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We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization., Competing Interests: Declaration of competing interest The authors indicated no potential conflict of interest., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: Pharmacologic cardioversion is an effective clinical strategy for fibrillation. Vernakalant is a novel drug used to treat atrial fibrillation (AF). This study aimed to evaluate the efficacy- and tolerability-related data on vernakalant from clinical trials., Methods: Literature from PubMed and the Cochrane Library was systematically reviewed, and 139 eligible studies were found after specific key words were identified. Twelve randomized clinical trials discussing vernakalant cardioversion in patients with AF were chosen for the meta-analysis after scrutiny. Ten of the 12 trials used placebo while two reported data on active and established drugs to compare the effects of vernakalant. Three of the 12 trials included relevant clinical states in addition to AF., Findings: In this meta-analysis of data from 12 studies (2365 patients, 887 events), the rate of cardioversion from AF to sinus rhythm (SR) was significantly greater with vernakalant compared with placebo and active comparators (risk ratio = 5.60; 95% CI, 2.83-11.09; I 2 test for heterogeneity, 92%). Tolerability-related data revealed that dysgeusia, paresthesia, atrial flutter, and hypotension were major adverse events that occurred with vernakalant use, but the data were not clinically significant compared to placebo and active drug (risk ratio = 1.13; 95% CI, 0.86-1.47). Eleven deaths were reported in 4 trials, with vernakalant directly implicated in two deaths. Vernakalant was well tolerated and effective in patients with rapid-onset AF., Implications: Vernakalant appears to be a good choice when AF is manifested postoperatively or exists with ischemic heart disease and valvular states. Tolerability-related data are promising, but a specific trial may be required to identify the causes of the deaths considered unrelated to vernakalant use., (Copyright © 2023. Published by Elsevier Inc.)

Sudden cardiac death due to arrhythmias, such as atrial fibrillation or ventricular tachycardia, account for 15-20% of all deaths. Myocardial infarction increases the burden of atrial fibrillation and ventricular tachycardia by structural and electrical remodeling of the heart. The current management of new-onset atrial fibrillation includes electric cardioversion with very high conversion rates and pharmacologic cardioversion, with less a than 50% conversion rate. If atrial fibrillation cannot be converted, the focus becomes the control of the symptoms ensuring a constant rhythm and rate control, without considering other contributory factors such as autonomic imbalance. Recently, a huge success was obtained by developing ablation techniques or addressing the vagal nerve stimulation. On the other hand, ventricular tachycardia is more sensitive to drug therapies. However, in cases of non-responsiveness to drugs, the usual therapeutic choice is represented by stereotactic ablative therapy or catheter ablation. This review focuses on these newly developed strategies for treatment of arrhythmias in clinical practice, specifically on vernakalant and low-level tragus stimulation for atrial fibrillation and stereotactic ablative therapy for drug-refractory ventricular tachycardia. These therapies are important for the significant improvement of the management of atrial fibrillation and ventricular tachycardia, providing: (1) a safer profile than current therapies, (2) higher success rate than current solutions, (3) low cost of delivery.

Introduction: Intravenous vernakalant is a therapeutic option for symptomatic, recent-onset atrial fibrillation (AF). This secondary analysis from the large SPECTRUM study assessed the safety and effectiveness of vernakalant when used in the emergency department setting (ED group) or in an inpatient hospital setting (non-ED group)., Methods: This post hoc analysis of the international, observational, post-authorization SPECTRUM study included 1,289 and 720 recent-onset AF episodes in adults in the ED and non-ED groups, respectively. Safety endpoints included the evaluation of pre-defined health outcomes of interest (HOIs) and other serious adverse events (SAEs) during vernakalant treatment and during the first 24 h after the last infusion. Effectiveness endpoints comprised the rate of successful vernakalant cardioversion, the time from the start of the vernakalant infusion to cardioversion, and the length of hospital stay. Data were analysed using descriptive statistics., Results: The safety profile of vernakalant was similar in the ED and non-ED groups. In the ED group, 12 pre-defined HOIs were reported in 11 patients (0.9%); all but one occurred within 2 h after start of the first infusion. These events comprised nine significant bradycardia cases, of which one was associated with transient hypotension and three with sinus arrest, and 2 cases of atrial flutter with 1:1 conduction. Five other SAEs were reported. All patients with vernakalant-related events recovered without sequelae. No Torsade de Pointes, ventricular fibrillation, or deaths occurred. Successful cardioversion was reported in 67.8% (95% confidence interval: 65.2-70.4) and 66.4% (62.5-70.1) of episodes, with a median time to conversion of 11.0 and 10.0 min in the ED and non-ED groups, respectively. Patients had a median length of hospital stay of 7.4 h and 17.1 h in the ED and non-ED groups, respectively., Conclusion: Intravenous vernakalant was well tolerated with similar cardioversion rates in patients treated in the ED or non-ED setting and does not require admission to a coronary care unit or intensive care unit. First-line treatment with vernakalant could allow an early discharge in patients with recent-onset AF treated in the ED., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF., Methods and Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed., Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Rapid restoration of sinus rhythm using pharmacological cardioversion is commonly indicated in patients with symptomatic recent-onset atrial fibrillation (AF). The objectives of this large, international, multicenter observational study were to determine the safety and effectiveness of intravenous (IV) vernakalant for conversion of AF to sinus rhythm in daily practice., Methods and Results: Consenting patients with symptomatic recent-onset AF (< 7 days) treated with IV vernakalant were enrolled and followed up to 24 h after the last infusion or until discharge, in order to determine the incidence of predefined serious adverse events (SAEs) and other observed SAEs and evaluate the conversion rate within the first 90 min. Overall, 2009 treatment episodes in 1778 patients were analyzed. The age of patients was 62.3 ± 13.0 years (mean ± standard deviation). Median AF duration before treatment was 11.1 h (IQR 5.4-27.0 h). A total of 28 SAEs occurred in 26 patients including 19 predefined SAEs, i.e., sinus arrest (n = 4, 0.2%), significant bradycardia (n = 11, 0.5%), significant hypotension (n = 2, 0.1%), and atrial flutter with 1:1 conduction (n = 2, 0.1%). There were no cases of sustained ventricular arrhythmias or deaths. All patients who experienced SAEs recovered fully (n = 25) or with sequelae (n = 1). Conversion rate to sinus rhythm was 70.2%, within a median of 12 min (IQR 8.0-28.0 min)., Conclusions: This large multicenter, international observational study confirms the good safety profile and the high effectiveness of vernakalant for the rapid cardioversion of recent-onset AF in daily hospital practice.

