vernakalant and Atrial-Fibrillation

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.. 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.. 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. 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.

Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Humans; Infusions, Intravenous; Pyrrolidines; Treatment Outcome

Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF.. A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm.. In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice.. PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).

Topics: Adult; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Flecainide; Humans; Network Meta-Analysis; Quinidine; Randomized Controlled Trials as Topic; Ranolazine; Systematic Reviews as Topic; Verapamil

We sought to indirectly compare and rank antiarrhythmic agents focusing exclusively on adults with paroxysmal atrial fibrillation in order to identify the most effective for pharmacologic cardioversion over different time settings (4 h as primary, and 12, 24 h as secondary outcomes).. We searched several databases from inception to March 2020 without language restrictions, ClinicalTrials.gov, references of reviews, and meeting abstract material. We included randomized controlled trials of patients with AF lasting ≤7 days comparing either two or more intravenous (i.v.) or oral (p.o.) pharmacologic cardioversion agents or an agent against placebo. For each outcome, we performed network meta-analysis based on the frequentist approach.. Forty-one trials (6013 patients) were included in our systematic review. Moderate confidence evidence suggests that i.v. vernakalant and flecainide have the highest conversion rate within 4 h, possibly allowing discharge from the emergency department and reducing hospital admissions. Intravenous and p.o. formulations of class IC antiarrhythmics (flecainide more so than propafenone) are superior regarding conversion rates within 12 h, while amiodarone efficacy is exhibited in a delayed fashion (within 24 h), especially if ranolazine is added.. Our network meta-analysis identified with sufficient power and consistency the most effective antiarrhythmics for pharmacologic cardioversion over different time settings, with vernakalant and flecainide exhibiting a safer and more efficacious profile toward faster cardioversion.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Flecainide; Humans; Pyrrolidines; Randomized Controlled Trials as Topic

Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent. Despite its good efficacy profile and rapid onset of action, there was still controversial evidence regarding vernakalant-related adverse events. We searched PubMed and Embase for studies that compared intravenous vernakalant with placebo or antiarrhythmic agents in patients with recent-onset atrial fibrillation (AF) lasting no more than 7 days. Efficacy and safety outcomes were the treatment-induced cardioversion rate within 90 minutes and adverse events after first exposure to study drug respectively. Nine randomized controlled trials enrolling 1296 patients were analyzed. Quantitative synthesis showed that vernakalant was superior to placebo for cardioversion of recent-onset AF within 90 minutes [49.7% vs. 6.2%, risk ratio (RR) 8.13, 95% confidence interval (CI) 5.35-12.36, P < 0.00001], and it did not achieve statistical significance in cardioversion when vernakalant was compared with ibutilide (62.4% vs. 47.3%, RR 1.32, 95% CI 1.00-1.73, P = 0.05). As for safety assessment, no significant differences were found in occurring serious adverse events (9.9% vs. 10.4%, RR 0.91, 95% CI 0.67-1.25, P = 0.57) and hypotension (5.3% vs. 3.3%, RR 1.53, 95% CI 0.86-2.73, P = 0.15) between vernakalant and comparator (either placebo, ibutilide, or amiodarone). There were trends that patients receiving vernakalant experienced more drug discontinuation (2.5% vs. 1.0%, RR 2.21, 95% CI 0.96-5.11, P = 0.06) and less any ventricular tachycardia (6.1% vs. 8.1%, RR 0.70, 95% CI 0.49-1.00, P = 0.05) than those receiving comparator, but the differences were not statistically significant. Furthermore, vernakalant was associated with a higher risk of bradycardia in comparison with comparator (6.3% vs. 1.1%, RR 4.04, 95% CI 1.67-9.75, P = 0.002). Vernakalant is effective in converting recent-onset AF to sinus rhythm rapidly, while significantly more bradycardia events are related to vernakalant in our meta-analysis.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Bradycardia; Heart Rate; Humans; Injections, Intravenous; Pyrrolidines; Randomized Controlled Trials as Topic; Treatment Outcome

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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines

To evaluate the efficacy and safety of vernakalant for the cardioversion of atrial fibrillation (AF).. 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.. Vernakalant should be a first line option for the pharmacological cardioversion of patients with haemodynamically stable recent-onset AF without severe structural heart disease.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines; Randomized Controlled Trials as Topic; Treatment Outcome

Atrial fibrillation is a common cardiac arrhythmia with increasing prevalence in the aging population. It is a major cause of emergency department visits worldwide. Vernakalant, a relatively new antiarrhythmic drug with selectively preferential effects on the atrial tissue is currently used in many European countries for the termination of recent-onset atrial fibrillation. Presently, the drug is still not approved by the United States Food and Drug Administration due to safety concerns. We evaluate the efficacy and safety of vernakalant for the conversion of recent-onset atrial fibrillation or atrial flutter into normal sinus rhythm (NSR).. PubMed/MEDLINE (1993-2017), the Cochrane Central Register of Controlled Trials (2000-2017), and reference lists of relevant articles were searched for randomized controlled trials (RCTs) comparing vernakalant to a control drug and extracted subsequently.. Nine RCTs were identified and included in the meta-analysis. Pooled analysis of events extracted for a total of 1421 patients with recent-onset atrial fibrillation showed a statistically significant increase in cardioversion within 90 minutes from drug infusion (Relative Risk [RR], 6.61; 95% Confidence Interval [CI], 2.78 - 15.71; p < .00001). In terms of adverse events, vernakalant was considered safe in comparison to control drugs (RR, 0.80; 95% CI, 0.61-1.05; p = .11).. Vernakalant is effective for rapid conversion of recent-onset atrial fibrillation into NSR. However, although it showed a safe profile in terms of side effects in this analysis, we are still hesitant about this conclusion and few safety issues should be addressed within specific patients' subgroups.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Infusions, Intravenous; Pyrrolidines; Time Factors

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.. 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.. 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.

Topics: Adrenergic beta-Antagonists; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Combined Modality Therapy; Critical Illness; Electric Countershock; Electrocardiography; Emergency Service, Hospital; Hemodynamics; Humans; Intensive Care Units; Propanolamines; Pyrrolidines

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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Administration Schedule; Heart Conduction System; Humans; Practice Guidelines as Topic; Pyrrolidines; Randomized Controlled Trials as Topic

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.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Humans; Pyrrolidines; Ranolazine

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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Administration Schedule; Evidence-Based Medicine; Heart Conduction System; Heart Rate; Humans; Infusions, Intravenous; Practice Guidelines as Topic; Pyrrolidines; Time Factors; Treatment Outcome

Atrial fibrillation often affects elderly people with cardiovascular disease and takes a progressive course with increasing resistance to treatment. For the latter, electrical and structural changes (remodelling) seem to be responsible that are directly related to the high excitatory rate in the atria. Therapeutic strategies for atrial fibrillation consist of (i) treating the underlying cardiovascular disease, (ii) re-establishing sinus rhythm and (iii) reducing ventricular rate. Rapid pharmacological or electrical cardioversion is expected to prevent remodelling. Classical antiarrhythmic drugs are notoriously ineffective and burdened with serious cardiac and extracardiac side effects so that there is an urgent need for effective and safe novel compounds. In this review the three recently introduced drugs dronedarone, vernakalant and ranolazine are discussed with respect to the use in atrial fibrillation. Other new antiarrhythmic agents are still in the developmental phase and aim at atria-selective mechanisms thereby excluding ventricular proarrhythmic effects. The mechanisms of action will be discussed in the context of the present understanding of the pathophysiology of onset and maintenance of atrial fibrillation.

Topics: Acetanilides; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dose-Response Relationship, Drug; Dronedarone; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Piperazines; Pyrrolidines; Ranolazine; Sodium Channel Blockers; Treatment Outcome

Intravenous vernakalant (Brinavess) has been developed and approved in Europe as a safe and efficacious drug to rapidly convert recent onset atrial fibrillation to sinus rhythm in patients with no minimal or structural heart disease.. The pharmacology of vernakalant and the pivotal Phase II and III clinical trials undertaken during its development are discussed with regard to safety and efficacy. An extensive PubMed search was used to identify suitable papers.. As yet, there is no evidence of benefit over and above intravenous flecainide or propafenone for patients in whom vernakalant has a class 1a recommendation. As such, it is likely to be most useful in centres where only amiodarone is available.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Humans; Injections, Intravenous; Pyrrolidines

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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines; Randomized Controlled Trials as Topic

The sudden onset of atrial fibrillation (AF) is often associated with rapid irregular palpitations, chest pain, shortness of breath and considerable anxiety. If a patient presents shortly after the onset of the arrhythmia the physician may adopt initially an expectant "wait and see" policy, perhaps with the help of mild sedation and drug therapy to reduce the ventricular rate. If the arrhythmia does not terminate spontaneously and has been present for less than 24-48 hours restoration of sinus rhythm by cardioversion should be considered. This manuscript reviews the option of electrical cardioversion versus pharmacologic and the data for, the role of, and the status of vernakalant with respect to the latter.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Chest Pain; Drug Approval; Dyspnea; Electric Countershock; Europe; Humans; Pyrrolidines; Time Factors; United States

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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Humans; Infusions, Intravenous; Pyrrolidines

In recent years, there has been a large amount of studies about the efficacy and safety of vernakalant or RSD1235, an antiarrhythmic agent, in treating the atrial fibrillation (AF). This study was designed to assess the efficacy and safety of vernakalant in the treatment of AF.. A total of 5 randomized controlled trials (RCTs) (n= 1153) met our inclusion criteria. Vernakalant was superior in achieving sinus rhythm (SR) for AF comparing to placebo or alternative anti-arrhythmic agents (relative risk [RR] = 11.56, 95% Confidence Interval [CI] = 7.12 - 18.75). There was no heterogeneity among the trials (X(2) =0.59, P = 0.96). In analysing the adverse effects of cardiac origin, there was no significant difference between the two groups (RR= 0.90, 95% CI = 0.52 - 1.57).. The Cochrane library, Pubmed NCBI, EMBASE and MEDLINE were systematically searched to identify all interventional trials of vernakalant with placebo or other antiarrhythmic drug in converting AF to SR. The primary outcome was rate of converting to SR, and the secondary outcome was the rate of adverse effects of cardiac origin due to vernakalant and the placebo or amiodarone. Meta-analyses were carried out using Mantel-Haenszel fixed-effects or random-effects models and heterogeneity was by the X(2) test.. In the conversion of AF to SR, vernakalant is highly effective without obviously raised side effects. Owing to only one study comparing vernakalant with amiodarone included in this study, the efficacy of vernakalant comparing to other antiarrhythmic agents needing more well-designed double-blinded RCTs to be confirmed.

