Antiarrhythmic drug initiation in patients with atrial fibrillation

Antiarrhythmic Drug Initiation in PatientsWith Atrial Fibrillation

Sergio L. Pinski and Marcelo E. Helguera

Antiarrhythmic drugs remain the mainstay of treat-ment of atrial fibrillation, but their potential proarrhyth-mic effects hamper their optimal use. Drug-inducedtachyarrhythmias (ventricular tachycardia or atrialtachyarrhythmias with rapid ventricular response)are life-threatening and often cause syncope. Be-cause these events tend to cluster shortly after druginitiation, it is common practice to routinely hospital-ize patients for drug initiation under continuouselectrocardiographic surveillance. The low inci-dence of serious proarrhythmia makes the cost-effectiveness of this practice controversial. Torsadesde pointes, in particular, can be predicted by thepresence of one or more of the following risk factors:female gender, structural heart disease, prolongedbaseline QT interval, bradycardia, hypokalemia, pre-vious proarrhythmic responses, and higher drugplasma levels. Proarrhythmia induced by class ICagents is seen almost exclusively in patients withstructural heart disease and ventricular dysfunction.A variety of monitoring devices permit electrocardio-graphic monitoring of patients in the outpatientsetting. Efficient clinical pathways for the safe initia-tion of antiarrhythmic drugs in patients with atrialfibrillation do not require universal hospital admis-sion. In patients without structural heart disease,outpatient initiation of most antiarrhythmic drugsappears safe. In patients with significant structuralheart disease, class IC drugs are contraindicated,and most other drugs should be initiated in thehospital under continuous monitoring. The inci-dence of severe proarrhythmia is very low whenloading doses of amiodarone of 600 mg/d or less aregiven to outpatients with structural heart disease.Copyright � 1999 by W.B. Saunders Company

Atrial fibrillation (AF) is a frequent, serious,and costly health care problem.1 Among

Medicare enrollees, AF is the most commonarrhythmia requiring hospital admission.2 Medi-care patients with newly diagnosed AF incursignificantly higher long-term acute care hospital

costs even after adjusting for concomitant cardiacand noncardiac morbidity.1 Despite advances innonpharmacological therapies,3-5 antiarrhythmicdrugs remain the mainstay of treatment of AF.Controlled studies have proved the efficacy ofseveral agents in suppressing AF,6,7 but theirpotential proarrhythmic effects8 hamper theiroptimal utilization.

Proarrhythmic events tend to cluster shortlyafter drug initiation or change in dosage.9-11

Therefore, many clinicians favor routine hospitaladmission for drug initiation under continuouselectrocardiographic surveillance. This strategyresults in significant resource consumption andfrequent patient dissatisfaction. The ambiguity ofcurrent practice guidelines12,13 and the potentialmedical liability associated with the occasionalunfavorable outcome complicate the issue, as theperspectives of patients, physicians, and medicalinsurers may be quite different. The presentreview summarizes the literature regarding therisks of antiarrhythmic drug initiation in patientswith AF and recommends strategies to be appliedin the clinical arena. The recommendations areaimed at adult patients without the Wolff-Parkinson-White syndrome.

Scope of the Problem

Proarrhythmia is defined as ‘‘the development of anew arrhythmia, or the worsening of a preexistingarrhythmia, following the institution of antiar-

From the Section of Cardiology, Rush Medical Collegeand Rush-Presbyterian-St Luke’s Medical Center, Chi-cago, IL; and the Departamento de Cardiologıa, HospitalItaliano, Buenos Aires, Argentina.

Address reprint requests to Sergio L. Pinski, MD, Rush-Presbyterian-St Luke’s Medical Center, 1750 W HarrisonSt, JS-1091, Chicago, IL 60612; e-mail: [email protected].

Copyright � 1999 by W.B. Saunders Company0033-0620/99/4201-0008$10.00/0

Progress in Cardiovascular Diseases, Vol. 42, No. 1 (July/August), 1999: pp 75-90 75

rhythmic therapy.’’14 Its clinical significance var-ies according to (1) its type (tachyarrhythmias orbradyarrhythmias), (2) hemodynamic conse-quences, and (3) temporal profile. Table 1 pro-vides a clinical-electrocardiographic classificationof drug-induced proarrhythmia in patients treatedfor AF. In general, drug-induced bradyarrhyth-mias are less clinically significant than tachyar-rhythmias. They are most often asymptomatic ormildly symptomatic, of gradual onset, and re-spond promptly to a decrease or discontinuationof the culprit drug.15 The uncommon provocationof infrahisian atrioventricular block by oral class Iagents in patients with preexistent His-Purkinjedisease represents an exception.16 On the otherhand, drug-induced tachyarrhythmias (ventricu-lar tachycardia or atrial tachyarrhythmias withrapid ventricular response) are life-threateningand often cause syncope. Therefore, we focus inthis article on strategies for the avoidance ofdrug-induced tachyarrhythmias.

Estimates of the incidence of proarrhythmiaduring initiation of antiarrhythmic drugs foratrial tachyarrhythmias differ according to popu-lations, definitions, drugs, and monitoring tech-nique used. Simons et al17 found an incidence ofsudden or unexplained death, cardiac arrest, orlife-threatening ventricular arrhythmias of 1.9%in 52 studies of drug treatment for supraventricu-lar arrhythmias. Most of the reports antecededwide awareness of the risk factors for proarrhyth-mia. The rates for individual drugs ranged be-tween 0.7% and 2.5% (Table 2). The weighted-average event rate during the first 72 hours oftreatment was 0.63% (95% confidence interval[CI], 0.22 to 1.2%). In a study of 417 patientsadmitted for initiation of antiarrhythmic drugsfor atrial tachyarrhythmias,11 there was a 13.4%incidence of cardiac adverse events, the mostcommon being bradyarrhythmias (8%) and QTprolongation warranting drug discontinuation(1.5%). Ventricular proarrhythmia occurred dur-ing 8 trials (1.3%), including one instance ofquinidine-induced torsades de pointes (TdP).The incidence of cardiac adverse events droppedfrom 7 per 100 patient-days during the first 24hours of therapy to 3.8 and 3.3 per 100 patient-days during the second and third 24 hours oftherapy, respectively. Patel et al18 reported an 18%incidence of cardiac side effects in 234 inpatientsstarted on antiarrhythmic drug for the cardiover-sion of AF. Most side effects were not life-threatening: 7% bradycardia, 5% excessive QT

