Atrial Fibrillation:When - and How - to Convert to Sinus Rhythm

April 1, 2006

Your patient with atrial fibrillation (AF)is hemodynamically stable and youhave successfully established rate control.Your next step is to weigh therisks and benefits of attempting to restoresinus rhythm. In up to one half ofpatients, AF of recent onset convertsspontaneously to normal sinus rhythmwithin 24 hours. Thus, in some cases,the most appropriate approach maybe to control the ventricular response,identify and treat comorbid conditions,initiate anticoagulation, and closelymonitor the patient.

Your patient with atrial fibrillation (AF)is hemodynamically stable and youhave successfully established rate control.Your next step is to weigh therisks and benefits of attempting to restoresinus rhythm. In up to one half ofpatients, AF of recent onset convertsspontaneously to normal sinus rhythmwithin 24 hours. Thus, in some cases,the most appropriate approach maybe to control the ventricular response,identify and treat comorbid conditions,initiate anticoagulation, and closelymonitor the patient.

Because a clot generally requires2 to 3 days to form, it is usually safe todelay cardioversion for the first 24hours in a stable patient with a controlledventricular rate. To attemptmedical cardioversion during this timemay confuse the issue. If cardioversiondoes occur, it will be unclear if thisis a result of medication or whether itis spontaneous.

On the other hand, recent findingsrelated to electrical remodelingsuggest that the longer the delay beforemedical or electrical conversion isattempted, the lower the likelihood ofacute conversion to and maintenanceof sinus rhythm.1,2 How much differencea delay of days or a few weeksmakes is unknown. Pharmacologicconversion appears to be most effectivewhen initiated within 7 days of theonset of AF.3

Here, we address the rationale forconversion to and maintenance ofsinus rhythm and describe the antiarrhythmicagents used in medical cardioversion.In part 1 of this series(page 526), we discussed rate controland prevention of thromboembolismin patients with AF.

RATIONALE FORCONVERSION TOSINUS RHYTHMSymptom control. Physiologically,it seems preferable to restore sinusrhythm whenever possible. Althoughthe condition of many patients improveswith rate control, some continueto have significant symptoms.4Even in the absence of concomitantheart disease, patients with AF havereduced exercise capacity5 and experi-ence higher heart rates during exercisethan those in sinus rhythm.6 Onestudy of patients with heart failureshowed that those in whom rate controlhad been achieved but who hadpersistent AF had only marginal improvementin left ventricular ejectionfraction and symptoms. In contrast, theejection fraction improved and symptomsdiminished significantly in patientsin whom sinus rhythm wasmaintained.7

Atrial contribution to ventricularfilling. Patients who depend moreon "atrial kick" for ventricular fillingmay have more to gain from restorationof sinus rhythm than other patientswith AF. This group includesthose with underlying left ventricular(systolic) dysfunction or with unusuallystiff ventricles (diastolic dysfunctionfrom hypertension or aorticstenosis). Loss of atrial kick (whichmay contribute 20% to 30% to ventricularfilling in such patients8) placesthese patients at increased risk forcontinued symptomatic heart failureeven after rate control.

Reduced need for anticoagulation.Another reason to considerrhythm conversion in patients with AFis to reduce the need for anticoagulation.The latter therapy is not withoutrisk, and it is not appropriate in certainpatients, such as those at high risk forfalls, those with active ulcer disease,and those who previously experiencedsignificant hemorrhage with anticoagulation.Many physicians stop anticoagulationonce sinus rhythm hasbeen restored. However, it is not yetentirely clear whether anticoagulationshould be discontinued in patients convertedto sinus rhythm, because somemay have other factors that continueto predispose them to embolization.9 Asignificant number of these patientsmay have occult paroxysmal AFwhich, without anticoagulation, placesthem at greatly increased risk forstroke.

Prevention of left atrial enlargement.AF may result from, and is arisk factor for, left atrial enlargement.10,11 AF leads to atrial dilation,which further predisposes to persistentAF and subsequent further dilation(ie, "AF begets AF"1). Left atrialsize affects impulse conduction propertiesassociated with electrical remodeling,which may be reflected in apatient's ability to undergo cardioversionsuccessfully and maintain sinusrhythm. The larger the left atrium, theless the likelihood of successful cardioversion.Once sinus rhythm is restored,the atrium often diminishes insize.12 Besides left atrial size, other factorsinvolved in maintenance of normalsinus rhythm include the duration ofAF, left ventricular function, electricalremodeling, and specific antiarrhythmictherapy.13,14

PREPARATION FORCARDIOVERSIONAnticoagulation. Before cardioversionis undertaken, several issuesneed to be addressed. If possible, determinehow long the patient hasbeen in AF. The American College ofChest Physicians strongly recommendsanticoagulation with warfarin(target INR, 2 to 3) for at least 3weeks before elective cardioversion ifAF has been present for more than48 hours or for an unknown amountof time.3,15 Continue anticoagulationfor 3 to 4 weeks after conversion tosinus rhythm. This recommendationis based on the high number of reportedembolic events (up to 5.6%)after cardioversion,16 which arethought to result from dislodging ofpreexisting clots or formation of newclots in the stunned atrium.17 Restorationof normal atrial function may bedelayed for several weeks or moreafter conversion to a normal electricalrhythm.

