Therapeutic use of ibutilide

INTRODUCTION — Ibutilide is a class III antiarrhythmic drug available only for intravenous use for the termination of atrial arrhythmias. An oral form is not available because of extensive first-pass metabolism [1].

The physiology and pharmacology of ibutilide use and the side effects that can occur will be reviewed here. The pharmacokinetics of ibutilide, drug interactions, and the various clinical settings in which ibutilide might be used are discussed in detail separately.

MECHANISMS OF ACTION

Cellular mechanisms — Like other class III antiarrhythmic agents (table 1), ibutilide prolongs repolarization in atrial and ventricular myocardium [1,2]. The class III drugs block IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period [1]. Ibutilide increases the refractoriness of atrial and ventricular myocardium, the atrioventricular node, His-Purkinje system, and accessory pathway [3]. In addition, ibutilide activates a slow, delayed inward sodium current that occurs early during repolarization [1,4]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs" and 'Major side effects' below.)

Effects on the ECG — Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, prolongation of the QT interval. There is no effect on the PR interval or QRS duration.

The degree of QT prolongation associated with ibutilide is related to the dose, the rate of infusion, and the serum concentration [5]. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. The QT interval returns to baseline within two to four hours after stopping the infusion. (See 'Proarrhythmia' below and 'Discontinuing ibutilide infusion' below.)

Mechanism of proarrhythmic effect — Like other drugs that prolong the QT interval and cause torsades de pointes, ibutilide blocks IKr, the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization [6]. IKr results from a heteromeric complex formed by a tetrameric potassium channel encoded by the KCNH2 gene (formerly called HERG gene) in complex with an accessory subunit encoded by the MirP1 gene (KCNE2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.)

Ibutilide exhibits "reverse use dependence", which is defined as an inverse correlation between the heart rate and QT interval. As a result, the QT interval decreases as the heart rate increases and lengthens as the heart rate slows. This explains why drug-induced polymorphic ventricular tachycardia (VT) is more commonly seen with bradycardia.

The effect of heart rate may be mediated by changes in the local extracellular potassium concentration [7]. Lower heart rates result in less potassium moving out of the cell during repolarization (before subsequent reuptake by the Na-K-ATPase pump), since there are fewer repolarizations. The associated reduction in extracellular potassium concentration enhances the degree of drug-induced inhibition of IKr, increasing the QT interval. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

PHARMACOKINETICS — Ibutilide has a half-life of 2 to 12 hours. It is extensively metabolized by the liver to eight metabolites. Only one metabolite exhibits antiarrhythmic activity, but its level is only approximately 10 percent of the parent drug level. As a result, this metabolite plays no role in the efficacy of ibutilide. Although almost 90 percent of the drug or its metabolites are detected in the urine, only 7 percent is excreted as the native, active drug.

CLINICAL USES — Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter of recent onset. Since there is no oral preparation of ibutilide, it has no role in the long-term prevention of these arrhythmias. Ibutilide is not approved for the treatment of ventricular arrhythmias, and its efficacy for these arrhythmias is unknown.

Atrial fibrillation — Intravenous ibutilide is useful and effective for the pharmacologic cardioversion of recent-onset atrial fibrillation [8]. As with other antiarrhythmic drugs, the efficacy of ibutilide is greatest when the atrial fibrillation is of short duration (figure 1) [9].

While it is of clear benefit in atrial fibrillation that has been present for seven days or less, the evidence is less robust but also suggests efficacy for atrial fibrillation of more than seven days duration. Most patients studied had arrhythmia for less than 90 days [9-11]. Similar efficacy has not been demonstrated with arrhythmia duration exceeding 90 days [12]. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.)

The indications for pharmacologic cardioversion of atrial fibrillation and the settings in which ibutilide might be used are discussed separately. (See "Atrial fibrillation: Cardioversion".)

In addition to the general use of ibutilide for cardioversion of atrial fibrillation, it has also been used in specific settings:

●As pretreatment before electrical cardioversion. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.)

●To convert atrial fibrillation to sinus rhythm in patients with Wolff-Parkinson-White syndrome. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Atrial fibrillation with preexcitation'.)

●To convert atrial fibrillation to sinus rhythm after cardiac surgery or cardiac transplantation [13,14]. (See "Atrial fibrillation and flutter after cardiac surgery".)

Ibutilide also appears to be a safe and effective antiarrhythmic agent for cardioversion of recent-onset atrial fibrillation and flutter in elderly patients. In a study of 32 patients (mean age 76 years) with recent-onset atrial fibrillation (19 patients) or atrial flutter (13 patients), the overall rate of successful conversion was 59 percent with a mean conversion time was 33 minutes [15]. Ibutilide-induced lengthening of the QTc interval was 17±21 milliseconds.

Atrial flutter — Ibutilide is effective for the cardioversion of atrial flutter [9-11,16], including atrial flutter that occurs after cardiac surgery [13]. (See "Restoration of sinus rhythm in atrial flutter" and "Atrial fibrillation and flutter after cardiac surgery".)

