Over the past few years, emerging data have created much concern about the potential hazards of antiarrhythmic drugs. The Cardiac Arrhythmic Suppression Trial (CAST) [1, 2] reported the harmful effects of flecainide, encainide, and moricizine in patients with ventricular premature beats who had had myocardial infarction. Compared with placebo, flecainide, encainide, and moricizine were associated with increased mortality from sudden cardiac death. In an earlier, noncontrolled trial [3], mexiletine was also associated with a trend toward increased mortality. In meta-analyses of studies of quinidine as therapy for nonsustained ventricular tachycardia and prevention of atrial fibrillation [4, 5], drug therapy was associated with increased mortality when compared with placebo or with no therapy. Such studies have resulted in growing therapeutic nihilism on the part of many physicians.

In contrast to many antiarrhythmic drugs, amiodarone has been reported to be effective in several patient populations and is not associated with increased mortality. Although in the United States amiodarone is currently indicated only for life-threatening ventricular arrhythmias refractory to other agents, it is highly effective for the suppression and prevention of other arrhythmias [6-8]. Of concern, however, has been the toxicity associated with this agent. Many patients have some side effects, but these are generally mild; serious toxicity involving the liver, lungs, and thyroid is infrequent and can usually be predicted with close monitoring and careful follow-up. Unlike the other antiarrhythmic agents, amiodarone administered orally has resulted in only isolated reports of arrhythmia aggravation [9, 10]. This aggravation has usually occurred in patients with concomitant hypokalemia or in patients receiving another antiarrhythmic agent, particularly a class IA drug. No studies involving patients with arrhythmia have shown amiodarone to be associated with increased mortality. Therefore, in view of the growing concern about class I antiarrhythmic drugs, it seems reasonable that the benefits, risks, and therapeutic role of amiodarone be reassessed. Unfortunately, few well-controlled trials have compared amiodarone with placebo, other drugs, or nonpharmacologic therapy. Controlled trials are now in progress and should provide important data. However, in this paper, I review available data about the pharmacology, electrophysiology, and toxicity of amiodarone and discuss the use of this agent in the treatment of atrial fibrillation and flutter; the treatment of nonsustained ventricular tachycardia in patients with cardiomyopathy and congestive heart failure; the treatment of patients who have recently had myocardial infarction; and the prevention of recurrent sustained ventricular tachycardia and ventricular fibrillation.

Electrophysiologic Actions and Pharmacologic Properties

Amiodarone is a unique and complex drug that was originally used as an antianginal agent because it is a potent vasodilator and significantly slows heart rate [11]. Although it is still used for this purpose, especially in patients with refractory angina who are not candidates for revascularization [12], amiodarone has gained wider use as an antiarrhythmic agent [13] because of its various pharmacologic actions on the heart [14]. Its most important direct electrophysiologic effect is prolongation of the action potential duration and repolarization time; this prolongation results from inhibition of the potassium ion fluxes that normally occur during phases 2 and 3 of the action potential [15] and from prolongation of the refractory periods. These actions represent the class III activity of amiodarone and occur in all cardiac tissue. The increase in the duration of repolarization and refractoriness reduces membrane excitability; this reduction represents the antifibrillatory property of amiodarone. Most class III antiarrhythmic drugs have a property called "reverse-use dependency," which causes the action potential duration (QT interval or repolarization time) to become progressively shorter as heart rate increases. However, amiodarone does not have this property; the prolongation of repolarization time that amiodarone causes persists at higher heart rates [16]. Amiodarone is also a weak sodium channel blocker and, as a result of its class I antiarrhythmic activity, slows the upstroke velocity of phase 0 of the action potential [17]. This reduces the rate of membrane depolarization and impulse conduction. Amiodarone also directly depresses the automaticity of the sinus and atrioventricular nodes.

In addition to these direct antiarrhythmic effects, amiodarone has several important actions, including ß-blockade, that indirectly affect the electrophysiologic properties of the myocardium. Unlike blockade using the standard ß-blocking agents, amiodarone's blockade of the ß-adrenergic receptors is noncompetitive and results from inhibition of adenylate cyclase formation and from a reduction in the number of ß-adrenergic receptors [18]. Amiodarone also shows noncompetitive -blocking activity and inhibits the slow inward calcium-ion current. Lastly, it is possible that some antiarrhythmic actions of amiodarone result from its antithyroid effect: The drug interferes with thyroid metabolism and with the effects of thyroxin on the heart [19]. It is important to note that amiodarone contains two iodine molecules and that 37.5% of the drug's weight is iodine (75 mg iodine/200 mg amiodarone).

Hemodynamic Effects

Because of its numerous pharmacologic actions, amiodarone causes many important hemodynamic effects [14, 20]. As a result of its direct effect on smooth muscle and its calcium channel and -adrenergic receptor blockade, amiodarone dilates coronary arteries and increases coronary blood supply. It also causes peripheral arterial vasodilation and decreases systematic blood pressure and afterload. Amiodarone has mild direct negatively inotropic actions and reduces the force of myocardial contraction; however, this is offset by the drug's peripheral vascular effects, primarily afterload reduction, and stroke volume and cardiac output are generally maintained [20]. As previously indicated, the drug slows the sinus rate through direct effects on automaticity, antisympathetic action, and inhibition of slow inward calcium-ion currents. The hemodynamic properties of amiodarone make it understandable that the drug was first used as an antianginal agent.

