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(Circulation. 1996;94:1499-1502.)
© 1996 American Heart Association, Inc.

Articles

Ibutilide and the Treatment of Atrial Arrhythmias

A New Drug-Almost Unheralded-Is Now Available to US Physicians

Dan M. Roden, MD

Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn.

Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 532C Medical Research Bldg-I, Nashville, TN 37232-6602.

Key Words: Editorials • atrial flutter • fibrillation • arrhythmia • drugs

	Introduction

Top Introduction Study Results In Vivo Mechanisms of... In Vitro Mechanisms of... Clinical Features of Torsade... Ibutilide and the Drug... A View to the... References

 
The concept that drugs that prolong ventricular repolarization, and hence refractoriness, might be effective antiarrhythmics was first advanced over 25 years ago.¹ Agents such as quinidine, sotalol, and amiodarone all prolong refractory periods in cardiac tissue at least partially through this mechanism, often termed a "class III" action. However, since these compounds also exert other important pharmacological actions, such as conduction slowing (by depression of sodium current or other mechanisms) or antiadrenergic effects, it has not been possible to establish that action potential prolongation is in fact antiarrhythmic in human subjects. The development of drugs whose sole pharmacological action is to prolong the cardiac action potential has now provided a tool to address this question, and indeed small clinical trials testing these agents do indicate antiarrhythmic activity.^{2 3} In this issue of Circulation, Stambler and colleagues⁴ report the results of a large, placebo-controlled, blinded trial of ibutilide, a "pure" action potential–prolonging agent, in patients with atrial fibrillation and flutter. The demonstration that ibutilide infusion can terminate atrial fibrillation or flutter was pivotal in the recent decision by the Food and Drug Administration (FDA) to approve marketing of the drug for this indication. Thus, ibutilide is the first of the "pure" action potential–prolonging agents to be available to practicing physicians.

	Study Results

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The patients reported by Stambler and colleagues represent a rather typical group of patients for whom conversion to sinus rhythm might be contemplated: 75% had a history of heart disease other than atrial fibrillation or flutter, 83% had an enlarged left atrium, 55% had depressed left ventricular systolic function, and 71% had valvular heart disease. Duration of arrhythmia and extent of underlying heart disease are known to exert a profound impact on the outcome of therapy for these arrhythmias: Only patients who had atrial fibrillation or flutter for 3 to 45 days and who were free of angina or heart failure were included. Ibutilide was administered as a single 1-mg intravenous infusion over 10 minutes followed, if sinus rhythm was not restored, by a second infusion of 0.5 or 1 mg. The trial was designed to include equal numbers of patients with atrial fibrillation and atrial flutter, presumably because preclinical data suggested that ibutilide and similar drugs might be especially effective in atrial flutter. Indeed, this was the case: The conversion rate among patients with atrial flutter treated with ibutilide was 63%, compared with 31% among those with atrial fibrillation and 2% among those receiving placebo. Half the conversions occurred during or just after the first infusion, and the average time to conversion was 27 minutes after the start of the first infusion. Aside from the presence of atrial flutter, important predictors of success were duration of the arrhythmia <7 days and normal left atrial size (both for patients with atrial fibrillation only). The extent of QT-interval prolongation and the presence of left ventricular dysfunction were not predictors of efficacy.

Preexisting prolongation of the QT interval (QT_c >440 ms), hypokalemia (serum K⁺ <4.0 mEq/L), and previous torsade de pointes were exclusion criteria. Nevertheless, 8% (15 of 180) of ibutilide-treated patients developed polymorphic ventricular tachycardia. Although clinical data were missing in some cases, it seems likely that all these cases were typical torsade de pointes, with marked QT prolongation, QT lability, and pause-dependent onset of the arrhythmia. Thus, ibutilide presumably targets ion channels that are present in both atrium and ventricle, suppressing atrial arrhythmias but occasionally markedly prolonging action potentials in the ventricle or conducting system to produce QT prolongation and torsade de pointes. In all cases, torsade de pointes developed during or shortly after ibutilide infusion. In most cases, no treatment beyond stopping the infusion and administering magnesium was necessary; 3 out of 15 subjects required cardioversion. One patient developed polymorphic ventricular tachycardia during the ibutilide infusion, and episodes persisted for many hours afterward.

