This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deedwania, P. C. Articles by Singh, S. N. Search for Related Content PubMed PubMed Citation Articles by Deedwania, P. C. Articles by Singh, S. N.

(Circulation. 1998;98:2574-2579.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation

Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT)

Prakash C. Deedwania, MD; Bramah N. Singh, MD, PhD; Kenneth Ellenbogen, MD; Susan Fisher, PhD; Ross Fletcher, MD; Steven N. Singh, MD; for the Department of Veterans Affairs CHF-STAT Investigators

From University of California, San Francisco School of Medicine, Fresno, Calif (P.C.D.); Stanford University, Stanford, Calif (P.C.D.); Veterans Affairs Medical Center, Fresno (P.C.D.), Los Angeles (B.N.S.), Richmond (K.E.), and Washington, DC (S.N.S., R.F.); Medical College of Virginia, Richmond (K.E.), and Cooperative Studies Program, Hines, Ill (S.F.).

Correspondence to Prakash C. Deedwania, MD, Cardiology Section, VAMC/UCSF Program, 2615 East Clinton Avenue, Fresno, CA 93703. E-mail deed{at}ucsfresno.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period.

Methods and Results—Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%, P<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%, P=0.001), at 6 months (18%, P=0.001), and at 12 months (16%, P=0.006). Maximal VR was reduced 22% (P=0.001) at 2 weeks, 19% (P=0.001) at 6 months, and 14% (P=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (²=9.23, P=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (²=12.88, P=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (P=0.04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug.

Conclusions—In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.

Key Words: fibrillation, atrial • heart failure • drugs • survival

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Atrial fibrillation (AF) has emerged as the most common cardiac arrhythmia requiring treatment for significant morbidity and possibly mortality associated with the arrhythmia.^{1 2 3 4} There are 2 fundamental therapeutic approaches: restoration and maintenance of sinus rhythm and anticoagulation to reduce thromboembolism and control ventricular rate to alleviate symptoms.^{5 6 7} The relative therapeutic merits of these 2 lines of treatment have not been clearly defined, but the issue is under investigation in a number of controlled clinical trials.^{5 6 7}

It is known that the incidence of AF increases with age and as ventricular function declines, especially with the onset of congestive cardiac failure.^{2 3} For example, the prevalence of AF increases from 10% in patients with NYHA class II symptoms to 40% in patients with NYHA class IV symptoms.⁸ However, the prognostic significance of AF in the setting of congestive heart failure is controversial, and it is not clear whether restoration of sinus rhythm will improve survival in patients with heart failure.

Barring digoxin,⁹ conventional antiarrhythmic drug therapy for rate control or for maintaining sinus rhythm in patients with AF in the setting of congestive heart failure is associated with an increased risk of potentially fatal proarrhythmia or aggravation of heart failure caused by negative inotropic effects.¹⁰ In this context, the multifaceted pharmacological profile of amiodarone is of particular interest.¹¹ Among class III agents, it has been shown to exhibit the lowest proarrhythmic potential¹² and it does not appear to exert a potent negative inotropic effect in heart failure. Indeed, it has been found to increase left ventricular ejection fraction (LVEF).¹³ A number of nonrandomized trials of low-dose amiodarone for AF have reported high efficacy for maintaining stability of sinus rhythm and relatively low incidence of toxicity in patients who are refractory to treatment with multiple conventional antiarrhythmic drugs.¹⁴ However, the potential of the drug for controlling AF in patients with congestive heart failure is not clearly defined.

In the Veterans Affairs (VA) Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT), long-term treatment with amiodarone therapy was compared with placebo in a group of 667 patients with dilated cardiomyopathy, decreased ejection fraction, and NYHA class II to IV symptoms of heart failure.¹³ One hundred three of these patients at baseline were in AF. The effects of amiodarone versus placebo in these patients on conversion to and maintenance of sinus rhythm relative to survival patterns form the basis of the present report.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Design and Patient Population
The details of the study design and baseline characteristics of the patients enrolled in the study have been described previously.¹³ In brief, patients with an established history of heart failure (3 months) and NYHA functional class II, III, or IV were enrolled at 25 VA Medical Centers in the US. All patients were required to have LVEF 40% as measured by radionuclide angiography and evidence of dilated cardiomyopathy as denoted by either a cardiothoracic ratio >0.50 on chest x-ray or left ventricular end-diastolic dimension 55 mm. In addition, all patients were required to have dyspnea on exertion or history of paroxysmal nocturnal dyspnea. Patients were also required to have frequent ventricular premature beats (10 per hour averaged over a 24-hour period) on 24-hour Holter monitoring, but they were excluded if they had evidence of sustained ventricular tachycardia or symptomatic arrhythmia. Although patients could be given digoxin and diuretic as needed by their primary care physicians, all patients were required to be on an angiotensin-converting enzyme inhibitor or another effective vasodilator regimen such as hydralazine and an oral nitrate.