Pharmacokinetics

The gastrointestinal absorption of amiodarone is slow and incomplete: A peak serum level is achieved 4 to 7 hours after an oral dose is received [21]. Only 50% of the administered dose is bioavailable because of first-pass intestinal mucosal and hepatic metabolism as well as incomplete absorption. Amiodarone is highly protein- and lipid-bound and is widely distributed throughout all adipose tissue [22]. As a result of the drug's avid affinity for adipose tissue, the estimated volume of distribution is 50 L, and approximately 15 g are necessary to saturate these large body stores. For these reasons, a long and variable loading period is necessary before antiarrhythmic activity is apparent.

Clearance of amiodarone involves deiodination, but the major route of elimination is by hepatic metabolism to one principal metabolite, desethyl-amiodarone, which has antiarrhythmic activity equivalent to that of the parent drug [23]. It has been reported that a serum concentration of at least 1 to 2 µg/mL is necessary for drug efficacy, but there is wide interpatient variability in the dose-concentration relation and in levels associated with efficacy or toxicity. Therefore, amiodarone levels in the blood have limited clinical usefulness. The elimination half-life of amiodarone is also highly variable but long, ranging from 16 to 180 days (mean, 52 days), because of the drug's extensive storage and avid binding to poorly perfused adipose tissue [22].

Because of the unique pharmacokinetic properties of amiodarone, the onset of the drug's action is delayed and may not be apparent for as long as 3 months. When administered orally, a loading dose of the drug is required. The dose used depends on the arrhythmia being treated, the need to achieve efficacy more quickly, and the occurrence of side effects, some of which are associated with higher doses. For the treatment of ventricular tachyarrhythmias, a recommended dosing schedule is 1200 to 1800 mg/d for 1 to 2 weeks, then 800 mg/d for 2 to 4 weeks, then 600 mg/d for 1 month, and 200 to 400 mg/d thereafter. For the treatment of supraventricular arrhythmia, the initial dose is 600 to 800 mg/d for 4 weeks, 400 mg/d for 2 to 4 weeks, and 200 mg/d thereafter. However, the actual duration of loading and the optimal dose used vary for individual patients and depend on efficacy and toxicity.

Although not yet approved for use in the United States, an intravenous preparation of amiodarone may be helpful for the acute management of life-threatening ventricular arrhythmias, especially when other intravenous therapies have failed [24, 25]. The drug is administered as a rapid infusion of 5 mg/kg body weight over 15 to 30 minutes and is followed by 1 g/24 h thereafter. Although there are no absolute guidelines for predicting the onset of drug activity or the time required for evaluating its effect, the onset of typical electrocardiographic changes associated with amiodarone is helpful. These changes include sinus bradycardia, lengthening of the PR interval, prolongation of the QT interval, and development of a prominent U wave not associated with hypokalemia.

Toxicity

Amiodarone is a highly effective antiarrhythmic agent, but it is associated with many side effects involving many different organ systems [26, 27]. Although as many as 80% of patients have some side effects, only 10% to 15% of patients require withdrawal of the drug because of serious or disturbing toxicity. The mechanism of toxicity is multifactorial and may result from the accumulation of substances such as iodine or amiodarone itself; the development of cellular phospholipidosis secondary to phospholipase inhibition; the formation of free radicals; altered cellular function; or immunologic injury [28]. Most side effects are not dose-related and occur only after weeks or months of therapy, as a result of the pharmacologic properties of amiodarone. It has been observed that the incidence of side effects increases over time and, therefore, that many side effects may be related to the total dose administered or the total dose given over time, that is, to the amount of drug that has accumulated.

Cardiovascular Toxicity

Signs of cardiovascular toxicity include accentuation of the normal electrophysiologic actions of the drug, specifically sinus bradycardia; conduction abnormalities in the atrioventricular node; and heart block. Because amiodarone has negatively inotropic actions, congestive heart failure may occur; the reported incidence of congestive heart failure in patients treated with amiodarone is 2% to 3%. When amiodarone is given intravenously, hypotension unrelated to dose is seen in about 28% of patients [24, 25]. Like all antiarrhythmic drugs, amiodarone can aggravate arrhythmia; this is reported in 3% to 5% of patients [29]. However, because of the long time course of drug action, it may be difficult to distinguish between the natural history of the underlying cardiac disease and the arrhythmia and a drug-related aggravation of arrhythmia. Although amiodarone markedly prolongs the QT interval, torsade de pointes is an infrequent complication and is most often reported in association with hypokalemia or with concomitant therapy using a class IA drug, especially quinidine [9, 10]. Amiodarone may increase the threshold energy for defibrillation or cardioversion; this is especially important when an implantable defibrillator is present [30].

