Chronic Arrhythmia Management191

Learning Objectives 1. Distinguish between the electrocardiographic

definitions of recurrent atrial fibrillation (AF),paroxysmal AF, persistent AF, permanent AF, lone AF,premature ventricular contractions (PVCs), ventriculartachycardia (VT), ventricular fibrillation (VF), andtorsades de pointes (TdP).

2. Evaluate the cardiac and noncardiac etiologies, clinicalmanifestations, and clinical consequences associatedwith AF, PVCs, VT, and VF.

3. Analyze the advantages and disadvantages of using -blockers, calcium channel blockers, and/or digoxin tocontrol the ventricular rate in AF.

4. Compare and contrast the effectiveness of variousVaughan Williams class Ic and class III antiarrhythmicagents for restoring and maintaining sinus rhythm inAF.

5. Evaluate the results of the most recent trials thatcompare rate- and rhythm-control strategies for thechronic management of AF.

6. Analyze and describe the most recent guidelines forprevention of thromboembolic events in AF.

7. Given patient-specific information, design anindividualized drug treatment plan for patients withparoxysmal, persistent, or permanent AF that includesmonitoring parameters, recommendations for managingadverse events or drug interactions, and patienteducation.

8. Assess the most recent scientific evidence examiningthe use of implantable cardioverter defibrillators (ICDs)versus antiarrhythmics for primary and secondaryprevention of sudden cardiac death.

9. Given patient-specific information, design anindividualized drug treatment plan for the primary andsecondary prevention of sudden cardiac death (SCD) inpatients with nonsustained VT (NSVT), sustained VT,

VF, or other high-risk conditions, that includesmonitoring parameters, recommendations for managingadverse events or drug interactions, and patienteducation.

10. Identify drugs that have been associated with QTinterval prolongation and/or TdP.

Introduction Throughout the past 2 decades, there has been a

prominent reduction in the prescribing of antiarrhythmics inthe United States. From 1986 to 2000, prescriptions written for antiarrhythmics decreased from 11.4 million to5.1 million, much of which was attributed to a decline in theuse of class I antiarrhythmics. Most notably, from 1995 to2000, the use of class I antiarrhythmics plummeted by morethan 50%. This downward trend can most likely beexplained by prescribers reactions to the conglomeration ofevidence that emerged during this time from clinical trialsthat associated class I antiarrhythmics with either no benefitor increased mortality. The heightened fear of using theseantiarrhythmics has been accompanied by a surge in thepopularity of class III agents, with the use of amiodarone, inparticular, increasing by 125% between 1995 and 2000.This increase reflects the trend toward using agents that areconsidered to be safer, especially in the increasing numberof patients with structural heart disease.

Part of the overall decline in the use of antiarrhythmicsalso is likely because of the increasing availability andrefinement of various non-pharmacological strategies fortreating tachyarrhythmias. The attractiveness of thesetherapies may stem from the desire of prescribers to avoidthe proarrhythmic effects and organ toxicities caused by the available antiarrhythmic agents. Although non-pharmacological therapies such as focal catheterablation and atrial pacing are just beginning to evolve asviable treatment options for atrial fibrillation (AF), the

CHRONICARRHYTHMIAMANAGEMENT

Pharmacotherapy Self-Assessment Program, 5th Edition

Cynthia A. Sanoski, Pharm.D.Reviewed by Cynthia A. Carnes, Pharm.D., Ph.D.; Eric Harvey, Pharm.D., M.B.A., BCPS; David J. Ritchie, Pharm.D., FCCP, BCPS

192Chronic Arrhythmia Management Pharmacotherapy Self-Assessment Program, 5th Edition

implantable cardioverter defibrillator (ICD) has rapidlysupplanted the use of antiarrhythmics in the chronicmanagement of ventricular tachyarrhythmias.

Despite the decreased use of antiarrhythmics overall forboth AF and ventricular arrhythmias, a significant role forthese agents in managing these rhythm disturbances stillremains. Because many non-pharmacological therapies forAF are still under investigation and have been limited todrug-refractory patients, antiarrhythmic drugs continue tohave a prominent role in managing this particulararrhythmia in clinical practice. Although the placement ofICDs has dominated the chronic management of ventriculartachyarrhythmias, antiarrhythmic drugs still possess a nicheas adjunctive therapy to minimize the frequency of ICDdischarges. Even though the pattern of use ofantiarrhythmic drugs has shifted from class I to class IIIagents, the need for monitoring the chronic toxicities ofthese drugs remains. In fact, with the use of amiodaroneincreasing, the obligation to monitor for development of itspotentially serious organ toxicities will likely becomegreater.

This chapter focuses on chronic arrhythmiamanagement. For AF, the discussion centers onpharmacological and non-pharmacological strategies for

chronically managing patients with recurrent or permanentAF. In addition, for ventricular tachyarrhythmias, the focusis on pharmacological and non-pharmacological strategiesbeing used for primary and secondary prevention of thesepotentially life-threatening arrhythmias. Please note thatthe Vaughan Williams classification scheme will be usedthroughout this chapter when referring to antiarrhythmicdrugs (i.e., class I, class II, class III, and class IV).

Atrial Fibrillation Pathophysiology

Although the basic theories of the mechanism of AF havebeen known and appreciated for decades, further insights tothe pathophysiology of this rhythm disturbance havecontinued to evolve that have subsequently stimulatedresearch aimed at developing newer treatment strategies.Through the years, two theories have been proposed toexplain the mechanism of AF. One theory supports theconcept that rapidly firing foci in the atria may initiate AFin susceptible patients. Recent research has shown thatthese areas of enhanced automaticity are most often locatedin left atrial tissue within and near the pulmonary veins.

Abbreviations in this ChapterACC American College of CardiologyAF Atrial fibrillationAFFIRM Atrial Fibrillation Follow-up:

Investigation of RhythmManagement

AHA American Heart AssociationAMIOVIRT Amiodarone versus Implantable

Defibrillator Randomized TrialAV AtrioventricularAVID Antiarrhythmics Versus Implantable

DefibrillatorsCASH Cardiac Arrest Study-HamburgCAST Cardiac Arrhythmia Suppression

TrialCAT Cardiomyopathy TrialCCB Calcium channel blockerCI Confidence intervalCIDS Canadian Implantable Defibrillator

StudyCrCl Creatinine clearanceCTAF Canadian Trial of Atrial FibrillationCYP Cytochrome P450DC Direct currentDFT Defibrillation thresholdDIAMOND-CHF Danish Investigations of

Arrhythmia and Mortality onDofetilide-Congestive HeartFailure

DIAMOND-MI Danish Investigations of Arrhythmiaand Mortality on Dofetilide-Myocardial Infarction

ECG Electrocardiogram

EP Electrophysiology;electrophysiological

ESC European Society of CardiologyFDA Food and Drug AdministrationICD Implantable cardioverter

defibrillatorINR International normalized ratioLV Left ventricularLVEF Left ventricular ejection fractionMADIT Multicenter Automatic Defibrillator

Implantation TrialMI Myocardial infarctionMOS SF-36 Medical Outcomes Study, short

form, 36 itemsMUSTT Multicenter Unsustained

Tachycardia TrialNSVT Nonsustained ventricular

tachycardiaNYHA New York Heart AssociationPIAF Pharmacological Intervention in

Atrial FibrillationPVC Premature ventricular contractionRACE Rate Control versus Electrical

Cardioversion for Persistent AtrialFibrillation

SAFIRE-D Symptomatic Atrial FibrillationInvestigative Research onDofetilide

SCD Sudden cardiac deathTdP Torsades de pointesVF Ventricular fibrillationVT Ventricular tachycardia

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Foci also originate less frequently in the superior vena cavaand the coronary sinus. This focal origin theory maypredominate more in patients with paroxysmal AF than inthose with persistent AF.

The other theory that has become more accepted forexplaining the mechanism of persistent AF is the multiplewavelet hypothesis. According to this theory, AF developsas a result of multiple (at least five) simultaneouslycirculating wavelets of reentry that arise in the atria. Thenumber of wavelets depends on many factors, including therefractory period, mass, and conduction velocity in variousareas of the atria. The combination of a shortened refractoryperiod, delayed conduction, and increased atrial mass islikely to precipitate the development of more reentrantwavelets that subsequently interact to facilitate persistenceof the arrhythmia.

Persistence of AF also may result from atrialelectrophysiological (EP) remodeling, which may beginwithin the first 24 hours after the initial onset of an episodeof AF. With repeated, prolonged occurrences of AF, theatrial refractory period progressively shortens, whichpredisposes the atria to developing more sustained episodesof the arrhythmia. These EP changes have given rise to thenotion that AF begets AF. Because these changes aremost likely to develop as the duration of the AF episodeincreases, the atria are likely to become resistant tocardioversion with time. Therefore, if possible, electrical orpharmacological cardioversion should be performed withinthe first 24 hours after the onset of AF to achieve highersuccess rates.

Definitions Atrial fibrillation is a supraventricular arrhythmia

characterized by uncoordinated atrial contraction that resultsin an irregular and often rapid ventricular response. On theelectrocardiogram (ECG), AF appears as an irregularlyirregular rhythm with a variable R-R interval and a lack oforganized P waves before each QRS complex. In AF, theatria are rapidly contracting at a rate of 350600beats/minute. This rapid atrial rate leads to the appearanceof fibrillatory waves (f waves) on the ECG that vary in size,shape, and timing. In the presence of normalatrioventricular (AV) conduction, the resulting ventricularresponse usually is between 120 and 180 beats/minute. Atypical ECG strip demonstrating AF is depicted in Figure 4-1.