prolongation, and 3% excessive QRS lengthening.Sustained ventricular tachycardia developed dur-ing 2% of the trials, without occurrences of TdP.Zimetbaum et al19 did not encounter ventricularproarrhythmia in 172 consecutive eligible outpa-tients initiated on antiarrhythmic drugs afterconversion of AF or flutter. Sotalol had to bediscontinued in 1 patient with asymptomaticexcessive QT prolongation. Three patients onflecainide developed atrial flutter with 1:1 conduc-tion and 2 patients (1 on flecainide and 1 onsotalol) developed symptomatic bradycardia. Allthe adverse events occurred more than 72 hoursafter drug initiation.

Financial Considerations

There is scarce data on the costs and effectivenessof different strategies for antiarrhythmic drug

TABLE 1. Manifestations of Proarrhythmia

Drug-induced bradyarrhythmiasExacerbation or induction of sinus node dysfunctionExacerbation or induction of atrioventricular block

Drug-induced tachyarrhythmiasExacerbation or induction of supraventricular arrhyth-

miasIncreased frequency or duration of paroxysmal AF

or flutterAcceleration of ventricular response due to

enhanced AV nodal conductionAcceleration of ventricular response in atrial flutter

due to decreased flutter cycle length and resul-tant 1:1 AV node conduction

Atrial tachycardia with AV blockNonparoxysmal junctional tachycardia

Exacerbation or induction of ventricular arrhythmiasIncreased in frequency, rate, or duration of under-

lying ventricular tachycardiaInduction of incessant ventricular tachycardiaTorsades de pointesInduction of bidirectional ventricular tachycardiaInduction of ventricular fibrillation

TABLE 2. Incidence of VentricularProarrhythmia According to Drug

Drug (n) Total Events (%) 95% CI

Disopyramide (261) 2 (0.8) 0.4-2.5Flecainide (606) 11 (1.8) 0.9-3.1Propafenone (460) 3 (0.7) 0.1-1.7Quinidine (1,240) 31 (2.5) 1.7-3.5Sotalol (255) 6 (2.4) 0.8-4.8Total (2,822) 53 (1.9) 1.4-2.5

Reprinted from Am J Cardiol, 80, Simons GR, EisensteinEL, Shaw LJ, et al: Cost-effectiveness of inpatient initiationof antiarrhythmic therapy for supraventricular tachycar-dias, pp 1551-1557, 1997, with permission from ExcerptaMedica, Inc.

PINSKI AND HELGUERA76

initiation in patients with AF. Helguera et alanalyzed 108 trials of in-hospital initiation ofclass I drugs for atrial tachyarrhythmias in 87patients (63% with structural heart disease) andfound an incidence of severe drug-induced bra-dyarrhythmia or tachyarrhythmia of 2.7%. Theyestimated that the cost of detecting a potentiallylife-threatening case of proarrhythmia in thatpopulation was $83,000 in 1993.20 Using activity-based accounting, they determined that the me-dian hospital cost of an elective admission forantiarrhythmic drug initiation was $2,841. Olderage was an independent predictor of highercosts.21 Based on local data, Eckman et al as-sumed a cost of $2,024 for elective cardioversionwith antiarrhythmic drug therapy requiring hospi-talization in a recent cost-effectiveness model ofdifferent long-term strategies for AF treatment.22

Simons et al modeled the cost-effectiveness ofinpatient initiation of antiarrhythmic drugs forsupraventricular tachyarrhythmias. Their assump-tions included a 0.63% rate of life-threateningevents during the first 72 hours of therapy and acost of $1,933 for uncomplicated initiation ofantiarrhythmic medication. They concluded thatthe cost-effectiveness was attractive (ie, less than$50,000 per year of life saved) in most scenarios.It was $19,231 for a 60-year-old patient withnormal life expectancy, and decreased to $33,310in a 60-year-old with structural heart disease.This represents a paradox because the risk ofproarrhythmia is higher in the latter. Sensitivityanalysis showed that in patients with normal lifeexpectancy, hospital admission became margin-ally cost-effective ($50,000 to $100,000 per yearlife saved) with risk levels of 0.12% to 0.24%.Even if routine hospital admission is financiallyfavorable from a broad societal perspective, thefiscal implications are quite different for healthcare organizations. Hospital admission is associ-ated with significant up-front costs, and potentialbenefits have to be discounted over many years.

Predisposing Factors forVentricular Proarrhythmia

The most common severe proarrhythmic eventduring drug therapy of AF is TdP, a rapid polymor-phic ventricular tachycardia that occurs withagents that prolong ventricular repolarization.23

Identification of patients at risk for TdP is diffi-cult because of the wide variation in individual

susceptibility.24 It has been hypothesized thatpatients who develop TdP as an idiosyncraticreaction may carry genetically abnormal ionicchannels. The identification of cardiac ion chan-nel mutations in patients with the congenital longQT syndrome25 has triggered the search for simi-lar abnormalities in patients with the acquiredcounterpart. Wei and colleagues could not findpreviously known mutations in HERG or SCN5A(genes encoding for a potassium and a sodiumchannel, respectively) in 25 patients with ac-quired long QT syndrome,26 but more recently,several groups reported novel missense mutationsin HERG and KVLQT1 (another gene encoding apotassium channel subunit) in patients with drug-induced TdP.27-29 Thus, many of these patientsmay carry a forme ‘‘fruste’’ of congenital long QTsyndrome with mutations resulting in less dys-functional channel subunits that manifest mainlyby prolonged repolarization in the presence ofoffending drugs. Identification of all potentialmutations will demand complete sequencing ofall the genes encoding for proteins involved inventricular repolarization. If a relatively smallnumber of discrete mutations underlie most in-stances of drug-induced TdP, genotypic analysisof peripheral blood lymphocytes could representa rapid, reliable, and efficient way of screeningpatients before elective exposure to antiarrhyth-mic drugs. In the meantime, evaluation of pa-tients for the presence of several well-establishedrisk factors for ventricular proarrhythmia30,31 willassist in the decision-making process. In thefollowing sections, we discuss demographic, clini-cal, and therapeutic variables that have beenassociated with the development of proarrhyth-mia.

