Maintaining Sinus Rhythm with Antifibrillatory Drugs in Atrial Fibrillation

Maintaining Sinus Rhythm with Antifibr1 Ilatmy Drugs in Atrial Fibrillation Elliott M. Antman,

MD

/ Management of atrialfibrillationisa commonandcom- butnecessitates long-termanticaagulation (whichmay plex clinicalproblem.Two ma@ treatment strategies alsobeneededdespiietheuseof antia+hmics tosuphaveemerged:suppression of recurrences versuscon- pressrecurrences of otrialfibrillation) withsomeriskof irolof ventricular roteandanticoogulation toreducethe bleeding.Randomized trialsare now neededto define riskof stroke.Maintaining sinusrhythmoffersthehemo- therelativebenefits of these2 treatment sirotegies. Such on the dynamicbenefits of improvingventricular performance trialsshouldbedesignedto provideinformation andexercise capacity butmayexposethepatienttok impactof the2 a roacheson symptoms, exercise cariskof proarrhythmia/sudden deathand drug-related pacity,qualityof Ii % , and mortalitymtein patients with morbidity.Controllingventricularrate helpsdecrease atrialfibrillation. symptomatic palpitations andimproveexercise capacity (AmJCardiol1996;78(suppl 4):67-72)

trial fibrillation is perhaps the most common cardiac arrhythmia, seen in up to 5% of the popA ulation over the age of 65 years.] There are several important clinical issues to be considered in the management of patients with this disorder. Among the critical factors are how the patient has presented and if, in fact, the patient is complaining of any symptoms. Assessment of the clinical presentation includes the patient’s age, gender, underlying cardiac status, and the possibility that the patient’s response to an antiarrhythmic drug may be different than expected. In considering the patient’s cardiac status, the specific factors that need to be assessed are the presence of an enlarged left atrium, the presence of left ventricular dysfunction, and whether atrial fibrillation is occurring in the setting of a preexcitation syndrome, in which a very rapid ventricular rate could be an epidemiologic marker for sudden death, despite the absence of structural heart disease. Clinicians naturally wish to alleviate symptoms in patients complaining of rapid palpitations and should expeditiously treat the increased ventricular rate in atria.1fibrillationthat frequently leads to an increase in pulmonary capillary wedge pressure or reduction in cardiac output. Sometimes, however, clinicianstranslate their experience in the management of synzptomatic atrial fibrillationinto the managementof asyrnpkmzatic atrial fibrillation,despite the lack of clinical guidelines or supportive data. It should be noted that atrial fibrillation,even if asymptomatic,may put individuals with poorly controlled ventricularrate at risk for a “tachycardiomyopathy.”2’3 The various etiologies underlying atrial fibrillation also need to be considered in patient management. For example, is fibrillation the result of an From the Deportmentof Medicine, Harvard Medical School, and Samuel A. Levine Cardiac Unit, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts. Address for reprints: Elliott M. Antman, MD, Harvard Medical School, Samuel A. Levine Cardiac Unit, Cardiovascular Divisian, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts02115.

01996

by Excerpta Medico,

All rights reserv?d.

Inc.

acute, potentially reversible process such as pneumonia, pericarditis, or thyrotoxicosis, or a chronic process such as rheumatic heart disease or chronic coronary artery disease with congestive heart failure? IS the pattern of atrial fibrillation paroxysmal or chronic? Although the understanding of the electrophysiologic effects of antiarrhythmic agents in maintaining sinus rhythm is improving, it is still incomplete. This is especially true with respect to how antiarrhythmic drugs either terminate the arrhythmia or prevent its recurrence. Thus, it is difficult to translate the existing information into an algorithm for managing a particular patient with atrial fibrillation. TREATMENT STRATEGIES FIBRILLATION

