Circ J 2005; 69: 1508–1513

Nifekalant Hydrochloride Suppresses Severe Electrical Storm in Patients With Malignant Ventricular Tachyarrhythmias

Takashi Washizuka, MD; Masaomi Chinushi, MD; Hiroshi Watanabe, MD; Yukio Hosaka, MD; Satoru Komura, MD; Hirotaka Sugiura, MD; Takashi Hirono, MD; Hiroshi Furushima, MD; Yasutaka Tanabe, MD; Yoshifusa Aizawa, MD

Background Some patients with an implantable cardioverter-defibrillator (ICD) suffer from burst of inappropri- ate multiple discharges (severe electrical storm), and because the current therapeutic options are limited, the effect of nifekalant hydrochloride, a new class III drug, on severe electrical storm was investigated in the present study. Methods and Results Ninety-one consecutive patients treated with ICD were included in the study (M 70; mean age 58 years; left ventricular ejection fraction 45±15%). Severe electrical storm was defined as more than 10 ICD discharges within 1h. During a mean follow-up period of 30±13 months, 41/91 (45%) patients had ap- propriate ICD therapy for arrhythmias and severe electrical storm occurred in 11 of them (12%) at 20±18 months after ICD implantation. The mean number of ICD discharges/h during severe electrical storm was 18±12. In 4 of 10 patients, severe electrical storm was successfully suppressed by a combination of deep sedation andβ-blocking agent; 6 other patients were refractory to this treatment, but severe electrical storm was successfully suppressed by intravenous administration of nifekalant hydrochloride with no adverse effects. Conclusions Nifekalant hydrochloride is an effective and safe treatment for severe electrical storm. (Circ J 2005; 69: 1508–1513) Key Words: Implantable cardioverter defibrillator; Nifekalant hydrochloride; Severe electrical storm

n implantable cardioverter-defibrillator (ICD) effec- available for clinical use.11 It is a nonselective K channel tively terminates (VT) and blocking agent and does not inhibit either the Na channel or A ventricular fibrillation (VF) and can diminish the β-receptors.12–14 In an experimental model of previous myo- incidence of sudden cardiac death in patients with malig- cardial infarction nifekalant was effective against ven- nant ventricular tachyarrhythmias.1–3 Although the total tricular tachyarrhythmias,15–18 and moreover, this effect number of ICD shocks is restricted, some patients experi- was recently reported in patients with ischemic heart dis- ence ‘severe electrical storm’; that is, more than 10 shocks ease.19–23 therefore, we investigated the efficacy and safety within 1h. Prior studies have reported a 10–30% incidence of nifekalant for the control of severe electrical storm in of electrical storm defined as 3 shocks per day.4–6 Further- patients with an ICD. more, recent studies have shown that multiple shocks lead to myocardial injury,7 and recurrent episodes of VF are also associated with increased intracellular calcium levels8 that Methods may result in progressive left ventricular dysfunction9 and Patients the induction of tachyarrhythmias.8 These findings suggest This study began in June 2000 when nifekalant was that severe electrical storm might contribute to mortality,6,10 became clinically available. From June 2000 to May 2003, but there are very limited therapeutic options currently 91 patients received a transvenous ICD (Medtronic, MN, available for suppressing severe electrical storm and the USA) and were included in the present analysis. All de- current clinical management of these patients is suboptimal. vices were capable of storing RR intervals and/or electro- In recent clinical trials, class III antiarrhythmic drugs grams during ICD discharge. All patients fulfilled the were found to be effective in suppressing life-threatening following criteria: (1) clinical documentation of VF, VT or ventricular tachyarrhythmia, so they might be a useful ther- unexplained syncope; (2) induction of VF or VT during an apy for severe electrical storm. Nifekalant hydrochloride electrophysiological study; and (3) failure of antiarrhythmic (nifekalant, Nihon Schering K.K., Osaka, Japan), is a new drugs to prevent spontaneous and/or induced ventricular class III antiarrhythmic drug that has recently become tachyarrhythmias. There were 70 men and 21 women with a mean age of 58±15 years (range 13–80 years). Both VT (Received February 2, 2005; revised manuscript received August 30, and VF were documented clinically in 12, and VF or VT 2005; accepted September 9, 2005) only was documented in 30 and 46 patients, respectively. First Department of Internal Medicine Niigata University Hospital, Asahimachi, Niigata, Japan The remaining 3 patients had unexplained syncope. The Mailing address: Takashi Washizuka, MD, First Department of Inter- left ventricular ejection fraction (LVEF) ranged from 17% nal Medicine, Niigata University Hospital, 1-754 Asahimachi, Niigata to 73% (mean 45±15%). Underlying conditions included 951-8510, Japan. E-mail: [email protected] coronary artery disease (n=30), idiopathic dilated cardio-