Gender

Drug-induced TdP is significantly more commonin women.32,33 This is not explained by theadministration of higher weight-adjusted doses orby a higher prevalence of subclinical hypothyroid-ism.34 Women not only have longer baseline QTcintervals,35 but they also respond to drug therapywith larger QT increments.36 For example, at aquinidine concentration of 3 µg/mL, women hada 30 ms greater QTc increase than men.37 Femalerabbit ventricular myocytes have a lower densityof potassium repolarizing currents than malecells.38 The observation that sex hormones can

ANTIARRHYTHMIC DRUG INITIATION FOR ATRIAL FIBRILLATION 77

regulate the expression of potassium channelsand thus affect their density39 may help explainthese gender differences.

Presence and Type of Structural Heart Disease

The presence and type of structural heart diseaseare important determinants of the risk of proar-rhythmia. Proarrhythmia associated with class ICdrugs (including incessant sinusoidal ventriculartachycardia and ventricular fibrillation) is seenalmost exclusively in patients with structurallyabnormal hearts, particularly those with priormyocardial infarction,40,41 left ventricular dysfunc-tion,42 or both. In dogs given high doses offlecainide, spontaneous ventricular tachycardiadue to reentry occurred frequently in those with aprior myocardial infarction, but never in healthyones.43 Proarrhythmia with agents that prolongrepolarization may also be more common inpatients with left ventricular dysfunction,44,45 al-though the association is not as strong. TdP inpatients with structurally normal hearts is welldocumented.46

The proarrhythmic risk conferred by valvular,congenital, or myocardial disease with minimal orno left ventricular dysfunction is less clear. Ven-tricular hypertrophy with preserved left ventricu-lar function is common in patients with AF.47

Several tissue and cellular characteristics of thehypertrophic myocardium, including prolongedaction potential duration, increased dispersion ofrefractoriness, and slower conduction may am-plify responses to antiarrhythmic drugs and pro-mote proarrhythmia.48 In the dog with chroniccomplete heart block (a model of biventricularhypertrophy), TdP can be reproducibly inducedby class III drugs combined with pacing.49 Theinducibility of TdP depends on the developmentof early afterdepolarizations and increased inho-mogeneity in action potential duration.50 Al-though plausible, an independent effect of mild tomoderate left ventricular hypertrophy in the inci-dence of drug-induced proarrhythmia has notbeen conclusively shown.

Baseline QT Interval

A longer baseline QT interval (due to congenitalor acquired prolongation of repolarization) predis-poses to the development of TdP.51 Therefore,drugs that prolong repolarization should beavoided in patients with even mild baseline QT

prolongation, as well as in apparently nonaffectedrelatives of patients with congenital long QTsyndrome until a normal genotype is confirmedbecause of the incomplete penetrance of manymutations.52

Patients with drug-induced TdP and normalbaseline QT may, in the drug-free state, showparadoxical increases in the QTc interval withfaster heart rates during exercise stress test53 orambulatory electrocardiography.54 These findingsalso suggest the presence of subtle baseline abnor-malities in the modulation of ventricular repolar-ization in patients with acquired TdP. Thesemeasurements have not found widespread clini-cal application because they are cumbersome toobtain, especially in patients in AF at the time ofthe recordings.

Heart Rate

Antiarrhythmic drugs commonly exert frequency-dependent actions secondary to the kinetics ofdrug-induced blockade and the recovery of ioniccurrents. Most drugs that prolong repolarizationhave greater effects at slower rates (reverse ratedependence). Bradycardia and pauses, therefore,promote drug-induced TdP. The highest inci-dence of TdP is observed immediately after con-version to normal sinus rhythm.55,56 This may bedue to the decrease in rate that often accompaniescardioversion57 and frequent underlying sinusnode dysfunction. Furthermore, the negative chro-notropic effects of most antiarrhythmic drugs canamplify the bradycardia that follows conversion.

Antibradycardia pacing protects against TdP,provided the ventricular pacing rate is not pro-grammed too low (Figs 1 and 2). Programmablefeatures that could result in a functional pacedrate below the programmed lower rate (eg, hyster-esis,58 circadian (sleep) algorithms, atrial-basedtiming after ventricular premature depolariza-tions, extension of the postventricular atrial refrac-tory period after a ventricular premature depolar-ization59) should also be avoided. Chung et alidentified the presence of backup pacing as theonly protective factor against the development ofproarrhythmia in a series of 120 inpatients startedon sotalol for atrial tachyarrhythmias.60 A criticalpacing rate above which TdP is completely pre-vented has not been described. From a review ofpublished cases, it appears that TdP is unlikely inpatients with functional pacemakers programmed


greater than 70 bpm.61 In pacemakers capable of‘‘rate-smoothing,’’ enabling of this function couldprevent pauses without the need to program rela-tively rapid baseline pacing rates.62

Most reported cases of proarrhythmia inducedby class IC agents in patients without significantleft ventricular dysfunction represent examples ofmonomorphic ventricular tachycardia or ventricu-lar fibrillation triggered by rapid AF rates duringexercise.42 The amplification of the slowing ofintraventricular conduction induced by the ICagents during rapid rates,63 in combination withthe sympathetic activation during exerecise, mayresult in the creation of a substrate suitable forreentrant ventricular tachyarrhythmias. Ensuringa sufficient level of AV nodal blockade with theconcomitant use of a �-blocker, verapamil ordiltiazem is crucial to avoid this complication, aswell as rapid conduction during atrial flutter.

