A randomized, double-blind, placebo-controlled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias.
BACKGROUND
Dofetilide is a new antiarrhythmic agent with potent IK blocking properties in vitro. We developed a dose-ranging, placebo-controlled study design to define the range of effective doses and to evaluate the clinical electrophysiology of intravenous dofetilide in patients in whom sustained ventricular tachycardia or fibrillation was reproducibly inducible at baseline electrophysiologic testing.


RESULTS
The initial four patients received low doses that were increased in subsequent groups of four if adverse effects were absent. In each group of four patients, one patient was randomly assigned to placebo (double blind). Twenty-four patients were studied at six incremental loading and maintenance infusion regimens. Dofetilide (0.1 to 8.0 ng/mL) produced concentration-related increases in the % delta of QT (r = 0.79, P < 0.001), QTc (r = 0.60, P = 0.02), RR (r = 0.62, P < 0.02), and right ventricular effective refractory period (cycle length 600 msec; r = 0.68, P = 0.04). Placebo produced no changes in any of these measurements. Sustained ventricular tachycardia or ventricular fibrillation was no longer inducible in 1 of 6 patients receiving placebo and 8 of 18 receiving dofetilide (4 to 13 sec nonsustained ventricular tachycardia was induced in 4 of these 8). One patient developed torsades de pointes at a high concentration (5.3 ng/mL).


CONCLUSIONS
We conclude that: (1) dofetilide produces concentration-related IK blocking effects in patients; (2) an incremental dose-ranging study design aids in identifying the range of doses demonstrating electrophysiologic effects and efficacy; (3) a concomitant placebo group provides important data to assess reproducibility of results over time; and (4) further studies of dofetilide's efficacy and toxicity should be conducted.
Echt
D S
DS
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Lee
J T
JT
Murray
K T
KT
Vorperian
V
V
Borganelli
S M
SM
Crawford
D M
DM
Friedrich
T
T
Roden
D M
DM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010627:Phenethylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide