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Circulation. 1996;94:1613-1621

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(Circulation. 1996;94:1613-1621.)
© 1996 American Heart Association, Inc.

Articles

Efficacy and Safety of Repeated Intravenous Doses of Ibutilide for Rapid Conversion of Atrial Flutter or Fibrillation

Bruce S. Stambler, MD; Mark A. Wood, MD; Kenneth A. Ellenbogen, MD; Kimberly T. Perry, PhD; Linda K. Wakefield, BS; James T. VanderLugt, MD; and the Ibutilide Repeat Dose Study Investigators

the West Roxbury Veterans Administration Medical Center and Harvard Medical School (B.S.S.), West Roxbury, Mass; McGuire Veterans Administration Medical Center and Medical College of Virginia (Richmond) (M.A.W., K.A.E.); and the Pharmacia & Upjohn Company (K.T.P., L.K.W., J.T.V.), Kalamazoo, Mich.

Correspondence to Bruce S. Stambler, MD, Cardiology Section (111A), West Roxbury VA Medical Center, 1400 VFW Pkwy, West Roxbury, MA 02132.


*    Abstract
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Background Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter.

Methods and Results Two hundred sixty-six patients with sustained atrial fibrillation (n=133) or flutter (n=133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo (P<.0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%, P<.0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%).

Conclusions Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.


Key Words: atrial flutter • ibutilide • fibrillation • antiarrhythmia agents • arrhythmia


*    Introduction
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Restoration of sinus rhythm in patients with atrial fibrillation or flutter is often attempted to improve the adverse symptomatic and hemodynamic consequences and potentially to prevent the embolic risks associated with these atrial tachyarrhythmias. Electrical cardioversion is effective in restoring sinus rhythm but requires anesthesia and is not successful in all cases. Antiarrhythmic drugs, such as class IA, IC, or III agents, can be given to terminate these atrial tachyarrhythmias. The efficacy of currently available agents is highly variable, depends on the duration of the arrhythmia, and is significantly lower in atrial flutter than fibrillation.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 In addition, placebo-controlled trials that establish the efficacy and safety of these pharmacological therapies for acute conversion are not available. An effective pharmacological alternative to existing methods of cardioversion would benefit patients with atrial flutter or atrial fibrillation.

In animal models of atrial flutter and fibrillation, ibutilide fumarate, a new class III antiarrhythmic agent, is effective in terminating and preventing the reinduction of these arrhythmias.17 18 19 In an initial dose-response study in humans with atrial fibrillation or flutter, a single intravenous infusion of ibutilide (doses of 0.005 to 0.025 mg/kg) terminated the arrhythmia in 34% of patients.20 The present study was designed to examine the efficacy and safety of repeated administration of ibutilide using fixed milligram dosing to evaluate a potential clinical regimen for rapid termination of atrial flutter and fibrillation.


*    Methods
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 *Methods
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This study was prospectively designed as a double-blind, placebo-controlled, randomized, dose-response, multicenter trial. Patients were stratified on the basis of the enrollment arrhythmia (atrial flutter or atrial fibrillation) and were randomized to receive up to two 10-minute intravenous infusions, separated by 10 minutes. Infusions were placebo followed by placebo, 1.0 mg followed by 0.5 mg ibutilide fumarate, or 1.0 mg followed by 1.0 mg ibutilide. Doses for patients weighing <60 kg were weight adjusted (1.0 mg=0.01 mg/kg, 0.5 mg=0.005 mg/kg). If the arrhythmia did not terminate during or within 10 minutes after the end of the first infusion, the second infusion was administered. The study protocol was approved by the institutional review boards at each of the participating sites (see "Appendix"), and patients gave written informed consent.

