Low-dose Amiodarone Research Articles

Combination therapy with carvedilol and amiodarone in patients with severe heart failure.

Carvedilol and at least in some studies, amiodarone have been shown to improve symptoms and prognosis of patients with heart failure. There are no reports on the outcome of combined treatment with both drugs on top of angiotensin-converting enzyme inhibitors (ACEI), diuretics and digitalis. In 109 patients with severe heart failure submitted for heart transplantation at one single center between the years 1996 and 1998 [left ventricular ejection fraction (LVEF) 24.6+/-11%, 85% males, 52% idiopathic dilated cardiomyopathy (DCM), mean observation time 1. 9+/-0.4 years] a therapy with low-dose amiodarone (1000 mg/week) plus titrated doses of carvedilol (target 50 mg/day) was instituted. In addition, patients received a prophylactic dual chamber pacemaker (PM) in order to protect from bradycardia and for continuous holter monitoring. The devices were programmed in back-up mode with a basal rate of 40 i.p.m. with a hysteresis of 25%. Significantly, more patients were in sinus rhythm after 1 year than at study entry (85% vs. 63%, P<0.01). In 47 patients, under therapy over at least 1 year, the resting heart rate fell from 90+/-19 to 59+/-5 b.p.m. (P<0.001). Ventricular premature contractions in 24-h holter ECGs were suppressed from 1.0+/-3 to 0.1+/-0.3%/24 h (P167 b.p.m. detected by the pacemaker (1.2+/-2.8 episodes/patient/3 months vs. 0.3+/-0.8 episodes/patient/3 months after 1 year (P<0.01). The LVEF increased from 26+/-10 to 39+/-13% (P<0.001). NYHA class improved from 3. 17+/-0.3 to 1.8+/-0.6 (P<0.001) as well as right heart catheterization data. From the total cohort, seven patients (6%) developed symptomatic documented bradycardic rhythm disturbances requiring reprogramming of their pacemakers to DDD(R)/VVI(R) mode with higher basic rates. Two of these patients developed AV block, four sinu-atrial blocks or sinus bradycardia and one patient had bradycardic atrial fibrillation. During the observation period five patients died (3 sudden, 1 due to heart failure and 1 due to mesenteric infarction). Two patients had undergone heart transplants. The 1-year survival rate (Kaplan-Meier) without transplantation was 89%. Compared to historic control patients with amiodarone only (n=154) or without either agent (n=283) this rate was 64 and 57% (P<0.01). Heart failure patients benefit from a combined therapy with carvedilol and amiodarone resulting in a markedly improved NYHA stage, an increase in LV ejection fraction, a stabilization of sinus rhythm, a significant reduction in heart rate, a delay of electrical signal conduction and a suppression of ventricular ectopies. Approximately 6% of patients under such a regime became pacemaker-dependent in the first year. Compared to historic controls prognosis was better and the need for heart transplantation was lower. The exact role of either agent in combination or alone should be clarified in larger randomized studies.

Oral amiodarone reduces incidence of postoperative atrial fibrillation

Background. Atrial fibrillation (AF) is a common occurrence after heart operations that use cardiopulmonary bypass. It can cause life-threatening complications as well as delay discharge and increase hospitalization costs. The purpose of this study was to evaluate the effect of orally administered low-dose amiodarone on the incidence of new onset postoperative AF.Methods. In this prospective study, 226 consecutive adult patients (group A) who had various heart operations utilizing cardiopulmonary bypass between April and November of 1998 at the University of Miami/Jackson Memorial Hospital, were given oral amiodarone (200 mg three times a day), starting immediately after arrival in the intensive care unit until the day of hospital discharge. The incidence of new AF in this group of patients was assessed and compared with a historical group of 239 patients (group B) who had had cardiac operations with cardiopulmonary bypass in the preceding 9 months at the same institution.Results. Preoperative patient characteristics and procedure types were similar in the two groups. Among the 226 patients in group A, 13 (5.7%) had history of AF. Of the remaining 213 patients, new-onset AF occurred postoperatively in 10 (4.7%). Among the 239 patients in group B, 16 (6.7%) had history of AF. Of the remaining 223 patients, 44 (19.7%) developed new-onset AF (p < 0.001). Group A patients had a shorter length of hospital stay than those in group B (6.5 versus 7.8 days) but had a similar incidence of complications other than AF (23 of 226 patients in group A versus 24 of 239 in group B). The drug was well tolerated.Conclusions. Postoperative low-dose amiodarone given orally to patients who had cardiopulmonary bypass was well tolerated and appeared to reduce the incidence of new-onset AF and decrease the length of hospital stay.

Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy

OBJECTIVESThe aim of this study was to evaluate the survival of patients with hypertrophic cardiomyopathy (HCM) after resuscitated ventricular fibrillation or syncopal sustained ventricular tachycardia (VT/VF) when treated with low dose amiodarone or implantable cardioverter defibrillators (ICDs).BACKGROUNDProspective data on clinical outcome in patients with HCM who survive a cardiac arrest are limited, but studies conducted before the widespread use of amiodarone and/or ICD therapy suggest that over a third die within seven years from sudden cardiac death or progressive heart failure.METHODSSixteen HCM patients with a history of VT/VF (nine male, age at VT/VF 19 ± 8 years [range 10 to 36]) were studied. Syncopal sustained ventricular tachycardia/ventricular fibrillation occurred during or immediately after exertion in eight patients and was the initial presentation in eight. One patient had disabling neurologic deficit after VT/VF. Before VT/VF, two patients had angina, four had syncope and six had a family history of premature sudden cardiac death. After VT/VF all patients were in New York Heart Association class I or II, three had nonsustained VT during ambulatory electrocardiography and 11 had an abnormal exercise blood pressure response. After VT/VF eight patients were treated with low dose amiodarone and six received an ICD. Prophylactic therapy was declined by two patients.RESULTSMean follow-up was 6.1 ± 4.0 years (range 0.5 to 14.5). Cumulative survival (death or ICD discharge) for the entire cohort was 59% at five years (95% confidence interval: 33% to 84%). Thirteen (81%) patients were alive at last follow-up. Two patients died suddenly while taking low dose amiodarone, and one died due to neurologic complications of his initial cardiac arrest. Three patients had one or more appropriate ICD discharges during follow-up; the times to first shock after ICD implantation were 23, 197 and 1,124 days.CONCLUSIONSThis study shows that patients with HCM who survive an episode of VT/VF remain at risk for a recurrent event. Implantable cardioverter defibrillator therapy appears to offer the best potential benefit regarding outcome.

Predicting mode of death in heart failure

Improvements in medical therapy for advanced heart failure have improved prognosis. Nonetheless, mortality from both sudden and nonsudden death remains high. In addition, sudden death may occur in association with heart failure exacerbation. Clearly, avoidance of Type I antiarrhythmic agents and increased use of low dose amiodarone and transvenous ICD therapy decreases total mortality in a subset of patients. Further studies will help define the role of these therapies in sudden death prevention.

Low-Dose Amiodarone Versus Sotalol for Suppression of Recurrent Symptomatic Atrial Fibrillation

To compare the safety and efficacy of amiodarone and sotalol in the treatment of patients with recurrent symptomatic atrial fibrillation (AF), 70 patients were entered into a randomized, double-blind study. Of these, 35 received amiodarone and 35 sotalol. There were no significant differences in baseline clinical characteristics between groups. Patients with ejection fraction <40% or clinically significant heart disease were excluded. Patients randomized to amiodarone began with 800 to 1,600 mg/day for 7 to 14 days orally. After the initial loading phase, the drug dose was tapered to maintenance levels over 7 to 12 days; thereafter, therapy was generally maintained at a dosage of 200 mg/day. The sotalol dosage was 80 to 360 mg twice daily, as tolerated. Follow-up clinical evaluations were conducted at 1, 2, 4, 6, 9, and 12 months. The proportion of patients remaining in sinus rhythm on each agent was calculated for the 2 groups using the Kaplan-Meier method. Ten of the 35 patients who were taking amiodarone developed AF during the 12-month observation period, compared with 21 of the 35 who were taking sotalol (p = 0.008). No significant effect of sex, age, left atrial size, or type of AF could be detected that increased the risk of development of AF. We conclude that both amiodarone and sotalol can be used for the maintenance of normal sinus rhythm in patients with recurrent symptomatic AF but that amiodarone is the more effective of the 2 drugs for this purpose.

