Europace Advance Access originally published online on May 10, 2006
Europace 2006 8(6):403-407; doi:10.1093/europace/eul038
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ATRIAL ARRHYTHMIAS
Pro-arrhythmic effects of amiodarone and concomitant rate-control medication
Department of Medicine/Cardiology, University of Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Manuscript submitted 24 April 2005. Accepted after revision 28 February 2006.
* Corresponding author. Tel: +49 228 287 5507; fax: +49 228 287 6264. E-mail address: jan.schrickel{at}ukb.uni-bonn.de
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Abstract |
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Aims Amiodarone is one of the most efficient and safe antiarrhythmic drugs in the treatment of atrial fibrillation (AF). Although pro-arrhythmic effects of amiodarone therapy are rare, the aim of the present study was to identify clinical constellations which may lead to amiodarone-associated pro-arrhythmia.
Methods and results Sixty-three consecutive patients (pts) (49 males; 64±10.3 years; 35 with coronary heart disease, 17 with lone AF) were retrospectively included in this study. All received an oral (92.1%) or iv (7.9%) loading dose of amiodarone for the treatment of AF. Cardiac diseases, concomitant medical treatment, and incidence of pro-arrhythmic effects were analysed. Three pts (4.8% of the total population) developed a clinical relevant, polymorphic ventricular tachyarrhythmia, 3–48 h after initiation of amiodarone loading. Coronary heart disease was present in all of these pts, and in two of them left ventricular ejection fraction was severely reduced. The mean QTc in these pts was only slightly prolonged; mean heart rate was significantly decreased compared with the total study population (61.0±7.5 vs. 74.5±24.1 bpm; P
0.05). In all pts with pro-arrhythmia, amiodarone (two pts iv, one patient oral) was initiated during concomitant beta-blocker/digitalis therapy. Twenty-five per cent of the patients receiving this ‘triple’ therapy developed ventricular arrhythmia.
Conclusion The present study implies that initiation of amiodarone therapy in pts with structural heart disease and AF that are concomitantly treated with beta-blockers and digitalis may have an increased risk of amiodarone-associated pro-arrhythmia.
Key Words: Amiodarone, Beta-blockers, Digitalis, Torsade de pointes, Proarrhythmia
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Introduction |
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Amiodarone is an essential antiarrhythmic agent in the management of tachyarrhythmias. Because of its excellent therapeutic efficacy and low rate of pro-arrhythmic effects compared with other antiarrhythmic agents, it is of major relevance in the long-term therapy of cardiac arrhythmias and, in particular, atrial fibrillation (AF).1
Amiodarone expresses properties of all four Vaughan-Williams classes, which is presumed to be responsible for its outstanding antiarrhythmic effectiveness. Predominantly, amiodarone exhibits a class III antiarrhythmic effect, resulting in a typical prolongation of the repolarization phase and effective refractory periods. At ventricular level, this prolongation might provoke early after-depolarizations and spatial as well as temporal dispersion of repolarization.2 In turn, these may induce short-coupled premature ventricular complexes leading to malignant ventricular tachyarrhythmia. In accordance with this, typical torsade de pointes (TdP) tachycardias have been seen during amiodarone therapy. Yet, the rate of such life threatening pro-arrhythmia is comparatively low, which has been attributed to amiodarone's complex electrophysiological properties that are supposed to contribute to homogenization of ventricular repolarization.3
The clinical safety of amiodarone was documented in a meta-analysis including more than 2800 patients over a period >20 years. In the evaluated studies, TdP were observed in <1% of the patients treated with amiodarone.3 However, various publications report increased incidence of amiodarone-associated pro-arrhythmia under various pathological conditions.4–12 The aim of the present retrospective analysis was to identify clinically relevant risk factors and predictors of amiodarone-associated pro-arrhythmic events in patients treated with amiodarone loading for therapy-refractory AF.
