Asian Cardiovasc Thorac Ann 2005;13:47-52
© 2005 Asia Publishing EXchange Ltd
Diltiazem versus Amiodarone to Prevent Atrial Fibrillation in Coronary Surgery
Dimitrios Mikroulis, MD,
Vassilios Didilis, MD,
Fotios Konstantinou, MD,
Kosmas Tsakiridis, MD,
Georgios Vretzakis, MD,
Georgios Bougioukas, MD
Department of Cardiothoracic Surgery, Medical School, University of Thrace, Alexandroupolis, Greece
For reprint information contact: Dimitrios Mikroulis, MD Tel: 30 255 107 4166 Fax: 30 255 107 4164 Email: dmikrou{at}med.duth.gr, Department of Cardiothoracic Surgery, General University Hospital of Alexandroupolis, Alexandroupolis P.C. 68100, Greece.
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ABSTRACT
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The prophylactic effect of amiodarone on atrial fibrillation after coronary bypass grafting with extracorporeal circulation was compared with that of diltiazem in two groups of 60 patients each. Patients were monitored continuously for 8 days. The incidence of atrial fibrillation was recorded retrospectively in a control group of 60 patients who received our standard prophylactic regimen of an oral beta blocker. The incidence of postoperative atrial fibrillation was not significantly different in the two test groups: 11.7% for the amiodarone group and 10% for the diltiazem group. The incidence of atrial fibrillation in the control group was 23.3% and the differences were marginally significant when compared to the amiodarone ( p = 0.093) and diltiazem groups ( p = 0.050). The prophylactic use of diltiazem or amiodarone is feasible and safe for patients undergoing coronary bypass, with similar rates of atrial fibrillation.
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INTRODUCTION
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Atrial fibrillation (AF) is a common complication of cardiac surgery, ranging in incidence from 10% to 65%. It is associated with increased morbidity, mortality, and extended hospitalization, and usually occurs between the second and fifth postoperative day.1 Prophylaxis and atrial overdrive pacing remain the options for patients at risk of developing postoperative AF. In such cases, management strategies are directed towards restoration of sinus rhythm or control of ventricular rate.2 Beta blockers and amiodarone are considered as standard and effective prophylactic agents in decreasing AF and sudden cardiac death after cardiovascular surgery, with minimal adverse effects.3,4 Diltiazem is also considered an effective prophylactic agent for AF.5 The prophylactic value of diltiazem and amiodarone, administered intravenously (IV) before weaning from extracorporeal circulation (ECC), was investigated for effects on postoperative AF in patients undergoing coronary artery bypass grafting (CABG). Ventricular arrhythmias, heart rate, and hemodynamic parameters were also studied.
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PATIENTS AND METHODS
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In this prospective randomized study, 120 consecutive patients underwent CABG under ECC without a concomitant cardiac procedure. Patients with unstable angina, re-operation, simultaneous noncardiac operations, history of AF, left or right bundle branch block, history of premature ventricular contractions, and those given amiodarone preoperatively were excluded. The institutional review board of the hospital approved this study, and each patient gave written informed consent. The study was performed in accordance with the Helsinki Declaration of 1975, as revised in 1983, and according to European guidelines for good clinical practice.
Preoperative treatment with nitrous and Ca2+ competitor medication was interrupted one night prior to the operation, administration of beta blockers continued until the morning of the operation. Patients were randomly divided into two groups of 60 each to receive diltiazem (group D) or amiodarone (group A). Standard CABG operations were performed on all patients using mammary artery and a variable number of saphenous vein grafts. A normothermic operative technique was employed with Calafiore cardioplegia. Group A patients received 300 mg amiodarone IV prior to weaning from ECC, followed by 1 g IV daily for 48 h, then 400 mg IV daily for a further 48 h, and subsequently, an oral beta blocker until hospital discharge. In group D, a continuous infusion of diltiazem was administrated for 24 h immediately following aortic declamping (minimum dose, 0.l mg·kg–1·h–1), followed by an oral beta blocker for the remainder of their hospitalization. In cases of hypertension (mean arterial pressure > 90 mm Hg) in group D, the diltiazem dose was increased, whereas in the amiodarone group, the situation was controlled by administration of nitroglycerin. When inotropic support was mandatory, dobutamine (maximum dose, 10 mL·kg–1·min–1) was administered. To estimate the efficacy of each drug in preventing AF, a third group of 60 control patients (group C) was selected retrospectively. They had been operated on immediately prior to this study and fulfilled the inclusion criteria. They did not receive amiodarone or diltiazem but were given the routine treatment administered in our department, with a beta blocker to prevent AF being administered until discharge, beginning between the first and the third postoperative day.
