Download Pause-dependent polymorphic ventricular tachycardia

Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 37, No. 4, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(01)01106-8
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,†
Dan M. Roden, MD, FACC*
Nashville, Tennessee and Groton, Connecticut
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. (J Am Coll Cardiol 2001;37:1100 –5) © 2001 by the American College of
Cardiology
OBJECTIVES
Drugs that prolong the QT interval can suppress arrhythmias by lengthening myocardial refractoriness but also may
produce the pause-dependent polymorphic ventricular
tachycardia (PVT) torsade de pointes (TdP). Most agents
causing TdP block the rapid component of the outward
delayed rectifier repolarizing potassium current, IKr, and
See page 1106
most cases of drug-related TdP are recognized within days
of initiating therapy (1). Thus, close in-hospital monitoring
during initiation of antiarrhythmic therapy is generally
From the *Departments of Medicine and Pharmacology, Vanderbilt University
Medical Center, Nashville, Tennessee, and †Pfizer Central Research, Groton,
Connecticut. This work was supported by NIH grants HL46681, HL49989 (to
DMR), HL03727, HL62494 (to MEA), by American Heart Association Grant in
Aid, S.E. Affiliate (to MEA) and by Pfizer Central Research. Dr. Roden is the holder
of the William Stokes chair in Experimental Therapeutics, a gift of the Dai-ichi
Corporation. Dr. Mazur was supported in part by the Israeli Pacing Foundation. This
work was performed in part to fulfill requirements for cardiology certification in Israel
for Dr. Mazur.
Manuscript received July 26, 2000; revised manuscript received October 16, 2000,
accepted December 13, 2000.
advocated to reduce potential risk for TdP (2– 4). Reports of
the incidence of TdP with various QT interval-prolonging
agents (0.5% to 8%) usually refer to the first several hours or
days of therapy (2,4 –7). Although it is well recognized that
drug-related TdP can occur during long-term therapy (2,3),
the incidence during chronic therapy is unknown.
Drug-related TdP is associated with a pause-dependent
(“short-long-short”) pattern of initiation and with QT
interval dispersion in the surface electrocardiogram (ECG)
(1,8). These patterns are consistent with experimental data
implicating pause-dependent afterdepolarizations as the
trigger and dispersion of refractoriness as a marker for
favoring functional reentry to sustain TdP (8,9). Studies
utilizing analysis of stored implantable cardioverterdefibrillator (ICD) recordings found that 14% to 26% of
episodes of monomorphic VT (MVT) had a pausedependent onset similar to that preceding TdP (10,11). It
has also been reported that this mode of onset is associated
with increased QT dispersion in the surface ECG (10).
These observations suggest a role for enhanced dispersion of
refractoriness not only in TdP but also in MVT. It is
conceivable, therefore, that action potential prolonging
JACC Vol. 37, No. 4, 2001
March 15, 2001:1100–5
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
agents might facilitate the initiation of MVT in patients
with an underlying anatomical substrate for reentry.
Dofetilide is a new, highly selective and potent IKrblocking antiarrhythmic agent (12,13). The drug has been
shown to prolong action potential and QT interval duration
in a concentration-dependent manner (12,14). Data from
two large randomized, placebo-controlled clinical trials
indicate that dofetilide is effective in the conversion to and
maintenance of sinus rhythm in patients with persistent
atrial fibrillation (15,16). In another large placebocontrolled study, dofetilide did not affect mortality in
high-risk patients with congestive heart failure and severe
left ventricular dysfunction (17). In small dose-ranging
studies, dofetilide was also found to be effective in acute
suppressing inducible sustained VT during serial electrophysiologic testing in 43% to 46% of patients (18,19).
Torsade de pointes has been well recognized early in
treatment with dofetilide (15–18,20). However, as with
other drugs, the incidence of this problem during long-term
treatment is unknown. In a double-blind, placebocontrolled study in patients with ICDs, dofetilide did not
affect the time to first ICD intervention (antitachycardia
pacing or shock) for VT or ventricular fibrillation (VF) (20).
The availability of this large cohort of patients at risk for
TdP (due to advanced structural heart disease) prompted
the analysis of ICD electrograms that we now report from
that study. Our goal was to determine the pattern of
arrhythmia onset (on surface ECG or from intracardiac
electrograms) in order to assess whether dofetilide enhances
the risk of TdP or polymorphic VT during long-term therapy.