Vernakalant is an intravenous anti-arrhythmic drug available in Europe, Canada and some countries in Asia for the restoration of sinus rhythm in acute onset atrial fibrillation. Currently, it is not available in USA because the US FDA have ongoing concerns about its safety. Vernakalant has a unique pharmacological profile of multi-ion channel activity and atrial-specificity that distinguishes it from other anti-arrhythmic drugs. This is thought to enhance efficacy but there are concerns of adverse events stemming from its diverse pharmacology. This ambiguity has prompted a review of the available clinical evidence on efficacy and safety to help re-evaluate its place in clinical practice.

Aims: To evaluate the efficacy and safety of vernakalant for the cardioversion of atrial fibrillation (AF)., Methods and Results: We reviewed the literature for randomized trials that compared vernakalant to another drug or placebo in patients with AF of onset ≤7 days. We used a random-effects model to combine quantitative data and rated the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation). From 441 total citations in MEDLINE, EMBASE, and CENTRAL (December 2018), we identified nine trials evaluating 1358 participants. Six trials compared vernakalant to placebo, two trials compared vernakalant to ibutilide, and one trial compared vernakalant to amiodarone. We found significant methodological bias in four trials. For conversion within 90 min, vernakalant was superior to placebo [50% conversion, risk ratio (RR) 5.15; 95% confidence interval (CI); 2.24-11.84, I2 = 91%], whereas we found no significant difference in conversion when vernakalant was compared with an active drug (56% vs. 24% conversion, RR 2.40; 95% CI 0.76-7.58, I2 = 94). Sinus rhythm was maintained at 24 h in 85% (95% CI 80-88%) of patients who converted acutely with vernakalant. Overall, we judged the quality of evidence for efficacy to be low based on inconsistency and suspected publication bias. There was no significant difference in the risk of significant adverse events between vernakalant and comparator (RR 0.95; 95% CI 0.70-1.28, I2 = 0, moderate quality evidence). Vernakalant is safe and effective for rapid and durable restoration of sinus rhythm in patients with recent-onset AF., Conclusion: Vernakalant should be a first line option for the pharmacological cardioversion of patients with haemodynamically stable recent-onset AF without severe structural heart disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background:: Pharmacological cardioversion of atrial fibrillation is a reasonable alternative for electrical cardioversion in acute atrial fibrillation. We compared the efficacy and safety of intravenous vernakalant and intravenous flecainide in patients with recent-onset (< 48 h) atrial fibrillation., Methods:: A total of 200 consecutive patients, 100 patients undergoing cardioversion with intravenous vernakalant and 100 patients undergoing cardioversion with intravenous flecainide, were included in this single centre non-randomized retrospective study. The primary endpoint was conversion to sinus rhythm within 120 minutes from the drug administration., Results:: Cardioversion was successful in 67% of patients treated with vernakalant and in 46% of patients treated with flecainide ( p=0.003). Vernakalant (odds ratio 1.99, 95% confidence interval 1.08-3.69, p=0.029) and female gender (odds ratio 2.48, 95% confidence interval 1.22-15.05, p=0.012) were significant predictors of successful cardioversion. The success rate of cardioversion was lowest among men treated with flecainide (36.9%). Patients treated with vernakalant were discharged earlier from the emergency department compared with those treated with flecainide (8.2 ± 4.7 h vs. 12.0 ± 6.0 h, p < 0.001). There was no difference in the complication rate between the groups. Vernakalant treated patients were older (59.3 ± 12.5 vs. 55.4 ± 13.0 years, p=0.03), had higher CHA 2 DS 2 -VASc score (1.4 ± 1.3 vs. 0.9 ± 1.2, p = 0.002) and were more often on beta-blocker medication (59% vs. 42%, p= 0.016) than flecainide treated patients., Conclusion:: Vernakalant was safe, more effective and faster than flecainide in the cardioversion of recent-onset atrial fibrillation. The difference in efficacy was especially apparent among men.

