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CLINICAL STUDY: ELECTROPHYSIOLOGY

Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide

A placebo-controlled, implantable cardioverter-defibrillator-based evaluation

Alexander Mazur, MD^*, Mark E. Anderson, MD, PhD^*, Sharon Bonney, MD and Dan M. Roden, MD, FACC^*

^* Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Pfizer Central Research, Groton, Connecticut, USA

Manuscript received July 26, 2000; revised manuscript received October 16, 2000, accepted December 13, 2000.

Reprint requests and correspondence: Dr. Dan M. Roden, Division of Clinical Pharmacology, Vanderbilt University, 532C Medical Research Building I, 23rd Avenue South at Pierce Avenue, Nashville, Tennessee 37232-6602
dan.roden{at}mcmail.vanderbilt.edu

OBJECTIVES

To compare the incidence of pause-dependent polymorphic ventricular tachycardia (PVT) in patients with implantable cardioverter-defibrillators (ICDs) randomly assigned to the QT-prolonging antiarrhythmic dofetilide or placebo.

BACKGROUND

Drug-related torsade de pointes (TdP) is usually recognized within days of initiating therapy, but its incidence during long-term therapy is unknown.

METHODS

We assessed the frequency of TdP and ICD electrograms compatible with TdP in a multicenter study that randomized ICD patients to placebo (n = 87) or dofetilide (n = 87). As reported elsewhere, the number of patients with a primary trial end point (ICD intervention for VT or ventricular fibrillation) was similar in the two groups. For this analysis, a qualifying event was TdP (on electrocardiogram) or an intracardiac electrogram showing pause-dependent PVT.

RESULTS

A total of 620 electrograms obtained in 131 patients were analyzed blindly by prospectively defined criteria for episodes of pause-dependent polymorphic VT. These were identified in 15/87 (17%) patients receiving dofetilide and 5/87 (6%) patients on placebo (p < 0.05). Five of these episodes were early (<3 days), all of which were TdP on dofetilide. There were 15 late events, 10 on dofetilide and five on placebo (p = 0.29). The median time to a late event was 22 days (range 6 to 107 days) for dofetilide and 99 days (range 34 to 207 days) for placebo.

CONCLUSIONS

Pause-dependent PVT was more common among patients receiving dofetilide, although total VT incidence was similar in the two groups. These data suggest that in ICD patients either long-term dofetilide therapy is associated with an increased risk of TdP or the drug alters VT morphology.

Abbreviations and Acronyms   ICD = implantable cardioverter-defibrillator   MVT = monomorphic ventricular tachycardia   PVT = polymorphic ventricular tachycardia   TdP = torsade de pointes   VF = ventricular fibrillation   VT = ventricular tachycardia

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