In the past, the nomenclature used for defining differenttypes of AF has been inconsistent, vague, and confusing.With different definitions being used to describe the varioustypes of AF (e.g., acute, chronic, paroxysmal, and recurrent)in clinical trials, the process of determining an appropriatetreatment regimen for a patient could be challenging.However, recent treatment guidelines for AF developedjointly by the American College of Cardiology (ACC),American Heart Association (AHA), and the EuropeanSociety of Cardiology (ESC) provide a more simplisticclassification scheme to describe the various patterns of AF,enabling clinicians to select the best therapies for theirpatients with this arrhythmia.

In this updated classification system, AF is no longercategorized as acute or chronic. Instead, an initiallydetected episode of AF is classified as either paroxysmal orpersistent. Atrial fibrillation is characterized as paroxysmalif it terminates spontaneously. Episodes of paroxysmal AFmay occur sporadically or frequently, may last from minutesto up to 7 days, and may be asymptomatic. Persistent AF issustained and requires pharmacological or electricalcardioversion to restore sinus rhythm. The duration ofpersistent AF is usually more than 7 days. If a patient hadtwo or more episodes of either paroxysmal or persistent AF,the arrhythmia also may be broadly referred to as recurrentAF. When persistent AF cannot be successfully convertedto sinus rhythm or when cardioversion is not indicated, AFis considered permanent. The overall classification of thearrhythmia should ultimately be made by the clinician afterperforming a detailed history and physical examination.

Atrial fibrillation that develops in the absence of clinical,electrocardiographic, radiographic, and echocardiographicevidence of structural heart disease is defined as lone AF.This term applies to patients younger than 65 years of agebecause various cardiac abnormalities (e.g., left atrialenlargement, left ventricular [LV] dysfunction, and coronaryartery disease) that may trigger AF are more likely todevelop in elderly patients.

Etiologies Atrial fibrillation most commonly develops in the

presence of some form of structural heart disease.Cardiovascular conditions commonly associated with thedevelopment of AF include coronary artery disease,hypertension (especially when LV hypertrophy is present),valvular (usually mitral) heart disease, dilated orhypertrophic cardiomyopathy, and congenital heart diseases

Chronic Arrhythmia ManagementPharmacotherapy Self-Assessment Program, 5th Edition

Figure 4-1. Electrocardiographic appearance of atrial fibrillation, characterized by lack of identifiable P waves, an undulating baseline and a variable R-Rinterval.

(especially atrial septal defect). Patients with LV systolicdysfunction are especially predisposed to developing AF,with up to 35% of patients with heart failure beingdiagnosed with AF at some point throughout the course oftheir disease. Other conditions associated with thedevelopment of AF include restrictive cardiomyopathies,such as amyloidosis or hemochromatosis, cardiac tumors,constrictive pericarditis, chronic obstructive pulmonarydisease, sick sinus syndrome (tachycardia-bradycardiasyndrome), and other supraventricular arrhythmias such asWolff-Parkinson-White syndrome or AV nodal reentranttachycardias.

Atrial fibrillation also may be precipitated by acutecauses, including excessive alcohol ingestion (holidayheart syndrome), excessive caffeine intake, overuse ofsympathomimetic drugs, acute myocardial infarction (MI),surgery, pericarditis, myocarditis, electrocution, pulmonaryembolism, acute obstructive pulmonary disease, pneumonia,thyrotoxicosis, and electrolyte abnormalities. When AFdevelops under these circumstances, successful treatment ofthe underlying condition often leads to resolution and a lackof recurrence.

Clinical Characteristics Patients with AF can be symptomatic or asymptomatic.

Asymptomatic patients may have AF diagnosed simply on aroutine ECG. Patients who present with symptoms oftencomplain of palpitations, exertional fatigue,lightheadedness, exercise intolerance, or dyspnea.Uncontrolled ventricular rates can be associated with thedevelopment of myocardial ischemia and subsequent anginain patients with underlying coronary artery disease. Inaddition, patients with LV systolic or diastolic dysfunctionmay develop worsening signs and symptoms of heart failurein the presence of a rapid ventricular rate. This arrhythmiaalso may initially manifest as a thromboemboliccomplication, with the most notable event being a stroke.Although syncope is uncommon in most patients with AF, itcan develop in patients with sick-sinus syndrome or inpatients with aortic stenosis, hypertrophic cardiomyopathy,or cerebrovascular disease. The severity of symptoms in AFis directly related to the rapidity of the ventricular rate, thepatients underlying LV function, and the duration of thearrhythmia.

Atrial fibrillation can be associated with potentiallyserious hemodynamic and thromboembolic consequencesthat may have a significant impact on long-term morbidityand mortality. Hemodynamic function can be adverselyaffected in AF not only by the loss of coordinated atrialsystole, but also by the irregular and rapid ventricularresponse. Synchronized atrial contraction can contribute upto 30% to a patients overall cardiac output. Therefore, lossof this atrial contraction (or atrial kick) can lead to aconsiderable reduction in cardiac output, especially inpatients with LV systolic dysfunction who depend on thecontribution of their atrial kick toward their alreadydiminished cardiac output. An irregular ventricularresponse, as demonstrated by an inconsistent R-R interval,also reduced cardiac output by about 10% in humans.Persistently rapid ventricular rates have been associatedwith the development of a tachycardia-induced

cardiomyopathy, which can be partially or completelyreversed once the ventricular rate is adequately controlled.As a result, ventricular rate control remains an importantstrategy to consider initially in patients presenting with bothAF with a rapid ventricular rate and symptoms of heartfailure because the arrhythmia may be the ultimate cause ofthe heart failure. In one study, the median left ventricularejection fraction (LVEF) improved from 25% to 52% inpatients with AF when their ventricular rate wasappropriately controlled.

Thromboembolic complications, particularly ischemicstroke, also can be a potentially devastating and debilitatingsequela of AF. Loss of coordinated atrial contraction duringAF can lead to the pooling of blood and subsequentthrombus formation, which occurs most commonly in theleft atrial appendage. Although this stasis theory has longbeen perceived as the primary mechanism of thrombusformation in patients with AF, recent investigations havesuggested that other hemostatic factors may play a role inthis phenomenon. The presence of endothelial dysfunctionin patients with AF has been proposed as one suchmechanism that may lead to thrombus formation. It also hasbeen suggested that the development of AF may lead to ahypercoagulable state. In recent studies, AF has beenassociated with elevated fibrinogen, fibrin d-dimer, andplatelet factor-4 levels, which may indicate that activation ofthe coagulation cascade and platelets is stimulated by thisarrhythmia.

Diagnosis Because many patients are asymptomatic when AF

develops, the gold standard for diagnosis remains the 12-lead ECG (Figure 4-1). In the absence of AV nodaldysfunction and/or the use of AV nodal blockers (e.g., -blockers, nondihydropyridine calcium channel blockers[CCBs], and digoxin), patients often present with a rapidventricular response. The ECG may help detect potentialetiologies of AF, such as myocardial ischemia or LVhypertrophy. If paroxysmal AF is suspected, based on aclinical history that suggests intermittent symptoms, either a24-hour Holter monitor or an event recorder could be used,depending on the frequency of symptoms. Patients with AFusually have an irregular pulse on palpation.

Once AF is diagnosed by ECG, further evaluation of thepatient should include a detailed medical history todetermine the presence and type of symptoms, the pattern ofthe arrhythmia (first episode vs. paroxysmal vs. persistentvs. permanent), the date of onset of the first symptomaticepisode, the frequency and duration of symptomaticepisodes, the conditions under which the episodes occur,and risk factors for AF. The duration of the most recentepisode of AF is particularly important to obtain during themedical history, as this information will assist in theselection of the best treatment strategy. A thorough drughistory also should be performed to rule out drug-inducedcauses of AF, such as illicit drug use (e.g., cocaine) orexcessive use of over-the-counter or prescriptionsympathomimetics (e.g., pseudoephedrine or -adrenergicagonists). The patient also should be questioned aboutrecent alcohol intake.

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As part of the initial workup of all patients with AF, atwo-dimensional transthoracic echocardiogram should beperformed to determine the presence and severity of anycardiac abnormalities that may be causing AF and toidentify risk factors for stroke. Useful information that canbe obtained from a transthoracic echocardiogram in patientswith AF includes left atrial size, LV wall thickness andfunction, and valvular function. In patients with AF lastingmore than 48 hours or when an intracardiac thrombus issuspected, a transesophageal echocardiogram should beperformed because a transthoracic echocardiogram is unableto clearly visualize the left atrial appendage, where mostthrombi arise. Additional tests that should be performed aspart of the workup of patients with AF include electrolyteconcentrations as well as thyroid function tests.

Epidemiology Atrial fibrillation is the most common sustained

arrhythmia encountered in clinical practice Overall, thisrhythm disturbance affects about 12% of the generalpopulation. Because many patients with AF areasymptomatic and unaware of their rhythm disturbance,recent reports suggest that the overall prevalence of AF maybe significantly underestimated. The development of AFbecomes increasingly common with advancing age. Theprevalence of AF appears to double with every decade of life after the age of 60, increasing from 2% in patients6069 years of age to almost 10% in those 8089 years ofage. The prevalence of AF also appears to be higher inpatients with more severe heart failure, increasing from 4% in patients with asymptomatic New York HeartAssociation (NYHA) functional class I to 50% in patientswith NYHA functional class IV heart failure.

Prognosis Atrial fibrillation usually begins in a paroxysmal pattern.

Spontaneous conversion is fairly common in patients withparoxysmal AF, with reported conversion rates ranging from50% to 60% in patients with AF less than 72 hours induration. However, because of the electrical and structuralremodeling changes that occur in the atria with time,patients initially presenting with paroxysmal AF are likelyto progress to persistent or even permanent AF. About 40% of patients have persistent AF, whereas more than 10% of patients with paroxysmal AF go on to developpermanent AF.