No other drug has been studied for the acute termination of atrial fibrillation or flutter in as rigorous a fashion in as large a number of subjects. In Europe, sotalol, amiodarone, propafenone, and flecainide have been used, with success rates that seem to be comparable to those with ibutilide, although it is difficult to match for crucial determinants of outcome such as duration of arrhythmia.^{5 6 7} In this country, intravenous procainamide is sometimes used in this situation, but again its efficacy is not well established. Ongoing and unreported studies from the sponsor, presented to the FDA, suggest that ibutilide is demonstrably superior to intravenous sotalol for this indication. The other option, of course, is cardioversion. The efficacy of cardioversion seems higher than most drugs, but the procedure is more cumbersome and, probably, more expensive; a randomized trial comparing not only efficacy but also complication rates and costs would be of interest.

	In Vivo Mechanisms of Action

Top Introduction Study Results In Vivo Mechanisms of... In Vitro Mechanisms of... Clinical Features of Torsade... Ibutilide and the Drug... A View to the... References

 
Action potential–prolonging agents should inhibit reentrant arrhythmias by prolonging refractoriness and hence decreasing the likelihood that premature beats might initiate reentry.⁸ When reentry is sustained, as in the patients studied here, it has been considered that increasing refractory period should eventually result in extinction of a tachycardia by increasing the likelihood that a reentrant impulse will encounter refractory tissue. As Stambler and colleagues point out, two fundamentally different reentrant mechanisms have been identified: functional reentry (typified by atrial fibrillation) and reentry in a defined anatomic circuit (typified by atrial flutter). In the latter type of reentry, an excitable gap—the region of the defined circuit that has completely recovered excitability before the arrival of the next reentrant impulse—is often present, whereas excitable gaps in functionally defined arrhythmias are small or nonexistent.

The Sicilian Gambit, an attempt to provide a new framework for examining antiarrhythmic drug effects on the basis of arrhythmia mechanisms, suggested that action potential–prolonging drugs would be less effective in arrhythmias with a large excitable gap.⁸ However, Stambler and colleagues have now demonstrated that ibutilide is more effective in atrial flutter than in atrial fibrillation, and smaller clinical trials suggest that this may be a common effect of action potential–prolonging drugs.⁹ Conversely, the sodium channel blocker flecainide may be somewhat more effective in atrial fibrillation than in atrial flutter,⁹ although this finding is difficult to interpret mechanistically because flecainide blocks not only cardiac sodium channels but also (at roughly comparable concentrations) potassium currents¹⁰ and prolongs action potentials in the human atrium.¹¹ It seems likely not that the approach of the Sicilian Gambit is incorrect but that the concept of atrial flutter as a single reentrant impulse utilizing a circuit with homogeneous electrophysiological properties is an oversimplification. Indeed, in animal models, action potential–prolonging drugs terminate experimental atrial flutter (which may not use exactly the same circuits as that observed in humans) by multiple and occasionally unexpected mechanisms. One example is the demonstration that action potential–prolonging drugs can terminate the arrhythmia by a "failure of the lateral boundary"; that is, by allowing impulses to leave the circuit and repenetrate and terminate it at some later critical time.¹² Another mode of termination is by conduction block due to prolongation of repolarization at some critical point within the reentrant circuit (eg, the commonly used isthmus between the coronary sinus and the tricuspid valve).^{12 13 14} Thus, the finding that ibutilide terminated atrial flutter more readily than it terminated atrial fibrillation may provide a further tool for clinical electrophysiologists to understand further the detailed mechanisms underlying reentry in these two arrhythmias.

	In Vitro Mechanisms of Action

Top Introduction Study Results In Vivo Mechanisms of... In Vitro Mechanisms of... Clinical Features of Torsade... Ibutilide and the Drug... A View to the... References

 
Most currently available antiarrhythmic drugs interact with multiple ion channels and receptors. This wide range of target molecules, along with the fact that none of the drugs are particularly potent, probably underlies the relatively high incidence of nonspecific side effects with available compounds. Ibutilide, in contrast, appears to target only cardiac ion channel(s) in the nanomolar range and, importantly, is devoid of other significant other pharmacological effects. This specificity of action probably accounts for the fact that aside from the predicted pharmacological outcome of excessive drug action (torsade de pointes), other adverse effects during ibutilide therapy were rare.