A complete history, including risk factors and angiographic data, was recorded for all patients preoperatively. The number of grafts and durations of ECC and aortic clamping were recorded during surgery. Patients were closely followed for complications postoperatively. Continuous 12-lead electrocardiographic monitoring was carried out in the first 4 postoperative days. Additionally, 3-lead telemetry was recorded continuously from the 4th to 8th postoperative day. Hemodynamic parameters including heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were measured at 2, 8, and 24 h postoperatively. These were determined using a Quantitative Sentinel clinical information system and a Marquette MARS 5000 full disclosure system (GE Medical Systems, Freiburg, Germany). Patients were monitored for myocardial infarction (new Q waves and raised creatine kinase-MB values), and arrhythmias were fully analyzed. Analyses included incidents of AF (if symptomatic or with a duration exceeding 3 min), atrioventricular block, premature ventricular complexes, R on T (premature ventricular complexes with R on the previous T), bigeminies, trigeminies, and incidents of ventricular runs (3 or more sequential premature complexes). For group C, incidences of AF and major postoperative complications were recorded.
Statistical analysis of the data was performed using SPSS version 10 software (SPSS, Inc., Chicago, IL, USA). The Kolmogorov-Smirnov one-sample test was used to examine the normality of the data. Normally distributed continuous variables were expressed as mean ± standard deviation, while non-normal variables were expressed as median and range. Categorical variables were expressed as frequencies and percentages. Student’s t test or the Mann-Whitney U test was used to determine differences between 2 groups (A and D), one-way analysis of variance was used to determine differences between 3 groups (A, D, and C), post-hoc analysis was performed using Student’s t test with the Bonferroni correction, and the chi-squared test was used to evaluate any potential association between categorical variables. Differences in hemodynamic data between the two groups of patients were assessed with analysis of variance for repeated measurements with 2 factors. All tests were 2-tailed and statistical significance was considered for p-values less than 0.05.
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RESULTS
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Analysis of the preoperative demographic and clinical characteristics of the patients eligible for this study showed that the 3 groups were well matched (Table 1
). No statistically significant differences were observed for the parameters recorded. There was one death in group C. Two perioperative myocardial infarctions were recorded in each group. In the diltiazem group, 3 patients were excluded from the study: one due to bradycardia and 2 due to hypotension. No other serious morbidity was observed.
No statistically significant differences were observed for the mean values of hemodynamic parameters between group A and D patients (Table 2), except for MAP (patients in the diltiazem group had significantly lower MAP, and for this reason, 2 patients were excluded from the study). The mean values of heart rate for the first 96 h postoperatively are summarized in Table 3. No statistically significant differences were observed, although heart rate in the diltiazem group was lower in the first 24 h postoperatively, with the difference approaching statistical significance at 1 h and 24 h. One patient in the diltiazem group was excluded because of low heart rate.
Analysis of electrocardiographic monitoring revealed that cases of AF that were either symptomatic or for longer than 3 min were observed in 6 patients in the diltiazem group (10%), compared to 11.7% in the amiodarone group and 23.3% in the control group. The chi-squared test revealed that the difference was not statistically significant ( 
2 = 0.086, df = 1, p = 0.769) between group A and D, but a marginally significant difference was found between groups A and C ( p = 0.093) and D and C ( p = 0.050). Restoration of sinus rhythm was obtained in all patients: in group D, by IV amiodarone administration; and in group A, either by dose increase (5 patients) or by addition of verapamil (2 patients). The duration of AF was 10.86 ± 8.03 h in group A, 10.56 ± 6.48 h in group D, and 21.36 ± 9.01 h in group C. One-way analysis of variance showed statistically significant differences among the 3 groups of patients ( p = 0.010). When the Bonferroni adjustment was made for the number compared, there was no statistically significant difference between groups A and D ( p = 0.943), while both of these groups were significantly different compared to the control group ( p = 0.017).
The AF occurred after a mean 2.43 ± 1.06 days in group A, 2.33 ± 0.88 days in group D, and 2.50 ± 1.13 days in group C ( p = 0.949). Ventricular arrhythmias in the first 8 postoperative days did not show any significant differences between groups A and D (Table 4). Four instances of first-degree atrioventricular block were recorded in groups A and D. In all cases, the block was transient and no therapeutic intervention was required. There were no cases of ventricular fibrillation or ventricular tachycardia (more than 10 consecutive premature ventricular complexes).
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DISCUSSION
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Atrial fibrillation is the most common complication after open heart surgery. Use of temporary atrial cardioversion wires has been proposed recently as a safe and effective method of treatment, but prophylaxis still remains the main modality and a point of controversy.6 Amiodarone has been used as an antiarrhythmic and antianginal drug since the 1970s. It is a structural analog of thyroid hormone and some of its antiarrhythmic properties and toxicity may be attributable to interactions with nuclear thyroid hormone receptors.7 The lipid solubility of amiodarone gives it an exceptionally long half-life, it has a wide antiarrhythmic profile, and when administered intravenously, has a faster onset of action than when delivered orally. Intravenous amiodarone also reduces sudden death after myocardial infarction.4,7 On the other hand, diltiazem is a calcium channel blocker known to be effective in the treatment of angina pectoris, postoperative hypertension, and supraventricular arrhythmias.8 Diltiazem is metabolized to desacetyl diltiazem, both having no effect on renal function. More recently, there is evidence suggesting that diltiazem can enhance thrombolytic therapy.9
We decided to administer IV diltiazem 0.1 mg·kg–1·h–1 continuously for 24 hours postoperatively because a previous study demonstrated very promising results (5% incidence of AF) with this mode and dosage.5 Also, myocardial injury during open heart surgery is mediated in part by intracellular calcium overload, a possible reason for postoperative AF. Therefore, improved myocardial protection is expected from agents that block transmembrane calcium movements. This suggested a possible role for diltiazem, especially during aortic declamping and in the early postoperative hours. Furthermore, we had unpublished observations regarding low tolerance to protracted diltiazem administration of more than 0.1 mg·kg–1·h–1 during the early postoperative period. For a simple and practical mode of administration of amiodarone, a loading dose of 300 mg, followed by 1g IV daily for 48 h was feasible via the central venous line, and well tolerated during the first 2 postoperative days. On the 3rd day, patients usually leave the intensive care unit and the central venous catheters are removed; therefore, low dose administration (400 mg·day–1) was adopted for the next 2 days, based on a previous study by Hohnloser and colleagues10 who used a similar dosage (total of 4.5 g for 4 days) and obtained a very low incidence of AF (5%).
