Nifekalant Administration Research Articles

Development and Validation of a Novel Prognostic Model Predicting the Atrial Fibrillation Recurrence Risk for Persistent Atrial Fibrillation Patients Treated with Nifekalant During the First Radiofrequency Catheter Ablation

BackgroundThis study aimed to establish and assess a prediction model for patients with persistent atrial fibrillation (AF) treated with nifekalant during the first radiofrequency catheter ablation (RFCA).MethodsIn this study, 244 patients with persistent AF from January 17, 2017 to December 14, 2017, formed the derivation cohort, and 205 patients with persistent AF from December 15, 2017 to October 28, 2018, constituted the validation cohort. The least absolute shrinkage and selection operator regression was used for variable screening and the multivariable Cox survival model for nomogram development. The accuracy and discriminative capability of this predictive model were assessed according to discrimination (area under the curve [AUC]) and calibration. Clinical practical value was evaluated using decision curve analysis.ResultsBody mass index, AF duration, sex, left atrial diameter, and the different responses after nifekalant administration were identified as AF recurrence-associated factors, all of which were selected for the nomogram. In the development and validation cohorts, the AUC for predicting 1-year AF-free survival was 0.863 (95% confidence interval (CI) 0.801–0.926) and 0.855 (95% CI 0.782–0.929), respectively. The calibration curves showed satisfactory agreement between the actual AF-free survival and the nomogram prediction in the derivation and validation cohorts. In both groups, the prognostic score enabled stratifying the patients into different AF recurrence risk groups.ConclusionsThis predictive nomogram can serve as a quantitative tool for estimating the 1-year AF recurrence risk for patients with persistent AF treated with nifekalant during the first RFCA.

Intraprocedural Conversion Efficacy of Intravenous Nifekalant Administration for Persistent Atrial Fibrillation after Pulmonary Vein Isolation.

The aim of this study was to prospectively assess the efficacy, safety, and predictive effect of intravenous nifekalant administration for persistent atrial fibrillation (PerAF) after pulmonary vein isolation (PVI) with second-generation cryoballoon ablation (CBA) on 1-year atrial tachyarrhythmia (ATa) -free survival by examining the pharmacological conversion rate.One hundred and two drug-refractory, consecutive PerAF patients undergoing PVI were enrolled in this prospective observational study. After PVI, nifekalant (50 mg) was given followed by 30 minutes of observation and no further intervention. PerAF was successfully converted to sinus rhythm (SR) in 60 patients (58.8%) after a median time of 7.75 (4.13-12) minutes (group N). In the remaining 42 patients (41.2%) (group C), PerAF was successfully converted to SR by external electrical cardioversion. Nonsustained ventricular tachycardia occurred in 1 patient in group N. The left atrial volume (LAV) in group C was larger than that in group N (128.2 ± 28.2 versus 111.8 ± 24.5 mL, P = 0.002). Phrenic nerve injury occurred in 4 of 102 patients (3.9%). No other complications occurred during the procedure or within the 1-year follow-up period. At the 1-year follow-up, after a 3-month blanking period (BP), ATa-free survival during 1-year follow-up in group C was significantly lower than that in group N (50.0% versus 71.7%, P = 0.026), and the overall ATa-free survival rate was 62.7%. Two patients in group C and 4 patients in group N underwent a second procedure with radiofrequency catheter ablation. Multivariate Cox regression analysis demonstrated that unsuccessful conversion to SR (P = 0.025), ATa relapse during the BP (P = 0.000), and larger LAV (P = 0.016) were independent predictors of ATa recurrence at the 1-year follow-up.In conclusion, at the 1-year follow-up, the ATa-free survival rate after PVI with CBA for PerAF patients was 62.7%, and successful conversion to SR with nifekalant could serve as a clinical predictor of reduced ATa recurrence.

Usefulness of an IKr blocker for ablation of non-pulmonary vein ectopies that are unmappable due to easily initiated atrial fibrillation.

