Europace Advance Access originally published online on November 5, 2008
Europace 2009 11(1):70-74; doi:10.1093/europace/eun302
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Atrial Fibrillation
Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate
2nd Cardiology Department, General Hospital G. Papanikolaou, Exochi, Thessaloniki, Greece
Manuscript submitted 1 July 2008. Accepted after revision 13 October 2008.
* Corresponding author. Tel: +30 694 426 7643; fax: +30 231 330 7676. E-mail address: nfrag{at}vodafone.net.gr
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Abstract |
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Aims: Activation of beta-adrenoceptors attenuates prolongation of action potential duration induced by blockade of the delayed rectifier potassium current. We examined whether acute administration of beta-blocker could enhance ibutilide (IB) efficacy in conversion of atrial fibrillation (AF) with a rapid ventricular rate.
Methods and results: Ninety patients (aged 63 ± 13.5 years) with rapidly conducting AF were randomized in to two groups. Group A (n = 44) received esmolol titrated to achieve a heart rate of <100 bpm followed by IB co-administration, while Group B (n = 46) were treated with IB as monotherapy. In Group A, 29 patients (67%) converted to sinus rhythm (SR) compared with 21 (46%) in Group B (P = 0.04). The use of esmolol was the most important predictor for cardioversion (P = 0.009). The slower the heart rate at the time of IB initiation, the higher the likelihood for cardioversion (P = 0.015). Patients in Group A had significantly shorter corrected QT interval (QTc) at the time of conversion than those in Group B (433 vs. 501 ms, P = 0.003). Two patients in Group A developed severe bradycardia, whereas three patients in Group B developed severe ventricular tachycardia (VT).
Conclusion: Compared with IB monotherapy, the combination therapy of esmolol and IB appears to be more effective in conversion of rapidly conducting AF back to SR. The addition of beta-blocker reduces QTc prolongation and diminishes the risk of VT at the expense, however, of increased bradycardic events.
Key Words: Ibutilide, Esmolol, Cardioversion, Atrial fibrillation
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Introduction |
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Ibutilide (IB) is an antiarrhythmic agent used for the rapid conversion of atrial fibrillation (AF) and atrial flutter.1
Its primary mechanism of action to increase action potential duration (APD) is achieved not only by activating slow inward sodium current but also by blocking the rapid component of the cardiac-delayed rectifier potassium current, IKr.2–4 In every day clinical practice, however, many centres are reluctant to use IB due to its relatively limited efficacy and the risk of proarrhythmia.1,5 Ibutilide-reduced effectiveness may be attributed to catecholamine surges that have been reported to reverse the antiarrhythmic action of IKr blockers.6–8 Conversely, beta-adrenoceptor inhibition was found to eliminate fully the reverse frequency dependency of IKr blockers in the left atrial myocardium of guinea-pigs.8
Ibutilide carries also a risk of excessive QT prolongation with associated polymorphic ventricular tachycardia (VT).9 In patients with long QT syndrome, beta-adrenergic stimulation has been reported to delay repolarization and promotes early after depolarization-related arrhythmias by inhibiting IKr, an action which is counteracted by beta-blockade.10 Administration of beta-blockade is therefore likely to produce a beneficial modulation of the effect of IKr blockers in the setting of sympathetic hyperactivity which usually accompanies episodes of AF with rapid ventricular rate.
Esmolol hydrochloride is a selective intravenous (i.v.) adrenergic receptor antagonist frequently used for rate control of atrial tachyarrhythmias.11
The purpose of this study was to test the hypothesis that pre-treatment with esmolol followed by concomitant administration of IB and esmolol would be more effective and safer than a standard IB regimen in conversion of AF with a rapid ventricular rate.
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Methods |
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Study population
Between September 2006 and March 2008, we enrolled 90 patients from a total of 112 consecutive subjects with rapidly conducting AF, who came to the emergency department or were referred to our clinic for elective cardioversion. Atrial fibrillation with a rapid ventricular rate was defined as AF with heart rate of >110 bpm derived from the average eight consecutive intervals measured in the same lead.
The inclusion criteria were the following: age 
18 or 
80 years, estimated duration of arrhythmia episode 1 day, and average arrhythmia heart rate of >110 bpm.
Patients were excluded if they had symptoms or clinical signs of congestive heart failure, an acute ischemic event, history of a recent myocardial infarction, impaired left ventricular systolic function with ejection fraction (EF) <40%, severe hepatic, renal, or obstructive pulmonary disease, abnormal serum electrolytes levels, pregnancy or lactation, concomitant use of other antiarrhythmic agents (apart from beta-blockers), known sick sinus syndrome, and the presence of major atrioventricular conduction disturbances. Patients were also excluded if they had a previous episode of torsades de pointes (TDP) and systolic blood pressure (SBP) that remained <100 mmHg despite the administration of i.v. fluids.
