Original Contribution

Ibutilide to expedite ED therapy for recent-onset Atrial fibrillation flutter^B

Stavros E. Mountantonakis MD^a,b,c,*, Dimitrios A. Moutzouris MD^a, Ramon V. Tiu MD^c,

Georgios N. Papaioannou MD^a, Craig A. McPherson MD^b

^aInternal Medicine and cardiology department, Livadia General Hospital, 32100 Livadia, Greece

^bInternal Medicine and Cardiology Department, Yale University/Bridgeport Hospital, Yale New Haven Health,

Bridgeport, CT 06610, USA

^cInternal Medicine Department, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA

Received 14 November 2005; accepted 6 December 2005

Abstract

Objective: Ibutilide is a type III antiarrhythmic agent approved for the pharmacologic conversion of Atrial fibrillation and atrial flutter (AFl). Previous studies conducted outside the ED setting have demonstrated conversion rates of 60% to 80%. This response has been highest in patients with recent- onset AF-AFl. These observations and the 4-hour half-life of ibutilide suggest that it may be an excellent drug with which to treat AF-AFl in the ED. The purpose of the study was to examine the efficacy and safety of ibutilide in terminating AF-AFl in patients who present to the ED with symptoms of less than 3 days’ duration, neither angina nor heart failure, and no comorbid conditions that require admission. Methods: Among 36 enrolled patients, the admission electrocardiogram demonstrated AF in 26 and AFl in 10. Ibutilide 1 mg was administered intravenously for 10 minutes. If sinus rhythm was not present 10 minutes after the infusion concluded, a second infusion of 1 mg was given. Successful conversion was defined as restoration of sinus rhythm within 1 hour after the last dose of ibutilide. Results: Sixteen (61.5%) of 26 patients with AF and 9 (90%) of 10 patients with AFl converted to sinus rhythm (overall conversion rate = 69%). The mean time to arrhythmia termination was 19 F 9 minutes. The mean stay in the ED was 16.2 hours. No significant complications occurred.

Conclusion: We conclude that ibutilide is an excellent therapy option for restoring sinus rhythm in the ED. Its use may obviate the need for admission, avoid the risks and inconveniences of general anesthesia to perform electrical cardioversion, and reduce the ED length of stay in selected patients with recent-onset Atrial arrhythmias.

D 2006

^B This study was presented at the 70th Annual Meeting of the American College of Chest Physicians, bCHEST 2004,Q October 23 to 28, 2004, Seattle, Wash.

* Corresponding author. Internal Medicine Department, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. Tel.: +21 16 702 3374.

E-mail address: [email protected] (S.E. Mountantonakis).

Introduction

• 1. Background

Atrial fibrillation is the most common arrhythmia in clinical practice and the most commonly encountered

0735-6757/$ - see front matter D 2006 doi:10.1016/j.ajem.2005.12.006

arrhythmia among patients who present to the ED with palpitations [1]. The management of AF in the ED can be summarized as the 3 Cs: (1) Correction of precipitating factors; (2) Control of ventricular response; and (3) Con- sideration of restoration of normal sinus rhythm (NSR) [2]. Correctable precipitating factors include hypoxia, hypoka- lemia, and hypomagnesemia.

If the patient does not require admission for other comorbidities, 1 immediate question becomes whether admission is indicated for AF per se. This is not always the case. In a retrospective analysis of patients presenting to the ED with AF, Mulcahy and Coates [3] reported that two thirds might not have required admission after careful triage in the ED. Furthermore, they found that almost all patients who required admission could have been identified during the ED evaluation.

If admission is not needed, the question then becomes whether to restore sinus rhythm or control the ventricular response and observe the patient. The bobservationQ approach is justified by the fact that many patients who presented with atrial arrhythmias convert to sinus rhythm spontaneously. The main drawbacks of this approach are (1) the extra time the patient must spend in the ED and (2) that those patients who do not convert spontaneously may miss the critical window of 48 hours in which cardioversion may be safely performed without administering systemic anti- coagulation and possibly performing transesophageal echo- cardiography to identify formation of atrial thrombi [4]. Other concerns include the fact that protracted observation lengthens ED stay and increases cost.