FOR

ATRIAL

The overwhelming array of issues to consider in patient management can complicate the choice of treatment regimen. Until recently, the clinical strategy for managing atrial fibrillation focused on restoration of sinus rhythm. Recent analyses indicate, however, that the use of antiarrhythmic agents to maintain sinus rhythm may be associated with considerable risk. Consequently, many clinicians have chosen an alternative strategy: accepting the presence of either chronic or paroxysmal atrial fibrillation but controlling the ventricular rate while anticoagulating the patient. Strategy1: Suppressing recurrences of atrialfibrillationandmaintaining normalsinusrhythm:Maintaining

sinus rhythm and suppressing the recurrence of atrial fibrillation have hemodynamic benefits that can improve ventricular performance, exercise capacity, and symptom relief. It is hoped, but by no means timorously proven, that maintaining sinus rhythm will obviate the need to give patients anticoagulants thereby eliminating the risk of bleeding. The hemodynamic benefits to be gained from restoration of sinus rhythm following cardioversion from longstanding atrial fibrillation have been demonstrated. In a study by Gosselink et al,4 peak oxygen consumption was measured in 63 patients before 0002-9149/96/$15.00 Pll S0002-9149(96)00455-9

67

35.

, p
30.

&15 >

5-

0.

Heart disease (N=28) -Before

LoneAF (N=9)

cardioversion

monthof SR

FIGURE 1:peakoxvaenconsummation (VOZ1 in rxrtients withhmastunding atrialfibrfi~tion (AF),6efore’car~iav&sion andafteri monthof sinusrhythm(SR).Improvement wasnotedbathinpotients w.A underlying heartdisease andinthasewithloneatrial fibri[blion.(Reprinted withpermission from13rHeartJ?)

100 t

*

,

-Qulnidine

mControl

I

..

L

*

.-c

e 50-

E 8 k

0-

20-

0

3

6 Time (months)

Quinidine vs control

12

*p
FIGURE 2. Proportion of patients remaining innormalsinus aftercardioversion wassi nifirhythmat3, 6, and 12 months candygreaterinquin.kfine-treated patients thaninconfr 0!satall .nts.NSR= normalsinusrhythm.(Reprinted wfthpermisCircuksbss?) %;L

and 1 month after electrical cardioversion. In patients who remained in sinus rhythm, peak oxygen consumption increased 1190,whereas in those with a recurrence of atrial fibrillation, peak oxygen consumption was unchanged. The benefits of maintaining sinus rhythm extended even to patients with underlying heart disease (Figure 1); improvement in peak oxygen consumption was unrelated to functional capacity or left ventricular function before cardioversion. The currently available pharmacologic options for suppressing recurrences of atrial fibrillation are class IA and IC and class 111drugs, used alone or in combination. The conventional choice for this purpose is quinidine. However, evidence exists of increased mortality risk with this approach. A metaanalysis of 6 randomized trials evaluating the role of quinidine in the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation indicated that at the end of 1 year, about 259?0of patients maintained sinus rhythm in the control group and 68

THE AMERICAN JOURNAL OF CARDIOLOGY@

about 5070maintained sinus rhythm in the quinidine group (Figure 2).5 However, the odds of dying were about 3 times higher in the quinidine-treated patients than in the control group (12 deaths in the quinidine group vs 3 deaths in the control group). Thus, quinidine treatment is more effective than no antiarrhythmic therapy in suppressing the recurrence of atrial fibrillation but may be associated with increased total mortality. It should be emphasized, however, that the precise cause of death in the quinidine-treated patients was known in 7 of 12 cases and included sudden cardiac death (3 cases), myocardial infarction ( 1 case), cerebrovascular accident (2 cases), and suicide ( 1 case). In the other 5 deaths in the quinidine group, the precise cause of death was unclear, but important concurrent medical illnesses were present in some patients, including carcinoma (2 cases), pneumonia ( 1 case), and hepatic failure ( 1 case). The cardiac arrests in patients receiving quinidine highlight the potential role of this agent in precipitating serious ventricular arrhythmias. The relation between cardiac mortality and antiarrhythmic drug therapy was also analyzed in the Stroke Prevention in Atrial Fibrillation study,G which was a randomized clinical trial comparing warfarin, aspirin, and placebo for the prevention of ischernic stroke or systemic embolism in patients with nonvalvular at@ fibrillation, In patients also receiving antiarrhythmic drug therapy, cardiac mortality and arrhythmia death were increased approximately 2.5-fold. Among patients with a history of congestive heart failure, those given antiarrhythmic drug therapy had a 3-fold increase in the risk of cardiac death (Table I). Most of these patients were receiving class IA antiarrhythmic drugs; few of them were receiving class IC chugs. These data also suggest that the risk of such therapy may outweigh the potential benefit of maintaining sinus rhythm in selected patients with severe underlying organic heart disease. Strategy 2: Controllingventricularroteand chronic anficoogulation: Recently, control of the ventricular rate plus anticoagulation to reduce the risk of stroke has become an attractive treatment option for atrial fibrillation. There are several reasons for this. The first is illustrated by a case study of a 55year-old female patient, reported by Grogan et al,’ with a history of atrial fibrillation and congestive heart failure. The patient initially presented with atrial fibrillation, severe left ventricular dysfunction, and a ventricular rate of 150 beats/rein. Three months after the ventricular rate was controlled with amiodarone to an average of 75 beatshmin, the patient’s ejection fraction increased dramatically from 20% to 61%, and sinus rhythm was then restored. The patient relapsed back into atrial fibrillation 51 months after initial presentation, again with rapid ventricular response and depressed ejection fraction. Following rate control and, ultimately, conversion to sinus rhythm, the patient again demonstrated marked

