vernakalant and Heart-Failure

Atrial fibrillation (AF) is a prevalent condition particularly amongst the elderly, which contributes to both morbidity and mortality. The burden of disease has lead to significant increases in health care utilization and cost in recent years. Treatment of Atrial fibrillation consists of either a rate or rhythm control strategy. Rhythm control is achieved using medical management and/or catheter ablation. In spite of major strides in catheter ablation, this procedure remains a second line treatment of AF. Anti-arrhythmic medications represent the main treatment modality for the maintenance of sinus rhythm. Amiodarone has been used for decades because of its efficacy and lack of pro-arrhythmia despite numerous extracardiac side effects. Novel agents such as Dronedarone were designed to emulate Amiodarone without the extra-cardiac side effects. Unfortunately recent trials have raised concerns for the safety of this medication in certain patients. Other agents such as Vernakalant and Ranolazine are in development that promise to be more atrial selective in their action, thereby potentially avoiding pro-arrhythmia and heart failure side effects. It remains to be seen however if one or more of these agents achieves the required high efficacy and safety threshold. This review summarizes the main anti-arrhythmic clinical trials, early phase trials involving novel agents and examines the conflicting data relating to Dronedarone.

Topics: Acetanilides; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Digoxin; Dronedarone; Forecasting; Heart Failure; Humans; Phenethylamines; Piperazines; Pyrrolidines; Ranolazine; Sulfonamides; Technology, Pharmaceutical; Ventricular Dysfunction, Left

Atrial fibrillation, which is associated with a worsening of congestive heart failure symptoms, an increased rate of stoke, and increased mortality, is still difficult to treat. New therapies must not only increase effectiveness, but also have to have an improved safety profile, in order to avoid sodium channel block in the ventricle of older patients with atrial fibrillation, and also prevent electrical and morphological remodeling. Dronedarone is less effective compared to amiodarone, but has a better side effect profile which leads to fewer discontinuations of treatment. The atrial ion channels are specifically blocked by a number of prospective antiarrhythmic substances. The most advanced is the testing of vernakalant (RSD1235), which primarily suppresses the I(Kur) current. Ranolazine is a new antianginal substance which influences the atrial ion channels and leads to a significant reduction of atrial and more specifically ventricular tachyarrhythmias. A number of other drugs are in development. They will lead to a better understanding of which form of atrial fibrillation can be best treated with which antiarrhythmic agent.

Topics: Acetanilides; Aged; Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Drug-Related Side Effects and Adverse Reactions; Drugs, Investigational; Electrocardiography; Heart Atria; Heart Failure; Heart Ventricles; Humans; Piperazines; Potassium Channels; Pyrrolidines; Ranolazine; Sodium Channels; Stroke

Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia's formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure-response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (E (max)) models. For QTcF, the model was characterized by a typical E (max) of 20.3 ms, and by a vernakalant median effective concentration dependent (EC₅₀) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E (max) of 3.05 mmHg and EC₅₀ of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Computer Simulation; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Heart Failure; Humans; Hypotension; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines

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.. 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.. 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).. In our study, the absence of any kind of structural heart disease and preserved systolic function were associated with greater conversion rate with vernakalant.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Pyrrolidines; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Treatment Outcome

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).. 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.. 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.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Resynchronization Therapy; Disease Models, Animal; Electrocardiography; Female; Heart Conduction System; Heart Failure; Heart Ventricles; Models, Cardiovascular; Pyrrolidines; Rabbits