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Atrial Fibrillation: PharmacologicalTherapy

Chinmay Patel, MD, Mohammed Salahuddin, MD,Andria Jones, DO, Aashay Patel, MBBS,

Gan-Xin Yan, PhD, and Peter R. Kowey, MD, FAHA

Abstract: Atrial fibrillation (AF) is the most commoncardiac arrhythmia encountered in clinical practice.Although once considered a nuisance arrhythmia,recent clinical trial evidence suggests that the pres-ence of AF is an important independent predictor ofmortality and morbidity. The primary goals of AFtreatment are relief of symptoms and prevention ofstroke. The value of anticoagulation with warfarinhas been proven unequivocally. Control of ventricu-lar rate with atrioventricular nodal blockingagents—the so-called rate control strategy—is leastcumbersome and sometimes the best approach. Bycontrast, efforts to restore and maintain sinusrhythm using antiarrhythmic drugs—the rhythmcontrol approach—although tedious, may be ideal inpatients who are young or highly symptomatic and inthose with new-onset AF. The relative merits of bothtreatment strategies are discussed in this article,emphasizing the excellent clinical trial data that
support each. (Curr Probl Cardiol 2011;36:87-120.)
roblem Statement

T he epidemic of atrial fibrillation (AF) affects approximately 1% ofthe adult population of the United States. It is projected that by theyear 2050, there will be almost 15 million patients with AF.1-3 It

s a very common cardiac arrhythmia in clinical practice. Thirty years ofollow-up data from the Framingham Study cohort have suggested that

ompeting Interests. None.urr Probl Cardiol 2011;36:87-120.
146-2806/$ – see front matteroi:10.1016/j.cpcardiol.2011.01.001
urr Probl Cardiol, March 2011 87

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he lifetime risk of developing AF is 1 in 4 for men and women older than0 years with a higher predisposition for men and white Americans.4,5

lthough AF is uncommon before the age of 60 years, its prevalencencreases markedly thereafter, affecting about 10% of the population by0 years of age.2 Additionally, the presence of AF is associated withigher long-term risk of stroke, heart failure, and all-cause mortality.6,7

ith the aging population, this disease burden contributes enormously toorbidity and mortality.8 The total direct costs of treating patients withF in the year 2005 were estimated at more than $6bn.9 Thus, AF is a

ostly public health problem.

urrent Therapy of Atrial FibrillationToday, therapy for AF is multidimensional with treatment options

panning from pharmacologic therapy to invasive electrophysiologicalntervention.10 The principle goals of these treatments are relief ofymptoms and prevention of stroke. Pharmacologic therapy principallyncludes anticoagulation with warfarin, control of heart rate or rhythm,nd supportive nonarrhythmic drug therapy. There is a consensus regard-ng the indications and benefits of anticoagulation in AF; however, debateontinues regarding whether to pursue the strategy of control of theentricular rate (rate control) or the strategy of maintenance of sinushythm (SR) (rhythm control), to prevent and even reverse atrial remod-ling.11,12 Catheter-based radiofrequency ablation is a promising ap-roach that can be used as an alternative or as an adjunct to antiarrhythmicrugs.13 This article discusses the strategy of rate vs rhythm control,urrently available antiarrhythmic drugs, and the role of adjuvant phar-acotherapy of prevention of AF. Radiofrequency ablation and antico-

gulation in AF are beyond the scope of this article and are discussedlsewhere.10

lassification of Atrial FibrillationAccording to the American College of Cardiology/American Heartssociation/European Society of Cardiology (ACC/AHA/ESC) Taskorce on Clinical Guidelines for the management of AF, AF can belassified into 4 types: first detected episode, paroxysmal, persistent, andermanent.10 Paroxysmal AF terminates spontaneously, with episodesypically lasting less than 24 hours and up to 7 days. Persistent AFequires cardioversion (pharmacologic or electrical) to terminate and thepisodes last more than 7 days. Permanent AF describes continuous AFhat has failed cardioversion or where cardioversion has never been
ttempted. Recurrent AF describes 2 or more episodes of paroxysmal or
8 Curr Probl Cardiol, March 2011

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ersistent AF. The term “lone AF” defines young patients who developF in the absence of readily identifiable cardiopulmonary or systemicisease that can lead to AF. These patients in general tend to have a betterrognosis.Irrespective of AF type, symptoms due to AF are quite variable.pwards of 45% of patients were diagnosed with AF incidentally during

n electrocardiogram for unrelated reasons in 2 major population stud-es.14,15 However, many patients have subtle symptoms, such as nonspe-ific fatigue, listlessness, and anxiety, that potentially remain undetectednless specifically probed by a physician. Many such patients feel morenergetic after restoration of SR. By contrast, some patients are clearlyymptomatic with palpitation, lightheadedness, fatigue, and reducedxercise tolerance. Patients with hypertension, left ventricular hypertro-hy, and restrictive cardiomyopathy are particularly sensitive to the lossf atrioventricular (AV) synchrony and decreased diastolic filling. Deter-ining how symptomatic the patient is because of AF remains a principle

roblem because patients who are not having many symptoms may beppropriate for simple rate control strategy and patients who haveunctional decline may benefit from rhythm control.

hythm vs Rate ControlThe initial therapy for AF is often directed toward restoration of SR byeans of cardioversion and maintenance of SR by antiarrhythmic drugs.he proposed advantages of the rhythm control strategy are symptomatic

mprovement, improved exercise tolerance, reduced risk of stroke, andossibly discontinuation of anticoagulation. The alternative approach isimply control of the ventricular rate using AV nodal blocking therapy orate control. This decision is empiric. The strategy of rhythm control wasresumed superior to rate control because of its proposed benefits ofreservation of ventricular function, improved quality of life (QoL), andossible mortality advantage. However, contradictory results were ob-ained from a series of randomized prospective clinical trials summarizedn Table 1.16-20 The largest of these 5 trials, Atrial Fibrillation Follow-upnvestigation of Rhythm Management (AFFIRM)20 and Rate Control vslectrical Cardioversion for Persistent Atrial Fibrillation (RACE),19

ailed to show any mortality benefit of maintaining SR in AF patients.nstead, a tread toward greater mortality was seen with the rhythm controltrategy overtime. AFFIRM enrolled more than 4000 patients aged 65ears or more with paroxysmal and persistent AF and randomized themo receive rate control or antiarrhythmic drug therapy. In the rhythm
ontrol group, antiarrhythmic drugs and cardioversion were necessary to

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aintain SR. In the rate control group, �-blockers, calcium-channellockers, digoxin, or combinations of these drugs were used to control theentricular rate to �80 bpm at rest and �110 bpm after a 6-minute walk.he rate control group received continuous anticoagulation during theeriod of the study. In the rhythm control group, continuous anticoagu-ation was encouraged but could be stopped at the physician’s discretionf SR was maintained for at least 12 weeks.At an average follow-up of 3.5 years, a trend toward a lower all-causeortality was observed in the rate control group (21%) compared with the

ABLE 1. Major clinical trials comparing rate control vs rhythm control strategy in AF

Study Type of AF No./Mean follow-up

FFIRM Paroxysmal persistent n � 4060 followed for 3.5 y

ACE Persistent recurrent (�24 h-1 yr) n � 522 followed for 2.3 y

IAF Persistent (7 d to 1 yr) n � 252 followed for 1 y

OT CAFÉ Persistent (7 d to 2 yr) n � 205 followed for 1.7 y

TAF Persistent (�4 wk-1 yr) n � 200 followed for 19.6 mo

F-CHF Paroxysmal or persistent (�1 yr) � LVEF�35% � HF (NYHA Class 2 to 4)

n � 1276 followed for 36 mo

bbreviations: AF, atrial fibrillation; Pt, patients; HR, hazard ratio; HF, heart failure; QoL, qualityf life; CVA, cerebrovascular accident; CV, cardiovascular; HF, congestive heart failure.