VOL 78 (4A]

AUGUST

29,

1996

TABLE i

increased

Risk

of Mortalityfromthe Useof Antiarrhythmic Drugsin the Stroke Prevention in Atrial Fibrillation Study* Unadjusted No.

All

Deaths

Hazord

p Value

Hazard

p Value

1,307

39

1.6

0.24

1.8

0.20

23’9

19

2.9

0.04

3.3

0.05

20

0.81

0.78

0.77

0.72

Definite CHF No definite CHF

Cardiac

Ad@ed

1,068

‘ Amalysisrestricted to patients for whom antiarrhythmic treatmentwas prescribed for atrial fibrillation, t CHF = congestive heart failure, Reprinted with permission from J Am Co// Cardio/.6

improvement in ventricular function (ejection fraction rose from 20% to 52%; Figure 3), The second reason is demonstrated by an analysis of pooled data from 5 randomized controlled trials by the Atrial Fibrillation Investigators comparing anticoagulation with placebo for prevention of ischemic stroke in patients with chronic nonvalvular atrial fibrillation (Table II) ,s The overall annual risk of stroke in the control group was 4.590,versus only 1.4% with warfarin, representing a 68% reduction in the annual risk of stroke (95% confidence interval, 50-79%). The efficacy of aspirin was less consistent. Additional trials are under way to determine whether the level of anticoagulation that was achieved in these trials with warfarin was higher than needed to achieve a reduction in riskof stroke.

HOW EFFECTIVE AND SAFEARE THE NEWER ANTIARRHYTHMIC DRUGS? Recent studies have assessed the benefits of some of the newer antiarrhythmic drugs, such as propafenone and sotalol, in suppressing the recurrence of atrial fibrillation in patients who were unresponsive to or intolerant of previous therapy. As yet, the data on the safety and efficacy features of the so-called “pure” class III compounds (such as dofetilide and azimilide, which are still under development) remain to be defined. Sot&l versuspropafenone: In a randomized, comparative trial of 100 patients with refractory atrial fibrillation who had unsuccessful therapy with class IA antiarrhythmic agents, the ability of sotalol and propafenone to suppress symptomatic recurrences of

atrial fibrillation was determined.9The baseline characteristicsof the 2 groups were similar. The period of highest risk for recurrence of atrial fibrillation was the first 3 months after restoration of sinus rhythm (Figure 4). At 3 months following cardioversion, 46% of patients randomized to propafenone and 49% of patients randomized to sotalol were in sinus rhythm (p = NS ), This percentage is consistent with other trials of this nature in patients receiving antiarrhythmic drugs for suppression of recurrences of atrial fibrillation. At 6 and 12 months after restoration of sinus rhythm, the proportion declined at about the same rate for both drugs (Figure 4). The response rates were not affected by arrhythmia pattern (paroxysmal versus chronic) or left atrial size. It was concluded that propafenone and sotalol were equally effective in maintaining sinus rhythm in patients with recurrent atnal fibrillation. Incapacitating side effects that required withdrawal of medication occurred in about 8% of the propafenone group and in 12% of the sotalol group (Table III).’ There were 2 deaths during follow-up in the sotalol group and none in the propafenone group. In 1 case, the patient developed a serum potassium level of 2.8 mEq/dL due to habitual ingestion of tea while on sotalol. This death emphasizes the changing substrate that can place a previously stable patient at risk for sudden death. The other patient developed sudden cardiac death and either had a mofound bradvcardiac event or torsade de .nointes: n; fi-wtherinfo~ation is available.