On the other hand, in restoring normal sinus rhythm, several issues should be addressed. First, the arrhythmia should be of less than 48 hours’ duration or the patient must be adequately anticoagulated [5]. Second, if long-term suppressive antiarrhythmic therapy is indicated, the selected drug should be administered before cardioversion, usually in a monitored situation. Finally, if direct current cardioversion (DCCV) is used, the patient must fast for at least 6 hours before administration of intravenous general anesthesia.

Although DCCV is effective in restoring sinus rhythm, the need for anesthesia and fasting may limit its timely use in the ED. An alternative to DCCV is to perform pharmacologic cardioversion with a rapid-onset antiarrhyth- mic agent. Agents such as intravenous procainamide, oral flecainide, and oral propafenone have been used for pharmacologic cardioversion in the ED setting [6,7].

An alternative pharmacologic approach is ibutilide, a comparatively new type III antiarrhythmic agent with very appealing pharmacokinetic properties. As a type III agent that blocks the inward potassium rectifier current (I_Kr) [8], ibutilide prolongs atrial refractoriness thereby diminishing the propensity of the atriae to fibrillate. In the ventricles, I_Kr blockade lengthens the QT interval, which creates risk for Torsades de pointes [9]. Ibutilide has a very short half-life of elimination, clearing approximately 4 hours after its infusion. It does not interact with most of the medications

that are used for Rate control, such as b-blockers, diltiazem, verapamil, and digoxin [10]. Furthermore, its dosing requires no adjustments for diminished renal or Hepatic function. Finally, ibutilide is a very rapidly acting agent with mean conversion time of approximately 20 minutes [11].

The properties of ibutilide make it a potentially excellent antiarrhythmic agent to achieve rapid pharmacologic car- dioversion of AF. The purpose of this study was to examine the efficacy and safety of ibutilide in converting new-onset atrial arrhythmias in a selected group of patients in the ED setting. Our hypothesis was that ibutilide can expedite outpatient management of atrial arrhythmias by rapidly reestablishing normal sinus rhythm, avoiding electrical cardioversion, reducing ED length of stay, and obviating the need for admission.

Methods

The study represents a prospective, consecutive case series conducted at the ED of a community hospital. The chief inclusion criterion was palpitations of less than 48 hours’ duration (72 hours if the patient was receiving Oral anticoagulation). Exclusion criteria included systolic blood pressure of less than 100 mm Hg or heart rate of more than 120 beats per minute after administration of metoprolol 5 mg (intravenous) up to 3 times. We also excluded patients with history of congestive heart failure (CHF), unstable angina, cerebrovascular accident, or hyperthyroidism. Prolonged QT interval (QTc N460 milliseconds) on initial electrocar- diogram (ECG) as well as echocardiographic findings of left ventricular (LV) hypertrophy were other reasons for exclusion. Finally, patients who required admission for other comorbid illnesses such as acute coronary syndrome, pulmonary embolism, chronic obstructive pulmonary dis- ease exacerbation, and Hypertensive crisis were not included in the study. The study did not aim to prove the efficacy of ibutilide, which has been substantiated by previous studies, so no control group was included.