hythm control patients (24%).20 A higher risk for ischemic stroke was


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een in the rhythm control group primarily due to inadequate anticoagu-ation. At 5 years of follow-up, only 62% of patients were in SR in thehythm control group and the actuarial rate of crossover from rhythmontrol to rate control group was almost 37%. Inability to maintain SRnd drug intolerance were the principle reasons for crossover.The results of AFFIRM underscored nonsuperiority of either strategy

or treatment of AF and limited efficacy and significant adverse effects ofurrent antiarrhythmic drugs and need for therapeutic anticoagulation.imilarly, RACE enrolled 522 patients with persistent AF and random-

zed them to rate control or rhythm control. At a mean follow-up of 2.3ears, no difference was found between the 2 groups in the compositendpoint.19 Similar but smaller scale trials like Pharmacological Inter-

ABLE 1. Continued

Patients in SR (%)rhythm vs rate control

Outcomes

Primary rhythm vs rate controlSecondary rhythm vs rate

control

2.6% vs 34.6% All-cause mortality:No difference(HR: 1.15)

Composite of death, CVA,major bleeding, andcardiac arrest: Notdifferent. Rhythm control:more hospitalization trendtoward higher mortality.

9% vs 10% Composite of CV death, HFhospitalization, bleedingthromboemboliccomplications, pacemaker,severe adverse effects: 22.6%vs 17.2% (no difference)

6% vs 10% Symptomatic improvement: nodifference

Rhythm control: improveexercise tolerance butmore hospitalization andside effects. QoL notchanged.

3.5% Composite of all-cause mortality,thromboembolic events, majorbleeding: No difference

Rhythm control: improveexercise tolerance butmore hospitalizations

0% vs 12% at 1 y; 26%vs 11% at 2 y; 23% vs0% at 3 y

Composite of death, CVA,cardiopulmonary resuscitation:No difference

Rhythm control: trend towardimproved QoL butincreased hospitalizations.

oughly 73% vs �30% CV death: No difference All-cause mortality, CVA,CHF,QoL: No difference

Rhythm control: frequenthospitalization.

ention in Atrial Fibrillation (PIAF),17 The Strategies of Treatment of


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trial Fibrillation (STAF),16 and How to Treat Chronic Atrial FibrillationHOT CAFE)18 failed to prove superiority of rhythm control over rateontrol or vice versa with respect to their primary clinical endpoints thatncluded mortality (Table 1).Three meta-analyses that combined the results of these 5 studies showedonsuperiority of either strategy with regard to all-cause mortality, but arend favoring better outcome with rate control over rhythm control.21-23

dditionally, patients in the rate control strategy had a reduced risk of theombined endpoint of all-cause death and thromboembolic stroke (oddatio 0.84, 95% CI 0.73-0.98, P � 0.02)23 and reduced rates ofospitalization.22 Moreover, the recently published Atrial Fibrillation andongestive Heart Failure (AF-CHF) trial failed to show any benefit of

hythm control strategy even in patients with a left ventricular ejectionraction of �35% and symptoms of CHF in whom there is a theoreticalenefit of rhythm control. In light of the above, the strategy of maintain-ng SR in AF has fallen out of favor and many primary care physiciansave resorted to the passive and less complex approach of rate control foranagement of AF.

elvin M. Scheinman: The primacy of appropriate anticoagulant therapyas apparent in the AFFIRM trial for both the rhythm and the rate controlroups in terms of stroke prevention. The current practice of warfarin therapyas important limitations in terms of need for frequent checks of INR,rug-drug interactions, dietary restrictions, and genetic variations in warfarinetabolism. These problems have led to interest in the use of alternative

nticoagulant therapy. A recently published trial (RE-LY Randomized Evalu-tion of Long-Term Anticoagulation Therapy) 1 compared a direct thrombin

nhibitor (Dabigatran) in 2 doses vs (110 mg and 150 mg) with warfarinherapy. There was noninferiority in terms of risk of stroke between eitherose of Dabigatran compared with warfarin and the higher dose proveduperior to warfarin therapy. Major bleeding was less for those treated withhe lower dose. The direct thrombin inhibitors do not require blood monitor-ng, have no significant drug-drug interactions, and thus promise to revolu-ionize anticoagulant therapy (Connolly SJ, Ezekowitz MD, Yusuf S, et al.abigatran versus warfarin in patients with atrial fibrillation. N Engl J Med009;361:1139-51).

s There a Role of Rhythm Control in Pharmacologicanagement of Atrial Fibrillation?

Although trial evidence clearly supports the strategy of rate control overhythm control for management of AF, a prudent quest for optimal rhythm
ontrol pharmacotherapy continues.24,25 Before abandoning rhythm control,

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everal important questions need to be addressed. The arguments supportinghythm control can be outlined as follows:

. It should be noted that the results from the AFFIRM and RACE trialbear more relevance to an elderly population (mean ages of patientswere 70 and 68, respectively) with nonrheumatic AF and few or nosymptoms (episodes of AF that occurred less than once per month).26

For young, symptomatic patients with rheumatic AF, rhythm controlstrategy has been shown to reduce mortality and to improve QoL.27

. Antiarrhythmic drugs are frequently perceived as highly proarrhythmic,perhaps more proarrhythmic than they really are. Although increasedmortality with rhythm control is frequently ascribed to proarrhythmicdrug effects, a post-hoc analysis of cause-specific mortality and mode-of-death of AFFIRM data showed that the trend toward increased mortalityin the rhythm control arm was in fact due to noncardiovascular death,specifically, pulmonary disorders and cancer. Mortality related to cardio-vascular causes was the same in both groups.28 Complementing thesedata, a post-hoc analysis of the AFFIRM population showed that thepresence of SR was an important determinant or a marker for survival.29

However, in this analysis, antiarrhythmic drug therapy was not associatedwith improved survival.29 This mismatch suggests that benefits ofantiarrhythmic drugs may have been offset by potential adverse effects.The rhythm control strategy might provide better outcomes if saferantiarrhythmic drugs become available. By contrast, in the rate controlarm of AFFIRM, achieving resting or exercising heart rate targets failedto predict any of the clinical outcomes, including survival, QoL, andfunctional status.30

. In addition to cardiac and extracardiac side effects, limited efficacy ofcurrent antiarrhythmic drugs may also account for lack of benefit ofmaintaining SR. In the clinical trials comparing the efficacy of the ratevs rhythm control strategy in patients with AF, at the end of the trialperiod only 39-63.5% patients randomized to the rhythm controlstrategy were found to be in SR. In AFFIRM only 62.5% patientsdosed with antiarrhythmic drugs were in SR at the end of the 5-yearstudy period.16-20 It can be argued that if effective antiarrhythmicdrugs become available for maintenance of SR, it could swing thependulum in favor of the rhythm control strategy.

