From the Departments of Medicine and Pharmacology, Divisions of Clinical
Pharmacology and Cardiology, Vanderbilt University School of Medicine,
Nashville, Tenn.
Ibutilide
is an antiarrhythmic drug that was recently marketed for the rapid
conversion of atrial fibrillation and atrial flutter. After
intravenous administration, ibutilide is moderately
effective in achieving prompt cardioversion to sinus rhythm, with
greater efficacy in patients who have atrial flutter. Like other drugs
that prolong ventricular repolarization, ibutilide
administration carries a risk of excessive QT prolongation, or the
acquired long-QT syndrome, with associated polymorphic
ventricular tachycardia (torsade de pointes),
necessitating careful patient selection and clinical monitoring during
drug administration.
Pharmacology
Ibutilide is a methanesulfonamide derivative with structural
similarities to the antiarrhythmic agent sotalol. This drug increases
action potential duration as its primary mechanism of action, so-called
class III effect, largely by blocking the rapid component of the
cardiac delayed rectifier potassium current,
IKr. In isolated cardiac myocytes,
ibutilide also prolongs action potential
duration,1 2 although its mechanism of action is
unique among available class III drugs. At nanomolar concentrations,
ibutilide appears to activate a slow inward current, largely
carried by sodium ions, that is unresponsive to
IKr blockers.1 2 3 In
addition, ibutilide blocks IKr on the basis
of both binding studies of 3H-dofetilide in
guinea pig ventricular myocytes4 and
patch-clamp studies in an atrial tumor cell line in which
IKr is the major repolarizing
current.5 Over a limited range of stimulation
rates, ibutilide can increase action potential duration without
significant reverse use dependence or loss of effect at rapid pacing
rates.6 7 In humans, ibutilide causes a dose- and
concentration-related increase in the uncorrected and rate-corrected QT
interval in both healthy volunteers and patients with atrial
fibrillation and atrial flutter.8 9 10 Recent
studies11 indicate that the congenital long-QT
syndrome can arise from ion channel mutations that cause either reduced
IKr current or enhanced inward sodium
current. Therefore, it is not surprising that ibutilide administration
can cause excessive QT prolongation associated with the development of
triggered activity (early afterdepolarization) in animal
models12 13 and torsade de pointes in
patients.9 10
Action potential prolongation by ibutilide leads to an increase in
atrial and ventricular refractoriness in
vivo.7 14 15 16 In canine models of atrial flutter,
this was associated with arrhythmia termination, with an
increase in atrial flutter cycle length before conversion, suggesting
slowed conduction in some area of the reentrant
circuit.14 15 16 The drug was also effective in
termination of atrial fibrillation in a model of coronary
occlusion with ischemic left ventricular
dysfunction.17 In patients with atrial flutter,
ibutilide caused greater prolongation of repolarization (and therefore
refractoriness) than slowing of conduction18 ;
this effect would cause a reduction in the excitable gap of a reentrant
circuit and likely contributes to arrhythmia termination under
these circumstances.19 In a canine model of
recent myocardial infarction, ibutilide was also effective at
suppressing inducible ventricular
arrhythmias.20 Additional evidence
indicates that the drug can lower the energy threshold required for
ventricular defibrillation.21
Although administration of ibutilide can cause mild slowing of sinus
rate and AV nodal conduction,22 there was no
significant effect on heart rate, PR interval, or QRS interval during a
dose-response study of ibutilide in healthy
volunteers.8
Ibutilide administration is associated with minimal
hemodynamic effects both in animal models of
ischemic left ventricular
dysfunction17 and in
patients.9 10 23 In a study of
hemodynamic function in patients with a range of
ejection fractions (including <35%), intravenous
ibutilide had no clinically significant effects on cardiac output, mean
pulmonary arterial pressure, or pulmonary
capillary wedge pressure after doses up to 0.03
mg/kg.23 24 There has been no clinically
significant effect of ibutilide to lower blood pressure or worsen
congestive heart failure in published clinical
trials.9 10 23
In reproduction studies in rats, orally administered ibutilide
was both teratogenic and embryocidal.25 The
excretion of the drug into breast milk has not been studied. Ibutilide
has not been shown to be genotoxic in multiple tests including the Ames
assay, although no animal studies have been conducted to determine its
carcinogenic potential.24
Pharmacokinetics
Ibutilide is not available for long-term oral use because of
extensive first-pass metabolism when administered by this
route. After intravenous administration, the plasma
concentration declines in a multiexponential manner, with a high
systemic plasma clearance that approximates liver blood
flow.23 24 Pharmacokinetic properties are linear
with respect to dose.22 The volume of
distribution is large, with minimal (40%) protein binding. The
elimination half-life is variable and ranges from 2 to 12 hours,
with a mean of 6 hours. Ibutilide is extensively metabolized with the
parent drug and at least eight metabolites excreted, largely in the
urine. Although at least one of these metabolites has
electrophysiological activity, plasma
concentrations during therapy are considerably less than those of
ibutilide and likely do not contribute to its antiarrhythmic effect.