Pulmonary Toxicity

The most serious noncardiac side effect of amiodarone is pulmonary toxicity, which has been reported in as many as 15% of patients, although the overall incidence is about 6% to 8% [26]. The pathogenesis of this toxicity is multifactorial but may be dose-related and appears to be more common in patients with underlying lung disease. Pulmonary toxicity may occur within the first few weeks of therapy and presents with an acute onset of nonspecific symptoms, including fever, shortness of breath, and cough, which are probably symptoms of a hypersensitivity reaction to the drug and are associated with an eosinophilic lung infiltrate. More common is a delayed pulmonary reaction occurring after several months or years of therapy. This reaction is generally insidious in onset and associated with nonspecific cough, fatigue, low-grade fever, and shortness of breath, or it may be more acute, presenting with respiratory failure [31]. Chest radiographs show diffuse monocellular infiltrates or diffuse and extensive pulmonary fibrosis. Pleural effusions may also be present. This toxic response has been confused with congestive heart failure and pneumonia, and, if the correct diagnosis is missed or delayed, respiratory failure and death can occur. Although discontinuation of amiodarone therapy is mandatory, pulmonary toxicity can persist for weeks or months and may actually initially progress as a result of the large stores of the drug in the body, the drug's long half-life, and the prolonged time needed for elimination. Steroids may increase the rate of resolution [32]. Unfortunately, pulmonary function tests are not predictive of pulmonary toxicity because their results are almost always abnormal in patients receiving amiodarone. Most often seen is a reduced diffusion capacity similar to that of a restrictive lung disease. The chest radiograph is the best screening technique for this complication.

Thyroid Abnormalities

Abnormalities of the thyroid occur in 30% of patients [26]; this is not unexpected because amiodarone has substantial iodine content. The drug interferes with the conversion of thyroxine to triiodothyronine, which is the active form of thyroxin [19]. The abnormalities are usually minor, particularly the elevation of thyroid-stimulating hormone levels. Clinically important hypothyroidism and hyperthyroidism have each been reported in 5% to 10% of patients [26].

Gastrointestinal Side Effects

Commonly seen during the initial period of loading, gastrointestinal side effects may be dose-related and include nausea, vomiting, anorexia, abdominal discomfort, and constipation. Altered taste is also reported. Abnormalities on liver function tests, especially elevated aminotransferase and alkaline phosphatase levels, are seen in 25% of patients. Hepatitis is rare and may be related to prolonged therapy with a high dose. Liver failure and death have been reported.

Dermatologic Side Effects

These side effects are common and include an allergic rash, photosensitivity, and an unusual blue-gray skin discoloration. Hair loss has been infrequently reported.

Neurologic Toxicity

Tremor, ataxia, peripheral neuropathy, fatigue, and weakness may all result from neurologic toxicity. These side effects are often dose-related and are more commonly reported during the loading period. They may also be seen if high doses of the drug are continued over long periods.

Ophthalmologic Side Effects

Corneal microdeposits, caused by the secretion of amiodarone by the lacrimal gland with accumulation on the corneal surface [33], are among the ophthalmologic side effects of amiodarone therapy. These deposits are almost universal and usually do not cause visual disturbances, but, if they are heavy, they can cause corneal cysts and abscesses. Macular degeneration has been observed, but the relation of this degeneration to amiodarone remains uncertain.

Drug Interactions

Amiodarone frequently interacts with other drugs [34]. One of the most common interactions is with warfarin; amiodarone can potentiate the effect of this drug by interfering with hepatic metabolism. The prothrombin time is elevated, necessitating a reduction in the warfarin dose. This interaction may be erratic; hence, frequent measurement of the prothrombin time, especially during the first few weeks of loading, is essential. Because amiodarone can elevate the serum digoxin level, reduction of the digoxin dose may be necessary. Amiodarone may also increase the serum level of other antiarrhythmic drugs, including quinidine, procainamide, mexiletine, and propafenone. When combined with class IA drugs, amiodarone may cause an exaggerated QT prolongation, increasing the risk for torsade de pointes. Potentiation of the effects of anesthetic agents, including hypotension and bradycardia, has been reported. The combined use of amiodarone and ß-blockers or calcium channel blockers may result in marked depression of sinus or atrioventricular nodal function and enhancement of the negatively inotropic effects of these blocking agents.

Clinical Use of Amiodarone for Management of Arrhythmia

Atrial Fibrillation and Flutter

Amiodarone exerts significant effects on atrial tissue and, as expected, is effective for the treatment of atrial arrhythmias, particularly atrial fibrillation and atrial flutter [6, 7, 13, 35-44]. Currently, the most effective therapy for these arrhythmias is pharmacologic, and, as seen in Table 1, amiodarone is completely or partially effective for the prevention of atrial fibrillation or flutter in approximately 80% of patients. This can be compared with the approximate 50% rate of sinus rhythm maintenance seen at 1 year when class I drugs, particularly quinidine, are used [44]. In a study of low-dose amiodarone, Gosselink and colleagues [44] found that with a dose of 200 mg/d, 53% of patients remained in sinus rhythm at 3 years. Among patients with severe left ventricular dysfunction, 93% remained in sinus rhythm. It is important that the use of low-dose amiodarone was associated with a low incidence of side effects (17%) and that proarrhythmia was not seen. Only one patient died; the death was unrelated to use of the drug. These results contrast markedly with those of class I drugs [4].