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Methods |
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Patient selection and data acquisition
Database search (35581 patients; 3-year interval) identified a total of 2217 patients with symptomatic AF admitted to our tertiary referral centre (Heart Center, University of Bonn, Germany). In 63 consecutive patients with paroxysmal (58.7%) or persistent (41.3%) AF, amiodarone-loading therapy was first initiated in hospital (clinical characteristics outlined in Table 1). Fifty-eight patients (92.1%) were treated with oral and five patients (7.9%) with iv loading therapy. Patients were retrospectively analysed for age, gender, accompanying cardiac diseases, medical treatment, and ECG characteristics. Electrocardiographic parameters were analysed in the 12-lead ECG, and QTc was calculated by Bazett's formula.13
At least two surface ECGs of each patient (before and after initiation of amiodarone) were analysed. Biochemical analyses (serum electrolytes) and complete blood counts were locally performed, and plasma levels of digitalis and amiodarone were evaluated by standard pharmacological testing. Left ventricular ejection fraction (LVEF) was determined by trans-thoracic echocardiography, LVEF of <30% was regarded as severely reduced. A subgroup analysis of the cohorts with concomitant beta-blocker and digitalis therapy was performed to correlate pro-arrhythmia with iv or oral amiodarone, gender, age, concomitant diseases, medical therapy, QT interval, ECG abnormalities, and left ventricular function.
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Statistics
Analysis included a multivariate ANOVA, two-tailed Student's t-test (continuous variables) and Mann–Whitney U test, when appropriate. Discrete variables were analysed by Fisher's test. P
0.05 was regarded as statistically significant. |
Results |
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Ventricular arrhythmia detection
Three male individuals (4.8% of the total population, 6.1% of the male patients) (Table 1) developed symptomatic polymorphic TdP, 3–48 h after initiation of amiodarone-loading therapy for symptomatic AF. Two patients received amiodarone iv, one patient orally (Table 1). Only one patient was orally anticoagulated. All of these patients presented with a history of coronary heart disease (51.7% in the total population). In two patients, LVEF was severely reduced (16.6% in the total population, P<0.001). Two patients received previous long-term oral digitalis/beta-blocker (digitoxin 0.1 mg/carvedilol 6.25 mg and acetyldigoxin 0.2 mg/nebivolol 2.5 mg daily) combination therapy for rate control. One patient was acutely treated with metoprolol (100 mg) and digitoxin (0.4 mg) iv before and continuously during amiodarone loading. All three patients with TdP were treated with this triple therapy. Thus, 25% of the 12 patients with this triple medication developed TdP. Demographic data showed no significant differences from the total population (Table 1). ECGs of typical polymorphic tachycardia/TdP episodes are shown in Figure 1.
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For a comparison of standard ECG parameters and heart rates before and after initiation of amiodarone, see Tables 2 and 3. Females had a higher heart rate (92.2±29.3 vs. 70.0±20.6 bpm; P<0.035) and QRS was prolonged in male individuals (100.3±18.2 vs. 86.5±18.0 ms; P=0.05) after initiation of amiodarone therapy. When compared with patients without ventricular arrhythmia, patients with TdP showed a significantly lower, but still normal heart rate, QTc was only slightly prolonged. Patients with and without triple therapy showed no significant differences regarding surface ECG parameters nor were relevant differences present in the compared subgroups (analysed cohorts: total population; beta-blocker therapy; digitalis therapy; digitalis/beta-blocker therapy with and without TdP) before and after initiation of amiodarone therapy. In all patients with TdP, digitalis and amiodarone plasma levels were within the therapeutic range (data not shown). Potassium levels were within the normal range (Table 3).
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To estimate the severity of the underlying cardiovascular disease as a possible co-factor contributing to pro-arrhythmia, comparison of LVEF was performed. No significant difference was found in patients with triple therapy [mean LVEF (SD): 40.8 (10.8)%] compared with patients on amiodarone and beta-blocker [42.7 (11.9)%] or digitalis [48.9 (11.9)%] alone. LVEF in subjects treated with amiodarone alone [53.3% (9.8)] was significantly higher compared with patients on concomitantly administered beta-blocker (P=0.023) or triple therapy (P=0.0039), but not digitalis (P=0.230).
All patients with TdP were successfully resuscitated. They survived without long-term complications and all were prophylactically given an implantable cardioverter defibrillator.
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Discussion |
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When compared with sotalol and class I antiarrhythmic agents, amiodarone-associated cardiac toxicity and, in particular, the incidence of pro-arrhythmic complications are low. Nevertheless, cardiovascular side effects of iv and oral amiodarone therapy have been described, including depression of sinus nodal automaticity,14
–16 atrioventricular block and intraventricular conduction abnormalities.17 Hohnloser et al.3 found amiodarone-associated ventricular tachycardia (VT) in <1% of the cases. Other studies showed a similarly low TdP incidence that was significantly less than with sotalol (3–5%) or quinidine (5–8%).3,18–20 Later studies with 462 and 589 patients on long-term amiodarone therapy (max. 98 months) found no TdP at all.21,22 Likewise, no case of pro-arrhythmia was documented in various randomized and controlled studies between 1989 and 1994.23–28 These results prove the safety of amiodarone regarding pro-arrhythmic events.
