Full text of DOI:10.1002/clc.4960250904

Clin. Cardiol. 25, 411–415 (2002)
Cardioversion of Atrial Fibrillation with Ibutilide: When Is It Most Effective?
MITHILESH KUMAR DAS, M.D., MRCP, KURUVILLA CHERIPARAMBIL, M.D., ASHWINI BEDI, M.D.,* JOHN KASSOTIS, M.D., PH.D., FACC, *
CHATLA V. R. REDDY, M.D., FACC, * BARRY SAUL, M.D., FACP, FACC,* MAJESH MAKAN, M.D., FACC*
New York Presbyterian Hospital-Cornell University Medical College; *New York Methodist Hospital, New York, New York, USA
Summary
Background: Atrial fibrillation (AF) is found in 1% of per-
tients with CAD and in patients without MVD and/or marked-
ly enlarged left atrium.
sons above the age of 60 years. More than 5% of the popula-
tion older than 69 years and about 14% of octogenarians are at
risk for this arrhythmia. It is estimated that 1.5 to 3 million per-
sons in the United States alone suffer from AF. The public
health implications and attendant morbidity are a significant
drain on our health care system.
Key words: ibutilide, atrial fibrillation
Introduction
Hypothesis: The purpose of this study was to determine the
clinical and echocardiographic predictors of success in con-
verting AF of ≥24 h duration.
Methods: Demographic and clinical and echocardiograph-
ic parameters of 101 patients with recent onset AF (> 24 h)
who received ibutilide were studied.
Results: Of 101 patients, 56 (55%) converted to sinus
rhythm. Age, gender, hypertension, diabetes mellitus, left
ventricular ejection fraction (≤35%), congestive heart failure,
and previous medication for rate control had no significant ef-
fect on the conversion rate. Conversion rate was only 30%
(9/30 patients) in the presence of an enlarged left atrium
(LA ≥5 cm) and 37.7% (23/61 patients) in the presence of mi-
tral valve disease (MVD), whereas the conversion rate was
82.5% (33/40 patients) in the absence of MVD and 85%
(29/34 patients) in the absence of both enlarged LA and MVD
(p = < 0.001). Patients with coronary artery disease (CAD)
also exhibited a significantly greater response to ibutilide than
patients without CAD (77 vs. 46%, p-value 0.005).
Atrial fibrillation (AF) is found in 1% of persons above the
age of 60 years. More than 5% of the population older than 69
years and about 14% of octogenarians are at risk for this ar-
rhythmia.1, 2 It is estimated that 1.5 to 3 million persons in the
United States alone suffer from AF. The public health impli-
cations and attendant morbidity are a significant drain on our
health care system.3 The morbidity and mortality associated
with AF include stroke, heart failure, syncope, and risk of
sudden death.4, 5 Whether maintaining sinus rhythm (SR) as
opposed to achieving rate control will impact mortality is the
primary focus of the ongoing Atrial Fibrillation Follow-up
Investigation of Rhythm Management (AFFIRM) trial.6 Si-
nus rhythm improves cardiac hemodynamics by restoring
atrial contribution to the cardiac output and by controlling the
heart rate, thereby improving exercise tolerance and function-
al capacity.7 It was shown in goat models that repeated induc-
tion of AF by rapid burst pacing reduced the atrial refractory
period, which led to “electrical remodeling” and refractory
AF (“atrial fibrillation begets atrial fibrillation”).8, 9
Conclusion: As a therapy for cardioversion of AF, ibutilide
is most effective in a selected subgroup patients, such as in pa-
Therefore, apart from preventing complications related to
this arrhythmia, conversion to SR also prevents complications
related to prolonged drug therapy including anticoagula-
tion.10–12 In general attempts are made to convert new onset to
sinus rhythm.13
Both pharmacologic and nonpharmacologic methods are
available for cardioversion of AF.14, 15 Among the pharmaco-
logic methods available, ibutilide, a class III antiarrhythmic
agent, has been shown to be effective in the acute treatment of
AF.16–21 The spontaneous conversion rate in new onset AF
within the first 24 h is as high as 50–70% with highest inci-
dence in the first 8 h, and it drops to < 8 % after 24 h. There-
fore, only half of the patients with new onset AF will require
cardioversion if monitored for > 24 h. It has also been shown
to be cost effective when the patients are treated with direct
current (DC) cardioversion.22
Address for reprints:
Mithilesh K. Das, M.D.