Continuous home ambulatory intravenous inotropic drug therapy in severe heart failure: Safety and cost efficacy

Some patients with dilated cardiomyopathy who are inotrope dependent but remain well by undergoing infusions can be managed by ambulatory infusions at home. We report our results in 20 patients awaiting heart transplantation, unable to be weaned from intravenous inotropic therapy on 2 or more occasions, but who were well while receiving inotropes and received home ambulatory infusions. The patients were treated with ACE inhibitors, digoxin, diuretics, vasodilators, close electrolyte management, and low-dose amiodarone for those with more than four-beat ventricular tachycardia. Infusions were delivered by a tunneled subclavian catheter and syringe driver. Thirteen patients received dopamine, four received dobutamine, and three received both. Mean duration of inotropic therapy was 5 months with 70% of the time spent as an outpatient. Eleven patients received transplants, two remain on the waiting list, and seven died after being removed from the list because of general deterioration or renal dysfunction. There were no sudden deaths. Actuarial survival was 71% at 3 months, which is not less than that expected for an inotrope-dependent population. All patients with idiopathic dilated cardiomyopathy survived to transplantation. In contrast, all three with right heart failure caused by pulmonary vascular disease and four of seven with ischemic cardiomyopathy died. Inpatient days were reduced by 70%, leading to considerable cost savings. Home ambulatory inotropic therapy is safe, cost-effective, best suited to those with idiopathic dilated cardiomyopathy, and dramatically reduces inpatient hospital duration.

Pilot Study and Protocol of the Canadian Trial of Atrial Fibrillation (CTAF)

Antiarrhythmic drug prophylaxis in patients with atrial fibrillation (AF) is associated with a high incidence of arrhythmic recurrence. Uncontrolled studies have suggested that low-dose amiodarone may be superior in terms of efficacy to other antiarrhythmic drugs while having an acceptable side effect profile. The Canadian Trial of Atrial Fibrillation (CTAF) is a 25-center study sponsored by the Medical Research Council of Canada to determine the best treatment strategy to maintain sinus rhythm in patients with persistent or paroxysmal AF. Recruitment began in November 1996 and will continue for 1.5 years. Patients are randomized to receive either low-dose amiodarone or conventional antiarrhythmic drug therapy. Patients assigned to the amiodarone group will receive an oral loading regimen of 10 mg/kg/day during a minimum 14-day period. Patients assigned to conventional antiarrhythmic therapy will receive 1 of 2 agents commonly used in AF prophylaxis: sotalol or propafenone. Drug selection and loading, and electrical cardioversion, if necessary, will be performed within 21 days of randomization. The long-term maintenance dose of amiodarone is 200 mg/day. We have planned a minimum follow-up period of 1 year. The primary end point is the time to the first relapse of AF. Data will be analyzed on an intention-to-treat basis. Secondary outcomes are medication toxicity, mortality, major clinical events, costs of each approach, and quality of life. For the purpose of sample size calculations, it is anticipated that recurrence of AF at 1 year will occur in 50% of patients on conventional treatment compared with 35% in those receiving amiodarone. In order to have an 80% power and a 2-tailed type I error of 0.05, assuming a 15% loss to follow-up rate, a total sample size of 400 patients will be required. A pilot study done at the Montreal Heart Institute has shown that the research protocol is feasible.