METHODS
Study design. Stored intracardiac electrograms and surface
ECGs were obtained from 174 ICD patients randomized to
receive dofetilide (n ⫽ 87) or placebo (n ⫽ 87) during
therapy planned for up to one year (20). All ICDs were
capable of storing intracardiac electrograms; the vast majority (165/174) were Ventritex Cadence (St. Jude Medical,
St. Paul, Minnesota) devices. Drug therapy was initiated in
hospital for ⬎2 days in all subjects. Prior to initiation of
drug therapy, serum K⫹ level was ⱖ4 mEq/L. The starting
dofetilide dose, 500 ␮g twice daily, was adjusted downward
on the basis of estimated creatinine clearance or if the
corrected QT interval increased by 15% over baseline after
the start of dosing. Patients with a history of congenital or
drug-associated QT prolongation, and those with baseline
Mazur et al.
Dofetilide and Polymorphic VT
1101
Figure 1. An example of pause-dependent polymorphic ventricular tachycardia (VT) from stored implantable cardioverter-defibrillator recordings.
The initiation of VT (arrow) starts with a “short-long-short” sequence that
is followed by tachycardia with successively different electrogram morphologies. The numbers above the horizontal arrows show duration of RR
intervals in milliseconds. Asterisks indicate electrograms with morphologies similar to those in baseline rhythm.
QT prolongation or receiving QT prolonging drugs, were
not eligible for the study.
ICD therapies occurred in 131 patients. A total of 620
stored ICD electrograms obtained in these patients were
reviewed by two investigators blinded to the study group,
and only those recordings demonstrating arrhythmia onset
(at least three RR intervals preceding the arrhythmia event)
were accepted for further analysis. The following interval
measurements were made for each tachycardia: 1) two cycle
lengths preceding the last baseline electrogram; 2) mean
cycle length of the first 10 beats of tachycardia; and 3) the
coupling interval of the last baseline beat to the first beat of
tachycardia. All measurements were performed using calipers. Treatment groups were analyzed on an intention-totreat basis.
Definitions. The following prospectively formulated ICD
electrogram definitions were used: VT was defined as a
sudden change in rate and electrogram morphology compared with baseline rhythm. The tachycardia was considered
monomorphic when it displayed uniform electrogram morphology. The tachycardia was considered polymorphic
when: 1) each electrogram morphology was different from
the previous (a minimum 10 consecutive beats), and 2) the
mean cycle length of tachycardia in the first 10 beats was
ⱖ240 ms. Ventricular fibrillation was diagnosed if the
arrhythmia displayed a polymorphic electrogram morphology at a mean cycle length of ⬍240 ms or no distinct
isoelectric segment was present. Pause-dependent onset was
present when the cycle preceding the last baseline beat was
longer than both the preceding cycle and coupling interval
by more than 10% (“short-long-short” sequence). Pausedependent PVT was diagnosed if the duration of a PVT
episode was ⱖ10 beats (Fig. 1). This duration limit was set
because of the common phenomenon of the first beats of
MVT being different from the rest (11). Torsade de pointes
was defined by surface ECG as pause-dependent PVT
associated with QT interval prolongation and lasting ⱖ10
beats.
Statistical analysis. Mean ⫾ SD was calculated for continuous variables, and absolute and relative frequencies were
measured for discrete variables. Continuous variables were
compared between groups using Student t test, and categorical variables using Fisher exact test. The number of
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Dofetilide and Polymorphic VT
JACC Vol. 37, No. 4, 2001
March 15, 2001:1100–5
Table 1. Analyzed Stored ICD Electrograms
Placebo (n ⫽ 231)
Dofetilide (n ⫽ 174)
Total (n ⫽ 405)
Total VT/VF
PVT
MVT
VF
228 (99%)
166 (95%)
394 (97%)
32 (14%)
38 (22%)
70 (17%)
192 (84%)
127 (73%)
319 (79%)
4 (2%)
1 (1%)
5 (1%)
The data are presented as number of recordings (% of Total number of recordings for which there was an onset in the
corresponding group). n ⫽ total number of recordings for which there was an onset in the corresponding group.