All subjects underwent a full medical history, physical examination, 12-lead electrocardiogram (ECG), echocardiogram, chest X-ray, serum electrolytes measurement, and renal and hepatic function tests before recruitment in the study.
Study protocol
The study was approved by the Institutional Medical Ethics Committee. After informed consent was obtained, patients were randomly assigned to one of two treatment groups. Patients in Group A were treated initially with esmolol titrated to achieve a heart rate of <100 bpm followed by concurrent intravenous esmolol and IB administration, whereas patients in Group B were treated with IB as monotherapy.
Esmolol infusion was titrated to achieve and maintain a heart rate between 70 and 100 bpm according to the following protocol. Patients received a bolus dose of esmolol 0.5 mg/kg of body weight (mg/kg) over 1 min, followed by a continuous infusion initiated at a rate of 0.05 mg/kg/min. After 5 min, patients with heart rate >100 bpm received another bolus dose of 0.5 mg/kg followed by a 0.05 mg/kg/min increment in their maintenance infusion rate. This was repeated up to four times for a total of 20 min and a maximum infusion rate of 0.2 mg/kg/min, until a heart rate of <100 bpm was achieved. Beyond 20 min, the infusion rate remained at maximum dose. If at any time the target heart rate was achieved, esmolol dose escalation stopped and IB infusion was added, so that a concomitant IB and esmolol infusion regimen was subsequently given. Ibutilide was also added if the heart rate remained >100 bpm despite esmolol administration at a maximum titrated dose for 2 h.
Esmolol infusion was decreased by 50% if heart rate was reduced to <60 bpm or SBP fell to <100 mmHg, and discontinued if heart rate and/or SBP remained below the aforementioned levels despite the dose reduction. Esmolol infusion was also terminated on AF conversion.
Ibutilide was administered in up to two 10-min i.v. infusion of 1 mg through a peripheral vein, separated by a 10 min observation period. The infusion was terminated on conversion of AF or when there was safety concern due to the development of VT or SBP decrease to <100 mmHg.
During the infusion period, the patient's rhythm and blood pressure was continuously monitored. Conversion was considered successful if sinus rhythm (SR) was restored within 90 min of the onset of IB infusion, even if it was short-lived.1 If arrhythmia conversion failed within the predetermined time, a transthoracic electrical cardioversion followed immediately, without further use of antiarrhythmic drugs.
The corrected QT intervals (QTc) were calculated by applying the Bazett's formula. The estimations were performed by two independent blinded observers.
When AF had started >48 h from presentation, anticoagulation therapy for at least 3 weeks was required before any attempt for cardioversion. Heparin was given in cases where the duration of AF was <48 h.
Patients had continuous ECG and blood pressure monitoring throughout the drug administration process on the coronary care unit and for at least 6 h after IB discontinuation.
Statistical analysis
Binary logistic regression analysis with forward entry based on likelihood ratio test was used to examine the prognostic value of a number of parameters for AF conversion to SR. A logistic regression analysis was performed on the relationship between ventricular cycle length before and after IB administration. One way ANOVA was employed to examine the impact of the two different therapies on the required time and IB dose for AF cardioversion. Comparison of the mean QTc at the time of arrhythmia conversion between treatment groups was performed using one-way ANOVA. The mean change of heart rate before and after esmolol administration was tested using paired samples t-test. For all comparisons, a P-value of <0.05 was considered statistically significant.
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Results |
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A total of 90 patients (62% females, age 63 ± 13.5 years) were assigned randomly in the two groups. The mean duration of arrhythmia episodes was 17 ± 35 days, while 36 patients (40%) had history of previous episodes of AF. In Group A (n = 44), 35 patients (80%) had paroxysmal AF (<7 days) compared with 34 patients (75%) in Group B (n = 46). Underlying heart disease was present in 62% of the study patients. The majority had hypertension (52% in Group A vs. 46% in Group B) while coronary artery disease was present in five patients (11%) in Group A vs. four patients (9%) in Group B. The characteristics of patients in the two groups are displayed in Table 1. There were no significant differences between the two groups in terms of age, gender, frequency of AF episodes, duration of AF, ventricular rate at the time of enrolment, concomitant use of beta-blocker, EF, left atrial size, and presence of underlying heart disease. Patients were taking oral beta-blocker either due to chronic coronary artery disease (all on metoprolol), or as a result of hypertension (11 patients on atenolol, 3 on carvedilol, and 2 on nebivolol). No antiarrhythmic drugs had been previously used in patients taking oral beta-blocker.