Only a few randomized trials have compared amiodarone with other therapies for atrial fibrillation. Zehender and coworkers [45] randomly assigned 40 patients with atrial fibrillation (present for > 4 weeks but < 2 years) to receive therapy with amiodarone, quinidine, or quinidine plus verapamil. Sinus rhythm was restored in 25% of patients receiving quinidine, in 55% of patients receiving quinidine and verapamil, and in 60% of patients receiving amiodarone. Unfortunately, long-term efficacy data are not available from this study because, at the end of 3 months, patients receiving amiodarone were switched to quinidine and verapamil. Vitolo and coworkers [46] randomly assigned 54 patients to receive quinidine or low-dose amiodarone. At 6 months, more patients in the group receiving amiodarone than in the group receiving quinidine were in sinus rhythm (79% compared with 40%; P = 0.01). Similar results were reported by Martin and colleagues [47] in a study of 70 patients randomly assigned to receive disopyramide or amiodarone. Although these small, short-term studies indicate that amiodarone is effective and safe for the prevention of atrial fibrillation, long-term controlled trials comparing amiodarone with other drugs or other approaches to therapy are not available. On the basis of studies in the literature, Disch and coworkers [48] used a Markov decision analysis to compare four strategies for the management of atrial fibrillation: no therapy; warfarin and rate control; electrical cardioversion and quinidine maintenance therapy; and electrical cardioversion followed by low-dose amiodarone therapy. When this analysis was used in a hypothetical cohort of patients with atrial fibrillation who were between 65 and 70 years of age, the percentage of patients with disabling events was lower with amiodarone (1.4%) than with quinidine (1.8%), warfarin and rate control (2.6%), or no therapy (7.4%). Moreover, the 5-year mortality rate was lower with amiodarone (13.6%) than with warfarin and rate control (14.4%), quinidine (15.2%), or no therapy (18.2%). In this analysis, amiodarone therapy was the preferred strategy.

Amiodarone prevents episodes of paroxysmal atrial fibrillation or flutter. It only infrequently reverses chronic or sustained arrhythmia, but it prevents recurrence of arrhythmia after electrical cardioversion, especially if the duration of atrial fibrillation before therapy was less than 1 year. In most studies reporting on clinical predictors of drug efficacy, the response to amiodarone has been unrelated to left atrial size; this is in contrast to that which has been observed with some other agents. Side effects caused by amiodarone have been reported in 35% of patients with atrial fibrillation, but the effects in most cases are mild. Discontinuation of amiodarone therapy is necessary in only 9% of patients. Among patients with atrial fibrillation and flutter, aggravation of arrhythmia or increased mortality as a result of therapy have not been reported. Generally, the effective dose of amiodarone is low, often 200 mg/d or less, which probably accounts for the low incidence of serious side effects and the high degree of patient tolerance.

Although amiodarone is also effective for preventing atrioventricular nodal reentrant tachycardia, radiofrequency ablation is a useful approach that is widely used as a first-line therapy [49, 50]. Similarly, amiodarone is effective for preventing atrial tachyarrhythmias (atrial fibrillation, atrial flutter, and atrioventricular reentrant tachycardia) in patients with the Wolff-Parkinson-White syndrome [51]. However, ablation of the accessory pathway has become a preferred therapy [52, 53].

Recommendations for Use in Atrial Fibrillation

Although it is effective for atrial fibrillation, amiodarone is not approved for this indication. Most physicians prefer conventional antiarrhythmic drugs (class IA or IC) for initial therapy to prevent atrial fibrillation. If arrhythmia recurs despite these agents, therapeutic options are maintenance of atrial fibrillation as the rhythm of choice, use of atrioventricular nodal blocking drugs for rate-slowing and anticoagulation, and amiodarone for prevention. A decision about the best approach needs to be made for each individual patient on the basis of the benefits and risks of chronic atrial fibrillation compared with the benefits and risks associated with long-term amiodarone therapy. For some patients, such as those with a cardiomyopathy and poor left ventricular function, prevention of atrial fibrillation is important for hemodynamic stability. In such patients, amiodarone may be the preferred initial therapy because other agents are less effective and are associated with a substantial risk for cardiac toxicity. Amiodarone is often well tolerated and is effective for maintaining sinus rhythm in these patients.

Postmyocardial Infarction

Several studies involving patients who have had myocardial infarction have found that ventricular arrhythmia, primarily runs of nonsustained ventricular tachycardia in association with left ventricular dysfunction, is an independent risk factor for sudden death during follow-up [54, 55]. Unfortunately, no data show that suppression of arrhythmia with standard antiarrhythmic drugs will reduce mortality from sudden death. Although in most of the trials of drugs for arrhythmia after myocardial infarction, investigators did not give therapy to suppress arrhythmia, CAST did involve the suppression of arrhythmia with an antiarrhythmic drug [1]. In this study, mortality from sudden death was significantly increased by drug therapy involving encainide, flecainide, and moricizine. Many large trials involving various ß-blockers, in contrast, have shown that therapy with these agents reduces total mortality and mortality from sudden death [56, 57]. This beneficial effect is especially striking in patients with left ventricular dysfunction and congestive heart failure. A recent report suggests that verapamil is also beneficial in patients who have had myocardial infarction and who do not have congestive heart failure [58]. The protective mechanism of these agents is unknown but is probably related to their blockade of the effects on the heart of the sympathetic nervous system and circulating catecholamines. In fact, the reduction in mortality appears to be related to the degree to which heart rate is slowed and not to any direct antiarrhythmic action.

