Amiodarone appears to be effective in the management of a wide variety of ventricular as well as supraventricular arrhythmias. Because of amiodarone's potentially life-threatening adverse effects and the management difficulties associated with its use, the drug previously was not considered a first-line antiarrhythmic but generally was reserved for use in life-threatening ventricular arrhythmias. The drug also was used infrequently for the suppression or prevention of any type of arrhythmia and only when conventional antiarrhythmic therapy was considered ineffective or was not tolerated. However, amiodarone generally appears to exhibit greater efficacy and a lower incidence of proarrhythmic effects than class I or other class III antiarrhythmic drugs and therefore has become a mainstay in the management of various tachyarrhythmias, including expert recommendations for advanced cardiovascular life support (ACLS), despite labeling that continues to recommend more limited use. In addition, although no antiarrhythmic agent given routinely during cardiac arrest has been shown to increase survival to hospital discharge, amiodarone has been shown to increase short-term survival to hospital admission relative to lidocaine or placebo. Amiodarone should be used only by clinicians who are familiar with and have access to, either directly or through referral, the use of all currently available modalities for the management of recurrent life-threatening ventricular arrhythmias and who have access to appropriate evaluative and monitoring procedures, including continuous ECG monitoring and electrophysiologic techniques for evaluating the patient in both ambulatory and hospital settings.
Amiodarone is used orally or IV to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents are not tolerated. Amiodarone is designated an orphan drug by the FDA for use in this condition. Amiodarone may be used IV to treat patients with ventricular tachycardia or fibrillation in whom oral amiodarone therapy is indicated, but who are unable to take oral medication.
It is difficult to assess the overall efficacy of amiodarone since response to the drug depends on many factors, including the specific cardiac arrhythmia being treated, the criteria used to evaluate efficacy, the presence of underlying cardiac disease in the patient, the number of antiarrhythmic agents used prior to amiodarone, the duration of follow-up, and the concomitant use of other antiarrhythmic agents. In addition, overall arrhythmia recurrence rates (fatal and nonfatal) appear to be highly variable and depend on many factors, including response to programmed electrical stimulation (PES) or other measures, and whether patients who do not appear to respond initially are included. When considering only those patients who responded well enough to amiodarone to be placed on long-term treatment, ventricular arrhythmia recurrence rates have ranged from 20-40% in most studies having an average follow-up period of 1 year or longer.
Life-Threatening Ventricular Arrhythmias and Advanced Cardiovascular Life Support
There is relatively limited experience from controlled studies with the use of amiodarone for suppression and prevention of recurrent life-threatening ventricular arrhythmias. Although comparative data are lacking, the efficacy of amiodarone in the management of severe refractory arrhythmias generally is considered to be at least comparable to and probably better than that of other antiarrhythmic agents (e.g., quinidine, procainamide). Data from most clinical studies indicate that the drug is effective in approximately 50-80% of patients with life-threatening ventricular arrhythmias, including those refractory to other antiarrhythmic agents. Previously, the potential severity of the drug's adverse effects generally had precluded amiodarone from being considered a first-line agent in the management of life-threatening ventricular arrhythmias, and use of the drug generally was reserved for patients in whom other antiarrhythmic agents were ineffective or not tolerated. Currently, however, amiodarone is considered a preferred or alternative agent for the management of various life-threatening ventricular arrhythmias, in part because of comparable or better efficacy and its apparent reduced risk of proarrhythmic activity.
Shock-Resistant Ventricular Fibrillation or Pulseless Ventricular Tachycardia
Amiodarone is used as adjunctive therapy for the treatment of ventricular fibrillation or pulseless ventricular tachycardia resistant to cardiopulmonary resuscitation (CPR), defibrillation, and a vasopressor (e.g., epinephrine).
Antiarrhythmic drugs are used during cardiac arrest to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in patients with refractory (i.e., persisting or recurring after at least one shock) ventricular fibrillation or pulseless ventricular tachycardia; however, there is no evidence that these drugs increase survival to hospital discharge when given routinely during cardiac arrest. High-quality CPR and defibrillation are integral components of ACLS and the only proven interventions to increase survival to hospital discharge. Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation. The principal goal of pharmacologic therapy during cardiac arrest is to facilitate return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use. If an antiarrhythmic agent is needed for the treatment of refractory ventricular fibrillation or pulseless ventricular tachycardia during adult cardiac arrest, the American Heart Association (AHA) recommends amiodarone as the first-line drug of choice because of its proven benefits in improving rates of ROSC and hospital admission; lidocaine may be used as an alternative. Results of several studies suggest that amiodarone is more effective than lidocaine in improving rates of ROSC and hospital admission in patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. In pediatric advanced life support (PALS), current evidence supports the use of either amiodarone or lidocaine for these arrhythmias.
Results of a randomized, double-blind, placebo-controlled study in patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias (i.e., ventricular fibrillation, pulseless ventricular tachycardia) who received a single 300-mg dose of IV amiodarone hydrochloride (after at least 3 precordial electrical shocks were administered) indicate that the drug improved the rate of survival to hospital admission by 29%. In a randomized, double-blind, comparative study with lidocaine, approximately 23% of patients with out-of-hospital cardiac arrest due to defibrillation-refractory ventricular arrhythmias who received IV amiodarone hydrochloride (5 mg/kg) or its matching placebo survived to hospital admission compared with 12% of those who received IV lidocaine (1.5 mg/kg) or its matching placebo following at least 3 precordial electrical shocks, IV epinephrine, and an additional precordial electrical shock. Among patients for whom the time from dispatch of the ambulance to the administration of the drug was equal to or less than the median time (24 minutes), approximately 28% of those given amiodarone and 15% of those given lidocaine survived to hospital admission. Despite these results, only about 5% of patients receiving IV amiodarone who survived to hospital admission lived to be discharged from the hospital compared with about 3% of those receiving IV lidocaine. Evidence supporting the use of amiodarone and lidocaine in pediatric cardiac arrest is more limited and principally based on extrapolation of data from the adult population. In a retrospective cohort study that included data from 889 pediatric patients with in-hospital cardiac arrest, improved ROSC was observed with lidocaine compared with amiodarone. Neither drug was associated with improved survival to hospital discharge.
IV amiodarone also may be used for the treatment of regular wide-complex tachycardias during the periarrest period and is included as a recommended antiarrhythmic agent in current ACLS guidelines for both adult and pediatric tachycardia.
Monomorphic and Polymorphic Ventricular Tachycardia
Some experts recommend that sustained monomorphic ventricular tachycardia not associated with angina, pulmonary edema, or hypotension (blood pressure less than 90 mm Hg) be treated with amiodarone or synchronized electrical cardioversion. Other experts recommend amiodarone for control of hemodynamically stable monomorphic ventricular tachycardia. Drug regimens including amiodarone or procainamide may be used initially for the treatment of patients with episodes of sustained ventricular tachycardia that are associated with myocardial infarction and somewhat better tolerated hemodynamically. If IV antiarrhythmic therapy is used for ventricular fibrillation or tachycardia, it probably should be discontinued (at least temporarily) after 6-24 hours so that the patient's ongoing need for antiarrhythmic drugs can be reassessed.
Amiodarone also may be used for the treatment of polymorphic (irregular) ventricular tachycardia associated with myocardial ischemia in the absence of QT interval prolongation. Although rare, episodes of drug-refractory sustained polymorphic ventricular tachycardia (electrical storm) have been reported in cases of acute myocardial infarction. Some experts state that these episodes should be managed by aggressive attempts at reducing myocardial ischemia, including therapies such as an IV β-adrenergic blocking agent, IV amiodarone, left stellate ganglion blockade, intra-aortic balloon counterpulsation (IABP), or emergency revascularization (percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft [CABG] surgery); IV magnesium also may be used. Polymorphic ventricular tachycardia associated with QT interval prolongation usually is treated with IV magnesium sulfate.
Prevention of Ventricular Arrhythmias and Death Associated with Cardiac Arrest
Oral amiodarone has been used for primary prevention of sustained ventricular tachycardia (i.e., ventricular tachycardia lasting greater than 30 seconds and/or associated with hemodynamic compromise), ventricular fibrillation, or sudden cardiac death in patients with nonsustained ventricular arrhythmia following myocardial infarction. Such use of the drug was once thought to prevent sudden cardiac death because ventricular premature complexes (VPCs) were believed to be harbingers of more serious ventricular arrhythmias (e.g. ventricular fibrillation or tachycardia). However, conflicting results have been reported in studies evaluating the efficacy of antiarrhythmic agents on the risk of sudden death from cardiac causes in post-myocardial infarction patients.
Results of 2 multicenter, randomized, placebo-controlled studies in patients with frequent or repetitive ventricular premature complexes (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT]) or with left ventricular dysfunction (European Myocardial Infarct Amiodarone Trial [EMIAT]) indicate that therapy with oral amiodarone in patients who had survived a recent myocardial infarction appeared to reduce resuscitated cardiac arrest or ventricular fibrillation or arrhythmic death but was not associated with reduction of total mortality after 1-2 years of follow-up. These data are consistent with results of pooled analysis of small controlled trials in patients with structural heart disease, including post-myocardial infarction patients. However, in a smaller study (Basel Antiarrhythmic Study of Infarct Survival [BASIS]) comparing amiodarone with usual care in patients with persisting asymptomatic complex arrhythmias (multiform or repetitive ventricular arrhythmias [Lown class 3 or 4b]) after acute myocardial infarction, long-term therapy with amiodarone was associated with a reduction in mortality at 1 year compared with no antiarrhythmic therapy, possibly as a result of a decreased incidence of sudden death from ventricular tachycardia and fibrillation. In addition, analysis of pooled data from several other randomized studies in patients at risk of sudden cardiac death (e.g., those with congestive heart failure or left ventricular dysfunction, recent myocardial infarction, prior cardiac arrest) suggested that amiodarone therapy may reduce total mortality by 10-19%, and such risk reduction associated with the drug may be similar in the mentioned patient populations.
Findings from the National Heart, Lung, and Blood Institute (NHLBI)'s Cardiac Arrhythmia Suppression Trial (CAST) study indicated a substantially increased rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild to moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent VPC) who received encainide or flecainide (class I antiarrhythmic drugs) compared with placebo after an average of 10 months of follow-up, which resulted in considerably modified clinicians' use of not only class IC antiarrhythmics, but also class I antiarrhythmic agents in general, in post-myocardial infarction patients. Although it has been suggested that the applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or to predominantly class III antiarrhythmic agents such as amiodarone (a drug that has some characteristics of class IA and IC antiarrhythmic agents) is uncertain, the American College of Cardiology (ACC) and AHA state that β-adrenergic blocking agents are preferred over amiodarone for general prophylaxis. In addition, results of prospective, randomized clinical studies indicate improved survival following use of implantable cardioverter defibrillator (ICD) therapy compared with conventional drug therapy, including amiodarone, in patients with nonsustained ventricular tachycardia, reduced ejection fraction (less than 40%), and/or a history of myocardial infarction. However, preliminary reports suggest that only a small proportion of patients with a previous myocardial infarction would benefit from ICD therapy and it remains unclear whether routinely screening patients with impaired left ventricular function for prophylactic ICD therapy is clinically feasible and cost-effective.
