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Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomized controlled trial at the emergency department.

ABSTRACT: 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.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.Vernakalant was superior to ibutilide in converting recent-onset atrial fibrillation to sinus rhythm in the emergency department setting.

SUBMITTER: Simon A

PROVIDER: S-EPMC5400093 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomized controlled trial at the emergency department.

Simon Alexander A Niederdoeckl Jan J Skyllouriotis Ekaterini E Schuetz Nikola N Herkner Harald H Weiser Christoph C Laggner Anton N AN Domanovits Hans H Spiel Alexander O AO

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 20170201 2

<h4>Aims</h4>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.<h4>Method ...[more]

PMID: 28175295

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Project description: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.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.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.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.NCT00989001 .

Project description:GSE2240 contains two different experimental subsets: 1) Comparison of atrial and ventricular gene expression (atrial tissue of patients with sinus rhythm vs. human left ventricular non-failing myocardium) The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions (Barth AS et al., Eur J Physiol, 2005). 2) Comparison of atrial gene expression in patients with permanent atrial fibrillation and sinus rhythm. Atrial fibrillation is associated with increased expression of ventricular myosin isoforms in atrial myocardium, regarded as part of a dedifferentiation process. Whether re-expression of ventricular isoforms in atrial fibrillation is restricted to transcripts encoding for contractile proteins is unknown. Therefore, this study compares atrial mRNA expression in patients with permanent atrial fibrillation to atrial mRNA expression of patients with sinus rhythm as well as to ventricular gene expression using Affymetrix U133 arrays. In atrial myocardium, we identified 1.434 genes deregulated in atrial fibrillation, the majority of which, including key elements of calcium-dependent signaling pathways, displayed down-regulation. Functional classification based on Gene Ontology provided the specific gene sets of the interdependent processes of structural, contractile and electrophysiological remodeling. In addition, we demonstrate for the first time a prominent up-regulation of transcripts involved in metabolic activities, suggesting an adaptive response to an increased metabolic demand in fibrillating atrial myocardium. Ventricular-predominant genes were five times more likely to be up-regulated in atrial fibrillation (174 genes up-regulated, 35 genes down-regulated), while atrial-specific transcripts were predominantly down-regulated (56 genes up-regulated, 564 genes down-regulated). Overall, in atrial myocardium, functional classes of genes characteristic of ventricular myocardium were found to be up-regulated (e.g. metabolic processes) while functional classes predominantly expressed in atrial myocardium were down-regulated in atrial fibrillation (e.g. signal transduction and cell communication). Therefore, dedifferentiation with adoption of a ventricular-like signature is a general feature of the fibrillating atrium, uncovering the transcriptional response pattern in pmAF (Barth AS et al., Circ Res, 2005). Keywords = human myocardium Keywords = atrial fibrillation Keywords = sinus rhythm Keywords = left ventricular gene expression Keywords: other

Project description:Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (?KPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 ?M) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ?KPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 ?M) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Dataset Information

Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomized controlled trial at the emergency department.

Publications

Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomized controlled trial at the emergency department.

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