Clinical Study of the Acute Effects of Intravenous Nifekalant on the Deﬁbrillation Threshold in Patients with Persistent and Paroxysmal Atrial Fibrillation

Circ J 2008; 72: 76–80

Clinical Study of the Acute Effects of Intravenous Nifekalant on the Deﬁbrillation Threshold in Patients With Persistent and Paroxysmal Atrial Fibrillation

Kaoru Okishige, MD; Hiroki Uehara, MD; Naoto Miyagi, MD; Kentarou Nakamura, MD; Kouji Azegami, MD; Hirofumi Wakimoto, MD; Kageyuki Ohba, MD; Kenzo Hirao, MD*; Mitsuo Shimabukuro, MD**; Mistuaki Isobe, MD*

Background Antiarrhythmic agents are considered to have significant effects on the defibrillation energy requirement, so this study investigated the effects of nifekalant on defibrillation. Methods and Results Forty-two patients with persistent atrial fibrillation (AF) underwent electrical cardioversion via intracardiac electrode catheters prior to and after the intravenous administration of nifekalant. The success rate of the defibrillation and change in the defibrillation threshold using sequential incremental defibrillation energy deliveries was investigated. In addition, the parameters that could predict the beneficial effects of nifekalant were also assessed. Nifekalant significantly decreased the defibrillation energy requirement in 13 of the 42 cases, and nifekalant also converted AF to sinus rhythm with an identical energy to that of the last unsuccessful defibrillation in 21 of 42 cases. The success of defibrillation seemed to be dependent on significant prolongation of the intracardiac atrial electrogram intervals during AF by the nifekalant. Conclusions Intravenous nifekalant significantly improved the electrical defibrillation efficacy in patients with persistent AF that was resistant to defibrillation, without any serious adverse effects. (Circ J 2008; 72: 76–80) Key Words: Antiarrhythmic agent; Atrial fibrillation; Defibrillation; Defibrillation threshold; Nifekalant

arious factors have been suggested for altering the energy requirements for ventricular defibrillation Methods V in animals and humans, including underlying heart Study Population disease, changes in autonomic tone, acid–base and electro- Between 2003 and 2005, we enrolled a total of 42 pa- lyte imbalances, and various antiarrhythmic agents.1–7 With tients with persistent and paroxysmal AF lasting longer than regard to the effects of antiarrhythmic drugs on the defib- 24h, and which was refractory not only to antiarrhythmic rillation threshold (DFT), studies have shown that drugs drugs, but also to external cardioversion, and who had sub- which prolong the cardiac repolarization, but do not affect sequently underwent internal catheter cardioversion with and the conduction velocity, lower the DFT. Nifekalant hydro- without the concomitant administration of nifekalant. The chloride is a pure class III antiarrhythmic drug that inhibits research protocol was approved by the institutional ethics the rapid component of the delayed rectifier potassium cur- committee. Patients were excluded if they were less than 18 rent, transient outward potassium current, and inward rectifier years old, had a corrected QT interval >450ms or QRS potassium current without affecting the inward sodium cur- duration >140ms, had third-degree atrioventricular block rent, inward calcium current, or β-adrenergic activity.8,9 A or a serum potassium level <3.5mmol/L. Written informed previous report demonstrated that nifekalant significantly de- consent was given by all patients prior to cardioversion and creased the DFT of ventricular fibrillation in canine hearts,10 nifekalant administration. The average duration of parox- so the aim of this study was to determine whether short-term ysmal AF was 46.8±8.2h (ranging from 35.8 to 49.5h). All intravenous administration of nifekalant would alter the patients were refractory to direct current cardioversion in DFT in humans with paroxysmal and persistent atrial fibril- the control state, and necessitated further therapeutic inter- lation (AF). ventions, such as administration of nifekalant, in order to restore sinus rhythm (SR).

Defibrillation Procedure The patients were placed under general anesthesia, (Received February 15, 2007; revised manuscript received August 13, which was maintained with ultra-rapid barbiturates. Under 2007; accepted September 6, 2007) fluoroscopic guidance, 2 multipolar electrode catheters Heart Center, Yokohama-city Bay Red Cross Hospital, Yokohama, were introduced from the right femoral vein and positioned *Cardiovascular Division, Tokyo Medical and Dental University, at the lateral wall of the right atrium and inserted into the Tokyo and **The Second Department of Medicine, Ryukyu Univer- coronary sinus (Fig1). The internal leads were connected to sity, Naha, Japan Mailing address: Kaoru Okishige, MD, Heart Center, Yokohama-city a battery-operated external cardioverter-defibrillator (DVX, Bay Red Cross Hospital, Yokohama 231-8682, Japan Tokyo, Japan) that could be preset to deliver a variable All rights are reserved to the Japanese Circulation Society. For per- amount of energy from 5 to 100 joules in 5 J increments. The missions, please e-mail: [email protected] defibrillating pulse was in the form of a truncated exponen-