Exclusion criteria included women of childbearing age; myocardial infarction or revascularization within 3 months; heart failure due to uncorrected primary valvular disease or restrictive or infiltrative cardiomyopathy; a history of aborted sudden death, symptomatic ventricular arrhythmia, or need for continuing antiarrhythmic therapy; QRS duration of 180 milliseconds or QT_c of 500 milliseconds; active drug or alcohol abuse; uncontrolled thyroid disease; noncardiac conditions or malignancy that was likely to be fatal within 3 years; and symptomatic hypotension or systolic blood pressure of <90 mm Hg. Treatment with ß-blockers or investigational medications was not permitted.

The protocol was approved by the institutional review board of each participating medical center and by the Human Rights Committee of the Hines VA Cooperative Studies Program Coordinating Center. The conduct of the study was monitored by the executive committee and by an external data and safety monitoring board. All participants provided written informed consent before entering the study.

Study Enrollment and Follow-up
Patient enrollment began in September 1989 and continued for 3.5 years, with a minimum follow-up period of 1 year for all patients. During the initial baseline phase, medical therapy for heart failure was optimized, drug compliance was tested, and radionuclide angiography and 24-hour Holter monitoring were performed. Patients fulfilling the enrollment criteria were randomly assigned to amiodarone or placebo by the use of a stratification scheme for cause of heart failure (ischemic or nonischemic), LVEF (30% versus <30%), and participating medical center. The cause of heart failure was classified as ischemic if patient had a history or EKG evidence of myocardial infarction, current or previous history of angina pectoris, positive stress test, or angiographic evidence of coronary artery disease. The remaining patients were classified as having nonischemic cause.

Treatment with amiodarone or matching placebo began on an outpatient basis at a total daily dose of 800 mg for the first 2 weeks, 400 mg QD for the next 50 weeks, and 300 mg QD for the remainder of the 4.5-year trial. Dose reduction or temporary discontinuation was permitted if limiting side effects occurred, but reinstitution of the protocol-stipulated therapy was encouraged. Patients who permanently discontinued the study drug were followed to the end of the trial and analyzed by the intention-to-treat principle. Clinic visits were scheduled after 2 weeks and monthly thereafter; these visits included an interim history and complete cardiovascular examination. Laboratory testing was performed at appropriate intervals.

Twelve-lead EKGs and 24-hour Holter monitoring were repeated at 2 weeks, 3 months, 6 months, 12 months, and 24 months after randomization. To evaluate the effects of amiodarone versus placebo on AF in the present study, we identified all patients who had AF on baseline 12-lead EKG and 24-hour Holter recordings. Of those identified as having AF, 14% and 13% of the amiodarone and placebo patients, respectively, had intermittent AF on 24-hour Holter monitoring. On subsequent visits at 2 weeks, 6 months, and 12 months, 12-lead EKGs were evaluated for the presence or absence of AF and, when AF was present, average ventricular rate was calculated. In addition, for patients with AF, we evaluated the average ventricular rate, minimum ventricular rate, and maximum ventricular rate during the 24-hour period from Holter recordings obtained at baseline and at 2 weeks and 6 months after randomization to the study medications. We specifically evaluated the effects of amiodarone versus placebo on rate control versus conversion to sinus rhythm in patients who had AF detected on baseline 12-lead EKG and during 24-hour recording sessions. Because patients with CHF have a tendency to frequently go into AF, we also evaluated the occurrence of new AF in patients who were in sinus rhythm at baseline. In addition, we compared the survival patterns in AF patients who converted to sinus rhythm to those who remained in AF during the follow-up period.

