Influence of Dofetilide on QT-Interval Duration and Dispersion at Various Heart Rates During Exercise in Humans
Background The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects.
Methods and Results Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest 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. QTmax and QTmin were calculated similarly, and QT-interval dispersion was measured as QTmax−QTmin at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration 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 heart 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 dofetilide at either dose significantly increased QT-interval dispersion at any heart rate.
Conclusions Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.
Dofetilide is a selective potassium-channel blocker1 currently in the late phase of development for the treatment of a broad range of supraventricular and ventricular tachyarrhythmias and the prevention of sudden cardiac death. Dofetilide acts primarily by prolonging action-potential duration.2 This effect is associated with a parallel increase in the amount of time during which myocardial cells remain inexcitable. The latter effect is presumed to be the main mechanism of action of class III antiarrhythmic drugs. However, experimental as well as clinical data suggest that the prolongation of ventricular repolarization corresponding to a long QT interval on ECG recordings can be both antiarrhythmic and arrhythmogenic3 because it may be a possible risk factor for torsade de pointes arrhythmia.4 5 6
Another potentially arrhythmogenic effect has been identified as QT dispersion. QT dispersion has been defined as the difference between the maximum and minimum QT intervals measured from any of the 12 standard ECG leads. QT dispersion could reflect inhomogeneity of myocardial repolarization. Therefore, QT dispersion may provide a potential measure of arrhythmogenic risk7 8 9 10 because heterogeneity of repolarization times in adjacent areas of the heart can lead to a situation in which some cells are fully repolarized and others are not. The current flow (“boundary current”) between such areas of different transmembrane potentials may be sufficient in some cases to generate cardiac arrhythmias. Thus, dispersion of refractoriness may contribute to the genesis and maintenance of cardiac arrhythmias because of facilitation of nonuniform activation of ventricular muscle by a propagating wave front.11
The effects of class III antiarrhythmic agents on ventricular repolarization have been studied extensively.12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Most antiarrhythmic agents that lengthen action-potential duration exhibit reverse rate dependence, ie, the prolongation of the action-potential duration is most marked at slow heart rates, and the magnitude of the prolongation declines as the heart rate is increased.14 16 17 Several animal studies19 23 28 have shown an increase in action-potential duration and a reverse rate dependence of this effect with dofetilide. Moreover, dofetilide has been shown to reduce the dispersion of repolarization in anesthetized dogs by rapid pacing.13 In humans, Sedgwick et al24 25 showed that dofetilide was able to increase the duration of the QT interval but that it did not induce any significant QT dispersion. No reverse rate-dependence phenomenon was observed for the QT-prolongation effect.25 29 However, in those studies, only a limited range of changing heart rates was screened to study reverse rate dependence, and the physiological effects of heart rate on QT dispersion were not evaluated.
Thus, the aim of the present study was to analyze the effects of heart rate on QT-interval duration and dispersion at different dofetilide plasma concentrations in healthy subjects. Physiological stress tests were performed to induce a wide variation of heart rate (between 60 and 150 bpm, ie, 400 ms ≤RR interval ≤1000 ms) after repeated administration of dofetilide and placebo.
The rate dependence of dofetilide-induced QT prolongation and QT dispersion was studied in a controlled, randomized-sequence, three-period, crossover study in 12 healthy, nonsmoking, male volunteers (age, 22.3±3.0 years [mean±SD]). No subject showed any abnormalities on routine medical examination, 12-lead ECG, 24-hour ambulatory Holter ECG recording, or standard laboratory tests. Each of them gave informed written consent to participate in the study. The protocol was approved by the Committee for the Protection of Human Subjects in Biomedical Research of Pitie´-Salpeˆtrie`re University Hospital, Paris, France.