. Additionally, it can be argued that although these trials demonstratedequivalency of rate and rhythm control strategy in terms of mortality,they lack precision in determining what constitutes optimal rate or
rhythm control.31

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. It is clear that patients with AF have poor QoL32 and impairedfunctional status, and several lines of evidence suggest that restorationof SR can improve vitality.33-36 Evidence supporting the role ofcurrent antiarrhythmic drugs in improving QoL and functional statusin patient with AF is inconsistent, but may favor their use.17,18,37-39 Inthe absence of any mortality difference, patients who are symptomaticfrom AF may benefit from an attempt to restore SR.

ate Control AgentsThe rate control strategy in AF is fairly straightforward. It constitutessing drugs that slow conduction through the AV node, thus avoidingxcessively rapid ventricular rates. A persistently high ventricular rate inF may not only make the patient more symptomatic, but also can lead

o tachycardia-induced cardiomyopathy. Conduction through the AVode is in turn influenced by the presence or absence of intrinsiconduction system disease and sympathetic and parasympathetic tone.he AV node characteristically displays the property of decrementalonduction. That is, as more impulses arrive at the AV node per unit ofime, conduction progressively becomes slower. An intrinsically highertrial rate may be one of the reasons rate control is easier during AFompared with atrial flutter.The choice of agent for rate control strategy depends on the patient’semodynamic status, presence of contraindications, and indications for aarticular drug and drug tolerance. It may also be simply a matter ofhysician preference. Intravenous formulations of drugs have faster onsetf action than oral administration and are therefore valuable in acuteettings.What is considered adequate rate control is controversial.31 As men-

ioned earlier, the degree of heart rate control achieved has failed toredict survival, QoL, or functional status.30 A recent trial, RACE II,ompared Lenient vs Strict rate control in management of AF andompared their effects on cardiovascular morbidity and mortality.40 Aotal of 614 patients with permanent AF were randomly assigned to eitherlenient (resting heart rate �110 bpm) or a strict (resting heart rate �80pm and heart rate �110 bpm with moderate exercises) rate controltrategy. At 3-year follow-up, lenient rate control was noninferior to strictate control in the prevention of major cardiovascular events andortality rate. Contrary to the commonplace belief, lenient rate controlas not associated with worsening of heart failure or frequent hospital-

zations.40 Both groups had similar improvement in their symptoms and
enient rate control was easier to achieve. The result of RACE II may lead

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o a revision of the current ACC/AHA guidelines that recommend theentricular rates of 60-80 bpm during rest and 90-115 bpm duringxercises when rate control strategy is employed for AF management.10

Choices for rate control are limited. Candidates include �-blockersclass II), calcium channel blockers (class IV), and digoxin. Some of thesegents have additional antihypertensive properties and their selection mayerve multiple purposes. All �-blockers are effective in rate control forF, particularly in AF associated with adrenergic drive. They prevent

hortening of refractoriness at all levels in the heart. They blockdrenergic activation of calcium channels and thereby prolong theefractoriness of the AV node as conduction through the AV node isalcium dependent. The effectiveness of �-blockers as first-line drugs forate control was demonstrated in the AFFIRM substudy.41 Overall rateontrol was achieved in 70% of patients given �-blockers as the first drugwith or without digoxin), 54% with calcium channel blockers (with orithout digoxin), and 58% with digoxin. In the acute setting, intravenous

smolol, metoprolol, propanolol, or atenolol has a rapid onset and can beiven in a postoperative or acute setting. Esmolol may be given as aontinuous infusion and has a short half-life, which is beneficial inritically ill patients. The choice and route of administration should beased on the patient’s hemodynamics and other comorbidities. �-Block-rs should be used with caution in patients who are hypotensive or haveeart failure.Nondihyrdopyridine calcium channel blockers, verapamil and dilti-

zem, are commonly used for rate control in AF. These agents arealuable in patients who are intolerant or have contraindications to-blockers, such as severe obstructive lung disease. These agents affectalcium-dependent slow action potential upstroke in the sinus and AVode, resulting in slowing of conduction. As they have no effect on fastodium-dependent conduction, they have no effect of QRS duration.alcium channel blockers can also be given intravenously when rapidnset of action is needed. Non-dihydropyridine calcium channel antago-ists should be avoided in patients with heart failure and in the presencef acute left ventricular systolic dysfunction.Once a first-line agent for AF, digoxin is primarily useful in controllingeart rates at rest or in combination with other AV nodal blocking drugs.igoxin enhances vagal activity and thus reduces sinus node automaticity

nd prolongs AV nodal conduction and refractoriness. Digoxin is usuallyolerated in patients with heart failure or hypotension but is less effectiven high sympathetic states. Intravenous digoxin requires 60 minutes to
ake effect and its peak effect can be delayed up to 6 hours. Digoxin

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hould be administered carefully in elderly people, in patients with renalnsufficiency, and with medications that may potentiate its toxic effects.One interesting study by Farshi et al evaluated 5 different drug regimens–igoxin, atenolol, diltiazem, digoxin � atenolol, and digoxin � diltiazemor rate control in patients with permanent AF.42 The same 12 patientsere assigned to receive all 5 treatments for a 2-week interval. The

ombination of atenolol, 50 mg with digoxin, 0.25 mg d�1, was the mostffective regimen in controlling the ventricular response during dailyctivity; however, exercise duration in all groups was similar.42

hythm ControlThe rhythm control strategy includes restoration of SR and maintenance

hereafter. Upwards of 70% patients with new-onset AF of �72 hoursonvert to SR spontaneously with most spontaneous cardioversion occur-ing within first 24 hours.43 Electrical remodeling of the atria starts asarly as at the onset of AF.44 Therefore, timely restoration of SR shoulde accomplished using electric or pharmacologic cardioversion in patientsho do not cardiovert spontaneously. Management of patients withew-onset AF deserves special mention here. New-onset AF, but notersistent AF, has been shown to be associated with substantially higherortality within the first 4 months and has been found to be an

ndependent predictor of mortality.45,46 Although the exact reasons forhese findings are not clear, restoration of SR by cardioversion should betrongly considered in patients with new-onset AF. Many of these patientsay remain in SR especially if precipitating causes are corrected.uidelines for therapeutic anticoagulation before and after cardioversion

re outlined in the ACC/AHA consensus statement.10

ardioversion: Electrical and PharmacologicDC cardioversion is an effective and frequently preferred method for

estoration of SR in AF. In an appropriate setting, DC cardioversion islmost 95% effective, safe, and well tolerated, with the major risk beinghromboembolic stroke that can be minimized with appropriate anticoag-lation. Patients need to be fasting for at least 6-8 hours and require painontrol and analgesia. Digitalis toxicity should be ruled out beforeonsidering DC cardioversion for atrial arrhythmia. Pretreatment with anppropriate antiarrhythmic drug may improve the success rate of DCardioversion and prevent recurrence.10

elvin M. Scheinman: The authors well emphasize the efficacy of direct-
urrent cardioversions for treatment of atrial fibrillation for patients who

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annot be converted to sinus despite maximal energy and correct chestaddle position. The clinician should consider use of adjuvant drug therapy.or example, it has been shown that the use of ibutilide may decrease theefibrillator threshold and has been shown to be effective in increasingfficacy of direct shock therapy (Oral H, Souza JJ, Michaud GF, et al.acilitating transthoracic cardioversion of atrial fibrillation with ibutilide pre-reatment. N Engl J Med 1999:340:1849-54).