TABLE II Efficacy of Warfarin Versus Control in 5 Studies af the Incidenceof IschemicStrake in Patients with Nonvalvular Atrial Fibrillation

61

Incidenceof Stroke: Warfarin Control Group

Treatment Group

Risk Reduction

[%/year)

(%/year]

(%)

AFASAK

4.8

1.9

52

SPAF

7.4

2.3

67

8AATAF

2.98

0.41

86

CAFA

5,2

3.5

37

SPINAF

4.3

0.9

79

Study*

h

20

20

20

10

m

0

Initial

Heart rate

(bPm)

AF 150

3 months AF 75

51months

56 months

AF 140

SR 80

‘ AFASAK = Atrial Fibrillation, Aspirin, Anticoagulotion study; BAATAF =

I

FIGURE 3. Serialeiection fraction (EF)meosuremenk ina 55yeur-ofdwomanwithatrialfibrillation (AF)irecsksd withamiodarssne forratecontrolSR= sinusrfsyifsm. (Reprinted withpermissionfromAm J CadioLT

BostonArea Anticoagulation Trial for Atrial Fibrillation;CAFA = Canadian Atrial FibrillationAnticcugulotion stidy; SPAF = Stroke Preventionin Atrial Fibrillation study; and SPINAF = Veterans Affairs Stroke Preventionin Nonrheumatic Atrial Fibrillation study. Adapted from [oncet,’9 Circulation,*”N

A SYMPOSIUM:

PHARMACOTHERAPY

Eng/JMed,2’23 JAm Co/l Cardiol.22

OF CARDIAC ARRHYTHMIAS

69

90+ 807060504030-

—

PPFN I

—

SOT

TA8LE Ill Adverse Effects with Propafenone or Satalol Therapy for Recurrent Symptomatic Atrial Fibrillation Propafenone No. Bradycordio Congestive

heart foilure

Edemo

L-————J

Proarrhythmia

1

2

3

4

5

8

7

8

9 10 11 12

Months 4. Pqatmrs“ of patienkwithrecurrents ptomatk FIGURE ~“al fibriliatian (#J remaining insinusrhylhmr“ursngIreatnwnt none(PPFN) or eatrslol (SO~.(Reprinted withperwith AmJCar$iaL~ mission *

Sotalal No.

%

4

8

4

8

0

0

2

4

0

0

0

0

2

A

3

6 14

9

18

7

Gastrointestinal

8

16

0

o’

Abnormal

5

10

0

0

Impotence

1

2

3

6

Death

0

0

2

4

4

8

6

12

Central

O

(ventricular)

%

Stopped

nervous system taste

medication

owing

ta side effects * P = 0.056.

Reprinted with permission from AmJ Cardio/.9

---

a

80

.-c

80

C/l 0)

.-c .-C

40

g

~ s

1

20

1

— —

Sotalol Quinidine

I

FIGURE 5. Percenta e al patients withchronic akialfibrillation witheatakrl Or remaining insinus%ythm(S~ aftermealment qsrinidine. (Reprinted withpermission karss Circu/atian.’Y

Sot&l versusquinidine:An open, randomized study compared quinidine (n = 85) and sotalol (n = 98) starting after sinus rhythm had been restored for at least 2 hours by direct current conversion in patients with chronic atrial fibrillation (present for 2 months to 1 year) .10At the end of the sixth month of treatment, there was no significant difference in the proportion of patients who remained in sinus rhythm (52?Z0in the sotalol group and 48Y0in the quinidine group; Figure 5 ). Among patients who relapsed into atrial fibrillation, however, heart rate and the incidence of symptoms were both lower with sotalol than with quinidine. Thus, sotalol appears to be an effective alternative for maintenance of sinus rhythm after direct current conversion of chronic atrial fibrillation and appears to control ventricular rate in patients who relapse into atrial fibrillation. Two deaths occurred in the trial, 1 in each treatment group. In addition, 2 cases of torsade de pointes occurred, 1 in each treatment group, but neither was fatal. Sotalol is also well tolerated. In this comparative study of sotalol versus quinidine,1080 mg and 160 mg of sotalol were used twice daily compared with a median of 160 m twice daily in the sotalol versus propafenone study.5 There was no significant difference in the number of adverse reactions reported or efficacy between the 2 sotalol dosages in the sotalol 70

