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Egon Toft - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Vernakalant in patients with atrial flutter a randomized double blind placebo controlled trial
Europace, 2012Co-Authors: John A Camm, Gregory N. Beatch, Christian Torppedersen, Egon Toft, Pugazhendhi Vijayaraman, Steen Juulmoller, John H Ip, Garth Dickinson, George D WyseAbstract:AIMS: Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of Vernakalant in converting atrial flutter (AFL) to sinus rhythm. METHODS AND RESULTS: This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg Vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg Vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving Vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving Vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that Vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. CONCLUSION: Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.
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usefulness of Vernakalant hydrochloride injection for rapid conversion of atrial fibrillation
American Journal of Cardiology, 2010Co-Authors: Craig M Pratt, Christian Torppedersen, Egon Toft, Steen Juulmoller, George D Wyse, Enrique Retyk, David Humphrey DrenningAbstract: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
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Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery a randomized double blind placebo controlled trial
Circulation-arrhythmia and Electrophysiology, 2009Co-Authors: Peter R Kowey, Paul Dorian, Brent L Mitchell, Craig M Pratt, Peter J Schwartz, Jerzy Sadowski, Dorota Sobczyk, Andrzej Bochenek, Egon ToftAbstract: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) following cardiac surgery. Methods and Results —This was a prospective, randomized, double-blind, placebo-controlled trial of Vernakalant for the conversion of AF or AFL following coronary artery bypass graft, valvular surgery, or both. Patients were randomized 2:1 to receive a 10-minute infusion of Vernakalant 3 mg/kg or placebo. If AF or AFL was present after a 15-minute observation period, then a second 10-minute infusion of Vernakalant 2 mg/kg or placebo was given. The primary endpoint was the conversion of post-cardiac surgery AF or AFL to sinus rhythm (SR) within 90 minutes of dosing. In patients with AF, 47 of 100 (47%) patients who received Vernakalant converted to SR compared with 7 of 50 (14%) patients who received placebo ( P <.001). The median time to conversion was 12 minutes. Vernakalant was not effective in converting postoperative AFL to SR. 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 SR in patients who developed AF post-cardiac surgery. Clinical Trial Registration —http://www.clinicaltrials.gov/ct/show/[NCT00125320][1]?order=3, [NCT00125320][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00125320&atom=%2Fcircae%2Fearly%2F2009%2F10%2F02%2FCIRCEP.109.870204.atom
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Vernakalant hydrochloride for rapid conversion of atrial fibrillation a phase 3 randomized placebo controlled trial
Circulation, 2008Co-Authors: Craig M Pratt, Christian Torppedersen, Egon Toft, Steen Juulmoller, George D Wyse, Ian G Stiell, Tonny Nielsen, Lind S Rasmussen, Benoit Coutu, John H IpAbstract:Background— The present study assessed the efficacy and safety of Vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and Results— 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). Ove...
Gregory N. Beatch - One of the best experts on this subject based on the ideXlab platform.
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Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents Vernakalant and flecainide in human isolated vascular and cardiac tissues.
Journal of Cardiovascular Pharmacology, 2013Co-Authors: Joseph J Lynch, Christopher P. Regan, Gregory N. Beatch, Gilbert W. Gleim, Christopher J. MorabitoAbstract: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.
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efficacy and safety of Vernakalant in patients with atrial flutter a randomized double blind placebo controlled trial
Europace, 2012Co-Authors: John A Camm, Gregory N. Beatch, Christian Torppedersen, Egon Toft, Pugazhendhi Vijayaraman, Steen Juulmoller, John H Ip, Garth Dickinson, George D WyseAbstract:AIMS: Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of Vernakalant in converting atrial flutter (AFL) to sinus rhythm. METHODS AND RESULTS: This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg Vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg Vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving Vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving Vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that Vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. CONCLUSION: Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.
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a randomized active controlled study comparing the efficacy and safety of Vernakalant to amiodarone in recent onset atrial fibrillation
Journal of the American College of Cardiology, 2011Co-Authors: John A Camm, Gregory N. Beatch, Stefan H Hohnloser, Alessandro Capucci, Christian Torppedersen, Isabelle C Van Gelder, Brian Mangal, Avro InvestigatorsAbstract: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 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]; NCT00668759 )
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pharmacokinetics of novel atrial selective antiarrhythmic agent Vernakalant hydrochloride injection rsd1235 influence of cyp2d6 expression and other factors
The Journal of Clinical Pharmacology, 2009Co-Authors: Zhongping L Mao, Gregory N. Beatch, Jeffery Jerome Wheeler, Lilian Clohs, James KeirnsAbstract: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.