Although DC cardioversion is more effective in restoring SR, pharma-ologic cardioversion may be useful if electrical cardioversion cannot beerformed. It is particularly effective if AF is paroxysmal or recent innset. Although multiple agents have been used for pharmacologicardioversion historically, current ACC/AHA guidelines recommendecainide, ibutilide, amiodarone, and dofetilide for pharmacologic car-ioversion of AF of less than 7 days’ duration.Intermittent oral administration of a single high dose of flecainide,00-300 mg, or propafenone, 450-600 mg, may be effective as aPill-in-Pocket” approach for reliable patients with structurally normalearts and paroxysmal AF.47

Ibutilide is a class III antiarrhythmic agent that blocks the rapidlyctivating delayed rectifier potassium (IKr) current and prolongs refrac-oriness of atrial and ventricular cells. Ibutilide is approved for rapidardioversion of AF of short duration and it is given in a single dose ofmg over 10 minutes. Termination of AF is usually seen within 40-60inutes, and if not, 1 more dose can be given. The efficacy of intravenous

butilide for rapid conversion of atrial flutter is in the range of 50-70%,hereas its efficacy for conversion of AF is 30-50%. Approximately 80%f atrial tachyarrhythmias that terminate do so within 30 minutes after thenitiation of the intravenous infusion. Ibutilide infusion leads to QTnterval prolongation and torsade de pointes (TdP) may develop in up to% of the patients. Electrolyte disturbances, such as hypokalemia andypomagnesemia, must be corrected before ibutilide administration. Afternfusion, irrespective of cardioversion, patients need to be monitored for

hours and QT interval must be normal before discharge.Vernakalant is a novel intravenous antiarrhythmic agent that blocks ase-dependent sodium current and early activating potassium current ands relatively atrially selective.48 The US Food and Drug Administrationas not yet approved the drug for use in the United States, but it has beeniven preliminary approval in Europe. Initial studies have demonstratedernakalant to be effective in terminating acute episodes of AF. In a phaseclinical trial, infusion of 2 mg/kg vernakalant in patients with AF led to

ardioversion of up to 61% within first 30 minutes without any proar-


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hythmic effects.49 Atrial Arrhythmia Conversion Trial I randomized AFatients to receive vernakalant or placebo and stratified them according touration of AF �7 days or 8-45 days.50 Vernakalant was more effectiven short-duration AF with a cardioversion rate of 51%. Similar efficacynd safety of vernakalant was recently reported in patients with postop-rative AF who were evaluated in Atrial Arrhythmia Conversionrial II.51

hythm Control AgentsMost cardiologists do not start antiarrhythmic drug therapy after

ardioversion of the first episode of AF. However, antiarrhythmic drugsre required to maintain SR in patients with recurrent paroxysmal orersistent AF. Without antiarrhythmic drug therapy, recurrence of AF islmost 71-84% at 1 year and it can be reduced to 44-67% by appropriatelyelected antiarrhythmic drug therapy.52 The choice of antiarrhythmic drugust be individualized and should balance the benefits of maintaining SR

gainst side effects. The major clinical trials demonstrating efficacy ofarious antiarrhythmic drugs in the maintenance of SR are listed in Table 2nd their principle mechanism of action and side effects are listed inable 3.Amiodarone. The cardiac safety and efficacy of amiodarone have beenemonstrated in multiple randomized and nonrandomized trials. Forxample, the Sotalol Amiodarone Atrial Fibrillation Efficacy TrialSAFE-T) was a double-blind, placebo-controlled trial that assigned 665atients with persistent AF on anticoagulants to receive amiodarone (267atients), sotalol (261 patients), or placebo (137 patients) and followedhem for 1-4.5 years.39 The primary endpoint was the time to firstecurrence of AF beginning on day 28. Patients who failed pharmacologicardioversion by the 28th day received DC cardioversion.In total, 27.1% of the amiodarone group, 24.2% of the sotalol group,

nd 0.8% of the placebo group spontaneously cardioverted. Duringong-term follow-up, the median times to recurrence of AF were 487 daysn the amiodarone group, 74 days in the sotalol group, and 6 days in thelacebo group according to intention to treat analysis. Amiodarone was 6imes as effective as sotalol in preventing first AF recurrence. Interest-ngly, in a subgroup of patients with ischemic heart disease, amiodaronend sotalol were equally effective in preventing the first recurrence of AFmedian time to recurrence of AF was 569 days with amiodarone therapynd 428 days with sotalol therapy, P � 0.53). The rate of maintenance of
R was significantly higher at 1 year with amiodarone than sotalol or

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lacebo (52 vs 32% and 13% on intention to treat analysis). Restorationnd maintenance of SR significantly improved QoL and exercise capacityithout significant adverse effects across all the groups.39

Similar results were found in the Canadian Trial of Atrial FibrillationCTAF) that randomized 403 patients who had at least 1 episode ofymptomatic AF in the preceding 6 months to receive either amiodarone,otalol, or propafenone.53 During a mean follow-up of 16 months, only5% of patients on amiodarone treatment had recurrence of AF comparedith 63% patients on sotalol or propafenone, and there was a longeredian time to recurrence with amiodarone, �468 vs 98 days. Similarnding were reported in a substudy of AFFIRM comparing the efficacy ofmiodarone, sotalol, and a class I drug.54 At 1-year follow up, theikelihood of achieving the primary endpoint that included maintainingR was significantly higher in the amiodarone group (60-62%) comparedith sotalol (38%), or class I drug.54 However, 18% patients treated with

miodarone discontinued the drug due to adverse events.A recent systemic review assessing safety and efficacy of current

ntiarrhythmic drugs that included 44 trials enrolling about 11,322atients with AF showed that at 6-month follow-up, amiodarone (oddsatio (OR), 0.19) reduced recurrences of AF significantly more thanombined class I drugs (OR, 0.31) and more than sotalol (OR, 0.43).52

SAFE-T and CTAF excluded patients with AF who had New Yorkeart Association (NYHA) class III or IV heart failure. This group was

ddressed in post-hoc analysis of Veterans Affairs Congestive Heartailure: Survival Trial of Antiarrhythmic Therapy Trial.55 Treatment withmiodarone in patients with reduced ejection fraction in this trialecreased the incidence of AF and provided better rate control in thoseatients who developed AF. About 31% of patients who were in AF at theeginning of enrollment spontaneously converted to SR. These patientslso had a mortality benefit compared with those who did not cardiovert.owever, the recently reported AF-CHF trial failed to substantiate thiseneficial effect of amiodarone in patients with CHF.56 The rhythmontrol strategy primarily with amiodarone had a neutral effect onortality.The efficacy and cardiac safety of amiodarone may be explained by itsultireceptor affinity.57 Traditional, pure class III agents like dofetilide,

redominantly block IKr, the rapidly activating delayed rectifier potas-ium current, a major current implicated in drug-induced arrhythmia. Thiseads to prolongation of action potential duration of cardiac myocytesith preferential prolongation of action potential of midmyocardial M

ells leading to an increase in dispersion of repolarization, thus creating


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ABLE 2. Major clinical trials investigating role of antiarrhythmic drugs in AF management

Study Inclusion criteriaSpecific exclusion

criteria Treatment follow-up

AFE-T Persistent AF �72 h andAF at randomizationon therapeuticanticoagulation

Paroxysmal AF A flutterNYHA class 3/4 CHF

Placebo vs amiodaronevs sotalol. followedfor 1-4.5 y

TAF Paroxysmal AF with atleast 1 episode of AFin last 6 mo

Persistent AF �6 moNYHA class 3/4 HF

Amiodarone vs sotalolvs propafenonefollowed for 16 mo

AFT Symptomatic AF withinlast 12 mo who werein SR at randomization

Permanent AFNYHA class 3/4 HFRecent myocardial

infarction

Placebo vspropafenone SR(425, 325, 225 bid)followed for 39 wk

AFIRE-D AF or A-flutter from 2 to26 wk

Uncompensated HF Placebo vs dofetilide125, 250, 500 �gbid followed for 1 y

THENA Paroxysmal/persistentAF/A-flutter with atleast 1 risk factor:HTN, DM, stroke, TIA,LA �50 mm or LVEF�40%