Although not initially perceived to be a life-threateningarrhythmia, recent data have shed new light on the impact ofAF on mortality. Patients with AF have a mortality rate thatis about 2 times that seen in patients with sinus rhythm. Itis somewhat unclear whether the arrhythmia itself confers agreater risk of mortality or whether the interaction betweenAF and other comorbid conditions provides a substrate forincreased mortality. However, data from several studieshave linked the increased mortality in this patient populationwith the presence of underlying structural heart disease.The presence of AF has a detrimental effect on survival inpatients with LV dysfunction. Data from the Studies of LeftVentricular Dysfunction suggest that the presence of AF atbaseline is a strong independent predictor of death becauseof pump failure and rehospitalization for heart failure

exacerbations in patients with either symptomatic orasymptomatic LV dysfunction. Although the mechanismsfor increased mortality in this patient population are mostlikely multifactorial, one potential theory suggests that theadverse hemodynamic consequences associated with AFmay lead to eventual pump failure and subsequent death.The potential proarrhythmic effects of antiarrhythmics usedfor AF also may contribute to the increased mortality rateobserved in patients with heart failure. Of interest, thepresence of lone AF has not been associated with anincrease in mortality.

As previously discussed, the presence of AF is asignificant independent risk factor for thromboembolicstroke. In fact, 1520% of all strokes occur in patients withAF. Patients with nonrheumatic (nonvalvular) AF haveabout a 5-fold higher risk for stroke than patients in sinusrhythm. Patients with rheumatic AF are at an even higherrisk for stroke, with their risk being increased 17-foldcompared to patients in sinus rhythm. The risk of strokealso dramatically increases with age, with the annualattributable risk increasing from 1.5% in individuals 5059 years of age to almost 24% in those 8089 years ofage. In patients older than 80 years of age, AF remains thesingle most important contributor to the incidence of stroke.

The risk of stroke in patients with AF significantlyincreases when other risk factors for stroke are present. In apooled analysis of data from five randomized trialscomparing warfarin or aspirin with control in patients withAF, the risk of stroke in those younger than 65 years with norisk factors was 1%. According to the definition previouslydiscussed, this group of patients would be characterized ashaving lone AF, and would thereby be at a relatively lowrisk of stroke. When patients of this same age group had oneor more risk factors, the risk of stroke increased to 4.9%.Patients older than 75 years with no additional risk factorshad a risk of stroke of 3.5% that increased to 8.1% whenother risk factors were present. Risk factors other thanincreasing age in this pooled analysis included history ofhypertension, previous transient ischemic attack or stroke,and diabetes.

When considering the pattern of AF, a common questionthat arises is whether patients with paroxysmal AF have thesame risk of stroke as those with sustained (persistent orpermanent) AF. Although it has been a common belief thatpatients with paroxysmal AF may have a lower risk ofstroke than those with sustained AF, the literature providesconflicting evidence. Several studies have suggested thatpatients with sustained AF have a 23-fold higher risk ofstroke than patients with paroxysmal AF. In contrast,another group of studies has suggested that patients withparoxysmal AF have stroke rates that are similar to patientswith sustained AF. Despite these conflicting data, it shouldbe realized that patients with paroxysmal AF still have ahigher risk of stroke than those in sinus rhythm. Therefore,in these patients, the stroke risk should be determinedwithout taking into consideration the pattern of AF.

Therapeutic Goals/Outcomes The disease-specific goals of therapy for AF include

controlling the ventricular response, preventingthromboembolic events, restoring sinus rhythm, and

Chronic Arrhythmia ManagementPharmacotherapy Self-Assessment Program, 5th Edition

maintaining sinus rhythm. The effects of variouspharmacological and non-pharmacological regimens onthese specific goals have been examined extensively innumerous clinical trials, some of the most important ofwhich are discussed in the Quality Pharmaceutical Caresection. In addition, because AF is a progressive diseaseassociated with significant morbidity and mortality, theimplementation and optimization of preventive measuresthat focus on identifying and managing contributing riskfactors are essential.

There also are many global goals that are optimal toachieve when treating AF, including 1) reducing overall andcardiovascular mortality; 2) improving quality of life; 3)decreasing the number of hospitalizations and emergencydepartment visits; and 4) optimizing the cost-effectivenessof treatment. Until recently, studies examining the effects ofachieving each of the above disease-specific goals on theseglobal outcomes were lacking. However, with thepublication of the Pharmacological Intervention in AtrialFibrillation (PIAF), Rate Control versus ElectricalCardioversion for Persistent Atrial Fibrillation (RACE), andthe Atrial Fibrillation Follow-up: Investigation of RhythmManagement (AFFIRM) trials, more compelling data arenow available to describe the effects of variouspharmacological regimens on total mortality, cardiovascularmortality, quality of life, and hospitalizations.

Quality Pharmaceutical Care Pharmacological Therapy Chronic Ventricular Rate Control

-Blockers. Oral -blockers are effective treatment forchronic ventricular rate control in patients with AF. Theseagents effectively control heart rate at rest and duringexercise. In a systematic review of 45 randomized,controlled trials that evaluated the efficacy of various drugsfor ventricular rate control in patients with AF, -blockerswere effective at controlling heart rate at rest in seven of 12 placebo-controlled comparisons. Of the seven different-blockers evaluated in this review, nadolol and atenololappeared to be the most effective at reducing resting heartrate. All the -blockers used in nine trials significantlyreduced heart rate during exercise compared with placebo.However, exercise intolerance was observed in three ofthese nine trials, which is not surprising because this is arelatively common adverse effect associated with -blocker therapy.

Given their mortality benefits in patients with LVdysfunction, -blockers increasingly are being used tocontrol ventricular rate in this particular patient populationwhen AF develops. However, few randomized, prospectivetrials have evaluated the hemodynamic and clinical effectsof specifically initiating -blocker therapy to controlventricular rate in patients with LV dysfunction. Theprospective trials conducted in patients with heart failurehave used -blockers with intrinsic sympathomimetic

activity (e.g., xamoterol, pindolol, and practolol), a propertythat may be detrimental in this particular population withlong-term use. Nonetheless, with short-term use of these -blockers, the ventricular rate was significantly reduced atrest and during exercise, and the majority of the patientsexperienced symptomatic improvement.

Recently, the hemodynamic and clinical effects ofcarvedilol in patients with AF and symptomatic heart failurewere retrospectively evaluated in an analysis of data fromthe United States Carvedilol Heart Failure Trials Program.In this relatively small analysis of 136 patients with AF(carvedilol n=84; placebo n=52), carvedilol use wasassociated with a significant improvement in LVEF andphysician-determined global assessment. Trends toward areduction in overall mortality and in the combined end pointof death or hospitalizations for heart failure also wereobserved in the carvedilol group. Of interest, the heart ratereduction achieved was similar in the carvedilol and placebogroups, which may have been attributed to the high baselineuse of digoxin in both treatment groups. However, becausethis analysis only evaluated resting heart rates, thecomparative effects of carvedilol and digoxin in controllingventricular rate during exercise are not known. Preliminarydata from a separate trial evaluating the effects ofconcomitant carvedilol and digoxin therapy in patients withAF and heart failure also suggest that the eventualwithdrawal of digoxin results in worsening heart failuresymptoms and acceleration of the ventricular rate.

Despite the limited data describing the effects of -blockers in patients with concomitant AF and heartfailure, it seems reasonable to use these agents incombination with digoxin for ventricular rate control inpatients with stable heart failure. Because the -blockerdose must be titrated slowly in these patients to minimizethe development of worsening heart failure symptoms, theconcomitant use of digoxin may provide added heart ratecontrol, especially when lower doses of the -blocker arebeing used.

Nondihydropyridine Calcium Channel Blockers. The oral nondihydropyridine CCBs, verapamil anddiltiazem, also are effective treatment options for long-termventricular rate control in AF. Like -blockers, these agentscan adequately control the heart rate during exercise and atrest. In the systematic review of ventricular rate-controllingtherapies previously discussed, both verapamil anddiltiazem significantly reduced heart rate at rest and duringexercise compared with placebo in all the trials that wereevaluated (five trials for each drug). An improvement in exercise tolerance was observed in almost all of theplacebo-controlled comparisons with these CCBs.

These drugs should be avoided in patients with LVdysfunction, as their potent negative inotropic effects arelikely to precipitate worsening heart failure symptoms.However, these agents are preferred over -blockers forchronic use in patients with chronic obstructive pulmonarydisease.

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Segal JB, McNamara RL, Miller MR, et al. The evidence regarding the drugs used for ventricular rate control. J Fam Pract 2000;49:4759.Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventriculardysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am Heart J 2001;142:498501.

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Digoxin. Through the years, the overall use of digoxinto chronically control ventricular rate in patients with AFhas declined. This trend has been particularly observed inpatients with normal LV function, in whom either -blockers or CCBs are preferred. The declining use ofdigoxin, particularly in this patient population, can mostlikely be attributed to its relatively slow onset of action andits inability to control heart rate during exercise and evenduring normal daily activities. Even after an appropriateloading dose is administered, digoxins peak onset of effectis delayed for up to 68 hours. Achievement of steady-stateconcentrations with digoxin may take up to a week to occurin patients with normal renal function and even longer inpatients with renal insufficiency. The widely held belief thatdigoxin is ineffective for controlling ventricular rate underconditions of increased sympathetic tone was againvalidated by the previously discussed systematic literaturereview that demonstrated that heart rate was notsignificantly reduced with digoxin during exercise in fourplacebo-controlled trials. However, digoxin monotherapywas more effective than placebo in decreasing resting heartrate in seven of eight evaluated trials.