Circulation Journal Vol.69, December 2005 Suppression of Electrical Storm 1509

Fig1. Example of severe electrical storm in a 63-year-old patient with dilated cardiomyopathy and ventricular tachy- arrhythmias (Case 4). Arrhythmic cluster was observed during a short time. Each tachycardia was successfully terminated by cardioversion from the implantable cardioverter-defibrillator. myopathy (n=13), arrhythmogenic right ventricular cardio- myopathy (n=7), cardiac sarcoidosis (n=6), hypertrophic Results cardiomyopathy (n=6), and idiopathic VF (n=18) including Electrical Storm 13 patients with Brugada syndrome and others. During a mean follow-up period of 30±13 months, 41/91 All patients were seen routinely in our out-patient clinic (45%) patients had ≥1 appropriate ICD therapy for VT/VF. at 3-month intervals or as soon as possible after ICD Electrical storm and severe electrical storm occurred in 19 discharge for device interrogation and retrieval of stored and 11 patients at 15±13 and 20±18 months, respectively, ECGs. An ICD discharge was considered inappropriate following ICD implantation. Analysis of stored electro- when stored ECGs demonstrated a rhythm other than grams showed that severe electrical storm consisted of sustained VT or VF. repeated episodes of VT in 9 patients and both VT and VF in 2 patients. The mean number of ICD discharges for Definition of Severe Electrical Storm and Therapeutic severe electrical storm was 18±12 /h (range 10–50) per Regimen patient. The stored electrograms showed no evidence of Electrical storm was defined as the occurrence of 3 or device malfunction or inappropriate discharge for supra- more episodes of VT/VF within a 24-h period.4,6 ICD ventricular tachyarrhythmias. The clinical characteristics of discharges included anti-tachycardia pacing, low energy these 11 patients are shown in Tables1 and 2. One patient shock and high energy shocks. Severe electrical storm was died just after severe electrical storm because of electro- defined as the occurrence of 10 or more episodes of VT/VF mechanical dissociation; 3 patients experienced near syn- within 1h (Fig1). For each arrhythmia, the appropriateness cope during the episodes, and the remaining 7 patients had of the ICD therapy was assessed by device interrogation. palpitations or light-headedness. One of the patients experi- Patients who had severe electrical storm were treated ac- enced progressive left ventricular dysfunction during the cording to the following therapeutic regimen. Deep sedation severe electrical storm and in 3 patients, severe electrical (thiamylal 100–150mg iv or propofol 0.2mg/kg iv) and the storm was the first episode of ICD discharge after implanta- aβ-blocking agent was administered. Intravenous admin- tion, but the other 8 patients had experienced prior episodes istration of nifekalant was commenced if the severe electri- of ventricular tachyarrhythmias that were terminated by cal storm was not suppressed by this treatment. Nifekalant single ICD discharge. was administered as a loading infusion of 0.1–0.3mg/kg Shocks only were used to treat 9 of the 11 patients dur- for 5min with a maintenance dose of 0.2–0.4mg·kg–1·h–1. ing the initial severe electrical storm episodes with anti- tachycardia pacing being added in the remaining 2 patients. Statistical Analysis Precipitating factors for severe electrical storm could be All values are presented as the mean±SD, unless other- identified in only 3 patients and included hypokalemia wise specified. A p-value of <0.05 was considered statisti- (<3.5mmol/L), a pneumonic illness with a high fever, and cally significant. congestive heart failure. There was no apparent precipitat- ing factor evident in the remaining 8 patients.

Circulation Journal Vol.69, December 2005 1510 WASHIZUKA T et al.