When atrial fibrillation (AF) is initiated by a single or several non-pulmonary vein (PV) trigger ectopic beats, mapping the ectopy is often difficult, requiring a number of electrical cardioversion applications. Nifekalant is a rapidly activating delayed rectifier potassium channel (IKr) blocker which may suppress AF initiation without inhibiting ectopy development, thereby allowing the target ectopy to be mapped. To assess the efficacy of nifekalant in the ablation of non-PV ectopies that are unmappable due to easily initiated AF. Eleven consecutive patients were administered nifekalant to map a non-PV ectopy that was unmappable using a conventional method due to easily initiated AF. Nifekalant was intravenously administered as a bolus dose of 0.2mg/kg, and electrical cardioversion was delivered. Additional boluses of 0.2mg/kg were repeatedly administered until AF initiation was prevented or until the appearance of significant prolongation of QT interval. AF suppression without inhibition of ectopy development was achieved in 7 patients. These patients had a higher rate of acute elimination of the ectopy than the remaining 4 patients without AF suppression (7 [100%] vs. 1 [25%] patients, p = 0.024). In addition, patients with suppression of AF initiation had a higher AF recurrence-free rate than those without (7 [100%] vs. 1 [25%] patients, p = 0.024). Nifekalant administration appears useful in the ablation of non-PV ectopies that easily initiate AF.

Effect of the ATP-Sensitive K+ Channel Opener Nicorandil in a Canine Model of Proarrhythmia

Increased action potential duration (APD) induces early afterdepolarization (EAD) in vitro and torsade de pointes in vivo, and ATP-sensitive K(+) channel openers decrease APD in cardiac tissue. We tested whether the ATP-sensitive K(+) channel opener nicorandil has antiarrhythmic effects on class III antiarrhythmic drug-induced ventricular arrhythmia. In 10 anesthetized dogs with chronic atrioventricular block, we recorded monophasic action potentials (MAPs) from the left and right ventricular (LV and RV) endocardium. The class III antiarrhythmic drug nifekalant (1 mg/kg, IV) was administered at 5 minute intervals (total doses; 2-6 mg/kg) until the appearance of EADs, premature ventricular contractions (PVCs), or polymorphic ventricular tachycardias (PVTs). Five minutes after the end of nifekalant administration, nicorandil (1.0 mg/kg) was administered over 5 minutes. Nifekalant decreased the ventricular escape rate from 75 ± 5 beats/minute to 45 ± 10 beats/minute and increased RV-MAP duration (MAPD) from 217 ± 32 msec to 308 ± 2 msec (P < 0.01) and LV-MAPD from 232 ± 32 msec to 353 ± 82 msec (P < 0.01). EADs were recorded in 9 dogs, frequent premature ventricular contractions (PVCs) developed in 10 dogs, incessant PVTs developed in 3 dogs, and monomorphic ventricular tachycardia developed in 3 dogs after nifekalant administration. Nicorandil decreased RV-MAPD to 267 ± 57 msec and LV-MAPD to 279 ± 44 msec. It suppressed EADs, decreased the incidence of PVCs, and abolished PVT. Nicorandil may be clinically useful for treatment of PVCs and PVTs accompanying acquired long QT syndrome.

A Case of Ventricular Tachycardia with Dilated Cardiomyopathy Controlled by D-Sotalol and Catheter Ablation

A 76-year-old man, with previous history of dilated cardiomyopathy and ventricular tachycardia treated with amiodarone was admitted to our hospital because of intestitial pneumonia. After discontinuation of amiodarone, VT was occurred frequently. VT’s cycle length (CL) was 465 ms and QRS morphology was LBBB+LAD. Even after nifekalant administration, VT storm was uncontrollable. Frequent cardioversion and sedation were needed. After d-sotalol administration, cathether ablation was performed with electro-anatomical mapping (CARTO). The substrate map of RV revealed low voltage zone in anterior wall and RVOT. VT was inducted easily with programmed stimulations at RVA and RVOT, so this VT’s mechanism thought to be reentry. But the centrifugal electric potential from RVOT anterior wall was confirmed in activation map. The CL on activation map was covered only 200 ms, the reentry circuits may be located in the epicardium. The earliest ventricular activation site was 100 ms prior to the QRS onset on endocardium at RVOT. Radiofrequency energy was delivered around this site and linear ablation was performed in low voltage zone between tricuspid annulus and anterior wall. Finally, clinical VT couldn’t be inducted by programmed stimulation and didn’t occurred during follow up period. In this case, VT origin may present at RV epicardium which was controlled with ablation and d-sotalol.

