Ibutilide and the Treatment of Atrial Arrhythmias
1996; Lippincott Williams & Wilkins; Volume: 94; Issue: 7 Linguagem: Inglês
10.1161/01.cir.94.7.1499
ISSN1524-4539
Autores Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeCirculationVol. 94, No. 7Ibutilide and the Treatment of Atrial Arrhythmias Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBIbutilide and the Treatment of Atrial ArrhythmiasA New Drug−Almost Unheralded−Is Now Available to US Physicians Dan M. Roden Dan M. RodenDan M. Roden Vanderbilt University School of Medicine, Departments of Medicine and Pharmacology, Nashville, Tenn. Originally published1 Oct 1996https://doi.org/10.1161/01.CIR.94.7.1499Circulation. 1996;94:1499–1502The 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.23 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 ResultsThe 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 440 ms), hypokalemia (serum K+ 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 ProcessThere 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 FutureContemporary 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.333435 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.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 532C Medical Research Bldg-I, Nashville, TN 37232-6602. References 1 Singh BN, Vaughan Williams EM. A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacologic actions of MJ1999. Br J Pharmacol.1970; 39:675-689.CrossrefMedlineGoogle Scholar2 Suttorp MJ, Polak PE, van't Hof A, Rasmussen HS, Dunselman PH, Kingma JH. 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Roden D (1997) A practical approach to torsade de pointes, Clinical Cardiology, 10.1002/clc.4960200318, 20:3, (285-290), Online publication date: 1-Mar-1997. October 1, 1996Vol 94, Issue 7 Advertisement Article InformationMetrics Copyright © 1996 by American Heart Associationhttps://doi.org/10.1161/01.CIR.94.7.1499 Originally publishedOctober 1, 1996 Keywordsatrial flutterdrugsfibrillationarrhythmiaEditorials Advertisement
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