Average Minimum Maximum No. of SVE a 20 (4 97) 59 (6 287) No. of VE b 32 (4 257) 92 (18 583) Forms of SVE b Couplet 33 (44) 23 (49) NS Run of SVT 27 (36) 22 (47) NS Sustained SVT 2 (2) 9 (19) Forms of VE b Couplet 23 (31) 22 (47) Triplet 4 (5) 3 (6) NS Bigeminism 7 (9) 6 (13) NS AIVR 1 (1) 0 (0) NS Run of VT 4 (5) 5 (11) NS a Values expressed as median (25th to 75th percentile) number of events per patient. b Values expressed as number of patients (%) presenting these forms of arrhythmia. AIVR accelerated idioventricular rhythm; NS not significant; SVE supraventricular event; VE ventricular event; VT ventricular tachycardia. Comment Supraventricular arrhythmia frequently occurred after CABG. A meta-analysis [13] of randomized control trials, including only those in which the ECG monitoring technique was clearly defined and some with Holter monitoring, reported a pooled proportion of patients with SVT in the control group of 26.9% which rose to 41.3% in trials using Holter monitoring (n 10) compared with 19.9% in trials without Holter monitoring (n 14). Prophylactic treatment with various -blocking agents, digoxin, or verapamil remained a controversial issue [6, 13, 20]. Although some recent studies recommended -blocking therapy for prevention of SVT shortly after CABG [2, 10, 13, 14, 18], other studies [1, 4, 7] did not. This large-scale, randomized control trial assessed the efficacy and safety of oral low-dose sotalol in preventing not only supraventricular but also ventricular arrhythmias. Another objective was to identify risk factors for developing SVT early after CABG. The prophylactic use of oral low-dose sotalol led to a substantial reduction in SVT (67%). Whether it was related to -blockade or class III antiarrhythmic action remained unclear, however, the -adrenoreceptor antagonism explained the significantly lower heart rate after two doses of 80 mg of sotalol and during Holter monitoring but also the adverse effects observed. Strikingly, as described by Suttorp and colleagues [2], atrial flutter or atrial tachycardia did not occur in sotatoltreated patients and was more likely related to the -blockade reduction in the hyperadrenergic state of the immediate postoperative period [10]. Atrial fibrillation has been reported to be the predominant arrhythmia shortly after CABG [2, 14]. This is confirmed by our study, in which 88% of all atrial arrhythmias were atrial fibrillations in the control group. The open design of the study makes possible a bias in the collection and identification of arrhythmic events. Another concern arises from the arrhythmia documentation that was performed only in patients whose arrhythmia lasted long enough to be recorded. Short periods of SVT might have been missed. Nevertheless, despite the use of Holter monitoring, we did not find a strong increase in sustained SVT. All but two in the control group reoccurred, were clinically detected, and treated. Nonsustained episodes of SVT might be underestimated but only Holter records of patients free from previous SVT were analyzed. In contrast with other studies, Holter

5 Ann Thorac Surg EVRARD ET AL 2000;70:151 6 SOTALOL AND CABG ARRHYTHMIAS 155 monitoring was not relevant for clinical monitoring of supraventricular arrhythmias necessitating prompt intervention for control of ventricular rate and for conversion to sinus rhythm [6, 11, 13]. As stated earlier, in prior studies conflicting data were reported regarding the efficacy and safety of -blocking drugs for prevention of SVT after CABG operations [5, 6, 17]. However, only a few reports have described the preventive effects of sotalol after CABG [2, 14 16, 18]. The incidence of SVT spread from 2.4% to 16% with a sotalol regimen varying between 120 and 320 mg divided into two to three doses per day. Neither the incidence nor the adverse effects (0% to 10.7%) were dose related. Even after our careful hemodynamic selection, 8 patients had to discontinue our regimen therapy due to a drop in the CI in 3 of them. None of these studies included hemodynamic evaluation for the selection of patients. The detection of hemodynamic side effects would unify but also increase the incidence of adverse effects [21]. Considering this hemodynamic selection, the results of the study only apply to very low-risk patients. It is interesting to note that the proportion of excluded patients is described, which is rarely reported. Recently presented multivariate analyses of predictors for the development of SVT after cardiac operations [1, 4, 7] conflict with those presented earlier [5, 13, 22]. We did not observe that male gender, withdrawal of -blocking agents, longer aortic cross-clamp time, or surgical technique were independent risk factors [1, 4, 7]. Similarly, in a randomized prospective study, Rubin and associates [5] demonstrated that no preoperative, intraoperative, or postoperative characteristics predicted patients at risk for SVT. Nevertheless, the likelihood of developing a SVT in sotalol-treated patients is markedly decreased (odds ratio 0.20) and confirms the results of large prospective therapeutic studies [2, 14 16, 18]. In contrast to other investigators [2, 5, 13], we found a negative effect of a lower LVEF essentially in treated patients. Mathew and coworkers [1] also reported history of congestive heart failure as an independent risk factor of SVT. Older age as a risk factor was the most uniform finding in a number of previous studies [1, 2, 4, 7] but this effect was masked in our treated group probably related to the power of sotalol. The safety and efficacy of sotalol on ventricular arrhythmia after CABG were not fully addressed. The drug has the additional property of lengthening the cardiac action potential and prolonging the effective refractory period (Vaughan-William class III action). In accordance with other authors [5, 11, 22], we observed a high incidence of different forms of ventricular disturbances. Despite the proarrhythmic activity related to the lengthening of the QT interval [19, 23], we report a reduction in the ventricular events, mostly isolated premature ventricular beats, and the absence of proarrhythmia, even torsades de pointes. This protection against ventricular arrhythmias was also reported in other studies at a higher dose and not specifically in the early CABG operative period [23, 24]. Many instances of sotalol-induced torsades de pointes have occurred in patients with an intentional overdose or predisposing factors, such as hypokalemia, bradycardia, or concomitant use of other drugs that prolong repolarization [25]. The absence of conditions qualifying patients for torsades de pointes and the hyperadrenergic state of the early postoperative period may explain the lack of proarrhythmic effects. 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