Division of Cardiology (Starr 4)
New York Presbyterian Hospital –
Cornell University Medical College
525 East 68th Street
New York, NY 10021, USA
e-mail: mithileshdas@hotmail.com
We evaluated the response rate of ibutilide in AF of >24 h
duration to minimize the chance of spontaneous conversion.
Received: June 27, 2001
Accepted with revision: November 21, 2001

412
Clin. Cardiol. Vol. 25, September 2002
Statistical Analysis
The clinical and echocardiographic determinants associated
with successful ibutilide therapy were also characterized.
Comparisons of clinical and echocardiographic parameter
between responders and nonresponders to ibutilide were done
by chi-square analysis. A p value of < 0.05 was considered
statistically significant. Multivariate logistic regression mod-
eling was performed to identify independent predictors of
conversion to sinus rhythm. Adjusted odds ratio and 95% con-
fidence interval from the logistic model were derived. The fol-
lowing parameters were evaluated: (1) response to ibutilide in
the presence of hypertension, coronary artery disease, dia-
betes mellitus (DM), congestive heart failure (CHF), large LA
size, valvular heart disease (mitral regurgitation, mitral ste-
nosis or history of mitral valve replacement), left ventricular
hypertrophy (LVH), and significant left ventricular systolic
dysfunction (EF ≤ 35%); (2) drug therapies that include beta
blockers, calcium-channel blockers, and digoxin; (3) the time
of conversion to sinus rhythm; and (4) proarrhythmias.
Methods
Study Population
In all, 150 patients (mean age: 68.7 ± 13.7 years; 52 male)
with recent onset AF (> 24 h and ≤3 months), admitted be-
tween February 1997 and November 1999, were selected for
study. Patients treated with atrioventricular (AV) nodal block-
ing agents, including long-term digoxin, beta blockers, or cal-
cium-channel blockers, were included in the study. Patients
were excluded if they had hemodynamic instability, recent
myocardial infraction (< 48 h), unstable angina, class I or class
III antiarrhythmic therapy, previous history of torsade de
pointes, digoxin toxicity, hyperthyroidism, left atrial thrombus,
overt liver disease, or pregnancy. After enrolling in the study,
44 patients were excluded because of spontaneous conversion
to sinus rhythm, three patients required urgent DC cardiover-
sion for hemodynamic instability, and two had hyperthyroid-
ism; 101 patients (mean age: 69 ± 10 years; 52 male) under-
went ibutilide therapy.
Results
The overall conversion rate to sinus rhythm was 55.4%
(56/101 patients). The mean conversion time was 44 min
(range 8–210) with 87.5% of the patients responding within
1 h of initiation of ibutilide infusion (Fig. 1). The mean dose of
ibutilide required for conversion was 1.8 mg ± 0.5 (± 1 stan-
dard deviation [SD]) and 88% (89/101 patients) required a
second dose of ibutilide.
Tables I and II summarize the demographics and impact of
various parameters studied on the success rate of ibutilide.
Clinically significant mitral valve disease (MVD) was pre-
sent in 35 patients, 28 of whom had a previous history of mi-
tral regurgitation (MR), 3 had both MR and aortic regurgita-
tion (AR), 2 patients had mitral valve replacement (MVR) for
rheumatic mitral stenosis, 1 had MR related to hypertrophic
cardiomyopathy, and 2 had mitral valve prolapse. An addi-
tional 25 patients without clinical evidence of MR were
found to have at least mild MR on echocardiography and
were included in the subset. Mitral valve disease was present
in 38 of 45 patients (84%) who did not respond to ibutilide;
on the other hand, only 23 of 56 (37.7%) of the responders
exhibited any evidence of MVD. The success rate of ibutilide
was only 37.7% (23/61 patients) in the presence of MVD, but
Protocol
All patients admitted with recent onset AF underwent a
complete medical evaluation, which included assessment of
risk factors, medication, and laboratory values including
thyroid function. Ventricular rate control was achieved with
AV nodal blocking drugs including, beta blockers, calcium-
channel blockers, and digoxin. All patients underwent con-
tinuous electrocardiographic (ECG) monitoring. Transthor-
acic echocardiography was performed in patients with AF of
< 48 h duration to assess for structural heart disease, while
transesophageal echocardiography was performed for AF of
> 48 h duration to exclude left atrial (LA) clot. Left ventricu-
lar ejection fraction (EF) was obtained by Simpson’s method.