ICD ⫽ implantable cardioverter-defibrillator; MVT ⫽ monomorphic ventricular tachycardia; PVT ⫽ polymorphic
ventricular tachycardia; VT ⫽ ventricular tachycardia; VF ⫽ ventricular fibrillation.
patients displaying pause-dependent polymorphic arrhythmia (PVT or TdP) on each therapy was compared by Fisher
exact test. A p value ⱖ0.05 was considered statistically
significant.
RESULTS
The clinical characteristics and preliminary analysis of the
study’s primary end point have been presented in abstract
(20). In brief, the placebo and dofetilide groups were
well-matched for gender (88% male), age (mean 64 years),
New York Heart Association functional class (57% class II),
percentage with ejection fraction ⬍35% (77%), concurrent
medications and primary arrhythmia diagnosis (21% VF;
79% VT). The 620 stored ICD electrograms were recorded
in 59 patients on dofetilide (266 recordings) and in 72
patients on placebo (354 recordings). A total of 405 recordings, 174/266 (64%) in the dofetilide group and 231/354
(65%) in the placebo group, included the onset of the
tachycardia and so were accepted for further analysis. Of
these, 166 (95%) electrograms from 49 patients receiving
dofetilide and 228 (99%) electrograms from 56 patients on
placebo met the criteria for VT/VF. A summary of stored
ICD electrograms analyzed according to the mode of
therapy and type of arrhythmia is presented in Table 1. The
total incidence of ventricular arrhythmia identified from
intracardiac electrograms or surface ECG did not differ
between the two groups: 56/87 (64%) on placebo and 55/87
(63%) on dofetilide.
Pause-dependent polymorphic ventricular arrhythmia
(PVT and TdP). Qualifying events were identified in
15/87 patients (17%) receiving dofetilide versus 5/87 patients (6%) on placebo (p ⬍ 0.05; Table 2). Five of these
events were early (⬍3 days on therapy), all of which were
typical ECG-defined TdP on dofetilide. There were 15 late
events (ⱖ3 days), 10 on dofetilide and five on placebo (p ⫽
0.29). Of the 15 patients with late events, the median time
on therapy was 22 days (range 6 to 107 days) for dofetilidetreated patients and 99 days (range 34 to 207 days) for
patients on placebo. The 15 late events included 12 cases of
pause-dependent PVT and three late cases of documented
TdP, two during treatment with dofetilide (days 8 and 289)
and one on placebo (day 64). The case of TdP in the placebo
group occurred shortly after treatment with amiodarone was
started following discontinuation of double-blind therapy
for lack of efficacy. Nine of 15 patients (60%) on dofetilide
and three of five patients (60%) on placebo had more than
one episode of the arrhythmia (range 2 to 6 for dofetilide
and 2 to 3 for placebo). All episodes of documented TdP
were terminated by a single ICD shock. Eight of 24 (33%)
late pause-dependent PVT episodes in the dofetilide group
and six of nine episodes (66%) in the placebo group
terminated spontaneously; the remaining episodes were
terminated by the ICD. The first QTc interval recorded in
13 patients after the occurrence of the first pause-dependent
episode of PVT did not differ significantly between those
receiving dofetilide (n ⫽ 9) versus placebo (n ⫽ 4); 495 ⫾
26 ms (range 447 to 530 ms) for dofetilide, and 468 ⫾
70 ms (range 380 to 576 ms) for placebo.
VT morphologies. Twenty-three percent of patients receiving dofetilide had either PVT or TdP, compared with
10% in the placebo group (p ⬍ 0.05; Table 2).
Monomorphic ventricular tachycardia was common and
its incidence was similar in the two groups: 47/87 (54%) on
placebo and 39/87 (45%) on dofetilide. Among patients
with MVT, multiple episodes occurred in 38/47 (80%)
patients on placebo and in 24/39 (61%) on dofetilide (p ⬍
0.05). Electrogram morphologies were similar among episodes in 25/38 (66%) patients on placebo and 18/24 (75%)
patients on dofetilide. The incidence of pause-dependent
MVT (Fig. 2) was similar in the two groups: 18% for
dofetilide and 20% for placebo. The pattern of initiation of
MVT in patients with multiple episodes was reproducible in
Table 2. Incidence of Polymorphic Ventricular Tachycardia by Patient
Placebo (n ⫽ 87)
Dofetilide (n ⫽ 87)
p
Total (n ⫽ 174)
Pause-Dependent
PVT*
TdP
Pause-Dependent
PVT ⴙ TdP†
Nonpause-Dependent
PVT
5 (6%)
9 (10%)
NS
1 (1%)
7 (8%)
NS
5 (6%)
15 (17%)
⬍ 0.05
4 (5%)
5 (6%)
NS
8 (5%)
20 (13%)
9 (5%)
14 (8%)
The data are presented as actual number of patients (% of total number of patients in the corresponding group). *Not including
TdP; †one patient in each group had both TdP and PVT on separate occasions.
