Therapeutic use of dofetilide
- Raymond L Woosley, MD, PhD
Raymond L Woosley, MD, PhD
- Professor of Medicine and Pharmacology
- University of Arizona
- President and CEO
- The Critical Path Institute
Dofetilide is a class III antiarrhythmic agent (table 1) available for use in the United States and other countries for the acute termination of atrial fibrillation or flutter as well as prevention of atrial fibrillation or flutter recurrence. Dofetilide has also been used in an off-label manner to treat paroxysmal supraventricular tachycardias. Some investigators have studied the efficacy of dofetilide in the treatment of life-threatening ventricular arrhythmias, although the drug is not approved for this indication. In contrast to some other antiarrhythmic medications, dofetilide appears to be hemodynamically safe for use in patients with heart failure or a prior myocardial infarction . Because of a relatively high risk of torsades de pointes as an adverse effect of dofetilide, it has a formal risk evaluation and mitigation program that requires training and certification of treatment sites. (See 'Drug interactions' below.)
The basic pharmacologic properties of dofetilide, its clinical uses, and its safety profile are discussed in detail here. Alternative treatment approaches for supraventricular and ventricular arrhythmias are discussed separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrioventricular nodal reentrant tachycardia", section on 'Therapy' and "Sustained monomorphic ventricular tachycardia in patients with a prior myocardial infarction: Treatment and prognosis".)
Dofetilide is a class III antiarrhythmic agent that blocks the delayed rectifier cardiac potassium channel and prolongs repolarization (table 1). Dofetilide has relative selectivity for blocking the rapidly-activating component of the delayed rectifier potassium current (IKr) at concentrations of 10 to 30 nanomole/L [2,3]. At these concentrations, it does not block the slow component of the delayed rectifier potassium current (IKs) or the inward rectifier (IKi) and does not affect calcium currents. Evidence from one study shows that dofetilide and several other drugs known to cause torsades de pointes (d-sotalol, thioridazine, and erythromycin) increase the late sodium current (INaL) in cardiac cells, an action (IC50 = 0.1 micromole/L) that could contribute to their arrhythmogenic potential .
As a result of its electrophysiologic actions on IKr and possibly INaL, dofetilide has a selective effect on the QT interval of the surface ECG. In clinical electrophysiologic studies, it prolongs the QT interval with little, if any, effect on QT dispersion . Purkinje fibers from female dogs are more sensitive to dofetilide than fibers from male dogs, which is consistent with the threefold greater incidence of torsades de pointes in women . (See "Acquired long QT syndrome".)
Like other class III agents, dofetilide exhibits reverse use dependency (greater prolongation of repolarization and the refractory period during slower heart rates). The drug prolongs the effective refractory period of atrial and ventricular myocardium and accessory pathways, but it has no effect on conduction parameters, sinus cycle length, or sinus node recovery [7,8]. (See "Myocardial action potential and action of antiarrhythmic drugs".)
- Mounsey JP, DiMarco JP. Cardiovascular drugs. Dofetilide. Circulation 2000; 102:2665.
- Carmeliet E. Use-dependent block of the delayed K+ current in rabbit ventricular myocytes. Cardiovasc Drugs Ther 1993; 7 Suppl 3:599.
- Kiehn J, Lacerda AE, Wible B, Brown AM. Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation 1996; 94:2572.
- Yang T, Chun YW, Stroud DM, et al. Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current. Circulation 2014; 130:224.
- Démolis JL, Funck-Brentano C, Ropers J, et al. Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans. Circulation 1996; 94:1592.
- Abi-Gerges N, Small BG, Lawrence CL, et al. Evidence for gender differences in electrophysiological properties of canine Purkinje fibres. Br J Pharmacol 2004; 142:1255.
- Sedgwick ML, Rasmussen HS, Cobbe SM. Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris. Am J Cardiol 1992; 69:513.
- Cobbe SM, Campbell RW, Camm AJ, et al. Effects of intravenous dofetilide on induction of atrioventricular re-entrant tachycardia. Heart 2001; 86:522.
- Smith DA, Rasmussen HS, Stopher DA, Walker DK. Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man. Xenobiotica 1992; 22:709.
- Rasmussen HS, Allen MJ, Blackburn KJ, et al. Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol 1992; 20 Suppl 2:S96.
- Le Coz F, Funck-Brentano C, Morell T, et al. Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization. Clin Pharmacol Ther 1995; 57:533.
- Walker DK, Alabaster CT, Congrave GS, et al. Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos 1996; 24:447.