Topics: Anisoles; Atrial Fibrillation; Humans; Placebos; Pyrrolidines; Randomized Controlled Trials as Topic

Intravenous vernakalant has recently been approved in Europe as an atrial-selective antiarrhythmic drug for the conversion of recent-onset atrial fibrillation (AF). It inhibits atrial-selective K(+) currents (I(K,ACh) and I(Kur)) and causes rate-dependent atrial-predominant Na(+) channel block, with only a small inhibitory effect on the rapid delayed rectifier K(+) current (I(Kr)) in the ventricle. Due to its atrial-selective properties, vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, being associated with a low proarrhythmic risk for torsades de pointes arrhythmias. Five pivotal clinical trials consistently demonstrated that vernakalant rapidly terminates AF with stable maintenance of sinus rhythm for up to 24 hours. A head-to-head comparative trial showed that the 90-minute conversion rate of vernakalant was substantially higher than that of amiodarone. Initially, a longer-acting oral formulation of vernakalant was shown to be effective and safe in preventing AF recurrence after cardioversion in a Phase IIb study. However, the clinical studies testing oral vernakalant for maintenance of sinus rhythm after AF cardioversion were prematurely halted for undisclosed reasons. This review article provides an update on the safety and efficacy of intravenous vernakalant for the rapid cardioversion of AF.

Topics: Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Heart Conduction System; Humans; Infusions, Intravenous; Potassium Channel Blockers; Pyrrolidines; Refractory Period, Electrophysiological; Sodium Channel Blockers; Time Factors; Treatment Outcome

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.

Topics: Administration, Oral; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Humans; Pyrrolidines

Vernakalant is an emergent antiarrhythmic drug that, in preclinical studies, has demonstrated high efficacy in restoring sinus rhythm and safety in patients with rapid recent-onset atrial fibrillation. The aim of this work was to evaluate the efficacy and safety of vernakalant for cardioversion of recent-onset atrial fibrillation. PubMed, EMBASE, Clinical Trials Registry, and European Medicines Agency public reports were searched for randomized clinical trials, until May 2011, of vernakalant compared with controls (placebo/other antiarrhythmic drug) in enrolled patients with high ventricular rate atrial fibrillation. Five randomized trials that met inclusion criteria enrolled a total of 1099 patients. Among these, 810 had recent-onset atrial fibrillation. When compared with controls (placebo/other oral antiarrhythmic drugs), vernakalant was associated with a significant increase in cardioversion within 90 minutes from drug infusion (relative risk, 8.4; 95% confidence interval, 4.4-16.3; P < .00001). Compared with controls, vernakalant was not associated with a significant difference in serious adverse events (relative risk, 0.9; 95% confidence interval, 0.6-1.4; P = .64). The authors conclude that compared with controls, vernakalant is effective and safe for rapidly converting recent-onset atrial fibrillation. Questions remain surrounding safety because 1 unpublished trial was discontinued for this reason. Further cost-effective analysis and comparison with other antiarrhythmic agents, such as class I antiarrhythmic agents, should be investigated, especially in the emergency department.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Approval; European Union; Government Regulation; Humans; Membrane Transport Modulators; Pyrrolidines

Rate and rhythm control are two well established treatment objectives for atrial fibrillation (AF) patients. While symptom reduction is a primary treatment goal, therapeutic practice related to cardioversion varies by region and patient, with several precautions associated with the use of current therapies. No comprehensive literature review on the relative efficacy of existing cardioversion approaches compared to newly available therapies has been conducted.. A systematic literature review and meta-analysis were undertaken to evaluate the efficacy of pharmacologic therapies in eliciting cardioversion within 2 and 8-24 h among patients with recent-onset, short duration AF. Eligible studies included randomized controlled trials in which cardioversion rates were evaluated in at least 2 treatment groups. Bayesian mixed-treatment comparisons estimated odds ratios (95% credible intervals) for successful cardioversion. Results within 2 h showed vernakalant IV, propafenone IV and flecainide (IV and oral) were more efficacious in pair-wise comparisons to placebo. Results were mixed in analyses comparing efficacy rates between 8 and 24 h. Few adverse events were reported, with the most common being bradycardia and hypotension.. In pair-wise comparisons of active treatment arms to one another, results suggest vernakalant IV, propafenone IV and flecainide appear to be effective in achieving rapid cardioversion in patients with short duration AF compared to other agents. Application of these findings to clinical practice need to account for the variable comorbidity profiles of patients, important determinants in the selection of appropriate therapy for individual patients. Though best practice methods were used, further research comparing treatments through direct head-to-head comparisons may be warranted to confirm these findings and further inform clinical practice.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Bayes Theorem; Electric Countershock; Female; Flecainide; Humans; Male; Middle Aged; Propafenone; Pyrrolidines; Randomized Controlled Trials as Topic; Treatment Outcome

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that due to its frequent hospitalizations and increased complication rates imposes a significant health economic burden. Many patients with recurrent AF are admitted to the hospital for cardioversion to restore sinus rhythm. Given this knowledge, it is clearly important to identify a feasible and effective approach for cardioversion of these patients. Cardioversion always requires careful assessment of potential complications, which apart from thromboembolic risks, include proarrhythmias and those related to the deep sedation required for electrical cardioversion. Even though electrical cardioversion is proven to be safe and effective, the need for anesthesia makes alternative strategies more attractive.. The research discussed is the alternative strategies for cardioversion, including electrical cardioversion and the new relatively atrial-selective antiarrhythmic drug, vernakalant. The literature search methodology undertaken included search in PubMed (cardioversion, vernakalant, conversion as key words).. Vernakalant is shown to have good conversion rates, an apparently safe antiarrhythmic profile and is well tolerated in patients with a history of ischemic heart disease. In most cases of recent-onset AF, pharmacological cardioversion can provide a probably more cost-effective and safer alternative to electrical cardioversion, which can then be used as a second option for those who failed the first attempt of cardioversion.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Electrocardiography; Heart Rate; Humans; Myocardial Ischemia; Potassium Channels; Pyrrolidines; Sodium Channels

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

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 (AF) is associated with a significant burden of morbidity and increased risk of mortality. Beyond outstanding advances in catheter ablation procedures, antiarrhythmic drug therapy remains a corner-stone to restore and maintain sinus rhythm. However, potentially life-threatening hazards (proarrhythmia) and significant non-cardiac organ toxicity have made new drug development of prominent relevance. Multichannel blocking, atrial selectivity, and the reduction of the risk of adverse events have all constituted the main theme of modern antifibrillatory drug development. Dronedarone, an analog of amiodarone, has the unique characteristic of being the first antiarrhythmic drug demonstrated to reduce hospitalizations in AF. Dronedarone is associated with less systemic toxicity than amiodarone, although being less effective for sinus rhythm maintenance. Atrial selective agents have been developed to target ion channels expressed selectively in the atria. Among the most promising drugs of this class is vernakalant, which has been shown effective for the acute conversion of AF with small risk of proarrhythmia. Finally, increasing evidences support antiarrhythmic effectiveness of traditional non-antiarrhythmic drugs, such as renin-angiotensin system blockers, statins, and omega-3 fatty acids. In this article, we will focus on recent advances in antiarrhythmic therapy for AF, reviewing the possible clinical utility of novel antifibrillatory agents.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Antioxidants; Atrial Fibrillation; Clinical Trials as Topic; Dronedarone; Fatty Acids, Omega-3; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrrolidines; Renin-Angiotensin System; Treatment Outcome

Vernakalant is a novel anti-arrhythmic drug, recently approved for the cardioversion of recent-onset atrial fibrillation. Its action is mainly due to the blockade of atrial-selective channels responsible of the ultra-rapid delayed rectifier current I(Kur), but has also important interactions with other channels and currents, such as I(Na) (inward sodium current), and I(KACh) (acetylcholine-regulated potassium current). Due to the relatively selective blockade of the I(Kur), vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, thus minimizing the risk of proarrhythmia. Thus far vernakalant has been tested in three placebo-controlled trials (ACT I, ACT II and ACT III) and in one amiodarone-controlled study (AVRO). Vernakalant has been demonstrated more effective than both placebo and amiodarone for the rapid conversion of atrial fibrillation, without significant adverse events. This article will review the recent patents on this novel atrial-selective agent, discussing its mechanisms of action and possible clinical applications in the real-world practice.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Evidence-Based Medicine; Heart Conduction System; Heart Rate; Humans; Ion Channels; Patents as Topic; Pyrrolidines; Treatment Outcome

Intravenous vernakalant (Brinavess®) is an atrial-repolarization-delaying agent that is currently approved in the EU for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. Vernakalant blocks atrial-specific potassium and sodium ion channels, prolonging atrial refractory periods and rate-dependently slowing atrial conduction, without promoting ventricular arrhythmia. In pivotal randomized, phase III trials, intravenous vernakalant 3 mg/kg administered as a 10-minute infusion, followed by a 2 mg/kg 10-minute infusion after 15 minutes if atrial fibrillation persisted, was effective in the rapid termination of recent-onset atrial fibrillation in nonsurgical patients (≥3 hours' to ≤7 days' duration) and in those with postoperative atrial fibrillation (3-72 hours' duration) following cardiac surgery. Conversion to sinus rhythm occurred rapidly following infusion of vernakalant, with the majority of patients converting after the first dose, and conversion to sinus rhythm was generally associated with a rapid resolution of symptoms. These antiarrhythmic effects of vernakalant were durable, with most responders remaining in sinus rhythm 24 hours after treatment initiation. In nonsurgical patients with recent-onset atrial fibrillation of 3-48 hours' duration, vernakalant was more effective than intravenous amiodarone, with a significantly higher proportion of patients converting to sinus rhythm within the first 90 minutes of treatment. Vernakalant was generally well tolerated in clinical trials, with most adverse events being of mild or moderate severity and not treatment limiting. Increases in QRS or QT intervals were transient, and there was no increased incidence of ventricular arrhythmia observed with vernakalant compared with placebo. Therefore, intravenous vernakalant provides an effective option for the management of recent-onset atrial fibrillation.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Humans; Infusions, Intravenous; Pyrrolidines