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the effect of Vernakalant rsd1235 an investigational antiarrhythmic agent on atrial electrophysiology in humans
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Paul Dorian, Arnold Pinter, Iqwal Mangat, Victoria Korley, Suzan Cvitkovic, Gregory N. BeatchAbstract:Objectives:To determine the acute effects of Vernakalant (RSD1235) on electrophysiologic (EP) properties in humans.Background:Vernakalant is an investigational mixed ion channel blocker that can terminate acute atrial fibrillation (AF) in humans at 2 to 5 mg/kg and may be more “atrial-selective” tha
George D Wyse - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Vernakalant in patients with atrial flutter a randomized double blind placebo controlled trial
Europace, 2012Co-Authors: John A Camm, Gregory N. Beatch, Christian Torppedersen, Egon Toft, Pugazhendhi Vijayaraman, Steen Juulmoller, John H Ip, Garth Dickinson, George D WyseAbstract:AIMS: Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of Vernakalant in converting atrial flutter (AFL) to sinus rhythm. METHODS AND RESULTS: This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg Vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg Vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving Vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving Vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that Vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. CONCLUSION: Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.
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usefulness of Vernakalant hydrochloride injection for rapid conversion of atrial fibrillation
American Journal of Cardiology, 2010Co-Authors: Craig M Pratt, Christian Torppedersen, Egon Toft, Steen Juulmoller, George D Wyse, Enrique Retyk, David Humphrey DrenningAbstract: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
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Vernakalant hydrochloride for rapid conversion of atrial fibrillation a phase 3 randomized placebo controlled trial
Circulation, 2008Co-Authors: Craig M Pratt, Christian Torppedersen, Egon Toft, Steen Juulmoller, George D Wyse, Ian G Stiell, Tonny Nielsen, Lind S Rasmussen, Benoit Coutu, John H IpAbstract:Background— The present study assessed the efficacy and safety of Vernakalant hydrochloride (RSD1235), a novel compound, for the conversion of atrial fibrillation (AF). Methods and Results— 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). Ove...
John A Camm - One of the best experts on this subject based on the ideXlab platform.
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2012 focused update of the esc guidelines for the management of atrial fibrillation
European Heart Journal, 2012Co-Authors: John A Camm, Gregory Y H Lip, Irene Savelieva, Jeroen J Bax, Raffaele De Caterina, Dan Atar, Paulus Kirchhof, Gerhard Hindricks, Stefan H Hohnloser, H. BaumgartnerAbstract:ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American–Australian–African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association ANDROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d. for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid (ASA) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospective, randomized, double-blind, Active-controlled, superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die (twice daily) b.p.m. : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex category (female) CHADS2 : Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke (doubled) CI : confidence interval CRAFT : Controlled Randomized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : Randomized Double blind trIal to evaluate efficacy and safety of drOnedarone (400 mg b.i.d.) vs . amiodaroNe (600 mg q.d. for 28 daYS, then 200 mg qd thereafter) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v. : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d. : omni die (every day) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy PCI : percutaneous coronary intervention PREVAIL : Prospective Randomized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ROCKET-AF : Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d. : ter in die (three times daily) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on …
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efficacy and safety of Vernakalant in patients with atrial flutter a randomized double blind placebo controlled trial
Europace, 2012Co-Authors: John A Camm, Gregory N. Beatch, Christian Torppedersen, Egon Toft, Pugazhendhi Vijayaraman, Steen Juulmoller, John H Ip, Garth Dickinson, George D WyseAbstract:AIMS: Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent for conversion of atrial fibrillation (AF) to sinus rhythm. This study examined the safety and efficacy of Vernakalant in converting atrial flutter (AFL) to sinus rhythm. METHODS AND RESULTS: This was a phase 2/3, randomized, double-blind, placebo-controlled trial. Adults with AFL received either a 10 min infusion of 3.0 mg/kg Vernakalant (n = 39) or placebo (n = 15). If AFL or AF persisted at the end of a 15 min observation period, a second 10 min infusion of 2.0 mg/kg Vernakalant or placebo was administered. The primary efficacy outcome was the proportion of patients who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 min within 90 min after the start of the first infusion. No patient in the placebo group met the primary outcome. Only one patient receiving Vernakalant (1 of 39, 3%) converted to sinus rhythm. A reduced mean absolute ventricular response rate occurred within 50 min in patients receiving Vernakalant (mean change from baseline -8.2 b.p.m.) vs. patients receiving placebo (-0.2 b.p.m.) (P = 0.037). A post-hoc analysis revealed that Vernakalant increased AFL cycle length by an average of 55 ms, whereas the AFL cycle length was unchanged in the placebo group (P < 0.001). There was no occurrence of 1 : 1 atrio-ventricular conduction. Dysgeusia and sneezing were the most common treatment-related adverse events, consistent with previous reports. CONCLUSION: Vernakalant did not restore sinus rhythm in patients with AFL. Vernakalant modestly slowed AFL and ventricular response rates, and was well tolerated.