The following criteria were required 10 minutes before infusion for participation. The patient had to have a rhythm of sustained atrial flutter or atrial fibrillation with a duration of >3 hours and <45 days. If the duration of atrial fibrillation was >3 days, >=2 weeks of anticoagulation before enrollment was needed. The patient could not be <18 years of age, of child-bearing potential, weigh >300 lb, have a history of torsade de pointes or a corrected QT interval (QTc) of >440 ms, have received ibutilide previously, have had a myocardial infarction or cardiac surgery within the previous 30 days, or have clinical evidence of digoxin toxicity or hyperthyroidism. The patient had to be hemodynamically stable (systolic blood pressure >90 mm Hg and diastolic blood pressure <105 mm Hg) without symptoms of angina or congestive heart failure, have normal serum electrolytes (potassium >=4.0 mEq/L), and have liver enzymes less than twice maximal normal values. The patient could not be receiving class I or III antiarrhythmic agents unless the medication was discontinued more than five half-lives before enrollment. ß-Adrenergic–blocking agents, calcium antagonists, and digoxin were permitted, but heart rate could not be <60 bpm. An echocardiogram was performed within 2 weeks before enrollment, and the criteria used to determine left atrial enlargement were based on the standards at each site.

The primary efficacy end point of this study was the treatment-induced termination of atrial fibrillation or flutter. Success was defined as termination for any length of time by hour 1.5 after initiation of the first infusion. Drug or placebo was infused according to the study protocol schedule (first 10-minute infusion, a 10-minute wait, second 10-minute infusion). A rhythm strip was continuously monitored, blood pressure and heart rate were recorded every 5 minutes, and 12-lead ECGs were obtained before dosing at minute -10, at minutes 30 and 90, and at the time of arrhythmia termination or significant rhythm changes. ECGs were interpreted by individual investigators who were blinded to study treatment. Venous blood was drawn for ibutilide plasma concentrations at minutes -10, 20, 40, and 90 and at termination or significant rhythm changes. The infusion was discontinued if the arrhythmia terminated, systolic blood pressure decreased to <90 mm Hg, any change in rhythm or atrioventricular conduction occurred that in the investigator's opinion was a threat to patient safety, a new bundle-branch block developed, QRS increased >50%, QTc increased to >600 ms, or new or repetitive forms of ventricular premature depolarizations were noted. If atrial fibrillation or flutter persisted past hour 1.5, pacing or electrocardioversion was permitted. The use of other antiarrhythmic agents was discouraged until 4 hours after the infusion unless the investigator considered it necessary to restore sinus rhythm earlier, in which case drugs to facilitate conversion were permitted at 1.5 hour.

Data Analysis
All 266 patients who received study medication were included in the safety analysis, and 242 patients were evaluated for efficacy. Twenty-four patients were not included in the efficacy analysis because of significant protocol deviations, which included receiving a dose of study drug that was inconsistent with the protocol (n=13), having an arrhythmia duration of >45 days (n=8), receiving other antiarrhythmic drugs within three half-lives of the study (n=3), having a rhythm that was not atrial fibrillation or flutter at minute -10 (n=1), or being electrically cardioverted before hour 1.5 (n=1) unless cardioversion was required for ventricular tachycardia (VT). Patients who converted and then relapsed were analyzed as successful conversions.

Data are presented as mean±1 SD, and P<=.05 was considered significant unless stated otherwise. Compatibility of dose groups with respect to baseline clinical characteristics was assessed using a one-way ANOVA for continuous variables and a {chi}2 test for categorical variables. Analysis of the relationship between termination of atrial fibrillation or flutter and ibutilide dose was performed using a {chi}2 analysis. Assessment of the significance of mean change from baseline to each follow-up reading of ECG intervals (QRS, QT, QTc), blood pressures, and heart rates were made within dose groups using paired t tests, and comparisons among dose groups were made using a one-way ANOVA. The relationship among response (conversion or nonconversion), ibutilide dose, and either arrhythmia duration, cardiac structure/function variables (left atrial diameter, ejection fraction, or valvular heart disease), or use of concomitant medications (digoxin, ß-adrenergic blockers, or calcium channel blockers) was each analyzed separately using logistic regression. The test for interaction was significant if it generated a value of P<=.10, and if the test for interaction was not significant, the interaction term was removed from the model. A one-way ANOVA was used to compare QT and QTc intervals and ibutilide plasma concentrations between convertors and nonconvertors. Polymorphic VT was defined as a rhythm of >3 beats with continuously varying QRS complex morphology in any recorded ECG lead >100 bpm. A univariate correlation analysis was performed between incidence of polymorphic VT and the following variables: sex, race, weight, age, pulse, dose received, concomitant medications, presenting arrhythmia, ejection fraction, left atrial size, congestive heart failure, hypertension, and previous myocardial infarction. Variables reasonably correlated (P<=.20) with polymorphic VT were then analyzed using stepwise logistic regression to determine the association of these variables with polymorphic VT.