Ibutilide in children and in patients with congenital heart disease — The safety and efficacy of ibutilide for cardioversion of atrial flutter and atrial fibrillation in children and in patients with congenital heart disease was reviewed in a report of 19 patients, age 6 months to 34 years (median 16 years) [17]. Ibutilide successfully restored sinus rhythm in 71 percent of arrhythmia episodes, with success during the first administration in 12 of 19 (63 percent). Fourteen episodes in six patients required electrical cardioversion after ibutilide failed. There were no episodes of symptomatic bradycardia, and only one episode each of polymorphic and monomorphic ventricular tachycardia. With careful monitoring, ibutilide can be effective for children and young patients with congenital heart disease for cardioversion of atrial arrhythmias.

Chemical cardioversion of atrial fibrillation or flutter with ibutilide and other antiarrhythmic drugs — Similar to ibutilide, intravenous esmolol has a short half-life, which makes it appealing for use in the acute conversion of atrial fibrillation. A randomized, prospective study comparing the combination of intravenous esmolol plus ibutilide with ibutilide monotherapy for conversion of recent-onset atrial fibrillation with a rapid ventricular rate showed improvement in the rate of conversion to sinus rhythm in the combined ibutilide/esmolol group (67 percent with the combination versus 46 percent for ibutilide monotherapy) [18]. The slower the ventricular rate at the time of ibutilide administration, the greater was the probability of conversion to sinus rhythm. In addition, there was a marked reduction in the incidence of immediate atrial fibrillation recurrence in the group receiving both esmolol and ibutilide. The ibutilide/esmolol combination was also associated with a lower risk of torsade de pointes.

Patients receiving amiodarone — Combination therapy may be a useful cardioversion method for chronic atrial fibrillation or flutter for patients on amiodarone who are treated with ibutilide. The efficacy and safety of cardioversion with combination amiodarone and ibutilide was evaluated in patients on long-term oral amiodarone and referred for elective cardioversion of atrial fibrillation (81 percent) or atrial flutter (19 percent) [12]. Patients, who were in the arrhythmia for a mean of 196 before cardioversion and were taking amiodarone for a mean of 153 days, were administered 2 mg intravenous ibutilide. Within 30 minutes of infusion, ibutilide converted 54 percent with atrial flutter and 39 percent with atrial fibrillation. One episode of torsade de pointes occurred although QT-interval prolongation after ibutilide was noted. Thirty-five (90 percent) of 39 patients who did not convert with ibutilide underwent successful electrical cardioversion.

Patients receiving propafenone — In a trial using combination therapy, concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent atrial fibrillations was found safe and more effective than ibutilide alone [19]. Among 100 consecutive patients (66 men, mean age 65 years) with persistent atrial fibrillation (mean duration 99 days) who were admitted for elective pharmacological cardioversion and were randomly assigned to either intravenous ibutilide (1 mg plus an additional 1 mg, if required) or oral propafenone (600 mg) plus intravenous ibutilide, successful cardioversion occurred in 41 percent with ibutilide alone, compared with 71 percent with propafenone plus ibutilide. A comparable increase in the QTc interval was observed in both groups, but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group.

Patients undergoing catheter ablation for atrial fibrillation — In patients with persistent atrial fibrillation undergoing catheter ablation, ibutilide administration was not shown to increase procedural efficacy and long-term freedom from atrial arrythmias [20]. In patients with persistent atrial fibrillation who are undergoing a catheter-based ablation, incorporation of electroanatomic mapping allows for the detection and targeting of complex fractionated atrial electrograms (CFAEs). Since ibutilide reduces CFAEs, it was hypothesized that ibutilide administration prior to CFAE ablation would identify sites critical for persistent atrial fibrillation maintenance, allowing for improved procedural efficacy and long-term freedom from atrial arrhythmias. In the MAGIC-AF trial, 200 patients undergoing a first-ever persistent atrial fibrillation catheter ablation procedure were randomly assigned to 0.25 mg of intravenous ibutilide or saline placebo upon completion of pulmonary vein isolation. CFAE sites were then targeted with ablation. The study found that despite a reduction in CFAE area and greater atrial fibrillation termination during CFAE ablation, procedure efficacy was not statistically higher when CFAE ablation was guided by ibutilide administration versus placebo (56 versus 49 percent) [20]. (See "Atrial fibrillation: Catheter ablation" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".)

ADMINISTRATION

Dosing — The recommended dose of ibutilide varies with patient size:

●For patients weighing less than 60 kg, the dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) may be given.

●For patients weighing more than 60 kg, the dose is 1 mg over 10 minutes. Again, if the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes may be given.

