View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 44, No. - 4,Publisher 2004 Connector © 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.04.056 Ibutilide Added to for the Conversion of Atrial Fibrillation and John A. Chiladakis, MD, FESC, Andreas Kalogeropoulos, MD, Nikolaos Patsouras, MD, Antonis S. Manolis, MD, FACC, FESC Patras and Athens, Greece

OBJECTIVES We evaluated the safety and efficacy of ibutilide when added to propafenone in treating both paroxysmal and chronic atrial fibrillation (AF) and atrial flutter (AFL). BACKGROUND The effects of ibutilide in patients with paroxysmal or chronic AF/AFL who were pre-treated with propafenone have not been previously evaluated. METHODS Oral propafenone was initially given in 202 patients with AF/AFL without left ventricular dysfunction. Intravenous ibutilide was administered in 104 patients in whom propafenone failed to convert the . Two different propafenone dosage regimens were used according to the duration of the presenting arrhythmia: patients with paroxysmal arrhythmia (n ϭ 48) received 600 mg loading dose, and patients with chronic arrhythmia (n ϭ 56) were receiving 150 mg three times a day as stable-dose pre-treatment. RESULTS Ibutilide offered an overall conversion efficacy of 66.3% (69 of 104 patients), 70.8% for patients with paroxysmal AF/AFL and 62.5% for patients with chronic AF/AFL. Ibutilide significantly decreased the heart rate (HR) and further prolonged the QTc interval (p Ͻ 0.0001). The degree of HR reduction after ibutilide administration emerged as the sole predictor of successful arrhythmia termination (p Ͻ 0.001). After ibutilide, one patient (1%) developed two asymptomatic episodes of non-sustained torsade de pointes, and 10 patients (9.6%) manifested transient bradyarrhythmic events; however, all bradyarrhythmic effects were predictable, occurring mostly at the time of arrhythmia termination. None of 82 patients who decided to continue propafenone after successful had immediate arrhyth- mia recurrence. CONCLUSIONS Our graded approach using propafenone and ibutilide appears to be a relatively safe and effective alternative for the treatment of paroxysmal and chronic AF/AFL to both rapidly restore sinus rhythm in nonresponders to monotherapy with propafenone and prevent immediate recurrences of the arrhythmia. (J Am Coll Cardiol 2004;44:859–63) © 2004 by the American College of Cardiology Foundation

Managing atrial fibrillation (AF) or atrial flutter (AFL) is a efficacy of this stepped-care combination therapy in the continuing therapeutic challenge. Antiarrhythmic drugs management of both paroxysmal and chronic AF/AFL. play a major role during attempts to promptly restore and maintain sinus rhythm (SR), by which disabling symptoms are diminished and atrial electrophysiologic and structural METHODS remodeling is averted (1,2). Of the currently available Patient population. Our study population included 202 agents, intravenous ibutilide fumarate is considered one of patients with AF/AFL who were treated initially with the most effective in rapidly terminating AF/AFL (3–6). propafenone. Two groups of patients were prospectively However, ibutilide is not available as an oral preparation, studied; those with persistent paroxysms of arrhythmia and and thus, it cannot be subsequently used as long-term patients with chronic arrhythmia. Patients with paroxysmal therapy to prevent recurrences of arrhythmia. On the other AF/AFL (n ϭ 146) had prolonged and non-self- hand, the use of oral propafenone has been proven effective terminating arrhythmia episodes of Ͻ36 h duration with a in terminating AF of recent onset and in preventing well-defined clinical history of abrupt onset of palpitations arrhythmia recurrences after cardioversion, but it has shown and electrocardiographic (ECG) evidence of the arrhyth- little promise for the conversion of chronic AF (7–9). We mia. Patients with chronic AF/AFL (n ϭ 56) had persistent hypothesized that the addition of ibutilide in nonresponders arrhythmia of Ͻ6-month duration and were under contin- to monotherapy with propafenone might be a useful method uous oral anticoagulation therapy for at least four weeks to improve subsequent cardioversion rates and maintenance before cardioversion (international normalized ratio, 2.5 to of SR thereafter. This study evaluated the safety and clinical 3.0). Only patients with normal left ventricular (LV) func- tion as judged by two-dimensional echocardiography were enrolled in this trial. From the Cardiology Department, Patras University Hospital, Rio, Patras, Greece. Manuscript received February 1, 2004; revised manuscript received April 12, 2004, Ibutilide in addition to propafenone was given to 104 accepted April 18, 2004. patients who did not convert to SR with propafenone, in 48 860 Chiladakis et al. JACC Vol. 44, No. 4, 2004 Ibutilide and Propafenone for AF August 18, 2004:859–63