Transesophageal echocardiography.Specific echocardiographic factorshave been identified that may correlatewith an increased risk of strokein patients with nonrheumatic chronicAF.18,19 Transesophageal echocardiography(TEE) may be used to identifythese factors, which include:

  • Left atrial clot.
  • Large atrial size (or depressed atrialappendage function).
  • Complex aortic plaque.
  • Spontaneous echocardiographiccontrast.

However, the absence of thesefactors does not eliminate the risk ofembolization after cardioversion.20Therefore, although TEE before cardioversion is not routinely recommended,it may clearly be helpful in selectedcases.

Whether to initially attempt cardioversionpharmacologically (andwith which agent) or electrically dependson the individual patient.21 Typically,pharmacologic cardioversion istried first, followed by electrical cardioversionif it fails. This approach isreasonable in many cases becausemedical therapy is less invasive. Furthermore,the probability of successwith electrical cardioversion is increasedwhen the patient is alreadytaking an antiarrhythmic agent.22

The initial choice of an antiarrhythmicmust be individualized. Ingeneral, long-term efficacy is relativelysimilar among the various agents, witha reported range for maintaining sinusrhythm of 50% to 70% after 1 year and40% to 50% after 3 years.19,23 Table 1lists factors to consider in selecting anantiarrhythmic.

 Table 1 –Factors to consider in selecting an antiarrhythmic for cardioversion
Extent of the patient's symptoms 
Safety profile of the agent (including the potential for proarrhythmia, organ toxicity, and drug interactions) 
Presence and severity of underlying heart disease (structural and electrical abnormalities) 
Additional comorbid conditions (eg, hepatic, renal, or electrolyte abnormalities) 
Cost (of drugs and monitoring)* Dosing convenience* 

*The importance of these factors varies with each patient.

It is difficult to compare the conversionrates of the various pharmacologicagents because a number ofvariables affect the ultimate successrate. These include left atrial size, leftventricular function, length of timethe patient has been in AF, the presenceof concomitant cardiovasculardisease, and electrophysiologic milieu.Even placebo has documentedshort-term conversion rates as highas 48%.24,25 Conversely, AF tends torecur in many patients regardless ofthe drug used. The efficacy of treat-ment is best judged by reduction inthe rate of recurrence or severity andduration of AF episodes, rather thanelimination of AF.26

Several classes of pharmacologicagents have shown good rates of conversionand maintenance of sinusrhythm, with broad ranges reportedfor each drug depending on study conditions.27 Certain clinical situationsmay make one agent initially preferableto another.26 A listing of agentsused to maintain sinus rhythm, withsuggested dosages and adverseevents, is provided in Table 2.

The class IA agents (disopyramide,procainamide, and quinidine); class ICagents (flecainide and propafenone);and class III agents (amiodarone,dofetilide, ibutilide, and sotalol) are all effectiveto varying degrees in restoringor maintaining sinus rhythm.

 Table - Drugs for maintenance of sinus rhythm*
Drug class and drug Daily dosePotential adverse effects
Class IA  
Disopyramide 400 - 750 mgTorsades de pointes, heart failure, glaucoma, urinary retention, dry mouth

Procainamide 1000 - 4000 mgTorsades de pointes, systemic lupus erythematosus– like syndrome, GI symptoms

Quinidine 600 - 1500 mgTorsades de pointes, GI upset, enhanced AV nodal conduction

Class IC   

Flecainide 200 - 300 mgVentricular tachycardia, congestive heart failure, enhanced AV nodal conduction (conversion to atrial flutter)

Propafenone 450 - 900 mgVentricular tachycardia, congestive heart failure, enhanced AV nodal conduction (conversion to atrial flutter)

Class III   
Amiodarone† 100 - 400 mgPhotosensitivity, pulmonary toxicity, polyneuropathy, GI upset, bradycardia, torsades de pointes (rare), hepatic toxicity, thyroid dysfunction
Dofetilide‡ 500 - 1000 .gTorsades de pointes

Sotalol‡ 240 - 320 mgTorsades de pointes, congestive heart failure, bradycardia, exacerbation of chronic obstructive or bronchospastic lung disease

AV, atrioventricular. *Drugs and dosages determined by consensus based on published studies. †A loading dose of 600 mg/d is usually given for 1 month or 1000 mg/d for 1 week. ‡Dosage should be adjusted for renal function and QT-interval response during in-hospital initiation phase. Adapted from Fuster V et al. Circulation. 2001.

