Dofetilide—Tikosyn

By William T. Elliott, MD, FACP,and James Chan, PharmD, PhD

In october, the fda approved a new anti-arrhy-thmic drug for the maintenance of, and conversion to, normal sinus rhythm in patients with highly symptomatic atrial fibrillation/atrial flutter. Dofetilide, marketed as Tikosyn by Pfizer, is a Vaughan Williams Class III antiarrhythmic agent that prolongs action, potential duration, and the effective refractory period.

Indications

Dofetilide is indicated for the maintenance of normal sinus rhythm in patients with atrial fibrillation/atrial flutter of longer than one week duration who have been converted to normal sinus rhythm. It is also indicated for the conversion of atrial fibrillation and atrial flutter to normal rhythm. Due to the potential for life threatening ventricular arrhythmias it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic.

Dosage

The dose must be individualized according to calculated creatinine clearance and QTc. The usual dose is 500 mcg twice daily. Prior to the administration of the first dose, the QTc must be determined using an average of 5-10 beats. The drug is contraindicated if the QTc is greater than 440 msec or 500 msec in patients with ventricular conduction abnormalities. If the heart rate is less than 60 beats per minute, QT interval should be used. Use in patients with more than 50 beats per minute has not been studied. The QTc should be monitored 2-3 hours after the first dose and adjusted for QTc prolongation and monitored after each subsequent dose for a minimum of three days.1 This requires initiation of the drug in a monitored inpatient setting.

Dofetilide is available as 125 mcg, 250 mcg, and 500 mcg capsules.

Potential Advantages

Results from pooled data of randomized trials in patients with supraventricular arrhythmias (n = 2023) indicated that treatment with dofetilide does not adversely affect survival compared to placebo (hazard ratio 1.1, 95% CI 0.3-4.3).2 In patients with congestive heart failure and left ventricular dysfunction (n = 1518), dofetilide, compared to placebo, reduced the risk of hospitalization for worsening heart failure (odds ratio 0.75, 95% CI, 0.63-0.89).3 Patients with atrial fibrillation (AF) at baseline (n = 391) had a higher overall rate of conversion at 12 months (44% vs 13%; P < 0.001) and were less likely to have recurrence (hazard ratio 0.35, 95% CI 0.22-0.57). In sinus rhythm at baseline, fewer patients developed atrial fibrillation (2% vs 6.6%; P < 0.001). Dofetilide does not appear to adversely affect survival in patients with heart failure with or without a recent MI, or AF at study entry.1,3

Potential Disadvantages

Dofetilide does not appear to reduce mortality. It prolongs QT interval in a dose-dependent manner and can cause serious ventricular arrhythmias (i.e., torsades de points).1 In the supraventricular tachycardia study population, the incidence of torsades de pointes was 0.8% while in the heart failure population it was 3.3%.1,2 The majority, 76%, of these episodes have been reported to occur within the first three days of therapy.3 Dofetilide should be initiated in the hospital with three days of cardiac monitoring. The concomitant use of dofetilide and other drugs that can prolong the QT interval should be avoided. These include macrolides, cisapride, tricyclic antidepressants, and phenothiazines. Cimetidine has been reported to increase dofetilide plasma levels by 58%.1

Comments

Dofetilide is a selective inhibitor of the rapid component of the delayed rectifier potassium current, which results in prolongation of the action potential duration and the effective refractory period. It does not affect repolarizing potassium channels, sodium channels, adrenergic alpha-receptors, or beta receptors.1,4 The drug does not affect AV node conductance, sinus node function, or cardiac output. In patients with chronic atrial fibrillation and/or atrial flutter, dofetilide had a conversion rate of about 30% at a dose of 500 mcg twice daily and an estimated probability of 58-66% of remaining in normal sinus rhythm for 12 months.1 In the two survival studies, the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND), dofetilide did not appear to increase the risk of mortality in patients with structural heart disease.1,3 Dofetilide can cause torsade de pointes and the dose must be carefully initiated and titrated based on creatinine clearance and QTc. Therapy should be initiated in the hospital or an equivalent setting with appropriate EKG monitoring. Pfizer is developing a comprehensive educational program for health care professionals on the required in-hospital initiation of therapy and the use of the dosing algorithm. Their marketing suggests that the drug will only be available to physicians and hospitals that have participated in the educational program.

Dofetilide costs $3.60 per day for 250 mcg or 500 mcg taken twice daily.

Clinical Implications

AF is the most common form of cardiac arrhythmia. Its incidence increases with age and is associated with cardiovascular disorders such as coronary heart disease, valvular heart disease, or cardiomyopathy.5 Management of AF is generally divided between conversion and maintenance of sinus rhythm or control of ventricular rate and prevention of thromboembolic events. Management strategies depend on the clinical presentation and the patient’s need for restoration and maintenance of sinus rhythm.5 Antiarrhythmics have been used to convert as well as to maintain sinus rhythm, but their effect on survival has generally not been favorable, especially in patients with heart failure or post-myocardial infarction. Post-MI patients treated for premature ventricular beats with encainide, flecainide, or moricizine have increased risk of mortality compared to placebo in the Cardiac Arrhythmia Suppression Trials (CAST, CAST II).6,7 D-sotalol and class I antiarrhythmics have been shown to increase mortality compared to placebo in patients with AF and heart failure in the Stroke Prevention in Atrial Fibrillation trial (SPAF) and the Survival with Oral D-Sotalol trial (SWORD).8,9 Amiodarone, on the other hand, may have neutral or slightly improved mortality.10 In the Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT), amiodarone showed improved survival in patients who converted to sinus rhythm compared to those who did not convert.11 Amiodarone has not been approved by the FDA for the management of AF. Dofetilide appears to be neutral with regard to mortality and, thus, is an option for patients with AF and heart failure. Implantable cardioverter defibrillators may be another treatment option in the future.

References

1. Tikosyn Product Information. Pfizer. November 1999.

2. Pritchett EL, et al. Am Heart J 1999;138:994-997.

3. Torp-Pedersen C, et al. N Engl J Med 1999;341:857-865.

4. Gwilt M, et al. J Pharmacol Exp Ther 1991;256:318-324.

5. Jung F, et al. Am J Med 1998;104:272-286.

6. Echt DS, et al. N Engl J Med 1991;324:781-788.

7. CAST II Investigators. N Engl J Med 1992;327:227-233.

8. Flaker GC, et al. J Am Coll Cardiol 1992;20:527-532.

9. Waldo AL, et al. Lancet 1996;348:7-12.

10. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997;350:1417-1424.

11. Deedwania PC, et al. Circulation 1998;98:2574-2579.