There has been some controversy as to whether digoxinis effective for preventing episodes of paroxysmal AF.Older data suggest that digoxin is not an effectiveantiarrhythmic agent and may even trigger AF by slowingconduction and reducing the atrial effective refractoryperiod through its vagomimetic effects. However,conflicting data from a prospective, placebo-controlled,crossover trial suggest that digoxin may be effective inreducing the frequency of symptomatic episodes ofparoxysmal AF. Compared to previously conducted studiesinvolving class Ic antiarrhythmic agents, the estimatedtreatment effect observed with digoxin in this study wasdeemed to be relatively small. The authors concluded that itwas unlikely that digoxin exerted true antiarrhythmic effectsin reducing the frequency of symptomatic episodes of AF.Instead, by reducing the ventricular rate or irregularityduring AF, digoxin most likely just converted previouslysymptomatic episodes of AF into asymptomatic episodes.Therefore, based on the overall data accumulated thus far,digoxin appears to be an inappropriate treatment option forpreventing AF.

Despite the increasing use of -blockers in patients withLV dysfunction, digoxin continues to be an important drugfor ventricular rate control in this patient population whenAF develops because of its positive inotropic effects. Inpatients with stable heart failure, digoxin can provideeffective heart rate control without increasing the risk forworsening heart failure symptoms. However, ventricularrate control may be compromised in patients who developheart failure exacerbations because sympathetic tone isheightened.

Combination Therapy. Combination therapy withdigoxin and either -blockers or nondihydropyridine CCBsoccasionally may be required to achieve adequate heart ratecontrol during AF. These agents act synergistically with

digoxin to reduce the ventricular rate at rest and duringexercise. The effects of various AV nodal-blocking drugregimens were evaluated in a relatively small crossover, open-label study that enrolled 12 patients withchronic AF. Five treatment regimens were evaluated:digoxin 0.25 mg/day; diltiazem CD 240 mg/day; atenolol 50 mg/day; digoxin 0.25 mg/day plus diltiazem CD 240 mg/day; and digoxin 0.25 mg/day plus atenolol 50 mg/day. Each drug regimen was assigned in a randomsequence and was administered for 2 weeks. In this study,monotherapy with either digoxin or diltiazem was leasteffective for controlling ventricular rate during dailyactivity. The most effective regimen for controlling theventricular rate during the daytime, the nighttime, and withexercise was the combination of digoxin and atenolol.Adding diltiazem to the digoxin regimen significantlyattenuated the exercise-induced increase in ventricular ratethat is commonly seen with digoxin monotherapy.However, this combination regimen did not consistentlylower ventricular rate throughout the 24-hour period andduring exercise to the same extent that was observed in thedigoxin and atenolol treatment group. Although this studyis potentially limited by its small sample size and unblindedtrial design, the results do lend additional support to thepractice of using combination therapy to achieve adequateventricular rate control in patients with AF.

Restoration of Sinus Rhythm Restoration of sinus rhythm in patients with AF can be

achieved by either electrical (direct current [DC]) orpharmacological cardioversion. Although the efficacy ofthese two strategies has never been directly compared in arandomized trial, DC cardioversion appears to be associatedwith higher overall success rates that range from 80% to90%. Despite its higher success rates, DC cardioversion isprimarily limited by its need for general anesthesia, which isused to minimize the pain related to the electrical shockdelivery. Even though short-acting intravenous anestheticsare commonly used during DC cardioversion, patients maystill be at risk for respiratory depression or aspiration fromthese drugs. Other potential complications of DCcardioversion may include ventricular arrhythmias, a shortperiod of sinus arrest after restoration of sinus rhythm,bradycardia, skin burns, pulmonary edema, andthromboembolism.

In the past, pharmacological strategies for cardioversionof AF to sinus rhythm traditionally had focused on the useof class Ia antiarrhythmics. However, throughout the pastdecade, the use of class Ia antiarrhythmics to restore sinusrhythm in patients with AF has significantly declined, whichcan most likely be attributed to increasing concern abouttheir proarrhythmic effects. In the place of these agents, theclass Ic and III antiarrhythmics have been increasingly usedfor pharmacological cardioversion. The antiarrhythmicsmost commonly used to convert paroxysmal or persistentAF to sinus rhythm include the class Ic antiarrhythmics(flecainide and propafenone) and class III antiarrhythmics

Chronic Arrhythmia ManagementPharmacotherapy Self-Assessment Program, 5th Edition

Farshi R, Kistner D, Sarma SM, Longmate JA, Singh BN. Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise:a crossover open-label study of five drug regimens. J Am Coll Cardiol 1999;33:30410.

(ibutilide, amiodarone, and dofetilide). The discussion laterin this section focuses only on the efficacy of the oralantiarrhythmics that are most commonly used for restoringsinus rhythm. A discussion of the efficacy of intravenousagents for restoration of sinus rhythm can be found in theAcute Management of Arrhythmia chapter.

Flecainide. Numerous trials have demonstrated theefficacy of oral flecainide for the conversion of recent onsetAF (less than 7 days in duration). Although studies inpatients with persistent AF are limited, the data suggest thatflecainide is associated with lower conversion rates in thisparticular patient population. When used for cardioversion,flecainide typically is administered as a single oral loading dose of 300 mg. When using this dose in patientswith recent-onset AF, a response is usually observed within3 hours, with conversion rates of 5768% being reported.At 8 hours, conversion rates of up to 90% have beenreported. Several studies also have shown oral flecainide to be as effective as oral propafenone for conversion ofrecent-onset AF.

Recently, a meta-analysis of 25 studies assessed theefficacy of various antiarrhythmics for conversion of AF.All of the included studies compared antiarrhythmics to acontrol treatment (e.g., placebo, digoxin, verapamil, ordiltiazem). Four flecainide studies were included in thismeta-analysis, all of which used the intravenousformulation. The odds ratio (95% confidence interval [CI])for conversion to sinus rhythm with flecainide comparedwith control was 24.7 (9.068.3). Next to ibutilide anddofetilide, flecainide had the strongest evidence of efficacycompared with control for conversion of AF. Althoughthese data are impressive, the clear limitation for applyingthese particular results into clinical practice is that efficacyof only the intravenous formulation was evaluated. Only theoral formulation of flecainide is currently available in theUnited States. However, a more recent systematic review oftrials that assessed the efficacy of antiarrhythmics for AFconversion has been performed. Although thiscomprehensive review did not use meta-analytic techniques,after evaluating seven trials involving oral flecainide, theauthors concluded that this antiarrhythmic is effective forconverting recent-onset AF (less than 7 days in duration) tosinus rhythm. In the three placebo-controlled trialsevaluated in this systematic review, oral flecainide wassignificantly more effective than placebo for conversion ofrecent-onset AF at 3 and 8 hours.

In general, single doses of oral flecainide are welltolerated. However, proarrhythmic effects such asconversion of AF to atrial flutter with 1:1 conduction andmonomorphic ventricular tachycardia (VT) may occur,especially in patients with structural heart disease.Flecainide also has potent negative inotropic properties thatmay precipitate worsening heart failure symptoms in

patients with structural heart disease. Therefore, in patientswith structural heart disease, which can be defined as anyevidence of LV dysfunction, coronary artery disease,valvular heart disease, or LV hypertrophy, flecainide use forcardioversion of AF should be avoided.

Propafenone. Oral propafenone also is effective atconverting recent-onset AF to sinus rhythm. Studiesevaluating the use of propafenone in patients with persistentAF are limited but suggest that efficacy is reduced in thispatient population. With the use of single, oral loadingdoses of 450600 mg in patients with recent-onset AF,propafenone exerts a relatively quick effect, converting AFto sinus rhythm in 23 hours. These single doses also areassociated with a high rate of efficacy in these patients, withconversion rates at 8 hours ranging from 72% to 76%. Afterevaluating 18 studies involving propafenone, the authors ofthe systematic literature review concluded that thisantiarrhythmic should be considered effective forconverting recent-onset AF to sinus rhythm. In 11 placebo-controlled trials, propafenone was associated withsignificantly higher conversion rates compared to placebowhen administered either as a single dose of at least 600 mgor a daily dose of 9001200 mg.

Given the negative data associated with the use of classIc antiarrhythmics in patients with structural heart disease, itis interesting that the safety and efficacy of propafenone inthis particular patient population has been evaluated in amulticenter study. In this trial, 240 hospitalized patientswith recent-onset AF were randomized to receive either asingle 600 mg oral dose of propafenone or placebo.Although patients with structural heart disease wereincluded in this trial, only patients with mild disease werepermitted. Patients with more severe structural heartdisease, including those with NYHA class II, III, or IV heartfailure, an MI within the previous 6 months, or unstableangina, were excluded. At 8 hours, the conversion rateswere similar in patients with and without structural heartdisease (81% vs. 78%, respectively). The incidence ofadverse effects also appeared to be similar between thesetwo patient groups.

In the recently conducted meta-analysis ofantiarrhythmic drugs for conversion of AF, 12 controlledtrials with propafenone were evaluated, one-half of whichused the intravenous formulation that is not available in theUnited States. The odds ratio (95% CI) for conversion tosinus rhythm with propafenone compared with control was4.6 (2.68.2). The treatment effects of intravenous and oralregimens were evaluated separately, but were not found tobe significantly different. Although the magnitude oftreatment effect compared with control was less forpropafenone than for ibutilide, dofetilide, and flecainide, theevidence still suggests that propafenone is highly effectivefor converting AF to sinus rhythm.