Class IA agents. Historically,these agents were the most commonlyprescribed antiarrhythmics for AF.Oral quinidine is effective at both restoringand maintaining sinus rhythm.In one meta-analysis, quinidine demonstrateda mean efficiency of 41% inmaintaining sinus rhythm after a mediantime of 1 year.28 In another study,the 24-hour conversion rate with combinedquinidine and digoxin was 47%.29Intravenous procainamide was alsoshown to be effective in older, uncontrolledstudies, in which conversionrates were as high as 58%.30

Class IA agents have been associatedwith a number of serious side effects.A meta-analysis of randomizedcontrolled trials showed that long-termtreatment of AF with quinidine was associatedwith a 3-fold increase in mortalityin the ensuing 1 to 2 years.31Other significant risks associated withquinidine include organ toxicity andproarrhythmia (including suddendeath). Moreover, the efficacy of thisagent decreases with time.32

The principal side effects associatedwith short-term use of procainamideinclude hypotension andQRS and QT prolongation, which maypredispose to torsades de pointes.33Long-term use of procainamide is alsolimited because of the almost inevitabledevelopment of drug-inducedsystemic lupus erythematosus, nausea,and neutropenia.26

Disopyramide has a unique vagolyticeffect in addition to its class IAproperties. This may make it a preferredagent for a patient with AF thatresults from increased vagal tone(such as AF in a well-conditioned athleteor nocturnal AF).26

Class IC agents. When used appropriately,propafenone and flecainideappear to be the most effective drugsfor acute conversion of AF to sinusrhythm. Success rates of up to 78%with flecainide and 72% with propafenonehave been reported after a singleoral dose (usually twice the maintenanceoral dose); conversion isachieved in 8 to 12 hours.34

Although generally well tolerated,these drugs should not be used in patientswith structural heart disease becauseof the high risk of potentiallylethal proarrhythmia in this setting.This recommendation reflects the resultsof the Cardiac Arrhythmia SuppressionTrial (CAST), in which therisk of death significantly increasedwhen flecainide and encainide wereused to treat ventricular arrhythmiasin patients with coronary disease.35CAST specifically implicated flecainideand encainide, but these warnings aregenerally applied to all IC agents.

Although these restrictions limitthe broader use of class IC agents,they can be considered first-line therapyfor patients with true lone AF orthose with hypertension and minimalleft ventricular hypertrophy.26 Anotherconsideration is that arrhythmia oftenrecurs in the form of atrial flutter witha slow atrial rate of 180 to 220 beatsper minute. Concomitant use of anatrioventricular (AV) nodal blockingagent to prevent the possibility of 1:1AV conduction is recommended.36

Class III agents. Although their effectsvary, these agents appear to workby prolonging the QT interval. With theexception of ibutilide, they are generallyless useful for acute conversion of AFand are used more commonly to maintainsinus rhythm. Ibutilide has been reportedeffective in approximately 30% ofcases for acute conversion of AF tosinus rhythm.37 The drug works rapidly(usually within 60 to 90 minutes); abouthalf of patients in whom ibutilide is effectiveconvert to sinus rhythm withinthe first 10 minutes.37

Sotalol is unique in that it also possessessignificant nonselective β-blockingactivities. This may make it an antiarrhythmicof choice for patients withcoronary artery disease who have normalleft ventricular function.26

Unlike most other antiarrhythmics,amiodarone and the newest approvedclass III agent, dofetilide, appearrelatively safe for patients withsignificant systolic heart failure.38-41Amiodarone was also shown to be effectiveeven in some patients withlarge left atrial size (60 mm or more)and previous poor response to otheragents.42 Amiodarone is associatedwith a lower incidence of torsades depointes than other class III agents butcarries the risk of significant organ toxicity(such as pulmonary fibrosis, liverfunction abnormalities, and thyroiddysfunction) as well as ocular disturbances,skin discoloration, and adversedrug interactions (most notably withwarfarin and digoxin).43

Dofetilide has been associatedwith a significantly decreased numberof hospitalizations for heart failure exacerbationwith concomitant AF.39 Thisagent appears to be associated with alower incidence of organ toxicity butmore frequent occurrence of torsadesde pointes (0.8% overall, 3.39% in patientswith left ventricular dysfunction);consequently, the manufacturer has restrictedthe availability of dofetilide toprescribers who have participated in aspecial educational program.44

Unfortunately, class III agents areassociated with substantial risk. Becausethey prolong the QT interval,there is a significant likelihood ofproarrhythmia if excessive QT prolongationoccurs.45 Be sure patients arenot taking other drugs that prolongthe QT interval. Hypokalemia, hypomagnesemia,and hypocalcemia,which can also affect repolarization,must be avoided as well.46

If AF is refractory to pharmacologicor electrical cardioversion, considerreferral for surgical therapy. Optionsinclude pacing, AV nodal ablation,and circumferential pulmonaryvein ablation. Future management forcertain patients may include potentiallycurative ablation therapy of atrialreentry currents.




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