*    Results
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Study Population
Two hundred sixty-six patients were enrolled in this trial (133 with atrial flutter and 133 with atrial fibrillation) at a total of 21 centers between November 1992 and March 1994 with randomization as follows: placebo/placebo, 86; 1.0 mg/0.5 mg ibutilide, 86; and 1.0 mg/1.0 mg ibutilide, 94. The mean age of the evaluable patients (n=242) was 67 years, 80% were male, the average duration of the arrhythmia was {approx}2 weeks, 50% of patients had a previous episode of atrial flutter or fibrillation, and 75% had a history of heart disease other than atrial flutter or fibrillation (Table 1Down). Eighty-three percent of patients had an enlarged left atrium, 55% had a depressed left ventricular ejection fraction, and 71% had valvular heart disease. Baseline clinical characteristics were similar across dose groups except that a significantly greater number of patients in the placebo group were receiving ß-blockers than in the ibutilide dose groups.


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  		Table 1. Clinical Characteristics Evaluable for Efficacy Patients in Each Study Group

Conversion Efficacy
The overall cumulative conversion rate was 47% (75 of 161 patients) after two infusions of ibutilide and 2% (2 of 81 patients) after placebo. Paired comparisons indicated highly statistically significant differences (both P<.0001) between placebo (2%) and the 1.0 mg/0.5 mg (44%) and the 1.0 mg/1.0 mg (49%) ibutilide doses. There was no significant difference (P=.57) in the success rates between the 1.0 mg/0.5 mg (35 of 79 patients) and the 1.0 mg/1.0 mg (40 of 82 patients) ibutilide doses. Of the 75 successful terminations with ibutilide, 31 received both 10-minute infusions, 9 converted during the second infusion, and the remaining 35 converted either during the first infusion or during the 10 minutes between infusions.

The greater conversion efficacy of ibutilide compared with placebo was significant in both the atrial flutter and fibrillation groups. The conversion rate after two infusions of ibutilide was significantly (P<.0001) higher for atrial flutter (50 of 80 patients, or 63%) than for atrial fibrillation (25 of 81 patients, or 31%) (Fig 1Down). The conversion efficacy of the first 1.0 mg dose of ibutilide (assessed up to minute 20 after the start of the first infusion) was not significantly different in atrial flutter than in atrial fibrillation (24% versus 20%, P=NS). After the second 10-minute infusion of either 0.5 or 1.0 mg, greater cumulative conversion rates were observed in atrial flutter (54% and 71% for 0.5 and 1.0 mg doses, respectively) than in fibrillation (35% and 27%) (atrial flutter versus fibrillation, P=.092, P<.0001). The atrial flutter and fibrillation groups were not significantly different in arrhythmia duration (15±13 versus 16±14 days, P=.6982), in the percentage with valvular (76±5% versus 75±5%, P=.9235) or any (81±4% versus 70±5%, P=.1072) heart disease or with decreased ejection fraction (55±6% versus 54±6%, P=.9496) or increased left atrial size (81±5% versus 88±4%, P=.2425).



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  		Figure 1. Cumulative percentage of patients converting after two infusions of placebo, 1.0 mg/0.5 mg ibutilide or 1.0 mg/1.0 mg ibutilide, in patients with atrial flutter (AFL) or atrial fibrillation (AFIB). Conversion efficacy was significantly higher after ibutilide than after placebo (P<.0001) and was higher in AFL than in AFIB (P<.0001) but did not differ significantly between the two ibutilide dosing regimens.

The mean time to termination of the atrial arrhythmia was 27 minutes after start of the first infusion (range, 5 to 88 minutes). Thirty-five (19 flutter and 16 fibrillation) of the 75 patients (47%) who converted did so by minute 20, before the second infusion (Fig 2Down). The mean termination time was 30 minutes (range, 7 to 88 minutes) in the flutter group and 23 minutes (range, 5 to 75 minutes) in the fibrillation group. The total dose administered to those who were successfully converted with ibutilide ranged from 0.42 to 2.0 mg (mean, 1.33±0.45 mg) and to those who did not respond to ibutilide ranged from 0.6 to 2.0 mg (mean, 1.61±0.32 mg). Examination of the dose administered on a mg/kg basis revealed that there was a statistically significant (P=.0001) positive association between increased dose administered (mg/kg) and success rate.