Introduction: The main aim of current research on the field of atrial fibrillation (AF) treatment is to find new antiarrhythmic drugs with less side effects. Areas covered: Dronedarone and vernakalant showed promising result in term of efficacy and safety in selected patients. Ranolazine and colchicine are obtaining a role as a potential antiarrhythmic drug. Ivabradine is used in experimental studies for the rate control of AF. Moreover, new compounds (vanoxerine, moxonidine, budiodarone) are still under investigation. Monoclonal antibodies or selective antagonist of potassium channel are under investigation for long term maintenance of sinus rhythm. Clinical evidence and new pharmacological investigation on new drugs will be accurately reviewed in this article. Expert opinion: Dronedarone use is not recommended in patients with symptomatic heart failure (HF), NYHA class III-IV, depressed ventricular function and permanent AF, especially in patients assuming a concomitant therapy with digoxin. Vernakalant had superior efficacy than amiodarone, flecainide and propafenone in single studies and similar efficacy to direct current cardioversion. Several of the developing drugs examined in this paper show an interesting potential, in particular the research on selective ionic channel inhibition and on compounds which reduce the inflammation state, especially after ablation or surgery.

Background: Evidence has emerged that small-conductance Ca 2+ -activated K + (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses., Methods and Results: A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs., Conclusions: SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs., (© 2017 The Authors.)

Objectives: To study the effectiveness and safety of vernakalant for restoration of sinus rhythm in patients with atrial fibrillation (AF) in routine hospital emergency department care, and to evaluate factors associated with a more effective response., Material and Methods: Prospective multicenter cohort study enrolling consecutive patients who were administered vernakalant for medical cardioversion of AF between September 2014 through March 2016 in 5 hospitals in the Spanish autonomous community of Valencia., Results: We studied 165 cases. The median (interquartile range) was 68 years (56-77) years. Cardioversion with vernakalant was effective in 77.6% (95% CI, 71.1%-84%). The median time to conversion was 8 ( 6-12) minutes after a first dose and 34 (22-62) minutes after a second dose. A prior history of cardiac insufficiency was nonsignificantly less common in patients who converted with vernakalant (6.3%) than in those who did not (18.9%) (adjusted odds ratio [OR], 0.45 [95% CI, 0.13-1.56]; P=.208). Having no prior history of AF was nonsignificantly related to greater effectiveness (in 54.7% vs in 35.1% with prior AF). Duration less than 12 hours was significantly associated with greater effectiveness (83.6% vs 59.5%; adjusted OR, 2.76 [95% CI, 1.12-6.80]; P=.028). Adverse events were reported for 30 patients. None of the events had clinically important consequences, and in only 2 cases (1.2%) was it necessary to suspend treatment., Conclusion: Vernakalant is effective and safe for restoring sinus rhythm in the hospital emergency department.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with significant health risks. One strategy to mitigate the risks associated with long-term AF is to convert AF to sinus rhythm (SR). This study assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to SR., Methods: Patients with recent-onset (duration >3 h- ≤ 7 days) symptomatic AF and no evidence or history of congestive heart failure were randomized in a 2:1 ratio to receive vernakalant or placebo. Patients received an infusion of vernakalant (3 mg/kg) or placebo over 10 min, followed by a second infusion of vernakalant (2 mg/kg) or placebo 15 min later if AF had not been terminated. The primary efficacy endpoint was conversion of AF to SR for at least 1 min within 90 min of the start of drug infusion. The primary safety endpoint was a composite of: occurrence of clinically significant hypotension, clinically significant ventricular arrhythmia (including torsades de pointes, ventricular tachycardia or ventricular fibrillation) or death within 2 h of starting the drug infusion., Results: A total of 217 patients were randomized to receive vernakalant (n = 145) or placebo (n = 72). Of the 129 individuals who received vernakalant, 59 (45.7 %) converted to SR compared with one of the 68 patients (1.5 %) who received placebo (p < 0.0001). Conversion to SR was significantly faster with vernakalant than with placebo (p < 0.0001), and a greater proportion of patients who received vernakalant than those who received placebo reported no AF-related symptoms at 90 min (p = 0.0264). The primary composite safety endpoint was observed in one patient receiving vernakalant and in no patients receiving placebo. In the vernakalant arm, dysgeusia, paraesthesia and sneezing were the most common treatment-emergent adverse events, and three serious adverse events occurred that were considered to be related to study drug., Conclusions: Vernakalant resulted in rapid cardioversion of recent-onset AF in almost half of the study population and was generally well tolerated. The safety outcomes affirmed the need for careful selection and management of haemodynamically stable candidates for cardioversion., Trial Registration: NCT00989001 .

