| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 1997;96:4298-4306.)
© 1997 American Heart Association, Inc.
Articles |
Antiarrhythmic Actions of Intravenous Ibutilide Compared With Procainamide During Human Atrial Flutter and Fibrillation
Electrophysiological Determinants of Enhanced Conversion Efficacy
From the West Roxbury Veterans Affairs Medical Center and Harvard Medical School (B.S.S.), West Roxbury, Mass, and the McGuire Veterans Affairs Medical Center and Medical College of Virginia (M.A.W., K.A.E.), Richmond, Va.
Correspondence to Bruce S. Stambler, MD, Cardiology Section (111A), West Roxbury VA Medical Center, 1400 VFW Pkwy, West Roxbury, MA 02132.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background The selective class III antiarrhythmic agent ibutilide prolongs action potential duration and terminates atrial flutter (AFL) and fibrillation (AF), but the mechanism of its antiarrhythmic efficacy in humans has not been fully characterized. This study compared the antiarrhythmic effects of ibutilide with the class IA agent procainamide in humans during AFL and AF. Antiarrhythmic drug actions and electrophysiological characteristics of AFL and AF that enhanced pharmacological termination were investigated.
Methods and Results Right atrial monophasic action potentials
were recorded during 148 episodes of AFL (n=89) or AF (n=59) in 136
patients treated with intravenous ibutilide (n=73) or
placebo (n=22) as participants in randomized, double-blinded
comparative studies or intravenous procainamide
(n=53) in a concurrent open-label study. The conversion rates in AFL
with ibutilide, procainamide, and placebo were 64% (29 of 45
patients), 0% (0 of 33), and 0% (0 of 11), respectively, whereas in
AF the rates were 32% (9 of 28), 5% (1 of 20), and 0% (0 of 11),
respectively. In AFL, ibutilide increased atrial monophasic action
potential duration (MAPD) more (30% versus 18%, P<.001)
and prolonged atrial cycle length (CL) less (16% versus 26%,
P<.001) than procainamide. Ibutilide shortened and
procainamide prolonged action potential diastolic
interval during AFL (-12% versus 51%, P<.001). Ibutilide
increased MAPD/CL ratio, whereas procainamide tended to
decrease this ratio (13% versus -6%, P<.01). In AF,
ibutilide and procainamide induced similar increases in atrial
CL (48% versus 45%), but ibutilide induced a greater increase in MAPD
(52% versus 37%, P<.05). Independent
electrophysiological predictors of
pharmacological arrhythmia termination were increase in MAPD/CL
ratio (P=.005) in AFL and longer baseline mean MAPD
(P=.011) in AF. Termination of AFL with ibutilide was
characterized by significant increases in beat-to-beat atrial CL, MAPD,
and diastolic interval variability. Ibutilide was
significantly more effective in converting AF when the mean atrial CL
was 
160 ms (64% versus 0%, P<.001) or MAPD was 125 ms
(57% versus 0%, P=.002) at baseline.
Conclusions Enhanced conversion efficacy of ibutilide compared with procainamide in AFL is correlated with a relatively greater prolongation of atrial MAPD than atrial CL, and termination of AFL by ibutilide is characterized by oscillations in atrial CL and MAPD. Conversion of AF by ibutilide is enhanced by a longer baseline mean atrial CL or MAPD.
Key Words: antiarrhythmia agents • action potentials • fibrillation • electrophysiology
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Experimental studies of atrial fibrillation (AF) and atrial flutter (AFL) in animal models have provided knowledge of the antiarrhythmic mechanism of action of pharmacological agents and the vulnerable parameters of reentrant circuits.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Investigations in humans, however, often have focused on the electrophysiological properties of antiarrhythmic drugs rather than on determinants of antiarrhythmic action during atrial arrhythmias. Thus the mechanisms responsible for acute pharmacological conversion of atrial arrhythmias in humans remain incompletely understood. Clinical predictions of whether particular electrophysiological properties will be antiarrhythmic are far from ideal and at times have resulted in unexpected and proarrhythmic responses.
Ibutilide is an intravenous, selective class III antiarrhythmic agent that prolongs action potential duration and refractoriness by enhancing slow inward Na+ plateau current and blocking delayed-rectifier outward K+ current.18 19 20 Several clinical trials have demonstrated that ibutilide is effective in terminating AF or AFL, but the mechanism of its antiarrhythmic action in humans has not been fully characterized.21 22 23 In contrast, procainamide is a class IA drug that slows conduction velocity but also has other important pharmacological actions including action potential and refractory period prolongation.17 24 25 Procainamide blocks fast inward Na+ current and outward K+ current. Although data to support its efficacy are limited, intravenous procainamide is used clinically to terminate AF or AFL.
The objectives of this study were (1) to compare the atrial antiarrhythmic actions of intravenous ibutilide with procainamide during acute pharmacological conversion of AF and AFL, (2) to use atrial monophasic action potential recordings during AF and AFL to determine antiarrhythmic drug actions that favor tachyarrhythmia termination, and (3) to identify specific electrophysiological characteristics of AF and AFL that make a drug with particular electrophysiological properties antiarrhythmic.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Patients
The study population consisted of 136 patients (120 men and 16 women; mean±SD age, 67±8 years; range, 42 to 86) with 148 episodes of spontaneous, sustained AFL or AF referred between October 1991 and December 1994 to the McGuire Veterans Affairs Medical Center or the Medical College of Virginia electrophysiology laboratory for elective cardioversion. Patients received ibutilide or placebo as participants in one of two multicenter, double-blinded, randomized, placebo-controlled trials in which our center was a participating site.21 22 Patients received procainamide as participants in a concurrent open-label study conducted at our institution if they had previously received ibutilide (n=9) or placebo (n=2), if they were unwilling to receive an investigational agent or placebo (n=17), if ibutilide was not available at the time of cardioversion (n=9), or if they had specific exclusion criteria defined in the ibutilide investigational protocol (participants in another investigational study within the previous 30 days [n=2], cardiac surgery within the previous 30 days [n=4], serum potassium <4.0 mEq/L [n=2], serum creatinine >2.0 mg/dL [n=3], heart rate <60 bpm [n=5]).
Patients were excluded if any of the following were present: atrial tachyarrhythmia duration <24 hours or >90 days, hemodynamic instability (systolic blood pressure <90 mm Hg or diastolic blood pressure >105 mm Hg), unstable angina or congestive heart failure symptoms, acute myocardial infarction within the previous 30 days, lack of adequate anticoagulation if AF was present for >2 days, age <18 or >90 years, weight >300 lbs, history of torsade de pointes, QTc >440 ms on ECG, concurrent or within five half-lives before enrollment treatment with class I or III antiarrhythmic drugs, or inability or unwillingness to give informed consent. Patients were treated with digoxin, ß-adrenergic blocking agents, or calcium antagonists for heart rate control. All patients gave written informed consent, and the study protocol was approved by the Committee on the Conduct of Human Research of Virginia Commonwealth University.
Electrophysiology Study
A steerable catheter (EPT) with a pair of silver/silver chloride
electrodes at the distal tip and a pair of platinum ring electrodes
located adjacent to the tip was used for recording atrial
monophasic action potentials and bipolar electrograms, respectively,
and for attempting overdrive pace termination of the atrial
arrhythmia if conversion was not achieved with the drug
infusion. This catheter was inserted through the femoral vein into the
right atrium in a position where a stable monophasic action potential
recording was obtained, usually in the lateral right atrium or
appendage, and in patients with AF where relatively organized atrial
electrical activity was observed and was not moved during the course of
the study. Monophasic action potential signals obtained with a direct
current–coupled preamplifier, bipolar atrial electrograms and 3 ECG
leads (I, aVF and V1) were displayed
simultaneously and recorded at speeds of 100 to
200 mm/s.
Drug Studies
Seventy-three patients (45 with AFL, 28 with AF) were treated
with ibutilide, 53 (33 with AFL, 20 with AF) received
procainamide, and 22 (11 with AFL, 11 with AF) were given
placebo (Table 1
). Nine patients who
previously received ibutilide (5 of whom converted with ibutilide) and
2 patients previously given placebo were treated with
procainamide for a separate episode of AFL (n=7) or AF (n=4).
One patient received procainamide twice on separate occasions,
once for AFL and once for AF.
|
Patients given ibutilide received one of several dosing regimens as determined by the randomization code of the multicenter study in which they were participants. As part of a single-dose study, patients were randomly assigned to receive a 10-minute intravenous infusion of placebo (n=7) or ibutilide (n=28) with one of the following doses: 0.005 mg/kg (n=8), 0.010 mg/kg (n=4), 0.015 mg/kg (n=7), or 0.025 mg/kg (n=9) body weight.22 As part of a repeat-dose study, patients were randomized to receive up to two 10-minute intravenous infusions, separated by 10 minutes, of placebo (n=15) or ibutilide (n=45) with one of the following dosing regimens: placebo followed by placebo, 1.0 mg followed by 0.5 mg ibutilide, or 1.0 mg followed by 1.0 mg ibutilide.21 Patients who converted with the first 10-minute infusion did not receive the second dose. Fourteen patients each received 1.0 mg and 1.0+0.5 mg ibutilide and 17 received 1.0+1.0 mg ibutilide. Patients treated with procainamide were given an intravenous infusion at a dose of 15 mg/kg (mean dose, 1202±241 mg) at a rate not exceeding 50 mg/min. Drug infusions were discontinued when the arrhythmia terminated or the total dose was given. Patients were observed for arrhythmia termination for 1 hour after completion of the last infusion. A blood sample was obtained for measurement of ibutilide serum concentrations 5 (single dose study) or 10 (repeat dose study) minutes after the last ibutilide infusion or at the moment of conversion and for procainamide and N-acetylprocainamide (NAPA) serum concentrations 5 minutes after completion of the procainamide infusion. The mean serum concentration of ibutilide was 4.9±4.5 ng/mL and of procainamide and NAPA were 10.7±3.9 and 1.4±0.6 µg/mL, respectively.
Definitions and Data Analysis
Atrial flutter was defined as a regular atrial
tachyarrhythmia with a stable atrial cycle length (<20
ms difference in cycle length of 20 to 30 consecutive beats) and
characteristic flutter wave sawtooth appearance in the
inferior ECG leads. Atrial fibrillation was defined as a
tachyarrhythmia demonstrating irregularity in the
surface ECG baseline, ventricular response, and atrial
electrogram activity. On the basis of bipolar atrial electrograms and
monophasic action potential recordings from a single lead at
baseline and using the criteria of Wells et al,26 type I
AF was present in 27 ibutilide, 19 procainamide, and 9
placebo-treated patients, type II AF in 1 ibutilide, 1
procainamide, and 2 placebo-treated patients, and type III AF
in no patients.
The AFL or AF cycle length (CL) and the atrial monophasic action potential duration (MAPD) were determined from an average of at least 10 (AFL) or 25 (AF) cycles at baseline and after each pharmacological intervention. Drug measurements were made either just before arrhythmia termination in converters or 5 minutes after completion of drug or placebo infusion in nonconverters. Measurements were made by one nonblinded observer (B.S.S.) with an intraobserver variability of ±5 ms. When analyzing AF recordings, only segments demonstrating type I AF were analyzed, that is, atrial activity was acceptable for measurement if a clear action potential upstroke was present along with a discrete electrogram separated by an isoelectric segment in the atrial bipolar recording. The MAPD was measured from the action potential upstroke to the point where repolarization was 90% back to baseline. If repolarization was not complete before the next action potential, the baseline was selected using the points of intersection of the upstroke with the preceding action potential and the repolarization phase with the next upstroke. In AFL, the diastolic interval (DI) was defined as atrial CL minus MAPD and activation time as the interval from the ECG flutter wave onset to the action potential upstroke. The MAPD and activation time were used as indices of repolarization and conduction times, respectively, and the DI was used as an estimate of the excitable gap. The fraction of the AFL CL occupied by the action potential, that is, the ratio MAPD/CL was used as a measure of relative drug-induced changes in repolarization to conduction velocity. The coefficient of variation (SD/mean times 100) was used as an index of beat-to-beat variability in AFL CL, MAPD, and DI.
Since the electrophysiological effects of
the various doses of ibutilide were not significantly different, all
doses of ibutilide were analyzed together, and only combined
values for the ibutilide doses are presented. 