198Chronic Arrhythmia Management Pharmacotherapy Self-Assessment Program, 5th Edition

Miller MR, McNamara RL, Segal JB, et al. Efficacy of agents for pharmacological conversion of atrial fibrillation and subsequent maintenance of sinusrhythm: a meta-analysis of clinical trials. J Fam Pract 2000;49:103346.Slavik RS, Tisdale JE, Borzak S. Pharmacological conversion of atrial fibrillation: a systematic review of available evidence. Prog Cardiovasc Dis2001;44:12152.Boriani G, Biffi M, Capucci A, et al. Oral propafenone to convert recent-onset atrial fibrillation in patients with and without underlying heart disease: arandomized, controlled trial. Ann Intern Med 1997;126:6215.

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When used in a single-dose regimen, propafenone isusually well tolerated. Serious adverse effects areuncommon but may include transformation of AF into atrialflutter with 1:1 conduction, transient hypotension, andbradyarrhythmias. Although propafenone has beenrelatively safe and effective in patients with heart disease,these data are derived from a single study involving a smallnumber of individuals (n=62). Until additional databecomes available regarding propafenones safety inpatients with structural heart disease, as with flecainide, it isprudent to avoid using this antiarrhythmic in this particularpopulation.

Oral Amiodarone. Because the percentage of patientswith AF who have concomitant structural heart diseaseappears to be increasing, amiodarone use for managing thisarrhythmia also has dramatically increased because this isone of the few antiarrhythmics that has been proven to besafe in this particular patient population. Because ofamiodarones poor oral bioavailability, extensive volume ofdistribution, and long half-life, loading doses are initiallyessential to saturate the myocardial stores. When used atdoses greater than 1600 mg/day, oral amiodarone has beenmore effective than placebo in converting recent-onset AFto sinus rhythm. However, such data from placebo-controlled trials to describe the relative efficacy of oralamiodarone monotherapy in converting AF are limited.Studies have been performed to evaluate the efficacy ofcombining oral and intravenous amiodarone therapy duringthe first 24 hours, followed by ongoing oral therapy. Earlyefficacy of this combination therapy has primarily beenobserved in patients with recent-onset AF. In two placebo-controlled trials, conversion rates at 24 hours in thecombination amiodarone and placebo groups were 83% and55%, respectively, in one trial and 61% and 40%,respectively, in the other trial. However, in patients withpersistent AF, concomitant therapy with intravenous andoral amiodarone appears to be no more effective thanplacebo at converting AF to sinus rhythm at 24 hours. Theefficacy of combination intravenous and oral amiodaronetherapy in this particular patient population appears to bedelayed for 4 weeks compared with placebo, withconversion rates of 49% and 0%, respectively, beingachieved at this time point.

Although amiodarone typically is considered theantiarrhythmic of choice in patients with LV dysfunction, itsefficacy in patients with concomitant AF has not been wellcharacterized. A post hoc analysis of the Veterans AffairsCongestive Heart Failure Survival Trial of AntiarrhythmicTherapy evaluated the efficacy of oral amiodarone inconverting and maintaining sinus rhythm in patients withheart failure who were in AF at baseline. A total of 31% and8% of patients in the amiodarone and placebo groups,respectively, converted to and remained in sinus rhythm(p=0.002). The mean time to conversion was not specified.

Significantly fewer patients receiving amiodaronedeveloped new-onset AF during the study. Of interest,additional data from this analysis suggest that patients in theamiodarone group who converted to sinus rhythm hadsignificantly lower mortality rates than those who remainedin AF on the drug. Although these data regardingamiodarones potential survival benefits in this patientpopulation are by no means conclusive, given theretrospective nature of this analysis, it has spurred interest inconducting a prospective, randomized, placebo-controlledtrial to further examine these effects. One such trial, theAtrial Fibrillation and Congestive Heart Failure Trial, isongoing and is expected to have follow-up completed by2005.

Dofetilide. Dofetilide is the most recent antiarrhythmicto receive a Food and Drug Administration (FDA)-approvedindication to treat AF. It is officially indicated forconversion of AF or atrial flutter to sinus rhythm, and formaintaining sinus rhythm in patients with AF or atrial flutterof greater than 1 week in duration who have been convertedto sinus rhythm. Dofetilide is a class III antiarrhythmic thatprolongs refractoriness by blocking the rapid component ofthe delayed-rectifier potassium current. Like other class IIIantiarrhythmics, dofetilide exhibits reverse-use dependence,meaning its action potential-prolonging actions are lessenedat higher heart rates and increased at lower heart rates.

Most studies evaluating the safety and efficacy ofdofetilide in AF have been conducted with the intravenousformulation, which is not available in the United States. Theefficacy of oral dofetilide in patients with recent-onset AF isunknown because published trials currently are lacking.Based on data from several published trials, oral dofetilidedoes appear to be more effective than placebo in patientswith persistent AF.

The Danish Investigations of Arrhythmia and Mortalityon Dofetilide-Congestive Heart Failure (DIAMOND-CHF)trial was primarily conducted to evaluate dofetilides effectson morbidity and mortality in patients with congestive heartfailure and LV dysfunction. Of the 1518 patients enrolled inthis study, about 26% had AF at baseline. Initially, thedofetilide dose was 500 mcg 2 times/day in patients in sinusrhythm and 250 mcg 2 times/day in patients with AF.However, after 288 patients were enrolled, the dosingregimens were altered based on data derived from otherclinical trials. Subsequently, the initial dose for all patientswas based on creatinine clearance (CrCl). In patients withAF at baseline, spontaneous conversion to sinus rhythm at 1 month occurred in 12% and 1% of patients in thedofetilide and placebo groups, respectively (p

patients in the dofetilide group discontinued therapy as aresult of QT interval prolongation. Torsades de pointes(TdP) developed in 3.3% of patients in the dofetilide groupand in none of the patients treated with placebo.

In the similarly designed Danish Investigations ofArrhythmia and Mortality on Dofetilide-MyocardialInfarction (DIAMOND-MI) trial, 1510 patients with arecent MI and LV dysfunction were randomized to receiveeither dofetilide or placebo. The dosing regimens used werethe same as those in the DIAMOND-CHF trial. Only 8% ofpatients initially enrolled in this study had AF or atrialflutter at baseline. In this subset of patients, spontaneousconversion to sinus rhythm occurred in 25% of patients inthe dofetilide group and in 4% of patients in the placebogroup at 1 month. At 12 months, conversion rates improvedto 37% and 13% in the dofetilide and placebo groups,respectively. Discontinuation of drug therapy occurredmore often in the dofetilide than in the placebo group as aresult of QT interval prolongation. Seven patients (0.93%),all of whom were receiving dofetilide, developed TdP.

Recently, more data have become available regarding theefficacy of dofetilide in patients with AF. The primaryobjective of the Symptomatic Atrial FibrillationInvestigative Research on Dofetilide (SAFIRE-D) trial wasto evaluate the safety and efficacy of oral dofetilide inconverting AF or atrial flutter to sinus rhythm and inmaintaining sinus rhythm for 1 year. In this study, 325 patients with AF or atrial flutter were randomized toreceive dofetilide or placebo. At the beginning of the trial,patients assigned to the dofetilide group were randomized toreceive 125 mcg, 250 mcg, or 500 mcg 2 times/day.However, after 105 patients were enrolled, the protocol wasaltered so that the subsequent dosing regimens would bebased on the patients CrCl. Structural heart disease waspresent in more than 50% of the patients in this study and72% of the enrolled patients were in NYHA class II or IIIheart failure. The conversion rates in the dofetilide groupoccurred in a dose-dependent manner with 6.1%, 9.8%, and 29.9% of patients in the 125 mcg, 250 mcg, and 500 mcg groups, respectively, being restored to sinusrhythm. Only 1.2% of placebo-treated patients converted tosinus rhythm (250 mcg vs. placebo; p=0.015; 500 mcg vs.placebo; p

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the data suggested that sotalol may be less effective thanplacebo for conversion of AF.

Maintenance of Sinus Rhythm Throughout the years, there has been a significant

decrease in the use of antiarrhythmics overall to maintainsinus rhythm. Not surprisingly, much of this decline islikely attributed to the results of the Cardiac ArrhythmiaSuppression Trial (CAST), which demonstrated that theclass Ic antiarrhythmics flecainide and encainide wereassociated with a significant increase in mortality in patientswith a recent history of MI. Since then, evidence fromadditional trials has demonstrated the proarrhythmicpotential of other antiarrhythmic agents, such as quinidine,with long-term use. As a result of the heightened fear ofusing the traditional class Ia and Ic antiarrhythmics,practitioners have shifted toward using more of the class IIIantiarrhythmics when the decision is made to initiatepharmacological therapy to maintain a patient in sinusrhythm. Amiodarone has clearly become the antiarrhythmicof choice in patients with structural heart disease, althoughdofetilide is a reasonable alternative in this patientpopulation. In individuals without structural heart disease,flecainide, propafenone, and sotalol remain viable optionsfor maintaining sinus rhythm. However, the recentlypublished results of the PIAF, AFFIRM, and RACE trialsmay have a negative impact on overall antiarrhythmic use.

Class Ic Antiarrhythmics. Several trials have shownflecainide to be effective in prolonging the time to firstrecurrence of paroxysmal AF. Flecainides efficacy appearsto be comparable to that of quinidine, but it is associatedwith fewer adverse effects. Recently, a meta-analysis of 15studies assessed the efficacy of various antiarrhythmics formaintaining sinus rhythm. All studies analyzed comparedthe antiarrhythmic to a control treatment (e.g., placebo orverapamil). Three flecainide studies were included in thismeta-analysis. According to the results, flecainide wasassociated with strong evidence of efficacy for maintainingsinus rhythm, with the odds ratio (95% CI) being 3.1 (1.56.2).