Management of Severe Electrical Storm Ten of the 11 patients with severe electrical storm re- quired hospitalization for pharmacological therapy (patient days) No. 11 died). These 10 patients were treated according to the therapeutic regimen described earlier. The combined )(

–1 therapy of deep sedation andβ-blockade suppressed severe ·h

–1 electrical storm in 4 patients and in the remaining 6 patients were stabilized by intravenous administration of nifekalant. In 1 of these 6 patients, VT ceased during the administra- tion of the loading dose of nifekalant. Fig2 shows the ECG recordings from case 8, a 57-year-old male with hyper- (–)(–) 0.15(–) 0.2 (–)(–) 11 0.2 (–) 7 0.15(–)(–) – 21 (–) – 24 0.2 – – – 30 – – – Nd –trophic – cardiomyopathy and severe electrical storm. The Liver Nif dose Nif duration GPT116 GOT150, 0.4 4

dysfunction (mg·kg sustained monomorphic VT at a rate of 180 beats/min recurred immediately after successful cardioversion by ICD before nifekalant administration, despite the deep sedation andβ-blockade (Fig2A). In this patient, we also used overdrive pacing (120 beats/min) to diminish the trigger ventricular premature contractin, but VT recurred. The VT stopped during the administration of the loading Serum Serum

(mmol/L) (mg/dl) dose of nifekalant (0.15mg/kg) and did not recur (Fig2B). In the other 5 patients, the frequency of ICD discharges was markedly reduced after nifekalant administration. No CHF K Cre hemodynamic deterioration was evident during the admin-

istration of nifekalant in these 6 patients. Although the heart rate and QRS width did not change, QT and corrected QT intervals were significantly prolonged from 425±66 to -blockade 463±73ms and from 499±72 to 538±80ms, respectively, β CM, dilated cardiomyopathy; Sarcoid, cardiac sarcoidosis; LVA, idiopathic left ventricular LVA, sarcoidosis; cardiac Sarcoid, CM, dilated cardiomyopathy; angiotensin converting enzyme ihibitor; ARB, angiotensin receptor blocker; CHF, congestive congestive CHF, blocker; ARB, angiotensin receptor enzyme ihibitor; angiotensin converting by the administration of nifekalant (Fig3). No pro-arrhyth- mic events occurred and nifekalant was continued for 16± ARB ACE/ 10 days (range 4–30 days). In one of the 6 patients, severe electrical storm recurred despite treatment with nifekalant and an infusion of was required to suppress it. SE AA After the nifekalant therapy, 3 patients were given a combi- nation of and aβ-blocking agent and the other 3 patients were given dl-. eatment for SE -blockade -blockade

Tr Discussion β β In the present study, 11/91 (12%) patients experienced severe electrical storm as a relatively late phenomenon after ICD implantation. The trigger was evident only in 3 of the 11 patient. Intravenous nifekalant was an effective and safe treatment for severe electrical storm that was re- fractory to deep sedation and administration of aβ-block- ing agent. These findings suggest that nifekalant could be a therapeutic option for the treatment of severe electrical (months) during SE/h Occurrence ICD storm. The definition of severe electrical storm has not been standardized, although a working definition of electrical storm is more than 3 episodes of recurrent VT or VF during a 24-h period.4,6 Credner et al4 studied the incidence and prognosis of electrical storm in 136 consecutive patients with ICD. During a mean follow up of 403±242 days, 10% of patients experienced electrical storm and the cumulative probability of survival in these patients was not worse than that of patients without electrical storm. However, Exner et