Background: Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current., Objective: The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria., Methods: Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia., Results: Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing., Conclusion: The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Electrical cardioversion is one cornerstone for the rhythm control strategy of atrial fibrillation (AF), which is, however, hampered by immediate AF recurrence (IRAF) or failed electrical cardioversion (FECV). We aimed to investigate the potential role of vernakalant for facilitated electrical cardioversion in cardioversion-resistant AF., Methods and Results: The subjects of this study were 63 patients referred to the Heart Centre Leipzig between November 2011 and May 2014 for transthoracic electrical cardioversion of AF. All patients experienced after antiarrhythmic-naïve electrical cardioversion either IRAF (n = 44; 70%) or FECV (n = 19; 30%). After drug infusion, electrical cardioversion was successful in 66.7% of vernakalant-treated as opposed to 46.7% of amiodarone-treated patients (P = 0.109). Multivariate analysis revealed treatment with vernakalant (OR 0.057, 95% CI 0.006-0.540, P = 0.013), treatment with ACEI or ARB (OR 0.101, 95% CI 0.015-0.691 P = 0.019), and IRAF after initial CV (OR 0.047, 95% CI 0.004-0.498, P = 0.011) as predictors for successful, drug-facilitated electrical cardioversion. Subgroup analysis of 18 patients with previous AF ablation revealed a significantly higher success rate of electrical cardioversion after infusion of vernakalant than after infusion of amiodarone (66.7 vs. 11.1%, P = 0.016)., Conclusion: Vernakalant may therefore be considered as a useful agent for facilitated electrical cardioversion in cardioversion-resistant AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Atrial fibrillation is the most common arrhythmia in patients hospitalized in intensive care units and emergency departments and is associated with an increased morbidity and mortality. In critically ill patients, atrial fibrillation can cause hemodynamic instability and cardiogenic shock. The mechanisms and the management of atrial fibrillation are significantly different in critically ill patients compared to outpatients., Diagnosis and Treatment: The initial management includes the evaluation of the hemodynamic consequences of new-onset atrial fibrillation and the optimization of reversible causes. In patients with hemodynamic instability the rapid restoration of an adequate perfusion pressure is the initial goal. Often, a rapid conversion in sinus rhythm is required to achieve hemodynamic stabilization. Electrical cardioversion, if possible performed after pretreatment with an antiarrhythmic drug to increase the success rate, frequently plays a central role in the conversion to sinus rhythm of hemodynamically unstable patients. Stable patients are initially treated with a short-acting intravenous β-blocker to achieve heart rate control. A conversion to sinus rhythm may be achieved pharmacologically with vernakalant, an atrial-specific multichannel blocker., Evaluation: All patients with atrial fibrillation lasting more than 48 h should be evaluated for anticoagulation in order to reduce cardio-embolic complications. After recovering from the acute illness, atrial fibrillation persists only in a minority of patients.

Background: Vernakalant is a novel atrial-selective antiarrhythmic drug able to convert recent-onset atrial fibrillation (AF) with reportedly low proarrhythmic risk. Successful cardioversion predictors are largely unknown. We sought to evaluate clinical and electrocardiographic predictors of cardioversion of recent-onset AF with vernakalant., Methods: Consecutive patients with AF ≤48 hours admitted for cardioversion with vernakalant (n = 113, median age 62 years, 69 male) were included. Sinus rhythm (SR) within 90 minutes after infusion start was considered to be successful cardioversion. Predictive values of demographics, concomitant therapy, comorbidities, and electrocardiographic parameters were assessed. Atrial fibrillatory rate (AFR), exponential decay, and mean fibrillatory wave amplitude were measured from surface ECG using QRST cancellation and time-frequency analysis., Results: Cardioversion was achieved in 66% of patients. Conversion rate was higher in women than in men (80% vs 58%, P = 0.02) while none of other clinical characteristics, including index AF episode duration, could predict SR restoration. Female gender was predictive of vernakalant's effect in logistic regression analysis (OR = 2.82 95%CI 1.18-6.76, P = 0.020). There was no difference in AFR (350 ± 60 vs 348 ± 62 fibrillations per minute [fpm], P = 0.893), mean fibrillatory wave amplitude (86 ± 33 vs 88 ± 67 μV, P = 0.852), or exponential decay (1.30 ± 0.42 vs 1.35 ± 0.42, P = 0.376) between responders and nonresponders., Conclusions: Female gender is associated with a higher rate of SR restoration using intravenous (i.v.) vernakalant for recent-onset AF. ECG-derived indices of AF organization, which previous studies associated with effect of rhythm control interventions, did not predict vernakalant's effect., (© 2014 Wiley Periodicals, Inc.)