Data show that in patients who have had myocardial infarction, amiodarone (in contrast to class I drugs) reduces the incidence of sudden death due to ventricular tachyarrhythmia. Three studies have shown that total cardiac mortality rates and rates of mortality from sudden death were lower among patients receiving amiodarone than among those receiving placebo Table 2 [8, 59, 60]. In the Basel Antiarrhythmic Study of Infarct Survival (BASIS) [8], patients with multiform or repetitive ventricular arrhythmia (couplets or nonsustained ventricular tachycardia) that was documented 8 to 24 days after myocardial infarction were randomly selected to receive placebo, individualized treatment with various antiarrhythmic drugs, or amiodarone. The survival of patients receiving amiodarone was greater and arrhythmic events in these patients were fewer than those in patients receiving placebo or conventional therapy. The beneficial effect of amiodarone persisted despite discontinuation of therapy with the drug after 1 year [61]. Total cardiac mortality after 4 years was lower in the group treated with amiodarone than in the control group; this was entirely due to the effect of amiodarone during the first year. However, in a follow-up analysis of the 212 patients who had received either amiodarone or no therapy, it was found that the lower 5-year cardiac mortality rate (1.0% with amiodarone compared with 8.9% for controls) and the decrease in arrhythmic events were confined to the group of patients with a left ventricular ejection fraction of more than 40%. No significant difference was seen in patients with an ejection fraction of less than 40% [62]. This differentiates amiodarone from ß-blockers, which have been reported to be of greater benefit in patients with left ventricular dysfunction and congestive heart failure [63].

The Polish trial [60] enrolled 613 patients 5 to 7 days after myocardial infarction who were not eligible to receive ß-blockers. Patients were randomly selected to receive amiodarone (200 to 400 mg/d) or placebo. Amiodarone significantly reduced the incidence of nonsustained ventricular tachycardia (7.5% in patients receiving amiodarone compared with 29.5% in patients receiving placebo; P < 0.001). After 1 year of follow-up, total, cardiac, and sudden death mortality rates were reduced, but the reduction was not statistically significant.

In the pilot phase of the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) [59], 77 patients with acute myocardial infarction who had more than 10 ventricular premature beats per hour and more than one run of nonsustained ventricular tachycardia in 24 hours on ambulatory monitoring obtained within 6 to 45 days of the infarction were randomly assigned to receive amiodarone (300 to 400 mg/d) or placebo. Suppression of arrhythmia at 2 weeks was greater in the group treated with amiodarone (85%) than in the group receiving placebo (27%). After a 2-year follow-up, deaths from arrhythmia were fewer and all-cause mortality rates were lower in the group treated with amiodarone. The larger trial, now in progress, will enroll 1200 patients who will be followed for 2 years [64]. Another trial in patients who have had myocardial infarction, the European Myocardial Infarct Amiodarone Trial (EMIAT) [65], is currently in progress and will randomly assign 1500 patients within 5 to 21 days after acute myocardial infarction to receive either amiodarone or placebo. The entry criterion is a left ventricular ejection fraction of less than 40%, and a 3-year follow-up is planned.

Amiodarone has also been compared with ß-blocker therapy (metoprolol) or with no therapy in patients who have had myocardial infarction and have nonsustained ventricular tachycardia and a left ventricular ejection fraction of 20% to 45%; these patients were randomly assigned 10 to 60 days after the event to receive metoprolol, amiodarone, or no therapy [66]. The mortality rate at 2.8 years was 3.5% in the 115 patients receiving amiodarone (200 mg/d), 7.7% in the untreated group, and 15.4% in the group treated with metoprolol. Amiodarone was more effective than metoprolol for suppressing ventricular arrhythmia. It is not certain whether this beneficial effect was due to the class III (antifibrillatory) antiarrhythmic activity or to the ß –or calcium channel blocking actions of amiodarone.

Aggravation of arrhythmia involving amiodarone was seen in CAST but not in any of the trials discussed above. Unfortunately, the number of patients studied to date is small and the reduction of the mortality rate is of questionable clinical importance, especially when compared with the results of ß-blockade. Nevertheless, these studies do suggest that administration of amiodarone is safe in the patient who has had myocardial infarction and who has an arrhythmia that may require antiarrhythmic therapy.

Recommendations for Use in Patients after Myocardial Infarction

Although the results of trials using amiodarone after myocardial infarction are encouraging, prophylactic therapy with ß-blockers is still the preferred treatment for patients who have had an infarction. Amiodarone may be an alternative for the patient with a contraindication to ß-blocker therapy and may be preferred for the patient who has runs of nonsustained ventricular tachycardia despite treatment with ß-blockers. When sustained ventricular tachycardia or ventricular fibrillation occur in the period after infarction, amiodarone is a reasonable option for therapy because it appears to be safe. Amiodarone may also be the safest therapy for atrial arrhythmia, particularly that caused by atrial fibrillation, in the patient who has recently had an infarction.

