Cardioversion of Atrial Fibrillation

Cardioversion of Atrial Fibrillation

Subhashini A. Gowda, Arti Shah, and Jonathan S. Steinberg

A trial fibrillation (AF) is the most commonchronic arrhythmia encountered in clinical

practice, affecting an estimated 2.2 million

Americans and present in 8% to 10% of those

older than 80 years old. 1As the US population

ages, the incidence and prevalence of AF is

expected to increase. Although the Atrial Fibril-

lation Follow-up of Rhythm Management

(AFFIRM) study demonstrated no clinical ben-efit from attempts to maintain sinus rhythm in

patients with AF who have suppressive antiar-

rhythmic agents and repeated cardioversions,

cardioversion was used as initial management in

both arms of the study.2 In addition, restoration

of sinus rhythm may be an important therapeutic

goal in patients who are younger or highly

symptomatic. Therefore, cardioversion remainsan important and frequently used intervention in

patients with AF.

Historical Perspective

Electrical therapy was used commonly to treat a

variety of ailments during the 18th and 19thcenturies. It is now the treatment of choice for

many arrhythmias. Carl et al3 was the first to

describe ventricular fibrillation (VF) by applying

galvanic currents directly to a dog’s heart in

1850.

In 1889, John McWilliam documented that

electricity could induce VF in a canine model and

argued against the prevalent belief that suddendeath was caused solely by ventricular standstill.4

Progress in Cardiovascular Diseas88

From the Arrhythmia Service and Division of Cardiolo-

gy, St Luke’s and Roosevelt Hospitals, Columbia Univer-

sity College of Physicians and Surgeons, New York, NY.Address reprint requests to Jonathan S. Steinberg, MD,

Division of Cardiology, St Luke’s and Roosevelt Hospi-

tals, 1111 Amsterdam Avenue, New York, NY 10025.E-mail: [email protected]

0033-0620/$ - see front matter

n 2005 Published by Elsevier Inc.

doi:10.1016/j.pcad.2005.06.006

Batelli and Prevost substantiated this theory by

reporting that not only was a weak current able to

cause fibrillation, but a strong current was

capable of terminating fibrillation.5

In the late 1920s, the Electric Company and

Edison Power Company noted that many of their

employees were dying from complications of

working with live electricity. They commis-

sioned Kouwenhoven, Hooker, and Langworthy

at the Johns Hopkins University to study the

effects of electricity on the heart. This group was

able to confirm that weak shocks could induceVF and stronger shocks could eradicate VF. They

also discovered that these stronger shocks could

be delivered without opening the chest. The

subsequent shock that terminated VF was

termed bcountershock Q.6

In the 1940s, Beck et al7 developed the first

alternating current internal defibrillator, which

was used to resuscitate a pediatric patient whodeveloped VF during cardiac surgery. The

original alternating current defibrillators were

cumbersome and difficult to transport during an

emergency.8 Zoll et al developed the first

external alternating current defibrillator in

1955. They were able to demonstrate that

external defibrillation could be performed safely,

consistently, and effectively.In 1960, Lown and associates9 used direct-

current technique first on animals and then on

postoperative patients timed to avoid energy

delivery during the vulnerable period. This

procedure was a major therapeutic advance in

the treatment of heart disease.9

Animal studies conducted by Lown showed

that the rhythm disorders were due to abnormalreentry circuits. When these circuits were inter-

rupted by electrical depolarization, the sinus

node, at a higher rate of automaticity, would

reclaim its control. Lown et al developed a

direct-current capacitor based on the work of

William Kouwenhoven, so that they could apply

a targeted brief electrical discharge triggered by

es, Vol. 48, No. 2 (September/October), 2005: pp 88-107

CARDIOVERSION OF ATRIAL FIBRILLATION 89

the R wave of the electrocardiogram (ECG). Test

shocks, 3500 in all, were used to explore the

vulnerable period of the atrium and the ventricleto demonstrate that the induction of AF and VF

could be avoided, when performed accurately.10

Safety and effectiveness were then proved by

terminating 550 episodes of VF in 20 dogs.10

In a landmark perspective written in 1986

about cardioversion, Sidney Alexander,11 who

worked with Lown, commented: bThe develop-

ment of this method, so commonly used that wetend to take it for granted, is a paradigm of the