Background: Vernakalant is an available drug for the treatment of recent-onset atrial fibrillation, producing conversion between 55% and 87% of the patients treated. In this sense, little is known about the predictors of conversion with this agent. The aim of our study was to analyze the predictors of conversion in our 2-year experience using vernakalant for the treatment of recent-onset atrial fibrillation., Methods: One hundred twenty-one patients with recent-onset atrial fibrillation without hemodynamic impairment received pharmacological treatment with vernakalant. Clinical variables, history of cardiovascular diseases, and echocardiographic data were recorded., Results: Mean age was 58.1 ± 13.9 years and 13.4% of patients had structural heart disease. Conversion to sinus rhythm was achieved in 84.5% of patients, and 46% required the second dose of vernakalant. After analyzing the predictors of conversion, the presence of structural heart disease was significantly larger in the group without conversion (35.3 vs 9.7%; P = 0.02). The mean ejection fraction in the group with conversion was 61.05 ± 5.7% versus 54.9 ± 8.4% in the group without conversion (P = 0.016). After dichotomizing the variable ejection fraction, patients with ejection fraction <55% had a lower conversion rate (P = 0.001)., Conclusion: In our study, the absence of any kind of structural heart disease and preserved systolic function were associated with greater conversion rate with vernakalant., (© 2014 Wiley Periodicals, Inc.)

Atrial fibrillation (AF) is the most common sustained arrhythmia. Cardioversion is considered one of the best treatments for recent onset AF, especially with drugs for avoiding sedation. Vernakalant is a novel antiarrhythmic that acts selectively in the atrium, and inhibits potassium currents, with minor blockade of IKr currents in the ventricle. It has been recently approved for pharmacological cardioversion of recent-onset AF in the European Union. The aim of this review is to analyze the pharmacokinetic and pharmacodynamic of vernakalant, and to show the efficacy and safety of this drug for the conversion of AF to sinus rhythm.

Atrial fibrillation (AF) is a common arrhythmia associated with increased mortality and morbidity. Different studies have shown no significant difference between rhythm and rate control strategies in terms of mortality. Moreover, the use of antiarrhythmic drugs is afflicted by cardiac and extracardiac toxicity and related costs of hospitalization. Nevertheless, some patients require a rhythm-control strategy and new anti-AF agents are being sought. Only few novel agents showed promising results in term of efficacy and safety. Dronedarone and vernakalant are two of these compounds, respectively introduced for the chronic and acute rhythm control of AF. This article will review pharmacology and clinical evidence on the use of dronedarone and vernakalant and will mention currently investigated new antiarrhythmic drugs.

Background: The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF)., Methods and Results: In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias., Conclusion: In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Atrial fibrillation is the most common cardiac arrhythmia and is associated with increased mortality and morbidity. Conversion to sinus rhythm is usually appropriate in patients with acute, symptomatic atrial fibrillation in order to reduce symptoms and prevent complications. Electrical cardioversion is the most used and widespread technique, but requires deep sedation and a fasting state. Pharmacological alternatives are burdened by a delayed onset of action and potential proarrhythmic effects. Therefore, new therapeutic options are being sought. Among those, vernakalant, showed a good efficacy profile and a short onset of action, but with conflicting evidence regarding potential serious adverse events. This drug profile will summarize the pharmacology behind this new drug and review recent evidence in terms of safety and efficacy.

Atrial fibrillation (AF) contributes significantly to cardiovascular morbidity and mortality. The growing epidemic is associated with cardiac repolarization abnormalities and requires the development of more effective antiarrhythmic strategies. Two-pore-domain K(+) channels stabilize the resting membrane potential and repolarize action potentials. Recently discovered K2P17.1 channels are expressed in human atrium and represent potential targets for AF therapy. However, cardiac electropharmacology of K2P17.1 channels remains to be investigated. This study was designed to elucidate human K2P17.1 regulation by antiarrhythmic drugs. Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record K2P currents from Xenopus oocytes and Chinese hamster ovary (CHO) cells. The class III antiarrhythmic compound vernakalant activated K2P17.1 currents in oocytes an in mammalian cells (EC50,CHO=40 μM) in frequency-dependent manner. K2P17.1 channel activation by vernakalant was specific among K2P channel family members. By contrast, vernakalant reduced K2P4.1 and K2P10.1 currents, in line with K2P2.1 blockade reported earlier. K2P17.1 open rectification characteristics and current-voltage relationships were not affected by vernakalant. The class I drug flecainide did not significantly modulate K2P currents. In conclusion, vernakalant activates K2P17.1 background potassium channels. Pharmacologic K2P channel activation by cardiovascular drugs has not been reported previously and may be employed for personalized rhythm control in patients with AF-associated reduction of K(+) channel function., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Conversion of recent onset atrial fibrillation (AF) to sinus rhythm with antiarrhythmic drugs reduces the risk of hemodynamic instability, hospitalizations, and atrial remodeling seen with persistent AF. This is the main reason for pharmacological or electrical cardioversion to be considered first line of treatment for recent onset AF. Is there a role for new antiarrhythmic drugs in the conversion of AF as the first approach to a rhythm-control strategy? Vernakalant is a novel and relativity atrial selective drug which inhibits atrial-selective K(+) currents, with only a small inhibitory effect on the rapidly activating delayed rectifier K(+) current (IKr) in the ventricle. In this brief Review, we tell the journey of vernakalant to become an attractive alternative to achieve pharmacological cardioversion of AF., (© 2014 Wiley Periodicals, Inc.)