Atrial fibrillation (AF) is associated with increased mortality and morbidity. Although stroke prevention is the only way to improve prognosis, antiarrhythmic drugs (AADs) are of primary importance both in the conversion to sinus rhythm and in the long-term control of rhythm and rate.. We searched the Cochrane Library and Medline Database for articles published in English concerning efficacy and safety of AADs in AF. Particular attention was paid to the recently published European Society of Cardiology guidelines. This review provides an overview of the currently available drugs used in AF, with a particular emphasis on their comparative efficacy and safety in different kind of patients. Recent important findings, and advantages and disadvantages of recently approved drugs such as vernakalant and dronedarone, are also discussed.. AADs remain fundamental in the acute and long-term management of AF, to control symptoms and to reduce the negative impact of the arrhythmia on QoL. The choice of a rate- over rhythm-control strategy should be individualized and based on accurate evaluation of patient medical history and symptoms. New agents will contribute to improve treatment efficacy together with the guarantee of better safety profiles.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Heart Rate; Humans; Pyrrolidines; Stroke; Treatment Outcome

New features in the Finnish guidelines for management of patients with atrial fibrillation (AF) include a recommendation to use the EHRA score in evaluation of AF-related symptoms and introduction of comprehensive CHA DS VASc and HAS-BLED scoring systems for stratifying the risk of thrombotic and bleeding complications, respectively. Recommendations on the use of two new antiarrhythmic drugs are included. Vernakalant is indicated for pharmacological cardioversion and dronedarone for prevention of AF. They can be used by patients with cardiac disease, except for those with severe heart failure. Catheter ablation can be considered as a first-line treatment in selected patients with lone AF.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Catheter Ablation; Dronedarone; Finland; Humans; Patient Selection; Practice Guidelines as Topic; Pyrrolidines

Intravenous vernakalant (Brinavess®) is an atrial-repolarization-delaying agent that is currently approved in the EU for the rapid conversion of recent-onset atrial fibrillation to sinus rhythm. Vernakalant blocks atrial-specific potassium and sodium ion channels, prolonging atrial refractory periods and rate-dependently slowing atrial conduction, without promoting ventricular arrhythmia. In pivotal, randomized, phase III trials, intravenous vernakalant 3 mg /kg administered as a 10-minute infusion, followed by a 2 mg/kg 10-minute infusion after 15 minutes if atrial fibrillation persisted, was effective in the rapid termination of recent-onset atrial fibrillation in nonsurgical patients (≥ 3 hours' to ≤ 7 days' duration) and in those with postoperative atrial fibrillation (3-72 hours' duration) following cardiac surgery. Conversion to sinus rhythm occurred rapidly following infusion of vernakalant, with the majority of patients converting after the first dose, and conversion to sinus rhythm was generally associated with a rapid resolution of symptoms. These antiarrhythmic effects of vernakalant were durable, with most responders remaining in sinus rhythm 24 hours after treatment initiation. In nonsurgical patients with recent-onset atrial fibrillation of 3-48 hours' duration, vernakalant was more effective than intravenous amiodarone, with a significantly higher proportion of patients converting to sinus rhythm within the first 90 minutes of treatment. Vernakalant was generally well tolerated in clinical trials, with most adverse events being of mild or moderate severity and not treatment limiting. Increases in QRS or QT intervals were transient, and there was no increased incidence of ventricular arrhythmia observed with vernakalant compared with placebo. Therefore, intravenous vernakalant provides an effective option for the management of recent-onset atrial fibrillation.

Topics: Anisoles; Atrial Fibrillation; Humans; Pyrrolidines

Vernakalant is a new antiarrhythmic drug which is used for rapid conversion of atrial fibrillation. The drug is a relatively atrium-selective K' and Na+ channel blocker, prolonging the atrial refractory period. Clinical trials showed conversion rates of about 50% which is comparable to other antiarrhythmic drugs. Further trials will show if vernakalant is less pro-arrythmogenic than its competitors.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Potassium Channel Blockers; Pyrrolidines; Randomized Controlled Trials as Topic; Sodium Channel Blockers

2010 saw the introduction of dabigatran (Pradaxa; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT), following US Food and Drug Administration approval, into daily clinical practice in the United States as an alternative to Coumadin (Bristol-Myers-Squibb, New York, NY) therapy. Dronedarone (Multaq; Sanofi-Aventis, Bridgewater, NJ), originally approved for use in the United States in 2009, has seen further widespread deployment in contemporary clinical practice. Intravenous vernakalant (Cardiome Pharm, Vancouver, B.C., Canada; Merck & Co., Whitehouse Station, NJ) is being considered for approval in the United States and may serve as an alternative to current agents for safe and efficacious acute conversion from atrial fibrillation. We focus primarily on new information concerning these and other antiarrhythmic drug and anticoagulation therapies. We provide brief updates of recently published articles along with our perspective on how they will likely alter clinical practice now and in the future.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Dronedarone; Drug Approval; Evidence-Based Medicine; Factor Xa Inhibitors; Female; Humans; Infusions, Intravenous; Male; Practice Guidelines as Topic; Pyridines; Pyrrolidines; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Catheter Ablation; Dabigatran; Electric Countershock; Humans; Pacemaker, Artificial; Pyrrolidines; Stroke; Thromboembolism

Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation.

Topics: Acetanilides; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Atrial Fibrillation; Dronedarone; Humans; Piperazines; Pyrrolidines; Ranolazine; Renin-Angiotensin System

Vernakalant is a promising novel antiarrhythmic intravenous drug for the rapid conversion of atrial fibrillation to sinus rhythm. It blocks several ion currents important in cardiac action potential including IKr. Its difference to traditional antiarrhythmic drugs is a preferential effect on the atria, achieved by an inhibition of repolarizing potassium ion currents I(Kur), which is atrial-specific, and I(to), predominantly affecting atrial repolarization, as there is little atrial plateau potential. Furthermore vernakalant blocks frequency- and voltage-dependent sodium ion currents (I(Na)). Thus rapid action potentials in atrial fibrillation are particularly targeted by vernakalant: this leads to a conversion rate to sinus rhythm in about 50 % of recent-onset attacks (less than 7 days) of atrial fibrillation. Age, gender, organ function and concomitant medication seem to have no clinically significant influence on the pharmacokinetics of vernakalant. The number of patients included in the studies is still too small to provide a definitive answer on its cardiac toxicity. However, a demonstrated tendency towards proarrhythmia and little experience with this new drug demands precaution even after it has been officially approved.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Heart Rate; Heart Ventricles; Humans; Membrane Potentials; Pyrrolidines

The pharmacology, pharmacokinetics, safety, clinical efficacy, and role of intravenous vernakalant hydrochloride for the rapid conversion of atrial fibrillation (AF) to normal sinus rhythm are reviewed.. Vernakalant, currently being evaluated by the Food and Drug Administration (FDA), for the termination of atrial fibrillation, differs in pharmacology from other antiarrhythmics; it achieves action potential interference through blockade of sodium and potassium currents. Vernakalant's actions appear to be directed at relatively atrial-selective potassium currents, which result in lengthening of the atrial action potential and prolongation of the atrial action potential plateau, while not significantly affecting the Q-T interval or the ventricular effective refractory period. As a result, the proarrhythmic effects observed with all other agents approved by FDA for the treatment of AF are eliminated. In clinical trials of vernakalant versus placebo, a statistically significant number of patients converted to normal sinus rhythm after receiving vernakalant. For patients with atrial fibrillation continuing for 3-72 hours, the median time to conversion was between 8 and 14 minutes, with 79% of those who converted remaining in sinus rhythm at 24 hours.. Intravenous vernakalant, a novel, relatively atrial-selective antiarrhythmic agent, appears to offer an effective and safe approach to the rapid conversion of recent-onset AF to normal sinus rhythm.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Infusions, Intravenous; Potassium Channel Blockers; Pyrrolidines; Sodium Channel Blockers; Time Factors; United States; United States Food and Drug Administration

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

Management of atrial fibrillation (AF) has changed greatly in the past 10 years. The advent of a greater understanding of the pathophysiology of AF has resulted in major therapeutic breakthroughs, both in invasive and non-invasive strategies. New antiarrhythmic agents with fewer side effects, new anticoagulants and technical advances in ablation have changed the treatment of this condition. Molecular modification of the highly effective amiodarone, to improve safety and tolerability, has produced promising analogues such as Dronedarone. Although this drug seems less effective than amiodarone in preventing AF recurrence, the drug presented an interesting data on reduction of stroke and cardiovascular death, a novel effect that needs further investigation. New antiarrhythmics with atria selectiveness such Vernakalant, might be useful for cardioversion in AF without ventricular proarrhythmia. Dabigatran, a prodrug that directly inhibits thrombin, represents an alternative to warfarin for anticoagulant treatment in selected patients. In AF ablation, technological advances are sure to result in the necessary improvements in the safety and procedures efficacy. These technologies include ablation catheters designed to electrically isolate the pulmonary veins with improved safety, efficacy, speed, and precision and improved imaging and electrical mapping systems. Although pulmonary vein isolation remains essential for most ablation procedures, the role of substrate modification has taken on increasing importance. In this article, we review the advances in the treatment of AF, focus on the new medications and advances in invasive procedures.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Catheter Ablation; Dabigatran; Dronedarone; Drug Therapy, Combination; Heart Conduction System; Humans; Pyrrolidines; Treatment Outcome

Rhythm control remains of therapeutic value for many atrial fibrillation patients despite no evidence of survival benefit. This lack of benefit may relate to side effects of conventional antiarrhythmic drugs. The introduction of novel agents was a logical consequence.. Novel antiarrhythmics are currently being evaluated in preclinical or clinical studies. Among recently developed drugs, some affect one or more atrial targets, including I Kur, I KACh, INa or I SAC, allowing them to act selectively on atria over ventricles. Some drugs that exhibit atrial selectivity have not been successful in preliminary studies. Block of a single atrial-specific target may be insufficient for atrial fibrillation termination and prevention, and multichannel-blocking properties may be a useful alternate approach. Drugs such as vernakalant or ranolazine inhibit multiple channels but display effective and atrial-selective actions. Furthermore, dronedarone, a prototypic multichannel blocker with additional effects on ventricular myocardium, has proven well tolerated and effective in the treatment of atrial fibrillation and may even reduce cardiovascular mortality.. Efforts to develop atrial-selective antiarrhythmics are bearing fruit, but such compounds will need to exhibit equal or superior safety and efficacy compared with multichannel blockers such as dronedarone for atrial fibrillation suppression in order to prove their worth. It is still too early to tell whether atrial selectiveness is just hype or truly a hope for antiarrhythmic drug treatment of atrial fibrillation.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Dronedarone; Humans; Pyrrolidines