Various reports, however, point towards an enhanced pro-arrhythmic potential under certain clinical conditions, in particular in the initiation phase of amiodarone therapy.6,29–31 Abnormality of serum electrolytes, especially hypokalaemia, has been thought to contribute to the development of VT.5,10–12 Amiodarone-induced malignant ventricular arrhythmia was observed in patients with dilated cardiomyopathy7–9 and previous arrhythmia,4 such as VT on beta-blocker32 and quinidine therapy.33 In a similar way, the findings in the present study were amiodarone-associated ventricular arrhythmia very early after initiation of loading therapy. Yet, disorders of serum electrolytes were not present. Iv medication seems to be related to a higher risk in this setting. Structural heart disease was also a factor in the development of TdP in all three subjects suffering from pro-arrhythmia.
Patients with serious heart disease and chronic heart failure are more likely to be treated with combinations of two or more cardiovascular and/or antiarrhythmic drugs. Thus, in the present study, patients treated with amiodarone and additionally with a beta-blocker or both beta-blocker and digitalis showed significantly impaired LVEF compared with those on amiodarone alone. Changes in the therapeutic management of chronic heart failure have led to frequent use of beta-blockers and digitalis in seriously ill patients. Moreover, combination of different antiarrhythmics, in particular in AF, is common. Knowledge of the likely problems of these combinations including pro-arrhythmic effects is essential.
The results of this retrospective study suggest an increased risk of malignant polymorphic VT on combination therapy of amiodarone with beta-blockers and digitalis. Because the investigated cohort is comparatively small, general conclusions drawn from this study must be limited. Nevertheless, the high TdP rate in the study cohort receiving this triple therapy strongly points towards an enhanced pro-arrhythmic hazard of this combination, which is an important clinical finding. When compared with previous publications, we have seen a high rate of amiodarone-associated pro-arrhythmia in our study group. This might be due to the large number of patients who were seriously ill (>50% with reduced or severely reduced LVEF) and refractory to previous antiarrhythmic management of AF. Because of this, medication with beta-blockers and digitalis at the beginning of amiodarone administration was comparatively high in this study (19% of the total population). Of these, 25% developed TdP emphasizing the possible pro-arrhythmic danger of this combination.
In addition to class II typical prolongation of the repolarization phase and pro-arrhythmic QT prolongation, drug-induced bradycardia further contributes to prolongation of repolarization.2 An increased risk of pro-arrhythmia attributable to antiarrhythmic agents in combination with negative chronotropic drugs12 has been reported. This effect can be presumed to be more likely to occur when multiple heart rate lowering agents are simultaneously administered. The class III typical ‘reverse use dependent’ effect with an increased potassium channel blocking potential at low heart rates34 is likely to be a factor contributing to this bradycardia-induced TdP. Although our patients with TdP showed normal heart rates on the surface ECGs, occurrence of undocumented significant bradycardia as a factor in TdP cannot be ruled out, because continous ECG monitoring was not performed. Nevertheless, pro-arrhythmia can occur at normal heart rate and QT/QTc intervals. The absence of reliable predictors of pro-arrhythmic effects remains a major problem of antiarrhythmic therapy. Thus, clinical observations are often the only means of identification of possible risk factors and patients at higher pro-arrhythmic hazard.
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Conclusion |
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Knowledge of clinical risk factors contributes to identification of patients prone to development of pro-arrhythmic effects. This study demonstrates induction of TdP in three patients with AF, structural heart disease, and medication including amiodarone, beta-blockers, and digitalis. We conclude that this triple combination of antiarrhythmic agents may increase the danger of drug-associated arrhythmias. Use of digitalis and concomitant beta-blockers is nowadays more widespread due to the changes in the management of chronic heart failure. We suggest that amiodarone therapy in such patients should be started with special caution in hospital and under continuous ECG monitoring. Given the documented safety of the combination of amiodarone and beta-blockers35
on the one hand and pro-arrhythmia on triple therapy on the other, continuation of digitalis in these patients should be critically discussed. |
References |
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