Circulation Journal Vol.72, January 2008 Acute Effects of Nifekalant for AF 77

Fig1. Fluoroscopic images of the position of the electrode catheter. RA, right atrium; CS, coronary sinus; LAO, left anterior oblique projection; RAO, right anterior oblique projection. tial with a 60% tilt and the initial voltage varied depending Table 1 Clinical Characteristics of the Patients With Persistent and on the selected energy, but the pulse duration was constant Paroxysmal Atrial Fibrillation for a given impedance. The defibrillation energy was deliv- Total no. of patients 42 ered between the 2 electrode catheters. M/F36 (85%)/6 (15%) Age (years; average) 62.3±10.3 DFT Testing LA diameter (mm; average) 42.0±3.9 The initial test used 5 joules and if that was unsuccessful, Ejection fraction (%; average) 60.4±12.1 a 10- to 20-J shock was then tried. Unsuccessful attempts Valve disease (mitral stenosis) 2/47 (6%) were followed by a 25- to 30-J shock in some patients. The defibrillation trials were separated by at least 5min. The DFT was defined as the lowest energy that was able to terminate the AF. When 10–30 J failed to terminate the AF, by the shocks. 0.4 mg/kg of nifekalant was administered intravenously over 10min. Blood pressure, QT interval, QRS complex Determinants of Successful Defibrillation duration and cycle length of the intracardiac electrograms Intracardiac electrograms recorded from the distal elec- during AF were measured before and after drug adminis- trodes of the catheter positioned in the right lateral atrium tration, then the same protocol to determine the DFT was were analyzed before and after intravenous administration repeated. The initial energy was either always less than the of nifekalant in all the patients. The average intervals of the last unsuccessful attempt by 10 J or was the same as the last intracardiac atrial electrograms (AE-AE) during AF were attempt. When the attempt failed to terminate the AF, the measured in 20 consecutive beats in a random fashion. We energy was increased by 10 J until the AF was terminated compared the change in the average AE-AE interval be-

Fig2. Defibrillation energy of the last attempt before nifekalant was administered because of failure of defibrillation and that for successful defibrillation after nifekalant.

Circulation Journal Vol.72, January 2008 78 OKISHIGE K et al.

Results Patient Population The study group comprised 42 patients (average age 61.9±10 years; range, 43–78 years). The average ejection fraction was 56.4±13.8% (range, 47–61%); 3 patients had mitral valve stenosis and 4 had coronary heart disease (Table1). All patients were taking antiarrhythmic agents: 22 were receiving pilsicainide, 11 propafenone, 7 cibenzoline, and 2 ﬂecainide. Other drugs being taken wereβ-blocking agents in 25 patients, digoxin in 31, and verapamil in 8.

Effects of Nifekalant on DFT There was variability among the patients in the energy required for defibrillation, ranging from occasional successful defibrillation with 10 J in 11 patients, to 30 Joules for even just an occasional defibrillation in the other patients after intravenous administration of nifekalant. In 39 of the 42 patients, defibrillation was successful and normal SR resumed. Failure to defibrillate or immediate re-initiation of AF occurred in the other 3 patients, even after administration of intravenous nifekalant. In 1 patient, the final energy level was 50 J, given according to the physician’s discretion when 30 J failed to terminate AF. In 21 patients, an identical electrical energy requirement to the last unsuccessful one was able to defibrillate the AF to SR after intravenous administration of nifekalant. In 5 patients, the electrical energy level required for successful defibrillation after the nifekalant was greater that of the last unsuccessful attempt. In 13 patients, nifekalant significantly decreased the energy level required for successful defibrillation. The mean decrement in the DFT in response to intravenous nifekalant for each patient was 9.5±7 J. Fig2 compares the defibrillation energy of the last attempt before nifekalant was administered, because of failure of defibrillation, and that for successful defibrillation after nifekalant. Although there was no significant difference in the DFT between before and after intravenous nifekalant, nifekalant had a significant effect in lowering the defibrillation energy requirement because the majority of the cases in this study were successfully defibrillated with the same or a lower energy level than that of the last unsuccessful attempt after nifekalant but not before.