Low-dose amiodarone-related complications after cardiac operations

Objective: High-dose preoperative amiodarone therapy has been implicated as a risk factor for serious complications after cardiac operations. To investigate the effect of preoperative low-dose amiodarone treatment on early postoperative outcome after cardiac operations, we prospectively studied 88 patients. Methods: Forty-four patients were receiving amiodarone (mean daily dose ± standard deviation, 205 ± 70 mg/day) and 44 patients were controls matched in pairs. The following parameters were recorded after the operation in all patients: (1) the ratio of oxygen tension to inspired oxygen fraction on arrival in the intensive care unit and 2, 4, 6, 10, 14, 18, and 22 hours thereafter; (2) the occurrence of acute respiratory distress syndrome; (3) early postoperative cardiac complications; and (4) the type and number of inotropic agents or vasopressors (or both) needed. Results: No difference in the ratio of oxygen tension to inspired oxygen fraction was noted at the various time intervals between amiodarone-treated patients and control patients. Overall, only one patient had acute respiratory distress syndrome in the amiodarone group, but he had multiple other factors known to predispose to acute lung injury. Several cardiac complications, such as pulmonary edema, temporary pacing, and need for intraaortic balloon pump counterpulsation, were observed more frequently in amiodarone-treated patients than in control patients. In addition, amiodarone-treated patients required more frequent inotropic support (73% vs 43%, p = 0.003) and more inotropic drugs or vasopressors (or both) per patient than did control patients (1.4 ± 1.1 vs 0.6 ± 0.8, p = 0.002). Conclusion: Preoperative low-dose amiodarone therapy does not seem to be related to significant postoperative lung toxicity, but it is associated with various cardiac complications and an increased need for more intense inotropic support after cardiac operations. These findings may be related to the drug's depressant effect on the myocardium(J Thorac Cardiovasc Surg 1997;114:31-7)

Amiodarone in restoration and maintenance of sinus rhythm in patients with chronic atrial fibrillation after unsuccessful direct-current cardioversion.

When direct-current (DC) cardioversion is used, sinus rhythm can be restored, at least temporarily, in 80-90% of patients with atrial fibrillation. However, there is a small but significant group of patients with chronic atrial fibrillation in whom DC cardioversion has failed to restore sinus rhythm. The value of antiarrhythmic drug pretreatment before DC cardioversion is still controversial. The aim of our study was to assess (1) the effectiveness of repeat DC cardioversion in patients with chronic atrial fibrillation after pretreatment with amiodarone, and (2) the efficacy of amiodarone in maintaining sinus rhythm after repeat cardioversion. Forty-nine patients with chronic atrial fibrillation after ineffective DC cardioversion were included in the study. Repeat DC cardioversion was performed after loading with oral amiodarone, 10-15 mg/kg body weight/day for a period necessary to achieve the cumulative dose of over 6.0 g. Spontaneous conversion to sinus rhythm during amiodarone pretreatment was achieved in 9 of 49 patients (18%). Direct-current cardioversion was performed in 39 patients and sinus rhythm was achieved in 23 of these patients (59%). Mean heart rate decreased from 95 beats/min before to 68 beats/min after DC cardioversion (p < 0.001). Systolic blood pressure significantly (p < 0.05) decreased from 126 +/- 23 to 108 +/- 25 mmHg. Complications occurring in four patients just after electroconversion were well tolerated and of short duration. After 12 months, 52% of patients maintained sinus rhythm on low dose (200 mg/day) amiodarone therapy. Pretreatment with amiodarone and repeat DC cardioversion allows for restoration of sinus rhythm in about 65% of patients with chronic atrial fibrillation after first ineffective DC cardioversion. Direct-current cardioversion can be performed safely with the use of standard precautions in patients who are receiving amiodarone. At 12 months' follow-up, more than 50% of patients maintain sinus rhythm on low-dose amiodarone after successful repeat cardioversion.

Long-term low-dose amiodarone therapy in the management of ventricular and supraventricular tachyarrhythmias: efficacy and safety.