During three different study periods, two doses of dofetilide (0.25 and 0.75 mg) or placebo were administered BID to the subjects over a 3-day period, with one last dose given on day 4. These two doses were chosen because they represent the low and middle range of doses used in phase II and III clinical trials with dofetilide.32 33 The order of the periods was randomized. There was a washout phase of at least 1 week between each study period. Subjects were hospitalized at the Clinical Pharmacology Unit at Saint-Antoine University Hospital during each study period.
Exercise Tolerance Tests
On the morning of the fourth day of each study period, ie, after the pharmacokinetic steady state of dofetilide was reached,31 34 subjects performed two ETTs. The first was performed before dosing and the second 2 hours after administration of the last dose, ie, at the time of expected maximum dofetilide plasma concentration.31 Several ECG recordings were obtained before the test after the subject had rested for 10 minutes in the supine position in a quiet room and then with the subject in the sitting and standing positions. Additional recordings were obtained during the course of a submaximal exercise test performed on a bicycle ergometer (Siemens model EM840). The ETT involved successive load levels of 3 minutes each, increasing by 30 W until a heart rate of 160 bpm was reached. Tracings were recorded every 30 seconds during the test.
Measurement of QT Intervals
All ECG recordings were made simultaneously in 12 leads at a paper speed of 50 mm/s (amplitude, 1 mV=2 cm) with the use of a Case 15 recorder (Marquette Electronics, Inc). The tracings were recorded as median-linked complexes performed by the Case 15 device to obtain the best possible tracing quality, especially during exercise. For each subject and each ETT, a set of ≥30 ECGs was obtained for all recordings (resting supine, sitting, standing, and exercise). The ECG recordings were read by the same blinded investigator at the end of the three treatment periods. QT intervals were measured manually by use of a digitizing pad (SummaSketch II Professional MM II 1812, Summagraphics) connected to a microcomputer.
The anterior ECG lead in which the T wave had the largest amplitude was selected for QT-interval measurement in each subject (lead V2 was chosen in five subjects, lead V3 in six, and lead V4 in one). The QT interval was measured from the onset of the QRS complex to the end of the T wave, which was defined according to the criteria of Lepeschkin and Surawicz.35 Because a notched T wave could represent TU fusion, according to Lepeschkin and Surawicz,35 the intersection of the tangent to the downslope of the major repolarization wave with the isoelectric line was used in the presence of a TU wave.
For measurement of QT dispersion, QT intervals were measured in all interpretable leads in the same way as described above. For each simultaneous 12-lead ECG recording, QTmax and QTmin were assessed. When a flat T wave or P wave distorted the end of the preceding T wave (at fast heart rates), the duration of the QT interval could not be measured. ECG recordings with <5 measurable QT intervals were excluded from QT-dispersion analyses (Table 1⇓).
QT-interval dispersion was also measured as the standard deviation of QT-interval values in all measurable leads.36
Dofetilide Plasma Concentrations
Blood samples for the determination of plasma dofetilide concentration were drawn just before the last administration of drug or placebo on day 4 (trough at steady state) and before the second ETT (expected peak). A 10-mL blood sample was collected in a heparinized tube from an antecubital vein. Blood was immediately centrifuged and separated. Plasma samples were stored in screw-capped polypropylene tubes at −20°C. After completion of the study, the samples were assayed for dofetilide by use of a previously validated radioimmunoassay method37 (Huntington Research Centre).
For each subject and for each ETT, a set of ≥30 RR cardiac cycle length–QT interval pairs was obtained from all ECG recordings. The QT versus RR relation was analyzed during each ETT and was fitted to the monoexponential formula16 38 39 QT=A−B×exp(−C×RR), where QT and RR are the observed data and A, B, and C are the regression parameters. This formula has been shown to be optimal to describe the QT versus RR relation during exercise.16 38 39 The three regression parameters were used to calculate the QT interval of each subject during each ETT corresponding to predetermined RR intervals of 1000, 900, 800, 700, 600, 500, and 400 ms. QT intervals were calculated between the limits of RR intervals for which QT-interval measurement was actually feasible. Dofetilide-induced QT prolongation was analyzed during the ETT before administration of the last dose (steady-state trough) and the ETT performed 2 hours after the last administration (steady-state peak) and compared with placebo.