Statistical Analysis
Differences between treatment groups in categorical and continuous variables were detected with ²test and Student's t test, respectively. Changes in ventricular response rates between the treatment groups over time were examined based on application of Student's t test to the difference in ventricular rate from baseline to the time point of interest. Kaplan-Meier survival techniques were used to examine differences between various groups in time from randomization to cardiac death. Patients not experiencing the event were censored at the date of last follow-up visit or the date of death from another cause. In all cases, a 2-sided level of 0.05 was considered statistically significant. Data are presented as mean±SD.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Of the total 667 patients enrolled in the study, 103 patients (15%) had AF at baseline evaluation. In the study as a whole, there was no significant difference between patients randomized to amiodarone versus those assigned to placebo. Table 1 displays the comparison of baseline clinical variables in patients with AF at baseline who were randomized to amiodarone (n=51) versus those randomized to placebo (n=52). These results suggest that the 2 drug groups were comparable at baseline. Ninety-five percent of patients with AF were on digoxin at baseline.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Variables in Patients With AF Randomized to Amiodarone vs Placebo

Rate Control
Figure 1 shows the average ventricular rate in patients with AF on 12-lead EKG at baseline and at 2 weeks, 6 months, and 12 months after randomization. Although at baseline the average ventricular rate was comparable in the amiodarone and the placebo groups, at 2 weeks the average ventricular rate in the amiodarone group was significantly lower than in the placebo group. The beneficial effect of amiodarone on rate control was sustained throughout the evaluation periods at 6 months and 1 year. In contrast, there was no significant change in the average ventricular rate at any point of evaluation in the placebo group.

View larger version (49K): [in this window] [in a new window]   Figure 1. Mean VR in bpm in patients in persistent AF computed from 12-lead EKG recordings obtained at baseline at 2 weeks, 6 weeks, and 12 months after randomization. Numbers at the bottom of each bar indicate sample size at each point of evaluation. Note that compared with placebo, amiodarone reduced mean VR significantly after 2 weeks of drug therapy, an effect that was subsequently maintained. See text for further details.

Figure 2 illustrates the comparison of the minimum, average, and maximum ventricular rates in patients with AF during the 24-hour monitoring with Holter recordings performed at baseline and at 2 weeks and 6 months after randomization. At baseline evaluation, there was no significant difference in any of the 3 parameters between the patients randomized to placebo or amiodarone. At the 2-week evaluation after receiving the assigned study medication, when compared with placebo, the patients randomized to amiodarone demonstrated significant (P=0.001) reduction in both average and maximum ventricular rate. These beneficial effects of amiodarone in controlling ventricular rate during the 24-hour period were sustained at the 6-month evaluation. There was no significant change in the ventricular rates at the 2-week or 6-month Holter evaluations in the placebo group.

View larger version (43K): [in this window] [in a new window]   Figure 2. Effects of chronic amiodarone therapy on the minimal, mean, and maximal VR in patients with persistent AF. Data were obtained from serial Holter recordings. Numbers below each group of bars indicate sample size at each point of evaluation. Amiodarone had no significant effect on the lowest heart rate during 24 hours of recording but significantly reduced both average and maximal heart rate. See text for details.

Spontaneous Conversion to Sinus Rhythm
All patients with AF at baseline and those in sinus rhythm were evaluated at 2 weeks, 6 months, and yearly thereafter for any changes in the rhythm. In the amiodarone group, there were 51 patients who had AF at entry and, of these, 16 (31%) had converted to sinus rhythm and remained in sinus rhythm for the duration of the study (Table 2). In contrast, only 4 patients out of 52 in the placebo group had converted and remained in sinus rhythm for the duration of the study. The rate of conversion to sinus rhythm was significantly better (²²=9, P=0.002) with amiodarone therapy (Table 2).

