Dofetilide

Abstract

Dofetilide is a ‘pure’ class III antiarrhythmic agent which has demonstrated efficacy in the conversion of atrial fibrillation or flutter to sinus rhythm and the maintenance of sinus rhythm. By blocking the rapid component of the cardiac delayed rectifier potassium current (I_kr), dofetilide prolongs the cardiac action potential duration and the effective refractory period. This is thought to increase the likelihood of a re-entrant wavefront encountering refractory tissue and terminating the arrhythmia. Preliminary findings from the EMERALD (European and Australian Multicenter Evaluative Research on Atrial Fibrillation Dofetilide) and SAFIRE-D (Symptomatic Atrial Fibrillation Investigation and Randomized Evaluation of Dofetilide) studies suggest that oral dofetilide is effective in the conversion of atrial fibrillation or flutter to sinus rhythm. Both studies have yet to be published in full. In SAFIRE-D, dofetilide 500µg twice daily for 3 days achieved a conversion rate of 32% compared with a 1% rate for placebo. A similar conversion rate was achieved after 3 days in EMERALD with dofetilide 500µg twice daily (29%) which was significantly greater than that achieved with sotalol 80mg twice daily (6%; p < 0.05). Oral dofetilide also appears to be effective in the maintenance of sinus rhythm. An abstract report of EMERALD participants who had been converted to sinus rhythm showed that 71% of patients who received oral dofetilide remained in sinus rhythm after 6 months (compared with 26% of placebo and 59% of sotalol recipients; both p < 0.05). Restoration of sinus rhythm using intravenous dofetilide is more likely in patients with recent-onset versus prolonged-duration arrhythmia, and in those with atrial flutter rather than atrial fibrillation. Limitations of comparative data for intravenous dofetilide are such that few conclusions can be drawn. Although generally well tolerated in clinical trials, dofetilide has proarrhythmic potential. Torsade de pointes ventricular tachycardia was reported in up to3.3% of patients who received oral dofetilide in the DIAMOND (Diamond Investigations of Arrhythmia and Mortality on Dofetilide) studies, although only a small proportion of patients in these studies had atrial fibrillation; most episodes occurred within the first 3 days. Whether the propensity of dofetilide for this life-threatening arrhythmia is similar to that of other class III antiarrhythmic agents has yet to be determined. Importantly, the long term use of oral dofetilide in patients at high risk for sudden cardiac death is not associated with an increased risk of mortality, although these DIAMOND findings cannot necessarily be extrapolated to patients with atrial fibrillation. Conclusions: Dofetilide offers an alternative to currently available antiarrhythmic agents for the pharmacological conversion of atrial fibrillation or atrial flutter to sinus rhythm and for the maintenance of sinus rhythm after cardioversion. However, further comparative data are necessary before its definitive placecan be determined.