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  		Figure 2. Cumulative success rates (%) in atrial flutter and fibrillation based on time after the start of the ibutilide infusion. Cumulative success rates are shown (left) for the total number of ibutilide-treated patients and (right) for the ibutilide-treated convertors only. In atrial fibrillation, 64% of the conversions occurred before the second infusion, whereas in atrial flutter, only 38% of the conversions occurred before the second infusion.

ECG Effects of Ibutilide
The QT and QTc intervals were significantly (P<.0001) prolonged from baseline in the ibutilide-treated patients. From baseline QT and QTc intervals of 347±45 and 414±31 ms, respectively, the 1.0 mg/0.5 mg ibutilide dose prolonged these intervals by 73±75 and 62±66 ms to 420±78 and 477±62 ms, respectively, at minute 30 after the start of the infusion. From baseline QT and QTc intervals of 343±51 and 416±31 ms, the 1.0 mg/1.0 mg ibutilide dose prolonged these intervals by 71±82 and 63±68 ms to 414±92 and 478±70 ms at minute 30. These changes in QT and QTc were significantly greater (P<.0001) than the changes in the placebo group (5±29 and 9±34 ms). The QRS duration was not altered significantly across dose groups from baseline to minute 30.

Predictors of Arrhythmia Termination
The mean duration of atrial fibrillation or flutter over all dose groups for those who were successfully terminated was 12±12 days compared with 15±14 days for those who failed to convert. After adjustment for dose, there was a statistically significant (P=.0293) effect of arrhythmia duration on success rates in the atrial fibrillation but not the atrial flutter subgroup. In the atrial fibrillation group, the mean duration of arrhythmia over all dose groups was 10±13 days for those who were successfully terminated versus 18±15 days for those who did not convert. Patients with atrial fibrillation and an arrhythmia duration of <7 days had a 46% conversion rate with ibutilide (17 of 37 patients), which was significantly greater (P=.0070) than the 18% conversion rate with ibutilide in patients with atrial fibrillation and a duration of >=7 days (8 of 44 patients) (Fig 3Down). The success rate for ibutilide-treated patients was 44% (56 of 126) for those with an enlarged left atrium compared with 57% (13 of 23) for those with normal left atrial diameters. After adjustment for dose, there was a significant relationship between left atrial diameter and success rate in the fibrillation (P=.0359) but not the flutter group (P=.2954). In the fibrillation group, the success rate with ibutilide in patients with an enlarged left atrium was 27% compared with a 67% rate in patients with a normal left atrium (P=.0175). Decreased ejection fraction, presence of valvular heart disease, and use of concomitant cardiac medications had no significant effect on termination (Table 2Down). There were no significant differences in QT (1.0/0.5 mg dose, 412±84 versus 425±75 ms, P=.1545; 1.0/1.0 mg dose, 417±88 versus 412±96 ms, P=.3259) or QTc (463±55 versus 485±65 ms, P=.6535; 479±65 versus 478±75 ms, P=.5944) intervals at minute 30 among those whose arrhythmias were terminated by ibutilide compared with those whose arrhythmias failed to convert.



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  		Figure 3. Effect of arrhythmia duration on conversion efficacy with ibutilide in atrial flutter and atrial fibrillation. In atrial flutter, arrhythmia duration did not significantly affect conversion rates; however, in atrial fibrillation, conversion rates were higher in patients with an arrhythmia duration of <7 days.


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  		Table 2. Effects of Clinical Characteristics on Arrhythmia Conversion Rates With Ibutilide