THE AMERICAN JOURNAL OF Cardiology@

versus quinidine study.10However, the proportion of patients whose drugs were withdrawn because of incapacitating side effects was 1690 in the quinidine group versus 9% in the sotalol group.10 Amiodarone: Amiodarone appears to be the most promising of the antiarrhythmic drugs for suppressing the recurrence of atrial fibrillation or flutter. Six nonrandomized studies of amiodarone involving 320 patients have demonstrated that the proportion of patients who maintain sinus rhythm is between 53% and 79$%0, with an average follow-up time of about 15-22 months (Table IV).11-16 One of the 6 studies evaluated the efficacy and safety of low-dose amiodarone for maintenance of sinus rhythm after electrical conversion of atrial fibrillation or flutter in patients who had failed previous treaments.lb The study excluded patients who ‘ad paroxysmal atrial fibrillation, sick sinus syndrome, or hyperthyroidism. Because of the known interaction of amiodarone with digitalis, the dose of digitalis was reduced by 5070after initiating amiodarone treatment. Atrioven@cular nodal blocking drugs (such as digoxin, calcmm antagonists, or ~ blockers) were allowed during the loading period and discontinued thereafter. The initial dose of amiodarone was 600 mg/day administered orally for 4 weeks. Patients who did not revert to sinus rhythm during loading underwent electrical cardioversion. After cardioversion, patients were maintained on a dose of approximately 200 mg of amiodarone per day, guided by serum drug levels, to maintain a concentration of 1.0–2.5 mg/L. Of the 90Y0of patients who had sinus rhythm restored with electrical cardioversion, 53$Z0were still in sinus rhythm after 3 years (Figure 6). Intolerable side effects occurred in only 1 patient. Experience with amiodarone for suppression of atrial fibrillation in heart failure is limited but promising. Of the 89 patients studied by Gosselink et al, 16 14patients had symptomatic, severe congestive heart failure (mean left ventricular ejection fraction, 28Yo). Thirteen patients (93%) maintained sinus rhythm during 6 months of follow-up treatment. One

VOL 78 (4A)

AUGUST

29,

1996

TABLE IV Studies Demonstrating the Effectiveness of Amiodarone for Suppressing the Recurrenceof Atriol Fibrillation and Maintaining Sinus Rhythm*

Study Brodsky et al, ’

1967

Gold et 01,’2 1986 Horowitz

et al,’3

Blevins et al,’4

1965

1987

Potients

PoroxysmolAF

SpontaneousConversion

(n)

(%]

(%)

SR Maintenance (%)

Meon

Follaw-up (ma)

28

NA

43

75

22

68

79

71

79

21

38

71

30

71

15

38

33

32

53

16

Stevenson et al,”

1988

59

59

73

61

20

Gosselink

1992

89

0

16

53

21

●

et al,”

AF = atricrlfibrillation; NA = not applicable; SR = sinus rhythm.

Adapted with permission from AmJ

Cardio/.’7

patient died because of progressive heart failure 2 months following cardioversion; sinus rhythm had been maintained until the time of the patient’s death. Middlekauff et a117reported their experience in 25 patients with advanced heart failure and atrial fibrillation refractory to previous antiarrhythmic therapy. No patient discontinued amiodarone because of side effects. Sinus rhythm was restored by either pharmacologic therapy or direct current cardioversion in 8470 of the patients. Cardiopulmonary exercise testing was performed in 6 of the patients just prior to cardioversion and 28–42 days following cardioversion. Exercise capacity, as assessed by anaerobic threshold and peak oxygen consumption (Figure 7), was significantly improved following restoration of sinus rhythm. Thus, in advanced heart failure patients with atrial fibrillation, amiodarone is well tolerated, associated with improved exercise tolerance, and highly efficacious. Concerns about toxicity have limited the widespread use of low-dose amiodarone for the treatment of atrial fibrillation in clinical practice.17However, the incidence of cardiac toxicity is very low. The majority of amiodarone’s noncardiac side effects are dose related, occurring less frequently at the lower doses required to suppress atrial fibrillation. The most serious side effect is pulmonary toxicity. Dusman et al 1sretrospectively reviewed their experience with 573 patients treated with amiodarone