View this table: [in this window] [in a new window]   Table 2. Spontaneous Conversion to Sinus Rhythm and Onset of New AF With Amiodarone vs Placebo During 4-Year Follow-Up

New-Onset AF
Because patients with heart failure are known to be at increased risk of developing new-onset AF, we also evaluated the emergence of AF in patients who were in sinus rhythm at baseline evaluation. A total of 268 patients in the amiodarone group were in sinus rhythm at randomization. During the follow-up period, 11 of the 268 (4%) patients developed new-onset AF. In contrast, of the 263 placebo patients with sinus rhythm, twice as many, 22 (8%), developed new-onset AF. There was a significant difference between the 2 groups (²²=13, P=0.005) in the rate of development of new AF among patients who were in sinus rhythm at baseline (Table 2).

Effects of Conversion to Sinus Rhythm on Survival
Overall, there was no significant difference in survival of patients with AF at baseline between the drug groups (P=0.83). The long-term effects of treatment with amiodarone on the survival rates in patients with AF were assessed by Kaplan-Meier survival analyses based on conversion to sinus rhythm versus continued AF in the 2 groups. As shown in Figure 3, the amiodarone patients who spontaneously converted to sinus rhythm and maintained it during the follow-up period had significantly lower mortality compared with those who remained in AF.

View larger version (15K): [in this window] [in a new window]   Figure 3. Kaplan-Meier analysis of survival curves in heart failure patients with AF who converted (n=16) and did not convert (n=35) to sinus rhythm on treatment with amiodarone. Note that survival was significantly better in those who converted to sinus rhythm during the course of follow-up.

Predictors of Spontaneous Conversion to Sinus Rhythm
To identify specific predictors that might be associated with spontaneous conversion of AF to sinus rhythm, we evaluated the role of well-known factors associated with AF. These included age, NYHA class, cause of CHF (ischemic versus nonischemic), change in LVEF, left atrial size, left ventricular end diastolic dimension on echo, and use of digitalis. Multivariate regression analyses revealed that none of these factors was a predictor of conversion to sinus rhythm. Of interest was the finding that, although in this study a significantly greater proportion of patients with AF had nonischemic cardiomyopathy, the cause of heart failure was also not an independent predictor of conversion to sinus rhythm.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Numerous studies during the last 10 years have suggested that amiodarone exerts a powerful effect in maintaining stability of sinus rhythm in patients with paroxysmal and persistent AF.^{15 16 17 18 19 20 21 22} The drug has been shown to maintain stability of sinus rhythm in over 65% of patients for 1 year^{14 23} after direct current conversion. Few direct, controlled comparisons have been made with other antifibrillatory compounds in common use. However, the overall efficacy of such agents rarely exceeds 50% at the end of the first year of treatment.^{24 25} The most commonly used agent to date has been quinidine, but its therapeutic effect may be associated with an increase in mortality,²⁴ especially in patients with heart failure.²⁶ Thus, the potential of amiodarone for maintaining stability of sinus rhythm in patients with AF in the setting of heart failure is of particular interest. In the atria, the drug has been shown to consistently increase the effective refractory period after chronic administration in experimental animals^{27 28} and in humans.²⁹ The drug also exerts a noncompetitive antiadrenergic effect³⁰ that might be expected to modulate the ventricular response during relapses to AF. Furthermore, the drug has little or no negative inotropic action. Indeed, in patients with cardiac failure and systolic dysfunction, it increases the LVEF¹³ and improves exercise capacity.³¹ For these reasons, amiodarone may be used with relative impunity in patients with varying levels of ventricular dysfunction. As reported earlier,¹³ amiodarone was well tolerated in the CHF-STAT study. In this substudy, 7 amiodarone patients compared with 1 placebo patient had discontinued the study drug.

Our current data on the effects of the drug in AF, although not derived prospectively in terms of a primary hypothesis with stratified randomization, are in line with the unique combination of the drug's electrophysiological and pharmacological properties.^{11 30} The drug was not only more effective than placebo (31% versus 8%, P=0.002) in converting patients with AF during the course of the study but also in preventing the development of new-onset AF during the course of the study, a difference that was highly statistically significant (P=0.005) compared with placebo. Although the number of patients in which amiodarone was effective in converting AF to sinus rhythm was small, the Kaplan-Meier survival analysis indicated a significantly better survival in converters compared with the nonconverters. Moreover, amiodarone was uniformly effective in producing a sustained and significant slowing of the mean and maximal ventricular responses documented by 24-hour Holter recordings in patients who remained in AF while taking amiodarone. We believe this is the first report of a blinded, placebo-controlled study in which spontaneous conversion of AF to sinus rhythm and the prevention of new-onset AF on amiodarone in patients with heart failure have been documented during prolonged follow-up. Such an aggregate of clinical effects, combined with the drug's propensity to effectively modulate the ventricular rate control also found in this study, is clearly of therapeutic relevance.

