Rapid Conversion Of Atrial Fibrillation Research Articles

Implementing vernakalant: a novel approach to cardioversion.

Atrial fibrillation (AF) is the most common arrhythmia, and there is a one in four lifetime risk of developing the condition for people who are over the age of 40. Vernakalant, a new addition to intravenous antiarrhythmic drugs for cardioversion of AF, is the first atrial-specific antiarrhythmic drug for pharmacological cardioversion of recent onset AF and is more effective than placebo and amiodarone. The drug offers patients an alternative to other pharmacological agents for chemical cardioversion and avoids the risks associated with electrical cardioversion. Its main advantage is rapid conversion of AF, which potentially reduces atrial remodelling and it can be used in patients with little or no underlying cardiovascular disease and in those with moderate disease such as stable coronary and hypertensive heart disease. Post-marketing and clinical trials suggest a favourable rate of conversion to sinus rhythm. Jersey General Hospital was the first in the UK to obtain and introduce the drug in practice. This article describes the evidence and guidelines for its use and the local implementation process.

Effective suppression of atrial fibrillation by the antihistaminic agent antazoline: First experimental insights into a novel antiarrhythmic agent.

The antihistaminic antazoline (ANT) was reported to be highly effective and safe for rapid conversion of atrial fibrillation (AF). We therefore analyzed underlying mechanisms in an experimental whole-heart model. Isolated and retrogradely perfused rabbit hearts underwent a standardized protocol employing atrial burst pacing-induced AF in five of 20 hearts under baseline conditions (seven episodes). Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Two monophasic action potential recordings on the left- and two on the right atrial epicardium showed a decrease in atrial action potential duration (aAPD, -25msec, P<.05) and atrial effective refractory period (aERP; -52msec, P<.01) after infusion of acetylcholine (1μmol/L) and isoproterenol (1μmol/L). This led to induction of AF in 14 of 20 hearts (145 episodes). Simultaneous infusion of ANT (20μmol/L) led to a complete suppression of AF in all inducible hearts. Treatment with ANT also led to a significant increase in aAPD (+41msec, P<.01) and aERP (+74msec, P<.05), leading to a marked increase in atrial postrepolarization refractoriness (aPRR, +33msec, P<.01). Results were compared to 13 rabbits treated with flecainide. Flecainide induced a significant increase in aPRR and resulted in induction of AF in seven of 13 hearts (51 episodes) while 11 of 13 hearts were inducible with acetylcholine and isoproterenol (93 episodes). Administration of ANT was highly effective in suppressing AF. The antiarrhythmic effect could be explained by a significant increase in postrepolarization refractoriness as a result of a more marked increase in aERP as compared with aAPD.

Inhibition of cardiac two-pore-domain K+ (K2P) channels by the antiarrhythmic drug vernakalant – Comparison with flecainide

The mixed ion channel blocker, vernakalant (RSD1235), is effective in rapid conversion of atrial fibrillation (AF) to sinus rhythm (SR). Suppression of cardiac two-pore-domain potassium (K2P) channels causes action potential prolongation and has recently been proposed as a novel antiarrhythmic strategy. The objective of this study was to investigate acute effects of vernakalant on human K2P2.1 (TREK-1) and K2P3.1 (TASK-1) channels to provide a more complete picture of its antiarrhythmic mechanism of action. The class IC antiarrhythmic drug flecainide was studied as a comparator agent. 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. Vernakalant inhibited cardiac K2P2.1 channels expressed in Xenopus oocytes and in CHO cells. The IC50 value obtained from mammalian cells (13.3µM) was close to the range of vernakalant levels reported in patients (2–8µM), indicating potential clinical significance of K2P2.1 blockade. Open rectification characteristics and current–voltage relationships of K2P2.1 currents were not affected by vernakalant. Vernakalant did not significantly reduce K2P3.1 currents. Finally, the class I antiarrhythmic drug flecainide had no effect on K2P2.1 or K2P3.1 channels. In conclusion, the recently developed antiarrhythmic drug vernakalant targets human K2P2.1 K+ background channels. This previously unrecognized inhibitory property adds to the multichannel blocking profile of vernakalant and extends the mechanistic basis for its anti-fibrillatory effect.

Clinical efficacy of antazoline in rapid cardioversion of paroxysmal atrial fibrillation -- a protocol of a single center, randomized, double-blind, placebo-controlled study (the AnPAF Study)

BackgroundRapid conversion of atrial fibrillation (AF) to sinus rhythm may be achieved by the administration of class IA, IC and III antiarrhythmic drugs or vernakalant hydrochloride. However, that treatment may be related to potential pro-arrhythmia, lack of efficacy or the exceptionally high cost of a compound used. Antazoline is a first generation antihistaminic agent with chinidin-like properties. When administered intravenously, antazoline exerts a strong antiarrhythmic effect on supraventricular arrhythmia, especially on AF, facilitating rapid conversion to sinus rhythm. Despite a relative lack of published data antazoline has been marketed in Poland and widely used in cardiology wards and emergency rooms for many years due to its efficacy, safety and rapid onset of action within minutes of administration.Methods/designA randomized, double blind, placebo-controlled, superiority clinical trial was designed to assess clinical efficacy of antazoline in rapid conversion of AF to sinus rhythm. Eligible patients will present AF lasting less than 43 hours, will be in stable cardio-pulmonary condition and will have no prior history of advanced heart failure or significant valvular disease. Long-term antiarrhythmic therapy is not considered an exclusion criterion. Subjects who fulfill selection criteria will be randomly assigned to receive intravenously either antazoline or placebo in divided doses and observed for 1.5 hours after conversion to sinus rhythm or after the last i.v. bolus. Primary end point will be the conversion of AF to sinus rhythm confirmed in an electrocardiogram (ECG) during the observation period. Secondary end points will be comprised of time to conversion and return of AF during the observation period. Special consideration will be given to the observation of any adverse events. A sample size of 80 patients was calculated based on the following assumptions: two-tailed test, a type I error of 0.01, a power of 90%, efficacy of placebo 5%, efficacy of antazoline 50% and 20% drop-out rate to fulfill the criteria of intention-to-treat analysis. Due to the presumed lack of statistical power, the secondary end points and safety endpoints will be considered exploratory.Clinical trials registryClinicalTrials.gov, NCT01527279

