vernakalant and Arrhythmias--Cardiac

The usual aim of treatment for patients with symptomatic paroxysmal or recent-onset atrial fibrillation, including after cardiac surgery, is to slow the heart rate. Electrical and drug (amiodarone) cardioversion are other options. Vernakalant, an antiarrhythmic drug, has been authorised in the European Union for rapid reduction of recent-onset atrial fibrillation. It is only available in an injectable form. Vernakalant has not been compared in clinical trials with treatments slowing the heart rate, or with electrical cardioversion. The only available comparison with another antiarrhythmic agent is a clinical pharmacology study versus amiodarone, a slow-acting drug, based on the rate of cardioversion at 90 minutes in 240 patients. As expected, given the brief observation period, the rate was significantly higher with vernakalant (51.7% versus 5.2%). During clinical evaluation, 6 deaths occurred in the vernakalant groups versus none in the other groups (placebo or amiodarone). The main adverse effects of vernakalant are cardiac arrhythmias (ventricular arrhythmia, torsades de pointes, bradycardia) and severe hypotension. Altered taste, sneezing, paraesthesia, nausea and pruritus were frequent, and respiratory and neuropsychological effects were also reported. A trial in atrial flutter was interrupted when cases of cardiogenic shock occurred. Interactions are to be expected with drugs that prolong the QT interval, and also with drugs that lower the heart rate or the blood potassium concentration. In practice, it is better to continue to use amiodarone for drug cardioversion and to avoid using vernakalant.

Topics: Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Clinical Trials as Topic; Clinical Trials, Phase IV as Topic; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Humans; Hypotension; Pharmacovigilance; Pyrrolidines

In this review we discuss mechanisms of antiarrhythmic and adverse proarrhythmic action of class III drugs. Special attention is given to ionic currents and channels which determine specific features of their effects (IKr, IKa, IKur). We consider general patterns of changes of bioelectrical activity in atria and ventricles leading to development of arrhythmias or stabilization of rhythm. We also discuss value of QT interval as predictor of torsade de pointes. Perspectives and limitations of development of novel class III antiarrhythmic drugs are discussed as well. We present consideration of efficacy and mechanisms of action of such compounds as dronedarone and vernacalant suggested for termination of atrial fibrillation and maintenance of sinus rhythm. Special attention is given to RG 2 - a novel compound with class III activity.

Topics: Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Dronedarone; Electric Impedance; Electrocardiography; Heart Atria; Heart Rate; Heart Ventricles; Humans; Ion Channels; Long QT Syndrome; Mutation; Myocytes, Cardiac; Pyrrolidines; Rabbits; Rats

Topics: Acetanilides; Adenosine A1 Receptor Agonists; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzazepines; Benzofurans; Clinical Trials as Topic; Dronedarone; Humans; Ivabradine; Piperazines; Pyrrolidines; Ranolazine

Molecular dynamics simulations are employed to determine the inhibitory mechanisms of three drugs, 5-(4-phenoxybutoxy)psoralen (PAP-1), vernakalant, and flecainide, on the voltage-gated K

Topics: Amino Acid Sequence; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Binding Sites; Crystallography, X-Ray; Ficusin; Flecainide; Humans; Kv1.5 Potassium Channel; Molecular Dynamics Simulation; Protein Conformation; Pyrrolidines; Sequence Homology, Amino Acid

Ranolazine has been reported to have an antiarrhythmic potential. The aim of this study was to assess the electrophysiologic effects of ranolazine and to compare its effects to vernakalant in an experimental whole-heart model of short-QT syndrome.. Rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an IK. Endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (- 34 milliseconds, P < 0.05) and action potential duration (APD. In the present pharmacologic model of short QT syndrome treatment with pinacidil led to an increased inducibility of VF in association with a reduction in ERP. Additional treatment with ranolazine or vernakalant reversed this effect and demonstrated potent antiarrhythmic properties based on an increase of ERP.

Topics: Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Heart Rate; Isolated Heart Preparation; Pinacidil; Pyrrolidines; Rabbits; Ranolazine; Sodium Channel Blockers; Time Factors; Ventricular Fibrillation

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Brugada Syndrome; Cardiac Conduction System Disease; Electrocardiography; Female; Heart Conduction System; Humans; Male; Middle Aged; Pyrrolidines; Sex Factors; Time Factors; Treatment Outcome; Young Adult

The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia.. In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts.. In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.

Topics: Acetanilides; Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrophysiologic Techniques, Cardiac; Heart Conduction System; In Vitro Techniques; Models, Animal; Perfusion; Piperazines; Potassium Channel Blockers; Pyrrolidines; Rabbits; Ranolazine; Risk Assessment; Risk Factors; Sodium Channel Blockers; Sotalol; Time Factors