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Of the 44 patients randomized to Group A, one was converted to SR during esmolol administration only, and was not included in further analyses. In 41 patients (95%), the aimed heart rate (<100 bpm) was achieved. The mean administered dose of esmolol was 124 ± 44 µg/kg/min while the mean time of esmolol administration was 88 ± 63 min.
Conversion rates
In Group A, 29 out of 43 patients (67%) converted to SR compared with 21 out of 46 (46%) in Group B (P = 0.04). According to the calculated adjusted odds ratio, esmolol enhanced the odds of successful conversion by 2.5 (95% confidence intervals from 1.04 to 5.84). Of patients who failed to be cardioverted with IB, all but one had subsequently successful electrical cardioversion. None of the 29 patients who were converted with combined administration of IB with esmolol had immediate AF recurrence (IRAF) compared with 2 patients in Group B who relapsed to AF within 2 min after conversion to SR.
The estimated mean time to conversion from the beginning of IB administration was 15.50 ± 10 min for patients in Group A compared with 31.67 ± 21 min in Group B, P = 0.025. The dose of IB required for successful conversion was 1.35 ± 0.61 mg in Group A to 1.78 ± 0.46 mg in Group B, P = 0.011.
Predictors of conversion
To examine the role of various factors as potential predictors of conversion we performed binary logistic regression analysis with forward entry, based on likelihood ratio test with the following independent variables: age, gender, frequency of AF episodes, duration of AF, concomitant use of beta-blocker, EF, left atrial size, history of previous episodes of AF, underlying heart disease, esmolol and IB administration. Table 2 describes the independent predictors of conversion in order of significance. The use of esmolol appeared to be the most important predictor for successful cardioversion (P = 0.009) followed by the variables IB (P = 0.023), and absence of previous episodes of AF (P = 0.025). All the other variables were found to be statistically non-significant.
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Effect of therapies on electrocardiogram
Esmolol infusion reduced significantly the average heart rate at the time of IB administration in relation to the heart rate at the time of enrolment (585 ± 109 vs. 488 ± 58 ms, P = 0.01). The mean ventricular rate at the onset of IB administration in Group A was also significantly lower compared with the mean heart rate in Group B (585 ± 109 vs. 450 ± 57 ms, P = 0.022).
Overall, there was a statistically significant increase in QTc after IB (438 ± 46 to 495 ± 61 ms, P = 0.009). A significant difference in QTc at the time of SR conversion (QTcSR) between the two groups was also found. Patients in Group A had significantly shorter QTcSR interval compared with those in Group B (433 vs. 501 ms, P = 0.003).
A significant inverse relation between ventricular heart rate at the onset of IB administration and the success of cardioversion was also demonstrated (P = 0.015).
Adverse effects
A total of six patients (13.6%) developed side effects during esmolol administration. Five patients (11%) experienced hypotension but no one required discontinuation of esmolol infusion. In one patient, esmolol infusion was reduced by half due to bradycardia, without further need for infusion discontinuation. No patient required i.v. inotropes for hypotension or transvenous pacing for bradycardia.
In Group A, no VTs were recorded during concomitant administration of esmolol and IB. In two patients (4.5%), prolonged asystole was recorded on SR conversion. In one patient, asystole lasting 8 s was recorded with SR emerging after chest compression while in another patient a 4 s pause followed by junctional rhythm was recorded. In both cases, sinus bradycardia was restored rapidly without need for temporary pacing and without further haemodynamic compromise.
In Group B, three patients developed severe proarrhythmia (6.5%). One patient developed sustained polymorphic VT after conversion to SR. She was a hypertensive patient with normal EF and mild hypertrophy of left ventricle. A marked prolongation of QTc preceded the onset of VT (580 ms). In two more cases, episodes of non-sustained VT during IB infusion led to drug interruption while AF was continuing. In both cases, prolonged QTc was measured (
510 ms).
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Discussion |
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This is the first report evaluating the effect of concomitant use of IB and esmolol on conversion to SR in patients with rapidly conducting AF who were pre-treated with esmolol. This study demonstrates an augmentation of conversion to SR with the combined use of these two antiarrhythmic agents. This combination also proved to have a relatively low risk of proarrhythmia and small probability of IRAF compared with the use of IB alone.