Permanent AFNYHA class 4 HF

Placebo vsdronedarone, 400mg twice daily for 12mo

IAMOND-AF AF at time of enrollmentin patients with LVEF�35% and pasthistory of NYHA class3/4 HF or MI

Creatinine clearance�20 baseline QTc�460

Placebo vs dofetilide,250 �g bid

NDROMEDA NYHA class 3/4 HF plusLVEF �35%

Recent acute MIAcute pulmonary

edema

Placebo vsdronedarone, 400mg twice daily for12 mo

F-CHF Episode of AF in last 6mo plus LVEF �35%plus NYHA class 2-4 HF

AF �12 mo Placebo vs amiodaronein most of thepatients

bbreviations: AF, atrial fibrillation; SR, sinus rhythm; CAD, coronary artery disease; CV, cardio-ascular; QoL, quality of life; HF, congestive heart failure; HTN, hypertension; DM, diabetes; TIA,ransient ischemic attack; LVEF, left ventricular ejection fraction; RR, relative risk; MI, myocardialnfarction.
Significant P value.

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ABLE 2. Continued

Results

Primary end points Secondary end points

ime to AF recurrence: placebo:6amiodarone: 487 sotalol: 74 da

Spontaneous conversion to SR: Placebo 0.8%,Amiodarone, 27%, Sotalol, 25%a

Time to AF recurrence patient with CAD:Amiodarone: 569 dSotalol: 428 dSR at 1 y: Placebo 13%, Amiodarone, 52%, Sotalol, 32%

Rhythm control: improved QoL and exercise tolerance.Adverse events not significantly different.

ime to AF recurrence: Amiodarone:468 sotalol/propafenone, 98 da

Recurrent AF during follow-up: Amiodarone, 35%Sotalol/propafenone, 65%a

Adverse effect requiring drug discontinuation:Amiodarone, 18% Sotalol/propafenone, 11%

ime to AF recurrence: Placebo:41 d

ropafenone SR 425, 325, 225mg: �300, 291, and 112 d,respectivelya

Adverse effects requiring drug discontinuation:Propafenone SR 425 mg: 25% placebo: 13%a

onversion to SR: dofetilide 125, 250,500 �g bid: 6.1%, 9.8%, and29.9%, respectively placebo: 1.2%a

robability of maintaining SR at 1 y:Dofetilide 125, 250, 500 �g bid:0.40, 0.37, 0.58 placebo: 0.25a

Adverse effect: 0.8% on dofetilide developed TdP with1 sudden cardiac death

eath from all-cause or firstoccurrence of cardiovascularhospitalization: 24.2% RRreduction favoring dronedaronea

Death from any cause: 16% fewer deaths withdronedarone

Cardiovascular deaths: 29% RR reductiona

Cardiovascular hospitalization: 26% RR reductiona

Incidence of stroke 34% RR reductiona

Length of hospitalization: Reduced by 1.26 d/patient/yeara

onversion to SR: Dofetilide: 44%Placebo: 14a

robability of maintaining SR at 1 y:Dofetilide: 79%Placebo: 42%a

HF hospitalization: Dofetilide vs placebo was (RR, 0.69)a

All-cause hospitalization: Dofetilide vs placebo (RR, 0.70)a

SR was associated with significant reduction in mortality(RR, 0.44)a

eath from any cause or HFhospitalization:

ronedarone: 17% Placebo: 12%

All-cause mortality:Dronedarone: 8.1%Placebo: 3.8%a

Cardiovascular hospitalization: Dronedarone: 2.9%Placebo: 15.7%a

V death: 27% in rhythm control(mostly amiodarone) vs 25% inrate control. Not different.

All-cause mortality, HF worsening, hospitalization,QoL, cost of care, and composite of death due tostroke, HFor CV causes: No difference


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milieu for arrhythmia. They also exhibit reverse use-dependence; that is,ncreased block of these ion channels at slower heart rates predisposes toause-dependent TdP.58-60 Conversely, pure class I sodium channellocking agents exhibit positive use-dependence and slow conductionelocity and increase QRS width at higher heart rates.In contrast, amiodarone is predominantly a blocker of IKs—the slowly

ctivating delayed rectifier potassium current, which confers less reversese-dependence than IKr blockers.61 Additionally, amiodarone exhibitslass I use-dependence when dosed chronically.62 Amiodarone alsolocks L-type calcium channels and has �- and �-antiadrenergic activ-ty.62,63 Thus, amiodarone displays activity corresponding to all 4aughan Williams classes, which may explain higher efficacy of drug inaintaining SR.ACC/AHA/ESC guidelines for antiarrhythmic drug therapy to maintain

ABLE 3. Commonly used antiarrhythmic drugs

Drug Primary mechanism of action

lass IaProcainamide Use-dependent INa blockade

Quinidine Use-dependent INa blockade

Disopyramide Use-dependent INa blockade

lass IcFlecainide Use-dependent INa blockadePropafenone Use-dependent INa blockade

lass IIISotalol Reverse use-dependent blockade of IKr in addition to �-blockade

Amiodarone Blockade of IKr, IKs, INa, antiadrenergic property

Dronedarone Blockade of IKr, IKs, INa, antiadrenergic propertyDofetilide Blockade of IKr

Ibutilide Blockade of IKr

bbreviations: iv, intravenous; TdP, torsade de pointes; CHF, congestive heart failure; VT,entricular tachycardia.

R in patients with AF describe a role for amiodarone in patients with


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tructurally normal hearts, in the presence of low ejection fraction, in theresence of coronary artery disease, and with hypertension.10 Althoughmiodarone is considered one of the most efficacious drugs amongurrently available antiarrhythmic drugs, the potential for serious extra-ardiac side effects is a significant limiting factor. A meta-analysis of 4linical trial enrolling 1465 patients showed that 1 year of treatment withven low-dose amiodarone was associated with higher odds of experi-ncing thyroid (OR, 4.2), neurologic (OR, 2.0), skin (OR, 2.5), ocularOR, 3.4), cardiac (OR, 2.2), or pulmonary toxicity (OR, 2.0).64 The oddsor discontinuing amiodarone due to side adverse events was almost 1.5imes the control group.64

Amiodarone is an iodinated benzofuran derivative with a structuralormula that closely resembles that of thyroid hormone. It contains about7% iodine by weight, from which 10% is deiodinated to yield free

ABLE 3. Continued

Recommended dose

Side effectsCardioversion Rhythm control

00-1200 mg iv over30-60 min

2000-4000 mg/d Hypotension with (iv) dose. Drug-induced lupus

ot recommended 600-1200 mg/d Diarrhea, nausea, TdP, hypotension,QT prolongation, vagolytic effect

ot recommended 450-600 mg/d Anticholinergic (urinary retention, drymouth), negative iontropic, TdP,CHF.

