A Randomized, Double‐Blind, Placebo‐Controlled, Dose‐Ranging Study of Dofetilide in Patients with Inducible Sustained Ventricular Tachyarrhythmias

Echt, Debra S.; Lee, John Tayu; Murray, Katherine T.; Vorperian, Vicken R.; Borganeeli, S. Marcus; Crawford, Matthew; Friedrich, Tilman; Roden, Dan M.

doi:10.1111/j.1540-8167.1995.tb00445.x

Cited by 33 publications

(15 citation statements)

References 25 publications

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“…In addition, dofetilide treatment was associated with a significantly increased rate of successful antitachycardia pacing in ICD patients. These data are consistent with two small studies showing dofetilide was also effective in acutely suppressing inducible sustained ventricular tachycardia during serial electrophysiologic testing in approximately 45% of patients [41,42].…”

Section: Dofetilidesupporting

confidence: 92%

Pharmacological Treatment of Atrial Fibrillation: Mechanisms of Action and Efficacy of Class III Drugs

Lombardi¹,

Terranova

2006

CMC

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Atrial fibrillation represents a major clinical, social and economical matter, and its importance is expected to increase even more in the near future. The progressive ageing of population is associated with an inevitable rising in incidence and prevalence of this rhythm disorder, which limits functional capability, favours occurrence of cerebrovascular events and increases people's request for emergency room visits and hospital recovery. In spite of the increasing successes of the interventional non-pharmacological therapies, drug treatment of patients with atrial fibrillation in relation to conversion to sinus rhythm and prevention of recurrences, maintains a critical role. Several antiarrhythmic drugs are nowadays available, but their efficacy is limited by the high rate of arrhythmias recurrences and by side effects during acute and chronic treatment. Drugs interfering with potassium channels (Class III drugs) have been proposed and used in patients with atrial fibrillation. Aim of this review is to discuss the most recent data on the efficacy and feasibility of class III drugs in atrial fibrillation. Experimental and clinical data on dronedarone, ibutilide, dofetilide, azimilide, ersentilide and ambasilide will be hereby discussed.

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Section: Dofetilidesupporting

confidence: 92%

Pharmacological Treatment of Atrial Fibrillation: Mechanisms of Action and Efficacy of Class III Drugs

Lombardi¹,

Terranova

2006

CMC

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“…When administered to patients undergoing electrophysiological studies, 19,[47][48][49] the primary effects of dofetilide are seen on the refractory periods of atrial and ventricular muscle. Dofetilide has no effect on PR, QRS, or HV intervals.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…In a small dose-ranging study, Echt et al 49 showed that 8 of 18 patients had suppression of inducible sustained arrhythmia during serial electrophysiologic studies. Bashir et al 48 reported the results of an intravenous dose-ranging study in 41 patients with inducible sustained monomorphic ventricular tachycardia.…”

Section: Ventricular Arrhythmias and Mortality Trialsmentioning

confidence: 99%

Dofetilide

2000

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Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released. Basic ElectrophysiologyCardiac depolarization results principally from the flow of inward Na ϩ and Ca 2ϩ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K ϩ currents. Early repolarization results from a transient outward current, I TO , which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K ϩ currents, I K , which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.I K can be separated pharmacologically into 2 components: a rapidly activating component, I Kr , and a slower component, I Ks , each carried by a separate ion channel molecule. 1,2 HERG channels are responsible for I Kr , whereas I Ks flows through KvLQT1 channels. Specific blockers of I Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific I Kr blockers include the methanesulfonanilide agents dofetilide, E4031, almokalant, and D-sotalol. Effects of Dofetilide on I krDofetilide blocks I Kr in all myocardial tissues with high potency (50% effective concentration [EC 50 ] in the nanomolar range). Block is voltage dependent and most prominent at depolarized potentials. 1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval. 1 Dofetilide block of I Kr increases as extracellular potassium concentration ([K]o) is reduced. 6 This sensitivity of dofetilide block to [K]o is of obvious clinical importance. Even moderate hypokalemia would be expected to disproportionately increase action potential prolongation induced by dofetilide, and correction of hypokalemia is of crucial importance in treating QT prolongation and torsade de pointes caused by I Kr blockade. Conversely, hyperkalemia blunts the effect of dofetilide, 7 suggesting the possibility of reduced efficacy after acute coronary occlusion or during rapid heart rates, when local cardiac tis...

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“…In a study by Echt et al, 42 24 patients with inducible ventricular tachycardia received an intravenous dose of either placebo or dofetilide in a double-blind, dose-ranging investigation. A series of increasing dofetilide doses was administered in order to achieve plasma concentrations ranging from 0.25 to 4.5 ng/mL.…”

Section: Ventricular Dysrhythmiasmentioning

confidence: 99%