Similarly, separate fitted, monoexponential curves were obtained from the RR-QTmax and RR-QTmin pairs, and each predetermined RR was associated with one QTmax and one QTmin; QT-interval dispersion was the difference between QTmax and QTmin. The QT-dispersion analyses were made only from the ETT performed 2 hours after the last administration (steady-state peak).
Dofetilide-Induced Changes in QT-Interval Prolongation and Duration
The variation (Δ) of QT interval and QT dispersion during dofetilide was calculated as the ratio Δ (%)=100×(valuetreatment−valueplacebo)/valueplacebo. The analysis of heart rate influence was made only from the ETT performed 2 hours after the last administration (steady-state peak).
Analysis of QT-Interval Prolongation and QT Dispersion
Treatment comparisons were made with three-factor (treatment, subject, and period) repeated ANOVA. If this analysis indicated a significant difference, a Student-Newman-Keuls post hoc test was performed to compare mean QT interval or mean QT dispersion between active treatments and placebo.
Analysis of Rate Dependency
For each dofetilide period, variations of QT prolongation and QT dispersion were compared by use of a two-factor (RR interval and subject) ANOVA. If the analysis indicated a significant difference, a Student-Newman-Keuls post hoc test was performed to compare the variations of QT-interval prolongation and QT dispersion between the different RR intervals.
A value of P<.05 was considered statistically significant. Results are expressed as mean±SD unless otherwise indicated.
Effects of Dofetilide on QTU-Interval Morphology
No ECG showed a TU wave during administration of placebo. Two of the 12 subjects (subjects 11 and 12) exhibited significant TU waves 2 hours after administration of dofetilide 0.25 mg. Three additional subjects (subjects 1, 7, and 8) also had TU waves after administration of dofetilide 0.75 mg (Table 1⇑).
Effects of Dofetilide on QT-Interval Duration
QT-Interval Prolongation Before Dofetilide Administration
After 3 days of repeated administration, dofetilide significantly increased QT-interval duration at the higher dose of 0.75 mg BID, whereas the effects of the lower dose of 0.25 mg BID were not significantly different from placebo (Table 2⇑).
QT interval at rest (RR=1000 ms or HR=60 bpm) significantly increased from 372±20 ms with placebo to 396±26 ms with dofetilide 0.75 mg (P<.05). This corresponds to a 6.7±2.7% increase compared with placebo. The effects of the 0.25-mg dose of dofetilide did not reach the significance level.
During ETT, QT-interval duration decreased as heart rate increased. Fig 1a⇓ shows the QT versus RR curve in one representative subject during placebo and dofetilide administration. Fig 2a⇓ represents the mean±SD effects of dofetilide on QT interval compared with placebo. At the dose of 0.75 mg BID, dofetilide-induced QT prolongation remained significant at all tested heart rates compared with placebo in all subjects (Table 2⇑; Fig 2a⇓).
QT-Interval Prolongation 2 Hours After Dofetilide Administration
QT interval at rest significantly increased from 362±19 ms with placebo to 392±25 ms with dofetilide 0.25 mg (P<.01) and to 424±38 ms with dofetilide 0.75 mg (P<.01). These effects correspond to increases of 7.5±5.7% and 16.7±8.7%, respectively.
During ETT, a dofetilide-induced increase of QT-interval duration was observed at all RR intervals. This increase was significant with both doses but was significantly more pronounced with the higher dose (Fig 2b⇑).
The reverse rate-dependence phenomenon for QT duration was only observed with the higher dose of dofetilide (Fig 3b⇓). Indeed, compared with placebo, QT-interval prolongation decreased from 16.7±8.7% at RR=1000 ms (HR=60 bpm) to 7.4±8.2% at RR=400 ms (HR=150 bpm). However, the phenomenon was limited because there was no significant variation in the increase in QT interval between RR values ranging from 1000 to 500 ms (HR=120 bpm) (Table 3⇓). With the lower dose of dofetilide, no significant reverse rate-dependence phenomenon was observed (Table 3⇓; Fig 3a⇓).