Left atrial size was measured in the parasternal long axis in
transthoracic echocardiography, and in the long axis on trans-
esophageal echocardiography. Hypokalemia (K+ level <3.5
mEq/l) and hypomagnesemia (Mg++ < 1.5 mEq/l) were cor-
rected prior to ibutilide infusion. All patients who were not on
prior anticoagulation therapy received intravenous heparin.
A single dose of ibutilide, 0.01 mg/kg, in patients weigh-
ing ≤ 60 kg, and 1.0 mg in patients weighing > 60 kg, was
diluted in 50 cc of normal saline and was infused over 10
min. If the arrhythmia failed to convert to SR within 10 min
following the initial infusion, a second infusion of equal
strength was given over a 10-min period.23 The intravenous
infusion was stopped if the patient converted to SR or devel-
oped significant proarrhythmia.
250
200
150
100
50
Continuous ECG monitoring was continued for a 12-h peri-
od following ibutilide therapy. Patients were closely observed
for significant Q-T prolongation, proarrhythmia, occurrence
of arrhythmias, hemodynamic compromise, or any other unto-
ward effects of this therapy.
0
0
10
20
Patients (n = 56)
FIG. 1 Conversion time from ibutilide infusion to sinus rhythm.
30
40
50
60

M. K. Das et al.: When is ibutilide most effective?
413
TABLE I Baseline characteristics: Responder versus nonresponder
groups
90
80
70
60
50
40
30
20
10
0
82
66
Nonresponders
(n= 45)
Responders
(n= 56)
Characteristics
p Value
37
1
30
Age (years)
Male (%)
HTN (%)
CAD (%)
DM (%)
70 ± 11
22 (48.9)
20 (44.4)
7 (15.5)
6 (13.3)
10 (22.2)
11 (25)
16 (35.6)
12 (26.7)
10 (22.2)
10 (22.2)
11 (24.4)
38 (62.3)
21 (46.7)
418 ± 32
495 ± 68
67 ± 15
30 (54.4)
30 (54.4)
23 (41.0)
13 (23.2)
16 (28.6)
17 (13.9)
26 (46.4)
20 (35.7)
8 (14.3)
0.326
0.686
0.422
0.005
0.306
0.501
0.654
0.313
0.393
0.311
0.171
0.813
0.001
0.001
0.174
0.686
2
3
4
LA < 5 cm
MVD
present
MVD
absent
LA ≥ 5 cm
CHF (%)
FIG. 2 Response rate to ibutilide in the presence and absence of mi-
tral valve disease (MVD) and enlarged left atrium (LA).
Beta blockers (%)
Ca blockers (%)
Digoxin (%)
ACEI (%)
Low EF (%)
LVH (%)
6 (10.9)
12 (21.4)
23 (37.7)
9 (16.1)
431 ± 38
486 ± 85
50
40
46%
MVD (%)
(23 of 45)
30
Enlarged LA (%)
Baseline QTc
Maximum QTc
20
10
0
16%
(9 of 56)
Nonresponders
Responders
Abbreviations: HTN = hypertension, CAD = coronary artery disease,
DM = diabetes mellitus, CHF = congestive heart failure, ACEI =
angiotensin-converting enzyme inhibitor, EF = ejection fraction,
LVH = left ventricular hypertrophy, MVD = mitral valve disease,
LA = left atrium.
FIG. 3 Presence of a markedly enlarged left atrium (≥ 5 cm) in re-
sponders versus nonresponders to ibutilide (n = 101).
100
85
80
60
40
82.5% (33/40 patients) in the absence of MVD (p value
< 0.0001; Fig. 2).
21
The mean (± 1 SD) LA size was 4.2 ± 0.7 cm among
responder and 4.97 ± 0.7 cm in the nonresponder groups. A
markedly enlarged LA (≥ 5 cm) was present in 46% (21/45 pa-
tients) of nonresponders, compared with 16% (9/56 patients)
in the responder group (p< 0.001; Fig. 3).
Patients with MVD had a higher LA size than patients
without MVD, and 24 patients exhibited both markedly en-
larged LA (≥5 cm) and MVD. As expected, 19 of these 24
patients did not respond (response rate of 21%) to ibutilide
therapy (Fig. 4).