Our results therefore raise the issue of whether chronic amiodarone therapy alone or in combination with digoxin might be the preferred first-line therapy in many patients with AF and heart failure. This is the setting in which most other antifibrillatory (class IA, sotalol, or pure class III agents) or ventricular rate-controlling compounds (diltiazem, verapamil, and ß-blockers) may be poorly tolerated. In heart failure, their use may be associated with serious proarrhythmic or negative inotropic actions. Neither of these adverse drug effects was noted in the CHF-STAT study¹³ from which our current data have been derived. For these reasons, the precise role of amiodarone for the control of AF in patients with heart failure should be defined in prospectively controlled, blinded, and randomized studies. It is of interest that a recent trial, albeit in a different subset of patients,³² provides further evidence of a strong antifibrillatory protection against the development of AF when the drug is given prophylactically before and continued during the early postoperative phases of cardiac surgery. Postoperative AF developed in 16 of the 64 patients in the amiodarone group (24%) compared with the development of the arrhythmia in 32 of the 60 patients (53%, P=0.003) in the placebo group.

Our data indicate that patients who converted to sinus rhythm during chronic amiodarone therapy tended to have a significantly better prognosis. Our observations in this regard are consistent with those of Middlekauff et al⁸ who also found that both total mortality and the risk of sudden death were lowered by conversion of AF to sinus rhythm in patients with heart failure. However, these data need to be interpreted with caution because they are observations that are not derived from prospectively randomized studies. An alternative explanation might be that patients with an intrinsically better prognosis are inherently likely to be those who might respond more favorably to the antifibrillatory actions of amiodarone. Because of these limitations, our data neither prove nor exclude the possibility that amiodarone has the potential to improve survival in heart failure patients by decreasing the occurrence of new AF or conversion from existing AF. Rather, the data provide the rationale for a controlled study to examine this issue.

In summary, our data have shown that patients with AF in the setting of heart failure have a significantly greater tendency to spontaneously convert to sinus rhythm during chronic amiodarone therapy. Those with sinus rhythm at baseline are also less likely to develop new-onset AF, and if AF does supervene during chronic amiodarone administration, the ventricular response under these circumstances is significantly slower than it is in comparable patients on placebo. Such an aggregate of drug effects in a single agent raises the possibility that, in patients with congestive heart failure, amiodarone has the potential to be the first-line therapy in the pharmacological control of AF, a possibility that should be examined in prospectively designed, blinded, placebo-controlled trials.

	Acknowledgments

 
This study was funded by the US Department of VA Cooperative Studies Program, by Sanofi Winthrop Recherche (Paris), and by Wyeth-Ayerst Laboratories (Philadelphia).

Received June 25, 1998; revision received August 3, 1998; accepted August 13, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort study: the Framingham Heart Study. JAMA. 1994;271:840–844.[Abstract]
   
2. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Arch Intern Med. 1995;155:469–473.[Abstract]
   
3. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-up Study. Am J Med. 1995;98:476–484.[Medline] [Order article via Infotrieve]
   
4. Onundarson PT, Thorgeirsson G, Jonmundsson E, Sigfusson N, Hardarson T. Chronic atrial fibrillation: epidemiologic features and 14 years follow-up: a case-control study. Eur Heart J. 1987;3:521–527.
   
5. The AFFIRM Investigators. Atrial fibrillation following investigation of rhythm management (AFFIRM) study design. Am J Cardiol. 1997;79:1198–1202.[Medline] [Order article via Infotrieve]
   
6. Nattel S. Newer developments in the management of atrial fibrillation. Am Heart J. 1995;130:1094–1106.[Medline] [Order article via Infotrieve]
   
7. Sopher SM, Camm AJ. Atrial fibrillation: maintenance of sinus rhythm versus rate control. Am J Cardiol. 1996;77:24A–37A.[Medline] [Order article via Infotrieve]
   
8. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation. 1991;84:40–48.[Abstract/Free Full Text]
   
9. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–533.[Abstract/Free Full Text]
   
10. Singh BN. Controlling cardiac arrhythmias: an overview with a historical perspective. Am J Cardiol. 1997;80:4G–15G.[Medline] [Order article via Infotrieve]
    
11. Singh BN. Expanding indications for the use of class III antiarrhythmic agents in patients at high risk for sudden death. J Cardiovasc Electrophysiol. 1995;6:887–900.[Medline] [Order article via Infotrieve]
    
12. Hohnloser S, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects: a review with special reference to torsades de pointes tachycardia. Ann Intern Med. 1994;121:529–538.[Abstract/Free Full Text]
    
13. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D, for the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med. 1995;333: 77–82.
    
14. Middlekauff HR, Wiener I, Saxon LA, Stevenson WG. Low-dose amiodarone for atrial fibrillation: time for a prospective study? Ann Intern Med. 1992;116:1017–1020.
    
15. Graboys TB, Podrid PJ, Lown B. Efficacy of amiodarone for refractory supraventricular tachyarrhythmias. Am Heart J. 1983;106:870–876.[Medline] [Order article via Infotrieve]
    
16. Horowitz LN, Spielman SR, Greenspan AM, Mintz GS, Morganroth J, Brown R, Brady PM, Kay HR. Use of amiodarone in the treatment of persistent and paroxysmal atrial fibrillation resistant to quinidine therapy. J Am Coll Cardiol. 1985;6:1402–1407.[Abstract]
    
17. Chun SH, Sager PT, Stevenson WG, Nademanee K, Middlekauff HR, Singh BN. Long-term efficacy of amiodarone for the maintenance of normal sinus rhythm in patients with refractory atrial fibrillation or flutter. Am J Cardiol. 1995;76:47–50.[Medline] [Order article via Infotrieve]
    
18. Gosselink AT, Crijns HJ, Van Gelder IC, Hillige H, Wiesfeld AC, Lie KI. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA. 1992;267:3289–3293.[Abstract]
    
19. Gold RL, Haffajee CI, Charos G, Sloan K, Baker S, Alpert JS. Amiodarone for refractory atrial fibrillation. Am J Cardiol. 1986;57:124–127.[Medline] [Order article via Infotrieve]
    
20. Brodsky MA, Allen BJ, Walker CJ II, Casey TP, Luckett CR, Henry WL. Amiodarone for maintenance of sinus rhythm after conversion of atrial fibrillation in the setting of a dilated left atrium. Am J Cardiol. 1987;60:572–575.[Medline] [Order article via Infotrieve]
    
21. Blevins RD, Kerin NZ, Benaderet D, Frumin H, Faitel K, Jarandilla R, Rubinfire M. Amiodarone in the management of refractory atrial fibrillation. Arch Intern Med. 1987;147:1401–1404.[Abstract]
    
22. Skoularigis J, Röthlisberger C, Skudicky D, Essop MR, Wisenbaugh T, Sareli P. Effectiveness of amiodarone and electrical cardioversion for chronic rheumatic atrial fibrillation after mitral valve surgery. Am J Cardiol. 1993;72:423–427.[Medline] [Order article via Infotrieve]
    
23. Zarembski DG, Nolan PE, Slack MK, Caruso AC. Treatment of resistant atrial fibrillation. A meta-analysis comparing amiodarone and flecainide. Arch Intern Med. 1995;155:1885–1891.[Abstract]
    
24. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of randomized control trials. Circulation. 1990;82:1106–1116.[Abstract/Free Full Text]
    
25. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation. 1990;82:1932–1939.[Abstract/Free Full Text]
    
26. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. Am J Cardiol. 1992;20: 527–532.
    
