S. Hohnloser, T. Klingenheben, Bramahn . Singh
Oct 1, 1994
Citations
6
Influential Citations
371
Citations
Quality indicators
Journal
Annals of Internal Medicine
Abstract
Amiodarone, an antiarrhythmic agent with a complex electrophysiologic, pharmacokinetic, and pharmacodynamic profile [1, 2], has been used for almost 20 years to treat serious cardiac rhythm disorders, particularly life-threatening ventricular tachyarrhythmias resistant to other antiarrhythmic agents. During this time, various cardiac and extracardiac amiodarone-related side effects have been described [3, 4]. Perhaps the most striking electrophysiologic effect of amiodarone is that it markedly prolongs the duration of the ventricular action potential, which results in a profound increase in refractoriness and in the duration of the QT interval in the surface electrocardiogram during long-term drug administration [2]. Drugs that prolong the QT interval are particularly known for their potential to provoke polymorphic ventricular tachycardia of the torsade de pointes type [5]. However, the magnitude of the problem of amiodarone-induced proarrhythmic effects and the incidence of these serious unwanted reactions have been reported to vary and to depend on the patient populations involved, dosages used, length of follow-up, and, importantly, the study design. Until recently, no randomized, placebo-controlled studies examining the riskbenefit ratio of amiodarone were available to assess the arrhythmogenicity of the drug, nor were there any systematic studies comparing amiodarone with other antiarrhythmic agents. Because of the concerns about the safety of antiarrhythmic drug therapy, primarily as a result of the Cardiac Arrhythmia Suppression Trial (CAST) findings [6, 7], it appeared appropriate to reevaluate the proarrhythmic potential of amiodarone. Clinicians and researchers now focus increasingly on the utility and safety of class III compounds [8]. The specific proarrhythmic reaction of class III drugs is the development of polymorphic ventricular tachycardia of the torsade de pointes type. Because amiodarone is increasingly recognized as the most potent antiarrhythmic compound, its proarrhythmic effect is of particular interest. We therefore examine the proarrhythmic potential of amiodarone, with particular reference to its ability to provoke torsade de pointes. Methods Our review is based on reports from the world literature that were available as of June 1993. An English-language literature search was done by weekly reviews of Current Contents: Clinical Practice, by a MEDLINE search covering the past 20 years, and by supplementary manual searches of references in review articles. Literature entries were selected by providing key words such as amiodarone, torsade de pointes, proarrhythmia, and aggravation of arrhythmia. We did not consider articles that did not provide an English summary. We excluded review articles and articles with incomplete data with regard to the nature of the arrhythmias treated or the amiodarone-associated proarrhythmic effects. Special effort was made to eliminate obvious duplications in reported studies. For this purpose, published abstracts were included in the analysis only when we found no full-length report by the same investigators. However, some overlap was inevitable because some centers published multiple, discrete reports. As suggested previously [9, 10], two investigators independently evaluated the methods and results sections of all trials. We specifically screened the articles for features such as patient demographics, entry criteria, methods, major study end points, and descriptions of long-term outcome and side effects. Reports with unclear descriptions of the methods used or of the efficacy or side effects of amiodarone were excluded from the analysis. Three categories of articles were evaluated separately: case reports, retrospective studies evaluating amiodarone in at least 50 consecutive patients with an average follow-up of at least 6 months, and prospective controlled trials with amiodarone. In the identified reports, electrocardiographically documented episodes of torsade de pointes, incessant ventricular tachycardia, and ventricular fibrillation (if not previously present) had been considered by the individual investigators to be amiodarone-induced proarrhythmic effects. We included all such events in our analysis. Increases in premature ventricular contractions of any magnitude were not counted as proarrhythmic reactions and thus were not included. Results Case Reports Although amiodarone has been used for almost two decades in Europe and since the early 1980s in the United States, we found only 65 case reports of amiodarone-induced torsade de pointes. Since Jorens and colleagues' published report of 59 such cases [11], 6 additional patients with this amiodarone-related proarrhythmic effect have been described [12-17]. Although no definite conclusions with respect to risk factors for the development of torsade de pointes can be drawn from such case reports, torsade