Proarrhythmia
Polymorphic ventricular tachycardia developed in 15 of 180 ibutilide-treated patients (8.3%) and in no placebo-treated patients. Among the ibutilide-treated patients, 7 patients also developed episodes of nonsustained monomorphic VT. In 3 patients (1.7%), polymorphic VT was sustained and required DC cardioversion, and in 12 patients (6.7%), polymorphic VT was nonsustained and resolved spontaneously or with discontinuation of ibutilide (Table 3Down). Six patients with polymorphic VT were given magnesium sulfate (2 to 4 g IV) to prevent recurrences. In all patients, the first episode of polymorphic VT occurred either during or shortly after the end of the last ibutilide infusion. Eleven of 15 episodes (73%) occurred during or within 10 minutes of the first 1.0 mg ibutilide dose, and 4 episodes occurred in 144 patients (2.8%) who received the second 0.5 or 1.0 mg ibutilide dose. Episodes of late polymorphic VT occurred in a patient who identified herself early as being at risk of proarrhythmia and requiring further monitoring. This patient, who failed to convert with ibutilide and remained in atrial fibrillation, had 8 seconds of polymorphic VT just after 1.0 mg ibutilide, another nonsustained episode 2 hours later, and a sustained episode requiring cardioversion 2.5 hours after the infusion. One patient with ventricular ectopy and nonsustained VT before ibutilide developed increased ectopy and up to 6 beat runs of nonsustained VT, beginning 9 minutes after initiation of the infusion and lasting for {approx}3 hours. A patient with preexisting, intermittent heart block received an overdose of ibutilide (2.5 mg instead of 1.0 mg over 10 minutes) and developed complete heart block, which resulted in bradycardia, QT prolongation (QTc=643 ms), and nonsustained polymorphic VT.


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  		Table 3. Clinical Characteristics of Ibutilide-Treated Patients Who Developed Polymorphic Ventricular Tachycardia

Of the 15 patients with polymorphic VT, the mean age was 66±9 years, 8 were male, 10 were receiving ibutilide for atrial flutter, and 5 were receiving ibutilide for atrial fibrillation. The rhythm at the time of polymorphic VT was atrial fibrillation in 4 patients, atrial flutter in 8 patients, sinus rhythm in 1 patient who converted 11 minutes earlier from fibrillation, and sinus rhythm in 2 patients who had just converted from flutter (Fig 4Down). Stepwise logistic regression analysis indicated that sex (P=.0046), race (P=.0383), heart failure (P=.0305), and pulse (P=.0348) were statistically significantly associated with polymorphic VT. The incidence of polymorphic VT was 13.2% among women versus 3.8% among men, 15.9% among nonwhites versus 3.6% among whites, and 11.4% among patients with heart failure versus 3.6% among patients without heart failure. The mean pulse rate was 78±18 bpm among patients with polymorphic VT versus 95±26 bpm among those who did not develop proarrhythmia. After adjustment for dose, there was a statistically significant association between occurrence of polymorphic VT and change from baseline in QT (P=.0361) and QTc (P=.0132) intervals at minute 30. Among patients with polymorphic VT, at baseline their QT and QTc intervals were 389±43 and 424±22 ms, respectively. At minute 30, these intervals increased by 114±100 and 106±104 ms to 502±106 and 529±95 ms, respectively, and at the time of polymorphic VT, these intervals were prolonged by 150±93 and 160±99 ms to 542±105 and 581±89 ms, respectively. Rhythm strips from 10 patients that showed the initiating beat of polymorphic VT were available for review, and for 9 of the 10 patients, the strips demonstrated that the initiation occurred after a long-short coupling interval with a long cycle of >1 second (Fig 4Down). Both adverse events and successful arrhythmia termination were seen at similar ibutilide doses and plasma concentrations. The mean ibutilide dose given to patients who developed polymorphic VT was 1.25±0.54 mg (range, 0.47 to 2.5 mg), and that given to patients whose atrial arrhythmia was successfully terminated was 1.33±0.45 mg. The range of ibutilide plasma concentrations in patients with polymorphic VT was <0.91 to 13.5 ng/mL, and in ibutilide-treated patients whose atrial arrhythmia was terminated, the range was 0.469 to 89.2 ng/mL.



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  		Figure 4. Continuous ECG rhythm strip from a 73-year-old man with a history of hypertension and atrial flutter who developed polymorphic ventricular tachycardia (PVT) during treatment with intravenous ibutilide. The patient received the entire first 10-minute infusion of 1.0 mg ibutilide and converted to sinus rhythm. He then developed short runs of atrial fibrillation and then several episodes of nonsustained PVT. The corrected QT interval was increased from 394 ms at baseline to 452 ms during ibutilide, and the runs of PVT were initiated after long-short cycles. At the end of the strip, the patient is in sinus rhythm, which persisted along with resolution of the PVT during further observation.