Amiodarone hydrochloride is used orally or IV to suppress or prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., recurrent ventricular fibrillation and recurrent, hemodynamically unstable ventricular tachycardia) that do not respond to documented adequate dosages of other currently available antiarrhythmic agents or when alternative antiarrhythmic agents cannot be tolerated. The effectiveness of IV amiodarone in suppressing recurrent ventricular fibrillation or hemodynamically unstable (destabilizing) ventricular tachycardia is supported by 2 randomized, parallel, dose-response studies of approximately 300 patients each. In patients with recurrent ventricular fibrillation or destabilizing ventricular tachycardia that was refractory to first-line (e.g., lidocaine) therapy, amiodarone produced a dose-dependent decrease in arrhythmia recurrence, although not in mortality. Patients with at least 2 episodes of ventricular fibrillation or hemodynamically unstable ventricular tachycardia within the preceding 24 hours were randomly assigned to receive IV amiodarone hydrochloride doses of 125 mg or 1 g over 24 hours; one study also evaluated a dose of 500 mg. After 48 hours, patients were eligible to receive open access to any treatment deemed necessary (including IV amiodarone) to control their arrhythmias. Amiodarone was administered in a 3-phase sequence, with an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and a subsequent 18-hour maintenance infusion. Maintenance infusion was continued up through hour 48. Additional supplemental 10-minute infusions of 150 mg were administered for breakthrough arrhythmias; these occurred more frequently in patients receiving the 125-mg dosage regimen. Fewer patients receiving the 1-g IV amiodarone hydrochloride regimen required supplemental infusions. During treatment with IV amiodarone, median episodes of ventricular tachycardia or ventricular fibrillation were 0.02/hour in the group receiving the 1-g dosage regimen and 0.07/hour in the group receiving the 125-mg dosage regimen, or approximately 0.5 versus 1.7 episodes daily in patients receiving the 1-g versus 125-mg dosage regimen, respectively. In one study, the time to first episode of ventricular tachycardia or ventricular fibrillation was approximately 10 or 14 hours in patients receiving the 125- or 1000-mg amiodarone hydrochloride dosage regimens, respectively. Mortality rate was not affected by treatment in either of these studies.
Because there has been no evidence of improved survival with use of antiarrhythmic agents, including amiodarone and β-adrenergic blocking agents, whereas such evidence does exist for ICD therapy, ICDs have increasingly been used in the secondary prevention of life-threatening ventricular arrhythmias. In comparative studies, ICD therapy has been shown to be superior to antiarrhythmic drugs, principally amiodarone, for increasing overall survival of patients who had been resuscitated from near-fatal ventricular fibrillation or sustained ventricular tachycardia. Analysis of pooled data indicates that ICD therapy prolongs life by 2.1 or 4.4 months compared with amiodarone after a follow-up period of 3 or 6 years, respectively. Subgroup analysis of patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study indicates that patients with an isolated episode of ventricular fibrillation in the absence of cerebrovascular disease or history of prior arrhythmia who have undergone revascularization or who have moderately preserved left ventricular function (i.e., left ventricular ejection fraction greater than 27%) are not likely to benefit from ICD therapy compared with amiodarone therapy. However, results of this analysis must be considered speculative because the specific criteria used in defining the subgroups were not planned prior to collection of data, and additional studies are needed to verify these findings.