2
analysis was used to compare variables with discrete end
points such as study patient clinical characteristics. A
repeated-measures ANOVA was used to evaluate
electrophysiological variables within
each drug group in AFL and AF and where appropriate to compare changes
in other continuous, paired variables. A one-way ANOVA was used to
compare variables between drug groups, between AFL and AF, and
between converters and nonconverters. When significant F
values were demonstrated in the ANOVA, the Bonferroni multiple
comparisons test was used to determine significance of individual
comparisons. Linear regression analysis was used to examine the
relation between changes in atrial CL and MAPD. To assess the degree of
linear association between drug efficacy and
electrophysiological and clinical
variables, a Spearman rank correlation test was initially
performed. Those variables significantly associated with
arrhythmia termination based on the univariate
correlation analysis were then subjected to
multivariate analysis using stepwise logistic
regression to determine the independent association of these
variables with arrhythmia termination. A value of
P<.05 was considered statistically significant. Data are
reported as mean±1 SD.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical Characteristics of Study Patients
The mean arrhythmia duration was 23±20 days, and 56% of patients had a previous episode of AF or AFL. More than 90% had heart disease other than atrial arrhythmias, with coronary artery disease, hypertension, and cardiomyopathy being the most common. The mean left atrial diameter and left ventricular ejection fraction were 4.3±0.7 cm and 44±14%, respectively. Most patients were receiving atrioventricular nodal–blocking drugs, and the mean baseline heart rate and systolic and diastolic blood pressures were 85±22 bpm and 134±24 and 81±13 mm Hg, respectively. A higher proportion of patients in the placebo group were receiving ß-adrenergic–blocking drugs (P=.041), but there were no other significant differences in clinical characteristics between drug groups (Table 1
).
Termination of AFL and AF
Of 89 patients with AFL, ibutilide converted 29 of 45 patients
(64%), whereas procainamide and placebo converted 0 of 33 and
11 patients, respectively. Of 59 patients with AF, conversion was
achieved in 9 of 28 patients (32%) who received ibutilide, in 1 of 20
patients (5%) who received procainamide, and in 0 of 11
patients who received placebo. Ibutilide was significantly
(P<.05) more likely to convert AFL than AF (64% versus
32%). The mean time to arrhythmia termination after initiation
of ibutilide was 23±17 minutes (range, 5 to 30 minutes) in AFL and
16±9 minutes (range, 8 to 64 minutes) in AF. On the basis of surface
ECG and intracardiac electrogram criteria, conversion of AF to AFL was
not observed in any patient during or after drug infusion. See Fig 1.
|
Electrophysiological Effects of Ibutilide in
AFL and AF
Table 2 summarizes the
electrophysiological effects of ibutilide,
and Figs 2A and 3A
illustrate the effects of ibutilide in patients with AFL and AF,
respectively. In patients with AFL, ibutilide significantly prolonged
the AFL CL by 39±20 ms (P<.01; 16% increase from
baseline), the atrial MAPD by 49±20 ms (P<.001; 30%), and
the activation time from the flutter wave to the action potential
upstroke by 15±14 ms (P<.01; 30%). The ibutilide-induced
increase in atrial CL was less (P<.001) than the increase
in MAPD. Thus ibutilide shortened the action potential DI by 10±15 ms
(P<.01; -12%) and increased the MAPD–to–atrial CL ratio
(MAPD/CL) by 0.08±0.05(P<.05; 13%). The ibutilide-induced
increase in AFL CL was significantly correlated (r=.72,
P<.0001) with the change in MAPD. In patients with AF,
ibutilide prolonged atrial CL by 77±22 ms (P<.001; 48%)
and MAPD by 65±21 ms (P<.001; 52%). The ibutilide-induced
increase in AF CL was significantly correlated (r=.78,
P<.0001) with change in MAPD. Comparison of the
electrophysiological effects produced by
ibutilide in patients with AF with those produced by ibutilide in
patients with AFL (Fig 4) revealed
significantly greater increases in atrial CL and MAPD in AF than in AFL
(P<.001 and P<.01, respectively).
|
|
18 ms)
and MAPD (
|
|
P<.05 vs atrial flutter.
Electrophysiological Effects of
Procainamide in AFL and AF
Table 2 summarizes the effects of procainamide and Figs 2B and 3B illustrate the effects of procainamide in patients with
AFL and AF, respectively. In patients with AFL, procainamide
significantly increased AFL CL by 62±22 ms (P<.001; 26%),
MAPD by 30±20 ms (P<.05; 18%), and activation time by
28±16 ms (P<.001; 49%). The procainamide-induced
increase in atrial CL was significantly greater (P<.0001)
than the increase in MAPD. Thus in contrast to ibutilide,
procainamide prolonged DI during AFL by 32±23 ms
(P<.001; 51%) and tended to decrease MAPD/CL by 0.05±0.06
(P=NS; -6%), but the ratio was not significantly different
from baseline during procainamide. The increase in AFL CL
induced by procainamide was significantly but modestly
correlated (r=.44, P=.01) with the change in
MAPD. In patients with AF, procainamide prolonged atrial CL by
72±31 ms (P<.001; 45%) and MAPD by 45±27 ms
(P<.001; 37%). The procainamide-induced increase
in AF CL was significantly correlated (r=.81,
P<.0001) with the change in atrial MAPD. Changes in atrial
CL and MAPD induced by procainamide were not significantly
different in AF than AFL (Fig 4).
Comparison of Electrophysiological Effects of
Ibutilide With Procainamide in AFL and AF
In patients with AFL, ibutilide increased atrial MAPD
significantly more (P<.001) and prolonged AFL CL and
activation time significantly less (P<.001 and
P<.01, respectively) than procainamide. Ibutilide
shortened whereas procainamide prolonged the action potential
DI during AFL (P<.001 ibutilide versus
procainamide). Ibutilide increased whereas procainamide
tended to decrease the MAPD/CL ratio (P<.01, ibutilide
versus procainamide). In patients with AF, ibutilide and
procainamide induced similar increases in atrial CL, but
ibutilide induced a significantly greater (P<.05) increase
in atrial MAPD than procainamide. See Fig 4.
Among the 6 patients who received ibutilide and procainamide on separate occasions for AFL, ibutilide converted 3 patients, increased atrial CL and MAPD by 45±18 and 56±22 ms, decreased DI by 9±8 ms, and increased MAPD/CL ratio by 0.08±0.04, whereas procainamide converted no patients, increased atrial CL and MAPD by 66±35 and 35±16 ms, increased DI by 31±18 ms, and decreased MAPD/CL by 0.03±0.05. Among the 3 patients who received ibutilide and procainamide for AF, ibutilide converted 2 patients and increased atrial CL and MAPD by 87±19 and 70±20 ms, whereas procainamide converted no patients and increased atrial CL and MAPD by 86±56 and 51±42 ms.