Amiodarone hydrochloride has been in use for two decades for the control of ventricular and supraventricular arrhythmias. Established and emerging evidence indicates that amiodarone has an antiarrhythmic efficacy superior to that of most other drugs. The study was undertaken to evaluate the efficacy and acceptability of low-dose amiodarone therapy in the long-term management of supraventricular and ventricular tachyarrhythmias. A total of 124 patients with symptomatic drug-refractory or life-threatening arrhythmias managed with low-dose oral amiodarone therapy over a 10-year period was analyzed retrospectively. Of these, 45 patients (36%) had ventricular arrhythmias, 52 (42%) had atrial arrhythmias, and 27 (22%) had atrioventricular reentry tachycardia. Loading doses of amiodarone 600 mg daily for 1 week were administered for supraventricular arrhythmias and 600-1200 mg daily for 2 weeks for ventricular arrhythmias. Maintenance daily doses were 194 +/- 48 and 206 +/- 55 mg, respectively. Mean treatment duration was 32 +/- 28 months, with 326.3 patient years of therapy. Of 39 patients with sustained ventricular tachyarrhythmias, the actuarial incidence of satisfactory arrhythmia control (absence of sudden cardiac death or nonfatal arrhythmia recurrence) was 78% at 1 year and 71% at 2 years. Satisfactory control of supraventricular arrhythmias (mean ventricular rate < 100/min with significant symptomatic improvement for sustained atrial arrhythmias and < 1 attack per year for paroxysmal atrial or atrioventricular arrhythmias) was achieved in 73, 65, and 62% of patients at 1, 2, and 3 years, respectively. The cumulative incidence of amiodarone-related adverse effects was 5.8 per 100 patient years, with drug withdrawal required in 12 patients (9.7%). Fifteen patients had thyroid dysfunction, 2 had hepatic toxicity, and 1 developed nonfatal pulmonary fibrosis. Overall, the incidence of successful use of amiodarone (satisfactory arrhythmia control and freedom from side effects) was 67, 59, and 53% at 1, 2, and 3 years, respectively. The results of this study suggest that the efficacy of low-dose amiodarone therapy in the management of serious ventricular and supraventricular arrhythmias would be similar to those achieved with higher doses, but with a much more acceptable side effect profile.

HOW SAFE IS LOW-DOSE AMIODARONE?

Low-dose amiodarone is being used with increasing frequency to prevent atrial fibrillation and other supraventricular arrhythmias. To estimate the risk for side effects, this meta-analysis combined data on 1,465 patients who …

THERAPEUTIC STRATEGIES FOR ATRIAL FIBRILLATION: The Value of Decision Analysis

In the absence of randomized, controlled trials of low-dose amiodarone in atrial fibrillation or a randomized, controlled trial of ventricular rate control versus antifibrillatory therapy, a Markov decision analysis is useful in comparing different therapeutic strategies for atrial fibrillation. The decision analysis described compared warfarin, quinidine, and low-dose amiodarone in patients with asymptomatic or minimally symptomatic chronic, persistent atrial fibrillation. This model suggests that electrical cardioversion followed by low-dose amiodarone is a relatively safe, effective alternative to long-term warfarin therapy.

Comparison of time domain and spectral turbulence analysis of the signal-averaged electrocardiogram for the prediction of prognosis in idiopathic dilated cardiomyopathy.

Despite significant advances in the treatment of heart failure, the prognosis of patients with idiopathic dilated cardiomyopathy remains poor. Although several of prognostic variables have been shown to be useful in risk stratification of patients with idiopathic dilated cardiomyopathy, their predictive accuracy is low and clinical usefulness uncertain. This study was undertaken to assess the signal-averaged electrocardiogram (SAECG) in patients with idiopathic dilated cardiomyopathy and to compare the ability of time domain and spectral turbulence analytic techniques to predict clinical outcome. SAECG analysis was performed in 80 patients with idiopathic dilated cardiomyopathy. Nineteen patients had left bundle-branch block and eight were taking low-dose amiodarone for life-threatening arrhythmias. Conventional time domain and spectral turbulence analyses of the SAECG were performed using Del Mar 183 software. During a follow-up of 27 +/- 19 months, 24 patients developed progressive heart failure, while the others remained clinically stable. Late potentials were detected in 28% of patients and were equally frequent in patients with and without progressive heart failure (38 vs. 23%, p = 0.20). Spectral turbulence analysis was abnormal in 34% of patients, and patients with abnormal results developed progressive heart failure more frequently than those with normal results (50 vs. 17%, p = 0.01). All spectral turbulence analysis parameters were significantly different in patients with progressive heart failure compared with those who remained clinically stable (p < or = 0.01). Furthermore, progressive heart failure-free survival at 2 years was significantly lower in patients with abnormal compared with normal results (63 vs. 87%; p < 0.05), but was similar in patients with and without late potentials (72 vs. 83%; p = 0.30). The relative risk for developing progressive heart failure using spectral turbulence analysis was 3.4 (95% confidence interval 1.2-9.7) and 2.8 (95% confidence interval 1.1-8.7) using time domain analysis. The sensitivity, specificity, and the positive and negative predictive accuracy for identifying patients who developed progressive heart failure were 50, 83, 50, and 83%, respectively, (p = 0.01) for spectral turbulence analysis, and 36, 85, 45 and 80%, respectively, (p = 0.09) for time domain analysis. Abnormalities in the SAECG of patients with idiopathic dilated cardiomyopathy are common and appear to provide a noninvasive marker for development of progressive heart failure.