Ibutilide, a class III antiarrhythmic agent, was reported as an activator of a slow, inward sodium current but also has been demonstrated to be a potent blocker of IKr.2–4 It is an agent without effect on beta-adrenergic receptors, ability to reverse the effects of norepinephrine while its action is not antagonized by beta-blockers.9,12 The electrophysiological effects of drugs with class III antiarrhythmic properties diminish at higher heart rates and during sympathetic stimulation. Although this phenomenon has most clearly been documented for drugs that selectively block IKr, IB was also found to lose effect at very rapid stimulation frequencies.13,14 Duytschaever et al.15 showed that in remodelled atria the class III effect of IB was significantly reduced even after 2 days of AF, while the prolongation of the atrial refractory period was shorter at faster pacing rates.
Experimental and clinical studies have established that AF induces a shortening of atrial APD (electrical remodelling).16,17 Because IKr is activated later during the action potential, the actual contribution of this current may diminish. Under these conditions, blockade of IKr channels will obviously exert less effect. The reduced efficacy of IKr blockers may possibly be restored by reinstatement of the plateau phase of the remodelled atrial APD.18 Beta-blockade suppresses sympathetic signalling, tending to prevent Ca2+ overload.19
Our results of 67% efficacy of concomitant use of IB with i.v. beta-blocker in relation to 46% with use of IB alone support our hypothesis of IB efficacy enhancement by addition of beta-blocker at least in patients with rapidly conducting AF.
Comparison with other studies
In our study group, the mean duration of AF was 17 ± 35 days, patients with AF duration of <24 h were not included, while 25% of our patients had AF duration of >7 days. Thus, we assessed a group of patients with established AF where we do not anticipate great effectiveness of administered i.v. antiarrhythmic agents.
Nevertheless, our results compare favourably with the results of randomized studies comparing IB with other antiarrhythmic agents, which found 60–90 min IB conversion rate in a range of 32–51%.1,5 Our results compare also favourably with studies where IB was used in combination with other antiarrhythmic agents for AF conversion.20–23 Chiladakis et al.23 found conversion efficacy (66%) when IB was used in combination with propafenone, which is very similar to our results. Apart from class Ic properties, propafenone has also beta-blocking effects, which may explain the similarity in efficacy.
Although the incidence of IRAF was limited in both groups, its absence in patients treated with combined use of IB with esmolol may indicate a preventive role of beta-blockade for AF recurrences. Increased sympathetic activity may play an important role in ectopic impulse formation initiating AF and this triggering mechanism can be prevented by the use of beta-blocker.
Safety
The overall incidence of polymorphic VT was 6.5%, including 2.1% of patients in whom the arrhythmia was sustained and required cardioversion. All these events occurred in patients treated with IB as monotherapy while no patient treated with combined use of esmolol and IB developed VT. Polymorphic VT is associated with QT prolongation while one common clinical observation is that TDP often occurs in patients with AF after conversion to SR.24,25 In the present study, mean IB-induced QTc prolongation was attenuated at the time of SR conversion when IB used in combination with esmolol in comparison with the use of IB as monotherapy which at least in part explains the absence of polymorphic tachycardia. A functional link between IKr and the beta-adrenergic receptor as well as a sympathovagal imbalance with dynamic changes in QT interval have also been reported to play an important role in arrhythmogenesis that might both be modulated beneficially by the use of beta-blockers.26,27 Finally, beta-blockers can decrease transmural dispersion that reduces the probability of TDP occurrence.28
We had two episodes of severe bradycardia on SR conversion in Group A, which recovered spontaneously without transvenous pacing requirement. As IB has no effect at beta-adrenergic receptors and conduction block—bradycardia has been reported to occur at similar rates in the IB—and placebo-treated patients,9 these two events should be attributed to the esmolol action.
Study limitations
We have not tested the two therapy arms in patients with well controlled AF thus the efficacy beyond that of AF with a rapid ventricular rate is not known. Although evidence supporting beta-blocker efficacy to revert AF is limited,29,30 we cannot exclude that some patients reverted to SR due to esmolol action and not due to synergistic effect of esmolol with IB. The majority of study population had paroxysmal AF and therefore the results should not be extended to patients with persistent AF. The study population consisted mainly of patients with normal or mildly depressed EF. Thus, our results may not be applicable to patients with more severely depressed systolic function where the risk of exaggeration of heart failure from the administration of beta-blocker is increased and the risk of proarrhythmia is augmented.
Conclusions
Our suggested approach of first using esmolol and then IB concomitantly with esmolol appears to be an effective combination that enhances IB conversion rates in cases with rapidly conducting AF. This combination appears to limit IB proarrhythmic response at least as far as the occurrence of polymorphic tachycardia is concerned. A greater caution is required, however, for potential significant bradycardia. In view of the fact that the slower the ventricular heart rate at the time of IB initiation the higher the likelihood for cardioversion, the administration of i.v. beta-blocker acutely appears to have a significant role at cardioverting rapidly conducting AF.
Conflict of interest: none declared.
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