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Ibutilide revisited: stronger and safer than ever

Rakesh Gopinathannair , Brian Olshansky
DOI: http://dx.doi.org/10.1093/europace/eun337 9-10 First published online: 16 December 2008

When the cardioversion of atrial fibrillation is contemplated, many clinicians think only of one thing: electrical (DC) cardioversion. There are many reasons for this: (i) in most settings, the protocols to perform DC cardioversion are well established, easy to do, inexpensive, and efficient; (ii) manpower needed to perform DC cardioversion is relatively small; (iii) while no randomized controlled clinical trial demonstrates benefit, DC cardioversion is well established, carries a low risk, and is highly successful for most patients; and (iv) there is hardly a reason to think of any other alternative approach.

On the other hand, several oral and intravenous drugs are available, and have been used effectively, to convert patients from atrial fibrillation to sinus rhythm. Why is this approach so often ignored? The reasons are somewhat complex: (i) the technique takes time even for the use of intravenous medications; (ii) pharmacological cardioversion is generally not as effective as DC cardioversion; (iii) more manpower is needed to manage patients for additional hours in many cases; (iv) protocols are not as well established and, therefore, undefined risks for the patient may occur; and (v) there are potential proarrhythmic risks for all anti-arrhythmic medications.

Previous randomized controlled clinical trials have demonstrated the potential efficacy of anti-arrhythmic drugs to return patients to sinus rhythm using a ‘pill-in-the-pocket’ or intravenous infusion technique.13 Ibutilide, a class III anti-arrhythmic, is a potent blocker of the rapid component of the cardiac-delayed rectifier potassium current and also activates the slow inward sodium current.4 Ibutilide has been shown to be modestly effective in terminating both atrial flutter and atrial fibrillation, particularly if the arrhythmia is relatively short-lived, and may be more effective than other anti-arrhythmic drugs for this purpose.2 This drug, however, never enjoyed mainstream success because of modest efficacy, a potentially high risk of torsade de pointes in some patients,3 and the time commitment for physicians and other personnel. Older drugs, such as quinidine and procainamide, are not as effective as ibutilide and carry additional risks so that they have faded from the scene.

Other drugs, including intravenous β-blockers, terminate atrial fibrillation rarely, and most conversions noted after administration are probably spontaneous reversions.5 The only exception to this is post-operative atrial fibrillation, where adrenergic activation plays an important role, and intravenous esmolol was associated with superior conversion rates when compared with diltiazem.6

Newer drugs such as vernakalant hydrochloride, a multi-channel and partially specific atrial potassium channel blocker, also available as an intravenous infusion, but not yet approved for use in many countries, can terminate atrial fibrillation (but not atrial flutter) with similar efficacy and perhaps with a lower risk of developing torsade de pointes.7 Given these limitations, improved conversion rates and reduction in proarrhythmic risks with current pharmacological agents or newer agents are of significant interest.

Fragakis et al.8 compared the combination of intravenous esmolol and ibutilide with intravenous ibutilide alone to convert recent-onset atrial fibrillation with a rapid ventricular rate. This simple, straightforward, randomized, prospective study shows that intravenous β-blockade facilitates conversion with ibutilide (67% with the combination vs. 46% for ibutilide alone) with marked reduction in the incidence of immediate atrial fibrillation recurrence. The slower the ventricular rate at the time of ibutilide administration, the greater was the probability of conversion to sinus rhythm.

One highlight of the esmolol–ibutilide combination was that it was associated with a markedly lower risk of torsade de pointes. Of the 44 patients who received the combination, none developed polymorphic ventricular tachycardia, whereas 3 patients out of the 44 (6.5%) who received ibutilide alone developed polymorphic ventricular tachycardia. Now, we have a combination of two standard, well established, drugs that can be given safely and potentially effectively to help return patients to sinus rhythm without significant concern of immediate return of atrial fibrillation or proarrhythmia. We do not know that similar results would be achieved with different anti-arrhythmics or different β-blockers.

Other issues need consideration. The study protocol, with simultaneous IV administration of two drugs and with esmolol titration based on haemodynamics, appears complex, time-consuming and potentially difficult to learn and follow in busy emergency rooms and outpatient cardiology centres. This aggressive protocol, with its associated need for close monitoring, was only effective to convert two-third of the patients. The remainder required electrical cardioversion. This adds an extra burden in terms of resources and personnel when DC cardioversion, from the start, could be safe and effective.9 The potential risks of post-cardioversion bradycardia and/or asystole, even though minimal in this study, should be taken into account as well.

This study provides a moment for reflection. DC cardioversion is not 100% effective in terminating atrial fibrillation or atrial flutter. Furthermore, especially at high outputs, electrical cardioversion may have temporary damaging effects on the myocardium with impairment in the ventricular function and even an occasional episode of post-cardioversion congestive heart failure or pulmonary oedema.9,10 While uncommon, ibutilide pre-treatment can enhance efficacy of transthoracic cardioversion in permanent atrial fibrillation perhaps by a reduction in atrial defibrillation threshold.11 This may be especially important in obese patients with long-standing atrial fibrillation. Ibutilide may enhance the safety and efficacy one step further by reducing immediate or early return of atrial fibrillation after cardioversion by unclear mechanisms.

There are other potential advantages of anti-arrhythmic drug use to facilitate return of sinus rhythm as long as it can be done safely. Patients who present to an emergency room or clinic or who are early post-operative with acute-onset of atrial fibrillation, but have recently eaten, may benefit from pharmacological conversion. It would make sense to use drugs rather than wait but there are other potential benefits. Inability to tolerate deep sedation, lack of proper personnel to administer sedation, pacemaker-dependence with right-sided devices and the risk for transient pacemaker malfunction or exit block and patient preference against electrical shock would be other situations.

One of the primary reasons why ibutilide has been relegated to the dust bins of atrial fibrillation cardioversion was the unacceptably high rate (∼8%) of torsade de pointes,3 the risk of which was increased with worsening structural heart disease, female gender, and electrolyte abnormalities. This study offers a solution to this problem. Concurrent use of high doses (4 g) of magnesium sulphate enhances ibutilide efficacy in non-randomized evaluations12 and could potentially be an adjunct to the ibutilide–esmolol combination. However, the calcium antagonism from high dose magnesium might worsen the already-present bradycardic risk.

With this new ibutilide protocol and with the advent of newer drugs such as vernakalant, pharmacological agents may play an expanding role in converting patients from atrial fibrillation to sinus rhythm. What is apparent is that ibutilide, with its best pal esmolol, has emerged stronger and safer than ever before.

Conflict of interest: B.O. has received honoraria for speaking, funding for research and/or has engaged in consulting relationships with Boston Scientific, Medtronic, St. Jude, Novartis, Stereotaxis, Sanofi Aventis, Roche, Baxter, Boehringer Ingelheim, Glaxo Smith Klein, Reliant, Abbott, CV Therapeutics and Biocontrol. B.O. has served as an expert witness for the plaintiff and for the defense in several cases in the past five years, of which two went to trial. R.G. has no conflicts of interest to declare.


  • The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.