(Lateral) 6

(Anterior) al assessed the prognostic significance of electrical storm

(Broad anterior) (Broad in 457 patients registered in the AVID trial and of them 20% experienced electrical storm, which was considered to be a significant risk factor for subsequent cardiac death. It has been suggested that frequent shocks increases the 7 Sex Arrhythmia of SE discharges at cardiac troponin level, which indicates myocardial injury, whereas myocardial fibrosis and acute cellular injury may 24 10 M11 M 77 70 OMI OMI VT VF 40 19 4 3 14 10 Sedation (–) None (+) (–) (+) (+) (+) (–) 4.0 (–) 1.7 Nd Nd 7 8 9 F M M 55 57 71 MR HCM OMI VT VT VT 45 67 36 36 38 0.2 10 15 15 Sedation Nifekalant + Sedation AMD AMD Bep (+) (–) (+) (–) (–) (+) (–) (–) (–) 3.9 4.2 3.0 1.1 1.1 0.5 1 2 M 3 M M 4 72 5 41 M 6 65 HCM M DCM M 63 Sarcoid 67 VT 45 DCM VT VT LVA DCM 54 VT 30 35 VT VT 38 26 6 12 37 29 60 20 13 18 27 7occur Nifekalant 50 Nifekalant Nifekalantin (–) 10patients 13 Sot Sot Nifekalant (+) Nifekalant (+) Sedation Sot + (+)who AMD (+) (–)had (–) (–) (–) (–) recent (+) (–) (–) (–) (–) (–) shocks 4.5 (+) 4.0 4.4 (–) (–) from 1.3 (–) 1.7 0.6 3.8 4.2ICD. 4.1 0.9 1.0 More- 0.7 no. (years) disease (%) Case Age Heart EF

able 1 Electrical Storm Severe With Clinical Characteristics of Patients over, recurrent episodes of VT/VF are also associated with EF, ejection fraction; SE, severe electrical atorm; ICD, implantable cardioverter-difibrillator; AA, antiarrhythmic drug; ACE, ACE, AA, antiarrhythmic drug; electrical atorm; ICD, implantable cardioverter-difibrillator; SE, severe ejection fraction; EF, Sot, sotalol; D ventricular tachycardia; VT, cardiomyopathy; nifekalant; HCM, hypertrophic Nif, creatinine; Cre, heart failure; infarction. Bep, ; OMI, old myocardial AMD, amiodarone; aneurysm; T

Circulation Journal Vol.69, December 2005 Suppression of Electrical Storm 1511

Fig2. Effect of nifekalant administration on severe electrical storm in a patient with hypertrophic cardiomyopathy and a cluster of ventricular tachycardia (VT). Prior to nifekalant administration VT immediately recurred a few beats after successful cardioversion, but during nifekalant administration it ceased and did not recur.

Fig3. Change in the ECG parameters QT interval, corrected QT interval, heart rate (HR) and QRS width before and after nifekalant administration. QT and corrected QT interval were significantly prolonged after nifekalant administration, although HR and QRS width did not change. increased intracellular calcium levels,8 which may lead to frequency current ablation. Moreover, in patients with left progressive left ventricular dysfunction, apoptosis of car- ventricular dysfunction that is refractory to either of these diac cells and facilitation of arrhythmias. In the present treatments, mechanical circulatory support is needed.25 study, 1 patient experienced progressive left ventricular With the exception of intravenous amiodarone, antiarrhyth- dysfunction during a severe electrical storm, so it is very mic therapy has yielded frustrating results in patients with important to control this phenomenon. However, the cur- severe electrical storm. Credner et al4 recently reported that rent therapeutic options are antiarrhythmic drugs or radio- combined therapy with intravenous amiodarone and a β-