Cardiomyopathy and Ventricular Arrhythmia

Approximately 40% of deaths in patients with a cardiomyopathy and congestive heart failure are sudden and are usually the result of a ventricular tachyarrhythmia. Although their results are still controversial, most studies have reported that nonsustained ventricular tachycardia, documented in approximately 40% of patients with cardiomyopathy and congestive heart failure, is associated with an increased risk for sustained ventricular tachyarrhythmia and sudden death [67, 68]. Although the presence of nonsustained ventricular tachycardia and the risk for sudden death in these patients appear to be related, the role of suppression of arrhythmia using conventional antiarrhythmic drugs in preventing this outcome is unknown because no well-controlled trials have been done. Unfortunately, data suggest that antiarrhythmic drugs are associated with an increased risk for cardiac toxicity in such patients, particularly a worsening of congestive heart failure [69] and aggravation of arrhythmia [70].

In contrast, amiodarone has been administered to patients with cardiomyopathy and ventricular arrhythmia in several trials, and each found that the drug was effective for suppressing ventricular arrhythmia [71-80]. More importantly, in most of these studies, amiodarone reduced total cardiac mortality or mortality from sudden death compared with placebo or historic controls (Table 3). The relation between the suppression of nonsustained ventricular tachycardia and outcome is still uncertain, but, unlike other antiarrhythmic agents, amiodarone appears to be well tolerated in patients with a cardiomyopathy and ventricular arrhythmia, and aggravation of arrhythmia has not been observed.

These data are preliminary but encouraging. Several ongoing placebo-controlled trials involving patients with cardiomyopathy and ventricular arrhythmia are comparing amiodarone with placebo. The study from the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) [80] involved patients with class II to class IV congestive heart failure who had a cardiothoracic ratio of more than 0.55, an ejection fraction of less than 35%, and an end-diastolic echocardiographic diameter of more than 3.2 cm body surface area. Amiodarone reduced overall mortality compared with placebo (33.5% compared with 41.4%; P = 0.024); however, when analysis was done according to cause of death, amiodarone did not reduce mortality from sudden death (12.3% compared with 15.2%; P = 0.16) or death from heart failure (16.9% compared with 20.3%; P = 0.16). Amiodarone reduced total mortality and admissions for heart failure (45.8% compared with 58.2%; P = 0.0024). The largest trial, the Veterans Affairs Congestive Heart Failure Antiarrhythmic Trial (CHF-STAT) [81], randomized 674 patients with ischemic or nonischemic cardiomyopathy who had more than 10 ventricular premature beats per hour. Eligibility requirements were clinical congestive heart failure, a left ventricular ejection fraction of less than 40%, a left ventricular internal dimension by echocardiogram of more than 55 mm, or a cardiothoracic ratio on chest radiograph of more than 0.5. The dose of amiodarone used was 400 mg/d for 1 year and 200 to 300 mg/d thereafter. In a preliminary report, amiodarone significantly suppressed the frequency of ventricular arrhythmia, but all-cause mortality did not differ between the groups receiving amiodarone and placebo [82]. However, additional definitive data and subset analyses, particularly in patients with nonsustained ventricular tachycardia, are not yet available and will provide important information.

Patients with a hypertrophic cardiomyopathy and nonsustained ventricular tachycardia also have an increased risk for sudden death [83]. Some data show that amiodarone benefits these patients because it reduces total cardiac mortality and mortality from sudden death [84]. In a study by McKenna and colleagues [84], 24 patients with nonsustained ventricular tachycardia were treated with conventional antiarrhythmic drugs, 21 patients with nonsustained ventricular tachycardia were treated with amiodarone, and 123 patients without ventricular tachycardia were not treated. During a 36-month follow-up, no patients died in the group treated with amiodarone; the group receiving conventional drugs had a 21% mortality rate, and the group without ventricular tachycardia had a 4% mortality rate. However, data from the National Institutes of Health, reported by Fananapazir and colleagues [85], indicate that amiodarone may be harmful in patients with a hypertrophic cardiomyopathy who receive therapy for relief of hemodynamic symptoms rather than for suppression of arrhythmia. Fananapazir and colleagues prospectively evaluated amiodarone therapy (400 mg/d) in 50 patients with hypertrophic cardiomyopathy who had hemodynamic symptoms despite treatment with calcium channel blockers or ß-blockers. McKenna and colleagues [84] administered amiodarone only to patients with nonsustained ventricular tachycardia, but only 21 of the patients (42%) studied by Fananapazir and colleagues [85] had nonsustained ventricular tachycardia. Although amiodarone improved the patients' functional status and exercise duration, 7 sudden deaths occurred during the mean follow-up of 2.2 years, 6 within the first 5 months of therapy. As previously reported, survival was worse among patients who had had nonsustained ventricular tachycardia before therapy than among those without this arrhythmia (61% compared with 97% at 2 years; P < 0.01). However, sudden deaths occurred despite suppression of nonsustained ventricular tachycardia, and all occurred in patients in whom ventricular tachycardia was absent on ambulatory monitoring at 2 months. Fananapazir and colleagues observed that sudden death was associated with a decrease in left ventricular filling rate and suggested that amiodarone had a harmful effect on hemodynamics in patients with hypertrophic cardiomyopathy. Although these data are disturbing, the patients in this study differed from those in the study by McKenna and coworkers: Their therapy was for hemodynamic symptoms resulting from cardiomyopathy rather than for symptomatic arrhythmia.

