© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
Comparison of acute and long-term effects of single-dose amiodarone and verapamil for the treatment of immediate recurrences of atrial fibrillation after transthoracic cardioversion
aDepartment of Cardiology, University Hospital Basel Petersgraben 4, 4031 Basel, Switzerland; bDepartment of Cardiology, Vivantes Humboldt-Klinikum Berlin, Germany; cDepartment of Cardiology, Spreewald Hospital Burg, Germany; dDepartment of Cardiology, Charite-University Hospital Benjamin Franklin Berlin, Germany
Manuscript submitted 5 July 2004. Accepted after revision 25 May 2005.
*Corresponding author. Tel.: +41 61 265 5214; fax: +41 61 265 4598. E-mail address: csticherling{at}uhbs.ch(C. Sticherling)
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Abstract |
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AIMS: Amiodarone and verapamil have been employed to treat immediate recurrences of AF (IRAF) after cardioversion. This study compares the efficacy of these agents for the treatment of IRAF.
METHODS AND RESULTS: One hundred and eighty-five patients underwent transthoracic cardioversion (CV) for AF. AF recurred within 10 min in 20 patients (10.8%). These patients were randomized to verapamil (seven patients), or amiodarone (13 patients). After administration of verapamil and repeat CV, five patients (71%) experienced IRAF, compared with seven patients (54%) receiving amiodarone (P = 0.4). Including the results after crossover, IRAF occurred in 8/10 patients (80%) who received verapamil, compared with 7/15 patients (47%) who received amiodarone (P = 0.1). The combination of these agents prevented IRAF in 10/20 patients (50%). After a follow-up of 319 ± 189 days, 42% of the IRAF patients treated with verapamil and/or amiodarone remained in sinus rhythm, which did not differ from patients without IRAF (53%, P = 0.7).
CONCLUSIONS: IRAF occurs in 10% of patients undergoing CV. Amiodarone and verapamil are effective in preventing IRAF and result in a sinus rhythm maintenance rate of 50%. Since there is no difference in the long-term maintenance of sinus rhythm between patients with and without IRAF, attempts to restore sinus rhythm after pharmacological pretreatment are justified.
Key Words: atrial fibrillation, cardioversion, verapamil, amiodarone
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Introduction |
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Immediate recurrence of atrial fibrillation (IRAF) occurs in up to 25% of patients after successful cardioversion. It is known that this is in part due to atrial fibrillation (AF)-induced shortening of atrial refractoriness[1]
–[3]. Another contributing factor is the density of post-cardioversion premature atrial complexes (PAC) as a possible trigger for reinitiation of AF[4]. There is evidence that IRAF is preceded by bursts of pulmonary vein tachycardia in some patients[5],[6]. It has been shown that the occurrence of IRAF does not confer a worse long-term sinus rhythm rate if one succeeds in establishing sinus rhythm after pharmacological intervention[7]. Verapamil has been shown to attenuate this AF-induced shortening of atrial refractoriness and may, therefore, suppress recurrences of atrial fibrillation that occur shortly after conversion to sinus rhythm [3] [8]–[12].
Amiodarone is the most potent drug for prevention of recurrent AF[13]. Whether a single-dose of intravenously administered amiodarone suppresses IRAF as effectively as verapamil has never been compared. Therefore, the purpose of this prospective study was to evaluate the efficacy of intravenously administered verapamil and amiodarone for the prevention of IRAF and its impact on the occurrence of PACs after transthoracic cardioversion.
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Methods |
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Characteristics of study population
The subjects of this study were 185 consecutive patients referred to the University Hospital Benjamin Franklin in Berlin between January 2001 and March 2003 for transthoracic cardioversion of atrial fibrillation.
There were 59 women and 126 men, and their mean age was 64 ± 11 years (±1 standard deviation). The mean left ventricular ejection fraction was 0.54 ± 0.16 and the mean left atrial diameter was 46 ± 6 mm. The mean duration of atrial fibrillation was 309 ± 820 days. Sixty patients (32%) had undergone a mean of 1.1 ± 1.2 previous cardioversions (range 1–5). Structural heart disease was present in 143 patients (64%). Seventy-five patients had coronary artery disease, 26 had a non-ischaemic dilated cardiomyopathy, 41 had some other type of structural heart disease, and the remaining patients had no structural heart disease.
At the time of cardioversion, the patients were being treated with the following medications: amiodarone in 49 (26%), a beta-blocker in 116 (63%), a class Ic agent in 13 (7%), and digoxin in 51 (28%) patients and no patient was on sotalol or a calcium channel blocker.
