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Atrial fibrillation is the most common atrial arrhythmia after coronary artery bypass graft (CABG) and valvular surgery. Postoperative atrial arrhythmias are associated with increased morbidity, prolonged hospitalization and increased costs and rates of rehospitalization after discharge. Currently available antiarrhythmic drugs to treat post operative AF have variable efficacy and safety profiles and their use may some times be limited due to their negative inotropic or chronotropic effects. Vernakalant hydrochloride (RSD1235) is a relatively atrial-selective antiarrhythmic agent for the conversion of AF to SR. It acts by means of frequency-dependent blockade of sodium channels as well as blockade of early-activating potassium channels. Knowley et al ( Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial. Dr. Peter Kowey et al (Kowey PR, Dorian P, Mitchell LB, Pratt CM, Roy D, Schwartz PJ, Sadowski J, Sobczyk D, Bochenek A, Toft E; Atrial Arrhythmia Conversion Trial Investigators. Circ Arryth Electrophysiol. 2009 Dec;2(6):652-9) evaluated the efficacy of vernakalant in converting AF or AFL to sinus rhythm (SR) in patients recovering from CABG, valvular surgery, or both.
A prospective, randomized, double-blind, placebo controlled study was conducted at 43 sites in Canada, the United States, Denmark, Italy, Poland, Argentina, and India. Patients who are 18 years of age or over, with sustained AF or AFL (lasting 3 to 72 hours) occurring between 24 hours and 7 days after CABG, valvular surgery, or both, who were hemodynamically stable, and had documented SR before and after surgery, were enrolled. Patients were excluded from study if they had prolonged QT or QRS duration, bradycardia, higher degrees of AV block, a history of torsades de pointes, unstable class IV congestive heart failure, serious hepatic or renal disease, end-stage disease states, a reversible cause of AF, an uncorrected electrolyte imbalance, digoxin toxicity, oral use of amiodarone prior three months, IV amiodarone previous 24 hours, use of class I or class III antiarrhythmic drugs post surgery or had received another investigational drug or intravenous Vernakalant in the 30 days before enrollment.
The prespecified primary efficacy end point was the proportion of patients with AF/AFL after CABG, valvular surgery, or both who demonstrated conversion to SR, for a minimum duration of 1 minute, within 90 minutes of first infusion. The effect of Vernakalant on ECG parameters QRS duration and QT interval [the mean Fridericia corrected QT interval (QTcF) and the mean Bazett-corrected QT interval (QTcB) ] was assessed.
From June 2004 to February 2007, a total of 190 patients were randomly assigned to either vernakalant or placebo. However, 161 patients (54 placebo and 107 vernakalant) received treatment and were included in the efficacy and safety analyses. Of the 161 patients treated, 150 had AF and 10 had AFL at randomization (one patient was later adjudged to be in SR before and after treatment). The 2 treatment groups did not differ significantly in baseline demographic or clinical characteristics. Among patients in whom left ventricular ejection fraction (LVEF) was known, the majority in both groups had a normal LVEF. Most patients had undergone CABG surgery.
Serious adverse events (AEs) were reported for 9.3% and 11.1% of patients given vernakalant and placebo, respectively.Within 24 hours of dosing, 2 serious AEs occurred in patients who received Vernakalant (hypotension and complete heart block) and none occurred in patients given placebo. There were no deaths reported in this study.
The primary end point, conversion of AF/AFL to SR for a minimum duration of 1 minute within 90 minutes of first infusion, was achieved in 44.9% and 14.8% of patients given vernakalant and placebo, respectively (P < 0.001). In patients with AF at baseline, 47 % of patients given vernakalant reverted to SR, whereas only 14% of patients given placebo did so (P < 0.001). Of the patients with AFL at baseline, none of the 6 given vernakalant and 1 of the 4 given placebo reverted to SR. There was no significant differences in responder rates between patients who underwent CABG surgery and those who underwent valvular surgery. There was a significant difference in responder rates between Vernakalant and placebo in patients who underwent CABG surgery alone (47.9% vs 13.5%, P< 0.002). There was no effect of age, sex, LVEF, or left atrial diastolic dimension on the probability of conversion to SR. Patients given Vernakalant who received rate-control medications, however, were more likely to demonstrate conversion to SR than were patients who did not receive rate-control medications ( 53.7% vs 39.4%, P< 0.027).
Among patients with AF/AFL who responded to treatment with Vernakalant, the median time to conversion was 12.3 minutes (range, 0.5 to 57.1 minute). Excluding those with missing data, 60% of patients who responded to Vernakalant were in SR at 24 hours and 57% were in SR at day 7. Fewer patients given vernakalant had rapid heartbeats, palpitations, and irregular pulse rates compared with those given placebo. Patients given vernakalant who remained in AF or AFL had significant increases in QRS, QTcB, and QTcF intervals, with the latter 2 returning to placebo levels within 2 hours. In those who remained in AF or AFL, Vernakalant also had a small but significant HR-lowering effect, which resolved within 90 minutes.
This study demonstrates safe and effective use of Vernakalant for AF cardioversion in patients after cardiac surgery. The real question is how does Vernakalant perform the conventional therapy – direct current electrical cardioversion? Is it worth putting a patient through several hours of intense monitoring and the riks of QT prolongation and proarrhythmia when the acute conversion to SR using cardioversion is very high? Cardioversion has proven to be very safe and effective and can be done in most of the hospital settings at a reasonable cost? A randomized controlled trial comparing direct current external cardioversion will answer the quintessential question of the relative efficacy, safety and cost effectiveness of Vernakalant compared to cardioversion.
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