00-400 mg orally 150-300 mg/d QRS prolongation, CNS side effects50-600 mg orally 400-600 mg/d Gastrointestinal upset, modest

negative iontropic

ot recommended 80-320 mg/d Bradycardia, QT prolongation,bronchospasm

50 mg iv over 30min followed by0.5-1 mg/min

400-1200 mg for 7 dfollowed by 100-300mg/d

Thyroid, pulmonary, skin, liver,ocular, dyspepsia, QTprolongation.

ot recommended 400 mg twice daily Gastrointestinal-nausea, diarrheaot recommended 125-500 �g twice daily QT prolongation and TdP.mg iv over 10 min,may be repeatedonce

Not recommended QT prolongation, TdP, monomorphicVT, nausea, headache,hypotension, bundle branch block,AV nodal block

odide. With a daily maintenance dose of amiodarone between 100 and


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00 mg, about 3.5-31 mg of iodide is released into the systemicirculation that is equivalent to 35- to 140-fold excess of daily intake.65

his leads to critically high intrathyroidal iodine levels that may causeuppression of thyroid hormone biosynthesis leading to hypothyroidism.yperthyroidism may occur in the presence of an autonomous thyroidodule (type 1) or due to thyroiditis related to direct toxic effect ofxcessive iodine (type 2).66 Iodine also increases the lipophilicity of therug, resulting in significant accumulation of drug and its metabolitedesethyl-amiodarone) in adipose tissue and highly perfused organs, suchs liver, lung, and skin, leading to end-organ toxicity.Dronedarone. Despite its efficacy, a high propensity for extracardiac

ide effects and difficult kinetics is limiting factors in the clinical use ofmiodarone. This led to the development of an analogue drug, droneda-one, recently US Food and Drug Administration approved for AF.67

ronedarone is a benzofuran derivative that has a methane sulfonyl groupnstead of an iodine group. This reduces dronedarone’s potential ofoncardiac toxicity while reducing its half-life. Dronedarone displaysimilar electrophysiological properties to amiodarone and has effects onultiple cardiac ion channels. Like amiodarone, it displays characteristics

hat span the Vaughn Williams classification scheme (I to IV).Based on early preclinical and clinical studies, 400 mg bid wasetermined to be the optimal dose for dronedarone taken with food. Athis dose, dronedarone is well tolerated except for mild and occasionalastrointestinal upset and is devoid of significant thyroid, pulmonary,cular, hepatic, or proarrhythmic toxicities.68

The European Trial in Atrial Fibrillation or Flutter Patients Receivingronedarone for the Maintenance of SR (EURIDIS) and the American-ustralian-African Trial with Dronedarone in Atrial Fibrillation or Flutteratients for the Maintenance of SR (ADONIS) trials69 assessed thefficacy of dronedarone (400 mg bid) for the maintenance of normal SRfter electrical, pharmacologic, or spontaneous conversion of AF or Atrialutter (AFL). A majority of patients received concomitant antithromboticedication and �-blockers. Dronedarone significantly delayed the time to

ecurrence of AF to 116 days compared with 53 days in the placeboroup. At 12 months, the rate of recurrence was 64.1% in the dronedaroneroup and 75.2% in the placebo group (hazard ratio, 0.75; 95% confi-ence interval, 0.65-0.87; P � 0.001).The Efficacy and Safety of Dronedarone for the Control of Ventricularate During Atrial Fibrillation (ERATO) study70 showed that dronedar-
ne was well tolerated when added to standard rate control therapy

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�-blockers, digitalis, or calcium channel antagonists) in patients withermanent AF and reduced the ventricular response during rest andxercise.The ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Mod-

rate-to-Severe CHF Evaluating Morbidity Decrease) was a mortalityrial that investigated the effects of dronedarone in patients with AF andevere CHF.71 After enrollment of 627 patients, ANDROMEDA wastopped prematurely after a median follow-up of 2 months due to a higherortality with dronedarone, 8% compared with placebo (3.8%). The

easons for increased mortality in the ANDROMEDA trial remain unclearut may be related to the negative inotropic effect of the drug.ATHENA (Assess the Efficacy of Dronedarone for the Prevention ofardiovascular Hospitalization or Death from Any Cause in Patients withtrial Fibrillation/Atrial Flutter) enrolled 4628 patients with stable AFho had at least 1 cardiovascular risk factor.72 Treatment with droneda-

one in ATHENA was associated with a significant reduction in therimary endpoint of all-cause mortality and cardiovascular hospitaliza-ions. This was principally driven by reduced cardiovascular hospitaliza-ions. There was a trend toward a lower overall mortality with droneda-one treatment and importantly there was a statistically significanteduction in death because of cardiac arrhythmia (hazard ratio, 0.55, P �.01). The reduction in cardiovascular hospitalizations was accounted forostly by fewer admissions for AF. A post-hoc analysis demonstrated

hat dronedarone was associated with a significant reduction in thedjusted risk of stroke compared with placebo, a benefit that wasreserved in patients who were already receiving antithromboticherapy.73

Although dronedarone has shown excellent safety and tolerability in itslinical trials, it was shown to be less effective than amiodarone inreventing AF recurrence in Efficacy and Safety of Dronedarone vsmiodarone for the Maintenance of SR in Patients with AF trial.74

owever, dronedarone was better tolerated with fewer discontinuationsor side effects.In light of the above data, dronedarone is an important addition to the

ntiarrhythmic armamentarium for AF with a few caveats. Gastrointesti-al discomfort and diarrhea are the principle side effects of the drug.ronedarone causes partial inhibition of tubular transport of creatinine

nd may cause an increase in serum creatinine concentration that is notelated to glomerular filtration. Dronedarone also increases plasma
igoxin and simvastatin levels that may necessitate dose reduction.67 In

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ight of the ANDROMEDA trial, dronedarone should not be used in aatient with acute decompensated heart failure and in the presence of aery low ejection fraction.67

Class Ic Drugs: Flecainide and Propafenone. Class Ic drugs agents,ropafenone and flecainide, are useful agents for maintaining SR inatients with structurally normal hearts or minimal heart diseases. Theserugs cause use-dependent block of the peak inward sodium current, andhey significantly slow conduction velocity, leading to an increase inavelength of the reentrant waveform and also an increase in theost-repolarization refractory periods. Propafenone has �-blocking activ-ty as well. In the RAFT trial [Efficacy and Safety of Sustained-Releaseropafenone (propafenone SR) for Patients with Atrial Fibrillation], 523atients with a history of symptomatic AF who were in SR wereandomly assigned to receive placebo or propafenone SR 425, 325, or 225g twice daily. Recurrent symptomatic arrhythmias were documented

sing transtelephonic electrocardiographic monitoring.75 Propafenone SRignificantly prolonged the time to first symptomatic atrial arrhythmiaecurrence at all 3 doses compared with placebo. The median time toecurrence was 41 days in the placebo, �300 days in the propafenone SR25-mg group, 291 days in the 325-mg group, and 112 days in the25-mg group. Similar results were seen in ERAFT (the Europeanythmol Atrial Fibrillation Trial).76

Flecainide was shown to be effective in preventing recurrences of AF inhe Flecainide Multicenter Atrial Fibrillation Study, with an excellentolerability profile.77 In addition to preventing the recurrence of AF, bothf these drugs have been shown to be effective in terminating paroxysmalF using single oral loading doses. Class Ic agents also slow conductionver accessory pathways and thus may be useful for treatment ofrrhythmias associated with Wolff–Parkinson–White syndrome.78

Both drugs are well tolerated with the principle side effect ofropafenone being nausea and gastrointestinal discomfort and flecainideith mild neurologic side effects. Both of these agents have been

ssociated with hypotension and bradycardia after conversion to SR.lass Ic agents also may convert AF into slow atrial flutter conducts 1:1,

eading to wide complex tachycardia that may mimic ventricular tachy-ardia. To prevent rapid ventricular rates, class Ic agents should berescribed with AV nodal blocking agents like �-blockers or calciumhannel blockers. Class Ic agents are contraindicated in patients withschemic heart disease and congestive heart failure.79