brilliant wedding of clinical acumen and pro-

found understanding of good basic science,

when chance did indeed favor the prepared

mind.Q Now, more than 40 years after the initial

report by Lown et al, electrical cardioversion for

AF may be on the decline because of recent trials

that have suggested that it may not be asnecessary as we had believed in many patients

whose rate can be controlled.12

Cardioversion Technique

Cardioversion may be achieved by means of

drugs or by electrical shocks. Drugs were

commonly used before electrical cardioversion

became a standard procedure. The developmentof new drugs has increased the popularity of

pharmacological cardioversion, although some

disadvantages persist, including the risk of

drug-induced ventricular tachycardia or other

serious arrhythmias. Pharmacological cardiover-

sion is still less effective than electrical cardio-

version, but the latter requires conscious

sedation or anesthesia, whereas the former doesnot. There is no evidence that the risk of

thromboembolism or stroke differs between

pharmacological and electrical methods of car-

dioversion. The recommendations for anticoa-

gulation at the time of cardioversion are the

same for both methods.

Electrical Cardioversion

Mechanism of Electrical Cardioversion

Direct-current cardioversion synchronizes with

the intrinsic activity of the heart, and delivers an

electrical shock during systole, by sensing the R

wave of the ECG. This technique ensures that

electrical stimulation does not occur during the

vulnerable phase of the cardiac cycle, from 60 to

80 ms before to 20 to 30 ms after the apex of theT wave.13 Electrical cardioversion is used to

normalize all abnormal cardiac rhythms except

VF. Cardioversion terminates arrhythmia by the

delivery of a synchronized shock that depolarizes

the tissue involved in a reentrant circuit. Depo-

larization of all involved excitable tissue of the

circuit makes the tissue refractory, which is no

longer able to propagate or sustain reentry.Cardioversion is used for terminating those

arrhythmias resulting from a single reentrant

circuit, such as atrial flutter, atrioventricular

nodal reentrant tachycardia, atrioventricular re-

entrant tachycardia, or monomorphic ventricular

tachycardia.

The mechanisms responsible for termination

of fibrillation are still controversial.14 One theoryknown as the bCritical Mass HypothesisQ sug-

gests that high defibrillation energy levels can

completely eliminate fibrillatory activity. This

theory hypothesizes that; atrial or ventricular

fibrillation is sustained by a certain amount of

myocardium and terminated when the entire

myocardium is uniformly depolarized.15 Electro-

grams were recorded simultaneously from 120sites and analyzed using a computerized map-

ping system.16 Termination of fibrillatory activ-

ity at all sites was necessary for successful

defibrillation.

The other theory supports that; to successfully

defibrillate, the shock strength must be greater

than the largest shock that reinitiates fibrillation

(bThe Theory of the Upper Limit of Vulnera-bilityQ). Unsuccessful shocks are slightly weaker

than necessary for defibrillation.17 These lower

shocks abolish the activation fronts during

ventricular fibrillation and stimulate other

regions of myocardium during their vulnerable

period, giving rise to new activation fronts that

reinitiate ventricular defibrillation.18-20 Identical

changes in the upper limit of vulnerability andthe defibrillation threshold occur with changes

in electrode polarity and waveform duration.21

Transthoracic Cardioversion

Transthoracic direct-current cardioversion has

become the standard method for terminating AF

since Lown et al first described it in 1962. Since

GOWDA, SHAH, AND STEINBERG90

then, this technique has been used extensively,

and it has been determined to be safe and

effective. Extensive research completed overthe last decade has resulted in a better under-

standing of the mechanisms of defibrillation, the

development of newer technologies and energy

waveforms, and novel optimization strategies to

improve efficacy rates, patient safety, and success

in refractory cases.

Basic Technique

Successful cardioversion of AF depends on the

nature of the underlying heart disease and the

current density delivered to the atrial myocar-dium. The current density delivered is inverse-

ly related to the impedance for a electrode

surface area and also depends on the voltage of

the defribillator capacitor, the output wave-

form, and the size and position of the electro-

des. The thoracic impedance22 is related to the

size and composition of the electrodes, the

contact medium between the electrodes andthe skin, the distance between the electrodes,

body size, and phase of the respiratory cycle,

the number of shocks delivered, and the

interval between shocks.

Electrolyte-impregnated pads reduce the re-

sistance between the electrodes and the skin.