The last year has seen important advances in our understanding of the mechanisms underlying the congenital long QT syndrome, and it is clear that some of these findings have important implications for drug-induced torsade de pointes as well. A wealth of preclinical data indicate that two general mechanisms can underlie marked prolongation of the action potential and the QT interval: increased inward current or decreased outward current during the plateau of the action potential.¹⁵ Indeed, mutations causing either type of defect have now been identified in patients with the congenital long QT syndrome. In some of these patients, the disease is due to failure of sodium channels to inactivate appropriately, leading to increased inward current during the plateau of the action potential and QT prolongation.^{16 17} In other patients, the disease is due to a decrease in potassium currents, such as the rapidly activating component of the delayed rectifier I_Kr.^{18 19 20} It is now apparent that many drugs that cause torsade de pointes are potent, and in some cases quite specific, blockers of I_Kr: Examples include sotalol,²¹ quinidine,²² terfenadine,²³ and the investigational agent dofetilide.^{22 24} Although ibutilide is a structural analogue of dofetilide and of sotalol, initial reports indicated that it did not block I_Kr but rather that it produced its action potential–prolonging effect through a novel mechanism, enhancement of an inward sodium current during the plateau.²⁵ More recently, our laboratory and others have found that ibutilide does in fact target I_Kr in vitro.^{26 27} Whether the drug exerts its action potential–prolonging effects in humans by enhancing inward current during the plateau, by blocking I_Kr, or both, it seems clear from the evolving congenital long QT story that either mechanism can account for torsade de pointes with ibutilide. More generally, it now seems likely that torsade de pointes is a predictable risk with drugs that block I_Kr or that activate inward currents, failing some unusual state-dependent blocking mechanism. Ibutilide also has been reported to shorten the action potential at high concentrations,²⁵ a desirable effect if torsade de pointes is to be minimized. However, there are no data in human subjects that this effect occurs.

	Clinical Features of Torsade de Pointes

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The clinical features of torsade de pointes during the study of Stambler et al had features in common with many other reports. These include a greater prevalence among women (an observation that has been made repeatedly in both the congenital and drug-induced long QT syndromes,²⁸ but that remains unexplained), among patients with heart failure, and among patients with slower ventricular rates. In addition, they found a higher incidence among nonwhite subjects, a new observation whose mechanism will require further study. Another new finding was that torsade de pointes seemed to occur more frequently (10 of 80, 12.5%) among patients receiving the drug for atrial flutter than among those receiving it for atrial fibrillation (5 of 81, 6.2%). Plasma concentrations of the drug were not helpful in guiding therapy or identifying, even retrospectively, those at risk for torsade de pointes. Presumably, this reflects the fact that the drug is administered as a relatively rapid infusion, such that distribution, which often varies widely among individual subjects, is the predominant mechanism of drug elimination from plasma in the first few minutes after infusion. Under these conditions, even minor variations in the timing of blood samples can compound the variability in plasma concentrations observed. All episodes of torsade de pointes occurred during or shortly after ibutilide infusions, and most responded to merely stopping the drug and/or administering magnesium. In one patient, episodes of polymorphic ventricular tachycardia persisted for several hours after ibutilide administration. While the authors contend that this reflected an underlying tendency to torsade de pointes in this subject, the possibility that high concentrations of the drug persisted for hours was not formally eliminated. It would have been of interest to know the QT interval before ibutilide administration, the QT interval days after ibutilide administration, whether the episodes were indeed "typical" torsade de pointes with QT prolongation or had some other potential mechanism, and whether plasma concentrations of the drug were measured and were markedly elevated late after drug administration. In the absence of these data, it remains possible that a very small subset of patients may be at risk for torsade de pointes during ibutilide administration because of unusual drug disposition characteristics.