Recommendations for Use in Patients with Nonsustained Ventricular Tachycardia and Cardiomyopathy

At present, data from noncontrolled trials suggest that in patients with a cardiomyopathy and ventricular arrhythmia, and particularly in those with nonsustained ventricular tachycardia, amiodarone is effective for suppressing ventricular arrhythmia and for reducing mortality from sudden death and cardiac mortality. However, until the results from the large controlled Veterans Affairs study are reported, amiodarone cannot be recommended as therapy for all of these patients. For the patient with a cardiomyopathy who has frequent and symptomatic episodes of nonsustained ventricular tachycardia, amiodarone is a logical first drug because it appears to be more effective and safer than other agents. The value of antiarrhythmic therapy for patients with asymptomatic nonsustained ventricular tachycardia remains unproven, but if therapy is thought to be necessary, amiodarone might be preferred on the basis of its efficacy and safety.

Sustained Ventricular Tachyarrhythmias

Amiodarone has been used primarily in patients presenting with sustained ventricular tachyarrhythmia, ventricular tachycardia, or ventricular fibrillation refractory to other pharmacologic agents. In as many as 50% to 60% of patients, these arrhythmias may be refractory when therapy is evaluated with electrophysiologic testing. Before the widespread use of the implantable cardioverter- defibrillator, amiodarone was the only therapy available for patients with ventricular arrhythmia refractory to conventional antiarrhythmic drugs or for those without arrhythmia induced by electrophysiologic study. Many uncontrolled trials found that amiodarone was effective for the prevention of recurrence of a serious ventricular tachyarrhythmia and for prolonging life Table 4 [36, 37, 86-102]. The reported mortality from sudden death among such patients receiving amiodarone ranges from 3% to 15% per year, and nonfatal arrhythmia occurs in 3% to 25%. Unfortunately, because none of these trials was controlled, it is unclear whether amiodarone actually prevents arrhythmia and prolongs life, although most investigators have recognized that amiodarone is indeed effective.

It has been reported that amiodarone is effective for preventing recurrent arrhythmia when efficacy is based on the suppression of nonsustained ventricular tachycardia on ambulatory monitoring [89, 103] or prevention of ventricular tachycardia induction in the electrophysiologic laboratory [97, 100, 101]. Unfortunately, it has been observed that amiodarone only infrequently prevents the induction of sustained ventricular tachycardia, although it often slows the rate of the induced arrhythmia. It has been reported that if the ventricular rate is slowed by more than 100 ms and if the arrhythmia is hemodynamically stable and well tolerated, the survival rate is identical to that observed among the patients in whom arrhythmia is no longer inducible, although the incidence of nonfatal recurrence is still substantial [95, 96]..

One randomized trial, Conventional versus Amiodarone Drug Evaluation (CASCADE), involved cardiac arrest patients in Seattle [98]. A total of 228 patients with out-of-hospital ventricular fibrillation not caused by myocardial infarction were randomly assigned to receive therapy with amiodarone (mean dose, 183 mg/d) or conventional antiarrhythmic drugs guided by electrophysiologic study. The cardiac death rate, which included cardiac mortality, resuscitated cardiac arrest due to ventricular fibrillation, and syncope resulting in defibrillator shock, was 18% in the group receiving amiodarone and 31% in the group receiving conventional therapy at 2 years (P = 0.007). Similarly, patients treated with amiodarone had a lower incidence of cardiac death and sustained ventricular tachycardia than those receiving conventional drugs (22% compared with 48%; P < 0.001). Among the 105 patients receiving an implantable defibrillator, fewer of those treated with amiodarone had a syncopal shock (20 compared with 31; P = 0.014).

Although amiodarone appears to be effective for patients with sustained ventricular tachycardia or fibrillation, the implantable cardioverter-defibrillator is now widely used, and many patients who would be candidates for amiodarone therapy (those with arrhythmias refractory to other agents or without inducible arrhythmia) are receiving this device. Results to date with the defibrillator have been impressive; the reported incidence of sudden death is 1% to 2% per year [104, 105], although early, in-hospital deaths related to surgery or other complications from device implantation are usually not included in such data [105]. Additionally, concern about the beneficial role of the defibrillator in patients with significant left ventricular dysfunction has arisen because total cardiac mortality in these patients remains high despite the use of this device as a result of death from progressive congestive heart failure [105-107]. Indeed, in a recent study by Newman and coworkers [106], no difference was seen in survival at 3 to 4 years between 60 patients receiving the defibrillator and 120 patients receiving amiodarone. It should be pointed out that, in this study, the non-sudden-death rate in patients receiving the defibrillator was significantly lower than in those receiving amiodarone (17% compared with 39%), suggesting that patients receiving amiodarone were sicker and had worse ventricular function. The investigators concluded that although the defibrillator prevents sudden death, the early survival advantage is lost over time because of death from other cardiac and noncardiac causes.