The development of new antiarrhythmic agents for the treatment of atrial fibrillation is advancing simultaneously on several fronts. The molecular structure of existing agents such as amiodarone is being modified in an attempt to improve safety and reduce adverse effects. Similarly, atrial-selective antiarrhythmic drugs are being developed to minimize the occurrence of ventricular proarrhythmia. One of these atrial-selective compounds is vernakalant, which has demonstrated efficacy in terminating atrial fibrillation when given intravenously. In addition, preliminary data suggest that it could also suppress recurrences when used orally. This paper reviews the pharmacology, electrophysiology, efficacy and safety of intravenous and oral vernakalant.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines

Pharmacologic antiarrhythmic therapy is the most commonly used treatment in most patients with atrial fibrillation (AF), but currently available agents are limited by risks that may offset the benefits of sinus rhythm. The development of antiarrhythmic agents with the potential for fewer adverse ventricular effects and less extracardiac toxicity is a primary aim of current investigations. At present, pharmacologic research is actively focused on developing antiarrhythmic agents with multiple or novel ion channel effects. There are 4 agents that act by simultaneously blocking multiple ion channels that are currently under regulatory review: azimilide dihydrochloride, tedisamil, dronedarone, and vernakalant (RSD-1235). In addition, agents with mechanisms of action that differ from those of existing agents (eg, gap junction modulators) are under review, as is the use of nonantiarrhythmic agents (eg, renin-angiotensin system antagonists, statins, n-3 polyunsaturated fatty acids) to alter the cardiac substrate and suppress AF in some patient subtypes.

Topics: Amiodarone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cyclopropanes; Dronedarone; Humans; Hydantoins; Imidazolidines; Piperazines; Pyrrolidines

To review the pharmacology and clinical evidence of the use of vernakalant in the management of atrial fibrillation (AF).. Peer-reviewed articles published in the English language were identified from MEDLINE and Current Contents databases (both 1966-March 5, 2008) using the search terms RSD 1235 and vernakalant. Citations from available articles and recent meeting abstracts were reviewed for additional references. During the preparation of this article, vernakalant was being reviewed by the Food and Drug Administration (FDA). Therefore, information posted on the FDA Web site was also evaluated.. Phase 2 and Phase 3 clinical studies of both intravenous and oral vernakalant were reviewed. The design and results of the studies were critically evaluated.. Vernakalant is a sodium and ultra-rapid potassium channel blocker with atrial selective effects. In 2 clinical studies evaluating use of intravenous vernakalant in cardioversion of patients with recent-onset AF, vernakalant improved the chance of restoration of normal sinus rhythm (combined results 51% vs 3.8% with placebo; p < 0.001). In postoperative AF, intravenous vernakalant also improved the chance of restoration of normal sinus rhythm (45% vs 15% with placebo; p = 0.0002). Early Phase 2 studies demonstrated that oral vernakalant 300 mg or 600 mg twice daily successfully maintained sinus rhythm compared with placebo. No proarrhythmias relating to vernakalant have been reported to date. Common adverse effects include dysgeusia, sneezing, and paresthesia.. Vernakalant is a new atrial-selective antiarrhythmic agent. Phase 3 clinical trials of the intravenous formulation and early Phase 2 studies of the oral formulation demonstrated vernakalant to be efficacious and safe in converting recent-onset AF to sinus rhythm. Further studies are needed to explore the efficacy and safety of vernakalant use in patients with severe heart failure and AF, as well as its relative efficacy and safety compared with other antiarrhythmic agents, especially with long-term use.

Topics: Administration, Oral; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Interactions; Humans; Infusions, Intravenous; Potassium Channel Blockers; Pyrrolidines

This paper reviews the pharmacology, electrophysiology, efficacy and safety of intravenous and oral vernakalant hydrochloride (RSD-1235), a novel antiarrhythmic drug that has relative atrial selectivity by blocking potassium channels that are present in the atria and not the ventricle. In addition, this drug has important rate-dependent sodium channel blocking properties.. Currently, there few commercially approved intravenous antiarrhythmic agents for the conversion of atrial fibrillation. Intravenously, vernakalant has been demonstrated to be useful in terminating over 50% of recent-onset atrial fibrillation (< 7 days duration) with minimal ventricular proarrhythmic effects. Intravenous vernakalant is not effective in terminating atrial flutter. Oral vernakalant is currently undergoing study and appears to be effective in suppressing atrial fibrillation recurrences after cardioversion of persistent atrial fibrillation.. Intravenous vernakalant has the potential to be an important agent in the conversion of atrial fibrillation and oral vernakalant may be a useful drug for the suppression of atrial fibrillation recurrences.

Topics: Administration, Oral; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Drug Evaluation; Electric Countershock; Electrophysiology; Humans; Injections, Intravenous; Ion Channels; Pyrrolidines; Secondary Prevention

This review summarizes the mechanistic properties and the recent experience in the development of a new antiarrhythmic agent, RSD1235 (recently named vernakalant), for the acute conversion of atrial fibrillation to sinus rhythm. Atrial fibrillation is the most common sustained cardiac arrhythmia that is observed in clinical practice and is associated with increased morbidity and mortality, resulting from stroke and exacerbation of heart failure. At present, there is a lack of pharmacologic agents that are able to safely and effectively convert the arrhythmia back to sinus rhythm. Vernakalant has the electrophysiologic properties of a multiple ion channel blocker, developed using a novel approach to target potassium channels that are selectively present in human atria rather than ventricles, and using a rate-dependent blocking strategy for its additional sodium channel block. This paper reviews the mechanism of action of this drug, its performance in preclinical models of efficacy and human disease, and its actions on patients in the completed and published preregistration clinical trials for vernakalant. Overall, vernakalant converted 51.5% of patients who had < 7 days duration of atrial fibrillation and it did this without significantly more cardiovascular adverse events than placebo. Therefore, it must be considered as an important new agent for the treatment of this growing health problem.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drugs, Investigational; Heart Atria; Humans; Pyrrolidines

Postoperative atrial fibrillation (POAF) is one of the most frequent complications after cardiothoracic surgery and a predictor for postoperative mortality and prolonged ICU-stay. Current guidelines suggest the multi-channel inhibitor Vernakalant as a treatment option for rhythm control. However, rare cases of severe hypotension and cardiogenic shock following drug administration have been reported. To elucidate the impact of Vernakalant on hemodynamics, we included ten ICU patients developing POAF after elective cardiac surgery, all of them awake and breathing spontaneously, in this prospective trial. Patients received the recommended dosage of Vernakalant and were clinically observed and monitored (heart rate, invasive blood pressure, pulse oximetry, central venous pressure) in 1-minute-intervals for 20 minutes before- and 120 minutes after the first dose of Vernakalant. The median time from the end of surgery until occurrence of POAF amounted up to 52.8 [45.9-77.4] hours, it took 3.5 [1.2-10.1] hours from occurrence of POAF until the first application of Vernakalant. All patients received catecholamine support with epinephrine that was held steady and not dynamic throughout the observational phase. We noted stable hemodynamic conditions, with a trend towards a reduction in heart rate throughout the 120 minutes after drug administration. In 7 patients (70%), conversion to sustained sinus rhythm (SR) occurred within 8.0 minutes [6.0-9.0]. No serious adverse events (SAEs) were noted during the observation period. In this prospective trial in ICU-patients showing POAF after cardiac surgery, intravenous Vernakalant did not induce clinically relevant negative effects on patients' hemodynamics but resulted in conversion to sustained SR after a median of 8.0 minutes in 7 out of ten patients.

Topics: Aged; Anisoles; Atrial Fibrillation; Cardiac Surgical Procedures; Elective Surgical Procedures; Female; Hemodynamics; Humans; Intensive Care Units; Male; Middle Aged; Postoperative Complications; Pyrrolidines

Atrial fibrillation (AF) is a common clinically significant cardiac arrhythmia. This phase 3 randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to sinus rhythm in patients with recent-onset (>3 hours to ≤7 days) symptomatic AF from the Asia-Pacific region. Patients received an infusion of vernakalant (3 mg/kg) or placebo for 10 minutes. If AF had not been terminated 15 minutes later, a second infusion of vernakalant (2 mg/kg) or placebo for 15 minutes was administered. The primary efficacy end point was conversion of AF to sinus rhythm for >1 minute within 90 minutes. The study was terminated early for administrative reasons; 123 patients from Korea, Taiwan, and India were randomized to receive vernakalant (n = 55) or placebo (n = 56). A greater proportion of patients who received vernakalant (52.7%) than placebo (12.5%) met the primary end point (P < 0.001), and cardioversion was faster in the vernakalant group than in the placebo group (P < 0.001). Vernakalant was generally well tolerated; the incidence of treatment-emergent adverse events was similar between the groups. We conclude that vernakalant is efficacious in the rapid cardioversion of recent-onset AF in patients from the Asia-Pacific region.

Topics: Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Asia; Atrial Fibrillation; Double-Blind Method; Electric Countershock; Female; Humans; India; Male; Middle Aged; Pyrrolidines; Republic of Korea; Taiwan; Treatment Outcome

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.

Topics: Adult; Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Pyrrolidines; Sulfonamides; Time Factors; Treatment Outcome

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 .