n ⫽ number; PVT ⫽ polymorphic ventricular tachycardia; TdP ⫽ torsades de pointes.
JACC Vol. 37, No. 4, 2001
March 15, 2001:1100–5
Figure 2. Two examples of pause-dependent MVT. In both panels, the
initiation of MVT (open arrows) is preceded by characteristic “short-longshort” sequences. The numbers above the horizontal arrows show duration
of RR intervals in milliseconds. Asterisks in Panel A indicate electrograms
with morphologies similar to those in baseline rhythm. Closed arrows in
Panel B indicate pacing artifacts followed by the captured ventricular beats.
Because only the first four beats of VT in Panel B display polymorphic
morphology, the tachycardia was classified as monomorphic.
only 11/24 (46%) patients on dofetilide and in 18/38 (47%)
patients on placebo. The mean cycle length of MVT did not
differ significantly between the two groups: 331 ⫾ 49 ms for
dofetilide and 331 ⫾ 50 ms for placebo. Therapy with
dofetilide was associated with significantly greater success of
antitachycardia pacing: antitachycardia pacing successfully
terminated 97 of 98 (99%) MVT episodes in the dofetilide
group compared with 116 of 127 (91%) in the placebo group
(p ⬍ 0.02). Nevertheless, the mean cycle length of tachycardia episodes terminated by pacing in the dofetilide group
(338 ⫾ 41 ms) was significantly shorter than in the placebo
group (353 ⫾ 41 ms, p ⬍ 0.01).
DISCUSSION
Pause-dependent polymorphic arrhythmia. The major
finding of the present study is that therapy with dofetilide
was associated with a significantly higher incidence of
pause-dependent polymorphic ventricular arrhythmia, defined by intracardiac electrograms or TdP on the surface
ECG (15/87, 17%), compared with placebo (5/87, 6%, p ⬍
0.05). In 10 (11%) patients treated with dofetilide and five
(6%) patients receiving placebo, pause-dependent polymorphic ventricular arrhythmia occurred with a delay ⬎3 days
after initiation of therapy (p ⫽ 0.29).
Whether the cases of pause-dependent PVT identified in
the stored ICD recordings represent TdP cannot be determined from our study. All of them occurred late in an
out-of-hospital setting in which electrocardiographic documentation was not available. It is well-recognized that
pause-dependent PVT can occur in the absence of an
abnormally prolonged QT interval or antiarrhythmic treatment, particularly in patients with advanced ischemic heart
disease (21–23), and pause-dependent PVT did occur in the
placebo group in this study. The pause dependence suggests
that dispersion of repolarization may play a role, although
the issue of the effect of dofetilide on dispersion of repolarization is controversial (14,24 –26). The total incidence of
Mazur et al.
Dofetilide and Polymorphic VT
1103
ventricular arrhythmia was similar in the two groups.
Therefore, an alternative explanation for the higher incidence of PVT with dofetilide would be that dofetilide
changes VT morphology and/or initiation pattern. Selfsustaining reentrant activation due to spiral wave activity (or
scroll waves in three dimensions) has been proposed as a
common mechanism underlying both MVT and PVT
(27,28). According to this hypothesis, the electrocardiographic manifestation of the arrhythmia is determined by
the stability of the spiral core. Both action potential prolongation and dispersion of refractoriness may cause destabilization of the spiral core, thereby leading to irregular
patterns of activation with a polymorphic appearance of the
arrhythmia on the ECG (27,29).