mg/day for recurrent ventricular or supraventricular tachyarrhythmias. Amiodtione pulmonary toxicity was diagnosed in 33 of the patients (6%). Older patients developed it more frequently, with no cases diagnosed in patients who started therapy at s40 years of age. No patient receiving a mean daily maintenance dose s305 mg/day developed pulmonary toxicity. Other dose-related side effects, including tremor, nausea, hepatitis, and’peripheralneuropathy, respond to dose reduction, rarely requiring drug withdrawak17Non–dose-related side effects include dermatologic reactions and hypothyroidism or hyperthyroidism. The lowest optimal amiodarone dose that minimizes toxicity yet remains efficacious in the majority of atrial fibrillation patients remains unknown. 50–800

NEED FOR FUTURECLINICALTRIALS Randomized trials are now needed to compare directly the 2 major treatment strategies for atrial fibrillation: suppression of recurrences versus rate control and anticoagulation. An important issue to consider in the design of such trials is the definition of ‘‘success.’ A successful outcome could be defined as the prevention of recurrent atrial fibrillation in the suppression arm and control of symptomatic palpitation in Peak

100

25

60-

371 29

22 ‘

9

2 2

40-

<()

AFibvs SR, p=O.05

80

80-

-k

VO*(mUkg/min) —------,

20 15

‘

10 [ ~

6

18

24

30

36 41

Follow-up, months FIGURE 6. Actuarial arrhythmia-free episodes in patients with chronic atrialfibrillation or flutter aftercardioversian tosinus rhythmdurin amiadarone treatment. Numbers attheste limsindicate#re numberafpatietsts atrisk.(Reprin~wiWmission fromJM4A.’b)

AFib-(21days amio)

SR (35days post-CV)

FIGURE 7. peakoxygencarssumpfion (VOS)determined incardiapulmanary exercise testing in patients withadvanced heartfailureandatrialfibrilkstfan (AFib)faflowing amiodarcme loading (21days),anthedayofelectrical cardioversion, and28-42 ) fallowing cardioversian tosinusrhythm days(mean,35 v permissianfram (SR).(Reprinted wi AmJCardicd.’7)

“A SYMPOSIUM:

PHARlv’LACOTHERAP’f OF CARDIAC ARRHYTHMIAS

71

the rate control arm. However, the clinical response to the treatment regimen has not received sufficient attention in the past and deserves much more emphasis, since practicing clinicians need to know how their patients are likely to respond to a particular therapeutic option. How will the treatment regimen affect the patient’s functional capacity, symptoms, and overall quality of life? Drug-related mortality is clearly an important issue and is likely to require trials with a large sample size given the low event rates ( s5% ). Finally, given the heterogeneous nature of underlying cardiac pathology in patients with atrial fibrillation, it may be important to stratify the randomization process and data analysis by the presence or absence of structural heart disease.

1. Kerr CR, Chmrg DC. Atrird fibrillation: fact, controversy and future. Clin Prog Electrophysiol Pacing 1985;3:319-337. 2. Peters KG, Kienzle MG. Severe cardiomyopathy due to chronic rapidly conducted atrial fibrdlation: complete recovery after restoration of sinus rhythm. Am JMed 1988;85:242-244. 3. Sarembock IJ, Homk AR, Commerford PJ. Tachycardia-indrrced reversible left ventricular dysfunction: a report of 2 cases. SAj7Mea’J 1988;73:484–485. 4. Gosselirrk ATM, Crijns HJGM, Van Den Berg MP, Van Den Broek SAJ, Hillege H, Landsman MLJ, Lie KI. Functional capacity before and after cardiversion of atrial fibrillation: a controlled study, Br Heart J 1994;72:161– 166. 5. Coplen SE, Arrtman 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. 6. f%ker (3C, BhicksherrrJL, McBride R, Kronmal RA, Halperirr JL, Hnrt RG. Antiarrhythnric dmg therapy and cardiac mortality in atrial fibrillation. J Am Coil Cardiol 1992;20:527–532. 7. Grogarr M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570-1573. 8. Atriaf Fibrillation Investigators. Risk factora for stroke and efficacy of rmtitbrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:14491457.