Role of magnesium — Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter, and it can attenuate the QT interval prolongation associated with ibutilide therapy. Two cohort studies have shown that the concurrent administration of magnesium (doses of four to five grams administered intravenously) with ibutilide is associated with a greater chance of successful chemical conversion [21,22]. One of the two studies also reported a significantly lower rate of polymorphic ventricular tachycardia in patients who received the magnesium/ibutilide combination compared with patients who received only ibutilide [22].

MAJOR SIDE EFFECTS — Side effects with the use of ibutilide are infrequent and typically transient. In one report, the only noncardiac side effects that occurred more frequently than with placebo were nausea (1.9 percent), headache (3.6 percent), and renal failure (0.3 percent) [9]. The most serious side effects are those involving the cardiovascular system. As a result, ibutilide should not be used in patients with severe structural cardiac disease, prolonged QT interval, or underlying sinus node disease. Additional information about potential drug interactions can be found using the drug interactions program.

Proarrhythmia — Proarrhythmia, particularly nonsustained or sustained polymorphic (torsades de pointes) or monomorphic ventricular tachycardia (VT), is the most important toxic reaction. Because of the risk of ventricular tachycardia, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished and longer if needed until the QTc interval has returned to baseline.

In several large series, polymorphic VT was seen in between four and eight percent of patients [10,11,16,23]. Sustained episodes requiring cardioversion were seen in approximately two percent of patients. In addition to polymorphic VT, nonsustained monomorphic VT occurred in three to four percent of patients [10,11]. The majority of episodes of sustained polymorphic VT occurred within ten minutes of the first dose (before the second dose would be given, if necessary).

Torsades de pointes may be more common in women, occurring in six percent of women in one series (versus three percent of men) [23]. In addition, the risk was increased in patients with heart failure (eleven percent versus four percent in those without heart failure) [16].

Class IC antiarrhythmic drugs, which slow conduction by blocking sodium channels, also have the potential for proarrhythmia. However, since class IC drugs do not cause QT prolongation, it has also been suggested these drugs can be used safely with ibutilide. In two reports including a total of 175 patients with atrial fibrillation or atrial flutter, 150 were treated with propafenone and 25 were treated with flecainide [24,25]. All were treated with ibutilide up to 2 mg, which was successful in restoring sinus rhythm in 62 percent. Only two patients developed nonsustained polymorphic VT with one developing sustained polymorphic VT (two percent of patients), a rate consistent with that seen in patients not taking a class IC antiarrhythmic drug.

The potential for polymorphic VT is increased in patients who are being treated with another drug that prolongs the QT interval. However, the risk of proarrhythmia does not appear to be increased when ibutilide is given with amiodarone [12].

Other cardiac toxicities — Ibutilide has been associated with a number of cardiac side effects other than proarrhythmia [26]:

●Hypotension – 2 percent. Usually the degree of hypotension is mild and responds to fluid resuscitation.

●Sinus tachycardia or supraventricular tachycardia – 2.7 percent.

●Sinus bradycardia – 1.2 percent.

●Atrioventricular block – 1.5 percent.

●Bundle branch block – 1.9 percent.

All of the above arrhythmias and conduction changes have been reported transient with minimal or no associated symptoms.

Hemodynamic effects — Ibutilide produces no clinically significant changes in left ventricular function or hemodynamics, including mean pulmonary artery pressure or pulmonary capillary wedge pressure, even in patients with reduced left ventricular ejection fraction [27].

Discontinuing ibutilide infusion — In most patients who respond to ibutilide, arrhythmia termination is seen within 40 to 60 minutes after beginning the infusion (mean 27 to 33 minutes in two studies) [11,16]. The infusion should be stopped for the following reasons:

●The presenting arrhythmia is terminated.

●The patient develops ventricular tachycardia (sustained or nonsustained).

●The patient develops marked prolongation of the QT interval (to a corrected QT interval >500 msec with narrow QRS, or corrected QT >550 msec in patients with bundle branch block).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".)

SUMMARY AND RECOMMENDATIONS

●Mechanism and pharmacokinetics – Ibutilide, a class III antiarrhythmic drug, blocks IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period. (See 'Mechanisms of action' above.)

●Effects on electrocardiogram – Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, prolongation of the QT interval. There is no effect on the PR interval or QRS duration. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. (See 'Mechanisms of action' above.)

●Clinical uses – Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter and is most useful and effective for the pharmacologic cardioversion of atrial fibrillation less than or equal to seven days duration. (See 'Atrial fibrillation' above and 'Atrial flutter' above and "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.)

●Side effects – Proarrhythmia, particularly nonsustained or sustained polymorphic ventricular tachycardia (VT) (torsades de pointes) or monomorphic VT, is the most important toxicity associated with ibutilide. Because of the risk of VT, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished, or until the QTc interval has returned to baseline. (See 'Proarrhythmia' above.)

The ibutilide infusion should be stopped for the following reasons (see 'Discontinuing ibutilide infusion' above):

•The presenting arrhythmia is terminated.

•The patient develops VT (sustained or nonsustained).

•The patient develops marked prolongation of the QT interval.