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a randomized active controlled study comparing the efficacy and safety of Vernakalant to amiodarone in recent onset atrial fibrillation
Journal of the American College of Cardiology, 2011Co-Authors: John A Camm, Gregory N. Beatch, Stefan H Hohnloser, Alessandro Capucci, Christian Torppedersen, Isabelle C Van Gelder, Brian Mangal, Avro InvestigatorsAbstract: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 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]; NCT00668759 )
Joseph J Lynch - One of the best experts on this subject based on the ideXlab platform.
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the new antiarrhythmic drug Vernakalant ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation
Cardiovascular Research, 2013Co-Authors: Erich Wettwer, John K Gibson, Joseph J Lynch, Marc Pourrier, Torsten Christ, Sebastian Endig, Nadiia Rozmaritsa, K Matschke, David Fedida, Michael KnautAbstract:AIMS: Vernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown. METHODS AND RESULTS: 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 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. CONCLUSION: 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.
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the new antiarrhythmic drug Vernakalant ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation
Cardiovascular Research, 2013Co-Authors: Erich Wettwer, John K Gibson, Joseph J Lynch, Marc Pourrier, Torsten Christ, Sebastian Endig, Nadiia Rozmaritsa, K Matschke, David Fedida, Michael KnautAbstract:Aims Vernakalant is a newly developed antiarrhythmic drug against atrial fibrillation (AF). However, its electrophysiological actions on human myocardium are unknown. Methods and results 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 d V /d t max were reduced in a concentration- and frequency-dependent manner with IC50 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 Ca2+ currents (SR) were reduced with IC50 of 84 µM. Conclusion 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.
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Comparison of the intrinsic vasorelaxant and inotropic effects of the antiarrhythmic agents Vernakalant and flecainide in human isolated vascular and cardiac tissues.
Journal of Cardiovascular Pharmacology, 2013Co-Authors: Joseph J Lynch, Christopher P. Regan, Gregory N. Beatch, Gilbert W. Gleim, Christopher J. MorabitoAbstract: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.
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rate dependent effects of Vernakalant in the isolated non remodeled canine left atria are primarily due to block of the sodium channel comparison with ranolazine and dl sotalol
Circulation-arrhythmia and Electrophysiology, 2012Co-Authors: Alexander Burashnikov, John K Gibson, Joseph J Lynch, Marc Pourrier, Charles AntzelevitchAbstract:Background— Several clinical trials have shown that Vernakalant is effective in terminating recent onset atrial fibrillation (AF). The electrophysiological actions of Vernakalant are not fully understood. Methods and Results— Here we report the results of a blinded study comparing the in vitro canine atrial electrophysiological effects of Vernakalant, ranolazine, and dl-sotalol. Action potential durations (APD50,75,90), effective refractory period (ERP), post repolarization refractoriness (PRR), maximum rate of rise of the action potential (AP) upstroke (Vmax), diastolic threshold of excitation (DTE), conduction time (CT), and the shortest S1-S1 permitting 1:1 activation (S1-S1) were measured using standard stimulation and microelectrode recording techniques in isolated normal, non-remodeled canine arterially perfused left atrial preparations. Vernakalant caused variable but slight prolongation of APD90 ( P =not significant), but significant prolongation of APD50 at 30 μmol/L and rapid rates. In contrast, ranolazine and dl-sotalol produced consistent concentration- and reverse rate-dependent prolongation of APD90. Vernakalant and ranolazine caused rate-dependent, whereas dl-sotalol caused reverse rate-dependent, prolongation of ERP. Significant rate-dependent PRR developed with Vernakalant and ranolazine, but not with dl-sotalol. Other sodium channel-mediated parameters (ie, Vmax, CT, DTE, and S1-S1) also were depressed significantly by Vernakalant and ranolazine, but not by dl-sotalol. Only Vernakalant elevated AP plateau voltage, consistent with blockade of ultrarapid delayed rectified potassium current and transient outward potassium current. Conclusions— In isolated canine left atria, the effects of Vernakalant and ranolazine were characterized by use-dependent inhibition of sodium channel-mediated parameters, and those of dl-sotalol by reverse rate-dependent prolongation of APD90 and ERP. This suggests that during the rapid activation rates of AF, the INa blocking action of the mixed ion channel blocker Vernakalant takes prominence. This mechanism may explain Vernakalant's anti-AF efficacy.
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comparison of electrophysiological and antiarrhythmic effects of Vernakalant ranolazine and sotalol in canine pulmonary vein sleeve preparations
Heart Rhythm, 2012Co-Authors: Serge Sicouri, John K Gibson, Joseph J Lynch, Marc Pourrier, Charles AntzelevitchAbstract:Background 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. Methods 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. Results 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. Conclusions 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.