Study protocol
The study protocol was approved by the Ethical Committee of the Free University of Berlin. In each patient, the duration of atrial fibrillation was estimated based on the review of the history and prior electrocardiograms. A transthoracic echocardiogram was performed within 4 weeks of cardioversion. If atrial fibrillation had been present for more than 48 h, cardioversion was preceded by either a transoesophageal echocardiogram to rule out left atrial thrombi, or by therapeutic anticoagulation (international normalized ratio 2–3) with phenprocoumon for at least 3 weeks.
Cardioversion was performed with a rectilinear biphasic wave form (M Series, ZOLL Medical Corporation, Burlington, MA, USA). After sedation with intravenous midazolam hydrochloride and etomidate, transthoracic cardioversion was performed using a step-up protocol with 75, 120, 150, and 200 J biphasic shocks[14]. Successful cardioversion was defined as the presence of at least two clearly identifiable sinus complexes after delivery of a shock.
IRAF was defined as a recurrence of atrial fibrillation within 5 min after successful cardioversion. If IRAF occurred, cardioversion was repeated. If IRAF occurred a second time, the patient was randomly assigned to receive an infusion of either 0.15 mg/kg of verapamil at a rate of 2 mg/min, or 5 mg/kg amiodarone over 5 min. Ten minutes after completion of the drug infusion, transthoracic cardioversion was attempted again with a shock that had the same energy as the previous shock. In the event of another episode of IRAF, the alternative study drug was administered and cardioversion was repeated on one final occasion. A 12-lead electrocardiogram was recorded continuously after each cardioversion attempt in order to document the PAC density as well as the rhythm at the end of the study protocol.
Follow-up
Patients who were being treated with an antiarrhythmic drug at the time of cardioversion continued with the same drug regimen after restoration of sinus rhythm. Antiarrhythmic drug therapy was altered during follow-up at the discretion of the treating physicians. Anticoagulation therapy was maintained for at least one month after cardioversion in patients in whom atrial fibrillation had been present for more than 48 h. The mean duration of follow-up was 319 ± 189 days. In patients with recurrent atrial fibrillation, the time after cardioversion at which atrial fibrillation recurred was determined based on symptoms and/or electrocardiographic documentation during follow-up. Thirty-eight patients (21%) were lost to follow-up.
Statistical analysis
Continuous variables are expressed as the mean ± 1 standard deviation and were compared by Student's t-test. Categorical variables were compared by Chi-square analysis or Fisher's exact test. A Kaplan–Meier analysis with the log-rank test was used to compare the probability of freedom from recurrent atrial fibrillation after cardioversion between the patients who did not have IRAF and the patients who had IRAF that was suppressed by verapamil and/or amiodarone. P values < 0.05 were considered statistically significant.
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Results |
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Immediate recurrence of atrial fibrillation
In accord with the selection criteria in this study, all of the 185 patients in this study were successfully converted to sinus rhythm. The mean energy requirement using a biphasic defibrillator was 141 ± 67 J.
Eleven patients (5.9%) had only one episode of IRAF and remained in sinus rhythm after another electrical cardioversion. Twenty patients (10.8%) experienced two episodes of IRAF. The IRAF occurred at a mean of 41 ± 90 s after cardioversion. The patients who did and did not have two episodes of IRAF are compared in Table 1. Among the variables that were examined, there were no significant differences between the two groups.
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Primary comparison of amiodarone and verapamil
Twenty patients were randomly assigned to receive either verapamil (seven patients) or amiodarone (13 patients). The two groups did not differ in their demographic or clinical characteristics (Table 2).
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Each of the seven patients who received verapamil was successfully converted to sinus rhythm. However, five of the seven patients (71%) had another episode of IRAF. IRAF occurred at a mean of 42 ± 90 s after successful cardioversion.
Among the 13 patients who received amiodarone, all were successfully converted into sinus rhythm. IRAF occurred in seven patients (54%) a mean of 14 ± 19 s after successful transthoracic cardioversion. There was no difference between verapamil and amiodarone in their efficacy in preventing IRAF (P = 0.4).
Comparison of verapamil and amiodarone after crossover
Among the five patients who had IRAF after receiving verapamil, two patients then received amiodarone and again underwent successful transthoracic cardioversion. None experienced another episode of IRAF.
Among the seven patients who had IRAF after receiving amiodarone, three then received verapamil. They all experienced another IRAF after successful transthoracic cardioversion.
In total, IRAF occurred in eight of 10 patients (80%) who received verapamil, compared with seven of 15 patients (47%) who received amiodarone (P = 0.1). IRAF was successfully prevented by verapamil and/or amiodarone in 10/20 patients (50%).
