Efficacy and Safety of Intravenously Administered Dofetilide in Acute Termination of Atrial Fibrillation and Flutter: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial - Danish Dofetilide in Atrial Fibrillation and Flutter Study
The goal of this study was to assess the efficacy and safety of intravenous dofetilide for the acute termination of atrial fibrillation and atrial flutter.
Intravenous dofetilide will be superior to placebo for the acute termination of atrial fibrillation and atrial flutter.
Patients Enrolled: 96
NYHA Class: 47% of patients had NYHA class II or III congestive heart failure.
Mean Follow Up: 30 days
Mean Patient Age: 28-86
Sustained atrial fibrillation or atrial flutter of a duration from one hour to six months, hemodynamic stability, and discontinuation of class I or III antiarrhythmic medications for at least five half-lives
Symptoms of uncontrolled heart failure, prior myocardial infarction, unstable angina, or cardiac arrest; or cardiac surgery within 3 weeks, age <18 years, thyrotoxicosis, history of torsades de pointes, serum potassium level <3.6 or >5.5 mmol/l, resting heart rate <60 bpm, or QTc interval >440 ms
Conversion of atrial fibrillation or atrial flutter to sinus rhythm within three hours of initiation of therapy
Evaluation of ventricular rate before and after administration of therapy in patients not converting to sinus rhythm
Patients were randomized to dofetilide or placebo in a 2:1 distribution. Intravenous dofetilide (8 μg/kg) or placebo was administered over 30 minutes. Patients were monitored continuously with single-lead electrocardiography and a Holter recording throughout the study period up to 24 hours.
All patients had any class I or III antiarrhythmic medications discontinued for greater than five half-lives prior to enrollment. Prestudy medications continued through the study period included digoxin (73%), beta-blockers (13%), and calcium channel antagonists (32%).
Administration of intravenous dofetilide was associated with an increased rate of conversion to sinus rhythm within three hours of the infusion (30% vs. 3.3%, p<0.006). The median time from initiation of the infusion to conversion to sinus rhythm was 47 minutes (range 13 to 161). Patients with atrial flutter had a higher rate of conversion to sinus rhythm after dofetilide infusion than patients with atrial fibrillation (64% vs. 24%, p=0.012). Administration of dofetilide compared with placebo was not associated with significant changes in heart rate or mean blood pressure. Excessive prolongation of the QT interval occurred in 20 of 66 (30%) patients receiving dofetilide, and the infusion was prematurely stopped in 8 (12%).
The incidence of torsades de pointes was 3% in patients treated with dofetilide compared with no patients receiving placebo. All episodes of torsades de pointes occurred within 45 minutes of study drug infusion in patients in whom the infusion had been prematurely stopped due to excessive QT prolongation. On multivariate logistic regression analysis, independent predictors of conversion to sinus rhythm were the presence of atrial flutter, no prestudy treatment with digoxin, and a history of arterial hypertension.
Among patients with sustained atrial fibrillation or atrial flutter, intravenous dofetilide was associated with an increased rate of conversion to sinus rhythm. The rate of conversion to sinus rhythm was significantly higher in patients with atrial flutter than atrial fibrillation. Patients were carefully monitored during study drug administration and the incidence of significant side effects was low.
Norgaard BL, Wachtell K, Christensen PD, et al. Efficacy and safety of intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: A multicenter, randomized, double-blind, placebo-controlled trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group. Am Heart J 1999;137:1062-9.
Keywords: Potassium Channel Blockers, Digoxin, Heart Conduction System, Phenethylamines, Electrocardiography, Heart Rate, Torsades de Pointes, Logistic Models, Hypertension, Atrial Flutter, Sulfonamides
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