Dofetilide: a new drug to control cardiac arrhythmia

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Mortality, and especially morbidity caused by AF, are major and growing health problems in the western world. AF is strongly associated with arterial hypertension, congestive heart failure, valvular heart disease, ischaemic heart disease, and with prevalence increasing with age. A variety of drugs have been used to terminate or prevent AF but, as many antiarrhythmic agents have the potential life-threatening pro-arrhythmia, safety problems remain. Dofetilide (Tikosyn, Pfizer), a new Vaughan Williams class III antiarrhythmic agent, has been developed and approved for the treatment of AF. In contrast to most antiarrhythmic agents, the development programme included two safety studies in high-risk patients. Dofetilide is effective and safe when an elaborate procedure for dosing is implemented. Along with amiodarone and betablockers, dofetilide is the only antiarrhythmic drug, which is recommended by guidelines for the treatment of AF in a wide range of patients.

Surface Atrial Frequency Analysis in Patients with Atrial Fibrillation:

“…Management of AF currently is under intensive study, and novel drug, pacing, and ablation therapies are under evaluation 22–24 . The main mode of evaluation of any of these treatment modalities until to now has been whether and how often sinus rhythm is restored and maintained in different clinical situations.…”

Atypical Proarrhythmia with Dofetilide: Monomorphic VT and Exercise‐Induced Torsade de Pointes

“…In general, the risk is dependent upon the action of the drug selected (or drug class) and the nature of any ventricular disorder present 1,2 . For class III AADs, the typical ventricular proarrhythmic response is torsade de pointes (TdP) which can develop with a class III AAD in the normal heart but is more likely to occur with a hypertrophied ventricle, higher drug doses or tissue concentrations, greater QT prolongation, hypokalemia, hypomagnesemia, bradycardia, and/or female gender 1–9 . TdP is so typical of the class III AAD proarrhythmic response that it is the only specific proarrhythmia discussed in the package insert (PI) for dofetilide (brand name: Tikosyn) 5 .…”

“…No other ventricular tachycardia (VT) is morphologically described in the dofetilide PI or showed an incidence with any dose of dofetilide that was significantly different from placebo 5 . Additionally, the majority (91%) of episodes of TdP with dofetilide occur shortly after drug initiation (assuming stability of other clinical factors) 5,7–11 . This has led to the recommendation that dofetilide be started in‐hospital only.…”

“…These two cases illustrate several important lessons about ventricular proarrhythmic responses to AADs, or at least to dofetilide. Case 1 appears to reveal that proarrhythmia with dofetilide (proven with rechallenge) can appear as a monomorphic form of VT rather than just as TdP and that proarrhythmia with dofetilide can occur even in the absence of a proarrhythmic response to prior AADs; may not always link to QT prolongation; and can be essentially immediate, occurring at the time of anticipated peak serum level of the initial dose, 5,7–9 thus reemphasizing the need for monitoring during drug initiation. Speculatively, the mechanism seen in this case may be a drug‐induced prolongation of refractoriness locally in diseased ventricular tissue (rheumatic and postsurgical in this patient) that could have regionally impaired conduction such that the resulting inhomogeneity of repolarization and/or myocardial conduction produced a substrate for reentry.…”

Safety considerations in the pharmacological management of atrial fibrillation

“…However, most studies of the incidence of torsade de pointes during maintenance therapy have reported incidence levels of approximately 2% at current standard doses of class III AADs. For instance, early studies with dofetilide at a dose of 750 µg bid reported an incidence rate of 4.0%, although this fell to 1.7% when the dose was reduced to 500 µg bid [21], while Soyka et al documented 56 cases of proarrhythmia in 1288 patients in controlled clinical trials of sotalol, of whom 24 had torsade de pointes, a rate of approximately 2% [22]. Similarly, Hohnloser reported a 2.4% rate for torsade de pointes in a meta-analysis of 3257 patients treated with sotalol [23].…”