QT Prolongation and Dofetilide Plasma Concentration
Dofetilide plasma concentrations were measured four times during the study (peak and trough at steady state for each dosing). Mean trough dofetilide plasma concentrations were 0.53±0.13 μg/L (range, 0.22 to 0.72 μg/L) with dofetilide 0.25 mg and 1.73±0.18 μg/L (range, 1.49 to 2.14 μg/L) with dofetilide 0.75 mg. Corresponding values at peak were 1.14±0.28 μg/L (range, 0.64 to 1.65 μg/L) and 3.65±0.48 μg/L (range, 2.78 to 4.32 μg/L).
Fig 4⇓ shows that dofetilide-induced QT-interval prolongation was dose and plasma-concentration dependent. QT-interval prolongation appeared to be prolonged in relation to increased dofetilide plasma concentrations only when the relation was plotted with QT intervals obtained at RR intervals ≥500 ms. The QT interval tended to remain unchanged with increasing dofetilide plasma concentrations when the relation was plotted with QT intervals obtained at an interval of 400 ms.
Fig 5⇓ shows the QT-interval dispersion observed and the monoexponential curve fittings (QTmax and QTmin) in one representative subject after placebo and dofetilide administrations.
QT Dispersion and Placebo
At rest, mean QT-interval dispersion was equal to 27.2±10.7 ms. Heart rate did not influence QT-interval dispersion during placebo. Indeed, during ETT, when heart rate increased, mean QT-interval dispersion values remained between 22.9±18.1 and 33.4±12.9 ms (P=NS; Table 4⇓).
QT Dispersion and Dofetilide
Dofetilide at both administered doses did not significantly increase QT-interval dispersion at rest or during ETT (Table 4⇑; Fig 6⇓). Mean QT-interval dispersion during dofetilide 0.25 mg BID ranged from 22.9±7.3 to 39.4±16.6 ms at all heart rates tested. QT-interval dispersion during dofetilide 0.75 mg BID ranged from 38.2±16.1 to 52.5±34.3 ms at all heart rates tested. Heart rate had no significant influence on QT dispersion during dofetilide administration.
Similar results were obtained when QT dispersion was measured as the standard deviation of QT-interval values in all measurable leads.
Dofetilide was well tolerated by all subjects. No side effects were reported, and no arrhythmias were detected on Holter recordings during the first 2 days of each period.
The results of this study confirm that administration of dofetilide 0.75 mg BID prolongs ventricular repolarization time in humans as measured by QT-interval duration. After 3 days of treatment, these effects were significantly different from placebo at trough (before administration) and peak (2 hours after administration) steady-state plasma concentrations of dofetilide. However, administration of dofetilide at a lower dose of 0.25 mg BID was associated with significant QT-interval prolongation only at peak dofetilide plasma concentrations.
QT prolongation remained significant compared with placebo when heart rate increased during ETT. Reverse rate dependence was observed during administration of 0.75 mg dofetilide BID because QT-interval prolongation was less pronounced at the highest tested heart rate of 150 bpm than at lower heart rates. However, QT-interval prolongation remained significant compared with placebo at all heart rates, even 150 bpm.
Repeated dofetilide administration did not result in an increased QT-interval dispersion in healthy subjects even at peak plasma concentrations, and physiological variations in heart rate did not significantly modify the difference between maximal and minimal QT-interval values.
