Amiodarone Therapy

Ventricular arrhythmias are common in HF patients, and sudden cardiac death continues to account for a significant proportion of the mortality in this syndrome. Sudden death in HF may arise from a variety of causes, including bradyarrhythmias, conduction disturbances, electromechanical dissociation, acute MI, or pulmonary embolus. However, the majority of these deaths are thought to be due to ventricular tachyarrhythmias. Therefore, there has been considerable interest in the potential role of antiarrhythmic drug therapy in patients with HF.155 Randomized, placebo controlled trials of antiarrhythmic drug therapy for ventricular arrhythmias or atrial fibrillation has not been shown to improve survival in HF.5,155-157 The frequency of ambient ventricular ectopic activity is a marker for disease severity. Suppression of ventricular ectopy with amiodarone does not improve survival.155,157 Many antiarrhythmic drugs have adverse hemodynamic effects sufficient to have negative consequences in patients with HF. Patients with HF are at higher risk for proarrhythmic effects of antiarrhythmic agents. The major role for the use of these agents in HF is to reduce recurrences of symptomatic arrhythmias, usually in patients who have an implanted cardioverter defibrillator (ICD).158

Amiodarone blocks multiple cardiac ionic currents and has activity against ventricular and atrial arrhythmias, as well as slowing the sinus rate and the ventricular response to atrial fibrillation. Bradycardia is the major proarrhythmic effect, but the potential for multiple noncardiac toxicities (pulmonary, thyroid, liver, neurologic) require ongoing monitoring, and multiple potential drug interactions often require consideration. Amiodarone therapy has not been shown to improve mortality in randomized placebo controlled trials.155,157 The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) tested the hypothesis that either amiodarone or an ICD, or both, improve survival compared with placebo in patients with NYHA Class II or III HF and LVEF <35% of ischemic or nonischemic etiology.155 A total of 2521 patients were randomly assigned to ICD, amiodarone, or placebo. The patients were well treated: 87% were on ACE inhibitors or ARBs and 78% were on beta blockers at last follow-up. ICD, but not amiodarone improved mortality compared to placebo (Section 9).

Amiodarone was compared to placebo in a smaller double-blind, randomized trial that enrolled 674 patients with a mean age of 66 years. The majority (56%) had NYHA class II symptoms, and their mean LVEF = 26%.157 No differences were observed in all-cause or cardiac mortality or sudden death rates between the amiodarone and placebo groups. Another small randomized trial did suggest a beneficial effect of amiodarone, but there were significant limitations in the design and conduct of this trial. Treatment assignment was randomized, but not double-blind or placebo-controlled. The trial was discontinued prematurely when a 28% reduction was observed in all-cause mortality, the primary endpoint. Although not strictly involving HF patients, 2 post-MI trials found no benefit of amiodarone on mortality.159,160

A retrospective analysis of the COMET trial evaluated mortality among patients receiving amiodarone at baseline.161 Patients who were treated with amiodarone at baseline had a higher risk of death due to circulatory failure during follow-up than those who did not receive amiodarone, irrespective of functional class (HR 2.4, 95% CI 1.9-3.1, P<.001). Amiodarone was not associated with an increased risk of sudden death in this analysis.161

Amiodarone has significant long term toxicities, including lung, liver, and thyroid toxicity such that periodic monitoring is required during long term therapy. The most common cardiac adverse effect is bradycardia which can be potentiated by beta-adrenergic blockers. Bradycardia may also increase RV pacing from defibrillators which may have an adverse hemodynamic effect in some patients. Whether these effects contributed to the increased mortality observed in the subgroup of patients with more severe (NYHA Class III) HF in SCD-HeFT is not known.

Therapy with Vaughn Williams Class I drugs (quinidine, disopyramide, mexiletine, flecainide, propafenone) should be avoided. Flecainide has been shown to increase mortality when administered to patients with prior MI.162 These agents have been linked to increased mortality in HF patients with atrial fibrillation.163 Potential adverse effects can include a negative inotropic effect of sodium channel blockade and proarrhythmic effects. The Class III potassium channel blocking agents sotalol and dofetilide have not been shown to improve mortality in HF and are associated with a risk of proarrhythmia (most often the polymorphic ventricular tachycardia torsade de pointes, associated with QT prolongation). Impaired renal function that reduces excretion of these drugs and diuretic induced hypokalemia increase the proarrhythmia risk. The d-isomer of sotalol (d-sotalol) increased mortality in survivors of MI.164 A randomized trial of dofetilide in patients with ventricular dysfunction found no benefit on mortality, although hospitalizations were reduced, possibly due to decreased atrial fibrillation.165 A significant incidence of torsade de points was noted, despite precautions to exclude patients with renal insufficiency and other risk factors for QT prolongation.

Dronedarone blocks multiple cardiac ionic currents, and it has been shown to have activity to reduce atrial fibrillation and to reduce the ventricular response in atrial fibrillation when it recurs. Efficacy appears to be less than for amiodarone.166 It reduces tubular secretion of creatinine, increasing serum creatinine. A study in patients with HF and LVEF <35% was terminated early due to an two fold increased mortality in patients treated with dronedarone.167 The FDA approval states that dronedarone is contraindicated in patients with Class IV HF or those with Class II or III HF who have had a recent HF decompensation.

Amiodarone therapy modifies the pharmacokinetics of a number of drugs commonly used in patients with HF. In particular, it may substantially enhance the actions of digoxin and warfarin, with the definite potential of adverse clinical consequences. In general, the digoxin dose should be reduced by half, but follow-up determination of SDC is desirable to ensure a concentration of 0.5-0.9 ng/mL. The warfarin dose should be adjusted to maintain the INR target for the individual patient. Even after amiodarone is discontinued, these pharmacokinetic interactions can persist for months due to its long half-life. Since amiodarone also has beta-blocking properties, substantial bradycardia may occur with this combination of drugs. Amiodarone is not recommended for asymptomatic arrhythmias or those not causing HF due to the multiple drug-drug interactions and the serious side effect profile.