Comparison of Converters With Nonconverters
In AFL, correlation of
electrophysiological variables in the
pooled ibutilide and procainamide groups with antiarrhythmic
drug efficacy for arrhythmia termination revealed significant
correlations with changes in DI (r=-.471,
P<.0001), MAPD/CL ratio (r=.459,
P<.0001), atrial CL (r=-.334,
P=.003), and activation time (r=-.299,
P=.016) but no correlation with change in MAPD
(r=.174, P=.136) or with baseline atrial CL
(r=-.022, P=.850), MAPD (r=.125,
P=.285), MAPD/CL ratio (r=.064,
P=.588), DI (r=.010, P=.930), or
activation time (r=-.131, P=.302). In AF,
baseline atrial CL (r=.448, P=.001) and MAPD
(r=.439, P=.002) were significantly correlated
with arrhythmia termination; however, changes in atrial CL
(r=.-017, P=.911) and MAPD (r=.162,
P=.278) were not correlated with termination. Examination of
the association between clinical variables in the pooled ibutilide
and procainamide groups with arrhythmia termination
revealed significant correlation with left atrial size
(r=.288, P=.017) in AFL patients and with
arrhythmia duration (r=-.331, P=.027)
and left ventricular ejection fraction (r=.300,
P=.039) in AF patients. Thus univariate
predictors of arrhythmia termination in AFL specifically
included reduction in DI, increase in MAPD/CL ratio, smaller increases
in atrial CL and activation time and larger left atrial size, and in AF
longer mean baseline atrial CL and MAPD, shorter arrhythmia
duration and higher ejection fraction. Multivariate
analysis of these univariate predictors indicated
that independent predictors of arrhythmia termination were left
atrial size (P=.044) and increase in MAPD/CL ratio
(P=.005) in AFL and baseline MAPD (P=.011) in
AF.
Comparison of electrophysiological
variables in patients with AFL that converted with ibutilide (n=29)
with those not converted by ibutilide (n=17) revealed no significant
differences in mean AFL CL, MAPD, DI, MAPD/CL ratio, or activation time
at baseline. Furthermore, because the magnitude of changes in these
electrophysiological variables was
similar whether AFL terminated or persisted after ibutilide, there were
no significant differences in these variables between converters
and nonconverters after ibutilide. Ibutilide prolonged the mean atrial
CL and MAPD by 40±21 and 47±20 ms in converters compared with
increases of 38±19 and 54±20 ms in nonconverters (P=.70,
P=.25, respectively) and shortened DI by 7±10 and 17±20 ms
in converters and nonconverters (P=.11). Patients with AFL
who converted with ibutilide developed significant increases in
beat-to-beat atrial CL, MAPD, and DI variability just before
arrhythmia termination compared with baseline (CL: 1.5±0.9 to
8.3±5.6, P<.001; MAPD: 4.6±2.3 to 8.0±4.2,
P<.05; DI: 12.9±8.6 to 30.3±15.1, P<.001)
(Fig 2). The beat-to-beat AFL CL, MAPD, and DI variability that
preceded AFL conversion by ibutilide was significantly greater than the
beat-to-beat variability in these parameters observed in
patients with AFL who failed to convert after ibutilide (CL: 1.3±0.6,
P<.001; MAPD: 4.7±2.7, P<.05; DI: 14.2±7.4,
P<.01) and was significantly greater than the AFL CL and DI
variability observed after procainamide (CL: 1.3±1.0,
P<.001; MAPD: 5.8±3.3, P=NS; DI: 12.1±5.8,
P<.001).
Comparison of electrophysiological
variables in patients with AF that converted with ibutilide (n=9)
with those whose AF failed to terminate (n=19) revealed significantly
longer mean AF CLs at baseline (180±15 versus 155±12 ms,
P<.001) and after ibutilide (259±27 versus 231±25 ms,
P<.05) and longer mean atrial MAPDs at baseline (143±19
versus 119±12 ms, P<.001) and after ibutilide (216±31
versus 181±22 ms, P<.01) in converters than nonconverters.
The magnitude of the increases in atrial CL and MAPD in AF induced by
ibutilide were similar, however, whether AF was or was not terminated
(79±28 versus 76±20 ms, P=.82 and 73±27 and 62±18 ms,
P=.22). The conversion rate with ibutilide in patients with
AF was significantly higher in those with a baseline mean AF CL 160
ms or MAPD 125 ms (ie, median AF CL and MAPD for all
ibutilide-treated patients). The conversion rate with ibutilide was
64% (9 of 14 patients) in those with a baseline mean atrial CL 160
ms compared with 0% (0 of 14 patients) in those with an atrial CL
<160 ms (P<.001). In those with a baseline mean atrial
MAPD 125 ms, the conversion rate with ibutilide was 57% compared
with 0% in those with an atrial MAPD <125 ms (P=.002). The
baseline AF CL and MAPD were not significantly correlated with
arrhythmia duration (r=-.053, P=-.794;
r=-.163, P=.426, respectively) or with any other
clinical variable, and arrhythmia duration was not
significantly different between ibutilide converters and nonconverters
(19±9 versus 22±18 days, P=.660) with AF.
Adverse Effects
Ibutilide produced no significant changes in systolic or
diastolic blood pressure and slightly decreased heart rate
by 7±22 bpm (P<.05, -5%). Three patients (4%) who
received ibutilide for AFL developed nonsustained, polymorphic
ventricular tachycardia during or shortly after
the infusion, which did not require electrical cardioversion.
Procainamide reduced systolic blood pressure by
25±20 mm Hg (P<.001, -18%) and
diastolic pressure by 9±14 mm Hg (P<.05,
-10%) and produced no significant change in heart rate.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study demonstrated that the differing electrophysiological effects of intravenous ibutilide compared with procainamide during atrial arrhythmias correlated with the enhanced conversion efficacy of ibutilide. Pharmacological termination of AFL by ibutilide compared with procainamide was characterized by relatively greater prolongation of atrial MAPD than atrial CL and by oscillations in atrial CL and MAPD just before arrhythmia termination. Conversion of AF by ibutilide was enhanced by a longer mean atrial CL or MAPD at baseline during AF.