Although the metabolic pathways for ibutilide have not been
completely determined, they do not appear to involve the cytochrome
P450 isoenzymes CYP3A4 or CYP2D6, suggesting that previously described
drug interactions with other agents are unlikely. Coadministration of
digoxin, calcium channel blockers, or ß-adrenergic receptor blockers
with ibutilide has no apparent effect on the pharmacokinetics, safety,
or efficacy of the drug in clinical trials.24
Clearance appears to be unaltered by either a reduction in
creatinine clearance or left ventricular
dysfunction. Currently there is no recommended dosage change in the
presence of either hepatic or renal dysfunction. However, abnormal
liver function would likely lead to reduced clearance and prolonged
pharmacological effect and might necessitate longer periods of
monitoring in these patients after ibutilide
administration.24 In normal volunteers and
patients with atrial fibrillation and atrial flutter, ibutilide
pharmacokinetics are not influenced by patient age, sex, or type of
arrhythmia.22 24 26
Clinical Studies
Two full-length, peer-reviewed articles have been published to
support the clinical efficacy of ibutilide,9 10
whereas other data have appeared in abstract form or from the
pharmaceutical sponsor.24 The first major
clinical study was a double-blind, randomized, placebo-controlled,
dose-response trial9 that evaluated the efficacy
and safety of ibutilide in 200 patients with atrial flutter or
fibrillation from 3 hours to 90 days in duration. Patients were
randomized to receive a single intravenous dose of either
placebo or ibutilide at 0.005, 0.010, 0.015, or 0.025 mg/kg. The study
population consisted of patients who were
hemodynamically stable without uncontrolled heart
failure or angina. In the group, 72% of patients had structural heart
disease, with a similar percentage having significant left atrial
enlargement. The rates of successful arrhythmia termination
were 3% for placebo and 12%, 33%, 45%, and 46%, respectively, for
the doses of ibutilide administered. The overall success rate of
ibutilide-treated patients with atrial flutter (38%) tended to be
higher than for those with atrial fibrillation (29%). The mean time to
termination of the arrhythmia from beginning of infusion was
19±15 minutes (range, 3 to 70 minutes), with conversion in nearly 80%
of patients within 30 minutes from the start of the infusion. The
duration of the arrhythmia was a predictor of successful
conversion to normal sinus rhythm, with success in 42% of patients
having atrial flutter/fibrillation for
On the basis of these results, a second clinical
trial10 was conducted in which 266 patients with
atrial fibrillation or flutter with an arrhythmia duration of 3
hours to 45 days were randomized to receive up to two 10-minute
infusions of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo.
Patients at high risk for proarrhythmia, that is, those with
preexisting QT prolongation (QTc >440 ms), hypokalemia (<4.0 mEq/L),
and previous torsade de pointes, were excluded. As in the previous
trial, most patients had a history of heart disease and an enlarged
left atrium. Ibutilide administration resulted in arrhythmia
conversion in 47% of patients compared with 2% of patients receiving
placebo. The two ibutilide dosing regimens did not differ with respect
to conversion efficacy. Conversion occurred in a higher percent of
patients with atrial flutter than those with atrial fibrillation (63%
versus 31%). The average time for arrhythmia termination was
27 minutes (range, 5 to 88 minutes) after the start of the first
infusion. After adjustment for dose, there was a significant effect of
arrhythmia duration on efficacy in the atrial fibrillation but
not the atrial flutter group, with a mean duration of 10±13 days for
those who were successfully converted compared with 18±15 days for
those who did not convert. In addition, there was a significant
correlation between left atrial diameter and success in patients with
atrial fibrillation but not in those with atrial flutter. Once again,
the change in QT or QTc interval with ibutilide administration did not
predict arrhythmia termination. Polymorphic
ventricular tachycardia developed in 8.3% of
ibutilide-treated patients. In 1.7%, this arrhythmia was
sustained and required DC cardioversion. The risk of torsade de pointes
was higher in patients with atrial flutter (12.5%) than in those with
atrial fibrillation (6.2%). Episodes of late polymorphic VT
occurred in 1 patient at 2 to 2.5 hours; this patient had a prior
episode of nonsustained VT at the end of initial drug infusion. Plasma
concentrations were not obtained in this patient, and therefore the
relationship of late events to ibutilide concentration could not be
determined. Logistic regression analysis indicated that female
sex, nonwhite race, presence of heart failure, and low pulse rate were
significant risk factors for the development of
proarrhythmia.