Pharmacological rhythm control (often including electrical or pharmacological cardioversion) is an integral part of therapy for atrial fibrillation (AF) worldwide. Antiarrhythmic drug strategies would be preferred in many patients provided effective and safe antiarrhythmic agents are available. Also, pharmacological cardioversion could be the preferred option if the limitations of currently available drugs, such as restriction to patients without structural heart disease (flecainide and propafenone), risk of torsade de pointes (ibutilide), and slow onset of action (amiodarone), were overcome. The intravenous formulation of vernakalant (Brinavess, Cardiome) has been approved for pharmacological cardioversion of recent-onset AF (≤7 days) and early (≤3 days) post-operative AF in the European Union, Iceland, and Norway. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and has minimal effects in the ventricles and thus, is thought to have a low proarrhythmic potential. Vernakalant is administered as a 10 min infusion of 3 mg/kg, and if AF persists after 15 min, an additional dose of 2 mg/kg can be given. The efficacy and safety of the drug has been extensively investigated in randomized controlled trials against placebo and an active comparator (amiodarone). The placebo-extracted efficacy of vernakalant is ∼47%. A significant advantage is a rapid effect, with the median to conversion ranging between 8 and 14 min, with the majority of patients (75-82%) converting after the first dose. Vernakalant retained its efficacy in subgroups of patients with associated cardiovascular disease such as hypertension and ischaemic heart disease, but its benefit may be lower and risk of adverse effects is higher in patients with heart failure. In the post-market reports, cardioversion rates with vernakalant are 65-70%. This review focuses on the role of vernakalant in pharmacological cardioversion for AF.

Introduction: An oral loading dose of propafenone 600 mg is used in our center as in other places around the world for conversion of recent-onset atrial fibrillation (AF) in patients without structural heart disease. Vernakalant is a novel, safe, and effective drug used intravenously and has proved to be more rapid in converting recent-onset AF to sinus rhythm compared with placebo and amiodarone. There is no study that compares vernakalant with propafenone. The aim of our study is to compare the time taken for conversion of recent-onset AF in patients treated with vernakalant and propafenone., Methods: Thirty-six hemodynamically stable patients with recent-onset AF without structural heart disease were prospectively included. A single oral dose of propafenone 600 mg was administered to 19 patients and 17 received intravenous vernakalant. Clinical and laboratory variables, conversion rate, and time to conversion were recorded., Results: Baseline characteristics were similar in both groups. Time to conversion to sinus rhythm was of 166 min (120-300) in the propafenone group versus 9 min (6-18) in the vernakalant group (P = 0.0001). Conversion rate was of 78% in the propafenone group at 8 h and of 93% in the vernakalant group at 2 h; yet, this difference was not statistically significant (P = 0.4). Time to conversion had a direct impact in hospital stay, which was 43% shorter in the vernakalant group (P = 0.0001)., Conclusion: Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared with the propafenone group and was associated with shorter hospital stay., (© 2013 John Wiley & Sons Ltd.)

Background: An oral single dose of flecainide is used worldwide for conversion of recent onset atrial fibrillation (AF) in hemodynamically stable patients without structural heart disease. Vernakalant is a novel, rapid drug, which is used intravenously, with proven effectiveness and safety compared to placebo and amiodarone in randomized clinical trials. The aim of our study was to compare the time taken for conversion of recent onset AF in patients treated with vernakalant or flecainide., Methods: This is a sequential study in which 32 hemodynamically stable patients with recent onset AF without structural heart disease were prospectively and consecutively included in two periods, one for each drug. A single oral dose of flecainide 300 mg was administered to 15 patients and 17 patients received intravenous vernakalant. Clinical and laboratory variables, conversion rate and time to conversion were recorded., Results: Baseline characteristics were similar in both groups. Time to conversion to sinus rhythm was of 163 min (120-300) in the flecainide group versus 10 min (6-18) in the vernakalant group (p=0.0001)., Conclusion: Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared with the flecainide group, and was associated with shorter hospital stay. This reduction in hospital stay length may produce benefits in patients' medical care, costs and welfare., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Vernakalant is a new antiarrhythmic agent recently approved in Europe for the rapid cardioversion of recent-onset atrial fibrillation. It works by blocking early-activating K+ atrial channels and frequency-dependent atrial Na+ channels, prolonging atrial refractory periods and rate-dependent slowing atrial conduction, without promoting ventricular arrhythmia. Preclinical and clinical trials showed good toleration of this drug. The main purpose of our review is to describe all the trials that led to the incorporation of vernakalant into the current European atrial fibrillation guidelines., (© 2013 John Wiley & Sons Ltd.)