A 12-lead ECG was obtained to determine the arrhyth- mia and to measure baseline QT interval. The longest QT interval in any of the 12 leads, measured at 25 mm/sec paper speed, was divided by the square root of its preceding R-R interval to obtain the baseline QTc interval. Continuous cardiac monitoring was initiated, and heart rate was controlled by injecting metoprolol 5 mg for 2 minutes intra- venously every 5 minutes for up to 3 doses as needed to achieve a heart rate of less than 120 beats per minute. Base- line laboratory tests included chemistry profile, troponin T, creatine kinase-MB, thyroid-stimulating hormone (TSH), and digitalis levels in those taking it. Electrolyte abnormal- ities were corrected such that serum K⁺ was 4 mEq/dL or higher and Mg⁺⁺ was 2 mEq/dL or higher before ibutilide infusion. A standard echocardiogram was performed in each patient to assess LA size, valve function, and LV size, wall thickness and contraction. The measurements used for

analysis were those of the cardiologist who interpreted the echo in the course of routine clinical care.

Ibutilide was administered under continuous cardiac monitoring at a dose of 1 mg and infused over a 10-minute period. In patients less than 60 kg, the dose was reduced to

0.01 mg/kg, infused for 10 minutes. If the patient did not achieve conversion to sinus rhythm within 10 minutes after the infusion concluded, a second 10-minute infusion of equal dose was begun. The infusion was discontinued if conversion was achieved or if a new arrhythmia appeared. We defined successful conversion as termination of the arrhythmia within 1 hour after the last infusion. Normal sinus rhythm was confirmed at 12-lead ECG by at least 2 investigators. All patients were under continuous cardiac monitoring for at least 4 hours after the ibutilide infusion ended.

Characteristics of patients who did and did not respond to ibutilide were compared by unpaired t test or v² analysis, as appropriate. A 2-tailed P value of less than .05 was considered to indicate statistical significance. Data are reported as means F SD.

Results

Between January and December 2002, a total of 104 patients (64 men and 40 women) presented to our ED with palpitations of duration of less than 72 hours. Among these, 68 presented with 1 or more exclusion criteria.

The final study population included 36 white patients (22 men and 14 women). Their mean age was 67.6 F 11.9 years. The admission ECG demonstrated AF in 26 and atrial flutter (AFl) in 10. All but 3 patients presented with symptoms of less than 48 hours’ duration. These 3 had experienced palpitations for 48 to 72 hours but were included in the study because they were adequately anticoagulated. The duration of symptoms in the remaining patients was less than 24 hours in 27 and 24 to 48 hours in

9. Medical diagnoses on admission included hypertension in 28 patients (78%), chronic obstructive pulmonary disease in 13 (36%), valve disease in 11 (30%), and coronary artery disease in 10 (27%). Several patients had more than one of these conditions , whereas 4 (11%) patients carried no diagnosis. Nine patients (25%) had previously experienced atrial arrhythmias. Medications taken at time of presen- tation included b-blockers in 10 (28%), calcium-channel antagonists in 9 (25%), digoxin in 4 (11%), and coumadin in 3 (8%) patients. None of the patients were taking anti- arrhythmic drugs.

A total of 24 patients (67%) received metoprolol for heart rate above 120, including 14 who received 5 mg, 4 who received 10 mg, and 6 who received 15 mg. The mean dose in those who required this treatment was 8.3 (F4.3 mg). Repletion of electrolytes was required before ibutilide infusion in 13 patients. This included 6 who received KCl intravenously, 3 who received MgSO₄, and 4 who received both supplements.

Conversion to sinus rhythm occurred in 25 (69%) of the 36 patients. Conversion occurred in 77% of patients who had experienced symptoms of less than 24 hours’ duration and 90% of those who were in AFl. Of those who converted to NSR, 16 (64%) did so after the first ibutilide infusion and 9 (36%) converted more than 10 minutes after the second infusion. The mean time to arrhythmia termination was 19 F 9 minutes from the initiation of the infusion. The mean stay in the ED was 16.2 F 7.4 hours.

Hypotension was the most frequent adverse effect. A systolic blood pressure below 0 mm Hg occurred in 3 patients (8.3%). Premature ventricular depolarizations were observed in 1 patient (2.7%). This required no medical intervention beyond discontinuation of the ibutilide infusion. This par- ticular patient remained in AF. No patient developed ventricular tachycardia or torsades de pointes.