Both diltiazem and amiodarone have a well-established role in clinical management of cardiac arrhythmias in the nonsurgical environment. Diltiazem is rapidly effective in controlling ventricular rate, and it is safe; while amiodarone controls ventricular rate rapidly, and increases the rate of cardioversion.11 A recent comparative study of these two drugs in the treatment of atrial tachyarrhythmias in a nonsurgical intensive care unit showed that diltiazem afforded significantly better 24 h heart rate control but with a significant incidence of hypotension; the authors suggested that amiodarone may be an alternative in patients with severe hemodynamic compromise.12 Diltiazem and amiodarone have also been employed to manage atrial fibrillation, other arrhythmias, and cardiac failure following CABG. Both amiodarone and diltiazem have been assessed as prophylaxis in the postoperative period; amiodarone also demonstrated efficacy in suppressing ventricular arrhythmias.3,10,13 Amiodarone is as effective as sotalol in reducing the incidence of AF and atrial flutter following heart surgery.14 Preoperative oral treatment with diltiazem also ameliorates left ventricular diastolic dysfunction in patients after CABG.15
In the prophylactic perioperative setting, diltiazem displays no adverse effect on hemodynamics and systolic myocardial function, and provides potent anti-ischemic and antiarrhythmic protection by lowering the incidence of AF following CABG.5,16 Perioperative low-dose intravenous amiodarone demonstrates a significant reduction in the incidence, ventricular rate, and duration of AF after CABG at intravenous doses that are well tolerated and do not increase the risk of intraoperative or postoperative complications.17 In general, amiodarone is considered one of the first choices of drugs to reduce the incidence of postoperative AF in cardiac patients.18 However, there has been no previous comparison of amiodarone and diltiazem in preventing AF after CABG.
The lack of significant differences in hemodynamic parameters in this study supports the prophylactic administration of diltiazem or amiodarone in patients undergoing CABG. We did not perform echocardiography to assess a direct inotropic effect of diltiazem, but the values of cardiac index were nearly identical for the two groups. Colson and colleagues19 reported that heart rate, MAP, and inotropy were decreased during coronary artery surgery with diltiazem. In this context, diltiazem reduces myocardial oxygen demand through decreases in heart rate, inotropy, and systolic function, while increasing myocardial oxygen delivery through coronary vasodilatation. Nevertheless, many studies support our data, suggesting that perioperative diltiazem infusion does not produce any negative inotropic effect in patients undergoing CABG.20 Electrocardiographic monitoring of arrhythmias showed no significant differences between the two groups. However, diltiazem may cause low heart rate or hypotension in some patients.12 Three patients from the diltiazem group were excluded because of hypotension or bradycardia. This was especially evident in patients with pre-existing low heart rate or low arterial pressure; amiodarone may be preferable in such patients. Amiodarone is associated with several side effects, the most common being pulmonary and thyroid. These are presumed to be due to the fact that amiodarone is an iodinated benzofuran derivative that is a structural analogue of thyroid hormone. Diltiazem lacks the side-effect profile of amiodarone, and can thus be considered for protection against AF after CABG.
It was concluded from this study that treatment with diltiazem or amiodarone in the perioperative period of CABG is feasible and safe and reduces the rate of AF postoperatively. Diltiazem should be considered for postoperative prophylaxis as it demonstrates a generally lower toxicity profile than amiodarone. However, amiodarone remains the superior choice for patients with a low heart rate and low arterial pressure. Influence of the beta-blocker medication, which was routinely given to patients after the cessation of the antiarrhythmic drugs, cannot be excluded (especially for the diltiazem group). However, the efficacy of amiodarone and diltiazem as AF prophylaxis were compared with similar beta-blocker dosages. Additional studies will determine the optimal dose scheduling and the possible combination of these two antiarrhythmic agents with other drugs in the prevention of post-surgical complications.
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ACKNOWLEDGMENTS
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We thank Grigorios Tripsianis, PhD, Assistant Professor, Department of Medical Statistics, University of Thrace, Greece, for his help in statistical analysis.
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ABSTRACT
INTRODUCTION