Is the Degree of Arrhythmia Suppression a Predictor of Survival?

The effectiveness of an antiarrhythmic drug is judged by the degree of ventricular arrhythmia (VA) suppression. We evaluated the relationship between the degree of VA suppression and survival in a dose-adjusted trial of 110 symptomatic patients treated with amiodarone. Cohorts had left-ventricular ejection fraction (LVEF) of 41 plus minus 18%, ventricular premature contractions (VPCs) of 445 plus minus 571 h, couplets (C) of 733 plus minus 1498 24 h and nonsustained (N) ventricular tachycardia (VT) of 65 plus minus 217 24 h; these conditions were followed for 15 plus minus 11.5 months. Amiodarone was initiated with an oral loading of 670 plus minus 111.7 mg per day for 10 days and continued on maintenance of 274.9 plus minus 102 mg per day. Survival rates of responders and nonresponders with VPCs <70%, 70--89%, greater-than-or-equal90%; C greater-than-or-equal 90%; NVT (100%); and the response to all 3 criteria (suppresion of VPCs greater-than-or-equal70%, C greater-than-or-equal 90% and complete abolition of NVT) were not statistically significant. Survival rates as a function of LVEF <40% (51 patients) or greater-than-or-equal40% (59 patients), as well as responders or nonresponders to all three criteria, were not significant (p = NS). We conclude that, in patients treated with low-dose amiodarone, the degree of VA suppression of PVCs, C and NVT does not predict survival; the survival of patients with LVEF <40% improved irrespective of VA suppression; and criteria for VA suppression should be reassessed at lower levels of suppression for the improvement of the drug risk:benefit ratio. More improvement is not necessarily better.

Sotalol versus low-dose amiodarone for maintenance of sinus rhythm in patients with atrial fibrillation

Sotalol versus low-dose amiodarone for maintenance of sinus rhythm in patients with atrial fibrillation

Effect of low dose Amiodarone on the incidence of sudden death in elderly patients with congestive heart failure: A double-bind, placebo-controlled study

To determine if low-dose Amiodarone could reduce sudden death (SD) among patients with congestive heart failure, a prospective, double-blind, placebo-controlled study was conducted. The study group consisted of 46 patients (36 men and 10 women, mean age 71 +/- 5 years) with complex ventricular ectopy documented by 48-hour Holter monitoring. Randomization divided the patients into two treatment groups: the first group received Amiodarone (400 mg/day for 1 week and then 100 mg/day), while the second group received placebo. The drug significantly reduced ventricular arrhythmias, but then was no decrease in incidence of SD. This study demonstrates not only that low-dose Amiodarone can be safely administered to elderly patients with congestive heart failure and it will significantly suppress ventricular arrhythmias, but also that reduction in ventricular arrhythmias and the risk of SD are not linearly related.

Atrial fibrillation: Maintenance of sinus rhythm versus rate control

Atrial fibrillation represents a common and challenging arrhythmia. A rational approach to management of the individual case depends on careful assessment of the temporal pattern of the arrhythmia, any associated cardiovascular disease, and any particular features suggesting the advisability or risks of any particular treatment regimen. The nature of an arrhythmia and of individual patient factors change over time, requiring a flexible approach to long-term treatment that may be defined only after months or years. While new treatment options such as catheter ablation techniques and implantable atrial defibrillators are being tested, old therapies (e.g., low-dose amiodarone) are undergoing reappraisal. Increasing recognition of the dangers of antiarrhythmic therapy used to maintain sinus rhythm is focusing attention on nonpharmacologic methods. All patients with persistent atrial fibrillation merit serious consideration for direct current cardioversion before accepting that atrial fibrillation is permanent, and many patients may benefit from more than one attempt to restore and maintain sinus rhythm.