QT-Interval Prolongation and Reverse Rate Dependence
Sedgwick et al24 studied the pharmacodynamic effects of intravenous doses of dofetilide in 18 patients with coronary artery disease. After a 10-minute infusion, mean QT and QTc intervals increased in comparison with baseline values. There was a linear correlation between dofetilide plasma concentrations and changes in QTc. In a previous study,31 we also found a close relation between plasma concentration of dofetilide and QT-interval duration during intravenous and oral administration in healthy subjects. In another study, Sedgwick et al25 studied the effects of intravenous dofetilide or placebo on right ventricular monophasic action-potential duration and 12-lead ECG in 18 patients with ischemic heart disease. Monophasic action-potential duration increased significantly after dofetilide in comparison with placebo, and the mean peak QTc prolongation at the end of the loading infusion was prolonged by 10% compared with baseline. There was no evidence of reverse rate dependence of the monophasic action-potential duration when cardiac cycle lengths varied between 500 and 800 ms during pacing. Similarly, Yuan et al29 assessed the effects of dofetilide on ventricular repolarization and refractoriness as well as dispersion of repolarization during invasive electrophysiological testing in 10 patients with ventricular tachycardia. Monophasic action potentials were recorded before and after an intravenous infusion of dofetilide, and 12-lead ECGs were recorded. Monophasic action-potential duration, repolarization time, and QTc interval were significantly prolonged after dofetilide infusion during sinus rhythm and right ventricular pacing (cycle lengths of 600 and 500 ms). The effects of dofetilide on monophasic action-potential duration showed no reverse rate dependence. However, it should be noted that these studies using ventricular pacing were performed in patients with cardiac disease, in whom a wide range of heart rates could not be studied. Consequently, reverse rate dependence was difficult to determine within the range of the studied cardiac cycle lengths (500 to 800 ms). Moreover, dofetilide plasma concentrations observed in the study by Sedgwick et al25 were lower than in the present study and nearly corresponded to the trough dofetilide plasma concentrations we found during administration of dofetilide 0.75 mg BID (≈2 μg/L). Dofetilide has a terminal half-life between 6 and 12 hours, a peak plasma level 2 hours after oral absorption, and an absolute bioavailability of 92% and does not form active metabolite.31 34 In the present study, reverse rate dependence of dofetilide-induced QT-interval prolongation could be detected only at the higher dose of dofetilide when mean plasma concentrations were equal to 3.6±0.5 μg/L and when heart rate reached 150 bpm (400-ms cardiac cycle length). Consistent with previous studies in patients,25 29 no reverse rate dependence of dofetilide effects on ventricular repolarization was found at lower heart rates.
We studied the influence of heart rate on dofetilide-induced repolarization changes during the course of ETTs. Exercise is associated with an increase in plasma potassium levels.40 Such an increase in extracellular potassium level has recently been shown41 to decrease dofetilide-induced block of the IKr current. Therefore, the method we used to increase heart rate, ie, exercise, should have favored the documentation of a reverse rate-dependence phenomenon. It is conceivable that dofetilide-induced QT-interval prolongation at short cycle lengths would have been even more pronounced if we had used pacing to increase the heart rate. Thus, we believe that our results may be extrapolated to the changes in heart rates produced by ventricular or supraventricular arrhythmias.
Although not proven, it is generally considered that the reverse rate dependence of action-potential prolongation by class III antiarrhythmic drugs may limit their efficacy in the presence of tachyarrhythmia.14 17 Dofetilide has been shown to have this property in animal and in vitro studies.1 19 23 28 An in vitro electrophysiological patch-clamp study27 showed that sensitivity to block of the IKr current by dofetilide was rate independent. The magnitude of IKs was increased by rapid pacing, a result of incomplete deactivation of IKs during the abbreviated interpulse intervals. It was concluded that action-potential duration prolongation by dofetilide was a result of IKr block. However, incomplete deactivation of IKs partially offsets the rate-independent block of IKr, resulting in reverse rate dependence.
It must be emphasized that the reverse rate dependence of dofetilide-induced QT prolongation remains limited compared with the amplitude of this phenomenon, which has been found with other class III antiarrhythmic agents.16 17 Indeed, compared with placebo, dofetilide administration was associated with a significant QT-interval prolongation even at high heart rates (150 bpm). The persistence of a significant class III effect of dofetilide at rapid heart rates may be linked to the slow recovery rate of potassium-channel block with this drug.42 Persistent QT-interval prolongation at rapid heart rates could be of interest to explain the persistence of an antiarrhythmic effect of dofetilide during rapid ventricular tachycardia.