MVT. The incidence of MVT was similar in both groups
of patients, although multiple episodes occurred more frequently in patients on placebo. The latter finding suggests
that dofetilide may reduce the number of recurrences of this
type of VT. This is consistent with previous experimental
(30,31) and clinical (18,19) studies, which showed that
dofetilide reduced the inducibility rate of sustained MVT.
Such an effect on MVT is consistent with an increase in
wavelength of the reentry circuit due to lengthening of
tissue refractoriness (32). In contrast to previous experimental and clinical data showing an increase in the cycle length
of MVT by dofetilide (19,31), we found that the mean cycle
length of MVT did not differ significantly between dofetilide and placebo. An interesting finding relates to the effect
of dofetilide on antitachycardia pacing. In dofetilide-treated
patients, the efficacy of antitachycardia pacing (which was
programmed by individual investigators) was significantly
greater and yet the cycle length of pace-terminated arrhythmia was significantly shorter. The mechanism underlying
these findings is unclear. Both a faster VT rate and an
excitable gap narrowed by an action-potential-prolonging
drug would be predicted to unfavorably affect the ability to
penetrate the reentry circuit during pacing maneuvers (33).
It is possible, although highly speculative, that in patients
treated with dofetilide, a relatively narrow excitable gap may
permit a smaller increment in wavelength during pacing to
extinguish reentry (34). The magnitude of lengthening of
ventricular refractoriness during pacing may also be higher
in patients treated with dofetilide, although reverse usedependence of the effect of dofetilide on action potential
prolongation would argue against this mechanism (12).
Study limitations. Prestudy electrograms were not available to assess the possibility that one effect of dofetilide is to
alter VT morphology. Furthermore, only stored ICD electrograms for which an onset of tachyarrhythmia was present
were analyzed. This could affect the incidence of different
types of the tachyarrhythmia in the studied groups, although
the relative number of electrograms with and without an
onset was similar in the both groups. Lack of availability of
QT interval data at the instant of pause-dependent PVT
identified in the stored ICD electrogram hampers interpretation of the underlying mechanisms.
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Dofetilide and Polymorphic VT
Several potential limitations relate to the stored ICD
electrogram analysis. Local bipolar recordings from a closely
spaced ICD electrogram configuration may not reliably
reflect surface ECG morphology of VT (35). It is also
possible that a polymorphic pattern of VT could fail to be
detected by a single-lead recording. In addition, analysis of
stored ICD electrogram morphology in this study did not
allow definite discrimination between VT and supraventricular tachycardia with aberrant conduction. Short-lived (selflimited) episodes of TdP may not have been detected.
Clinical implications. Our findings pertain to a highly
selected population of patients with VT, those receiving
ICDs for clinical VT/VF. Generalization of these findings
to other populations of patients may be inappropriate.
Indeed, dofetilide has been approved for use in patients with
atrial fibrillation and flutter, and not VT/VF. The safety of
the drug was examined in the Danish Investigation of
Arrhythmias and Mortality on Dofetilide (DIAMOND)
study, which randomized patients with advanced left ventricular dysfunction to dofetilide or placebo (17,36). The
DIAMOND study showed that with in-hospital initiation
of drug (allowing detection and treatment of TdP), there
was no change in mortality compared to placebo, even in this
high-risk group; subset analysis shows the same result, and
a decreased rehospitalization rate in patients with AF. The
programmed antibradycardia pacing rate in the 20 patients
with pause-dependent PVT was ⬍70/min in all but one (in
whom it was 70/min). Hence, consideration should be given
to raising the antibradycardia pacing rate in patients with
ICDs receiving dofetilide or other QT prolonging agents.
Conclusions. Pause-dependent PVT occurred in placebotreated patients but was more common among those receiving dofetilide. Because the total incidence of VT or VF was
similar in dofetilide- and placebo-treated patients, this study
suggests either that long-term dofetilide therapy is associated with an increased risk of TdP or that the drug changes
VT morphology and/or initiation pattern.
Treatment with dofetilide did not affect the incidence,
initiation pattern or cycle length of MVT but was associated
with better response of the tachycardia to overdrive pacing.
The trend toward a lower incidence of multiple episodes
of MVT in patients receiving dofetilide suggests that the
drug may reduce the number of recurrences of this type of
VT.
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. E-mail: dan.roden@
mcmail.vanderbilt.edu.
JACC Vol. 37, No. 4, 2001
March 15, 2001:1100–5
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