Oral Dofetilide for Atrial Fibrillation/Flutter
Abstract & Commentary
Synopsis: Dofetilide is moderately effective for converting atrial fibrillation and atrial flutter to sinus rhythm and in maintaining sinus rhythm for one year.
Source: Singh S, et al. Dofetilide atrial fibrillation investigators. Circulation 2000;102:2385-2390.
Singh and colleagues report a double-blind, multicenter dose ranging study on the effect of dofetilide, a new antiarrhythmic drug for the conversion and maintenance of sinus rhythm in patients with atrial fibrillation and atrial flutter. The study group included 325 patients. Eighty-seven percent were male. The mean age was 67 years. Eighty-five percent of the patients had atrial fibrillation as their primary rhythm and 15% had atrial flutter. Ninety-two percent of the patients were in New York Heart Association class I or class II. Sixty-three percent had some form of structural heart disease, with hypertensive disease noted in 50%. At the time of entry, most of the patients were on digoxin for rate control with a small percentage on calcium channel blockers. All patients had a history of persistent atrial fibrillation that had lasted from two to 26 weeks. Patients with a QRS duration over 180 m/sec, a QT interval over 440 m/sec in the absence of bundle branch block (500 m/sec with a bundle branch block), RR intervals greater than 3.5 seconds, or a ventricular rate of less than 50 bpm on 12-lead ECG were excluded. Patients with a creatinine clearance of less than 20 mL/min were also excluded. Patients were admitted to the hospital and placed on continuous telemetry. Patients were assigned to receive either placebo or dofetilide in twice- daily doses of either 125 mcg, 250 mcg, or 500 mcg. Because of data from other trials indicating that doses needed to be adjusted for renal function, the prescribed dosage was cut in half if the creatinine clearance was between 40-60 mL/min and both cut in half and changed to a single-daily dose if the creatinine clearance was between 20-40 mL/min. Dosage adjustment was also permitted if the QT interval increased by greater than 15% over baseline. Patients with a QTc that exceeded 550 m/sec or increased greater than 25% over the baseline values at any time were withdrawn. Patients first received a minimum of five doses of study drug. If they failed to convert pharmacologically, electrical cardioversion was attempted. Patients in whom sinus rhythm could not be restored or maintained for 24 hours after conversion were not entered into the maintenance phase. All patients were anticoagulated according to current guidelines. During the conversion phase, only one of 84 patients who received placebo converted to sinus rhythm. In contrast, 6.1%, 9.8%, and 29.9% of the dofetilide patients treated with either 125 mcg b.i.d., 250 mcg b.i.d., or 500 mcg b.i.d. converted pharmacologically. Of the patients who converted pharmacologically, 70% did so within 24 hours and 91% within 36 hours. Pharmacologic conversion was more common in patients with atrial flutter than in those with atrial fibrillation. In the 500 mcg b.i.d. dosage group, the rates were 21.6% for atrial fibrillation and 66.7% for atrial flutter. There was a strong correlation between final dofetilide dose and the maintenance of sinus rhythm. Among the patients who converted and entered the maintenance phase, 25% of placebo patients remained in sinus rhythm whereas 40%, 37%, and 58% of the three dofetilide groups remained in sinus rhythm at 12 months. Time to recurrent episode was improved at the two higher doses. Patients with atrial flutter maintained sinus rhythm better than patients with atrial fibrillation.
Eleven patients were withdrawn from dofetilide therapy because of adverse events potentially related to treatment. Prolongation of the QT or QTc interval accounted for 10 of the withdrawals. There were seven proarrhythmic events. Singh et al considered three of these to be treatment related. There were two episodes of torsade de pointes. One episode was unwitnessed and death was presumed to be a sudden cardiac death on day eight of therapy. Four other events were noted but were thought to be due to another illness. There was no difference in all-cause mortality between the groups. By 12 months, 2.5% of dofetilide treated patients and 3.5% of placebo-treated patients had died.
Singh et al concluded that dofetilide is moderately effective for converting atrial fibrillation and atrial flutter to sinus rhythm and in maintaining sinus rhythm for one year. A careful program of in-hospital initiation and dosage adjustment based on QTc is recommended to minimize the risk of proarrhythmia.
Comment by John P. DiMarco, MD, PhD
Dofetilide is an antiarrhythmic drug recently released for treatment of patients with atrial fibrillation. Previously, studies in both heart failure and post- myocardial infarction patients had shown that dofetilide did not increase overall mortality and had a favorable effect in patients with atrial fibrillation at baseline. The study by Singh et al was specifically designed to assess the effects of various doses of dofetilide in patients with persistent atrial fibrillation.
The data reported here show that dofetilide is moderately effective in atrial fibrillation. Like other antiarrhythmic drugs, it is more effective in patients who present with only atrial flutter, but currently, most patients with only classic atrial flutter would be treated with ablation rather than antiarrhythmic drug therapy. However, the drug has a narrow therapeutic range and this observation led to some unusual FDA guidelines for therapy initiation.
Physicians who wish to prescribe dofetilide must undergo a training session provided by the manufacturer. Therapy must be begun in-hospital and long-term drug supplies can only be obtained from a national center. A careful program of QT interval monitoring during study initiation is recommended to minimize the risk of side effects. These restrictions are unique among antiarrhythmic drugs even though other drugs with a risk for producing QT prolongation and polymorphic ventricular tachycardia, such as sotalol or quinidine, would probably have enhanced safety if similar programs were followed. Even with this program, proarrhythmia may occur. In fact, this paper doesn’t really give up a final estimate of incidence since Singh et al don’t really define what they mean by proarrhythmia "related to other illnesses."
When choosing an antiarrhythmic drug for patients with atrial fibrillation, safety is often a more significant concern than efficacy since atrial fibrillation per se is not a life-threatening arrhythmia. Dofetilide can be used as an alternative to amiodarone in patients with congestive heart failure. Unlike sotalol, the other currently available class III antiarrhythmic drug, it does not have prominent beta-blocking activity and, therefore, can be used at an antiarrhythmic dose in patients with significant heart failure without a careful up titration to avoid excess beta-blocker effect. It also is not associated with bradycardia. Since bradycardia is a predisposing factor for drug-induced polymorphic ventricular tachycardia, this is an additional safety feature. Finally, dofetilide has few extra cardiac side effects. This allows it to be an alternative to amiodarone in patients in whom years of therapy are likely to be required.
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