27. Singh BN, Vaughan Williams EM. The effect of amiodarone, a new antianginal drug, on cardiac muscle. Br J Pharmacol. 1970;39:657–667.[Medline] [Order article via Infotrieve]
    
28. Ikeda N, Nademanee K, Kannan R, Singh BN. Electrophysiologic effects of amiodarone: experimental and clinical observations relative to serum and tissue drug concentrations. Am Heart J. 1984;108:890–898.[Medline] [Order article via Infotrieve]
    
29. Olsson SB, Brorson L, Varnauskas E. Class 3 antiarrhythmic actions in man: observations from monophasic action potential recordings and amiodarone treatment. Br Heart J. 1973;35:1255–1259.[Free Full Text]
    
30. Kodama I, Kamiya K, Toyoma K. Cellular electropharmacology of amiodarone. Cardiovasc Res. 1997;35:13–29.[Free Full Text]
    
31. Hamer AF, Ankles LB, Johns JA. Beneficial effects of low dose amiodarone in patients with congestive cardiac failure: a placebo-controlled trial. J Am Coll Cardiol. 1989;14:1768–1774.[Abstract]
    
32. Daoud EG, Strickberger A, Man C, Goyal R, Deeb GM, Bolling SF, Bita C, Meissner MD, Morady F. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med. 1997;337:1785–1791.In this multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone versus placebo were compared in patients with congestive heart failure and atrial fibrillation (AF). The effects of amiodarone on established and new-onset AF were evaluated. Of the 103 patients with AF, 51 had been randomly assigned to amiodarone and 52 to placebo. Compared with placebo, amiodarone was significantly more effective in controlling mean and maximal ventricular response rate. Of those patients in sinus rhythm at baseline, significantly fewer patients who had been randomly assigned to amiodarone developed new-onset AF during the follow-up. Conversion to sinus rhythm with amiodarone was also associated with improved survival in these high-risk patients with heart failure.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				D. Roy, M. Talajic, S. Nattel, D. G. Wyse, P. Dorian, K. L. Lee, M. G. Bourassa, J. M. O. Arnold, A. E. Buxton, A. J. Camm, et al. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure N. Engl. J. Med., June 19, 2008; 358(25): 2667 - 2677. [Abstract] [Full Text] [PDF]

				H.-R. Neuberger, C. Mewis, D. J. van Veldhuisen, U. Schotten, I. C. van Gelder, M. A. Allessie, and M. Bohm Management of atrial fibrillation in patients with heart failure Eur. Heart J., November 1, 2007; 28(21): 2568 - 2577. [Abstract] [Full Text] [PDF]

				P. Vassallo and R. G. Trohman Prescribing Amiodarone: An Evidence-Based Review of Clinical Indications JAMA, September 19, 2007; 298(11): 1312 - 1322. [Abstract] [Full Text] [PDF]

				B. N. Singh and E. Aliot Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G17 - G25. [Abstract] [Full Text] [PDF]

				I. C. Van Gelder and M. E.W. Hemels The progressive nature of atrial fibrillation: a rationale for early restoration and maintenance of sinus rhythm Europace, November 1, 2006; 8(11): 943 - 949. [Abstract] [Full Text] [PDF]

				Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]

				A. A. Elesber, A. G. Rosales, R. M. Herges, W.-K. Shen, B. S. Moon, J. F. Malouf, N. M. Ammash, V. Somers, D. O. Hodge, B. J. Gersh, et al. Relapse and mortality following cardioversion of new-onset vs. recurrent atrial fibrillation and atrial flutter in the elderly Eur. Heart J., April 1, 2006; 27(7): 854 - 860. [Abstract] [Full Text] [PDF]

				B. N. Singh {beta}-Adrenergic Blockers as Antiarrhythmic and Antifibrillatory Compounds: An Overview Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4_suppl): S3 - S14. [Abstract] [PDF]

				A. Verma, A. Natale, B. J. Padanilam, E. N. Prystowsky, A. Verma, A. Natale, B. J. Padanilam, and E. N. Prystowsky Why Atrial Fibrillation Ablation Should Be Considered First-Line Therapy for Some Patients Circulation, August 23, 2005; 112(8): 1214 - 1222. [Full Text] [PDF]

				J. H.K. Vogel, S. F. Bolling, R. B. Costello, E. M. Guarneri, M. W. Krucoff, J. C. Longhurst, B. Olshansky, K. R. Pelletier, C. M. Tracy, R. A. Vogel, et al. Integrating Complementary Medicine Into Cardiovascular Medicine: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine) J. Am. Coll. Cardiol., July 5, 2005; 46(1): 184 - 221. [Full Text] [PDF]

