Dofetilide arrhythmia with

Bashir Y, Thomsen PE, Kingma JH, Moller M, Wong C, Cobbe SM, Jordaens L, Campbell RW, Rasmussen HS, Camm AJ. Electrophysiologic profile and efficacy of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with sustained monomorphic ventricular tachycardia. Dofetilide Arrhythmia Study Group. Am J Cardiol 1995 76(14) 1040-4. 

Newly developed class III drugs comprise dofetilide, a specific Ik, blocker, and ibutilide, which blocks IKl and activates the slow iNa- Both drugs lack hemodynamic side effects. These drugs are scheduled for the treatment of atrial fibrillation and atrial flutter. As with class HI drugs, they can induce torsade de pointes arrhythmia. 

Moller M, Torp-Pedersen C, Kober L. Dofetilide in patients with congestive heart failure and left ventricular dysfunction safety aspects and effect on atrial fibrillation. The Danish Investigators of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group. Congest Heart Fail 2001 7(3) 146-50. 

Dofetilide is approved for the treatment of atrial fibrillation and atrial flutter. Because of the lack of significant hemodynamic effects, dofetilide may be useful in patients with CHF who are in need of therapy for supraventricular tachyarrhythmias. Dofetilide is not indicated for use in the setting of ventricular arrhythmias. 

The chapter ends with a complete synthesis of an important new drug. Cardiac arrhythmia (erratic and inefficient heart action) is a major problem in the modern world causing poor lifestyle (exhaustion) and death by blood clots. A new drug dofetilide (Tikosyn ) is being introduced by Pfizer to treat this problem. It works by blocking the passage of potassium ions out of heart muscle and so delays the onset of an irregular beat until the next normal beat takes over. 

The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) study comprised two studies in patients at high risk of sudden death one in patients with congestive heart failure and one in patients with acute myocardial infarction within the previous 7 days (50). 

Danish Investigations of Arrhythmia and Mortality ON Dofetilide. Dofetilide in patients with left ventricular dysfunction and either heart failure or acute myocardial infarction rationale, design, and patient characteristics of the DIAMOND studies. Clin Cardiol 1997 20(8) 704-10. 

Alternatives to amiodarone include the type Ic drugs (e.g., fle-cainide and propafenone) and the type III blockers (e.g., sotalol and dofetilide). Because of the risk of pro arrhythmia, the type Ic drugs should be reserved for those without heart disease (i.e., lone atrial fibrillation). Sotalol has been shown to be at least as effective as quinidine in preventing recurrences of atrial fibrillation." However, treatment with either quinidine or sotalol is associated with a similar incidence of torsade de pointes. Since this form of proarrhythmia occurs primarily with higher doses of sotalol (quinidine usually causes torsade de pointes at low or therapeutic concentrations), it may be predicted more easily and therefore avoided. Nonetheless, it is possible that sotalol increases mortality in patients with atrial fibrillation similar to quinidine, and this requires further study." ... 

Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function. The Danish Investigation of Arrhythmia and Mortahty ON Dofetilide (DIAMOND) substudy. Circulation 2001 104 292-296. 

On the basis of the above findings, the manufacturer contraindicates the use of dofetilide with hydrochlorothiazide alone or in combination with triamterene. Given the increase in QT interval, a risk factor for torsade de pointes arrhythmia, this appears a prudent precaution. Further study is needed. Any diuretic that depletes serum potassium (such as the loop diuretics) might be expected to increase the risk of QT prolongation and torsade de pointes with dofetilide, and serum potassium should be monitored. ... 

Cimetidine markedly increases plasma dofetilide levels, and hence increases dofetilide-induced QT prolongation and the risk of torsade de pointes arrhythmias. Its combined use with dofetilide should be avoided. Dofetilide appears not to interact with ranitidine. 

Ketoconazole markedly increases the plasma levels of dofetilide. This is likely to be associated with an increased risk of dofetilide-induced QT prolongation and torsade de pointes arrhythmias. 

The manufacturer of dofetilide notes that trimethoprim 160 mg (in combination with sulfamethoxazole 800 mg) twice daily given with dofetilide 500 micrograms twice daily for 4 days increased dofetilide peak levels by 93% and AUC by 103%. Trimethoprim inhibits the active renal tubular secretion mechanism by which dofetilide is eliminated, so reducing its loss from the body (see also Dofetilide + H2-receptor antagonists , p.255). There is a linear relationship between plasma dofetilide concentrations and prolongation of the QT interval, which increases the risk of torsade de pointes arrhythmia. For this reason, the manufacturer contraindicates the use of trimethoprim in patients on dofetilide. This would seem to be a prudent precaution. 

Verapamil transiently increases dofetilide plasma levels and QTc prolongation, and has been associated with an increased risk of torsade de pointes arrhythmia. Its use with dofetilide is contraindicated. 

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