Despite its efficacy in maintaining sinus rhythm, thenegative results of CAST have significantly limited thechronic use of flecainide, especially in patients withcoronary artery disease. Because of its potent negativeinotropic effects, flecainide also should be avoided inpatients with LV dysfunction. Because there is ageneralized concern of its safety in patients with any form ofstructural heart disease, the use of flecainide is usuallyavoided in patients with LV hypertrophy or valvular diseaseas well.

Propafenone is an effective drug for maintaining sinusrhythm. Several studies have shown that propafenonesignificantly prolongs the time to recurrence of AF andreduces the amount of time spent in AF. Based on the resultsof the Canadian Trial of Atrial Fibrillation (CTAF), whichare discussed in further detail in the Class IIIAntiarrhythmics section, the efficacy of propafenoneappears to be similar to sotalol, but inferior to amiodarone in

maintaining sinus rhythm. In the previously discussedmeta-analysis, propafenone, as with flecainide, also wasassociated with strong evidence of efficacy for maintaining sinus rhythm, with the odds ratio (95% CI)being 3.7 (2.45.7).

Although propafenone was not studied in CAST and hasnot been associated with increased mortality in other trials,there still tends to be an overall, negative perception of thisdrugs safety in patients with structural heart diseasebecause it resides in the same class of antiarrhythmics asflecainide. Because propafenone has added nonselective -blocking properties that differ from flecainide, it ispossible that the results observed in CAST may notextrapolate to propafenone. However, until the safety ofpropafenone can be demonstrated conclusively in a largerandomized, prospective trial in patients with mild,moderate, and severe structural heart disease, its use shouldbe avoided in this patient population.

Class III Antiarrhythmics All randomized trials evaluating the efficacy of

amiodarone in maintaining sinus rhythm have used active-control groups, which have included quinidine,sotalol, and propafenone. These trials have shownamiodarone to be either equivalent or superior to these otherantiarrhythmics in maintaining sinus rhythm. However,many of the older studies are limited by their small samplesize and limited treatment duration.

The largest randomized trial evaluating the efficacy ofamiodarone in maintaining sinus rhythm is the CTAF. Inthis study, patients who had at least one symptomaticepisode of AF within the previous 6 months wererandomized to receive amiodarone (n=201), propafenone(n=101), or sotalol (n=101) in an open-label fashion.Amiodarone was administered at 10 mg/kg/day for 14 days,then 300 mg/day for 4 weeks, and then a maintenance doseof 200 mg/day. The sotalol and propafenone doses werebased on many factors, including age, weight, gender,and/or serum creatinine. Almost one-half of the patients hadparoxysmal AF, and the other half had persistent AF.

At the end of 1 year, 69% of patients in the amiodaronegroup remained in sinus rhythm compared with 39% ofpatients treated with sotalol or propafenone (p

either sotalol or propafenone for maintaining sinus rhythm.Given the relatively low incidence of serious organtoxicities, this study also provides further data to support thesafety of low maintenance doses of amiodarone formanaging AF.

Dofetilide also is effective in maintaining sinus rhythm.In the SAFIRE-D trial, in addition to being moderatelyeffective for conversion of AF, dofetilide also wasmoderately effective for maintaining sinus rhythm in a dose-dependent manner. In patients with AF who convertedto sinus rhythm, the probability of remaining in sinusrhythm at 1 year was 36%, 38%, and 53% for the 125 mcg,250 mcg, and 500 mcg dofetilide groups, respectively, and15% for the placebo group (250 mcg vs. placebo; p=0.008;500 mcg vs. placebo; p=0.002).

The efficacy of dofetilide for maintaining sinus rhythmalso has specifically been demonstrated in patients with LVdysfunction, as evidenced by the results of a pooled analysisof data from the DIAMOND-CHF and DIAMOND-MItrials. Of patients with AF or atrial flutter who converted tosinus rhythm, the probability of remaining in sinus rhythmat 1 year was 79% and 42% for patients in the dofetilide andplacebo groups, respectively (p

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compared to the rate-control group. However, patients inthe rhythm-control group were hospitalized more frequentlyand had more drug-induced adverse effects compared to therate-control group. Although this trial provides importantinformation regarding the management of symptomatic andpersistent AF, it is limited by its relatively small sample sizeand by permitting only one antiarrhythmic to be used in therhythm-control group. Even though amiodarone waswarranted for patients with structural heart disease, it ispossible that patients without heart disease may haveresponded more favorably to another antiarrhythmic withfewer adverse effects.

The highly anticipated results of the RACE and AFFIRMtrials were published in the same issue of the New EnglandJournal of Medicine. In the RACE trial, 522 patients withrecurrent, persistent AF or atrial flutter were randomized to either a rate-control or a rhythm-control group. In therate-control group, digoxin, diltiazem, verapamil, or a -blocker could be used alone or in combination. Ifpatients had persistent symptoms, adverse effects, orprogressive LV dysfunction, cardioversion or AV nodalablation with pacemaker implantation could be performed.All patients in this group were anticoagulated withacenocoumarol or fenprocoumon to achieve an INR of2.53.5. Aspirin was permitted for patients with lone AF.

In the rhythm-control group, patients initially underwent electrical cardioversion and then received sotalol(450900 mg/day) for maintenance therapy. If there was arecurrence of AF within 6 months, electrical cardioversionwas repeated and the antiarrhythmic was changed to flecainide (200300 mg/day) or propafenone (160320 mg/day, depending on the weight and renalfunction). If there was another recurrence of AF within 6 months, loading doses of amiodarone (600 mg/day for 4 weeks) were given and electrical cardioversion wasrepeated. The amiodarone dose was then lowered to theusual maintenance dose of 200 mg/day. If recurrencedeveloped after 6 months of therapy with a particularantiarrhythmic agent, the regimen was continued. Patientsin this group were anticoagulated for 4 weeks before and 4 weeks after electrical cardioversion, after which theanticoagulant could be discontinued or replaced with aspirinif sinus rhythm was present.

This study was designed as a noninferiority trial with theprimary end point being the composite of death fromcardiovascular causes, heart failure, thromboemboliccomplications, bleeding, implantation of a pacemaker, andserious adverse effects of drugs. A two-sided 90% CI wascalculated for the absolute difference in the incidence of theprimary end point between the two treatment groups. Thenoninferiority of rate control compared with rhythm controlwas considered to be established if the upper boundary ofthis CI did not exceed 10%.

About 90% of the patients in this trial had at least onerisk factor for stroke. In the rate-control group, digoxinand/or -blockers were primarily used. The breakdown ofantiarrhythmics actually used in the rhythm-control groupwas not specified. After a mean follow-up period of 2.3 years, sinus rhythm was present in 39% of patients in therhythm-control group and 10% of patients in the rate-controlgroup. The primary end point occurred in about 17% and

23% of patients in the rate-control and rhythm-controlgroups, respectively. The upper boundary of the 90% CI forthe absolute difference in the primary end point was 0.4%,which fulfilled the criteria for noninferiority of rate controlcompared with rhythm control.

After evaluating the individual components of theprimary end point, the only significant difference was in theincidence of serious drug adverse effects, which was higherin the rhythm-control group. Patients in the rhythm-controlgroup tended to have a higher rate of thromboemboliccomplications compared to the rate-control group. Afterdiscontinuing anticoagulant therapy, five patients in therhythm-control group developed a thromboemboliccomplication despite being in sinus rhythm at the time of theevent. Therefore, the perception that rhythm-controlstrategies may reduce the risk of stroke by maintaining sinusrhythm is unfounded because patients with AF often haveother risk factors that continue to predispose them to strokeeven when sinus rhythm is maintained. The incidence of theprimary end point in the rhythm-control group was similarregardless of whether AF or sinus rhythm was present. In ahypothesis-generating subset analysis, the incidence of the primary end point was significantly higher in therhythm-control group than in the rate-control group amongwomen and patients with hypertension.

The findings of this trial suggest that a rate-controlstrategy is an acceptable alternative to rhythm control inpatients with recurrent, persistent AF. Given the increasedrisk of adverse effects with antiarrhythmics and the potentialthat cardiovascular risk may not be reduced even when sinusrhythm is maintained, it is reasonable to consider a rate-control strategy even earlier in the treatment process.Whether a rhythm-control strategy should be avoided inwomen and patients with hypertension needs to beconfirmed in a randomized, prospective trial.

The AFFIRM trial enrolled patients with AF and at leastone risk factor for stroke. Eligible patients had to haveexperienced an episode of AF within the previous 6 weeksand the duration of AF episodes in the previous 6 monthshad to have been at least 6 hours. A total of 4060 patientswere randomized to either a rate-control or a rhythm-controlgroup. In the rate-control group, digoxin, diltiazem,verapamil, or a -blocker could be used alone or incombination to achieve a resting heart rate of 80 beats/minute or less and a heart rate of 110 beats/minuteor less during the 6-minute walk test. All patients wereanticoagulated with warfarin to achieve an INR of 2.03.0.In the rhythm-control group, the choice of antiarrhythmictherapy was made by each patients physician. If needed,electrical cardioversion was permitted. Continuousanticoagulation was encouraged in this group, but could bediscontinued if sinus rhythm had been maintained for atleast 4 weeks. The primary end point of this study was all-cause mortality.

About 35% of the patients were enrolled with their firstepisode of AF. The mean duration of AF in the populationwas not specified. Although significant crossover occurredbetween the two groups, the crossover rate was higher inpatients initially assigned to the rhythm-control group,which was primarily because of drug failure and drug-induced adverse effects. In the rate-control group,

Chronic Arrhythmia ManagementPharmacotherapy Self-Assessment Program, 5th Edition

digoxin and -blockers were used more frequently thandiltiazem or verapamil. In the rhythm-control group, morethan 60% of patients had received at least one trial ofamiodarone. At least one trial of sotalol was used in about40% of the patients in the rhythm-control group. In therhythm control group, sinus rhythm was present in about82%, 73%, and 63% of patients at 1, 3, and 5 years,respectively.