Vernakalant: Conversion of atrial fibrillation in patients with ischemic heart disease

BackgroundVernakalant 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). MethodsThe 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 45days duration) who were exposed to study drug. ResultsA 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. ConclusionsVernakalant 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.

Disposition and Mass Balance of [&lt;sup&gt;14&lt;/sup&gt;C]Vernakalant After Single Intravenous and Oral Doses in Healthy Volunteers

Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [(14)C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [(14)C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC(0-∞); IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [(14)C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion.

Novel Agents for the Acute Conversion of Atrial Fibrillation: Focus on Vernakalant

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.

Usefulness of Vernakalant Hydrochloride Injection for Rapid Conversion of Atrial Fibrillation

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.

Vernakalant: A novel agent for the termination of atrial fibrillation

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.

Vernakalant

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.

Vernakalant Hydrochloride for the Rapid Conversion of Atrial Fibrillation After Cardiac Surgery

Background— 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. Methods and Results— 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 &lt;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. Conclusions— Vernakalant was safe and effective in the rapid conversion of AF to sinus rhythm in patients who had AF after cardiac surgery. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00125320.

Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo‐Controlled Trial

Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo‐Controlled Trial

Ibutilide for rapid conversion of atrial fibrillation or flutter in a mixed critically ill patient population

Ibutilide is an intravenous class III antiarrhythmic agent that has been shown to be effective in converting acute onset atrial fibrillation/flutter in stable medical and cardio-surgical patients. Data on its use in critically ill patients are rare. The aim of this open, non-randomized, prospective trial was to assess the potential role of ibutilide for conversion of recent onset atrial fibrillation/flutter in a mixed critically ill ICU-population. Twenty cardiac-surgical and 17 medical patients with acute tachycardic atrial fibrillation or flutter received up to two 10-min intravenous infusions of 1.0 mg ibutilide. The cumulative conversion efficacy of ibutilide was 56.8% (21 of 37 patients). The mean time to termination of the arrhythmia was 17.7 +/- 12.5 min (range 4 to 45 min) after the start of the first infusion. Conversion success was significantly higher in medical compared to cardiac-surgical patients (82.4 versus 35.0%, p=.0063). In a multivariate binary stepwise logistic regression analysis adjusted for age, heart rate and reduced left ventricular function, cardiac surgery remained significantly associated with a lower conversion probability (RR, .14; 95%CI, 0.02 to 0.76; p=.0190). Serious, ibutilide-induced ventricular arrhythmias developed in 3/37 patients (8.1%). Two of these 3 patients had a left ventricular ejection fraction < 20%. Ibutilide is an effective treatment for conversion of acute tachycardic atrial fibrillation/flutter in critically ill patients. Higher efficacy can be expected in medical than cardiac-surgical patients. Ventricular proarrhythmia, especially in patients with severely depressed left ventricular function represents the most important limitation of ibutilide treatment.

Rapid loading of sotalol or amiodarone for management of recent onset symptomatic atrial fibrillation: a randomized, digoxin-controlled trial

BackgroundAmiodarone and sotalol are commonly used for the maintenance of sinus rhythm, but the efficacy of these agents administered as high-dose infusions for rapid conversion of atrial fibrillation is unknown. Use in this context would facilitate drug initiation in patients in whom ongoing prophylactic therapy is indicated. MethodsWe assessed the efficacy and safety of rapid high-dose intravenous infusions of amiodarone and sotalol for heart rate control and rapid reversion to sinus rhythm in patients who came to the emergency department with recent-onset symptomatic atrial fibrillation. Patients (n = 140) were randomized to receive 1.5mg/kg of sotalol infused in 10 minutes, 10mg/kg of amiodarone in 30 minutes, or 500 μg of digoxin in 20 minutes. Electrical cardioversion was attempted for patients not converting to sinus rhythm within 12 hours. ResultsThe rapid infusion of sotalol or amiodarone resulted in more rapid rate control than digoxin. Each of the 3 trial strategies resulted in similar rates of pharmocological conversion to sinus rhythm (amiodarone, 51%; sotalol, 44%; digoxin, 50%; P = not significant). The overall rates of cardioversion after trial drug infusion and defibrillation were high for all groups (amiodarone, 94%; sotalol, 95%,; digoxin, 98%; P = not significant), but there was a trend toward a higher incidence of serious adverse reactions in the amiodarone group. ConclusionThe rapid infusion of sotalol or amiodarone in patients with symptomatic recent-onset atrial fibrillation results in rapid control of ventricular rate. Even with high-dose rapid infusions, all 3 agents are associated with a poor overall reversion rate within 12 hours. Almost all patients were returned to sinus rhythm with a combination of pharmacological therapy and electrical cardioversion.