Electrolyte Abnormalities

Hypokalemia, hypomagnesemia, or both are com-mon in patients who develop drug-induced TdP.64

In vitro, lowering of the extracellular concentra-

tion of potassium or magnesium magnifies boththe prolongation of action potential and the earlyafterdepolarizations induced by quinidine andother agents.65,66 This results from an amplifica-tion of the extent of blockade of the rapidcomponent of the delayed-rectifier current (IKr).67

In patients, modest elevations of serum potas-sium (within the physiologic range) can signifi-cantly reverse quinidine-induced QTUc prolonga-tion, QT dispersion, bifid T waves, and U waves.68

Ensuring plasma concentrations of potassiumand magnesium at the high end of the normalrange is crucial to prevent TdP.

Previous Proarrhythmic Responses

Patients who have developed TdP on one drug arelikely to develop it again when challenged withanother agent with similar electrophysiologicaleffects. Rarely, they may do so even in response todrugs not usually associated with this type ofproarrhythmia.69 The safety of amiodarone inpatients with previous drug-induced TdP is con-troversial. Some authors found that patients whodeveloped TdP with class I drugs could be treatedsubsequently with amiodarone safely,70,71 whereas

Fig 1. Continuous telemetry strip showing episode ofTdP in a patient with a dual-chamber pacemaker. This75-year-old woman with sinus node dysfunction wasstarted on quinidine and diltiazem in the hospital. Thenormally functioning pacemaker was programmed tothe DDD mode with a lower rate of 50 beats per minute.She developed a junctional escape rhythm at around50 bpm. Late-coupled ventricular bigeminy is followedby a three-beat run of ventricular tachycardia and thena 6-second run of TdP. The apparent ventricular under-sensing is the result of ‘‘safety pacing’’ after sensingthe ventricular electrogram in the nonphysiologic AVdelay period after the atrial artifact. Torsades de pointeswas suppressed by increasing the pacing rate.

Fig 2. Two-channel Holter monitor of an episode ofsotalol-induced ventricular fibrillation in a patient withan implantable defibrillator with single-chamber ven-tricular pacing. Sotalol had been started in the outpa-tient setting for the suppression of recurrent AF. Thepacing rate had been left programmed at 44 bpm in anattempt to maintain AV synchrony. He developed bra-dycardia with continuous ventricular pacing. A late-coupled ventricular premature beat initiates an epi-sode of TdP that rapidly degenerates into ventricularfibrillation. A 34-J shock from the defibrillator termi-nates the arrhythmia with reemergence of the ventricu-lar paced rhythm.


others reported high concordance rates for theprovocation of TdP between class I drugs andamiodarone.72,73 Middlekauff et al reported a highincidence of sudden cardiac death in patientstreated chronically with amiodarone after develop-ing proarrhythmic responses to other antiarrhyth-mic agents.74 It is unclear if it is prudent to useamiodarone for atrial fibrillation in patients whodeveloped TdP on other antiarrhythmic agents. Inview of the important contribution of severebradycardia to amiodarone-induced TdP, it ap-pears advisable to restrict its use in this patientpopulation to those with functional pacemakers.

Intravenous ibutilide is an effective new alterna-tive for the acute termination of atrial tachyar-rhythmias,75 which is associated with an up to 5%incidence of TdP.76 It seems prudent to avoiddrugs that prolong repolarization in patients whodevelop TdP with ibutilide. The possibility thatsafe termination of AF with ibutilide could beused as a screening maneuver to identify patientsat very low risk of TdP on other drugs thatprolong repolarization deserves exploration.

Dose Dependence

For most drugs, there is a direct relation betweendose or plasma levels and the incidence of proar-rhythmia. This relation has been most elegantlydescribed for d,l-sotalol. For this drug, the inci-dence of serious proarrhythmia increases propor-tionally from less than 1% with doses less than orequal to 160 mg/d to greater than 7% with dosesgreater than 640 mg/d.77 Pharmacokinetic consid-erations influence the relation between adminis-tered dose and incidence of proarrhythmia. Fordrugs with relatively long half-life (eg, flecain-ide), rapid escalation of dosage before the achieve-ment of steady-state plasma levels can result inaccumulation and concentration-dependent pro-arrhythmia. For procainamide, proarrhythmic ef-fects are related more directly to the plasma levelof its renally excreted metabolite N-acetyl-procainamide (NAPA), which blocks predomi-nantly potassium channels and produces concen-tration-dependent prolongation of the QTinterval.78 Clinically, TdP with procainamide oc-curs more often in patients with renal insuffi-ciency who accumulate NAPA. Sotalol is excretedunchanged in the urine, and patients with renal

insufficiency are at higher risk of TdP despiteattempts at dose adjustment.79

Pharmacokinetic interactions (including inhibi-tion of hepatic metabolism by a concomitantlyadministered drug) may also result in high drugconcentrations with usual doses. Propafenone,flecainide, and quinidine are metabolized by en-zymes of the cytochrome P450 superfamily thatcan be inhibited by a variety of drugs, includingmacrolide antibiotics, antifungals, cimetidine, andamiodarone. Drug dosage may need to be ad-justed accordingly. For example, flecainide dos-age should be decreased by at least one third inpatients with recent or concomitant amiodaroneadministration.80

For quinidine, there is an inverse relationshipbetween plasma levels and incidence of proar-rhythmia,81 and thus most episodes of proarrhyth-mia occur after the first few doses. This apparentparadox is due to the fact that at low plasma levelsquinidine predominantly blocks potassium chan-nels and prolongs action potential and QT inter-val. When plasma levels reach the ‘‘therapeuticrange’’ (2 to 5 µg/dL), the drug also blockssodium channels, an effect that tends to shortenaction potential duration. A similar dose-re-sponse relationship has been postulated for dis-opyramide, although the evidence is not as com-pelling.82,83 At very high doses (rarely used today),quinidine can produce sinusoidal ventriculartachycardia similar to that seen with IC antiar-rhythmic drugs.