A preliminary report from the only randomized trial to date, the Cardiac Arrest Study Hamburg (CASH) [108], also suggested that total mortality did not differ significantly between a group of patients receiving the implantable defibrillator and a group receiving amiodarone. At present, 230 survivors of sudden death have been randomly assigned to receive an implantable defibrillator, amiodarone, metoprolol, or propafenone. Although the rate of sudden death has been lower in the group receiving the defibrillator (0% compared with 8.6% in the group receiving amiodarone, 11.4% in the group receiving metoprolol, and 11.4% in the group receiving propafenone), the total mortality rate was 14.3% in the group receiving the defibrillator, 14.7% in the group receiving amiodarone, 14.3% in the group receiving metoprolol, and 20% in the group receiving propafenone. Total mortality did not differ significantly among the four groups. However, total mortality and mortality from sudden death were higher in the group receiving propafenone, and propafenone has been dropped from the trial.

Survival with long-term amiodarone therapy may be equivalent to that achieved with the defibrillator, especially in patients with poor left ventricular function (ejection fraction < 25%). Similarly, it is possible that patients with inducible ventricular tachycardia that becomes significantly slower during amiodarone therapy will have total and sudden death mortality rates on drug similar to those achieved with a defibrillator. However, the role of amiodarone in these patients remains uncertain because no randomized controlled trials have compared amiodarone with other antiarrhythmic drugs or with other forms of therapy, particularly the implantable defibrillator. Also of concern are the cost-effectiveness of amiodarone therapy compared with that of the implantable defibrillator and quality of life with either therapy. Two ongoing studies are addressing these issues. The Canadian Implantable Defibrillator Study (CIDS) [109] will randomly assign 400 patients with cardiac arrest or hemodynamically unstable ventricular tachycardia to receive therapy with amiodarone (>300 mg/d) or an implantable defibrillator. The primary outcomes are death from arrhythmia and total cardiac mortality within 30 days; secondary outcomes are all-cause mortality and nonfatal occurrence of ventricular tachycardia or ventricular fibrillation. A second trial, Antiarrhythmic Drugs versus Implantable Defibrillators (AVID), was begun by the National Institutes of Health in 1993. The pilot study, involving 200 patients, has been completed. In the main trial, 1000 patients will be randomly assigned to receive an implantable defibrillator, an antiarrhythmic drug such as sotalol (with efficacy evaluated invasively or noninvasively), or empiric therapy with amiodarone. The primary end point is total mortality; secondary end points are mode of death, quality of life, and cost-effectiveness.

Recommendations for Use in Patients with Sustained Ventricular Tachycardia

Currently, conventional antiarrhythmic therapy guided by electrophysiologic testing or ambulatory monitoring is usually the first approach to therapy in patients with sustained ventricular tachyarrhythmia. Options for patients with arrhythmia refractory to these agents are an implantable cardioverter-defibrillator or therapy with amiodarone. Until the final data from CASH and the results of the AVID and CIDS trials become available, no data show which approach is associated with the best outcome. The available data indicate that for the patient presenting with sustained ventricular tachycardia, amiodarone is a reasonable option if other agents are ineffective or poorly tolerated. Although the drug may not prevent recurrent ventricular tachycardia, it does often slow the ventricular rate, making the arrhythmia well tolerated and not life-threatening. Limited data suggest that this end point is associated with low mortality, equivalent to that reported when arrhythmia is no longer induced. For patients who have a symptomatic or potentially life-threatening recurrence of ventricular tachycardia despite amiodarone, an implantable cardioverter-defibrillator would be indicated.

When the patient presents with ventricular fibrillation and conventional agents are ineffective or poorly tolerated, the implantable defibrillator is preferred because the outcome of amiodarone therapy may be more unpredictable in such patients. However, for those patients who have poor left ventricular function and clinical congestive heart failure, amiodarone may still be a reasonable alternative because total cardiac and all-cause mortality rates appear to be equivalent with these interventions. Of particular concern are patients who have had a ventricular tachyarrhythmia but who do not have arrhythmia induced by electrophysiologic testing or spontaneous ectopy on ambulatory monitoring. For the patient with intact left ventricular function and no congestive heart failure, the implantable defibrillator may be preferred; for the patient with significant left ventricular dysfunction and congestive heart failure, amiodarone may be a better option.

Conclusion

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Amiodarone is unique among the antiarrhythmic drugs in many ways. It is highly effective against a wide range of arrhythmias, and its efficacy appears to be unrelated to the type and severity of the arrhythmia or to the nature and extent of underlying heart disease. However, controlled trials are now under way that will provide further information about amiodarone in different groups of patients, including those who have recently had myocardial infarction, those with a cardiomyopathy and nonsustained ventricular tachycardia, those with atrial fibrillation, and survivors of sudden death. Amiodarone has not been reported to aggravate arrhythmia or to increase mortality from sudden death or cardiac mortality in any group of patients studied to date. Unfortunately, it is associated with a wide range of side effects, some of which are potentially serious, such as liver, thyroid, pulmonary, and cardiac toxicity. Although many of the minor side effects are dose-related, serious toxicity is often unrelated to dose and is unpredictable. However, laboratory abnormalities can serve as markers of potential problems and can be observed before symptoms develop. Therefore, close monitoring of chest radiographs, liver and thyroid function, and cardiac status will often show potentially serious toxicity early, permitting discontinuation of amiodarone therapy before any serious symptoms or adverse events develop.