hospital. This dose of propafenone remained the same Abbreviations and Acronyms throughout hospitalization, when indicated, to assist in AF ϭ atrial fibrillation maintaining SR once the arrhythmia had been converted AFL ϭ atrial flutter with ibutilide. ϭ ECG electrocardiogram/electrocardiographic Ibutilide was administered to all patients with paroxysmal HR ϭ heart rate LV ϭ left ventricle/ventricular and chronic arrhythmia in the coronary care unit under QTc ϭ corrected QT (interval) continuous monitoring at the same dose of 1 mg over 10 SR ϭ sinus rhythm min intravenously, and if the arrhythmia was still present after 10 min, an additional dose of 1 mg over 10 min was infused. Drug infusion was terminated in case of any change patients with paroxysmal arrhythmia, and in the 56 patients in symptoms or rhythm or any adverse event that in the with chronic arrhythmia. opinion of the investigator was threatening patient’s safety. The following exclusion criteria were applied: symptoms Patients were monitored for at least 12 h after the admin- or clinical signs of congestive heart failure and unstable istration of ibutilide. Successful cardioversion was defined as angina; prior ; obstructive pulmonary termination of AF/AFL within 90 min of the start of the disease; depressed LV ejection fraction; severe valvular first ibutilide infusion. Electrical transthoracic direct- dysfunction; significant hepatic, renal, or metabolic distur- current cardioversion was attempted after a 4-h observation bances; known dysthyroidism; intake; known sick period if AF/AFL was not converted to SR. sinus syndrome; major atrioventricular and intraventricular Serial 12-lead ECGs were obtained to evaluate QRS, conduction disturbances; ventricular preexcitation and his- QT, and QTc intervals. A 24-h Holter recording was tory of torsade de pointes; concomitant use of other antiar- started in all patients before the onset of ibutilide adminis- rhythmic drugs or beta-adrenergic blocking agents; pace- tration to determine exact conversion time, arrhythmia, and maker dependence; and pregnancy. All patients had serum HR analysis. The three-channel Galix MA-3C Holter electrolyte values within normal limits before treatment. system (Galix Biomedical Instrumentation Inc., Miami Ibutilide was not administered if propafenone prolonged the Beach, Florida) was used, utilizing 3.0 Software. The QRS or the corrected QT (QTc) interval by Ͼ25%. following time periods were taken to assess the effects of the Pharmacologic therapy and ECG analysis. Ventricular drugs on the ECG variables: for propafenone, the last rate control in patients with paroxysmal arrhythmia was 5-min period before the initiation of the first ibutilide attempted, whenever necessary, with intravenous , infusion; for ibutilide, the last 5-min period before arrhyth- administered initially as a bolus of 25 mg over 15 min, mia termination if it was converted to SR or the first 5-min followed by continuous infusion of 10 mg/h to achieve a interval at the end of the second ibutilide infusion if the target resting heart rate (HR) Ͻ100 beats/min. In addition, arrhythmia was not terminated. heparin was administered upon admission with a bolus of Statistics. Continuous variables are reported as mean Ϯ 5,000 IU followed by infusion of 1,000 IU/h, further SD. A value of p Յ 0.05 was considered statistically adjusted as required to keep the activated partial thrombo- significant. The two-sided unpaired Student t test was used plastin time at twice the upper normal limit. In patients to compare normally distributed continuous data between with chronic AF/AFL, the use of oral diltiazem 90 mg three