Atrial Arrhythmia Conversion Efficacy
Although this study was not a randomized comparison of
intravenous ibutilide with procainamide or placebo,
the atrial arrhythmia conversion rates were consistent
with several previous randomized, double-blinded, multicenter, efficacy
studies. These previous studies demonstrated that ibutilide is
significantly more effective than placebo or procainamide for
conversion of AFL or AF and for conversion of AFL than
AF.21 22 23 In a multicenter, randomized trial that compared
the conversion efficacy of intravenous ibutilide (2 mg
total dose) with procainamide (1200 mg), ibutilide converted
76% of patients with AFL and 51% with AF, whereas
procainamide converted 12% with AFL and 20% with
AF.23 The lack of significant conversion efficacy of
intravenous procainamide contrasts with several
previous reports in which the AF conversion rates were in the 40% to
60% range.27 28 29 30 Arrhythmia duration, however, is
a potent predictor of pharmacological conversion of
AF.21 27 Previous reports that demonstrated significant
efficacy of procainamide evaluated patients with recent-onset
AF with arrhythmia durations <1 to 2 days. In contrast in the
present study, patients had chronic established AF, with a median
arrhythmia duration of 30 days. In a previous study,
procainamide (1.0 g IV) terminated AF in 9 of 10 patients
(90%) with an arrhythmia duration 
1 day but converted only 5
of 15 patients (33%) with a duration >1 day.27
Antiarrhythmic Drug Actions and AFL Conversion Efficacy
Ibutilide and procainamide produced
electrophysiological effects during AFL
consistent with class III and IA antiarrhythmic drug action,
respectively. Because the procainamide infusion was completed
within 30 minutes, minimal NAPA, a metabolite with class III
antiarrhythmic properties,2 3 4 was generated as
demonstrated by the very low serum levels. During AFL, ibutilide
prolonged right atrial MAPD more than CL (30% versus 16%), whereas
procainamide increased atrial CL more than MAPD (26% versus
18%). Importantly, these significantly different antiarrhythmic class
actions produced opposing effects on DI and MAPD/CL ratio. Ibutilide
shortened DI and increased MAPD/CL, whereas procainamide
prolonged DI and tended to decrease MAPD/CL. Examination of the pooled
ibutilide and procainamide data revealed that antiarrhythmic
drug efficacy for termination of AFL was significantly correlated in
the univariate analysis with increase in MAPD/CL
ratio, reduction in DI, and relatively smaller increases in atrial CL
and activation time. The magnitude of the increase in MAPD alone was
not correlated significantly with arrhythmia termination. Thus
ibutilide may have been more effective than procainamide in
terminating AFL because ibutilide, in contrast to procainamide,
prolonged atrial MAPD more than atrial CL.
Experimental studies suggest that wavelength (ie, product of refractory period and conduction velocity) is a critical determinant of antiarrhythmic drug effects on reentrant arrhythmias.5 15 16 17 Theoretically, in a reentrant circuit with a fixed path length, wavelength is proportional to refractory period divided by CL. Although tachycardia wavelength was not directly measured in this study, the MAPD/CL ratio provided a relative measure of drug-induced changes in repolarization to conduction velocity. An increase in this ratio that reflected a relatively greater drug-induced prolongation of atrial MAPD than CL provided the most significant independent predictor of AFL termination. Ibutilide prolonged action potential duration and thus refractory period during AFL more than it slowed conduction (ie, atrial CL and activation time), resulting in a 13% increase in MAPD/CL. In contrast, procainamide slowed conduction more than it prolonged action potential duration and thus decreased MAPD/CL by 6%. These effects are consistent with an ibutilide-induced increase and procainamide-induced decrease in wavelength. In support of these conclusions, the selective class III agent dofetilide was more effective than the class IA drug quinidine in terminating AFL in a canine crush-injury model.14 Dofetilide significantly increased wavelength by 11%, but quinidine tended to reduce wavelength by 2%. Efficacy was correlated with prolongation of wavelength and not with changes in refractoriness or conduction velocity alone. Thus the enhanced efficacy of ibutilide compared with procainamide in terminating AFL may be related in part to drug-induced changes in wavelength mediated by alterations in action potential duration and conduction.
In this study, termination of AFL with ibutilide was associated with an increase in beat-to-beat variability in atrial CL, MAPD, and DI, as previously described in animal models of reentrant arrhythmia termination.6 11 13 31 32 These oscillations were not observed in patients with AFL that was not terminated by ibutilide or procainamide. These findings extend our previous observations regarding AFL termination with ibutilide to a larger group of patients and further suggest that oscillatory termination is an important mechanism by which ibutilide but not procainamide results in AFL termination.33 In human AFL, there is a large, fully excitable gap that ranges in width from 14% to 25% of the AFL CL.34 35 On the basis of this study, it seems unlikely that action potential prolongation by ibutilide was sufficient to close the total excitable gap and extinguish the circuit. The increases in MAPD were partially offset by increases in CL, which would tend to maintain excitable gap. Thus DI was reduced by only 12% despite a 30% mean increase in MAPD. The size of the excitable gap, however, can vary throughout the AFL circuit. A local excitable gap might have been eliminated or reduced by the relatively greater increases in atrial MAPD than CL produced by ibutilide. This would result in CL-dependent alterations in conduction, action potential duration, and refractory period, which could produce transient oscillations in CL, MAPD, and DI and arrhythmia termination.11 13 31 32
Because ibutilide does not directly slow conduction velocity, the mechanism of AFL CL prolongation by ibutilide may be explained by conversion from a fully to a partially excitable gap. In a reentrant circuit with a fully excitable gap, tachycardia CL is proportional to conduction velocity and does not depend directly on action potential duration.36 Prolongation of action potential duration by a class III agent may slow conduction velocity and prolong tachycardia CL by propagation of the impulse in incompletely repolarized tissues.1 3 6 14 15 In contrast, by directly slowing conduction velocity, procainamide would tend to maintain the fully excitable gap with propagation of impulses in completely repolarized tissues.36
Electrophysiological Characteristics of AF and
Antiarrhythmic Drug Efficacy
To our knowledge, the finding of this study that the baseline
atrial CL and MAPD are electrophysiological
determinants of antiarrhythmic drug efficacy for termination of AF in
humans has not been previously reported. The conversion efficacy of
ibutilide in AF was significantly determined by whether patients had a
short or long mean atrial CL or MAPD at baseline. No patient with AF
and a mean right atrial CL <160 ms or MAPD <125 ms was converted by
ibutilide, whereas conversion was achieved in 64% and 57% of those
with a mean atrial CL 160 ms or MAPD 125 ms, respectively. Although
the duration of AF is a powerful predictor of drug efficacy in
terminating AF and may be an important determinant of AF CL and MAPD,
in this study a significant correlation between arrhythmia
duration and these electrophysiological
variables was not found. This may have been related to inclusion of
only a relatively small number of patients with recent-onset AF and to
the analysis of only recording segments demonstrating
type I AF.