Hemodynamic Effects
In ibutilide-treated patients, there were no clinically significant changes from baseline in systolic blood pressure, and there were no changes in blood pressure that were substantially different from those seen in the placebo group. Five cases of hypotension were reported: 2 in the placebo group, 1 in the 1.0 mg/0.5 mg group, and 2 in the 1.0 mg/1.0 mg group. There was a consistent and statistically significant (P=.0094) decrease in heart rate in both ibutilide dose groups (-13±24 and -11±24 bpm, respectively, at minute 40) compared with placebo (-3±13 bpm). This decrease in heart rate was most likely due to termination of the arrhythmia because in patients who did not convert, a statistically significant decrease in heart rate was not seen.

Other Adverse Events
A stroke occurred 1 day after successful conversion with ibutilide in a patient with atrial fibrillation of {approx}48 hours' duration. Two ibutilide-treated patients developed transient, acute renal failure, one of whom received angiographic dye and the other captopril and diltiazem. One patient received sotalol 2.5 hours after ibutilide for atrial flutter termination and developed congestive heart failure. One patient died of respiratory failure 3.5 hours after receiving placebo and being electrically cardioverted from atrial flutter to sinus rhythm.

Follow-up Through Hour 24
Electrical cardioversion was attempted in 52 of 71 placebo-treated (73%) and in 49 of 69 ibutilide-treated (71%) nonconvertors and was successful in 43 (83%) and 44 (90%) patients, respectively. Eighty-five percent of patients (63 of 74) whose arrhythmia was terminated by ibutilide and 92% of ibutilide-treated nonconvertors (54 of 59) who were cardioverted by other means did not have recurrences of atrial fibrillation or flutter through hour 24. Fifty-two percent of patients (40 of 77) converted by either ibutilide or placebo received follow-up therapy with antiarrhythmic agents to prevent recurrences. Among the 11 ibutilide-treated convertors who relapsed during the 24 hours after the study, atrial fibrillation or flutter recurred a mean of 759±561 minutes (range, 0.3 to 1418 minutes) after conversion.


*    Discussion
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This study demonstrated that two 10-minute intravenous infusions of ibutilide, a selective class III antiarrhythmic agent, given over 30 minutes were significantly more effective than placebo in the acute, rapid termination of atrial flutter and fibrillation. There was a small but potentially serious risk of proarrhythmia due to sustained and nonsustained polymorphic VT. The onset of polymorphic VT occurred during or immediately after the infusion, while the patients were monitored.

Comparison With Other Antiarrhythmic Drugs
Although electrical cardioversion is effective in rapidly restoring sinus rhythm, pharmacological methods obviate the need for anesthesia and might be associated with a more rapid return of normal atrial mechanical function.21 Recent experimental data suggest that longer atrial arrhythmia duration enhances the substrate for maintenance of atrial fibrillation and supports the potential clinical utility of early arrhythmia termination to prevent electrical remodeling.22 Oral antiarrhythmic agents usually require >=24 hours of therapy to convert atrial arrhythmias, whereas more rapid conversion might be achieved with intravenous agents.23 Studies in patients with atrial fibrillation of <2 or 3 days' duration usually have demonstrated high response rates to antiarrhythmic drugs.1 2 4 6 In recent-onset atrial fibrillation, uncontrolled studies of intravenous procainamide in small numbers of patients resulted in reversion to sinus rhythm in 43% to 65% of patients, and the intravenous class IC agents, flecainide and propafenone, have had efficacy rates of 60% to 90%.1 2 3 6 7 8 9 10 11 The currently available intravenous antiarrhythmic drugs are limited and often ineffective for acute termination of atrial flutter or chronic, established atrial fibrillation. The class IA and IC agents have response rates of only 0% to 40% in these groups of patients.1 5 6 7 8 9 10 11 Class I agents have a number of potential adverse effects, including proarrhythmia, depression of ventricular function, hypotension, and acceleration of the ventricular response.3 8 24 25 Although the published experience is quite limited, the reported efficacy rate of intravenous amiodarone is highly variable, with conversion rates in atrial fibrillation or flutter of 4% to 80%.12 13 14 15 In at least two studies, intravenous amiodarone was no more effective than placebo in converting atrial arrhythmias.14 15 In a recent study, intravenous sotalol, another agent with class III activity, was not effective in restoring sinus rhythm in patients with atrial fibrillation or flutter.16