After a mean follow-up of 3.5 years, the overall mortalityrate was higher in the rhythm-control group compared to therate-control group; however, this difference was notstatistically significant (24% vs. 21%; p=0.08). Thesurvival curves of these groups began to diverge after 2 years, which suggest that the problems associated with therhythm-control strategy may increase over time. Theincidence of stroke also was similar between the two groups.Most of these events occurred when warfarin wasdiscontinued or when the INR was subtherapeutic. About69% of patients who had a stroke in the rhythm-controlgroup were in sinus rhythm at the time of the event.Significantly more patients in the rhythm-control groupwere hospitalized or experienced drug-induced adverseeffects compared to the rate-control group, which isconsistent with the findings in the PIAF trial.

The efficacy of the various pharmacological strategies tocontrol ventricular rate was evaluated in a subset analysis ofAFFIRM. Data were gathered on 1968 of 2027 patientsrandomized to the rate-control group. Crossovers to adifferent rate-control therapy were common and the use ofcombination therapies occurred frequently. In fact,significantly more crossovers from CCBs to -blockers thanfrom -blockers to CCBs occurred. Based on the initialcriteria in this trial, heart rate control was adequate in 82%of the patients. No significant difference was observedbetween the proportion of patients attaining adequate ratecontrol with the use of either -blockers ornondihydropyridine CCBs at 1, 2, and 3 years.Furthermore, adding digoxin appeared to improve the ratecontrol achieved with -blockers or CCBs.

In a separate substudy of AFFIRM, the efficacy ofantiarrhythmic drugs used for rhythm control was evaluated.This substudy enrolled 410 of 2033 patients assigned to therhythm-control group in the main AFFIRM trial. Onceenrolled, patients were randomized to receive amiodarone(10 g given over at least 1 week), sotalol (initial dose of 160 mg/day), or a class I antiarrhythmic agent. Patients hadto be eligible to receive at least two of three of theseantiarrhythmic choices. Any contraindications to individualagents were taken into consideration when determiningwhich of the antiarrhythmic agents the patient wouldreceive. In particular, class Ic agents could not be used inpatients with structural heart disease. Class Ia drugs andsotalol were prohibited in patients with a history of VT orventricular fibrillation (VF). The doses used were left up tothe discretion of each patients physician. Similarly, ifpatients were randomized to receive a class I antiarrhythmic,their physicians selected a particular agent. The primaryend point of this substudy was the percentage of patientsalive, in sinus rhythm, with no additional electrical orpharmacological cardioversions, and still taking theassigned drug at 1 year.

In this substudy, three separate comparisons were madeamong the following groups: amiodarone versus class Iagents; amiodarone versus sotalol; and sotalol versus class Iagents. However, based on the randomization criteria, apatient may be represented in more than one two-waycomparison. About 3 years after enrollment began for thissubstudy, the amiodarone/class I antiarrhythmic comparisonwas halted after the superior efficacy of amiodarone wasdemonstrated. Consequently, because enrollment in theclass I antiarrhythmic group was terminated, thesotalol/class I comparison also was halted. Enrollment inthe amiodarone and sotalol treatment groups was permittedto continue for another year.

In the amiodarone/class I agent comparison, the primaryend point was achieved in 62% of patients receivingamiodarone and 23% of patients in the class Iantiarrhythmic group at 1 year (p

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in all patients with AF and risk factors may be warrantedregardless of whether the patient remains in sinus rhythm.

Preventing Thromboembolic Events Preventing thromboembolic events continues to be an

essential component of managing AF. Numerousrandomized trials have clearly demonstrated theeffectiveness of oral anticoagulants in preventing stroke inpatients with AF. Aspirin also appears to reduce the risk ofstroke, but to a lesser extent. A previous meta-analysisrevealed that adjusted-dose warfarin reduced the relativerisk of all strokes and ischemic strokes by 36% and 46%,respectively, compared with aspirin. However, since thepublication of this meta-analysis, the conclusions of othersystematic reviews have cast some uncertainty as to therelative benefit of oral anticoagulation over aspirin inpatients with AF. To better clarify the comparative efficacyof these two treatment regimens, a more recent meta-analysis was performed. Compared with the oldermeta-analyses, which used summary data reported in thepublished trials, this recent analysis used individual patientdata, which permitted more accurate and completecomparisons to be made between the two treatmentregimens. Six trials, in which 4052 patients withnonvalvular AF were randomized to receive adjusted-doseoral anticoagulation or aspirin with or without low-dose oralanticoagulants, were analyzed. Based on the results, oralanticoagulation significantly reduced the risk of any strokeand ischemic stroke by 45% and 52%, respectively,compared to aspirin (p

With its varied success rates and potential risks, thisprocedure is often limited to patients with drug-refractoryAF.

Implantable devices also are being examined forpreventing AF. Atrial pacing may prevent the onset of AFby suppressing triggers or by decreasing the dispersion ofatrial refractoriness. In patients with sick-sinus syndrome,atrial pacing has reduced the onset of AF compared withsingle chamber, ventricular pacing. The efficacy of biatrialpacing, in which the leads are placed in the high right atriumand the mid- or proximal coronary sinus, currently is beinginvestigated for preventing recurrent AF. However, biatrialpacing has been associated with a fairly high risk (15%) ofcoronary sinus lead dislodgment. As an alternative, theefficacy of dual-site pacing currently is being evaluated. Indual-site pacing, the leads are placed in the high right atriumand the coronary sinus ostium. Studies completed to datesuggest that dual-site atrial pacing reduces the frequency ofAF to a greater extent than single-site atrial pacing. Inaddition, this technique appears to be safe, with leaddislodgment only being reported in 1.5% of patients.

The success of the ICD for managing ventriculararrhythmias has triggered interest in developing animplantable atrial defibrillator to terminate episodes of AF.The initial devices were only programmed for atrialdefibrillation; however, these devices are no longermanufactured. The newer models are dual atrial andventricular defibrillators. The shocks for AF can bemanually activated by the patient or can be programmed tooccur while the patient is asleep. Consequently, the shockscould be delivered within 24 hours of the onset of AF, whichcould theoretically minimize the incidence ofthromboembolic events. Although these devices appear tobe safe and effective, one of the factors that limits theirwidespread use is patient comfort because the associatedshocks appear to be quite painful. Implantation of thisdevice does not appear to be warranted unless the patientalso requires an ICD to manage concomitant ventriculararrhythmias.

206Chronic Arrhythmia Management Pharmacotherapy Self-Assessment Program, 5th Edition

Recurrent or permanent AF

Assess LV function

Digoxin-Blockerc

-BlockerbDigoxin

Assess HR control (goal HR < 80 bpm at rest and < 100 bpm with exercise)

Continue therapy Increase dose of initialagent or consider adding asecond agent

-Blocker CCBa

Digoxin

HR goal achieved

LVEF > 40% LVEF < 40%(NYHA Class II-III HF)

LVEF < 40%(NYHA Class IV HF)

HR goal not achieved

Figure 4-2. Algorithm for ventricular rate control in recurrent or permanent AF. a Only the nondihydropyridine CCBs, verapamil and diltiazem, should be used to control ventricular rate in patients with AF.b -Blockers should only be used in patients with stable NYHA class II or III HF. Only carvedilol, metoprolol, or bisoprolol should be used to control

ventricular rate in these patients because of their added survival benefits in HF. Because the -blocker dose must be titrated slowly in these patients tominimize the development of worsening heart failure symptoms, concomitant digoxin therapy may be initiated to provide additional HR control, especiallywhen lower doses of the -blocker are being used.

c Digoxin should be considered the initial drug of choice in patients with NYHA class IV HF. If additional HR control is needed, carvedilol can be addedprovided that the patient has stable symptoms and is not receiving intravenous inotropes or vasodilators.

AF = atrial fibrillation; bpm = beats per minute; CCB = calcium channel blocker; HF = heart failure; HR = heart rate; LV = left ventricular; LVEF = leftventricular ejection fraction; NYHA = New York Heart Association. Adapted with permission from the American College of Clinical Pharmacy. Tisdale JE, Moser LR. Tachyarrhythmias. In: Mueller BA, Bertch KE, Dunsworth TS, et al, eds. Pharmacotherapy Self-Assessment Program, 4th ed. Kansas City, MO: ACCP, 2001:234.

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Treatment Plan Ventricular Rate Control

A suggested algorithm for controlling the ventricular ratein patients with recurrent or permanent AF is depicted inFigure 4-2. The recommended oral doses and adverseeffects of drugs commonly used for chronic ventricular ratecontrol in patients with AF are presented in Table 4-1.

The selection of a drug for ventricular rate control inpatients with recurrent or permanent AF is primarily basedon the patients LV function. In patients with normal LVfunction (LVEF greater than 40%), therapy with oral -blockers, diltiazem, or verapamil is preferred over digoxinbecause of their relatively quick onset and maintainedefficacy during exercise. The decision of whether to use a-blocker or nondihydropyridine CCB in these patientsoften depends on the presence of concomitant disease states.For example, -blockers are preferred in patients withcoronary artery disease, whereas diltiazem or verapamil ispreferred in patients with obstructive pulmonary disease.Digoxin can be added if additional ventricular rate control isneeded despite monotherapy with -blockers ornondihydropyridine CCBs.