Together, these two clinical trials demonstrate that ibutilide
administration is superior to placebo in terminating atrial
fibrillation and flutter, with most patients converting within 30
minutes of the start of drug infusion. The drug is more effective in
patients with atrial flutter but with an increased risk of torsade de
pointes. Predictors of successful arrhythmia conversion include
the duration of arrhythmia before treatment as well as left
atrial size. For atrial flutter, additional data suggest that
development of variation in the flutter cycle length predicts
successful termination.27 Initial clinical
results from a randomized, double-blind, placebo-controlled trial
indicate that ibutilide is also effective in terminating atrial
fibrillation and flutter after cardiac surgery.28
Although it is not approved for this indication, preliminary results
indicate that ibutilide can also prevent reinduction of sustained
ventricular tachycardia in patients with
coronary artery disease undergoing
electrophysiological
study.29
Comparison With Other Therapy
Although ibutilide is the only drug approved in the United States
for acute termination of atrial fibrillation and atrial flutter, other
therapies have been used for this purpose, including
intravenous administration of procainamide as well
as oral loading of multiple different agents such as quinidine,
procainamide, propafenone, and
flecainide.30 It is difficult to compare the
efficacy of ibutilide with other drugs using previously published
studies given the differences in arrhythmia duration, drug
administration, and patient characteristics that exist in the patient
populations studied. Several studies have reported that
intravenous procainamide can acutely terminate
atrial fibrillation/flutter with moderate
efficacy.31 32 33 One group of
investigators31 reported a conversion rate of
58% (15 of 26 patients) after administration of procainamide
1 g IV. Patients who converted had a shorter duration of
arrhythmia (6±7 days) than those who did not convert (79±88
days). In another study32 of 21 patients who
received 20 mg/kg procainamide, 43% (9 patients) converted to
normal sinus rhythm. The arrhythmia duration was
More limited data are also available from noncomparable clinical
studies for sotalol and amiodarone. A group of 48 patients
having atrial fibrillation/flutter for <7 days were randomized to
receive either placebo or sotalol at a dose of either 1.0 or 1.5 mg/kg
IV.34 Patients who received placebo initially
could subsequently receive 1.0 or 1.5 mg/kg sotalol in an open-label
phase. In total, 5 (19%) of 26 patients receiving placebo converted to
normal sinus rhythm compared with 4 (17%) of 23 and 4 (18%) of 22
patients receiving sotalol at doses of 1.0 and 1.5 mg/kg, respectively.
The success rate of acute conversion with intravenous
amiodarone has been similarly disappointing. In a comparative
trial35 with intravenous dofetilide,
administration of amiodarone (5 mg/kg) led to a conversion rate
of 4% compared with 4% for placebo and 35% for dofetilide (8
µg/kg). Finally, a recent study36 reported on
the success of oral loading regimens of propafenone (400 to 600 mg),
propafenone plus digoxin (0.75 to 1.0 mg in 24 hours), and quinidine
(1100 mg) plus digoxin for atrial fibrillation/flutter of <24 hours
duration. Not surprisingly, a high rate of conversion was seen not only
with propafenone plus digoxin (89%) and quinidine plus digoxin (84%)
but also with placebo (77%) at 24 hours.