Prediction of the efficacy of any antiarrhythmic agent in the long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial. Many authorities currently recommend the use of ambulatory ECG monitoring, programmed electrical stimulation (PES), or a combination of both to assess patient response to amiodarone. There is no consensus on many aspects of how best to assess patient response to the drug; however, there is reasonable agreement on some aspects. If a patient with a prior history of cardiac arrest does not manifest a hemodynamically unstable arrhythmia during ECG monitoring prior to treatment, some provocative approach such as exercise or PES is required to assess the efficacy of amiodarone. The need for provocation in patients who do manifest life-threatening arrhythmias spontaneously remains to be established, although there are reasons to consider PES or other means of provocation in such patients. In patients whose PES-induced arrhythmia is made noninducible by amiodarone, the prognosis is almost uniformly excellent, with very low rates of arrhythmia recurrence or sudden death. The meaning of continued inducibility during therapy with the drug is controversial. Although not clearly established, increased difficulty of arrhythmia induction by PES and/or the ability to tolerate the induced ventricular tachycardia without severe symptoms may be useful criteria for identifying patients who may benefit from amiodarone therapy despite continued inducibility of the arrhythmia during therapy with the drug. Generally, easier inducibility or poorer tolerance of the induced arrhythmia should suggest consideration of the need to revise treatment. Other criteria for predicting the efficacy of amiodarone therapy, including complete suppression of nonsustained ventricular tachycardia determined by ambulatory ECG monitoring and the documentation of very low rates of VPCs, also have been suggested. These issues remain unsettled for amiodarone as well as for other antiarrhythmic agents. Specialized references should be consulted for additional information.
Combination Antiarrhythmic Regimens
Amiodarone has been used in combination with numerous other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias; however, such combination therapy has not been evaluated in well-controlled studies and is associated with an increased risk of adverse cardiovascular effects.
(See Drug Interactions: Antiarrhythmic Agents.)
Other Ventricular Arrhythmias
Amiodarone has been used with good results in a limited number of patients experiencing life-threatening ventricular arrhythmias associated with post-infarction aneurysm or with chronic myocarditis induced by Chagas' disease. IV amiodarone has been used with some success in a limited number of patients for the management of ventricular tachycardia and ventricular fibrillation associated with cardiac glycoside intoxication.
Amiodarone appears to be effective in the suppression and prevention of various supraventricular tachycardias (SVTs); because of a higher risk of toxicity and proarrhythmic effects, antiarrhythmic agents generally should be reserved for patients who do not respond to or cannot be treated with AV nodal blocking agents (β-adrenergic blocking agents and nondihydropyridine calcium-channel blocking agents). Some experts state that amiodarone may be useful in situations where ventricular rate control is needed but AV nodal blocking agents are contraindicated, such as in patients with preexcited atrial arrhythmias associated with an accessory pathway. However, IV amiodarone is potentially harmful when used for the acute treatment of patients with preexcited atrial fibrillation since it has the potential to accelerate the ventricular response and precipitate fatal arrhythmias.
Atrial Fibrillation and Flutter
Amiodarone has been used orally and IV in the management of atrial fibrillation or flutter.
Amiodarone is one of several antiarrhythmic agents that may be used to maintain sinus rhythm in patients with atrial fibrillation or flutter. Long-term therapy with oral amiodarone alone or in combination with other antiarrhythmic agents has been effective for suppression and prevention of refractory atrial fibrillation. Limited data indicate that long-term amiodarone therapy may be effective in about 70% (range: 35-95%) of patients with atrial fibrillation, including those whose arrhythmia is refractory to conventional therapy. Although not clearly established, the efficacy of amiodarone in the suppression of atrial fibrillation may result from the drug's ability to maintain normal sinus rhythm (probably by increasing atrial refractoriness), suppress atrial premature complexes (which may precipitate atrial fibrillation), and control ventricular rate. There is some evidence that amiodarone may be substantially more effective than sotalol or propafenone for long-term prevention of recurrent atrial fibrillation. Whether maintaining sinus rhythm in patients with recurrent atrial fibrillation will result in improved survival or a reduction in the risk of thromboembolic complications remains to be established.
Oral or IV amiodarone may be effective for conversion of atrial fibrillation to normal sinus rhythm (i.e., rhythm control). In current expert guidelines, amiodarone is considered a reasonable option for pharmacological conversion of atrial fibrillation; however, other antiarrhythmic agents (e.g., flecainide, dofetilide, propafenone, ibutilide) are preferred. IV amiodarone may be harmful, and therefore should not be used, in patients with Wolff-Parkinson-White (WPW) syndrome who have preexcited atrial fibrillation because the drug can accelerate ventricular rate and potentially cause life-threatening ventricular arrhythmias. Conversion of atrial fibrillation to normal sinus rhythm may be associated with embolism, particularly when atrial fibrillation has been present for more than 48 hours, unless the patient is adequately anticoagulated.