Topics: Action Potentials; Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Administration Schedule; Electrocardiography; Female; Heart Conduction System; Heart Rate; Humans; Infusions, Intravenous; Israel; Male; Middle Aged; North America; Pyrrolidines; South Africa; South America; Time Factors; Treatment Outcome

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.. 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.. 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).. 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.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Length of Stay; Male; Middle Aged; Propafenone; Prospective Studies; Pyrrolidines

Vernakalant is a novel, relatively atrial-selective antiarrhythmic drug. This analysis assessed the efficacy and safety of intravenous vernakalant for the rapid conversion of atrial fibrillation (AF) to sinus rhythm in patients with a history of ischemic heart disease (IHD).. The presence of IHD was extracted from the medical history of patients from four randomized placebo-controlled studies and one open label study. The efficacy analysis included patients with recent onset AF (consistent with the European labeled indication), while the safety analysis included all patients with AF or atrial flutter (AFL) (3h to 45 days duration) who were exposed to study drug.. A total of 1052 adult patients were enrolled and treated; 274 patients (91 placebo, 183 vernakalant) with a history of IHD and 778 patients (224 placebo, 554 vernakalant) without IHD. Conversion of AF to sinus rhythm was not influenced by IHD. In patients with recent onset AF, the placebo-subtracted conversion rate with vernakalant was 45.7% in the IHD group and 47.3% in the non-IHD group. In the 24h following treatment, the rate of treatment-emergent serious adverse events and discontinuations due to adverse events was similar in both the IHD and non-IHD groups, and there was no case of torsades de pointes, ventricular fibrillation, or death in patients with IHD.. Vernakalant was safe and well tolerated in AF/AFL patients with a history of IHD, and was significantly more effective than placebo for the acute conversion of AF regardless of IHD status.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Ischemia; Pyrrolidines; Treatment Outcome

This randomized double-blind study compared the efficacy and safety of intravenous vernakalant and amiodarone for the acute conversion of recent-onset atrial fibrillation (AF).. Intravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo-controlled studies.. A total of 254 adult patients with AF (3 to 48 h duration) eligible for cardioversion were enrolled in the study. Patients received either a 10-min infusion of vernakalant (3 mg/kg) followed by a 15-min observation period and a second 10-min infusion (2 mg/kg) if still in AF, plus a sham amiodarone infusion, or a 60-min infusion of amiodarone (5 mg/kg) followed by a maintenance infusion (50 mg) over an additional 60 min, plus a sham vernakalant infusion.. Conversion from AF to sinus rhythm within the first 90 min (primary end point) was achieved in 60 of 116 (51.7%) vernakalant patients compared with 6 of 116 (5.2%) amiodarone patients (p < 0.0001). Vernakalant resulted in rapid conversion (median time of 11 min in responders) and was associated with a higher rate of symptom relief compared with amiodarone (53.4% of vernakalant patients reported no AF symptoms at 90 min compared with 32.8% of amiodarone patients; p = 0.0012). Serious adverse events or events leading to discontinuation of study drug were uncommon. There were no cases of torsades de pointes, ventricular fibrillation, or polymorphic or sustained ventricular tachycardia.. Vernakalant demonstrated efficacy superior to amiodarone for acute conversion of recent-onset AF. Both vernakalant and amiodarone were safe and well tolerated in this study. (A Phase III Superiority Study of Vernakalant vs Amiodarone in Subjects With Recent Onset Atrial Fibrillation [AVRO]; NCT00668759).

Topics: Acute Disease; Aged; Amiodarone; Anisoles; Atrial Fibrillation; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pyrrolidines; Treatment Outcome

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, a relatively atrial-selective antiarrhythmic drug, has previously demonstrated efficacy for the acute conversion of atrial fibrillation (AF) to sinus rhythm. This study was designed to determine the most appropriate oral dose of vernakalant for the prevention of AF recurrence postcardioversion.. Patients with nonpermanent AF were randomized to 150, 300, or 500 mg vernakalant or placebo twice daily for up to 90 days. The efficacy analysis was conducted on 605 of 735 patients who entered the maintenance phase on day 3 after cardioversion. The time to the first recurrence of symptomatic sustained AF was significantly longer in the 500 mg vernakalant group, with a median of >90 days versus 29 days in the placebo group (hazard ratio, 0.735; P=0.0275). No significant effect was seen at the lower doses. The percent of patients in sinus rhythm at day 90 was 41%, 39%, and 49% in the 150-mg (n=147), 300-mg (n=148), and 500-mg (n=150) vernakalant groups, respectively, compared with 36% in the placebo group (n=160). There were no vernakalant-related proarrhythmic events. Related serious adverse events occurred in 2 patients in the 150-mg vernakalant group and in 1 patient in each of the other groups.. Vernakalant, 500 mg twice daily, appears to be effective and safe for the prevention of AF recurrence after cardioversion. The absence of proarrhythmia and favorable safety profile is an important finding for the drug.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526136.

Topics: Administration, Oral; Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dose-Response Relationship, Drug; Double-Blind Method; Electric Countershock; Female; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidines; Recurrence; Sinoatrial Node; Treatment Outcome

The efficacy and safety of vernakalant, a relatively atrial-selective antiarrhythmic agent, in converting atrial fibrillation (AF) to sinus rhythm (SR) were evaluated in this multicenter, open-label study of patients with AF lasting >3 hours and < or =45 days (RCT no. NCT00281554).. Adult patients with AF and an indication for conversion to SR received a 10-minute intravenous infusion of vernakalant (3 mg/kg). If after a 15-minute observation period AF was present, a second 10-minute infusion of intravenous vernakalant (2 mg/kg) was given. The primary efficacy end point was the proportion of patients with recent-onset AF (AF lasting >3 hours to < or =7 days) who converted to SR within 90 minutes of the start of the first infusion. Safety evaluations included vital signs, telemetry and Holter monitoring, 12-lead electrocardiography, clinical laboratory tests, physical examinations, and adverse events (AEs).. A total of 236 hemodynamically stable patients with AF received intravenous vernakalant. Among them, 167 (71%) had recent-onset AF and were eligible for the primary efficacy end point. Vernakalant rapidly converted recent-onset AF to SR in 50.9% of patients, with a median time to conversion of 14 minutes among responders. The most common AEs were dysgeusia, sneezing, and paresthesia. These occurred at the time of vernakalant infusion, were transient, and resolved spontaneously. Ten patients (4.2%) discontinued vernakalant treatment because of AEs, most commonly (in 4 of 10) hypotension. There were no episodes of torsades de pointes, ventricular fibrillation, or sustained ventricular tachycardia.. Vernakalant rapidly converted recent-onset AF to SR, was well tolerated, and may be a valuable therapeutic alternative for reestablishing SR in patients with recent-onset AF.

Topics: Aged; Anisoles; Atrial Fibrillation; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines; Sinoatrial Node; Treatment Outcome

The objective of the present study was to assess the safety and effectiveness of vernakalant hydrochloride injection (RSD1235), a novel antiarrhythmic drug, for the conversion of atrial fibrillation (AF) or atrial flutter to sinus rhythm (SR). Patients with either AF or atrial flutter were randomized in a 1:1 ratio to receive vernakalant (n = 138) or placebo (n = 138) and were stratified by an arrhythmia duration of >3 hours to ≤7 days (short duration) and 8 to ≤45 days (long duration). The first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if the arrhythmia had not terminated. A total of 265 patients were randomized and received treatment. The primary end point was conversion of AF to SR for ≥1 minute within 90 minutes of the start of the drug infusion in the short-duration AF group. Of the 86 patients receiving vernakalant in the short-duration AF group, 44 (51.2%) demonstrated conversion to SR compared to 3 (3.6%) of the 84 in the placebo group (p <0.0001). The median interval to conversion of short-duration AF to SR in the responders given vernakalant was 8 minutes. Of the entire AF population (short- and long-duration AF), 47 (39.8%) of the 118 vernakalant patients experienced conversion of AF to SR compared to 4 (3.3%) of the 121 placebo patients (p <0.0001). Transient dysgeusia and sneezing were the most common adverse events in the vernakalant patients. One vernakalant patient who had severe aortic stenosis experienced hypotension and ventricular fibrillation and died. In conclusion, vernakalant demonstrated a rapid and high rate of conversion for short-duration AF and was well tolerated.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Chi-Square Distribution; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Placebos; Prospective Studies; Pyrrolidines; Treatment Outcome

Vernakalant is a relatively atrial-selective antiarrhythmic agent that has been shown to successfully convert atrial fibrillation (AF) to normal sinus rhythm for some patients whose onset of dysrhythmia occurred less than 7 days previously. This study sought to evaluate the efficacy and safety of vernakalant for patients with recent-onset AF.. This was a post hoc analysis of patients with recent-onset AF (> 3 to ≤ 48 hours) enrolled in the double-blind, placebo-controlled Atrial arrhythmia Conversion Trial (ACT) I and the open-label ACT IV trials. The studies enrolled adults presenting with AF to 78 emergency departments (ED) and cardiac clinics in six countries. Patients received a 10-minute intravenous infusion of vernakalant or placebo, followed by an additional infusion if necessary. Efficacy assessments included conversion to sinus rhythm within 90 minutes and median time to conversion. Safety evaluations included telemetry, Holter monitoring, and adverse events (AEs).. Of the 290 patients, 229 received vernakalant, 61 received placebo, and the overall mean age was 59 years. The vernakalant and placebo groups were similar. Of all patients given vernakalant, 136 (59.4%) converted to sinus rhythm within 90 minutes, compared with three (4.9%) placebo patients. The median time to conversion with vernakalant was 12 minutes (interquartile range = 7-24.5 minutes). Clinically significant bradycardia and hypotension were uncommon, and no cases of torsade de pointes or ventricular fibrillation occurred.. Vernakalant rapidly converted recent-onset AF to sinus rhythm in over half of patients, was well tolerated, and has the potential to offer an important therapeutic option for rhythm control of recent-onset AF in the ED.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Double-Blind Method; Emergency Service, Hospital; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Placebos; Pyrrolidines; Treatment Outcome

Vernakalant hydrochloride injection (RSD1235) is a relatively atrial-selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration-time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4-O-demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 "extensive metabolizer" or "poor metabolizer" phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10-minute intravenous infusion followed by a second 2 mg/kg 10-minute infusion if atrial fibrillation persisted after a 15-minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration-time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6-inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Cytochrome P-450 CYP2D6; Double-Blind Method; Drug Interactions; Female; Heart Atria; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines; Sex Factors; Single-Blind Method; Young Adult