In the present study, dofetilide did not change QT-interval dispersion compared with placebo. Sedgwick et al25 showed that no significant change in the dispersion of monophasic action-potential repolarization was detected at any cycle length during dofetilide administration. Dofetilide did not produce any increase in interlead QT-interval dispersion. In a study by Yuan et al,29 dispersion of the repolarization, defined as the difference in ventricular repolarization duration between two sites in the right ventricle, was not significantly changed by dofetilide.
Our study was performed in young, healthy, male volunteers. Women were not included in this phase I study to limit the sex-related source of variability in QT-interval duration. Therefore, it is conceivable that our results may not apply to women.
Also, the rate dependence of dofetilide-induced QT prolongation was examined during the diurnal period. QT-interval duration is influenced by the autonomic nervous system.43 Our study, therefore, does not exclude the possibility that dofetilide-induced QT prolongation exhibits reverse rate dependence during the night. This possibility is currently being examined by use of Holter recordings.
The clinical significance of a drug-induced lengthening of the QT interval is still controversial. There is no direct relation between the degree of lengthening of the QT interval and the risk of development of torsade de pointes. However, prolongation of the QT interval may provide the substrate for either an antiarrhythmic effect with a modulated lengthening of the effective refractory period (class III action) or a proarrhythmic effect (torsade de pointes) when a set of associated features, such as hypokalemia, bradycardia, and delayed conduction, alters membrane stability and induces triggered activity. In the present study, dofetilide increased the QT-interval duration in a dose- and plasma concentration–dependent way. We observed a limited reverse rate dependence of QT-interval prolongation only at the higher dose of dofetilide when plasma concentrations reached 1.7 μg/L at trough and 3.7 μg/L at peak. These effects might be more pronounced in patients with a slower elimination rate of the drug, and the dofetilide effects on QT-interval duration that we found in normal subjects might differ, for example, in patients with heart disease or renal failure.
If QT-interval dispersion represents an index of arrhythmogenicity, an action that leads to decreased QT-interval dispersion should also lead to a reduced risk. In contrast with other studies that used sotalol,7 20 we and others25 29 did not find any significant change in QT-interval dispersion during dofetilide administration. It has been suggested that the risk of drug-induced torsade de pointes is associated with increased QT-interval dispersion and that QT-interval prolongation without increased QT-interval dispersion may limit the risk of torsade de pointes. Our results suggest that dofetilide may have an appropriate pharmacodynamic profile in this respect. However, interpretation of results from studies performed to assess the clinical accuracy of QT-interval dispersion is difficult because the methodology used to determine QT-interval dispersion varies between studies.8
In conclusion, dofetilide increased QT-interval duration in a dose- and plasma concentration–dependent way but did not increase QT-interval dispersion in healthy volunteers. QT-interval prolongation remained significant even at high heart rates, although some degree of reverse rate dependence was observed at the high concentration of dofetilide. Because the effects of dofetilide on QT-interval duration are plasma-concentration dependent, special care should be taken and lower doses should be used in patients with slower elimination of the drug.
Selected Abbreviations and Acronyms
|bpm||=||beats per minute|
|ETT||=||exercise tolerance test|
|IKr||=||rapidly activated component of delayed K+ current|
|IKs||=||slowly activated component of delayed K+ current|
This work was supported by a grant from Pfizer Central Research. The authors also thank Franc¸oise Gloaguen, RN, for technical assistance.
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995, and published in abstract form (Circulation. 1995;92[suppl I]:I-276).
- Received January 10, 1996.
- Revision received April 16, 1996.
- Accepted April 24, 1996.
- Copyright © 1996 by American Heart Association
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