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF.Methods and Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed.Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of vernakalant for the cardioversion of atrial fibrillation (AF).Methods and Results: We reviewed the literature for randomized trials that compared vernakalant to another drug or placebo in patients with AF of onset ≤7 days. We used a random-effects model to combine quantitative data and rated the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation). From 441 total citations in MEDLINE, EMBASE, and CENTRAL (December 2018), we identified nine trials evaluating 1358 participants. Six trials compared vernakalant to placebo, two trials compared vernakalant to ibutilide, and one trial compared vernakalant to amiodarone. We found significant methodological bias in four trials. For conversion within 90 min, vernakalant was superior to placebo [50% conversion, risk ratio (RR) 5.15; 95% confidence interval (CI); 2.24-11.84, I2 = 91%], whereas we found no significant difference in conversion when vernakalant was compared with an active drug (56% vs. 24% conversion, RR 2.40; 95% CI 0.76-7.58, I2 = 94). Sinus rhythm was maintained at 24 h in 85% (95% CI 80-88%) of patients who converted acutely with vernakalant. Overall, we judged the quality of evidence for efficacy to be low based on inconsistency and suspected publication bias. There was no significant difference in the risk of significant adverse events between vernakalant and comparator (RR 0.95; 95% CI 0.70-1.28, I2 = 0, moderate quality evidence). Vernakalant is safe and effective for rapid and durable restoration of sinus rhythm in patients with recent-onset AF.Conclusion: Vernakalant should be a first line option for the pharmacological cardioversion of patients with haemodynamically stable recent-onset AF without severe structural heart disease. [ABSTRACT FROM AUTHOR]

Vernakalant is a new antiarrhythmic agent for the treatment of atrial fibrillation. While it has proven to be effective in a large share of patients in clinical studies, its underlying mode of action is not fully understood. In this work, we aim to link experimental data from the subcellular, tissue, and system level using an in-silico approach. A Hill’s equation-based drug model was extended to cover the frequency dependence of sodium channel block. Two model variants were investigated: M1 based on subcellular data and M2 based on tissue level data. 6 action potential (AP) markers were evaluated regarding their dose, frequency and substrate dependence. M1 comprising potassium, sodium, and calcium channel block reproduced the reported prolongation of the refractory period. M2 not including the effects on potassium channels reproduced reported AP morphology changes on the other hand. The experimentally observed increase of ERP accompanied by a shortening of APD90 was not reproduced. Thus, explanations for the drug-induced changes are provided while none of the models can explain the effects in their entirety. These results foster the understanding of vernakalant’s cellular mode of action and point out relevant gaps in our current knowledge to be addressed in future in-silico and experimental research on this aspiring antiarrhythmic agent.

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Aims: Besides the inhibition of the sodium inward current, vernakalant also inhibits the ultra rapid rectifier (IKur) and transient outward current (Ito). Inhibition of these currents increases contractility in canine atrial myocytes and goat atria. We investigated the effect of vernakalant on early repolarization and contractility in normal and electrically remodelled atria.Methods and results: Goats were implanted a pressure catheter, piezoelectric crystals, and electrodes to obtain atrial contractility and effective refractory period (ERP). The active component in pressure distance loops was used to compute the atrial work index (AWI). Experiments were performed in normal and electrically remodelled atria at clinically relevant plasma levels of vernakalant. As a positive control, the Ito/IKur blocker AVE0118 was investigated. Monophasic action potentials were recorded in anaesthetized goats and in explanted hearts to determine changes in action potential morphology. Vernakalant did not affect atrial work loops during sinus rhythm. Likewise vernakalant did not increase atrial fractional shortening or AWI during pacing with fixed heart rate and AV-delay. In contrast, AVE0118 did increase AWI, with a positive force frequency relation. Both in normal and remodelled atria, vernakalant strongly increased ERP but did not prolong early repolarization.Conclusion: In goat atria, vernakalant does not have an atrial positive inotropic effect and does not affect early repolarization. At high rates vernakalant may even have a negative inotropic effect. [ABSTRACT FROM AUTHOR]

Background: Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses.Methods and Results: A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs.Conclusions: SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs. [ABSTRACT FROM AUTHOR]