conversion and non-conversion groups. Normality was times a day was allowed. tested by the Kolmogorov-Smirnov statistic at the p ϭ 0.1 Propafenone therapy was initiated in patients with par- level. Changes in continuous ECG variables within groups oxysmal AF/AFL as an oral loading dose of 600 mg, and if before and after ibutilide treatment were evaluated using the SR was not restored after 6 h, a second single dose of 150 paired t test. Categorical data were compared with Fisher mg was repeated. In case of restoration of SR in the exact test. Multiple logistic regression models with a for- emergency department, patients were not admitted to the ward stepwise approach were used to identify significant hospital, and possible pharmacologic therapy was left to the predictors of conversion. Statistical analyses were conducted discretion of the treating physician. Patients with non- with SPSS-PC, Version 10.0 (SPSS Inc., Chicago, Illinois). converted paroxysmal AF/AFL at the end of an 8-h initial observation period proceeded to the treatment phase with RESULTS ibutilide. Most patients with chronic AF/AFL were asymp- tomatic (41 of 56, 73%) under continuous propafenone Conversion to SR. Oral loading propafenone restored SR therapy with or without diltiazem, and 7 (8%) of them had in 98 of 146 patients (67%) with paroxysmal arrhythmia. prior failed conversion attempts with , but they all Ibutilide was evaluated in 104 hospitalized patients with sought further treatment to restore SR. Thus, all patients AF/AFL: in the remaining 48 non-converters with parox- with chronic AF/AFL were referred for elective cardiover- ysmal arrhythmia and in the 56 patients with chronic sion after they had initially been administered oral arrhythmia receiving pre-treatment with propafenone (Ta- propafenone as outpatients, receiving 150 mg three times a ble 1). Overall, the co-administration of the two agents day for a minimum of four days before admission to the showed a conversion efficacy of 66.3% (69 of 104 patients), JACC Vol. 44, No. 4, 2004 Chiladakis et al. 861 August 18, 2004:859–63 Ibutilide and Propafenone for AF

Table 1. Clinical Characteristics of Study Patients Treated With Ibutilide and Propafenone Paroxysmal AF/AFL Chronic AF/AFL (56 ؍ n) (48 ؍ n) Age (yrs) 60.5 Ϯ 11.2 63.7 Ϯ 8.2 Men, n (%) 38 (79) 32 (57) Atrial flutter, n (%) 4 (8) 4 (7) Duration of AF/AFL 17.3 Ϯ 7.6 h 64.6 Ϯ 44.1 days Previous history of AF/AFL, n (%) 16 (33) 22 (39) Cardiovascular history, n (%) 17 (35) 26 (46) Minor valvular disease 9 (19) 15 (27) Coronary artery disease 3 (6) 5 (9) Systemic hypertension 5 (10) 6 (11) Left atrial diameter, mm 4.8 Ϯ 6.2 4.4 Ϯ 5.5 Concomitant drug therapy, n (%) Diltiazem 45 (94) 19 (34) 7 (15) 4 (7) ECG variables before treatment Mean ventricular rate (beats/min) 124 Ϯ 23 80.6 Ϯ 13.9 QTc (ms) 378.9 Ϯ 26.6 435.6 Ϯ 36.9

AF/AFL ϭ atrial fibrillation/atrial flutter; ECG ϭ electrocardiographic. 65.6% for AF (63 of 96 patients), and 75% (6 of 8 patients) prolongation of the QT interval (451.8 Ϯ 60.5 vs. 472.6 Ϯ for AFL. The success rates were 70.8% (34 of 48 patients) 37.6; p ϭ 0.04) than non-converters. On multiple logistic for patients with paroxysmal arrhythmia and 62.5% (35 of regression analysis, which evaluated age, gender, type of 56 patients) for those with chronic arrhythmia (Table 2). arrhythmia, onset of arrhythmia (paroxysmal or chronic), Addition of ibutilide. Among the entire study population, left atrium size, HR, QT and QTc intervals, and QRS compared with the effects of propafenone (paired t test), width, only the difference in mean HR after ibutilide was ibutilide significantly decreased the mean HR (from 81.1 Ϯ found to independently predict conversion to SR (p Ͻ 14.3 to 74.6 Ϯ 14.5; p Ͻ 0.0001), increased the QT (from 0.001). There was an inverse relation between the degree of 382.3 Ϯ 43.9 to 459.6 Ϯ 53.7; p Ͻ 0.0001) and the QTc HR reduction after ibutilide with the conversion success interval (from 443.1 Ϯ 49.2 to 515.6 Ϯ 43.6; p Ͻ 0.0001), (i.e., patients who exhibited higher HR reduction had lower and did not significantly change the QRS width (from 100.1 probability of conversion) (Table 2). Ϯ 11.4 to 103.3 Ϯ 10.1; p ϭ 0.3). The mean time to Thirty-three patients who did not convert with ibutilide termination of