Determinants of Successful Defibrillation We investigated the factors that might influence the efficacy of defibrillation of AF. The AE-AE interval during AF was analyzed in order to compare cases of successful and unsuccessful defibrillation. The AE-AE interval during AF Fig3. The average intervals of the intracardiac atrial electrograms was compared before and after administering intravenous (AE-AE) during atrial fibrillation before and after administering intra- nifekalant. In 38 of 39 patients, the average AE-AE interval venous nifekalant. was significantly prolonged from 167.9±40.3ms to 260.4± 40.1ms after nifekalant (p<0.001) (Fig3A). The average AE-AE interval was significantly prolonged from 155±16ms tween successful and unsuccessful cases of electrical defib- to 283±18ms after intravenous nifekalant in patients with rillation. successful electrical defibrillation (Fig3B). In contrast, in the patients with an unsuccessful defibrillation there was no Statistical Analysis significant difference in the average AE-AE interval after All data are presented as the mean values±standard de- intravenous nifekalant (from 181±21 ms to 204±23 ms) viation. Differences between groups were compared by (Fig3C). Wilcoxon signed-ranks test. A p value of less than 0.05 was considered significant. Adverse Effects In all patients, the QT interval significantly prolonged after nifekalant (380±37 vs 489±86ms, p<0.01). After successful defibrillation of AF, cardiac arrest with a maximum

Circulation Journal Vol.72, January 2008 Acute Effects of Nifekalant for AF 79

Fig4. Representative case of cardiac arrest with a maximum duration of 6s that was provoked in 3 patients after successful defibrillation of atrial fibrillation, but which did not require treatment. duration of 6 s was provoked in 3 patients but did not require venous ibutilide increased the success of cardioversion and treatment (Fig4). No other serious arrhythmias associated decreased the cardioversion energy requirement.12 In addi- with nifekalant infusion were observed. tion, Lai et al also reported that intravenous sotalol decreased the cardioversion energy requirement for chronic AF.13 In contrast, drugs that block the cardiac sodium channels and Discussion do not affect potassium conductance increase the energy re- Major Findings quired for successful defibrillation,1–3,14,15 and aof the class The major findings of this clinical study are that (1) the III antiarrhythmic agents, only amiodarone significantly DFT of AF significantly decreased after intravenous admin- increases the DFT.16–18 istration of nifekalant in the majority of the study patients, Nifekalant hydrochloride has proven to be an effective and (2) the average AE-AE interval after nifekalant was antiarrhythmic agent for treating life-threatening refractory significantly more prolonged in cases of successful AF ventricular tachyarrhythmias, such as ventricular tachycar- defibrillation than in unsuccessful cases. dia and ventricular fibrillation, by lowering the DFT,19–22 even in the cases with out-of-hospital cardiopulmonary Effects of Nifekalant on Electrical Defibrillation of AF arrest.23 We found that intravenous nifekalant was effective in terms of lowering the DFT in patients who demonstrated Proposed Mechanism for Effect of Nifekalant significant prolongation of the AE-AE interval after drug Ujhelyi et al considered that failure of defibrillation may administration. Murakawa et al demonstrated that the DFT be caused by (1) unidirectional conduction block as a result of ventricular fibrillation decreased as the fibrillation cycle of increased refractory dispersion; (2) unidirectional conduc- length prolonged during intravenous nifekalant administration velocity slowing; or (3) a short impulse wavelength and tion,10 and in the present study, we also observed an inverse an excitable gap.24 In the present study, nifekalant exerted relationship between the fibrillation cycle length during AF its pharmacological action by decreasing the dispersion of and the DFT. In general, the DFT for atrial flutter is rela- the AE-AE interval during AF, without affecting conduc- tively lower than that for AF.11 Prolongation of the AE-AE tion velocity or the wavelength of conduction. Nifekalant interval suggests conversion of AF to an atrial flutter-like has little pharmacological effect on the wavelength of fibril- excitation pattern in the atrium, which would renders it latory excitation in the cardiac tissue. Therefore, this phar- more amenable to defibrillation. This study did not uncover macological effect might be the principle mechanism of the the actual mechanism of the improvement in the DFT for results in the present study; however, the precise mecha- AF by intravenous administration of nifekalant, and it may nism of the decrease in the DFT by class III agents remains be the main factor in successful AF defibrillation. unclear.

Previous Studies Study Limitations The concomitant use of antiarrhythmic drugs and an im- Flaker et al demonstrated that repeated shocks had a plantable cardioverter defibrillator is an important tool for “sensitizing” effect on cardiac tissue, allowing for more managing patients with refractory supraventricular and ven- successful defibrillation with repeated shocks.25 However, in tricular arrhythmias. Regarding the class III antiarrhythmic that study the defibrillation energy determinant tests were agents, which are the most widely used drugs for the vari- carried out with a time interval of 30s, whereas we sepa- ous kinds of arrhythmias, Oral et al demonstrated that intra- rated them by at least 5min and this interval may be long

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Circulation Journal Vol.72, January 2008