de pointes did occur more frequently in women (62% of cases). Known predisposing factors for the occurrence of torsade de pointes, such as hypokalemia, were described in half the cases. Of particular interest is that 20% of the patients were receiving other antiarrhythmic drugs that prolonged the QT interval in addition to amiodarone. Thus, it is possible that torsade de pointes may have been provoked in at least some of these patients by combining class IA antiarrhythmic agents with amiodarone. Uncontrolled Studies Using the criteria described in the methods section, we selected 17 reports from the world literature that were published between 1982 and 1993 [18-34]. These studies involved 2878 patients treated with amiodarone for various types of arrhythmias. The most common presenting arrhythmia was sustained ventricular tachycardia or prehospital cardiac arrest caused by ventricular fibrillation in 2021 patients (70%) (Table 1). Most patients had coronary artery disease and a history of myocardial infarction. Dilated or hypertrophic cardiomyopathy was the next most frequently encountered diagnosis. In most of the patients, left ventricular function was depressed; these patients must therefore be considered as being at high risk for future arrhythmic events. Table 1. Overview of Observational Studies Reporting Data for Amiodarone-Induced Proarrhythmia* Cases of amiodarone-induced tachyarrhythmias considered to constitute proarrhythmic reactions were reported in 57 patients, or 2.0% of the total study population. The incidence of proarrhythmia ranged from 0% [20-22, 24, 26] to 7% [29] in the individual studies. The nature of the proarrhythmic events in 17 patients was not described (30%) (Table 1). In the remaining 40 patients, 15 (37.5%) developed torsade de pointes. In 8 patients (20% of patients with detailed information concerning the type of proarrhythmia), we considered the occurrence of ventricular fibrillation or the development of incessant ventricular tachycardia in patients with no history of this arrhythmia to be proarrhythmic events. Incessant ventricular tachycardia (n = 11) or sustained ventricular tachycardia (that is, when absent before amiodarone was given) other than torsade de pointes (n = 4) accounted for 37.5% of all described proarrhythmic effects. Controlled Studies As of June 1993, the results from seven prospective, placebo-controlled studies had been reported either in full-length articles [35-40] or in abstract form [41] (Table 2). Most patients enrolled in these studies were patients with a history of coronary artery disease and remote myocardial infarction. In these trials, the incidence of amiodarone-induced proarrhythmia was 0%. In addition, in an ongoing placebo-controlled Veterans Affairs trial involving patients with congestive heart failure caused by coronary artery disease or dilated cardiomyopathy, no proarrhythmic events were observed in 674 patients (half of whom received amiodarone) completing the enrollment phase (Singh BN. Personal communication). Table 2 Summary of Placebo-Controlled Amiodarone Trials* Amiodarone in Patients with Previous Drug-Induced Torsade de Pointes Three published reports describe the use of amiodarone in patients with previously documented torsade de pointes induced by antiarrhythmic agents [42-44]. In these studies, data have been reported for 32 patients who were considered to need continued antiarrhythmic drug therapy after recovering from torsade de pointes induced by other antiarrhythmic drugs. Most of these patients (66%) presented with a history of sustained ventricular tachycardia or ventricular fibrillation (Table 3). Torsade de pointes has been observed during initial treatment with class I agents (17 patients with quinidine [53%], 10 with procainamide (31%), and 2 with disopyramide [6%]) or class III compounds (3 patients with sotalol [10%]). During subsequent long-term amiodarone treatment that lasted from 1 to 46 months, one sudden cardiac death occurred. Neither recurrent episodes of torsade de pointes nor a different ventricular tachyarrhythmia were reported in any of the remaining patients. In these patients, the amiodarone-induced average prolongation of the QT interval was of the same magnitude as that observed when torsade de pointes developed while patients received other drugs in all three studies. Table 3. Studies Evaluating the Use of Amiodarone in Patients with Previous Drug-Mediated Torsade de Pointes* Discussion Because of the CAST trials [6, 7, 45, 46] and, more recently, the Electrophysiologic Study versus Electrocardiographic Monitoring [47] and the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation trials (CASCADE) [48], there is an increasing focus on the development of antiarrhythmic compounds [8] either as pure class III agents [49] or as those associated with antisympathetic actions producing substantial heart rate slowing (for example, sotalol). The use of these agents is associated with a particular incidence of proarrhythmic reactions, especially torsade de pointes, the pre