Abstract

Background: 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.

Results: 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 (X2 =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). Methods: 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 X2 test.

Conclusion: 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.

לקריאת המאמר:

Yan H, Aung TT, Guoqiang Z, Zhengnan Z, Lan J, Zhiyu Z. Meta-analysis of effect of vernakalant on conversion of atrial fibrillation. BMC Res Notes. 2013 Mar 13;6:94.

Objectives: 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).

Background: Intravenous vernakalant has effectively converted recent-onset AF and was well tolerated in placebo-controlled studies.

Methods: 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.

Results: 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.

Conclusions: 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].

לקריאת המאמר:

Camm A. J., Capucci A., Hohnloser S. H., Pedersen C. T. , Van Gelder I. C., Mangal B.,   Beatch G. (2011). A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol.,3, 313-321.

Summary: Vernakalant is an emergent AAD 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 RCTs, until May 2011, of Vernakalant compared with controls (placebo/other AAD) in enrolled patients with high ventricular rate AF.

Five RCTs that met inclusion criteria enrolled a total of 1099 patients. Among these, 810 had recent-onset AF. When compared with controls (placebo/other oral AAD), vernakalant was associated with a significant increase in cardioversion within 90 minutes from drug infusion (RR, 8.4; 95%; CI2, 4.4-16.3; P <.00001). Compared with controls, vernakalant was not associated with a significant difference in SAEs (RR, 0.9; 95%; CI2, 0.6-1.4; P = .64).

Conclusion: When 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.

לקריאת המאמר:

Buccelletti F, Iacomini P, Botta G, Marsiliani D, Carroccia A, Gentiloni Silveri N, Franceschi F. Efficacy and safety of vernakalant in recent-onset atrial fibrillation after the European medicines agencyapproval: systematic review and meta-analysis. J Clin Pharmacol. 2012 Dec;52(12):1872-8.

Summary: Recent-onset (duration ≤ 1 week) AF has a high rate of spontaneous conversion to SR; still AADs are given for conversion purposes. We assessed the effect of AADs by reviewing the literature regarding conversion rates of available drugs in a systematic manner. PubMed searches were performed using the terms "drug name", "atrial fibrillation", and "clinical study/RCT", and a list of 1302 titles was generated. These titles, including abstracts or complete papers when needed, were reviewed for recent-onset of AF, the use of a control group, and the endpoint of SR within 24 hours. Postoperative and intensive care settings were excluded. Five AADs were demonstrated to have an effect, and these were Amiodarone, Ibutilide (only one study and risk of torsade de pointes), Flecainide and Propafenone (only to be used in patients without structural heart disease) and Vernakalant. The time taken for conversion differed markedly; Vernakalant converted after 10 minutes, while Amiodarone converted only after 24 hours; Propafenone and Flecainide had conversion times in-between.

Conclusion: For a rapid response in a broad group of patients, Vernakalant appears to be a reasonable first choice, while Flecainide and Propafenone can be used in patients without structural heart disease.

לקריאת המאמר:

Heldal M, Atar D. Pharmacological conversion of recent-onset atrial fi brillation: A systematic review. Scandinavian Cardiovascular Journal, 2012; Early Online: 1–9.

This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1-10 μM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 μM) and maximal rates of force development and decline (3 and 10 μM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

לקריאת המאמר:

Lynch JJ Jr, Regan CP, Beatch GN, Gleim GW, Morabito CJ. Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents vernakalant and flecainide in human isolated vascular and cardiac tissues. J Cardiovasc Pharmacol. 2013 Mar;61(3):226-32.

Summary: 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. 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. The primary outcome was rate of converting to SR, and the secondary outcome was the rate of AEs 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. Vernakalant was superior in achieving SR for AF comparing to placebo or alternative anti-AADs (relative risk [RR] = 11.56, 95%; CI2 = 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% CI2 = 0.52 – 1.57).

Conclusion: 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.

לקריאת המאמר:

Yan H,  Aung TT, Guoqiang Z, Zhengnan Z, Lan J, Zhiyu. Meta-analysis of effect of vernakalant on conversion of atrial fibrillation. BMC Res Notes. 2013; 6: 94.

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

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

לקריאת המאמר:

Costabel JP¹, Lambardi F, Aragón M, Campos R, Urdapilleta M, Ariznavarreta P, Vergara JM, Conde D. Predictors of conversion of recent-onset atrial fibrillation treated with vernakalant. Pacing Clin Electrophysiol. 2015 Feb;38(2):196-200.

INTRODUCTION:

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 comparesvernakalant with propafenone. The aim of our study is to compare the time taken for conversion of recent-onset AF in patients treated withvernakalant and propafenone.

METHODS:

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.

RESULTS:

Baseline characteristics were similar in both groups. Time to conversion to sinus rhythm was of 166 min (120-300) in the propafenonegroup 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 thevernakalant 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).

CONCLUSION:

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.

לקריאת המאמר:

Conde D, Costabel JP, Aragon M, Lambardi F, Klein A, Corrales Barbosa A, Trivi M, Giniger A. Propafenone versus vernakalant for conversion of recent-onset atrial fibrillation.Cardiovasc Ther. 2013 Dec;31(6):377-80.

Primary efficacy endpoint was the proportion of subjects with short duration atrial fibrillation (3 hours to 7 days) who had a treatment-induced conversion of atrial fibrillation to sinus rhythm for a minimum duration of one minute within 90 minutes of first exposure to study drug. Efficacy was studied in a total of 390 haemodynamically stable adult patients with short duration atrial fibrillation including patients with hypertension (40.5%), ischaemic heart disease (12.8%), valvular heart disease (9.2%) and CHF (10.8%). In these studies treatment with BRINAVESS effectively converted atrial fibrillation to sinus rhythm as compared with placebo (see Table x). Conversion of atrial fibrillation to sinus rhythm occurred rapidly (in responders the median time to conversion was 10 minutes from start of first infusion) and sinus rhythm was maintained through 24 hours (97%). The vernakalant dose recommendation is a titrated therapy with two possible dose steps. In the performed clinical studies, the additive effect of the second dose, if any, cannot be independently established.

BRINAVESS was shown to provide relief of atrial fibrillation symptoms consistent with conversion to sinus rhythm.

No significant differences in safety or effectiveness were observed based on age, gender, use of rate control medications, use of antiarrhythmic medications, use of warfarin, history of ischaemic heart disease, renal impairment or expression of the cytochrome P450 2D6 enzyme.

Treatment with BRINAVESS did not affect the response rate to electrical cardioversion (including the median number of shocks or joules required for successful cardioversion) in cases when attempted within 2 to 24 hours of study medicine administration.

Conversion of atrial fibrillation in patients with longer-duration atrial fibrillation (> 7 days and ≤ 45 days) assessed as a secondary efficacy endpoint in a total of 185 patients did not show statistically significant differences between BRINAVESS and placebo.

References:

1. עלון לרופא עמודים 8-9