Is amiodarone safe in heart failure?
Authors: Michele Coceani, Rita Mariotti
Journal: BMJ (2006)

Is amiodarone safe in heart failure?Recent trials do not provide a definite answer H eart failure is a complex clinical syndrome that may lead to sudden cardiac death.Several trials have studied whether the antiarrhythmic agent amiodarone reduces such mortality in heart failure, 1 and two trials in particular have been at the centre of the debate: GESICA and CHF-STAT.In the GESICA trial, treatment with amiodarone was associated with reduced mortality, but the study was carried out in Argentina, with its genetically distinct population, where conditions other than a prior myocardial infarction-for example, Chagas disease-may be associated with heart failure.Therefore, caution should be used in extending the results to North American and European settings.Furthermore, GESICA was not blinded, and results, including an exceedingly optimistic 3% dropout rate, might have been affected by a treatment bias. 1 The CHF-STAT trial was placebo controlled, and more than 70% of the participants had heart failure of ischaemic origin.Despite the beneficial effect of amiodarone on left ventricular systolic function in this trial, the drug had no impact on survival.The conflicting results of the GESICA and CHF-STAT trials have been attributed to differences in the participants' severity of disease. 1 Patients in the GESICA study presented with advanced heart failure, and this may have increased the chance that amiodarone would reduce mortality.This explanation does, however, not accord with the results of the recently published SCD-HeFT trial, 2 which, besides having confirmed the importance of implantable cardioverter defibrillators in preventing sudden cardiac death, reported a significant increase in mortality among patients with New York Heart Association class III, but not class II, heart failure in the group treated with amiodarone.In addition, the trial found no association between aetiology of heart failure and outcome in the amiodarone arm of SCD-HeFT.This contradicts the findings of GESICA and CHF-STAT, that amiodarone provides greater benefit in non-ischaemic than in ischaemic cardiomyopathies. 1 The SCD-HeFT trial had good statistical power, with 2521 patients followed up for a median of 3.8 years.GESICA and CHF-STAT, on the other hand, enrolled 1190 patients combined, and both trials lasted only two years.Subgroup analysis may be misleading, but can the seemingly adverse action of amiodarone observed in SCD-HeFT really be dismissed?The answer to this question may be found by analysing the factors that may underlie any such undesired outcome.Amiodarone interferes with ion channels for sodium, potassium, and calcium as well as with and adrenergic receptors.These actions lead to diverse electrophysiological effects, including reduced automatism and decreased conduction velocity.Amiodarone's pharmacodynamics, with an exceedingly large distribution volume leading to accumulation in the myocardium, may also play a part.Bradyarrhythmias could ensue, leading to sudden cardiac death in advanced heart failure. 3miodarone has been associated with tachyarrhythmias as well, such as torsades de pointes, 4 which