AF/AFL from the beginning of ibutilide consented to electrical cardioversion, which was successful infusion was 38.9 Ϯ 22.5 min (36.4 Ϯ 23.8 min for in 32 (97%) of 33 patients. None of the overall 82 patients paroxysmal and 36.4 Ϯ 24.7 min for chronic arrhythmia; p who decided to continue propafenone therapy after success- ϭ 0.5). Between converted and non-converted patients ful cardioversion had immediate arrhythmia recurrence (unpaired t test), there were no statistically significant throughout their hospital stay (mean, 23.5 Ϯ 5.9 h). differences in demographics and clinical data (Table 2). Electrocardiographic effects of ibutilide. We chose to However, ibutilide converters had significantly higher HRs separately analyze the effects of ibutilide in 49 patients with (77.9 Ϯ 15.6 vs. 68.8 Ϯ 10.2; p ϭ 0.001) and lesser chronic AF who received long-term stable dosages of Table 2. Determinants of Conversion in 104 Patients With AF/AFL Treated With Ibutilide and Propafenone (56 ؍ Chronic AF/AFL (n (48 ؍ Paroxysmal AF/AFL (n Conversion No Conversion Conversion No Conversion p (21 ؍ n) (35 ؍ p (n (14 ؍ n) (34 ؍ n) Age (yrs) 60.7 Ϯ 10.2 59.9 Ϯ 13.8 0.8 63.4 Ϯ 8.6 64.2 Ϯ 7.7 0.7 Men, n (%) 25 (74) 13 (93) 0.5 22 (63) 10 (48) 0.3 Duration of arrhythmia 77.7 Ϯ 47.6 h 72.9 Ϯ 43.2 h 0.7 16.3 Ϯ 7.3 days 15.4 Ϯ 8.0 days 0.7 Cardiovascular history, n (%) 10 (21) 7 (16) 0.2 15 (27) 11 (20) 0.6 Left atrial diameter, mm 43.4 Ϯ 7 41.2 Ϯ 3.5 0.2 43.4 Ϯ 5.2 45.1 Ϯ 5.9 0.3 Propafenone Mean ventricular rate (beats/min) 83.3 Ϯ 15.2 88.2 Ϯ 9.1 0.3 79.0 Ϯ 15.7 73.0 Ϯ 10.3 0.1 QT (ms) 380.3 Ϯ 59.1 381.6 Ϯ 51.5 0.6 383.5 Ϯ 35.7 378.2 Ϯ 33.1 0.6 QTc (ms) 446.5 Ϯ 54.1 473.2 Ϯ 65.1 0.1 441.2 Ϯ 32.3 424.3 Ϯ 48.2 0.1 Ibutilide added to propafenone Mean ventricular rate (beats/min) 79.8 Ϯ 16.5 76.5 Ϯ 9.8 0.5 76.5 Ϯ 14.3 64.8 Ϯ 9.8 0.002 QT (ms) 458.1 Ϯ 78.3 472.1 Ϯ 39.7 0.5 450.7 Ϯ 46.6 470 Ϯ 40.4 0.1 QTc (ms) 531.0 Ϯ 58.1 539.1 Ϯ 22.7 0.6 509.3 Ϯ 38.6 499.7 Ϯ 35.8 0.3

AF/AFL ϭ atrial fibrillation/atrial flutter. 862 Chiladakis et al. JACC Vol. 44, No. 4, 2004 Ibutilide and Propafenone for AF August 18, 2004:859–63 propafenone with or without diltiazem assuming that the potassium current. In contrast with propafenone, ibutilide is findings before and after ibutilide treatment would be devoid of beta-blocking effects, causes mild slowing of sinus entirely due to the additional effects of ibutilide. In these rate and atrioventricular conduction, while having no sig- patients ibutilide significantly decreased the HR from 74.6 nificant effect on contractility (15,16). As a general consid- Ϯ 9.7 to 70.3 Ϯ 11.1 (p Ͻ 0.0001) and increased the QT eration, the possible enhanced antiarrhythmic efficacy by interval from 381.7 Ϯ 33.4 to 461.5 Ϯ 44.6 (p Ͻ 0.0001) adding ibutilide to propafenone may be primarily related to and the QTc interval from 428.1 Ϯ 32.9 to 502.8 Ϯ 37.8 overlapping effects on the duration and (p Ͻ 0.0001) (paired t test). particularly on the prolongation of the atrial effective refrac- Adverse effects. Propafenone treatment was discontinued tory period. in 3 (4.3%) of 69 patients after restoration of SR following In previous studies, ibutilide monotherapy was found ibutilide: in two patients due to dizziness and nausea and in superior to placebo in terminating 35.0% to 70.6% of one patient due to persistence of second-degree atrioven- patients with AF and 58% to 75% of patients with AFL, tricular block type I. None of the patients necessitated whereby a short duration of the arrhythmia emerged as the interruption of ibutilide treatment due to acute untoward main predictor of arrhythmia termination (3–6). In the effects. After ibutilide administration and immediately be- present study, we demonstrated that the initial conversion fore reversion of AF to SR, four patients were documented efficacy of oral loading propafenone in patients with parox- to have asymptomatic pauses (3.7 to 5.2 s), four patients had ysmal arrhythmia was 67% (98 of 146 patients). In the transient junctional rhythm for a mean of 7.5 Ϯ 6 s, and two remaining 48 non-converters, ibutilide was successful in 34 patients with chronic AF developed second degree atrioven- patients (71%). Thus, the addition of ibutilide offered an tricular block type I. None of these patients required