A correlation between the median AF interval and the complexity of AF has been demonstrated with the use of high-density mapping in humans.16 37 A longer median AF interval is associated with a smaller number of fibrillatory wavelets, and pharmacological termination of AF in animal models is preceded by an increase in mean AF CL, which is an index of local atrial refractoriness.38 Thus it is possible to speculate that patients in this study with a long mean AF CL had a long wavelength and a small number of wavelets, whereas those with a short mean AF CL had a short wavelength and multiple wavelets. In the group with a long mean AF CL, prolongation of AF CL and MAPD by ibutilide may have increased wavelength and critically reduced the number of wavelets that could coexist in the atria. This increased the statistical chance that all wavelets might extinguish simultaneously and the fibrillatory process would terminate spontaneously.16 39 Mapping studies in animal models indicate that antiarrhythmic drugs terminate experimental AF by this mechanism.9 10 12 13 16 In contrast, in the group with a short mean AF CL, although ibutilide increased AF CL, wavelength may not have prolonged sufficiently to critically reduce the number of wavelets and allow the arrhythmia to terminate. Because ibutilide induced similar increases in AF CL and MAPD in nonconverters as in converters, the AF CL and MAPD remained shorter after ibutilide in nonconverters than in converters. Finally, although the absence of a frequency-dependent effect of ibutilide on human AF has not been excluded, a previous study in dogs found no reverse use-dependent effect of ibutilide on atrial effective refractory period at paced cycle lengths from 150 to 400 ms.40
Despite inducing a similar increase in AF CL as ibutilide, procainamide was ineffective in terminating AF even in patients with long AF CLs at baseline. Procainamide prolonged atrial MAPD during AF less than did ibutilide; however, the mechanism of enhanced efficacy of ibutilide in terminating AF compared with procainamide will require further evaluation.
These data may provide insight into the greater efficacy of ibutilide in terminating AFL than AF. Prolongation of action potential duration and refractoriness by class III antiarrhythmic action may be effective for termination of atrial arrhythmias that have either a single broad wavefront (ie, AFL) or a relatively small number of circulating wavelets (ie, AF with a long mean CL). Whether greater prolongation of action potential duration with higher doses of ibutilide can reliably terminate AF with a short CL without prohibitively increasing the proarrhythmia risk may warrant further study. Measurement of AF CL might be used clinically to determine the likelihood of arrhythmia conversion by ibutilide.
Limitations
In the present study, only single-site recordings
during the atrial arrhythmias were obtained and the
tachycardia wavelength was not directly measured.
Therefore, the specific mechanisms of atrial arrhythmia
termination could not be evaluated. Recordings during AFL were
obtained from presumably normal atrial tissues that were not located in
critical areas of the circuit. The findings are valid only if the
measurements were representative of antiarrhythmic drug
effects on the circuit. Only recordings with type I AF were
analyzed, and signals from other atrial areas with more complex
types of AF were not evaluated. Refractoriness and conduction velocity
cannot be measured directly during AF and because programmed
stimulation might have terminated the arrhythmia were not
measured directly during AFL.
This study was not a randomized comparison, and the results of this study may not apply to all patients with atrial arrhythmias treated with these drugs. Procainamide was given in open-label, nonrandomized fashion, and some patients who received procainamide had previously received ibutilide. Including patients in the procainamide group who previously received ibutilide allowed a comparison of the two drugs in the same patients and did not appear to create a bias in the procainamide group by including patients who failed to respond to ibutilide. More than 50% of the procainamide patients who previously received ibutilide were ibutilide responders. The effects of only short-term intravenous drug administration were studied and because all ibutilide doses were analyzed together and only one dose of procainamide was examined, the possibility of differential electrophysiological effects of these drugs at escalating doses cannot be excluded. The electrophysiological effects and antiarrhythmic actions of intravenous procainamide may be modified during a longer infusion or observation period or by oral administration during which the class III antiarrhythmic agent NAPA would accumulate. Relatively few patients in this study had recent-onset AF in which the conversion rate of procainamide may be higher than placebo and electrophysiological effects may be altered.
|
Acknowledgments |
|---|
This study was supported in part by a grant from the Upjohn Company, Kalamazoo, Mich.
Received May 6, 1997; revision received August 11, 1997; accepted September 1, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Feld GK, Venkatesh N, Singh BN. Pharmacologic conversion and suppression of experimental canine atrial flutter: differing effects of d-sotalol, quinidine, and lidocaine and significance of changes in refractoriness and conduction. Circulation.. 1986;74:197-204.
2.
Wu KM, Hoffman BF. Effect of
procainamide and N-acetylprocainamide on atrial
flutter: studies in vivo and in vitro. Circulation. 1987;76:1397-1408.
3. Okumura K, Waldo AL. Effects of N-acetylprocainamide on experimental atrial flutter and atrial electrophysiologic properties in conscious dogs with sterile pericarditis: comparison with the effects of quinidine. J Am Coll Cardiol.. 1987;9:1332-1338.[Abstract]
4. Feld GK, Venkatesh N, Singh BN. Effects of N-acetylprocainamide and recainam in the pharmacologic conversion and suppression of experimental canine atrial flutter: significance of changes in refractoriness and conduction. J Cardiovasc Pharmacol.. 1988;11:573-580.[Medline] [Order article via Infotrieve]
5.
Rensma PL, Allessie MA, Lammers WJE, Bonke FIM,
Schalij MJ. Length of excitation wave and susceptibility to
reentrant atrial arrhythmias in normal conscious dogs.
Circ Res. 1988;62:395-410.
6.
Spinelli W, Hoffman BF. Mechanisms of
termination of reentrant atrial arrhythmias by class I and III
antiarrhythmic agents. Circ Res. 1989;65:1565-1579.
7. Inoue H, Yamashita T, Nozaki A, Sugimoto T. Effects of antiarrhythmic drugs on canine atrial flutter due to reentry: role of refractory period and depression of conduction to excitable gap. J Am Coll Cardiol. 1991;18:1098-1104.[Abstract]
8.
Schoels W, Yang H, Gough WB, El-Sherif N.
Circus movement atrial flutter in the canine sterile
pericarditis model: differential effects of procainamide on the
components of the reentrant pathway. Circ Res. 1991;68:1117-1126.
9. Kirchhof C, Wijffels M, Brugada J, Planellas J, Allessie MA. Mode of action of a new class IC drug (ORG 7797) against atrial fibrillation in conscious dogs. J Cardiovasc Pharmacol. 1991;17:116-124.[Medline] [Order article via Infotrieve]
10.
Wang Z, Page P, Nattel S. The mechanism of
flecainide's antiarrhythmic action in experimental atrial
fibrillation. Circ Res. 1992;71:271-287.
11. Boyden PA, Graziano JN. Activation mapping of reentry around an anatomical barrier in the canine atrium: observations during the action of the class III agent, d-sotalol. J Cardiovasc Electrophysiol.. 1993;4:266-279.[Medline] [Order article via Infotrieve]
12.
Wang J, Bourne G, Wang Z, Villemaire C, Talajic M,
Nattel S. Comparative mechanisms of antiarrhythmic drug action
in experimental atrial fibrillation: the importance of use-dependent
effects on refractoriness. Circulation. 1993;88:1030-1044.
13.
Fei H, Frame LH. d-Sotalol terminates reentry by
two mechanisms with different dependence on the duration of the
excitable gap. J Pharm Exp Ther. 1996;277:174-185.