Postoperative atrial arrhythmias are common and are associated with considerable morbidity. This study was designed to evaluate the efficacy and safety of vernakalant for the conversion of atrial fibrillation (AF) or atrial flutter (AFL) after cardiac surgery.. This was a prospective, randomized, double-blind, placebo-controlled trial of vernakalant for the conversion of AF or AFL after coronary artery bypass graft, valvular surgery, or both. Patients were randomly assigned 2:1 to receive a 10-minute infusion of 3 mg/kg vernakalant or placebo. If AF or AFL was present after a 15-minute observation period, then a second 10-minute infusion of 2 mg/kg vernakalant or placebo was given. The primary end point was the conversion of postcardiac surgery AF or AFL to sinus rhythm within 90 minutes of dosing. In patients with AF, 47 of 100 (47%) who received vernakalant converted to SR compared with 7 of 50 (14%) patients who received placebo (P<0.001). The median time to conversion was 12 minutes. Vernakalant was not effective in converting postoperative AFL to sinus rhythm. Two serious adverse events occurred within 24 hours of vernakalant administration (hypotension and complete atrioventricular block). There were no cases of torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation. There were no deaths.. Vernakalant was safe and effective in the rapid conversion of AF to sinus rhythm in patients who had AF after cardiac surgery.. clinicaltrials.gov. Identifier: NCT00125320.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Argentina; Atrial Fibrillation; Atrial Flutter; Coronary Artery Bypass; Double-Blind Method; Electrocardiography; Europe; Female; Heart Valve Prosthesis Implantation; Humans; India; Infusions, Intravenous; Male; Middle Aged; North America; Prospective Studies; Pyrrolidines; Time Factors; Treatment Outcome

The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF).. Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90 minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and received treatment (short duration, n=220; long duration, n=116). Of the 145 vernakalant patients, 75 (51.7%) in the short-duration AF group converted to sinus rhythm (median time, 11 minutes) compared with 3 of the 75 placebo patients (4.0%; P<0.001). Overall, in the short- and long-duration AF groups, 83 of the 221 vernakalant patients (37.6%) experienced termination of AF compared with 3 of the 115 placebo patients (2.6%; P<0.001). Transient dysgeusia and sneezing were the most common side effects in vernakalant-treated patients. Four vernakalant-related serious adverse events (hypotension [2 events], complete atrioventricular block, and cardiogenic shock) occurred in 3 patients.. Vernakalant demonstrated rapid conversion of short-duration AF and was well tolerated.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Canada; Double-Blind Method; Dysgeusia; Female; Humans; Male; Middle Aged; Placebos; Pyrrolidines; Scandinavian and Nordic Countries; Sneezing; Time Factors; Treatment Outcome; United States

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.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Dogs; Isoflurane; Rats; Torsades de Pointes

Atrial fibrillation (AF) is the most common tachyarrhythmia encountered in clinical practice and is associated with substantial morbidity and mortality. This study aimed to determine the efficacy and safety of vernakalant for cardioversion of recent-onset AF.. A comprehensive systematic literature search will be conducted in Cochrane Library, PubMed, Web of Science, EMBASE, for randomized controlled trials (RCTs) about the vernakalant with AF. Two reviewers will independently assess the quality of the selected studies according to the Cochrane Collaboration's tool for RCTs. The bias risk of the RCT will be assessed by the Cochrane risk of bias (ROB) tool. The quality of the evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE) system. Results from these questions will be graphed and assessed using Review Manager 5.3.. The results of this meta-analysis will be published in a peer-reviewed journal.. This review will evaluate the safety and efficacy of vernakalant for patients with AF, provide more recommendations for patients or researchers, and high-level evidence for clinical decision-making.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Humans; Meta-Analysis as Topic; Pyrrolidines; Review Literature as Topic; Systematic Reviews as Topic; Treatment Outcome

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).. 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.. 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.. 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.

Topics: Adult; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Emergency Service, Hospital; Humans; Treatment Outcome

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.. 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).. 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines; Time Factors; Young Adult

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.. 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.. 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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Heart Atria; Humans; Pyrrolidines

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.. 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.. 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. 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.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Resynchronization Therapy; Dose-Response Relationship, Drug; Female; Flecainide; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrrolidines; Retrospective Studies; Time Factors; Treatment Outcome

Postoperative, new-onset atrial fibrillation (POAF) is one of the most common complications after cardiosurgical procedures. Vernakalant has been reported to be effective in the conversion of POAF. The aim of this study was to evaluate the efficacy and safety of vernakalant for atrial fibrillation after cardiac operations, and to investigate predictors for the success of vernakalant treatment. Patients and Methods: Post-cardiac surgery patients with new-onset of atrial fibrillation (AF) were consecutively enrolled in this study. Demographic data as well as intraoperative and postoperative parameters were analyzed. Vernakalant administration was primarily started 5.5 hours after new-onset POAF: 3 mg/kg intravenously over 10 min, and in case of non-conversion, a second dose of 2 mg/kg intravenously over 10 min. Results: 129 consecutive patients (70.2 ± 9.1 years) were included: 61 patients with coronary artery bypass graft (CABG) surgery, 49 patients with isolated valve procedures, and 19 patients with combined procedures (CABG and valve). Conversion in sinus rhythm was achieved after the first vernakalant dose in 57 patients (44%), and after the second dose in 41 patients (32%). The mean time to conversion was 13.7 ± 14.1 min. The patients receiving valve procedures depicted a significantly lower conversion rate. The following variables lowered conversion rate: no preoperative beta blocker, postoperative troponin levels >500 ng/L, and systolic blood pressure >140 mmHg. At the first follow-up, 92% of the converted patients showed sinus rhythm, while 80% of the non-responders showed sinus rhythm (P < .01). Conclusions: The POAF was effectively converted by vernakalant. The conversion rate of POAF after valve surgery was lower when compared to isolated CABG.

Topics: Aged; Anisoles; Atrial Fibrillation; Cardiac Surgical Procedures; Delayed-Action Preparations; Dose-Response Relationship, Drug; Electrocardiography; Female; Follow-Up Studies; Humans; Injections, Intravenous; Male; Myocardial Ischemia; Pyrrolidines; Retrospective Studies; Treatment Outcome

Current guidelines recommend vernakalant for pharmacologic cardioversion of recent-onset atrial fibrillation. However, this drug is not established as chronic therapy.. In total, 15 rabbit hearts were Langendorff-perfused. A burst pacing protocol-induced atrial fibrillation in 7 of 15 hearts at baseline (10 episodes). Subsequently, a combination of acetylcholine and isoproterenol (ACH/ISO) has been administered to increase occurrence of atrial fibrillation resulting in a reduction of atrial action potential duration (-25 ms, P < 0.05) as well as atrial effective refractory period (aERP; -36 ms, P < 0.05). Then, atrial fibrillation occurred in all 15 hearts (124 episodes). Additional treatment with vernakalant (10 μmol/l) induced a significant reduction of atrial fibrillation (6 of 15 hearts, 63 episodes). Infusion of vernakalant did not significantly alter atrial action potential duration (+8 ms) but increased aERP (+16 ms, P < 0.05 as compared with ACH/ISO).Results were compared to 12 further rabbit hearts treated with ranolazine. Late sodium current inhibition by ranolazine also induced a significant increase of aERP. Here, atrial fibrillation was inducible after ranolazine infusion in 6 of 12 hearts (46 episodes). Of note, 10 of 12 hearts presented atrial fibrillation during sole treatment with ACH/ISO (174 episodes).. Vernakalant and ranolazine demonstrated a comparable antiarrhythmic efficacy. Therefore, vernakalant treatment may represent a potential therapeutic option to reduce atrial fibrillation recurrence.

Topics: Animals; Anisoles; Atrial Fibrillation; Cardiovascular Agents; Drug Evaluation, Preclinical; In Vitro Techniques; Pyrrolidines; Rabbits; Ranolazine

Evidence has emerged that small-conductance Ca. 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.. 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.

Topics: Acetamides; Animals; Anisoles; Atrial Fibrillation; Cardiac Pacing, Artificial; Disease Models, Animal; Disease Progression; Patch-Clamp Techniques; Pyrrolidines; Refractory Period, Electrophysiological; Small-Conductance Calcium-Activated Potassium Channels; Swine

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Potassium Channels, Calcium-Activated; Pyrrolidines; Swine

Vernakalant hydrochloride is a rapid-acting antiarrhythmic drug licensed in the EU since 2010 for the conversion of recent-onset atrial fibrillation with proven efficacy and safety when compared with placebo and amiodarone in randomized clinical trials.. The aim of our study was to determine the feasibility of same day discharge (following 2 h monitoring) from the emergency department after successful cardioversion using vernakalant hydrochloride.. Patients with recent-onset atrial fibrillation treated in the emergency department of a large Dublin academic teaching hospital. Patients received a maximum of two weight based 10 min infusions of vernakalant. Hypotensive events (>30% initial blood pressure), arrhythmias, conversion rates, and time to conversion were recorded.. Sinus rhythm was restored in 35 out of 42 patients (83%) in an average of 8.8 min (median 8 min), average CHA2DS2-VASc of 0.92, HAS-BLED of 0.21 and average symptoms duration of 12 h. There were no hypotensive or arrhythmogenic events. 41 out of 42 patients were discharged after 2 h of monitoring.. Vernakalant hydrochloride has provided a quick, safe, and practical means of achieving rapid restoration of sinus rhythm in our ED population with stable recent-onset AF who would otherwise not have undergone routine electrically cardioversion and same day discharge.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Electric Countershock; Emergency Service, Hospital; Humans; Male; Middle Aged; Patient Discharge; Pyrrolidines; Treatment Outcome

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.. 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).. Vernakalant may therefore be considered as a useful agent for facilitated electrical cardioversion in cardioversion-resistant AF.

Topics: Aged; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Combined Modality Therapy; Drug Therapy, Combination; Electric Countershock; Electrocardiography; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Premedication; Pyrrolidines; Treatment Failure; Treatment Outcome

Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.. The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.. 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.. 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.. 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.

Topics: Action Potentials; Animals; Anisoles; Atrial Fibrillation; Atrial Remodeling; Disease Models, Animal; Goats; Heart Atria; Pyrrolidines; Refractory Period, Electrophysiological

Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2-4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant.