The response rate in patients with CAD was higher than in
patients without CAD (23/30, 77%, vs. 33/71, 46%; Fig. 5).
Age, gender, hypertension, DM, LVH, left ventricular dys-
function (EF ≤35 vs. EF 35%), DM, and serum K+ and serum
Mg+ levels did not influence the conversion rate (Table I).
Treatment with calcium-channel blockers, beta blockers, or
digoxin, and prolongation of Q-Tc duration (baseline Q-Tc of
20
0
MVD with LA≥ 5 cm
No MVD, with LA< 5 cm
(n = 34)
(n = 24)
FIG. 4 Response rate to ibutilide in the presence and absence of mi-
tral valve disease (MVD) with marked left atrium (LA) enlargement.
100
77
80
60
40
20
0
46
CAD
No CAD
FIG. 5 Response rate to ibutilide in the presence and absence of
coronary artery disease (CAD).
TABLE II Multivariate analysis: Predictors of response to ibutilide
Predicting factors
p Value
Odds ratio
95% CI
Failure to
respond to
ibutilide
Mitral valve disease (MVD)
Enlarged left atrium (LA)
MVD and enlarged LA
0.0001
0.0001
0.0003
0.1284
0.2402
0.1342
0.0489–0.3379
0.1236–0.4679
0.0450–0.4000
Response to ibutilide
Coronary artery disease
0.001
5.598
1.510–20.683
Abbreviation: CI = confidence interval.

414
Clin. Cardiol. Vol. 25, September 2002
433 ± 38 to a maximum QTc of 485 ± 85 ms in the responder
group vs. baseline Q-Tc of 418 ± 32 to a maximum QTc of
495 ± 59 ms in the nonresponder group; p = 0.686) related to
ibutilide therapy also did not significantly affect the efficacy
of ibutilide.
in atrial geometry, even by a small MR jet, may to be respon-
sible for atrial myopathy and a substrate for the reentrant cir-
cuits or chaotic rhythm. This may sets up a milieu compatible
for AF and resistance to ibutilide therapy.35
The precise mechanism of AF in CAD is not known. Pa-
tient with and without CAD had comparable LA size; there-
fore, the response rate in the presence of CAD is not influ-
enced by concomitant atrial enlargement. Furthermore, the
drug has been shown to be effective in a canine model of coro-
nary occlusion and left ventricular dysfunction.36 We, there-
fore, speculate that atrial myopathy due to CAD represents a
different substrate than valvular heart disease, and the exact
mechanism needs to be evaluated with further studies.
As contrast to one of the previous studies, presence of CHF
and digoxin use was not associated with adverse response in
our group.37 This is because the etiology of CHF is multifacto-
rial and the response rate in the presence of CHF varies ac-
cording to the prevalence of negative predictors such as MVD
or positive predictor such as CAD in the population studied. It
may possibly be due to a smaller number of patients with CAD
(patients post coronary artery bypass graft [CABG]) in our
study group.38, 39 Digoxin has been shown neither to be an ef-
fective therapy for cardioversion nor to have an additive effect
on electrical or chemical cardioversion. Hence it is not expect-
ed to potentiate the response of ibutilide.
Premature ventricular beats, both monomorphic and poly-
morphic, were frequently present both during and within 4 h
after initiation of the therapy. The incidence of nonsustained
ventricular tachycardia was 5.8% (all of them were < 5 beats),
with no significant difference between responders and non-
responders. Two patients developed torsade de pointes. One
patient responded to 2 gm of intravenous Mg+ and the other
patients was cardioverted to sinus rhythm with DC shock.
Torsade in both patients was encountered within 1 h of initia-
tion of therapy. One patient developed sinus bradycardia,
which resolved spontaneously within 12 h. Global T-wave in-
version on ECG, that normalized within 24 h, was noted in
one of our patients without coronary artery diseases.
Discussion
Ibutilide is a pure class III agent that prolongs the action
potential duration by slowing the inward potassium rectifier
current (IKr) and by enhancing the slow inward depolarizing
sodium current.24–26 The resultant prolonging of the atrial re-
fractory period (ARP) organizes the microreentries circuitry
of AF resulting in SR. Prolongation of the action potential du-
ration also prolongs Q-T interval, making patients vulnerable
to torsade de pointes. After intravenous infusion, ibutilide is
rapidly distributed in the body and metabolized to an inactive
form. The first past clearance by the liver limits its oral use.