Class III Drugs: Sotalol and Dofetilide. Sotalol is a useful agent for
anagement of AF. Sotalol blocks the IKr in addition to its �-adrenergic

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locking effects. Thus, sotalol prolongs atrial and ventricular effectiveefractory periods and slows conduction in the AV node. It displayseverse use dependency with more pronounced IKr blockade at a slowereart rate that may lead to significant QT prolongation and risk of TdPuring bradycardia. Sotalol is a modestly effective drug in the preventionf AF as seen in the SAFE-T and CTAF studies above. It should bevoided in patients with significant left ventricular hypertrophy, heartailure, and severe asthma, and in patients with the congenital or acquiredong QT syndrome.Dofetilide is a pure class III antiarrhythmic drug that blocks the IKr and

s devoid of �-adrenergic blocking effects. Thus, dofetilide causesose-dependent prolongation of the QT interval without any effects on PRnterval or QRS duration and prolongs the atrial and ventricular effectiveefractory periods.The SAFIRE-D (Symptomatic Atrial Fibrillation Investigative Researchn Dofetilide) study investigated the safety and efficacy of dofetilide inatients with chronic AF for conversion to maintenance of SR.80

AFIRE-D randomized 325 patients with AF or atrial flutter to receive25, 250, or 500 �g of dofetilide twice daily based on QTc response andalculated creatinine clearance. Dofetilide was effective in pharmacologicardioversion at higher doses (30% at 250 �g twice daily doses vs 1.2%or placebo) with most cardioversions occurring within the first 36 hoursf treatment initiation. At 1-year follow-up, 58% patients on 500 �g bidofetilide maintained SR. Two cases of TdP occurred (0.8%).Because dofetilide does not have negative inotropic effects like sotalol

nd class Ic agents, it seemed a very attractive agent for treatment of AFn patients with CHF. This was studied formally in by the Danishnvestigations of Arrhythmia and Mortality on Dofetilide (DIAMOND)tudy group in 2 large randomized control trials, DIAMOND-CHF andIAMOND-AF.81,82 The DIAMOND-AF trial randomized 506 patientsf AF or atrial flutter with low ejection fraction and congestive heartailure or recent acute myocardial infarction to receive either adjustedose dofetilide or placebo in addition to traditional treatment.81 Over theourse of the study, 59% of patients cardioverted to SR on dofetilide. Inhose patients who converted to SR, the probability of maintaining SR at

year was 79% with dofetilide vs 42% with placebo (P � 0.001).lthough dofetilide had no effect on all-cause mortality, restoration andaintenance of SR was associated with a significant reduction inortality (risk ratio, 0.44; 95% CI, 0.30-0.64; P � 0.0001). In addition,

ofetilide therapy was associated with a 30% reduction in all-cause or
ongestive heart failure hospitalizations. TdP occurred in 4 (1.6%)

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ofetilide-treated patients who responded to discontinuation of drug.81

ncidence of TdP was 3.3% in the DIAMOND-CHF trial.82

Thus, due to its QT prolonging effect, dofetilide carries a small butethal risk of TdP. The risk can be minimized by carefully adjusting theose of dofetilide based on renal function, instituting a 72-hour in-ospital monitoring period after initiation of dofetilide, and correctinglectrolyte disturbances like hypokalemia and hypomagnesemia. Drugsike erythromycin, ketoconazole, and verapamil may increase plasmaofetilide levels by inhibiting its metabolism and hence should not bedministered concomitantly.

election of an Antiarrhythmic DrugCurrent ACC/AHA/ESC suggestions for selection of appropriate anti-

rrhythmic drug therapy for maintenance of SR are shown in Fig 1.ecause ventricular proarrhythmia is more common in patients with

tructural heart disease or congestive heart failure, choice of antiarrhyth-ic drug therapy is based on the presence or absence of structural heart

isease or CHF. Class Ic drugs are preferred for patients with structurallyormal hearts due to their long-term safety and tolerability profile. Sotalolan be used as an alternative in this group of patients. Class Ic drugs haveeen shown to increase mortality in patients with ischemic heart diseasend CHF,79 based on the finding that class Ic drugs should not be used forF management in this group of patients. In patients with coronary artery

IG 1. Choice of antiarrhythmic drugs for maintenance of sinus rhythm in patients with atrialbrillation.

isease, sotalol can be used as a first-line agent due to its �-blocking


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ffects in addition to antiarrhythmic efficacy and neutral effects onortality.83 In patients with hypertension and significant left ventricular

ypertrophy (LVH), amiodarone is the only recommended drug forhythm control; however, in the absence of “significant” left ventricularypertrophy, recommendations resemble those for patients with structur-lly normal hearts. Amiodarone and dofetilide can be used alternatively inost myocardial infarction patients if sotalol fails or is not well tolerated.In patients with CHF, amiodarone and dofetilide are the only drugs that

an be safely used for management of AF based on DIAMOND-AF,F-CHF, and Veterans Affairs Congestive Heart Failure: Survival Trialf Antiarrhythmic Therapy trials.55,56,81 Dronedarone is likely to find itslace in management of AF in all categories of patients except those withYHA class III-IV CHF. Additionally, patients who have vagallyediated AF may benefit from flecainide or disopyramide. Patients with

drenergically mediated AF may benefit from sotalol or �-blockers.Except for dofetilide and sotalol, almost any antiarrhythmic drug can be

nitiated in the outpatient setting. Before starting any antiarrhythmic drugith class III effects, it is important to check the baseline electrocardio-ram, electrolytes, and renal and hepatic function. Sotalol can be initiateds an outpatient unless there is baseline prolonged QT interval �450 msr there are predisposing risk factors for TdP. Class Ic drugs likeecainide, propafenone, and amiodarone and its analogue dronedaroneave been shown to be safe when started in the outpatient setting. Patientsn amiodarone require semiannual monitoring of thyroid, liver, andulmonary function tests and yearly ocular examinations.

elvin M. Scheinman: Patients with atrial fibrillation also frequently haveoncomitant atrial flutter and, as pointed out by the authors, atrial flutter maye associated with worsening of symptoms. The clinician should be mindfulf agents used for therapy of atrial fibrillation that may promote atrial flutter.he latter is particularly true for the 1c agents (propafenone and flecainide). Inontrast, the class III agents (particularly dofetilide but also sotalol) are moreffective for the prevention of atrial flutter.

djuvant TherapyThis section briefly reviews the evidence supporting adjuvant non-

ntiarrhythmic drugs for the prevention of AF. These drugs workrimarily by preventing atrial remodeling, as shown in Fig 2. Adjuvant
herapy for AF has been extensively reviewed in the current literature.84

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ngiotensin Converting Enzyme InhibitorsACE-I)/Angiotensin II Receptor Blocker (ARB)The Renin-Angiotensin-Aldosterone system (RAAS) has been shown to be

xtensively involved in the initiation and perpetuation of AF; hence, thelockade of RAAS with either ACE-I or ARB may have a role in therevention of AF.85 This has been demonstrated in several clinical trials. Forxample, the TRACE (TRAndolapril Cardiac Evaluation) study showedhat treatment with trandolapril led to a 50% reduction in the risk ofeveloping AF in patients with left ventricular dysfunction due to acuteyocardial infarction at 3-year follow-up.86 Similarly in SOLVD (Study

f Left Ventricular Dysfunction), enalapril markedly reduced the risk foreveloping AF in patients with heart failure.87