Discussion

Our study demonstrates conversion success rate in ED patients similar to those observed in other study populations [12]. In past studies, the success of ibutilide has been greater in AFl than AF; in recent-onset AF; and in the absence of structural heart disease, CHF, and left atrial (LA) enlarge- ment [9,13,14]. Our results echo these previous reports. Because patients often present to the ED soon after symptom onset, ibutilide may be particularly effective in restoring NSR in many. We included only patients who had normal ejection fraction and few who had enlarged left atria. This selection likely contributed to the high success rate observed in our study.

In clinical trials, ibutilide has been found to be more effec- tive than both sotalol [15] and procainamide [16] in convert- ing AF-AFl to NSR. In a recent metaanalysis, ibutilide was judged to be more effective than all other available antiar- rhythmic agents used for the conversion of AF. The odds ratio vs placebo for ibutilide was 30.7. This was 2-fold greater than flecainide; 5-fold greater than dofetilide; and 10-fold greater than propafenone, amiodarone, and quinidine [17]. Ibutilide is, therefore, a very effective antiarrhythmic agent.

In addition to its efficacy, a second characteristic that makes ibutilide an ideal agent in the ED setting is its rapid action. In our study, 23 (92%) of the 25 of atrial tachyar- rhythmia that converted did so within the first half-hour of the infusion. Ellenbogen et al [11] reported that 80% of patients with AF converted within 30 minutes, whereas Eversole et al

[12] reported a mean conversion time of 68.8 minutes. Our mean time of conversion of 19 minutes coincided with that observed by Ellenbogen et al. The rapid action of ibutilide makes it an attractive choice for the ED because it can expedite triage decisions.

The adverse effects of ibutilide that we encountered were occasional hypotension and premature ventricular depolari- zations. The most serious reported complication of ibu- tilide has been torsades de pointes, a consequence of its

QT-prolonging effects. In published studies, nonsustained polymorphic tachycardia has been observed in 2.3% to 7% of cases and sustained polymorphic tachycardia in 1.3% to 4% [11,14,18,19]. Reported risk factors for torsades include CHF, LV dysfunction, and baseline QT interval prolongation of more than 440 milliseconds [11]. Exclusion of patients with these characteristics may significantly increase the safety of ibutilide. Our patients had nearly normal LV wall thickness, LA size and no history of CHF. electrolyte abnormalities were corrected before administration of ibuti- lide. Furthermore, the selection of only recent-onset AF and flutter for ibutilide treatment, such as in our patients, may be another important precaution in avoiding dysrhythmic complications from the drug [20]. In all above studies, the continuous monitoring of the patients for 4 hours after administration of the last dose of ibutilide was sufficient to identify all cases of arrhythmia complications. Therefore, admission to the hospital is not required to monitor for arrhythmias caused by ibutilide.

The issue of rhythm vs rate control for patients with AF has been addressed in studies such as Atrial Fibril- lation Follow-up Investigation of Rhythm Management (AFFIRM) [21] and RAte Control Versus Electrical Cardioversion of Persistent Atrial Fibrillation (RACE) [22]. Those studies have demonstrated equivalent 5-year outcomes of rate control vs Rhythm control and have demonstrated that there is no difference in Thromboembolic events between the 2 approaches as long as adequate anticoagulation is maintained. However, there are settings in which cardioversion is warranted. First, many patients who presented to the ED with their first episode of AF have no underlying heart disease or precipitating factors. Many have blone atrial fibrillationQ and they are often Young people [23,24]. The decision to commit such young patients to life- long anticoagulation after their first episode of AF is questionable, especially because it has been shown that patients younger than 60 years have lower thromboembolic risk [25]. In such individuals, an initial strategy of cardioversion with outpatient visits to monitor rhythm may be a reasonable approach. Our study included a comparatively young group of patients in whom the decision to restore NSR seemed quite reasonable.