No data are available on the incidence of torsade de pointes during administration of equally effective dosages of other action potential–prolonging drugs, so it is not possible to compare the incidence with ibutilide with that with other drugs. The cited studies, conducted with oral therapy (and often in different patient groups, particularly with sotalol), do not really provide a good basis for comparison. Moreover, a definition of torsade de pointes is not given; a long cutoff (eg, >30 seconds) might underestimate the incidence. Additionally, studies in an experimental model of torsade de pointes have indicated that the rate of drug administration may be a particularly crucial determinant of whether the arrhythmia occurs or not.²⁹ Thus, the prediction would have to be that more rapid administration of even the same doses of ibutilide might lead to a higher incidence of torsade de pointes.

	Ibutilide and the Drug Approval Process

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There is another reason that the report of Stambler et al is so important: it is one of the first full-length, peer-reviewed publications of the clinical efficacy of ibutilide.³⁰ The data supporting the manufacturer's claim of efficacy were presented to the FDA's Cardiorenal Advisory Committee in late 1995. Final approval to market was granted in early 1996, and the drug was marketed in April. This may be the first example of a drug becoming available to the cardiovascular community with no clinical efficacy data available in the peer-reviewed literature. One can guess at many possible reasons for this patently undesirable outcome: A reluctance on the part of the sponsor to proceed with publication of small case reports, a certain amount of inertia on the part of participating investigators (and perhaps manuscript reviewers and editors), and an expedited review process at FDA (not so undesirable) are possibilities. With the prevailing drug development emphasis on in-house preclinical work, multicenter clinical trials, and an expedited drug review process, this scenario seems likely to be repeated. Thus, mechanisms to make peer-reviewed information such as this report available to practicing physicians before market release should be developed.

The investigation of preclinical and clinical efficacy of ibutilide has taught us a number of interesting and important lessons with regard to mechanisms of antiarrhythmic drug action at the level of the single channel and the whole heart. However, it is not clear that the drug represents a major advance in therapeutics. While it seems possible that ibutilide may have a place in the acute therapy of atrial flutter, since it was effective in 63% of patients, the 12.5% incidence of torsade de pointes in this group is worrisome. It is not clear what role, if any, the drug should assume in the therapy of atrial fibrillation, a much more common arrhythmia, since it was effective in only half as many patients (31%), albeit with half the incidence of torsade de pointes (6.2%). While it can be debated whether an episode of torsade de pointes that terminates spontaneously constitutes a "serious" side effect or merely an electrocardiographic epiphenomenon, I am inclined to the former view. The incidence of torsade de pointes was determined under tightly controlled clinical conditions, in a trial with investigators no doubt sensitized to the possibility of this adverse effect. As the drug becomes more widely used in less well-controlled situations, it seems likely that the incidence of torsade de pointes will be higher. Under appropriate conditions, the intravenous infusion of ibutilide may be a useful tool for physicians wishing to convert atrial fibrillation, and especially atrial flutter. Clinicians using this approach must be especially vigilant to avoid clinical circumstances that are likely to increase the risk: These include more rapid infusion, use of higher doses, preexisting QT prolongation, serum K⁺ <4 mEq/L, and administration to unstable patients or those with advanced heart disease.

	A View to the Future

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Contemporary therapy for cardiac arrhythmias is dramatically different from that even 5 or 10 years ago. Major progress in the field has come from advances both in understanding mechanisms of normal and abnormal electrophysiology and their response to drug therapy and in development of ablation and defibrillation technology. While improved and definitive therapy for patients with many arrhythmias (including atrial flutter) has resulted, atrial fibrillation remains the biggest remaining nut to crack. Studies are currently in progress to determine which of the available therapeutic strategies—rate control or rhythm control—is most appropriate in patients with recurring or established arrhythmia.³¹ Ibutilide is not available for chronic oral use, presumably because it undergoes extensive first-pass metabolism when it is administered orally,³² so maintenance of therapeutic plasma concentrations during chronic oral therapy would be difficult. In some centers, ablative procedures, performed intraoperatively or with a catheter, have been used successfully in atrial fibrillation.^{33 34 35} Even more exciting is the finding in animal models,³⁶ and the suggestion in very sporadic case reports in humans,³⁷ that the electrophysiological properties of the fibrillating atrium change over time. This implies that the poorer response to antiarrhythmics seen in chronic atrial fibrillation—with ibutilide and every other drug ever studied—may become a tractable problem if the underlying mechanisms can be identified and targeted with entirely new drugs or procedures.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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