The low incidence of proarrhythmia with amio-darone (combined with its slow accumulation)complicate the study of the relationship betweendose and risk of proarrhythmia. Although directcorrelations exist between the cumulative dose ofamiodarone, its plasma level (and that of itsmetabolite desethylamiodarone), and QT prolon-gation,84 these variables do not appear to predictthe risk of TdP during long-term amiodaronetreatment.

Drug Interactions

Examples of pharmacokinetic drug interactionsfavoring the development of proarrhythmic re-sponses were discussed in a previous section.Pharmacodynamic interactions can also promoteproarrhythmia. The most common example is theconcomitant use of diuretics that can provoke


hypokalemia.64 This interaction may contributeto the higher incidence of TdP in patients withheart failure and hypertension.

Several nonantiarrhythmic agents, includingmacrolide antibiotics, the antihistaminic agentsastemizole and terfenadine, antidepressants, phe-nothiazines, and cisapride, can prolong ventricu-lar repolarization.85 At usual doses, effects aremild and do not result in proarrhythmia, butsummation occurs when they are used concomi-tantly with antiarrhythmic drugs. Drug combina-tions reported to result in TdP because of possiblepharmacodynamic synergism include sotalol withtricyclic antidepressants64 or terfenadine,86 andquinidine87 or disopyramide88 with erythromy-cin.

Drug-Induced Accelerationof Ventricular Response

During AF or Flutter

Acceleration of the ventricular response to AF orflutter is a potentially life-threatening complica-tion of the use of class IA89 and IC90 drugs inpatients with atrial tachyarrhythmias. The ven-tricular response to atrial tachyarrhythmias isdetermined by the refractory period of the AVnode, the degree of concealed conduction withinthe node, the atrial rate, and the level of auto-nomic tone. Antiarrhythmic drugs can alter oneor more of these factors (eg, the vagolytic effectsof quinidine shorten the refractory period of theAV node). The most common mechanism respon-sible for rapid ventricular conduction duringsupraventricular tachyarrhythmias in patientstreated with class I agents is the conversion of AFto a relatively ‘‘slow’’ atrial flutter with 1:1 ventricu-lar response. Atrial flutter develops in up to 20%of patients with AF treated with oral class ICagents.91,92 Characteristically, the tachycardia hasa wide QRS duration (because of rate-relatedaberrancy and use-dependent effects of the drugs),and is frequently mistaken as ventricular tachycar-dia.93 This complication cannot be reliably pre-dicted,94 and so concomitant administration ofAV nodal blocking drugs is indicated in everypatient receiving class I drugs for atrial tachyar-rhythmias. Digitalis alone may not prevent atrialflutter with 1:1 conduction.95 Atrial flutter with1:1 conduction can also occur during mono-

therapy of atrial fibrillation with oral propafe-none, despite its mild �-blocking activity.96

Methods for Proarrhythmia Detection

Proarrhythmia should ideally be detected at apreclinical stage. Severe proarrhythmic events areoften preceded by self-limited, asymptomaticones.97 On the other hand, symptoms (eg, light-headedness, palpitation) are not sensitive norspecific markers of proarrhythmia, as they mayresult from the recurrence of the arrhythmiasbeing treated or from noncardiac side effects ofthe antiarrhythmic drugs.98 Therefore, monitor-ing of the heart rhythm is the most accurate wayto detect incipient proarrhythmia during initia-tion of antiarrhythmic drug therapy.

In-Hospital Surveillance

Admission to a telemetry ward with continuousmonitoring and recording of the cardiac rhythmrepresents the gold standard for proarrhythmiadetection. It is the safest approach because itallows a prompt response to any sign of drug-induced proarrhythmia, including the occasionalunheralded ventricular tachyarrhythmia requir-ing cardiopulmonary resuscitation. The patientshould be monitored continuously, without restric-tion of his or her physical activity, until steady-state plasma drug levels are achieved. This periodof time needs to be extended each time the dose isadjusted. This approach is precluded with amioda-rone because of its very long half-life.

Newer digital surveillance systems that allowstorage in magnetic media of the 24-hour electro-cardiogram (ECG) with on-line full-disclosuredisplay, review, and search for annotated eventsfacilitate monitoring. Runs of ventricular tachycar-dia are the most obvious examples of incipientproarrhythmia, but more subtle manifestationsmust also be recognized. The electrocardio-graphic precursors of drug-induced TdP havebeen well characterized. TdP frequently emergesafter a critical prolongation in the QTU interval,99

following a postectopic pause or decrease in sinuscycle length. Late-coupled ventricular beats emerg-ing from the T or U wave in bigeminal pattern arefrequently the first manifestation of proarrhyth-mia. This pattern may remain stable or mayintensify into longer, faster runs of ventriculartachycardia.100


The precursors of other forms of ventricularproarrhythmia are not well determined. Severedigitalis-toxic rhythms (eg, fascicular tachycar-dia, bidirectional ventricular tachycardia) appearto be preceded by milder forms such as acceler-ated junctional rhythm and ventricular bigeminy,but it is not known if sinusoidal incessant ventricu-lar tachycardia induced by class IC agents ispreceded by nonsustained episodes. Bradyarrhyth-mias, including intermittent AV block and spo-radic pauses, should also be carefully evaluated,as they could progress to the point of becomingsymptomatic or could promote the occurrence ofTdP. Finally, the possibility that runs of wide-complex tachycardia represent atrial tachyarrhyth-mia with aberrant intraventricular conductionshould always be kept in mind. Their differentia-tion may be difficult, but an irregular ventricularrhythm should suggest AF with aberrant conduc-tion.