Background: The pharmacological cardioversion of recent-onset atrial fibrillation (AF) is a challenge for the clinician. The aim of the study was to compare the efficacy, the safety, and the overall cost of intravenous (iv) administration of vernakalant, which is a relatively new atrial-selective antiarrhythmic agent, versus ibutilide, in cardioversion of recentonset AF. Methods: We enrolled in this study 78 patients (56 men, 22 women; mean age 63.72 ± 6.67 years) who presented with recent-onset AF. Cardioversion was attempted in 36 patients (group A: 24 men, 12 women; mean age 62.44 ± 7.24 years) by iv administration of vernakalant (3 mg/kg over 10 min and if needed after 15 min, a second dose 2 mg/kg over 10 min) while in 42 patients (group B: 32 men, 10 women; mean age 64.81 ± 6 years) iv ibutilide was administered (1 mg over 10 min and if needed after 10 min, a second dose 1 mg over 10 min). Results: AF was successfully converted in 52.78% of (n =19) patients of group A vs 52.38% of (n =22) patients of group B (p =0.58), with an average time of conversion 11.8 ± 4.3 min for group A patients vs 33.9 ± 20.25 min for group B patients (p <0.0001). The average length of hospital stay for patients of group A was 17.64 ± 15.96 hours vs 41.09 ± 17.6 hours for patients of Group B (p <0.0001). In one patient of group A, the administration of vernakalant was discontinued due to hypotension while two other patients reported dysgeusia during their hospitalization. In three patients of group B, the administration of ibutilide was discontinued due to development of nonsustained ventricular tachycardia, which resolved with discontinuation of the drug. The cost of administered drugs was estimated at 488.22 ± 170.34 € for patients of group A vs 142.43 ± 54.45 € for patients of group B (p <0.0001), however, hospitalization costs were significantly lower in patients of group A (258.5 8± 124.73 € over 414.43 ± 100.32; p =0.002). Conclusion: There was no significant difference in the efficiency of converting recent-onset AF between vernakalant and ibutilide. Although vernakalant is an expensive drug, we recorded fewer side effects and more rapid restoration, which reduced the overall cost of hospitalization of these patients. [ABSTRACT FROM AUTHOR]

Aims: Ibutilide is a rapid-acting antiarrhythmic drug with worldwide use for conversion of recent-onset atrial fibrillation. Vernakalant, approved in the EU in 2010, is likewise used intravenously, with proven efficacy and safety compared with placebo and amiodarone in randomized clinical trials. The aim of our study was to compare the time to conversion and the conversion rate within 90 min in patients with recent-onset atrial fibrillation treated with vernakalant or ibutilide.Methods and Results: A randomized controlled trial registered at clinicaltrials.gov (NCT01447862) was performed in 100 patients with recent-onset atrial fibrillation treated at the emergency department of a tertiary care hospital. Patients received up to two short infusions of vernakalant (n = 49; 3 mg/kg followed by 2 mg/kg if necessary) or ibutilide (n = 51; 1 mg followed by another 1 mg if necessary) according to the manufacturer's instructions. Clinical and laboratory variables, adverse events, conversion rates, and time to conversion were recorded. Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared with the ibutilide group (median time: 10 vs. 26 min, P = 0.01), and likewise the conversion success within 90 min was significantly higher in the vernakalant group (69 vs. 43%, log-rank P = 0.002). No serious adverse events occurred.Conclusion: Vernakalant was superior to ibutilide in converting recent-onset atrial fibrillation to sinus rhythm in the emergency department setting. [ABSTRACT FROM AUTHOR]

Aims: Electrical cardioversion is one cornerstone for the rhythm control strategy of atrial fibrillation (AF), which is, however, hampered by immediate AF recurrence (IRAF) or failed electrical cardioversion (FECV). We aimed to investigate the potential role of vernakalant for facilitated electrical cardioversion in cardioversion-resistant AF.Methods and Results: The subjects of this study were 63 patients referred to the Heart Centre Leipzig between November 2011 and May 2014 for transthoracic electrical cardioversion of AF. All patients experienced after antiarrhythmic-naïve electrical cardioversion either IRAF (n = 44; 70%) or FECV (n = 19; 30%). After drug infusion, electrical cardioversion was successful in 66.7% of vernakalant-treated as opposed to 46.7% of amiodarone-treated patients (P = 0.109). Multivariate analysis revealed treatment with vernakalant (OR 0.057, 95% CI 0.006-0.540, P = 0.013), treatment with ACEI or ARB (OR 0.101, 95% CI 0.015-0.691 P = 0.019), and IRAF after initial CV (OR 0.047, 95% CI 0.004-0.498, P = 0.011) as predictors for successful, drug-facilitated electrical cardioversion. Subgroup analysis of 18 patients with previous AF ablation revealed a significantly higher success rate of electrical cardioversion after infusion of vernakalant than after infusion of amiodarone (66.7 vs. 11.1%, P = 0.016).Conclusion: Vernakalant may therefore be considered as a useful agent for facilitated electrical cardioversion in cardioversion-resistant AF. [ABSTRACT FROM AUTHOR]