Comparison With Previous Studies of Ibutilide
Because of the shortcomings of currently available, particularly class I, antiarrhythmic drugs, increased interest and attention have focused on newer class III agents, which increase action potential duration without blocking sodium channels.26 Ibutilide is a selective class III antiarrhythmic agent that prolongs atrial action potential duration and effective refractory period.17 27 Ibutilide does not alter resting membrane potential or the upstroke of the action potential; has no significant effects, at clinically relevant doses, on conduction velocity or on contractility; and is devoid of interactions with the autonomic nervous system.27 28 Action potential prolongation by ibutilide has been attributed to activation of a slow inward plateau current carried by sodium and to blockade of the rapidly activating delayed rectifier potassium current.29 30 31 In animal models of atrial flutter and fibrillation, ibutilide is effective in terminating these arrhythmias. In a canine model of atrial flutter, ibutilide terminated the arrhythmia in eight of eight dogs within 1 minute after an effective dose (mean, 0.006±1.0 mg/kg IV), and in a canine model of acute atrial fibrillation, large doses (0.15 mg/kg IV) of ibutilide terminated the arrhythmia in seven of seven dogs.17 19

The present study confirms the previous preliminary findings in humans of the efficacy of intravenous ibutilide in terminating atrial arrhythmias and establishes the efficacy of a clinically practical approach of administering ibutilide using repeated fixed milligram doses.20 32 In a previous dose-response study that used a single 10-minute infusion, 30% of patients with atrial flutter and 37% of patients with atrial fibrillation converted at a dose comparable (0.010 mg/kg) to the initial 1.0 mg dose in the present study, and 53% and 40%, respectively, converted at the highest dose (0.025 mg/kg).20 The ECG effects of ibutilide were typical of a selective class III agent with increases in the QT and QTc intervals but with no significant change in the QRS duration. Prolongation of QT or QTc intervals, however, did not predict successful termination of the atrial arrhythmia with ibutilide. The finding that atrial fibrillation termination by ibutilide was enhanced by a shorter arrhythmia duration or a normal left atrial size is consistent with previous reports regarding the efficacy of other antiarrhythmic agents.1 6 8 These two variables may not be independent, however, because the left atrial size may be determined by the duration of the arrhythmia.33 Atrial flutter termination by ibutilide, however, was not affected by atrial arrhythmia duration, from 3 hours to 45 days, or by left atrial size.

Efficacy in Atrial Flutter Versus Fibrillation
The twofold greater efficacy of ibutilide in atrial flutter compared with atrial fibrillation is an interesting observation of this study that provides new insights into understanding the mechanisms of drug action. Singh et al26 suggested that an important hallmark of a class III agent is its antifibrillatory action. Atrial fibrillation is characterized by multiple wave fronts of excitation, which circulate through small reentrant circuits with very short or no excitable gaps.34 35 Prolongation of the wavelength of refractoriness by class III drugs is expected to reduce the number of wave fronts and then to cause block and collision in the remaining circuits, leading to arrhythmia termination.36 Atrial flutter is due to reentry in an anatomic or anisotropic reentrant circuit with a large fully or partially excitable gap.37 Class III drugs are thought to terminate reentry in atrial flutter by prolonging the action potential and refractory period and either eliminating the excitable gap, forcing the impulse to block in refractory, inexcitable myocardium, or interrupting the circuit through failure of a lateral boundary.36 38 It has been proposed that the size of the excitable gap may determine the conversion efficacy of class III drugs.36 39 According to this theory, short excitable gap circuits, such as atrial fibrillation or type II atrial flutter, are more likely to terminate with potassium channel blockers, which prolong refractory period, whereas long excitable gap circuits, such as type I atrial flutter, are more vulnerable to conduction block by sodium channel–blocking agents.

The greater efficacy of ibutilide in atrial flutter compared with fibrillation is in contrast to class IC agents, which have limited utility for termination of atrial flutter and greater efficacy in atrial fibrillation. The differential effects of class III agents compared with class IC agents in terminating atrial reentry depending on the atrial rate are supported by previous animal investigations. Feld et al40 41 found in a canine anatomic obstacle model of atrial flutter that the class III drugs d-sotalol and N-acetylprocainamide terminated atrial flutter in 93% and 66% of dogs, respectively, whereas the class IC agent recainam terminated atrial flutter in only 20% of dogs. In contrast, Wang et al42 43 demonstrated in a vagotonic atrial fibrillation model that the same dose of d-sotalol used by Feld et al (2 mg/kg IV) terminated atrial fibrillation in only 25% of dogs, but the class IC agents flecainide and propafenone terminated atrial fibrillation in 100% and 70% of dogs.