14. Cha Y, Wales A, Wolf P, Shahrokni S, Sawhney N, Feld GK. Electrophysiologic effects of the new class III antiarrhythmic drug dofetilide compared to the class IA antiarrhythmic drug quinidine in experimental canine atrial flutter: role of dispersion of refractoriness in antiarrhythmic efficacy. J Cardiovasc Electrophysiol. 1996;7:809-827.[Medline] [Order article via Infotrieve]
15. Feld GK. Pharmacological control of experimental atrial arrhythmias: significance of prolonging excitation wavelength. In: Singh BN, Wellens HJJ, Hiraoka M, eds. Electropharmacological Control of Cardiac Arrhythmias to Delay Conduction or to Prolong Refractoriness? Mount Kisco, NY: Futura Publishing Co; 1994:265-277.
16. Allessie MA. Reentrant mechanisms underlying atrial fibrillation. In: Zipes DP, Jalife J, eds. Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:562-566.
17.
Task Force of the Working Group on Arrhythmias
of the European Society of Cardiology. The
Sicilian Gambit: a new approach to the classification of antiarrhythmic
drugs based on their actions on arrhythmogenic mechanisms.
Circulation.. 1991;84:1831-1851.
18. Buchanan LV, Kabell GG, Gibson JK. Acute intravenous conversion of canine atrial flutter: comparison of antiarrhythmic agents. J Cardiovasc Pharmacol. 1995;25:539-544.[Medline] [Order article via Infotrieve]
19.
Lee KS. Ibutilide, a new compound with potent
class III antiarrhythmic activity, activates a slow inward
Na+ current in guinea pig ventricular
cells. J Pharm Exp Ther. 1992;262:99-108.
20.
Yang T, Snyders DJ, Roden DM. Ibutilide, a
methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly
activating delayed rectifier K+ current (Ikr)
in AT-1 cells. Circulation. 1995;91:1799-1806.
21.
Stambler BS, Wood MA, Ellenbogen KA, Perry KT,
Wakefield LK, VanderLugt JT, and the Ibutilide Repeat Dose Study
Investigators. Efficacy and safety of repeated
intravenous doses of ibutilide for rapid conversion of
atrial flutter or fibrillation. Circulation. 1996;94:1613-1621.
22. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley RC, Meissner MD, Zoble RG, Wakefield LK, Perry KT, VanderLugt, for the Ibutilide Investigators. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol. 1996;28:130-136.[Abstract]
23. Volgman AS, Stambler BS, Kappagoda C, Carberry PA, Dunn GH, Perry KT, VanderLugt JT, Kowey PR. Comparison of intravenous ibutilide versus procainamide for the rapid termination of atrial fibrillation or flutter. PACE. 1996;19:608. Abstract.
24.
Rosen MR, Gelband H, Hoffman BF. Canine
electrocardiographic and electrophysiologic changes induced by
procainamide. Circulation. 1972;46:528-536.
25. Hoffman BF, Rosen MR, Wit AL. Electrophysiology and pharmacology of arrhythmias, VII: cardiac effects of quinidine and procainamide. Am Heart J. 1975;90:117-122.[Medline] [Order article via Infotrieve]
26. Wells JL, Karp RB, Kouchoukos NT, MacLean WH, James TN, Waldo AL. Characterization of atrial fibrillation in man: studies following open heart surgery. PACE. 1979;1:426-438.
27. Fenster PE, Comess KA, Marsh R, Katzenberg C, Hager WD. Conversion of atrial fibrillation to sinus rhythm by acute intravenous procainamide infusion. Am Heart J. 1983;106:501-504.[Medline] [Order article via Infotrieve]
28.
Halpern SW, Ellrodt G, Singh BN, Mandel WJ.
Efficacy of intravenous procainamide
infusion in converting atrial fibrillation to sinus rhythm.
Br Heart J. 1980;44:589-595.
29.
Madrid A, Moro C, Marin-Huerta E, Mestre JL, Novo L,
Costa A. Comparison of flecainide and procainamide in
cardioversion of atrial fibrillation. Eur Heart
J. 1993;14:1127-1131.
30. Boahene KA, Klein GJ, Yee R, Sharma AD, Fujimura O. Termination of acute atrial fibrillation in the Wolff-Parkinson-White Syndrome by procainamide and propafenone. J Am Coll Cardiol. 1990;16:1408-1414.[Abstract]
31.
Frame LH, Simson MB.
Oscillations of conduction, action potential
duration, and refractoriness: a mechanism for spontaneous termination
of reentrant tachycardias. Circulation. 1988;78:1277-1287.
32.
Ortiz J, Igarashi M, Gonzalez HX, Laurita K, Rudy
Y, Waldo AL. Mechanism of spontaneous termination of stable
atrial flutter in the canine sterile pericarditis model.
Circulation. 1993;88:1866-1877.
33. Guo GBF, Ellenbogen KA, Wood MA, Stambler BS. Conversion of atrial flutter by ibutilide is associated with increased atrial cycle length variability. J Am Coll Cardiol. 1996;27:1083-1089.[Abstract]
34. Inoue H, Matsuo H, Takayanagi K, Murao S. Clinical and experimental studies of the effects of atrial extrastimulation and rapid pacing on atrial flutter cycle: evidence of macro-reentry with an excitable gap. Am J Cardiol. 1981;48:623-631.[Medline] [Order article via Infotrieve]
35. Della Bella P, Marenzi G, Tondo C, Cardinale D, Giraldi F, Lauri G, Guazzi M. Usefulness of excitable gap and pattern of resetting in atrial flutter for determining reentry circuit location. Am J Cardiol. 1991;68:492-497.[Medline] [Order article via Infotrieve]
36. Stambler BS, Wood MA, Ellenbogen KA. Pharmacologic alterations in human type I atrial flutter cycle length and monophasic action potential duration: evidence of a fully excitable gap in the reentrant circuit. J Am Coll Cardiol. 1996;27:453-441.[Abstract]
37.
Konings KTS, Kirchhof CJHJ, Smeets JRLM, Wellens HJJ,
Penn OC, Allessie MA. High-density mapping of electrically
induced atrial fibrillation in humans. Circulation. 1994;89:1665-1680.
38. Lammers WJEP, Allessie MA, Rensma PL. The use of fibrillation cycle length to determine spatial dispersion in electrophysiological properties and to characterize the underlying mechanisms of fibrillation. New Trends Arrhythmias. 1986;2:109-112.
39. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther. 1962;140:183-188.