Continuous monitoring often identifies mild,asymptomatic forms of proarrhythmia (eg, shortruns of ventricular tachycardia, persistent bi-geminy, nocturnal bradycardia) of uncertain clini-cal significance. This allows for early changes inthe therapeutic and a low incidence of severeproarrhythmia. At the same time, early interven-tion could result in decreased specificity, becauseit compels to modify a drug regimen that could beclinically successful.

Outpatient Ambulatory Monitoring

Several techniques for outpatient continuous orintermittent monitoring could be used duringinitiation of antiarrhythmic therapy.101 Advan-tages of these techniques include lower cost, lessinterference with patient’s routine with little lossof productivity, and observation of the patient inhis or her natural environment. Ingenious clini-cians have used variations of these techniques forthe last few years, but detailed reports are scant.Success with these techniques depends on acooperative patient who can replace the skinelectrodes when needed and can immediatelyreport telephonically abnormal symptoms. Frail,hard-of-hearing, or physically disabled patientsare therefore not good candidates, nor are thosewho live far from a medical center or do not havereliable means of transportation. The main draw-back of these techniques is that they do not allow

rapid institution of life-saving therapies in case ofunheralded, catastrophic arrhythmias.

Holter monitoring allows continuous ambula-tory recording of the heart rhythm. Use of thistechnique requires the patient to be seen daily inan outpatient setting for analysis of the recordingfrom the previous 24 hours. Digital recorderswith extended memory that measure, count, andclassify beats in real-time are well suited for thistask, because they allow rapid downloading of thestored data as well as full-disclosure printing forrapid visual inspection. Instructions regardingfurther drug dosing are based on the scannedrecording. It may be possible in the future toincorporate modem transmission capabilities tothe recorders to avoid the need for daily patientvisits.

Intermittent monitoring is possible with a vari-ety of sampling monitors that allow the patient totransmit selected ECG strips to a hospital-basedstation staffed 24 hours a day, 7 days a week.These units are convenient and inexpensive, butdue to the limited recordings provided, theirsensitivity for asymptomatic transient proarrhyth-mia is lower than that of continuous recordingtechniques. The simplest transmitters are real-time units commonly used for transtelephonicpacemaker checks. The patient is instructed totransmit at predetermined time intervals (mostcommonly 2 hours after a drug dose) and in caseof symptoms, but the lack of memory capabilitymakes these units less valuable when symptomsare fleeting. Event recorders permit the patient tostore ECG strips during transient symptoms forsubsequent transmission. Newer units can evenautomatically store rhythms classified as abnor-mal, including pauses and runs of tachycardia.102

The main disadvantage of event recorders is that,like Holter systems, they require continuouswearing of skin electrodes. Devices that allow thestorage of selected single-lead ECGs during symp-tomatic episodes without the need to wear chestelectrodes include wrist-watch monitors and creditcard–size recorders to be held in contact with thechest during ECG acquisition. Transtelephonictransmission of the ECG as an acoustic signal hasa suboptimal frequency response for low-fre-quency waves; the accuracy of QT interval mea-surement by these techniques has not been wellvalidated. Newer systems that incorporate a mo-dem for dial-up transmission of digital data pro-


vide high-fidelity recordings (Fig 3). The mostsophisticated models warn the patient upon detec-tion of abnormal rhythms, have automatic dial-upfeatures, and permit two-way voice communica-tion between the patient and the hospital-basedstaff.

Twelve Lead ECG

Periodic recording of the 12 lead ECG is com-monly used as a complement to monitoringduring initiation of antiarrhythmic drug therapybecause the determination of ECG intervals inHolter or monitor strips is not as accurate.103 Therecent availability of units capable of recordingand transmitting (digitally or acoustically104) a 12lead ECG over regular phone lines facilitate itsuse in outpatients. The rationale for monitoringof the 12 lead ECG is not the detection ofproarrhythmia per se, because the short durationof the recording results in poor sensitivity fortransient events. Instead, it aims to identify drug-induced electrophysiologic effects that could serveas substrate for proarrhythmia. It is not possible

to infer the effects of antiarrhythmic drugs onatrial electrophysiology from the standard ECGbecause atrial tissues are relatively silent in stan-dard surface electrocardiography. The P wavedoes not appear to be a sensitive marker ofchanges in the speed of intraatrial conduction,and atrial repolarization is hidden by the QRScomplex. On the other hand, the surface ECGprovides useful, low-cost information regardingdrug effects on the conduction system and theventricular myocardium.105 These effects corre-late with the likelihood of bradyarrhythmias andventricular proarrhythmia.

When using the same software, serial computer-aided measurements of QRS duration are accurateand precise (the values are generally higher thanfor manual determinations)106 and can be used tomonitor the sodium channel blocking effects ofclass I drugs. The dose-effect relation has beenextensively studied for flecainide. With therapeu-tic doses of this drug, a 20% to 25% increase frombaseline in QRS duration is expected; largerincreases are common with doses greater than400 mg/d.107 For individual patients, there is alinear relationship between free flecainide plasmalevels and QRS duration.108 There are no prospec-tive studies of the risk of serious proarrhythmiaassociated to the magnitude of QRS prolongationinduced by class I drugs, but patients who de-velop severe proarrhythmia tend to have longerpredrug and postdrug QRS duration. This, to-gether with the fact that both the incidence ofproarrhythmia and QRS prolongation are (at leastpartially) concentration dependent justifies thecommon practice of monitoring QRS duration inpatients on class IC drugs.109 Drug decrease orcessation should be considered when QRS prolon-gation greater than 30% of baseline is observed.Most clinicians would stop a drug that hasinduced greater than 50% QRS prolongation ornew fixed atrioventricular or intraventricular con-duction defect.