Topics: Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Remodeling; Bepridil; Cardiac Pacing, Artificial; Disease Models, Animal; Infusions, Intravenous; Male; Pyrrolidines; Rabbits; Sotalol

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Pyrrolidines; Treatment Outcome; Young Adult

Topics: Aged; Anisoles; Atrial Fibrillation; Catheter Ablation; Electrocardiography; Female; Humans; Intraoperative Period; Male; Pyrrolidines

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

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 rising incidence of atrial fibrillation (AF) has stimulated researches to identify novel therapeutic options for such most common and refractory cardiac arrhythmia in clinical practice. Rhythm control strategy is shown to be associated with a lower risk of progression to permanent AF and greater clinical benefit as compared with rate control. Remarkable progress has been witnessed in rhythm control strategy particularly along with the development of mapping and ablation technology, while still should pharmacological cardioversion serve as an integrated approach for the management of AF especially in the emergency department or centers not equipped with ablation professionals. Concerns regarding the safety and efficacy of existing conventional antiarrhythmic drugs (AADs) limit their clinical use. Vernakalant, with its relatively atrial selective antiarrhythmic profile, is developed as a novel AAD for pharmacological cardioversion of AF. Its mechanisms involve potassium and sodium channels blocking effects during atrial action potential. A series of clinical trials have demonstrated the rapid, efficacious and safe effect of vernakalant over placebo or conventional AADs in terminating recent-onset AF among patients with structurally normal or minimal heart disease; but current evidence does not show a superior role of vernakalant in treating long-duration AF or atrial flutter. More evidence with respect to comparisons of vernakalant with conventional AADs as well as their synergic effects is needed. Cost-effectiveness analyses of vernakalant applied in prospective and "real world" practice remain to be assessed.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines

Vernakalant is a new, safe and effective drug used intravenously, which has proved to be more rapid in converting recent onset atrial fibrillation (AF) to sinus rhythm compared to placebo, amiodarone, propafenone, and flecainide in clinical studies. Until now no study has been conducted comparing the perception of state of health in patients who received vernakalant versus propafenone or flecainide for conversion of recent-onset AF. The aim of our study is to compare the change of perception of state of health from screening to hour 2 in patients treated with vernakalant and propafenone or flecainide for conversion of recent-onset AF.. Eighty 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 30 patients, 30 patients received intravenous vernakalant and the remaining 20 patients received a single oral dose of flecainide 300 mg. Clinical, laboratory variables and perception of state of health from screening to hour 2 treated with these drugs measured by the EQ-5 D quality-of-life assessments visual analog scale were recorded.. Baseline characteristics were similar in the three groups. Treatment with vernakalant resulted in a significantly greater improvement in patient perception of state of health at hour 2 compared with propafenone and flecainide. In the vernakalant group, a mean increase (from baseline) of 12.1 points was seen compared with a mean increase of 5.4 points in the propafenone group or 5.2 points in flecainide group (p < 0.01).. The change of perception of state of health from screening to hour 2 treated with vernakalant had a significantly statistical improvement compared with propafenone or flecainide for conversion recent-onset AF.

Topics: Administration, Oral; Aged; Anisoles; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Flecainide; Health Status; Humans; Injections, Intravenous; Male; Middle Aged; Perception; Propafenone; Prospective Studies; Pyrrolidines; Quality of Life; Treatment Outcome; Voltage-Gated Sodium Channel Blockers

Topics: Adult; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Humans; Pyrrolidines; Treatment Outcome

Management of atrial fibrillation (AF) is hampered by frequent recurrences after restoration of sinus rhythm. Delayed interatrial conduction has been associated with the development of AF in different clinical settings. The aim of our study was to assess whether advanced interatrial block (aIAB) was associated with AF recurrence after pharmacological cardioversion with two different antiarrhythmic drugs.. We included 61 patients with recent onset AF without structural heart disease that underwent successful pharmacological cardioversion. Thirty-one patients received a single oral dose of propafenone, and 30 patients received iv vernakalant. A 12-lead ECG (filter 150 Hz, 25 mm/s, 10 mm/mV) after conversion was evaluated for the presence of interatrial block (IAB); partial (pIAB): P-wave duration > 120 ms, and advanced (aIAB): P-wave > 120 ms and biphasic morphology (±) in inferior leads. Clinical follow-up and electrocardiographic recordings were performed for a 12-month period.. Age was 58 ± 10.4 years and 50.8% were male. aIAB was present in 11 patients (18%) and pIAB in 10 (16.4%). At 1-year follow-up, 22 patients (36%) had AF recurrence. The recurrence rate with aIAB was 90.9% versus 70% in those with pIAB and 12.5% in normal P-wave duration (P = 0.001). The presence of aIAB was strongly associated with AF recurrence (odds ratio 18.4 in multivariable modeling). Recurrence was not affected by the drug used for cardioversion (P = 0.92).. Advanced interatrial block is associated with higher risk of AF recurrence at 1 year after pharmacological cardioversion, independent of the drug used.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Disease-Free Survival; Electrocardiography; Female; Heart Block; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Propafenone; Pyrrolidines; Recurrence; Risk Factors; Time Factors; Treatment Outcome

Advances in the therapy of atrial fibrillation (AF) have not come easily or quickly, despite the recognized need for significantly better antiarrhythmic agents for AF termination and prevention as well as for more user-friendly anticoagulants for the prevention of emboli in patients with AF. Rather, the road has been only slowly progressive and bumpy. This manuscript will introduce the recent issues with dronedarone, the complex development story for vernakalant, and the appearance of the new oral anticoagulants. Each of these three considerations will then be explored in more depth by the invited experts for this "mini-Thematic issue" in Current Cardiology Reviews.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Dronedarone; Drug Design; Humans; Pyrrolidines

The authors of this Mini-Hot-Topic collection of review manuscripts have provided an outstanding review of the development and current status of several of our most recently developed agents in the fight against atrial fibrillation (AF). They have also given the readers a glimpse into the difficulty of drug development and the contrasts that can exist with the same product in different geographies. For their efforts they have my deepest appreciation. It is my hope that these articles will assist those of you who are clinicians in your care of patients and those of you who are investigators in your appreciation of the drug development process and its hurdles. More specifically, this Mini-Hot-Topic symposium has reviewed for you: (1) the evidence supporting the new novel oral anticoagulants (NOACs) as first-line therapy for prevention of stroke and systemic embolism in patients with "nonvalvular" atrial fibrillation (NVAF); (2) the winding path taken by dronedarone in reaching its current place in our antiarrhythmic armamentarium - in which it still has a role; and (3) the contrasting decisions made with respect to the marketing of vernakalant in Europe versus the United States. Now, in this last manuscript of the collection, I will echo for emphasis some of their highlights and I will also bring you further up to date with respect to a possible future role for dronedarone, as hinted at by the HARMONY trial.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Dronedarone; Embolism; Humans; Pyrrolidines; Stroke

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

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.

Topics: Action Potentials; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; CHO Cells; Cricetinae; Cricetulus; Flecainide; Humans; Membrane Potentials; Oocytes; Patch-Clamp Techniques; Potassium Channels, Tandem Pore Domain; Pyrrolidines; Xenopus laevis

Topics: Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmia, Sinus; Atrial Fibrillation; Female; Heart Atria; Humans; Male; Pyrrolidines; Sodium Channel Blockers

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Electrocardiography; Europe; Flecainide; Humans; Practice Guidelines as Topic; Propafenone; Pyrrolidines

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.. 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.. 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).. 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.

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Female; Flecainide; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidines; Time Factors

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Decision Making; Heart Rate; Humans; Infusions, Intravenous; Pyrrolidines; Ventricular Dysfunction, Left

Topics: Administration, Oral; Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Flecainide; Humans; Injections, Intravenous; Propafenone; Pyrrolidines; Time Factors

Topics: Aged; Anisoles; Atrial Fibrillation; Electric Countershock; Female; Humans; Male; Pyrrolidines; Time Factors

Vernakalant has proved to be more rapid in converting recent onset AF to sinus rhythm compared to placebo, amiodarone, propafenone and flecainide. In many centers around the world the electrical cardioversion is the first line of treatment of acute atrial fibrillation. Recently a group published that vernakalant had a 90% conversion rate in patients with recent onset atrial fibrillation without structural heart disease versus 100% conversion rate in the electrical cardioversion group. In this study there was no statistical differences between both groups (p=NS). Vernakalant has been approved in Europe and South America, but it has not been approved in the United States and Canada. FDA wants a megatrial to show the real benefits of vernakalant compared to other drugs including electrical cardioversion. The trial ACT V has been canceled because one patient who received vernakalant died and this is the reason why FDA has not approved vernakalant yet. We do not know the real condition of the patient and if it was corrected to conclude that the severe adverse event had a direct relationship with the drug. I can conclude that it is time to design a megatrial to show if vernakalant is better or not for conversion of recent onset atrial fibrillation compared with other antiarrhythmic drugs and electrical cardioversion because all the topics about this drug have been published but in brief reports. We need a big trial to know the real safety of this drug.

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiac Resynchronization Therapy; Humans; Pyrrolidines; Treatment Outcome

Vernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown.. Action potentials (APs) and ion currents were recorded in right atrial trabeculae and cardiomyocytes from patients in sinus rhythm (SR) and chronic AF. Vernakalant prolonged early repolarization in SR and AF, but late only in AF. AP amplitude (APA) and dV/dtmax were reduced in a concentration- and frequency-dependent manner with IC50 < 10 µM at >3 Hz. Effective refractory period was increased more than action potential duration (APD) in SR and AF. INa was blocked with IC50s of 95 and 84 µM for SR and AF, respectively (0.5 Hz). Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current-time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 µM for SR and AF, respectively. Vernakalant had less effect on APD than the IKr blocker E-4031, blocked IK,ACh, and had a small inhibitory effect on IK1 at 30 µM. L-Type Ca(2+) currents (SR) were reduced with IC50 of 84 µM.. Rate-dependent block of Na(+) channels represents the main antiarrhythmic mechanism of vernakalant in the fibrillating atrium. Open channel block of early transient outward currents and IK,ACh could also contribute.