In studies (which have appeared in abbreviated form) that directly
compare the efficacy of ibutilide to other therapies, the drug was
found to be superior to intravenous administration of
either sotalol or procainamide in terminating atrial
fibrillation and atrial flutter.24 37 38 In a
double-blind study,24 319 patients with an
arrhythmia duration of 3 to 45 days were randomized to receive
either ibutilide (1 or 2 mg) or sotalol (1.5 mg/kg). In patients with
atrial flutter, 53% and 70% of patients who received 1 and 2 mg of
ibutilide, respectively, converted to normal sinus rhythm compared with
18% receiving sotalol. For patients with atrial fibrillation, the
rates of conversion were 22% and 43% for 1 and 2 mg of ibutilide
versus 10% for sotalol. Ibutilide has also been compared with
intravenous procainamide in a double-blind,
placebo-controlled trial of 127 patients with atrial
fibrillation/flutter lasting 3 hours to 90
days.37 Intravenous administration of
ibutilide (2 mg) led to conversion of 76% and 51% of patients with
atrial flutter and atrial fibrillation, respectively, compared with
12% and 20% for patients given intravenous
procainamide (1200 mg). In a nonrandomized comparison with
intravenous procainamide in 67 patients, ibutilide
(0.005 to 0.025 mg/kg) converted 42% and 37% of patients with atrial
fibrillation and flutter, respectively, versus 9% and 0% for
procainamide (12 to 15 mg/kg).38 The
efficacy of ibutilide in that study was attributed to greater
prolongation of monophasic action potential duration relative to
slowing of conduction; the resultant increase in refractoriness would
tend to close the excitable gap to facilitate arrhythmia
termination.19 In contrast, procainamide
caused a greater change in conduction than repolarization, which could
account for its lack of success relative to ibutilide. In a separate
study,18 both intravenous ibutilide
and procainamide enhanced termination of drug-refractory atrial
flutter by atrial overdrive pacing.
Adverse Effects
The safety of ibutilide in 586 patients with atrial fibrillation
and flutter in phase II and III clinical trials has been
reported.39 In general,
noncardiovascular adverse effects were rare and
typically similar in frequency to those experienced with placebo.
Nausea did occur at a higher rate in ibutilide-treated patients (1.9%)
than in placebo-treated patients (0.8%). Hypotension, conduction
block, and bradycardia all occurred at similar rates in the ibutilide-
and placebo-treated patients. The overall incidence of polymorphic
ventricular tachycardia diagnosed as torsade de
pointes was 4.3%, including 1.7% of patients in whom the
arrhythmia was sustained and required cardioversion. In almost
all cases, this occurred within 40 minutes of the start of the initial
ibutilide infusion. There has been no clear relationship between dose
or plasma concentration and the development of torsade de pointes.
Dosage and Administration
Ibutilide fumarate is available in 10-mL vials containing 0.1
mg/mL (1 mg total). Before drug administration, patients should be
screened carefully to exclude high-risk individuals, such as those with
a QTc interval exceeding 440 ms or bradycardia. Serum potassium and
magnesium levels should be measured, and replacement therapy should be
given to correct any deficits. Administration of ibutilide should be
avoided in patients receiving other QT-prolonging drugs, including
class Ia or III antiarrhythmic drugs, phenothiazines, tricyclic
antidepressants, and certain antihistamines, because there are no data
available regarding concomitant administration of such drugs. In
addition, the safety of ibutilide administration in patients already
taking antiarrhythmic drugs who develop recurrent arrhythmias
has not been established. For intravenous administration,
the recommended dose of ibutilide is 1 mg over a 10-minute period in
patients weighing
Clinical Use
Ibutilide is indicated for the rapid conversion of atrial
fibrillation or flutter of recent onset. Largely due to the risks of
proarrhythmia, the role of ibutilide in this clinical
circumstance is not well defined at the present time. To achieve
rapid termination of atrial tachyarrhythmias, both DC
and chemical cardioversion are available to the clinician. Although DC
cardioversion is highly successful,40
particularly when used with concomitant antiarrhythmic drug therapy, it
necessitates the use of anesthesia, which can be both
costly and time consuming. In selected patients, chemical cardioversion
also has a reasonable success rate and, if its use is uncomplicated,
can be associated with greater convenience for both patient and
physician, as well as potentially reduced costs. When considering
administration of ibutilide, it is essential that patients at low risk
for proarrhythmia be chosen. Arrhythmias of recent
onset, particularly atrial flutter, are more likely to be successfully
terminated. Ibutilide might be especially useful in patients
presenting with their initial episode of atrial fibrillation or
flutter, in whom it may be appropriate to subsequently withhold
long-term prophylactic antiarrhythmic drug therapy. In
addition, administration of ibutilide can be considered in clinical
settings in which the use of anesthesia is undesirable.