The half-life is 2 to 12 h (mean 6 h).20–25
Prolongation of the Q-Tc duration has no effect on ibutilide
efficacy because the Q-Tc prolongation is a global reflection
of ventricular repolarization and affects responders and non-
converters to the same degree. It does not reflect the prolonga-
tion of action potential duration of the atrial myocardium. We
also know from previous studies29, 40 that the degree of QT
prolongation does not correlate with pharmacologic response
and represents drug effect rather than its efficacy.
Among the class III and class I antiarrhythmic agents, ibu-
tilide is one of the most effective agents for cardioversion, and
most of the patients convert to sinus rhythm within 1 h of initi-
ation of therapy.27–30 All patients should be monitored closely
for 4 h, as there is a 2 to 3% risk of torsade de pointes and oc-
casional hypotension. Among the presently available modal-
ities of cardioversion, electrical cardioversion has a much
higher success rate of about 67–94%. Apart from a very low
but definite risk related to anesthesia, patients can sustain local
burns, and about 2 to 3% of patients may develop bradycardia
and even cardiac arrest.31–33 Ibutilide and other class I and
class III drugs are reasonable alternatives in those patients
who refuse DC treatment. Furthermore, pretreatment with
ibutilide has shown to increase the conversion rate of DC car-
dioversion to 100%.34
The design of our study differed from previous trials of ibu-
tilide in that we continued to observe these patients for 24 h. It
was intended to avoid the possible confounding phenomenon
of spontaneous conversion in the first 24 h (can be as high as
50–70%) and therefore to reduce the cost of therapy.22
Our study identifies the selective subgroups of the patients
who are likely to respond to ibutilide. The clinical and echo-
cardiographic parameters associated with a high response rate
include presence of CAD (77%), absence of MVD (82%),
absence of markedly enlarged LA (67%), and absence of en-
larged LA as well as absence of MVD (85%). Therefore, few-
er patients with these characteristics will require DC car-
dioversion (15–33%) if chemical cardioversion with ibutilide
is selected as first-line therapy.
In this study, a small LA size and absence of MVD predict-
ed success with ibutilide as well as the presence of CAD.
Nonresponders had significantly larger left atria than did the
responders (5.0 ± 0.7 vs. 4.2 ± 0.7 cm, p < 0.05). The mean
LA size of our study was comparable with previous studies
(mean 4.5 ± 0.9) and varied from 3.2 ± 1.2 to 4.3 ± 1.1 cm and
4.5 ± 0.7 to 4.6 ± 0.9 cm, respectively.22, 24 Patients were con-
sidered to have MVD even though it was clinically insignifi-
cant and echocardiography revealed only mild MR. Change
Limitations of the Study
This study has several limitations. It is not a randomized
placebo-controlled study, and the two treatment strategies
were not directly compared clinically. All patients had AF for
> 24 h, but exact time of onset (between 24 h and 3 months)
could not be ascertained in a few of these patients. We had very
few patients post CABG compared with previous studies.

M. K. Das et al.: When is ibutilide most effective?
415
19. Capucci A, Villani GQ, Aschieri D, Piepoli M: Effects of Class III
drugs on atrial fibrillation. J Cardiovasc Electrophysiol 1998;9(8
suppl):S109–120
Nevertheless, the study population is what one would expect
to see in a large general hospital.
20. Howard PA: Ibutilide: An antiarrhythmic agent for the treatment of
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Am J Cardiol 1996;78(8A):46–52
Conclusion
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WJ: Likelihood of spontaneous conversion of atrial fibrillation to
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23. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley RC,
Meissner MD, Zoble RG, Wakefield LK, Perry KT, Vanderlugt JT:
Efficacy of intravenous ibutilide for rapid termination of atrial fib-
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1996;28:130–136
Ibutilide is effective and safe in acute conversion of atrial
fibrillation. Most patients convert to sinus rhythm within an
hour of treatment. As a therapy for acute conversion of atrial
fibrillation, ibutilide is most effective in patients with CAD
or in patients without MVD and/or without markedly en-
larged LA.
24. Singh BN: Antiarrhythmic drugs: A reorientation in light of recent
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25. Foster RH, Wilde MI, Markhani A: Ibutilide: A review of its phar-
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