For most drugs (with the exception of amioda-rone), the degree of drug-induced QT prolonga-tion correlates with the risk of TdP.110,111 How-ever, exclusive reliance on the duration of the QTinterval as marker of proarrhythmic risk is ham-pered by the lack of consensus regarding measure-ment techniques, formulas to adjust for heartrate, and criteria to define an unacceptably pro-longed interval. Measurement is complicated by

Fig 3. Comparison of QT interval recorded with astandard ECG machine (A) and with a 12 lead digitalambulatory monitor (B). The recording from the ambu-latory monitor was transmitted via a modem overtelephone lines and a hardcopy printed at the receiv-ing station on a standard laser printer. The patient hadbeen started on sotalol 2 days before. The two record-ings were performed 1 minute apart and using thesame electrodes. Leads V1, V2, and V3 are presented.The morphology of the T and U waves is almostidentical in both recordings. The QT interval wasmanually measured at 440 ms in both recordings.


the large variability in identifying the end of the Twave between different observers and computerprograms,112 especially when a U wave is present.

It is difficult to establish firm rules regardinglimits of a clinically tolerable QT interval becauseno single value discriminates between patients atrisk and those who can be maintained on the drugsafely.113 The absolute duration of the QT intervalmay be a better marker of the risk for TdP thanthe rate-corrected QTc interval. Furthermore, QTinterval corrections assume a constant underlyingrate and thus do not take into account theimportance of post-pause QT prolongation.114

This is particularly problematic when antiarrhyth-mic drugs are initiated in patients in AF. Despitethese limitations, most experts would limit QTinterval prolongation to less than 520 to 550 msin patients receiving drugs that prolong the QT.Exceptions include some patients with bundlebranch block (in whom the QT interval may begreater than 600 ms at baseline) and patientsreceiving amiodarone who have a considerablysmaller risk of TdP for any given QT prolonga-tion.

In recent years, additional measures of thespatial heterogeneity and complexity of repolariza-tion have been described as markers of arrhyth-mic risk in different patient populations. Bothgross alterations in the morphology of the T wave(eg, notching115) or more subtle, computer-assisted determinations of heterogeneous ventricu-lar repolarization116 are common in patients withcongenital long QT syndrome, but their value inthe early identification of patients at risk ofdeveloping drug-induced proarrhythmia is uncer-tain. Determination of QT dispersion has alsobeen proposed as a tool to assess the risk of TdP. Awider QT dispersion may correlate with proar-rhythmia. The lower incidence of proarrhythmiawith amiodarone compared with class IA agentsdespite similar QT interval prolongation mayresult from a more homogeneous prolongation ofrepolarization with the former.69 Incorporation ofQT dispersion to the clinical arena appears prom-ising, but methodological issues limit its currentuse.

Exercise Testing

Serious ventricular tachyarrhythmias during exer-cise testing have been occasionally reported in

patients taking class IC agents for supraventricu-lar arrhythmia.42 Some clinicians propose routineuse of exercise testing to unmask ventricularproarrhythmia in such patients. The scarce pro-spective data available suggest that such approachis associated with a low yield.117,118 Furthermore,it is uncertain if marked exercise-induced QRSprolongation on a class IC agent (without induc-tion of ventricular tachycardia) identifies patientswith higher risk of late proarrhythmia and inwhom a change in drug regimen may be desirable.

Plasma Drug-Level Monitoring

Plasma drug-level monitoring appears attractivein patients treated with antiarrhythmic drugsbecause of the low therapeutic index of mostagents. However, several factors limit the useful-ness of drug-level monitoring in dose-adjustmentand prevention of toxicity. Therapeutic concentra-tion ranges have not been rigorously established.Although correlation between concentration andeffect is stronger for free (unbound) than for totaldrug concentration, free drug is rarely measuredbecause of technical limitations. Even when freedrug is measured, there is wide interpatientpharmacodynamic variation in the relation be-tween plasma concentration and pharmacologicaleffect (in part due to genetic polymorphisms ofthe drug receptors). Clinically, proarrhythmiafrequently occurs before steady-state plasma lev-els are achieved and routinely measured. Finally,most hospitals submit samples for antiarrhythmicdrug level determinations to outside laboratories,limiting their value in prompt decision-making.Because for most antiarrhythmic drugs, the sur-face electrocardiogram provides a more accurate,less expensive, and more readily available assess-ment of their pharmacological effects, there islittle role for the routine determinations of theirplasma concentration. These measurements maybe useful in selected patients with suspectedaltered pharmacokinetics or in whom noncompli-ance is suspected.

Clinical Strategies: InpatientVersus Outpatient Initiation

It may be possible to design efficient clinicalpathways for the safe initiation of antiarrhythmicdrugs in patients with AF without the need for


universal hospital admission. Assuming that theneed for antiarrhythmic drug therapy has beenestablished and that potentially reversible causesof the atrial tachyarrhythmias have been ruledout, a successful algorithm should consist of thefollowing steps: (1) definition of underlying struc-tural heart disease; (2) assessment of risk factorsfor proarrhythmia; (3) selection of the drug basedon the previous assessment, with appropriateconsideration to selective drug efficacy in somesyndromes and long-term extracardiac side ef-fects; (4) selection of a cautious initial dose, withup-titration as clinically required; and (5) selec-tion of a monitoring strategy based on the esti-mated risk of proarrhythmia. A similar approachmay be necessary when increasing the antiarrhyth-mic drug dose.

The evaluation for heart disease should beaimed at detecting ventricular dysfunction orhypertrophy, inducible ischemia, conduction dis-turbances, and prolonged baseline repolarization.It should include a complete history, physicalexamination, ECG, and echocardiogram in allpatients.119 An exercise test (with or withoutimaging techniques) should be performed whenmyocardial ischemia is suspected. Coronary angi-ography may be needed to rule out coronaryartery disease. Although the low incidence ofproarrhythmia may make screening for clinicallyunrecognized structural heart disease cost-ineffi-cient, it is prudent in view of the potentiallethality of proarrhythmia in patients with struc-tural heart disease.