Similar to ACE-I, treatment with valsartan in patients with heart failureeduced the risk of developing AF by 37% in Valsartan Heart Failurerial (Val-HeFT).88 Conversely, the irbesartan in patients with heart

ailure and preserved ejection fraction (I-PRESERVE) trial showed thatreatment with irbesartan did not affect the incidence of atrial arrhythmiasn patients with heart failure with preserved ejection fraction at 4-yearollow-up.89

Finally, a meta-analysis of 11 randomized control trials, including morehan 50,000 patients, showed that both ACE-I and ARBs were effectiven prevention of AF and reduced the risk of developing AF by 28%. This

IG 2. Atrial remodeling in atrial fibrillation and the role of adjuvant agents.

rotective effect was more pronounced in patients with reduced ejection


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raction but not in patients with only high blood pressure.90 Contrary tohe above, in Losartan Intervention For End-point reduction in hyperten-ion (LIFE) study, losartan significantly reduced the incidence of new-nset AF in hypertensive patients compared with atenolol.91

Additionally, 2 small studies showed that the patients with AF whoere electrically cardioverted were more likely to stay in SR during a 4-

o 8-week follow-up when concomitant ARB or ACE-I was administeredlong with amiodarone compared with amiodarone alone.92,93 However,n the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto

iocardico–Atrial Fibrillation (GISSI-AF) trial, valsartan was used aloneithout any antiarrhythmic drug therapy. It failed to reduce recurrence ofF at 1-year follow-up.94 Based on these data, we believe that RAASodulators should be used preferentially for the treatment of hyperten-

ion and congestive heart failure patients considered at risk for AF, but weannot recommend their use for AF suppression alone.

nti-Inflammatory AgentsInflammation appears to be involved in the early phase of electrical

emodeling that promotes AF. High-sensitivity C-reactive protein, aiomarker of inflammation, is elevated in patients with AF compared withhose in SR; hence, it has been assumed that anti-inflammatory agentsight have a role in the prevention of AF.Statins. Several studies have suggested therapeutic benefit of statins forrevention of AF.84 In a retrospective study involving patients with suspectedcute coronary syndrome, new-onset AF was significantly less likely to occurf they were on a statin at the time of presentation.95 Adabag et alemonstrated that AF was less common among statin-treated patients witheart failure.96 A prospective study by Tsai et al showed that in patients withermanent pacemakers, atrial high-rate episodes were significantly lower intatin-treated patients compared with a nonstatin group at 1-year follow-up.97

imilarly, in a prospective study of patients receiving an implanted cardio-erter-defibrillator, statin therapy was associated with a significant reductionn the development of AF or atrial flutter compared with the nonstatinroup.98 In the Atorvastatin for Reduction of Myocardial Dysrhythmia Afterardiac Surgery (ARMYDA-3) study, atorvastatin was shown to signifi-antly reduce postcardiac surgery AF vs placebo.99 Similar result were foundn 2 meta-analyses.100,101

Corticosteroids. Because of their anti-inflammatory effects, corticoste-oids may prevent AF. A recently published trial of patients undergoingoronary bypass graft surgery with or without aortic valve replacement
ound that perioperative use of corticosteroids decreased the incidence of

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ostoperative AF.102 The trial corroborated findings from smaller stud-es.103,104 However, the risk of long-term side effects may outweigh theirotential benefit in AF management and is a major limitation. Well-esigned prospective randomized controlled trials are needed to define theole of steroids for AF prevention.Fish Oils (�-3 PUFA). �-3 PUFA may inhibit the potassium currents

transient outward potassium current (Ito) and ultrarapid delayed rectifierotassium current (IKur)] and the voltage-gated sodium current (INa) inuman atrial myocytes, which may contribute to their antifibrillatoryffect in the atrium. In a prospective randomized trial of fish oil vslacebo, started in patients 5 days before undergoing coronary arteryypass grafting and continued throughout their hospital stay, the inci-ence of postoperative AF was significantly lower in the fish oil group.105

owever, the Rotterdam study prospectively examined the relationshipetween dietary fish intake, long-chain omega-3 fatty acid supplementa-ion, and the incidence of AF. After a mean follow-up of 6.4 years, neithermega-3 fatty acid nor dietary fish intake was linked to a lower incidencef AF.106 Role of �-3 PUFA in the prevention of AF remains an area ofctive research, and we anticipate the results of large randomized trialshat should provide conclusive information.107,108

alcium Channel Blocker (CCB) and the Other AgentsTheoretically, reducing calcium influx into atrial myocytes shouldrevent episodes of AF. De Simone et al demonstrated that administeringerapamil, 3 days before cardioversion, improved the maintenance of SRhen combined with propafenone or amiodarone.109 Other studies thatsed verapamil alone for the prevention of recurrent AF did not show austained improvement over 1 to 3 months of follow-up.110 CCB mayave a role if used in conjunction with other antiarrhythmic agents and/orlectrical cardioversion, but their value in maintaining SR is unclear.Based on the current data, it is probably premature to recommend anyarticular adjuvant agent solely for the prevention or treatment of AF. Thelinical use of these agents should be limited to their primary indicationsending conclusive evidence from prospective randomized clinical trialsf benefit and safety, specifically in AF patients.

onclusionsAs outlined above, there are multiple treatment options available foranagement of AF. An ideal approach to AF management should startith prevention of AF in the population at highest risk using adjuvant

herapy outlined above. When AF develops, it is reasonable either to


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ursue the strategy of simple rate control or to cardiovert the patient andaintain SR using antiarrhythmic drugs. The rhythm control strategy is

avored in patients with intolerable symptoms and those who are youngith structurally normal hearts. Available antiarrhythmic drugs are atost 60% effective in maintaining SR at 1 year. There are multiple novel

gents in development with new targets and include prevention oftructural and electrical remodeling. Availability of such agents willmprove our ability to prevent and treat AF.

elvin M. Scheinman: The authors have presented a truly masterful andomplete exposition covering modern pharmacologic management of patientsith atrial fibrillation. This is not only a worthy practical compendium useful for

he day-to-day management of these patients but also covers new potentiallymportant breakthroughs in terms of newer antiarrhythmics on the horizon, asell as the important potential role for “upstream” therapy including anti-

nflammatory and rennin-angiotensin inhibitors. The authors well explain theathophysiologic issues involved in the genesis of atrial fibrillation and theationale for drug use in terms of effects on ion channel function. The tables andgures provide ready access to appropriate drug therapy as well as dosage andajor side effects. This splendid essay is required reading for the clinician taskedith care of the patient with atrial fibrillation.

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2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation inadults: national implications for rhythm management and stroke prevention: theAnticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA2001;285:2370-5.

3. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrialfibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on theprojections for future prevalence. Circulation 2006;114:119-25.

4. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, andpredisposing conditions for atrial fibrillation: population-based estimates. Am JCardiol 1998;82:2N-9N.

5. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrialfibrillation: the Framingham Heart Study. Circulation 2004;110:1042-6.

6. Wattigney WA, Mensah GA, Croft JB. Increased atrial fibrillation mortality: UnitedStates, 1980-1998. Am J Epidemiol 2002;155:819-26.

7. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to strokein the elderly. The Framingham Study. Arch Intern Med 1987;147:1561-4.

8. Public health and aging: atrial fibrillation as a contributing cause of death andMedicare hospitalization---United States, 1999. MMWR Wkly 2008;52:128-31.

9. Coyne KS, Paramore C, Grandy S, et al. Assessing the direct costs of treating
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