Role of premature atrial contractions in the occurrence of IRAF
Within the first 5 min 13 ± 19 PACs occurred in the non-IRAF group compared with 5 ± 8 PACs in the group with IRAF (P = 0.08). The time elapsed until the occurrence of the first PAC was 37 ± 64 s in the IRAF and 36 ± 84 s in the non-IRAF group (P = 0.9). The mean coupling interval of the PACs was significantly shorter in the IRAF group (412 ± 65 ms) than in the non-IRAF group (525 ± 94 ms; P < 0.001).
Comparison of the effects of amiodarone and verapamil on premature atrial complexes after cardioversion
The number of PACs within the first 5 min after cardioversion was significantly lower in the verapamil group (0.5 ± 0.8) compared with the amiodarone group (16 ± 9, P = 0.04). Between the verapamil- and the amiodarone-group there were no significant differences with regard to the time until the first PAC (verapamil 94 ± 160 s, amiodarone 14 ± 28 s; P = 0.2), and the mean PAC coupling interval (verapamil 432 ± 88 ms, amiodarone 405 ± 60 ms; P = 0.6).
Adverse effects
There were no adverse effects after infusion of verapamil or amiodarone, either alone or in combination.
Freedom from recurrent atrial fibrillation during follow-up
Thirty-eight patients (21%) were lost to follow-up. After a mean follow-up of 50 ± 27 weeks, five of 12 patients with IRAF (42%) and 71 of 135 patients without IRAF (53%) remained in sinus rhythm, which was not statistically significantly different (P = 0.7) (Fig. 1).
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Discussion |
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Main findings
As shown in previous studies, approximately 10% of patients experienced IRAF after two successful transthoracic cardioversions[7]
,[15]. The IRAF rate of 11% in our study was well within the previously reported range of 5–26%[15]–[18]. The differences in the reported prevalence may be explained by different definitions of IRAF[19]. There were no clinical or demographic predictors for the occurrence of IRAF. Neither the number of PACs within the first 5 min after cardioversion nor the times to their occurrence or their mean coupling interval were predictive of the development of IRAF. In a randomized comparison, amiodarone did not prove to be more effective than verapamil in suppressing IRAF. In the case of another episode of IRAF after treatment with verapamil, the acute administration of amiodarone was safe and helpful in suppressing IRAF in some additional patients. In contrast, all patients who received verapamil after a failure of amiodarone experienced another relapse. Overall, in 50% of patients who had two episodes of IRAF, the IRAF was suppressed by a single-dose of verapamil and/or amiodarone. Since there is no difference in the long-term recurrence rate of AF among patients with IRAF suppressed by verapamil and/or amiodarone and those who were successfully cardioverted and did not have IRAF, suppression of IRAF by verapamil and/or amiodarone should be attempted in these patients.
Possible mechanisms
Based on the concept of atrial wavelength, prolongation of the atrial effective refractory period diminishes the probability that atrial fibrillation will occur[1]. Rapid atrial rates have been shown to result in a reversible shortening of the atrial ERP and an increased likelihood of AF recurrence, an observation that has been termed atrial electrical remodelling[1].
Short-term reversible shortening of atrial refractoriness has been shown to be due to intracellular calcium overload during rapid atrial rates and predisposes patients to recurrent AF in humans[2]. In an animal model, increase in intracellular calcium accentuated electrical remodelling[3]. Likewise, in humans the administration of digoxin, which also increases the intracellular calcium concentration, resulted in an accentuation of electrical remodelling after short episodes of AF and made the subjects more susceptible to AF recurrences[20]. The role of calcium channel blocking agents for the prevention of atrial remodelling is not yet clear. While some clinical studies indicated that verapamil attenuates these effects of AF when given prior to the induction AF[8], there are also data indicating that it may actually shorten the AF cycle length and impede the spontaneous conversion of AF[12].
Amiodarone has clinically been shown to be the most effective drug for prevention of AF recurrence[13]. While there is agreement in that amiodarone decreases the dispersion of atrial refractoriness[21],[22] there have been conflicting reports about its effects on atrial effective refractory period (ERP)[21],[23].
There is some evidence that IRAF is at least partially related to electrical remodelling and that it may be critical to overcome a "vulnerable period" after electrical conversion. In a goat study, a combined decrease in AERP and conduction velocity lead to a marked shortening of the atrial wavelength immediately after conversion of AF, which implies a highly vulnerable substrate for re-entry[24]. Theoretically, IRAF should become less likely if there is less electrical remodelling and if there are fewer premature atrial complexes to trigger IRAF[25]. Since the therapeutic effects of single-dose amiodarone and verapamil dissipate within a few hours, it is very likely that they exert their effect by overcoming a "vulnerable" period immediately after cardioversion. This suggests that maintenance of sinus rhythm for only a few hours may allow reversal of atrial remodelling, such that a predisposition to recurrent atrial fibrillation is markedly diminished once the effects of amiodarone and/or verapamil have dissipated.