Randomized, Double-Blind Comparison of Intravenous Amiodarone and Bretylium in the Treatment of Patients With Recurrent, Hemodynamically Destabilizing Ventricular Tachycardia or Fibrillation

After several days of loading, oral amiodarone, a class III antiarrhythmic, is highly effective in controlling ventricular tachyarrhythmias; however, the delay in onset of activity is not acceptable in patients with immediately life-threatening arrhythmias. Therefore, an intravenous form of therapy is advantageous. This study was designed to compare the safety and efficacy of a high and a low dose of intravenous amiodarone with bretylium, the only approved class III antiarrhythmic agent. A total of 302 patients with refractory, hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation were enrolled in this double-blind trial at 82 medical centers in the United States. They were randomly assigned to therapy with intravenous bretylium (4.7 g) or intravenous amiodarone administered in a high dose (1.8 g) or a low dose (0.2 g). The primary analysis, arrhythmia event rate during the first 48 hours of therapy, showed comparable efficacy between the bretylium group and the high-dose (1000 mg/24 h) amiodarone group that was greater than that of the low-dose (125 mg/24 h) amiodarone group. Similar results were obtained in the secondary analyses of time to first event and the proportion of patients requiring supplemental infusions. Overall mortality in the 48-hour double-blind period was 13.6% and was not significantly different among the three treatment groups. Significantly more patients treated with bretylium had hypotension compared with the two amiodarone groups. More patients remained on the 1000-mg amiodarone regimen than on the other regimens. Bretylium and amiodarone appear to have comparable efficacies for the treatment of highly malignant ventricular arrhythmias. Bretylium use, however, may be limited by a high incidence of hypotension.

Treatment of Resistant Atrial Fibrillation

Chronic atrial fibrillation (AF) is a common arrhythmia with significant morbidity and mortality. Maintenance of normal sinus rhythm (NSR) can be achieved with antiarrhythmic drug therapy. The antiarrhythmic effects of amiodarone hydrochloride and flecainide acetate in patients with resistant chronic AF have been investigated separately in several small studies. This investigation compared amiodarone to flecainide in maintaining NSR in patients with resistant chronic AF. Studies using amiodarone or flecainide in the treatment of patients with chronic AF refractory to class I antiarrhythmic drugs or sotalol hydrochloride were identified. The results of six trials of amiodarone (200 to 400 mg/d, 315 patients) and two trials of flecainide (200 to 300 mg/d, 163 patients) were aggregated using meta-analytic techniques. The percentages of patients taking amiodarone or flecainide and remaining in NSR at 3 and 12 months were compared relative to results for quinidine, which were acquired from a meta-analysis of quinidine used as first-line therapy for AF. After 3 and 12 months of treatment with amiodarone, 217 (72.6%) of 299 patients and 64 (59.8%) of 107 patients, respectively, remained in NSR. These percentages were significantly greater (P < .0001) than those for quinidine (70% and 50%, respectively). For flecainide, the percentage of patients remaining in NSR was significantly lower (P < .0001) than for quinidine: 79 (48.5%) and 56 (34%) of 163 patients, respectively. The aggregated percentages of patients requiring withdrawal of amiodarone and flecainide were similar: 9.5% and 8.6%, respectively. Mortality and proarrhythmia could not be assessed. This analysis suggests that low-dose amiodarone is more efficacious and equally well tolerated when compared with flecainide in the management of chronic, drug-resistant AF.

Long-Term Efficacy of Amiodarone for the Maintenance of Normal Sinus Rhythm in Patients With Refractory Atrial Fibrillation or Flutter

The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to > or = 1 class I antiarrhythmic agents (mean +/- SD 2.5 +/- 1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268 +/- 100 mg/day) to determine its efficacy to maintain normal sinus rhythm after chemical or electrical cardioversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60 +/- 13 years, and the mean follow-up was 36 +/- 38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1, 3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p < 0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary fibrosis (3.6%; none fatal), and thyroid toxicity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.