Effect of nifekalant on life-threatening ventricular arrhythmias in patients with cardiopulmonary resuscitation or during the perioperative state

Background: Nifekalant is a unique class III anti-arrhythmic agent with a strong effect on prolonging the myocardial refractoriness, but its clinical effect is still unclear. In this study, we evaluated the effect of nifekalant on life-threatening ventricular arrhythmias and compared the clinical background between the effective and non-effective patients in order to clarify the clinical factors which may have an influence on the efficacy of nifekalant. Methods: The study population consisted of 47 consecutive patients who underwent nifekalant administration for life-threatening ventricular arrhythmias (VT/VF). Their clinical characteristics and ECG parameters were retrospectively compared between patients with and without an effective result with the nifekalant administration. Results: Nifekalant was effective for refractory VT/VF in 26/47 patients. There was no significant difference in the age, gender or left ventricular ejection fraction, but the incidence of ischemic heart disease was higher in the effective group (17/26) than non-effective group (9/21, p=0.004). The incidence of in-hospital events was higher in the effective group than non-effective group (20/26 vs 10/21, p=0.037). A significant prolongation in the QTc interval was observed in all patients and the degree of QTc prolongation was greater in the effective group than in the non-effective group (0.46 ± 0.04 vs 0.43 ± 0.02 sec 1/2 , p=0.026). Conclusion: Nifekalant was effective in 55% of the patients for refractory VT/VF. It was considered that nifekalant was more effective for patients with ischemic heart disease, during the perioperative period or in those experiencing in-hospital events. The prolongation of the QTc interval might also be useful as an index for the efficacy of nifekelant administration.

Comparison of Efficacy of Sotalol and Nifekalant for Ventricular Tachyarrhythmias

Suppression of implantable defibrillator discharges associated with ventricular tachyarrhythmia (VTA) has been reported for sotalol. This study aimed to investigate the efficacy of intravenous nifekalant hydrochloride in predicting the effects of oral sotalol. The present study included 14 patients who had sustained VTA associated with structural heart disease. All patients also had inducible VTA. To compare the effects of nifekalant and sotalol, programmed electrical stimulation was performed, in the basal state, after nifekalant administration, and after sotalol administration. Nifekalant and sotalol similarly prolonged the corrected QT interval and ventricular effective refractory periods, but the heart rate was slowed by sotalol only. In 4 of 5 patients whose VTA became non-inducible by nifekalant, subsequent treatment with sotalol also suppressed the inducible VTA. In all of the 9 patients non-responding to nifekalant, VTA remained inducible during sotalol treatment. Nifekalant accurately predicted the response to sotalol during electrophysiologic study in 13 of 14 patients. Of 11 patients who remained on sotalol, VTA recurred in 3 non-responders during a follow-up of 46 +/- 11 months. Nifekalant and sotalol had similar effects on inducible VTA. The response of inducible VTA to nifekalant may predict the clinical efficacy of sotalol.

Enhancing Electrical Cardioversion and Preventing Immediate Reinitiation of Hemodynamically Deleterious Atrial Fibrillation with Class III Drug Pretreatment

Nifekalant for shock-resistant atrial fibrillation. In severely ill patients, the development of atrial fibrillation (AF) may provoke lethal hemodynamic instability requiring immediate electrical defibrillation, which often is unsuccessful. Using the novel potassium channel blocking agent nifekalant, we prospectively assessed the hypothesis that class III antiarrhythmic drugs facilitate electrical cardioversion and suppress the immediate recurrence of hemodynamically deleterious AF. Among 1896 adults admitted to the intensive care unit for cardiovascular diseases, hemodynamically destabilizing new-onset AF (systolic blood pressure<90 mm Hg) resistant to conventional electrical cardioversion occurred in 27 patients, and of these, 24 patients (70+/-12 years) were enrolled. Twenty-one patients had congestive heart failure and 11 patients had been mechanically ventilated. After three failed transthoracic cardioversions due to failure of conversion to SR (11 patients) or immediate reinitiation (13 patients), nifekalant (0.25+/-0.04 mg/kg) was administered intravenously, and electrical defibrillation was reattempted. In 18 patients (75%), sinus rhythm was restored and maintained after nifekalant infusion (6 patients) or subsequent transthoracic cardioversion (12 patients). Nifekalant administration significantly decreased the heart rate and increased systolic blood pressure during AF (P<0.001), and successful cardioversion rapidly further ameliorated these parameters (P<0.001). Logistic regression analysis showed that atrial defibrillation failure (relative risk [RR] 19.34, P=0.05) and age of >75 years (RR 15.25, P=0.03) were independent predictors of in-hospital death. Nifekalant renders electrical defibrillation and the prevention of the early recurrence of hemodynamically unstable AF more successful without deteriorating hemodynamics, and successful defibrillation is associated with a more favorable patient outcome. Pretreatment with other class III drugs, e.g., ibutilide or dofetilide, would also be efficacious in patients with failed urgent electrical cardioversion.