Circulation Journal Vol.69, December 2005 1512 WASHIZUKA T et al. blocking agent was effective in 6 patients who were refrac- produced marked QT prolongation and TdP, especially in tory to class I drugs. Intravenous amiodarone has also been patients with renal dysfunction or severe LV dysfunction. shown to decrease the frequency of unstable VT/VF.26 At Other precipitating factors for TdP (eg, hypokalemia and the current time, intravenous amiodarone is the only effec- bradycardia etc) need to be controlled and close monitoring tive antiarrhythmic drug for suppressing severe electrical of the QT interval is needed. storm, but it has some extracardiac side effects and is no longer able to be used in Japan. Thus, another intravenous Study Limitations antiarrhythmic drug is needed and we have demonstrated First, this study was not randomized and the number of the efficacy of nifekalant, a new class III drug, in the acute patients was small, because the number of patients who management of severe electrical storm. experienced severe electrical storm was limited and they Nifekalant is a novel class III 11 that needed emergency therapy. Second, we did not compare blocks the rapid component of the delayed rectifier K cur- the effect of nifekalant with that of other antiarrhythmic rent, the transient outward K+ current, the inward rectifier drugs. Most of the patients with severe electrical storm had K+ current and the ATP-sensitive K current without affect- left ventricular dysfunction such that the intravenous ad- ing either the Na+ current orβ-adrenergic activity.12–14 As a ministration of a class I drug was not favorable, apart from pure K , it does not have negative inotropic class Ib drugs. In addition, we cannot administer intrave- effects and does not affect cardiac conduction. In addition, nous amiodarone clinically in Japan at the current time, so it can be used only intravenously and its half-life is relative- we used nifekalant. Third, our results do not apply to ly short. Previous studies have shown that nifekalant sup- patients with arrhythmic storms related to VF unrelated to presses ventricular tachyarrhythmia in myocardial ischemia heart disease, such as idiopathic VF or Brugada syndrome. and infarction.15,16 More recently, Koizumi et al reported However, despite these limitations, the present study indi- the efficacy of nifekalant hydrochloride in the treatment of cates that nifekalant is effective in controlling severe elec- life-threatening ventricular tachyarrhythmias during reper- trical storm in patients with organic heart disease. fusion for acute myocardial infarction.19 Takenaka et al also reported the antiarrhythmic efficacy of nifekalant for severe ventricular tachyarrhythmias in 4 patients with acute myo- Conclusion cardial infarction and depressed left ventricular function Despite the limitation of this study, the results suggest (16±4% fractional shortening).20 In the present study, that short-term intravenous administration of nifekalant is nifekalant did not significantly depress cardiac function, as an effective and safe treatment for arrhythmic clusters. none of the patients who received nifekalant showed hemo- These findings indicate the therapeutic potential of this new dynamic deterioration despite the fact that 4 of the 6 class III antiarrhythmic drug in the treatment of severe elec- patients had left ventricular dysfunction (LVEF <0.40). trical storm in patients with ICD. In the present study, other class III drugs (amiodarone or sotalol) were administered to 5 of the 6 patients with severe References electrical storm. However, after nifekalant administration, the QT interval was significantly prolonged even in these 1. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, et al. Improved survival with an implanted defibrillator in patients with patients, so the class III effect of intravenous nifekalant coronary disease at high risk for ventricular arrhythmia: Multicenter might be superior to other oral class III drugs. We also used Automatic Defibrillator Implantation Trial Investigators. N Engl J aβ-blocking agent with nifekalant administration, because Med 1996; 335: 1933–1940. the SWORD trial reported excess mortality with d-sotalol, 2. The Antiarrhythmics versus Implantable Defibrillators (AVID) In- a pure class III drug, when used to treat patients surviving vestigators. A comparison of antiarrhythmic-drug therapy with 27 implantable defibrillators in patients resuscitated from near-fatal myocardial infarction with a left ventricular dysfunction. ventricular arrhythmias. N Engl J Med 1997; 337: 1576–1583. However, dl-sotalol, which has class III action and potenti- 3. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. ates β-blockade, was found to be more effective than 6 Prophylactic implantation of a defibrillator in patients with myocar- other class I drugs in the ESVEM trial.28 Thus the combi- dial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877–883. nation of a pure class III drug andβ-blocking agent appears 4. Credner SC, Klingenheben T, Mauss O, Sticherling C, Hohnloser SH. to be most effective in patients with VTs. However, exces- Electrical storm in patients with transvenous implantable cardiover- sive bradycardia caused by the β-blocking agent must be ter-defibrillators: Incidence, management and prognostic implica- avoided, because it would cause marked QT prolongation tions. J Am Coll Cardiol 1998; 32: 1909–1915. 5. Greene M, Newman D, Geist M, Paquette M, Heng D, Dorian P. Is leading to torsade de pointes (TdP). Moreover, the pacing electrical storm in ICD patients the sign of a dying heart? Outcome function of ICD should be used when bradycardia or exces- of patients with clusters of ventricular tachyarrhythmias. Europace sive QT prolongation is observed. Nifekalant has been also 2000; 2: 263–269. reported to decrease the defibrillation threshold (DFT). 6. Exner DV, Pinski SL, Wyse DG, Renfroe EG, Follmann D, Gold M, et al. 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