additive conversion effect of approximately 23%, increasing insertion of a temporary pacemaker. There were two asymp- the overall efficacy of the combination therapy up to 90%. tomatic self-terminating episodes of torsade de pointes (15 For the patients with chronic arrhythmia of Ͻ6 months and 8 QRS complexes, respectively) following ibutilide in duration, the success rate of 64% should be given particular one patient with chronic AF 5 min after conversion to SR. consideration if we keep in mind that all patients were During ibutilide infusion, transient asymptomatic ventricu- nonresponders to propafenone and that all previous studies lar not requiring intervention were noted in emphasize ibutilide’sefficacy in patients with AF of shorter three patients with chronic AF: one patient developed duration lasting approximately Ͻ3 months (3–6). More- non-sustained runs of of three con- over, it should be emphasized that our stepped-care ap- secutive beats, and two others had frequent premature proach of management prevented immediate recurrences; all ventricular complexes. successfully converted patients maintained SR during their short hospital stay (median, 24 h). This was not surprising DISCUSSION because previous studies have shown that propafenone is effective in preventing immediate re-initiation of arrhyth- To our knowledge, this is the first study evaluating the mia after the cardioversion procedure (17). effects of ibutilide in patients with both paroxysmal and Safety. In contrast with the overall incidence of 4.3% of chronic AF/AFL who were pre-treated with propafenone, polymorphic ventricular tachycardia in ibutilide-treated pa- which demonstrates the combined strength in improving tients reported in clinical trials, including 1.7% of patients in pharmacologic conversion rates with a low risk of proar- whom the arrhythmia was sustained and required cardio- rhythmia and low probability of immediate arrhythmia version (15), only 1% of our study patients developed recurrences. self-terminating episodes of torsade de pointes. The strict Effects of propafenone. Our results of 67% efficacy of a exclusion of patients with depressed LV function may be the single oral loading dose of 600 mg propafenone in convert- main reason for this low incidence of proarrhythmia. Other ing paroxysmal AF are consistent with the 56% to 87% potentially worrisome cardiac side effects manifested as success rates within 8 h reported in other studies, confirm- sinus pauses and atrioventricular conduction disturbances in ing a higher conversion ability compared with both placebo 9.6% of our study patients after instituting ibutilide therapy. and drugs that control the ventricular rate (10–12). The However, all minor bradyarrhythmic effects were predict- widely variable interindividual of the drug able, occurring within the first hours after the addition of and the lack of significant correlation between plasma ibutilide, mostly at the time of arrhythmia termination. concentrations and its antiarrhythmic efficacy may account Study limitations. The low risk of proarrhythmia of our for the usefulness of this convenient oral loading approach study population should not be extrapolated to patients with in clinical practice (13,14). depressed LV ejection function. It is important to note that Addition of ibutilide. Ibutilide’s antifibrillatory actions previous studies that have included patients with LV dys- result from its ability to prolong action potential duration function and valvular heart disease have expressed concerns and atrial effective refractory period predominantly by acti- over a higher incidence of torsade de pointes after ibutilide vating the sodium component of the plateau inward current (3,4). Besides, due to the lack of a patient group who and by blocking the rapid component of the delayed rectifier received ibutilide monotherapy, we cannot compare the JACC Vol. 44, No. 4, 2004 Chiladakis et al. 863 August 18, 2004:859–63 Ibutilide and Propafenone for AF proarrhythmia risk and the net ECG effects of our combi- 4. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intrave- nous ibutilide for rapid termination of atrial fibrillation and atrial nation therapy with ibutilide alone. 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