				K. Swedberg, L. G. Olsson, A. Charlesworth, J. Cleland, P. Hanrath, M. Komajda, M. Metra, C. Torp-Pedersen, and P. Poole-Wilson Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET Eur. Heart J., July 1, 2005; 26(13): 1303 - 1308. [Abstract] [Full Text] [PDF]

				P. Zimetbaum An Argument for Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation Circulation, June 14, 2005; 111(23): 3150 - 3156. [Full Text] [PDF]

				B. N. Singh, S. N. Singh, D. J. Reda, X. C. Tang, B. Lopez, C. L. Harris, R. D. Fletcher, S. C. Sharma, J. E. Atwood, A. K. Jacobson, et al. Amiodarone versus Sotalol for Atrial Fibrillation N. Engl. J. Med., May 5, 2005; 352(18): 1861 - 1872. [Abstract] [Full Text] [PDF]

				M. Lehto, S. Snapinn, K. Dickstein, K. Swedberg, M. S. Nieminen, and on behalf of the OPTIMAAL investigators Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience Eur. Heart J., February 2, 2005; 26(4): 350 - 356. [Abstract] [Full Text] [PDF]

				L.-F. Hsu, P. Jais, P. Sanders, S. Garrigue, M. Hocini, F. Sacher, Y. Takahashi, M. Rotter, J.-L. Pasquie, C. Scavee, et al. Catheter Ablation for Atrial Fibrillation in Congestive Heart Failure N. Engl. J. Med., December 2, 2004; 351(23): 2373 - 2383. [Abstract] [Full Text] [PDF]

				Y.-M. Cha, M. M. Redfield, W.-K. Shen, and B. J. Gersh Atrial Fibrillation and Ventricular Dysfunction: A Vicious Electromechanical Cycle Circulation, June 15, 2004; 109(23): 2839 - 2843. [Full Text] [PDF]

				T. Deneke, T. Lawo, B. Gerritse, B. Lemke, and for the European GEM DRTM Investigators Mortality of patients with implanted cardioverter/defibrillators in relation to episodes of atrial fibrillation Europace, January 1, 2004; 6(2): 151 - 158. [Abstract] [Full Text] [PDF]

				R. L. McNamara, L. J. Tamariz, J. B. Segal, and E. B. Bass Management of Atrial Fibrillation: Review of the Evidence for the Role of Pharmacologic Therapy, Electrical Cardioversion, and Echocardiography Ann Intern Med, December 16, 2003; 139(12): 1018 - 1033. [Abstract] [Full Text] [PDF]

				A. U. Khand, A. C. Rankin, W. Martin, J. Taylor, I. Gemmell, and J. G. F. Cleland Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1944 - 1951. [Abstract] [Full Text] [PDF]

				S. A. Tejan-Sie, R. D. Murray, I. W. Black, S. E. Jasper, C. Apperson-Hansen, J. Li, E. A. Lieber, R. A. Grimm, A. L. Klein, and ACUTE Investigators Spontaneous conversion of patients with atrial fibrillation scheduled for electrical cardioversion: An ACUTE trial ancillary study J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1638 - 1643. [Abstract] [Full Text] [PDF]

				J. Galperin, M. V. Elizari, P. A. Chiale, R. T. Molina, R. Ledesma, A. O. Scapin, M. V. Blanco, R. Bonato, M. Lago, and Grupo de Estudio de Fibrilacion Auricular Con Amio Pharmacologic Reversion of Persistent Atrial Fibrillation with Amiodarone Predicts Long-Term Sinus Rhythm Maintenance Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2003; 8(3): 179 - 186. [Abstract] [PDF]

				A. Capucci and D. Aschieri Antiarrhythmic drug therapy: what is certain and what is to come Eur. Heart J. Suppl., September 1, 2003; 5(suppl_H): H8 - H18. [Abstract] [PDF]

				T. J. Wang, M. G. Larson, D. Levy, R. S. Vasan, E. P. Leip, P. A. Wolf, R. B. D'Agostino, J. M. Murabito, W. B. Kannel, and E. J. Benjamin Temporal Relations of Atrial Fibrillation and Congestive Heart Failure and Their Joint Influence on Mortality: The Framingham Heart Study Circulation, June 17, 2003; 107(23): 2920 - 2925. [Abstract] [Full Text] [PDF]