In addition to those with lone AF, many patients with underlying heart disease may maintain NSR after conver- sion of AF after their first episode. Such patients typically have nearly normal LA size (b4.5 cm), AF of recent onset, no heart failure, reversible underlying disorders, absence of hypertensive heart disease, and high atrial appendage flow velocity [26,27]. Our patients shared many of these favorable characteristics.

One other potential advantage of ibutilide is that even if it does not restore NSR, it may enhance the success of DCCV and diminish reversion back to AF after DCCV in the 3 to 4 hours after its administration [28].

The population of ED patients who might be candidates for ibutilide therapy may be substantial. Many patients who

present in AF may not require admission to the hospital. The most common indications for admission are to treat underlying disorders, rule out myocardial infarction (MI), start anticoagulation, and initiate antiarrhythmic agents. Cameron et al [29] demonstrated AF to be a manifestation of coronary artery disease only in 0.6% of cases. Further- more, new-onset AF is rarely the sole ECG finding of ischemia. Zimetbaum et al [30] reported that of patients who are admitted from the ED with AF to brule out MI,Q only 5% of cases proved to be suffering MI.

A second potential indication for admission is to initiate anticoagulation. This is not required in patients who present with AF of less than 48 hours’ duration. Furthermore, patients younger than 60 years without underlying heart disease have low risk for thromboembolic events [25]. Israel et al [31] recommended starting anticoagulation in patients with paroxysmal AF after their second episode even if cardioversion is achieved. The rationale is that thrombi can form during asymptomatic periods of AF. Our study included 9 patients (25%) with history of previous AF,

Fig. 1 Proposed algorithm for decision to use ibutilide to convert AF flutter to NSR in the ED. COPD indicates chronic obstructive pulmonary disease; PE, pulmonary embolism.

3 of whom were already on anticoagulation. We recom- mended to the other 6 patients that they consult their primary physicians about potential need for long-term anticoagulation. Nonetheless, it was felt safe to proceed with cardioversion to relieve their palpitations. At discharge, all patients were advised to follow-up visit with their cardiologist and/or primary physician.

The arrhythmias potentially caused by ibutilide typical- ly occur within 4 hours after its infusion. Admission for more prolonged monitoring to detect drug-induced arrhyth- mias is not warranted. Furthermore, the profile of our patients did not require admission for initiation of long- term antiarrhythmic therapy, as outlined in recent guide- lines published by American College of Cardiology/ American Heart Association/European Society of Cardiol- ogy, which state, bThe initiation of long-term antiarrhyth- mic agent is not indicated in first episode of AF and in infrequent well tolerated paroxysmal AFQ [32]. Thus, patients such as ours, in whom initiation of long-term antiarrhythmic drug therapy is not generally initiated, will not require hospital admission if their AF can be converted in the ED.

The need to admit patients who present to the ED with uncomplicated new AF-AFl has been addressed in previous studies [33,34]. These studies have demonstrated that the approach of pharmacologic conversion of clinically stable cases of AF is safe and cost-effective [35]. Oral propafenone [7], oral flecainide, and IV procainamide [6] were the agents that were chosen mainly because of their safety profile. Our study shows that ibutilide has greater efficacy, has excellent safety profile, and achieves NSR more rapidly than other drugs. We consider it to be the treatment of choice in the boutpatientQ conversion of new onset or paroxysmal AF.

We conclude that because of its pharmacologic properties, proven efficacy, and safety profile, ibutilide is an excellent therapy option for restoring sinus rhythm in the ED. In fact, it is the drug of choice for this indication. Its use can obviate the need for admission, avoid the risks and inconveniences of general anesthesia to perform electrical cardioversion, and reduce the ED length of stay in selected patients with recent-onset atrial arrhythmias. Thus, we propose that patients similar to those described herein have their AF-AFl managed by ibutilide infusion in the manner described above and outlined in the adjacent algorithm (Fig. 1).

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