72

THE AMERICAN JOURNAL OF CARDIOLOGY@

9. Reimold SC, Carrtillon CO, Friedman PL, Antman EM. Propafenone versus sotafol for suppression of recurrent symptomatic atrial fibrillation. Arn JCardiol 1993;71:558–563. 10. Jurrl-Moller S, Edvardsson N, Refmqvist-Ahlberg N. Sotalrrl versus quinidine for the maintenance of sinus rhythm after direct current conversion of atriaI fibrillation. Circulation 1990;82:1932–1939. 11. Brodsky MA, Allen BJ, Walker CJ, 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 Carriiol 1987;60:572–575. 12. Geld RL, Haffajee CI, Charos G, Sloan K, Baker S, Alpert JS. Amiodaroue for refractory atrial fibrillation. Am J Cardiol 1986;57:124–127. 13.Horowitz LN, Spielmmr SR, Greensparr AM, Mintz GS, Morgarrroth J, Brown R, Brady PM, Kay HR. Use of amiodarmre in the treatment of persistent and paroxysmal aerial fibrillation resistant to quinidine Orerapy. JAm CCMCardiol 1985;6:1402-1407. 14. Blevins RD, Kerirr NZ, Benaderet D, Frumin H, Faitel K, JamrrdiUa R, Rubenfire M. Arniodarone in the management of refractory atriaf fibrillation. Arch Intern Med 1987;147:1401–1404. 15. Stevenson WG, Rieders D, Nademmree K, Weiss J, Singh BN. Amiodmone in the management of supraverrtricular tachycardias. In: Singh BN, ed. Control of Cardiac Arrhythmias by Lengthening Repohrrization. Mount Kisco, NY: Futnra, 1988:419–433. 16. Gosselirrk ATM, Crijns HJGM, Van Gelder IC, Hillege H, Wiesfeld ACP, Lie KI. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA 1992;267:3289–3293. 17. Middlekauff HR, Wiener I, Stevenson WG. Low-dose arniodarone for atriaf fibrillation. Am J Cardiol 1993;72(suPP1) :75F–81F. 18. Dusmarr RE, Starrton MS, Miles WM. fGein LS, Zipes DP, Fineberg NS, Heger JJ. Clinicaf features of arnindarone-indrrced pulmonary toxicity. Circulation 1990;82:51–59. 19. Petersen P, Boysen G, Godtfredsen J, Anderson E, Arrdersen B. Placebocorrtrokl, randomized trial of warfarirr and aspirin for prevention of tfrremboembolic complications in chronic ahial fibrillation: the Copenhagen AFASAK study. Lurrcet 1989;i:175–178. 20. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in Atrisf Fibrillation Study: final results. Circulation 1991;84:527. 21. The Boston Area Anticoagulation Trial for Atriaf Fibrillation Investigators. The effect of low-dose warfarirr on the risk of stroke in patients with norrrfreumatic atriaf fibrillation. N Engl JMed 1990;323:1505. 22. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation .krticoagulatimr (CAFA) Study. J Am COUCardio[ 1991;18:349–355. 23. Ezekowitz MD, Bridgerx SL, James KE, Carliner NH, Coiling CL, Gomick CC, Krarrse-Steirrrauf H,-Kurtzke JF, Nazariarr SM, Radford MJ, Rickfes FR, Shabetai R, Deykirr D, for the Veterans Affairs Stroke Prevention in Norrrheumatic Aerial Fibrillation Investigators. Warfarirr in the prevention of stroke asseciatcd with rrmrrheumatic atrial fibrillation. N Errgl J A4ed 1992;327:14061412.

VOL 78 (4A)

AUGUST

29,

1996