- Kobayashi Y, Atarashi H, Ino T, et al. Clinical and electrophysiologic effects of dofetilide in patients with supraventricular tachyarrhythmias. J Cardiovasc Pharmacol 1997; 30:367.
- Falk RH, Pollak A, Singh SN, Friedrich T. Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. Intravenous Dofetilide Investigators. J Am Coll Cardiol 1997; 29:385.
- Nørgaard 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.
- Frost L, Mortensen PE, Tingleff J, et al. Efficacy and safety of dofetilide, a new class III antiarrhythmic agent, in acute termination of atrial fibrillation or flutter after coronary artery bypass surgery. Dofetilide Post-CABG Study Group. Int J Cardiol 1997; 58:135.
- Bianconi L, Castro A, Dinelli M, et al. Comparison of intravenously administered dofetilide versus amiodarone in the acute termination of atrial fibrillation and flutter. A multicentre, randomized, double-blind, placebo-controlled study. Eur Heart J 2000; 21:1265.
- Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857.
- Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385.
- Coleman CI, Sood N, Chawla D, et al. Intravenous magnesium sulfate enhances the ability of dofetilide to successfully cardiovert atrial fibrillation or flutter: results of the Dofetilide and Intravenous Magnesium Evaluation. Europace 2009; 11:892.
- Khurshid S, Akerman S, Man JP, et al. Acute conversion of persistent atrial fibrillation during dofetilide loading does not predict long-term atrial fibrillation-free survival. J Interv Card Electrophysiol 2015; 42:117.
- Qin D, Leef G, Alam MB, et al. Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation. J Cardiol 2015.
- Tendera M, Wnuk-Wojnar AM, Kulakowski P, et al. Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. Am Heart J 2001; 142:93.
- Andersen HR, Wiggers H, Knudsen LL, et al. Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs. Cardiovasc Res 1994; 28:1635.
- Boriani G, Lubinski A, Capucci A, et al. A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease. Eur Heart J 2001; 22:2180.
- Mazur A, Anderson ME, Bonney S, Roden DM. Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter-defibrillator-based evaluation. J Am Coll Cardiol 2001; 37:1100.
- Baquero GA, Banchs JE, Depalma S, et al. Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies. J Cardiovasc Electrophysiol 2012; 23:296.
- Wallace AA, Stupienski RF 3rd, Brookes LM, et al. Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs. J Cardiovasc Pharmacol 1991; 18:687.
- Rousseau MF, Massart PE, van Eyll C, et al. Cardiac and hemodynamic effects of intravenous dofetilide in patients with heart failure. Am J Cardiol 2001; 87:1250.
- Brendorp B, Elming H, Jun L, et al. Qtc interval as a guide to select those patients with congestive heart failure and reduced left ventricular systolic function who will benefit from antiarrhythmic treatment with dofetilide. Circulation 2001; 103:1422.
- Køber L, Bloch Thomsen PE, Møller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356:2052.
- Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486.
- Pedersen HS, Elming H, Seibaek M, et al. Risk factors and predictors of Torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving Dofetilide. Am J Cardiol 2007; 100:876.
- Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994.
- Abraham JM, Saliba WI, Vekstein C, et al. Safety of Oral Dofetilide for Rhythm Control of Atrial Fibrillation and Atrial Flutter. Circ Arrhythm Electrophysiol 2015; 8:772.
- McBride BF, Min B, Kluger J, et al. An evaluation of the impact of oral magnesium lactate on the corrected QT interval of patients receiving sotalol or dofetilide to prevent atrial or ventricular tachyarrhythmia recurrence. Ann Noninvasive Electrocardiol 2006; 11:163.
- Varkevisser R, Houtman MJ, Linder T, et al. Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue. Br J Pharmacol 2013; 169:1322.
- Yu Z, Klaasse E, Heitman LH, Ijzerman AP. Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs. Toxicol Appl Pharmacol 2014; 274:78.
- Hreiche R, Plante I, Drolet B, et al. Lengthening of cardiac repolarization in isolated guinea pigs hearts by sequential or concomitant administration of two IKr blockers. J Pharm Sci 2011; 100:2469.
- ELECTROPHYSIOLOGIC ACTION
- PHARMACOLOGIC DATA
- DRUG APPROVAL AND RESTRICTIONS
- CLINICAL USE
- Oral dofetilide for atrial fibrillation/atrial flutter terminatinon and prevention
- Dofetilide for preventing recurrence of paroxysmal supraventricular tachycardia
- Ventricular tachyarrhythmias
- Heart failure
- Postmyocardial infarction
- Drug interactions