In patients with LV dysfunction (LVEF 40% or less),nondihydropyridine CCBs should be avoided because oftheir potent negative inotropic effects. Instead, -blockersand digoxin are preferred because these agents also areconcomitantly used to treat heart failure. The decision ofwhether to use -blockers or digoxin as a first-line agent forventricular rate control in patients with LV dysfunction can

be based on the patients functional status. In patients withstable NYHA functional class II or III heart failure, the -blockers carvedilol, metoprolol, or bisoprolol should beused as first-line therapy because of their documentedsurvival benefits in heart failure. Other -blockers shouldbe avoided in these patients because their effects onmortality in heart failure are unknown. Because the -blocker dose must be titrated slowly in these patients tominimize developing worsening heart failure symptoms,concomitant digoxin therapy may be initiated to provideadditional heart rate control, especially when lower doses ofthe -blocker are being used. Once the -blocker target doses for heart failure are achieved, thedigoxin should be continued to reduce the risk ofdeteriorating heart failure and heart rate control. In patientswith NYHA functional class IV heart failure, digoxin shouldbe considered first-line therapy. Although the results of theCarvedilol Prospective Randomized Cumulative Survivaltrial suggest that carvedilol is safe and improves survival inpatients with stable NYHA class IV heart failure who are notreceiving parenteral inotropes or vasodilators, these datacannot necessarily be extrapolated to patients with AF.However, if a patient with NYHA class IV heart failure withconcomitant AF still requires additional heart rate controldespite the use of digoxin, adding carvedilol can beconsidered as long as the patient is not in the midst of a heartfailure exacerbation.

Chronic Arrhythmia ManagementPharmacotherapy Self-Assessment Program, 5th Edition

Table 4-1. Drugs Used for Chronic Ventricular Rate Control in Atrial FibrillationDrug Usual Oral Dose Adverse Effects-BlockersMetoprolola IR: 25200 mg 2 times/day Bradycardia, heart block, hypotension,

SR: 50400 mg/day drowsiness, fatigue, heart failure exacerbation, depression, bronchospasm, cold extremities

Atenolol 25200 mg/day Same as for metoprolol

Propranolol 80480 mg/day (in 24 divided dosages) Same as for metoprolol

Nondihydropyridine calcium channel blockersDiltiazem SR: 120480 mg/day Hypotension, bradycardia, heart block,

headache, flushing, dizziness, lower extremity edema, heart failure exacerbation

Verapamil SR: 120480 mg/day (in 12 divided dosages) Same as for diltiazem, plus constipation

Cardiac glycosidesDigoxin 0.1250.25 mg/day Heart block, AV junctional tachycardia,

ventricular arrhythmias, visual disturbances (e.g., blurred vision or yellow/green halos), headache, dizziness, weakness, nausea, vomiting, anorexia, diarrhea

a Lower initial doses of metoprolol should be used in patients with left ventricular systolic dysfunction.AV = atrioventricular; IR = immediate-release; SR = sustained-release.

208Chronic Arrhythmia Management Pharmacotherapy Self-Assessment Program, 5th Edition

Heart disease?

FlecainideOR

PropafenoneOR

Sotalol

CAD HypertensionHeart failure

AmiodaroneOR

Dofetilide

AmiodaroneOR

Dofetilide Amiodarone FlecainideOR

Propafenone

AmiodaroneOR

DofetilideOR

Sotalol

DisopyramideOR

ProcainamideOR

Quinidine

DisopyramideOR

ProcainamideOR

Quinidine

DisopyramideOR

ProcainamideOR

Quinidine

AmiodaroneOR

Dofetilide

Sotalol LVH > 1.4 cm?

Yes

Yes No

No (or minimal)

Figure 4-3. Algorithm for selecting antiarrhythmic drug therapy for maintenance of sinus rhythm in patients with recurrent paroxysmal or persistent atrialfibrillationaa Drugs are listed alphabetically and not in order of suggested use.CAD = coronary artery disease; LVH = left ventricular hypertrophy.Reprinted with permission from the American College of Cardiology and American Heart Association. Fuster V, Rydn LE, Asinger RW, et al. ACC/AHA/ESCguidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force onPractice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelinesfor the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol 2001;38:1266i-lxx. Copyright 2001 by the American College of Cardiology andAmerican Heart Association, Inc.

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Restoration of Sinus Rhythm For patients who have severe symptoms during episodes

of recurrent paroxysmal or persistent AF, it is reasonable toconsider electrical or pharmacological cardioversion torestore sinus rhythm. The risk of thromboembolism issimilar regardless of whether electrical or pharmacologicalcardioversion is used to restore sinus rhythm. Therefore, thesame recommendations for anticoagulation apply for bothtreatment strategies. The discussion below regarding drugsthat are recommended to convert patients with paroxysmalor persistent AF to sinus rhythm is limited to oralantiarrhythmics. Discussion of the efficacy of intravenousantiarrhythmics and electrical cardioversion for acuterestoration of sinus rhythm are presented in the AcuteManagement of Arrhythmia chapter.

Pharmacological cardioversion appears to be mosteffective when initiated within 7 days after the onset of AF.Therefore, by definition, conversion rates areconventionally higher for patients with paroxysmal AF thanfor those with persistent AF. The ACC/AHA/ESC recentlydeveloped evidence-based treatment guidelines for AF.According to these guidelines, the oral antiarrhythmicagents that have proven efficacy for cardioversion ofparoxysmal AF include flecainide, propafenone, dofetilide,amiodarone, and quinidine. Sotalol is not effective forcardioversion of AF. The use of quinidine for cardioversionshould be avoided because the loading doses that are usedare often associated with intolerable side effects. Thedecision among the remaining antiarrhythmics should bebased on the presence of structural heart disease. In theabsence of any type of structural heart disease (e.g., coronary artery disease, LV dysfunction, valvularheart disease, and LV hypertrophy), the use of single loadingdoses of flecainide or propafenone is reasonable forcardioversion. However, in patients with underlyingstructural heart disease, these agents should be avoided andamiodarone or dofetilide should be used alternatively.

According to the ACC/AHA/ESC treatment guidelines,these same antiarrhythmics also have proven efficacy forcardioversion of persistent AF. However, based on limitedefficacy in this setting, the use of flecainide or propafenoneshould be considered second-line therapy. In addition,caution should be used with these two agents becausepatients with persistent AF often have underlying structuralheart disease that is perpetuating the arrhythmia. Because ofthe increased prevalence of structural heart disease, eitheramiodarone or dofetilide would be the preferred choice forpharmacological cardioversion.

For patients with structural heart disease, prescribersoften prefer amiodarone over dofetilide for many reasons.Most of the reluctance to use dofetilide stems from the strictguidelines for use that have been recommended by the FDAand the manufacturer. In addition, because many patientswith heart failure often have concomitant renalinsufficiency, continual dosage adjustments may be neededwith dofetilide to avoid potential proarrhythmic eventsbecause this agent is eliminated primarily by the kidneys.Therefore, in these patients, amiodarone often is preferredbecause it is metabolized by the liver and does not need tobe dose-adjusted in the presence of unstable renal function.

Maintaining Sinus Rhythm For patients who develop severe symptoms during AF

episodes, it is reasonable to consider antiarrhythmic drugtherapy to maintain sinus rhythm. An algorithm that can beused to guide the selection of antiarrhythmic drug therapy tomaintain sinus rhythm in patients with recurrent paroxysmalor persistent AF is depicted in Figure 4-3. Therecommended oral doses and adverse effects of theantiarrhythmic drugs used to manage AF are presented inTable 4-2.

Once again, selecting an antiarrhythmic drug formaintaining sinus rhythm is primarily based on the presenceof structural heart disease. In the presence of any type ofstructural heart disease, the class Ic antiarrhythmicsflecainide and propafenone should be avoided. If LVdysfunction is present (LVEF 40% or less), oral amiodaroneis considered the antiarrhythmic of first choice. Dofetilidecan be used as an alternative if patients are unable to tolerateamiodarones adverse effect profile. In patients withcoronary artery disease, it is reasonable to consider sotalolfor initial therapy as long as LV function is normal.Amiodarone or dofetilide could be considered as analternative therapy if sotalol is not tolerated. The presenceof LV hypertrophy may predispose the myocardium toproarrhythmic events. Because of its low proarrhythmicpotential, amiodarone should be considered first-linetherapy in these patients. For patients with no underlyingstructural heart disease, flecainide, propafenone, or sotalolshould be considered initially because they have the mostoptimal long-term safety profiles.

Preventing Thromboembolism An algorithm for selecting the best therapy to prevent

thromboembolism in patients with recurrent paroxysmal,recurrent persistent, or permanent AF is depicted in Figure4-4. The discussion regarding the need for anticoagulationtherapy before and after cardioversion and the role oftransesophageal echocardiogram in guiding anticoagulationfor cardioversion is presented in the Acute Management ofArrhythmia chapter.

To determine the best oral antithrombotic therapy forpatients with recurrent or permanent AF, risk stratification isessential. According to the Sixth American College of ChestPhysicians Consensus Conference on AntithromboticTherapy, patients with AF can be stratified into three riskcategories. Patients with AF who have at least one of thefollowing risk factors are considered to be at high-risk forstroke: age greater than 75 years, previous stroke, transientischemic attack or other systemic embolic event, history ofhypertension, LV systolic dysfunction, rheumatic mitralvalve disease, and prosthetic heart valve (mechanical ortissue valve). Moderate risk factors include 6575 years ofage, diabetes mellitus, and coronary artery disease withnormal LV systolic function. However, patients with morethan one of these moderate risk factors are considered athigher risk for stroke than patients with only one moderaterisk factor. Patients who are younger than 65 years of age and have no risk factors or evidence ofcardiovascular disease are considered to be at low risk forstroke.

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