Tailoring of the agent to the patient is animperfect science. Algorithms distilled by experi-enced clinicians represent a valuable startingpoint,120 but they need to be prospectively vali-dated. It appears safe to initiate antiarrhythmicdrugs in the outpatient setting (using one or moreof the monitoring techniques described above)for patients with little or no evidence of structuralheart disease. Quinidine and sotalol may repre-sent possible exceptions, especially in women orwhen higher doses (greater than 240 mg/d) of thelatter are used. Potentially reversible risk factors(hypokalemia, drug interactions) should be con-sidered and corrected before drug initiation.

Outpatient initiation is also feasible in patientswith pacemakers (which prevent drug-inducedbradycardia and make TdP much less likely to

occur). With drugs that increase pacing thresh-olds (eg, flecainide,121 propafenone), it is neces-sary to initially program the output with a widesafety margin and recheck the pacing thresholdafter the achievement of steady-state plasma lev-els. On the other hand, patients in AF anduncertain underlying sinus node function are athigher risk if bradycardia ensues on spontaneousconversion, and should be admitted to the hospi-tal for drug initiation. Alternatively, the antiar-rhythmic agent could be initiated shortly after asuccessful direct current (DC) cardioversion, oncesignificant bradycardia is excluded.122 Lack ofpharmacological protection at a time of high riskof arrhythmia recurrence123 is a potential draw-back of this approach.

The choice of agents and strategies is morerestricted in patients with significant structuralheart disease. In these patients, class IC antiar-rhythmic drugs are contraindicated, and mostother drugs should be initiated in the hospitalunder continuous monitoring. Amiodarone repre-sents an exception, provided electrolyte imbal-ances are avoided and modest loading doses (ie,less than or equal to 600 mg/d) are prescribed.The incidence of proarrhythmia is below 1%when these doses of amiodarone are started in theoutpatient setting in patients with heart failure orrecent myocardial infarction.124,125 The safety ofoutpatient initiation of amiodarone using a larger‘‘loading’’ dose in patients with AF is not wellestablished. Natale et al126 used an outpatientregimen of 400 mg of amiodarone 3 times a dayfor 5 days followed by 400 mg every day for amonth in 335 patients. For patients with persis-tent AF, elective cardioversion was planned be-tween 10 and 14 days after drug initiation. Nopatient developed severe bradycardia or life-threatening tachyarrhythmias. However, a rapidventricular response developed in 65 of the 199patients (33%) in whom amiodarone was startedduring AF. This was generally the result of prema-ture discontinuation of concomitant rate-control-ling drugs. On the other hand, Weinfeld et al127

initiated amiodarone for AF at a dose of 1,200mg/d in 37 hospitalized patients with advancedheart failure and reported significant bradycardia(requiring pacemaker implantation or digoxindiscontinuation despite a reduction in amioda-rone dose) in 15 (41%).


The Future

The relative merits of a strategy of rhythm versusrate control in patients with AF are still controver-sial.128 It appears obvious that sinus rhythm ispreferable to AF if it can be maintained withminimal side effects. Advantages include bettersymptomatic control and exercise tolerance, im-proved hemodynamics, and (probably) lower riskof embolization. Furthermore, it has been docu-mented that AF begets AF.129 Therefore, mainte-nance of sinus rhythm may prevent the electro-physiological abnormalities that result from AF.The less than perfect efficacy of antiarrhythmicdrug and, mainly, their proarrhythmic effects arethe arguments of those who favor rate control.Cost-effective strategies aimed at reducing therisk of proarrhythmia would remove many of theimpediments to more vigorous attempts at sinusrhythm maintenance.

Alternative, lower-cost physical settings forthe initiation of antiarrhythmic drugs may befeasible. Patients could be admitted to dedi-cated, sparsely staffed monitoring units wherethey would receive minimal assistance with ac-tivities of daily living. The ECG would be con-tinuously transmitted to a nearby hospital unitfrom which emergency support could be sum-moned immediately. Another possibility includesthe provision to ambulatory patients of devicescapable of continuously monitoring the heartrhythm and delivering automatic defibrillation. Abattery-operated, wearable unit incorporating de-fibrillation pads and sensing electrodes into apatient-worn garment is undergoing clinical inves-tigation.130 Although conceived as a safety net forhigh-risk patients (eg, those awaiting cardiactransplantation), it may eventually find an appli-cation in the outpatient initiation of antiarrhyth-mic drugs. However, this ingenious technologymay face extraordinary regulatory and patientacceptance obstacles and is unlikely to be avail-able in the near future.

The quest for safer and more efficacious antiar-rhythmic drugs continues. Major emphasis hasbeen placed in the development of ‘‘pure’’ class IIIantiarrhythmic drugs. Although their main actionconsists in blockade of potassium currents, theydiffer in their selectivity for different channels,rate-dependent effects, and ancillary properties.Therefore, the risk of ventricular proarrhythmia

associated with their use may not be uniform. Forexample, d-sotalol increased mortality in patientswith left ventricular dysfunction after myocardialinfarction,131 whereas dofetilide appeared safe in asimilar population. Drugs that block preferen-tially the slow component of the delayed-rectifiercurrent (Iks) may not present reverse rate-dependence effects on action potential durationand may have a lower risk of TdP.132 It is likelythat one or more of these drugs will becomewidely used for the treatment of AF in the nearfuture. However, as long as drugs target normalchannels, the risk of proarrhythmia will not beentirely eliminated. Hopefully, better understand-ing of the molecular mechanisms involved in AF(including the changes in channel density133,134

responsible for electrical remodeling135) will re-sult in the development of safer and more selec-tive antiarrhythmic drugs.

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Antiarrhythmic drug initiation in patients with atrial fibrillation