An important determinant of IRAF may be premature depolarizations that trigger atrial fibrillation. In a prior study, prevention of IRAF by verapamil was found to be associated with suppression of PACs after cardioversion[11]. In the present study, we also found a significant reduction in the number of PACs after administration of verapamil but not after amiodarone. However, this did not translate into a lower incidence of IRAF in the verapamil group.
Chugh et al. showed, in a subset of patients undergoing pulmonary vein isolation, mostly for paroxysmal AF, that all episodes of IRAF were preceded by a burst of atrial tachycardia in a pulmonary vein, not simply by premature depolarization. This finding highlights the important role of the pulmonary veins as a trigger, at least in patients with paroxysmal atrial fibrillation, which may, in turn, benefit from pulmonary vein isolation[5],[6].
Prior studies
In a study by Daoud and co-workers, 10 mg of verapamil was administered intravenously in 19 patients who had IRAF. This resulted in suppression of another episode of IRAF in 47% of patients[11]. Another study randomized 21 patients with IRAF to intravenous verapamil or ibutilide before performing another electrical cardioversion[7]. While 73% in the verapamil group experienced another IRAF this was only the case in 22% of patients in the ibutilide group. In the patients in whom AF recurred despite the use of ibutilide, an additional intravenous dose of verapamil resulted in overall suppression of IRAF in 85% of the patients. Comparing this study with our results, it appears that ibutilide is more effective than verapamil and amiodarone in preventing IRAF. Verapamil and ibutilide were compared previously when given to patients during induced atrial fibrillation[12]. Although verapamil resulted in an attenuation of the shortening of the AERP after conversion to sinus rhythm, it shortened the AF cycle length and impeded the spontaneous early conversion of AF. This may be explained by rate-dependent effects of verapamil on different channels. It decreases the plateau calcium current and thereby shortens the action potential duration and ERP[26]. Its effect of IKr blockade at relatively slow atrial rates explains why verapamil may lengthen or have no effect on ERP during sinus rhythm[27]. However, at rapid rates such as during atrial fibrillation, ICa blockade by verapamil is enhanced[28] whereas the effects of IKr blockade are attenuated[29],[30].
Another previous study demonstrated that 4 weeks of oral therapy with amiodarone prevented IRAF in 91% of patients with IRAF[18]. De Simone and co-workers compared the efficacy of oral flecainide, amiodarone, and combined oral therapy with flecainide plus verapamil as well as amiodarone plus verapamil on AF recurrence rates[30]. While there were no differences between the flecainide and amiodarone group, the addition of verapamil led to a significant reduction of AF recurrences. Furthermore, it also decreased the secondary AF recurrence rate. This is in contrast to our study, where the addition of verapamil to patients who previously failed on amiodarone did not yield an additional benefit. This may be explained by the fact that we used single intravenous doses of the respective agents, whereas amiodarone was given orally for 4 weeks and verapamil for 3 days prior to cardioversion in the study by De Simone.
Study limitations
A limitation of this study is that only single doses of verapamil and amiodarone were tested. It is also possible that higher dosages would have had a greater effect on IRAF but were avoided for possible adverse effects. Although left to the referring physician's discretion another limitation is the high number of previous cardioversion attempts indicating that some individuals may not have been ideal candidates for cardioversion. Also, it is unclear whether the administration of the respective agent exerted its effect by prevention of the shortening of the atrial ERP since we did not measure the ERP invasively. Lastly, another limitation is the relatively small number of patients which is due to the low prevalence of IRAF. Therefore, it cannot be ruled out that there is a statistical difference which could only be shown with a much larger study population.
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Conclusions |
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Cardioversion of atrial fibrillation may be unsuccessful either because of a complete inability to convert the atrial fibrillation to sinus rhythm, or because of IRAF. The failure of transthoracic shocks to restore sinus rhythm has been largely obviated by pretreatment with ibutilide[31]
or by the use of biphasic shocks[14]. Therefore, the most common cause of the failure of electrical cardioversion to result in sinus rhythm for at least 10 min is IRAF, which may occur in approximately 10% of patients undergoing cardioversion. The present study demonstrates that amiodarone and/or verapamil may suppress IRAF in 50% of the patients. There is no significant difference in the efficacy of the two drugs when given as a single intravenous bolus.
Since the long-term maintenance of sinus rhythm does not differ between patients who experienced an episode of IRAF and those who did not, attempts to suppress IRAF by a single-dose of verapamil and/or amiodarone are justified.
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References |
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