There is increasing evidence that class III antiarrhythmic agents may be superior to class I agents for the long-term treatment of life-threatening
ventricular tachyarrhythmias. This open study evaluated the acute electrophysiologic effects, antiarrhythmic efficacy, and safety of different doses of intravenous
dofetilide, a new class III
drug, in 50 patients with sustained monomorphic
ventricular tachycardia inducible by programmed electrical stimulation who had previously been unsuccessfully treated with 0 to 7 (median 3) other drugs. Intravenous
dofetilide was administered over 60 minutes at the following dose levels: 1.5, 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Significant class III activity was apparent at doses of 3.0 to 15.0 micrograms/kg, as evidenced by dose-related prolongation of the QTc interval by 13.4% to 14.2%, ventricular effective refractory period by 7.9% to 20.6%, and ventricular functional refractory period by 7.3% to 25.0%. The corresponding mean +/- SD plasma
dofetilide concentrations ranged from 1.45 +/- 0.52 to 6.48 +/- 1.31 ng/ml. There was no evidence of reverse use-dependence. At these electrophysiologically active dose levels, intravenous
dofetilide suppressed (complete response) or slowed (partial response) inducible
ventricular tachycardia in 17 of 41 patients (41%) compared with 0 of 9 patients receiving only 1.5 micrograms/kg. The response rate was fairly uniform among the groups receiving 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Intravenous
dofetilide was hemodynamically well tolerated.
Torsades de pointes (which was self-limiting) developed in only 1 patient, who was allocated to receive 15.0 micrograms/kg. There were no other proarrhythmic episodes or serious adverse effects. Further evaluation of the therapeutic potential of
dofetilide in the management of life-threatening ventricular arrhythmias is justified.