Further studies are needed to evaluate the comparative efficacy and safety of oral amiodarone, other antiarrhythmic agents, and cardioversion (direct-current countershock). Although cardioversion has been used safely and effectively following oral or IV amiodarone administration, decreased efficacy of cardioversion in patients receiving the drug has also been reported. Further studies are needed to evaluate the effect of amiodarone therapy on the efficacy of cardioversion.
Paroxysmal Supraventricular Tachycardia
Limited data suggest that IV amiodarone is effective in terminating paroxysmal supraventricular tachycardia (PSVT), including atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) (e.g., WPW syndrome). Some experts state that IV amiodarone may be considered for the acute treatment of hemodynamically stable patients with AVNRT when other therapies are ineffective or contraindicated. However, IV use of amiodarone can be potentially harmful in patients with preexcited atrial fibrillation because the drug may accelerate ventricular rate and cause life-threatening ventricular arrhythmias.
Long-term oral amiodarone therapy appears to be particularly effective in the suppression and prevention of paroxysmal reentrant supraventricular tachycardias (AVNRT and AVRT [e.g., WPW syndrome]) including those refractory to other antiarrhythmic agents. Some experts state that oral amiodarone may be reasonable for ongoing management of AVNRT or AVRT in patients who are not candidates for, or prefer not to undergo, catheter ablation and in whom first-line drugs (e.g., β-adrenergic blocking agents, diltiazem, verapamil) are not effective or contraindicated. Oral amiodarone also has been effective in some patients for the suppression and prevention of atrial fibrillation or flutter associated with WPW syndrome. Although amiodarone also has been used IV in such patients, IV use of the drug has resulted in acceleration of ventricular rate.
(See Cautions: Arrhythmogenic Effects.)
IV amiodarone may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and oral amiodarone may be reasonable for the ongoing management of such patients.
While evidence is more limited, amiodarone also has been used in patients with multifocal atrial tachycardia (i.e., rapid, irregular rhythm with at least 3 distinct P-wave morphologies). However, such arrhythmia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic therapy. Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity).
Amiodarone may be used for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia; however, efficacy data is available only for pediatric patients. β-Adrenergic blocking agents generally are considered the drugs of choice for terminating and/or reducing the incidence of junctional tachycardia.
Amiodarone has been effective in the prevention of supraventricular arrhythmias associated with bradycardia-tachycardia syndrome in a limited number of patients; however, the drug should be used with caution in such patients, since it may depress sinoatrial node function, possibly resulting in marked bradycardia. Some clinicians recommend insertion of a temporary or permanent artificial pacemaker prior to initiation of amiodarone therapy in patients with bradycardia-tachycardia syndrome.
Amiodarone has been used in a limited number of patients for the management of chronic stable angina pectoris. Limited data suggest that amiodarone is as effective as diltiazem and more effective than sublingual nitroglycerin in increasing exercise tolerance and decreasing ST-segment depression in patients with chronic stable angina pectoris. Amiodarone also has been used with good results in some patients with Prinzmetal variant angina. Because of the potential toxicity associated with amiodarone, the drug generally is not considered a first-line agent for the management of chronic stable angina pectoris or Prinzmetal variant angina but may have a beneficial antianginal effect in patients receiving the drug for the management of arrhythmias.
Amiodarone has been used with good results in some patients for the management of ventricular and supraventricular arrhythmias associated with hypertrophic cardiomyopathy. In addition to its antiarrhythmic effects, the drug may also relieve symptoms and increase exercise capacity in some patients, including those whose arrhythmias are refractory to conventional treatment. Pending further accumulation of data, some clinicians recommend that treatment with amiodarone be considered only in patients with refractory hypertrophic cardiomyopathy.