Emergency Treatment With Nifekalant, a Novel Class III Anti-Arrhythmic Agent, for Life-Threatening Refractory Ventricular Tachyarrhythmias Post-Marketing Special Investigation

Because class I anti-arrhythmic drugs sometimes suppress cardiac function caused by their negative inotropic effects, they are not adequate for use in patients with severe heart failure, even as emergency treatment for life-threatening ventricular tachyarrhythmias (ventricular tachycardia (VT)/ventricular fibrillation (VF)). An objective evaluation committee re-evaluated the effect of nifekalant in 191 patients with refractory VT/VF. The attack termination was achieved in 45 out of 93 patients (48.4%). Nifekalant was administered to 39 patients with direct-current (DC) shock-resistant VT/VF and directly terminated VT/VF in 9 patients. In 15 of the remaining 29 patients (51.7%), VT/VF was successfully cardioverted by additional DC shock after nifekalant administration. Prevention of recurrence was achieved in 60 out of 99 patients (60.6%). Corrected QT interval (QTc) was significantly prolonged after initial administration of nifekalant (0.463+/-0.056 to 0.504 +/-0.072), and during maintenance infusion (0.470 +/-0.056 to 0.547+/-0.070). As an adverse reaction, excess prolongation of QTc was noted in 11 patients including 3 patients with torsades de pointes. Hemodynamic parameters tended to improve after maintenance infusion of nifekalant. Nifekalant is effective and useful for life-threatening refractory ventricular tachyarrhythmias, although careful observation of the QT interval is required.

Efficacy of Nifekalant Hydrochloride in the Treatment of Fatal Ventricular Arrhythmia in Patients With Ischemic Heart Disease

Ventricular tachycardia (VT), which causes hemodynamic instability, and ventricular fibrillation (VF) sometimes occur in patients with severe underlying cardiovascular disease such as myocardial ischemia or infarction, and are associated with high mortality. This report presents the efficacy of nifekalant hydrochloride (nifekalant), a pure class III antiarrhythmic agent, in treating life-threatening ventricular arrhythmia in such patients. From June 2000, when nifekalant became commercially available in Japan, to May 2003, 30 ischemic heart disease (IHD) patients with VT/VF resistant to direct-current (DC) countershock received nifekalant in our hospital. These 30 patients served as the nifekalant group in this study. As a control group, we also included 33 IHD patients with VT/VF that had been resistant to DC countershock upon or during hospitalization between January 1996 and May 2000 before nifekalant became commercially available. No significant differences were observed in patient background factors and treatments between the two groups. The rates of death within 48 hours of occurrence of VT/VF were significantly lower in the nifekalant group (7%, 2/30) than in the control group (27%, 9/33; P < 0.03). The rates of cardiac death during hospitalization were also significantly lower in the nifekalant group (40%, 12/30) than in the control group (67%, 22/33; P < 0.03). The rates of survival until hospital discharge were significantly higher in the nifekalant group (57%, 17/30) than in the control group (30%, 10/33; P < 0.03). Multivariate analysis of all 63 patients revealed nifekalant administration was the factor that significantly improved the mortality (odds ratio for cardiac death, 0.26; 95% confidence interval (CI), 0.07 to 0.95; P = 0.041). Nifekalant improves the prognosis for life-threatening ventricular arrhythmia in IHD patients.