Proarrhythmia
The present investigation demonstrated that ibutilide can cause potentially serious proarrhythmia in patients with atrial fibrillation or flutter. The incidence of nonsustained polymorphic VT (6.7%) in the present study is higher than that observed in a previous study of ibutilide (1.3%) in which the dose was given as a single infusion.20 The incidence of sustained polymorphic VT requiring cardioversion is similar between the two studies (1.7% versus 2.5%). In all patients, the onset of the initial episode of polymorphic VT occurred during the infusion period or shortly afterward. Thus, the risk of ibutilide-induced polymorphic VT is primarily present during the acute period after the infusion, while the patient is being monitored. Patients with proarrhythmia had marked increases in QT and QTc intervals with ibutilide, and initiation of VT occurred after long-short cycles. Increased risk of polymorphic VT was associated with female sex, a history of congestive heart failure, and slower heart rates. These findings are consistent with previous observations regarding torsade de pointes.44

A comparison of the proarrhythmia risk of ibutilide with other intravenous class IA or III agents is not possible due to a lack of available data. Although the true incidence of proarrhythmia with oral quinidine cannot be assessed from previous studies due to small sample sizes, variable dosing regimens, and the frequent lack of cardiac monitoring, it has been estimated to be at least 1.5% per year.45 In a recent study of oral quinidine in 25 patients with persistent atrial fibrillation, torsade de pointes developed in 3 (12%) and sustained VT occurred in 1 patient (4%).23 Among 3257 patients treated for cardiac arrhythmias with oral sotalol, the overall incidence of proarrhythmia was 4.3% and the incidence of torsade de pointes was 2.4%.46 The incidence of proarrhythmia with intravenous amiodarone in patients with atrial arrhythmias is not well defined, but in patients with life-threatening ventricular arrhythmias, the incidence is {approx}1%.47 48

Conclusions
Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter. Efficacy is highest in atrial flutter and in atrial fibrillation with either a short arrhythmia duration or a normal left atrial size. There is an associated risk of proarrhythmia, but in all patients the initial episode of polymorphic ventricular tachycardia occurred during or shortly after the infusion period. Under monitored conditions, ibutilide is an alternative to current cardioversion options, particularly when rapid atrial arrhythmia termination is desirable.


*    Acknowledgments
 
This study was supported in part by a grant from The Upjohn Company, Kalamazoo, Mich.

Investigators
Freddy M. Abi-Samra, MD, Ochsner Clinic; Thomas S. Ahern, MD, Humana Hospital-Sunrise; Andrew J. Burger, MD, New England Deaconess Hospital; Dennis M. Cassidy, MD, St Joseph's Hospital; Stephen T. Denker, MD, St Luke's Medical Center; John P. DiMarco, MD, PhD, University of Virginia School of Medicine; Nancy C. Flowers, MD, Medical College of Georgia; Marandapalli R. Sridharan, MD, Augusta VA Medical Center; Scott H. Hessen, MD, Hahnemann University Hospital; John M. Kalbfleisch, MD, St Francis Hospital; Peter R. Kowey, MD, The Lankenau Hospital; Thomas A. Mattioni, MD, Healthwest Regional Medical Center; Marc D. Meissner, MD, Allen Park VA Hospital; Arthur S. Portnow, MD, Albany Medical Center and Samuel S. Stratton VA Medical Center; Philip T. Sager, MD, Wadsworth VA Medical Center; Arjun D. Sharma, MD, Sutter Memorial and Mercy General Hospitals; Bruce S. Stambler, MD, McGuire VA Medical Center; Robert C. Wesley, Jr, MD, Long Beach VA Medical Center; John R. Windle, MD, University of Nebraska Hospital; Mark A. Wood, MD, Medical College of Virginia; and Robert G. Zoble, MD, PhD, James A. Haley VA Hospital.

Received February 5, 1996; revision received May 13, 1996; accepted May 13, 1996.


*    References
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