Jl. Demolis et al., INFLUENCE OF DOFETILIDE ON QT-INTERVAL DURATION AND DISPERSION AT VARIOUS HEART-RATES DURING EXERCISE IN HUMANS, Circulation, 94(7), 1996, pp. 1592-1599
Background The objective of this study was to assess the influence of
heart rate on QT-interval duration and dispersion during administratio
n of the new selective potassium-channel blocker dofetilide in normal
subjects. Methods and Results Dofetilide 0.25 and 0.75 mg was administ
ered for 4 days to 12 subjects in a randomized-sequence, double-blind,
three-period, placebo-controlled, crossover study. QT-RR pairs were m
easured on study day 4 over a wide range of RR intervals obtained at r
est and during an exercise test. QT-interval durations were calculated
at seven predetermined RR intervals ranging from 400 ms (150 bpm) to
1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QT
(max) and QT(min) were calculated similarly, and QT-interval dispersio
n was measured as QT(max)-QT(min) at each predetermined RR interval. M
inimal effects were found with 0.25 mg dofetilide. Two hours after adm
inistration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 /- 8.7% at a heart rate of 60 bpm (P<.01) and by 7.4 +/- 8.2% at a hea
rt rate of 150 bpm (P<.05). QT prolongation at a heart rate of 150 bpm
was less pronounced than at lower heart rates. Neither placebo nor do
fetilide at either dose significantly increased QT-interval dispersion
at any heart rate. Conclusions Dofetilide increases QT-interval durat
ion but does not increase QT-interval dispersion in healthy subjects.
QT-interval prolongation remains significant at high heart rates, alth
ough some degree of reverse rate dependence is observed at high concen
trations.