Topics: Action Potentials; Aged; Anisoles; Anti-Arrhythmia Agents; Arrhythmia, Sinus; Atrial Fibrillation; Calcium Channels; Chronic Disease; Female; Heart Atria; Humans; Male; Middle Aged; Myocytes, Cardiac; Potassium Channels; Pyrrolidines; Sodium Channels

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Topics: Adult; Age Factors; Aged; Anisoles; Anti-Arrhythmia Agents; Area Under Curve; Atrial Fibrillation; Atrial Flutter; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Creatinine; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Female; Genotype; Humans; Injections, Intravenous; Male; Middle Aged; Models, Biological; Pyrrolidines; Randomized Controlled Trials as Topic; Time Factors; Young Adult

Vernakalant (VER) is a relatively atrial-selective antiarrhythmic drug capable of blocking potassium and sodium currents in a frequency- and voltage-dependent manner. Ranolazine (RAN) is a sodium-channel blocker shown to exert antiarrhythmic effects in pulmonary vein (PV) sleeves. dl-Sotalol (SOT) is a β-blocker commonly used in the rhythm-control treatment of atrial fibrillation. This study evaluated the electrophysiological and antiarrhythmic effects of VER, RAN, and SOT in canine PV sleeve preparations in a blinded fashion.. Transmembrane action potentials were recorded from canine superfused PV sleeve preparations exposed to VER (n = 6), RAN (n = 6), and SOT (n = 6). Delayed afterdepolarizations were induced in the presence of isoproterenol and high-calcium concentrations by periods of rapid pacing.. In PV sleeves, VER, RAN, and SOT (3-30 μM) produced small (10-15 ms) increases in action potential duration. The effective refractory period, diastolic threshold of excitation, and the shortest S(1)-S(1) cycle length permitting 1:1 activation were significantly increased by VER and RAN in a rate- and concentration-dependent manner. VER and RAN significantly reduced V(max) in a concentration- and rate-dependent manner. SOT did not significantly affect the effective refractory period, V(max), diastolic threshold of excitation, or the shortest S(1)-S(1) cycle length permitting 1:1 activation. All 3 agents (3-30 μM) suppressed delayed afterdepolarization-mediated triggered activity induced by isoproterenol and high calcium.. In canine PV sleeves, the effects of VER and RAN were similar and largely characterized by concentration- and rate-dependent depression of sodium-channel-mediated parameters, which were largely unaffected by SOT. All 3 agents demonstrated an ability to effectively suppress delayed afterdepolarization-induced triggers of atrial arrhythmia.

Topics: Acetanilides; Action Potentials; Adrenergic beta-Agonists; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Biological Availability; Cardiac Electrophysiology; Cell Membrane; Dogs; Heart Rate; Humans; Isoproterenol; Membrane Potentials; Piperazines; Pulmonary Veins; Pyrrolidines; Ranolazine; Sodium Channels; Sotalol

Topics: Acetanilides; Animals; Anisoles; Atrial Fibrillation; Humans; Piperazines; Pulmonary Veins; Pyrrolidines; Ranolazine; Sodium Channels; Sotalol

Emergency medicine physicians aim to stabilize or restore vital functions, establish diagnosis, initiate specific treatments and adequately orientate patients. This year, new evidences have improved our knowledge about diagnostic strategy for patients with acute non traumatic headache, treatment of acute atrial fibrillation and outpatient management of acute pulmonary embolism. Reducing injection pain of local anesthetics, reducing irradiation by using alternative diagnostic tools in appendicitis suspicion, and identification of trauma patients who benefit from tranexamic acid administration are other illustrations of the efforts to improve efficacy, safety and comfort in the management of emergency patients.

Topics: Acute Disease; Ambulatory Care; Anisoles; Antifibrinolytic Agents; Appendicitis; Atrial Fibrillation; Craniocerebral Trauma; Electrocardiography, Ambulatory; Emergencies; Emergency Medicine; Emergency Service, Hospital; Evidence-Based Medicine; Headache; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrrolidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Syncope; Tomography, X-Ray Computed; Tranexamic Acid; Ultrasonography; Wounds and Injuries

Topics: Aged; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Electric Countershock; Electrocardiography; Heart Conduction System; Humans; Male; Pyrrolidines; Sodium Channel Blockers

Topics: Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Color Vision Defects; Humans; Pyrrolidines

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and a difficult-to-treat arrhythmia. Conventional antiarrhythmic drugs, including flecainide, propafenone, sotalol and amiodarone, have several limitations in terms of efficacy and tolerability, and have made new drug development crucial. In the last decade, intensive research was undertaken to find new pharmacological options for the treatment of AF, and two new drugs are now available. Vernakalant is an atrial-selective drug specifically designed to block sodium channels at the atrial level, and its intravenous formulation has recently been recommended for approval by the Food and Drug Administration for pharmacological conversion of AF. Dronedarone is a chemical derivative of amiodarone (though having a significantly different clinical profile) with effects on multiple ion channels that proved effective in reducing the rate of the combined endpoint of death from any cause and cardiovascular hospitalization in patients with non-permanent AF enrolled in the ATHENA study. The available evidence on the efficacy of dronedarone has led to approval for recommendation in many clinical situations in which rhythm control is desirable. The complexity of the mechanisms underlying AF and the large variability of associated comorbidities render the AF patient a unique entity, making the identification of patients who may benefit from these novel approaches challenging.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Humans; Pyrrolidines

Topics: Acute Disease; Anisoles; Atrial Fibrillation; Electric Countershock; Evidence-Based Medicine; Humans; Pyrrolidines; Treatment Outcome

Topics: Abdomen; Aged; Anisoles; Atrial Fibrillation; Critical Illness; Female; Heart Rate; Humans; Ileus; Kv1.5 Potassium Channel; Laparotomy; Postoperative Complications; Pyrrolidines

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Pyrrolidines; Randomized Controlled Trials as Topic

Despite being the most common arrhythmia currently treated by cardiologists, safe and effective treatments for atrial fibrillation (AF) remain elusive. To address this issue, Astellas Pharma Inc, Merck & Co Inc and Cardiome Pharma Corp are developing vernakalant (RSD-1235), a drug which dose-dependently inhibits sodium channels and several potassium repolarizing currents. Of particular note, vernakalant inhibits I(Kur) (K(v)1.5), a current that is more predominant in atrial than in ventricular tissue. Consistent with this observation, vernakalant produced increases in atrial refractory period with minimal actions on QTc interval or ventricular refractory period in both humans and animals. Intravenous vernakalant terminated recent-onset AF in several animal models, and also in patients with short-duration AF or AF following cardiac surgery enrolled in phase II and III clinical trials. Vernakalant was well tolerated and adverse reactions were transient and mild. Thus, vernakalant holds considerable promise for the treatment of recent-onset AF; however, given its relatively short half-life, continuous dosing may be required in order to maintain sinus rhythm following conversion from AF. The efficacy and safety of vernakalant for the long-term management of AF remains to be determined. Phase III clinical trials with intravenous vernakalant are ongoing, and phase II clinical trials are also being conducted with an oral formulation intended for chronic use.

Topics: Animals; Anisoles; Atrial Fibrillation; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Humans; Kv1.5 Potassium Channel; Macaca fascicularis; Male; Potassium Channel Blockers; Pyrrolidines; Rabbits; Sodium Channel Blockers

Pharmacotherapy of atrial fibrillation (AF) is demanding, because currently available antiarrhythmic drugs have low efficacy and many side effects. In drug development, the focus has been on amiodarone-like multichannel blockers, atrial-specific ion channel blockers, and novel non-channel agents targeting atrial remodelling. Dronedarone, an amiodarone analogue without iodine, was recently approved for treatment of AF. It is less effective than amiodarone, but serious adverse events are rare. Vernakalant, an atrial-selective drug with low proarrhythmic risk, is effective in cardioversion and it may also prevent AF recurrences. So-called upstream therapy with angiotensin converting enzyme and angiotensin receptor inhibitors, statins and omega-3 fatty acids needs further clinical validation.

Topics: Amiodarone; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Drug Design; Electric Countershock; Humans; Membrane Transport Modulators; Pyrrolidines

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmia, Sinus; Atrial Fibrillation; Disease Models, Animal; Humans; Pyrrolidines; Randomized Controlled Trials as Topic

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Rhythm control strategy for AF is limited by drug toxicity and side effects, and recent trials have shown that this strategy is not superior to a rate control one. New antiarrhythmic drugs, free of undesired effects, would enhance rhythm control, with the possibility of sinus rhythm restoration and maintenance. A promising find in the search for new antiarrhythmic therapies is atrial-tissue specific ion channels. The findings that the ultrarapid delayed rectifier (I(Kur)) and the inwardly rectifying, acetylcholine-regulated current (I(K-Ach)) exist in atrial but not ventricular tissue increase the probability that atrioselective drugs without ventricular proarrhythmic toxicity can be developed for treatment of patients with AF. There are also other potential targets for atrial-selective therapy: transient outward current (I(to)), rapidly and slowly activating delayed rectifier currents (I(Kr) and I(Ks)), atrial sodium current (I(Na)) and atrially expressed connexins. New drugs under development with promising atrial-selectivity include: tertiapin, NIP-142, NIP-141, JTV-519, AVE0118, AVE1231, DPO-1, AZD7009 and many others. Among such new agents, vernakalant hydrochloride is currently in an advanced phase of development and has already been evaluated in clinical trials. In this overview, we describe the history and current state of developmental process of the drug, as well as its mechanism of action and influence on electrophysiological parameters. Vernakalant seems to be effective in terminating recent-onset AF, but is not efficacious in long-lasting AF and atrial flutter. The drug may be relatively free of proarrhythmic effects, and exerts a protective effect on ventricular tissue and ventricular repolarization. It is expected that the intravenous formulation will soon be approved for the pharmacological termination of recent-onset AF.

Topics: Administration, Oral; Animals; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Clinical Trials as Topic; Electrophysiologic Techniques, Cardiac; Humans; Injections, Intravenous; Pyrrolidines

The prevalence of atrial fibrillation (AF) is forecast to rise to 2-5% of the general population by 2050. Of the two fundamental treatment strategies for AF management, rhythm control is the approach which is generally preferred for active, symptomatic, and/or younger patients, whereas rate control is all that is found necessary in the more elderly, sedentary, asymptomatic individual. In many cases, at neither extreme, there remains a genuine choice of therapy, and for those patients, antiarrhythmic strategies would be preferred if effective and safe antiarrhythmic medications were available. Many new antiarrhythmic agents exploiting new mechanisms of action or novel combinations of established antiarrhythmic activity are currently being investigated. Agents which selectively inhibit ion channels specifically involved in atrial repolarization, so-called atrial repolarization delaying agents, are widely acknowledged as potentially ideal antiarrhythmic treatments, as they will probably be both effective and safe, at the very least (free of pro-arrhythmic effects at the ventricular level). Modified analogues of traditional antiarrhythmic drugs with different combinations of ion channel and receptor blocking effects, novel mechanisms of action, and less complicated metabolic profiles are also under development. Completely innovative antiarrhythmic agents with new antiarrhythmic mechanisms, such as stretch receptor antagonism, sodium calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation are also being explored. In addition, there is increasing evidence in support of the antiarrhythmic action of non-antiarrhythmic drugs. Treatments with statins, omega-3 fatty acids, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and aldosterone antagonists are all potentially valuable, over and above any effect related to the treatment of underlying heart disease.

Topics: Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Anisoles; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function; Dronedarone; Humans; Pyrrolidines