Given the need for careful observation during drug administration,
ibutilide may also find increasing use to terminate arrhythmias
in patients who are already in a monitored environment, such as the
surgical intensive care unit after cardiac
surgery28 41 or other intensive care units, the
cardiac catheterization laboratory, and the
electrophysiological laboratory under
selected circumstances (eg, ibutilide can facilitate pace conversion of
atrial flutter). Ibutilide has been shown to lower the
ventricular defibrillation threshold in animal models. If a
similar effect can be demonstrated for the atrial defibrillation
threshold, ibutilide may potentially facilitate DC cardioversion by
either external or internal means. Undoubtedly, the clinical use of
ibutilide will become more widespread if therapeutic maneuvers can be
identified (eg, prophylactic magnesium administration) that
lower the proarrhythmic risk of drug administration.
In summary, ibutilide is an effective agent for use in the termination
of atrial fibrillation and atrial flutter. However, close monitoring by
a physician is required during administration of this drug due to the
relatively high incidence of torsade de pointes. Because alternative
strategies are available, the risks and benefits of ibutilide
administration should be carefully considered for each patient to
minimize proarrhythmic adverse events.
Footnotes
Reprint requests to Katherine T. Murray, MD, Division of Clinical Pharmacology, Room 559 Medical Research Building II, Vanderbilt University School of Medicine, 23rd Ave S and Pierce Ave, Nashville, TN 37232-6602.
References
© 1998 American Heart Association, Inc.
Cardiovascular Drugs
Ibutilide
Key Words: ibutilide • Cardiovascular Drugs • fibrillation • drugs
30 days compared with 16% of
those with an arrhythmia duration >30 days. Both QT and QTc
intervals were significantly prolonged from baseline by ibutilide in
all dose groups, although the degree of prolongation did not predict
efficacy of arrhythmia termination. Polymorphic
ventricular tachycardia developed in 6 patients
(3.6%) receiving ibutilide. It occurred in patients receiving doses
0.010 mg/kg and did not correlate with plasma ibutilide
concentration. All 6 patients had reduced left ventricular
function, and 3 had a baseline QTc interval that was >440 ms. 5 days in 19
of the 21 patients. In a comparative study with intravenous
flecainide,33 procainamide at a dose of
1 g converted 25 (65%) of 40 patients with atrial
fibrillation/flutter of <24 hours' duration. Although these studies
indicate that intravenous procainamide is useful in
this clinical setting, particular caution should be used when
conversion rates are compared with other drugs such as ibutilide,
because most patients in these trials had arrhythmias of
relatively recent onset. Substantial clinical data now indicate that
probably the most important predictor of successful pharmacological
conversion of atrial fibrillation/flutter with any agent is the
pretreatment duration of the arrhythmia. Therefore, data
regarding comparative efficacy can only be obtained in randomized
clinical trials in which drugs are compared in the same patient
population. 60 kg.24 Ten minutes after
the end of the initial infusion, a second 10-minute infusion of equal
strength can be given if the arrhythmia has not terminated. For
patients weighing <60 kg, the recommended dose is 0.01 mg/kg
initially, with a second dose of the same strength 10 minutes later if
necessary. Given the data available from the clinical studies described
above, proarrhythmic events should be anticipated. Skilled personnel
trained in recognizing arrhythmias such as
ventricular tachycardia, and specifically
torsade de pointes, should be present along with facilities for
continuous cardiac monitoring, proper equipment including a
defibrillator, and pharmacological therapy to treat sustained
ventricular tachycardia such as torsade de
pointes. The ibutilide infusion should be stopped as soon as the
arrhythmia is terminated or in the event of
nonsustained/sustained ventricular tachycardia
or marked prolongation of the QT/QTc interval. Patients should be
monitored for at least 4 hours after the infusion or until the QTc has
returned to baseline, with a longer monitoring period if nonsustained
ventricular tachycardia develops. Patients with
hepatic dysfunction should also be monitored for an extended period of
time given the likelihood of reduced drug clearance in this situation.
It is currently recommended that therapy with antiarrhythmic drugs that
prolong the QT interval (class Ia and class III) be withheld for at
least 4 hours after ibutilide administration. Ibutilide should not be
administered to pregnant women unless it is determined that the
clinical benefit outweighs potential risks to the fetus. The safety and
efficacy of ibutilide in persons younger than 18 years of age has not
been determined.
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