40. Buchanan LV, LeMay RJ, Gibson JK. Comparison of the class III agents d,l-sotalol HCl and ibutilide fumarate for atrial reverse use dependence and antiarrhythmic effects. PACE. 1996;19:687. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  J.#x.;n. Farré, H. J.J. Wellens, J.#x. M. Rubio, and J. Benezet CHAPTER 28 Supraventricular Tachycardias ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Roy, C. M. Pratt, C. Torp-Pedersen, D. G. Wyse, E. Toft, S. Juul-Moller, T. Nielsen, S. L. Rasmussen, I. G. Stiell, B. Coutu, et al. Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo-Controlled Trial Circulation, March 25, 2008; 117(12): 1518 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Husser, D. S. Cannom, A. K. Bhandari, M. Stridh, L. Sornmo, S. B. Olsson, and A. Bollmann Electrocardiographic characteristics of fibrillatory waves in new-onset atrial fibrillation Europace, August 1, 2007; 9(8): 638 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bollmann, D. Husser, L. Mainardi, F. Lombardi, P. Langley, A. Murray, J. J. Rieta, J. Millet, S. B. Olsson, M. Stridh, et al. Analysis of surface electrocardiograms in atrial fibrillation: techniques, research, and clinical applications. Europace, November 1, 2006; 8(11): 911 - 926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Holmqvist, M. Stridh, J. E.P. Waktare, L. Sornmo, S. B. Olsson, and C. J. Meurling Atrial fibrillatory rate and sinus rhythm maintenance in patients undergoing cardioversion of persistent atrial fibrillation Eur. Heart J., September 2, 2006; 27(18): 2201 - 2207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): 854 - 906. [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): 700 - 752. [Full Text] [PDF]
|
|
|
|
|
|
Authors/Task Force Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Eur. Heart J., August 2, 2006; 27(16): 1979 - 2030. [Full Text] [PDF]
|
|
|
|
 |
|
 O Viktorsdottir, A Henriksdottir, and D O Arnar Ibutilide for treatment of atrial fibrillation in the emergency department Emerg. Med. J., February 1, 2006; 23(2): 133 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Chou, S. Zhou, A. Y. Tan, H. Hayashi, M. Nihei, and P.-S. Chen High-density mapping of pulmonary veins and left atrium during ibutilide administration in a canine model of sustained atrial fibrillation Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2704 - H2713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Hongo, S. Themistoclakis, A. Raviele, A. Bonso, A. Rossillo, K. A. Glatter, Y. Yang, and M. M. Scheinman Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents J. Am. Coll. Cardiol., August 18, 2004; 44(4): 864 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Reisinger, E. Gatterer, W. Lang, T. Vanicek, G. Eisserer, T. Bachleitner, C. Niemeth, F. Aicher, W. Grander, G. Heinze, et al. Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset Eur. Heart J., August 1, 2004; 25(15): 1318 - 1324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cheng, K. Glatter, Y. Yang, S. Zhang, R. Lee, and M. M. Scheinman Electrophysiological Response of the Right Atrium to Ibutilide During Typical Atrial Flutter Circulation, August 13, 2002; 106(7): 814 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Miyata, J. D. Dowell, D. P. Zipes, and M. Rubart Rate-dependent [K+]o accumulation in canine right atria in vivo: electrophysiological consequences Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H506 - H517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology Circulation, October 23, 2001; 104(17): 2118 - 2150. [Full Text] [PDF]
|
|
|
|
|
|
K. A. Glatter, P. C. Dorostkar, Y. Yang, R. J. Lee, G. F. Van Hare, E. Keung, G. Modin, and M. M. Scheinman Electrophysiological Effects of Ibutilide in Patients With Accessory Pathways Circulation, October 16, 2001; 104(16): 1933 - 1939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology Eur. Heart J., October 2, 2001; 22(20): 1852 - 1923. [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1231 - 1265. [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, L. E. Ryden, R. W. Asinger, D. S. Cannom, H. J. Crijns, R. L. Frye, J. L. Halperin, G. N. Kay, W. W. Klein, S. Levy, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1266 - 1266. [Full Text] [PDF]
|
|
|
|
|
|
M. Duytschaever, F. Mast, M. Killian, Y. Blaauw, M. Wijffels, and M. Allessie Methods for Determining the Refractory Period and Excitable Gap During Persistent Atrial Fibrillation in the Goat Circulation, August 21, 2001; 104(8): 957 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ramanna, A. Elvan, F. H. M. Wittkampf, J. M. T. de Bakker, R. N. W. Hauer, and E. O. Robles de Medina Increased dispersion and shortened refractoriness caused by verapamil in chronic atrial fibrillation J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1403 - 1407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Glatter, Y. Yang, K. Chatterjee, G. Modin, J. Cheng, S. Kayser, and M. M. Scheinman Chemical Cardioversion of Atrial Fibrillation or Flutter With Ibutilide in Patients Receiving Amiodarone Therapy Circulation, January 16, 2001; 103(2): 253 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bollmann Quantification of electrical remodeling in human atrial fibrillation Cardiovasc Res, August 1, 2000; 47(2): 207 - 209. [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Hohnloser, Y.-G. Li, B. Bender, and G. Gronefeld Review : Pharmacological Management of Atrial Fibrillation: An Update Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(1): 11 - 16. [Abstract] [PDF]
|
|
|
|
|
|
H. Oral, B. P. Knight, C. Sticherling, M. H. Kim, R. L. Baker, S. P. Chough, K. Wasmer, F. Pelosi JR, G. F. Michaud, A. M. Fendrick, et al. Cost Analysis of Transthoracic Cardioversion of Atrial Fibrillation With and Without Ibutilide Pretreatment Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 259 - 266. [Abstract] [PDF]
|
|
|
|
|
|
A. Bollmann, K. Sonne, H.-D. Esperer, I. Toepffer, J. J Langberg, and H. U Klein Non-invasive assessment of fibrillatory activity in patients with paroxysmal and persistent atrial fibrillation using the Holter ECG Cardiovasc Res, October 1, 1999; 44(1): 60 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Biffi, G Boriani, G Bronzetti, A Capucci, A Branzi, and B Magnani Electrophysiological effects of flecainide and propafenone on atrial fibrillation cycle and relation with arrhythmia termination Heart, August 1, 1999; 82(2): 176 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Oral, J. J. Souza, G. F. Michaud, B. P. Knight, R. Goyal, S. A. Strickberger, and F. Morady Facilitating Transthoracic Cardioversion of Atrial Fibrillation with Ibutilide Pretreatment N. Engl. J. Med., June 17, 1999; 340(24): 1849 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M A Vos, S R Golitsyn, K Stangl, M Y Ruda, L Van Wijk, J D Harry, K T Perry, P Touboul, G Steinbeck, and H J J Wellens Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation Heart, June 1, 1998; 79(6): 568 - 575. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||