Shocks delivered during expiration and with

chest compression deliver higher levels of energyto the heart. Larger skin electrodes result in

lower impedance, but when the paddles are too

large, current density through cardiac tissue is

insufficient to achieve cardioversion. On the

other hand smaller sized paddles may produce

too much current density and cause injury. The

optimum paddle size for cardioversion of AF is a

diameter of 8 to 12 cm22 as recommended byDazell et al. The likelihood of successful car-

dioversion is decreased by a combination of high

impedance and low energy. This could be

overcome by measuring the impedance to short-

en the duration of the procedure, reduce adverse

responses, and imrove outcome.23,24

Older equipment for external cardioversion

utilized a monophasic waveform. Rectilinearbiphasic waveforms have proven to be more

superior to monophonic waveforms as shown by

a randomized trial wherein 77 patients treated

with monophasic shocks had a cumulative

success rate of 79%, whereas 94% of 88 subjects

treated with biphasic shocks were successfully

converted to sinus rhythm. Patients in the lattergroup required lesser energy for cardioversion.

Anterior-posterior electrode configuration has

been shown to be superior to anterior-anterior

positioning.25 The former position allows

enough current to reach a sufficient mass of

atrial myocardium to effect defibrillation when

the pathology associated with AF involves both

the RA and the LA (as in patients with atrialseptal defect or cardiomyopathy). But this uses a

comparatively wider electrode separation with a

large amount of pulmonary tissue between the

anterior paddle and the heart. Placing the

anterior electrode to the left of the sternum

reduces the electrode separation and also the

amount of interposed pulmonary tissue. For

better results the paddles should be placeddirectly against the chest wall, under rather than

over breast tissue.

In a randomized controlled study of 301

subjects undergoing elective external cardiover-

sion, patients were allocated to anterior-lateral

(ventricular apex and right infraclavicular) or

anterior-posterior (sternum and left scapular)

paddle positions.26 The overall success (addingthe outcome of low-energy shocks to that of

high-energy shocks) was greater with the ante-

rior-posterior configuration (87%) than with the

anterior-lateral alignment (76%), as was the en-

ergy requirement, which was lower with the

anterior-posterior paddle configuration. If the

initial position proves unsuccessful, variations of

paddle size could be tried.

Amount of Energy and Mode of Delivery

A good lead which shows clear P and R waveshas to be selected, for synchronizing with the

QRS complex and triggering, by monitoring the

R wave. Higher energy is required for AF

cardioversion, starting with at least 200 J (mono-

phasic waveform) or 100 J (for biphasic wave-

form) as opposed to success with lower energy in

atrial flutter, such as 25 J. The energy output is

increased successively in increments of 100 Juntil a maximum of 400 J is reached. Some

physicians begin with the higher energies to

reduce the number of shocks (and thus the total

energy) delivered. Lower energies are required

Fig 1. Different waveforms for defibrillation. (Top)Traditional damped sinusoidal monophasic. (Middle)Truncated exponential biphasic adjustment of currentaccording to transthoracic impedance occurs bychanges in the pulse duration of the first phase.(Bottom) The rectilinear biphasic waveform maintainsa constant current during the first phase to adjust fordifferences in transthoracic impedance.33


with a biphasic waveform (see below). There

should be a minimum interval of 1 minute

between 2 consecutive shocks to avoid myocar-dial injury.27

As elaborated, an important advance over the

last decade has been the development of alter-

nate waveforms for defibrillation. With mono-

phasic defibrillators, the electrical energy is

delivered in a single polarity, meaning that it

travels in a single direction, primarily with a

damped sinusoidal waveform. Biphasic defibril-lation waveforms were developed in an attempt

to improve conversion rates.28 In contrast to

monophasic waveforms, biphasic waveforms

involve a reversal of current at a specific time

in the energy shock. The advantage of biphasic

shocks derives from its ability to lower the

defibrillation threshold by creating longer post-

shock refractoriness in a greater percentage ofmyocytes than with monophasic shocks.29 Bi-

phasic waveforms are used in all implantable

defibrillators, because they have been shown to

reduce energy requirements by 25% to 45%.30,31

Biphasic waveforms are also used in automated

external defibrillators.32 Another advantage of

biphasic defibrillators is that they adjust deliv-

ered current according to transthoracic imped-ance (Fig 1).32

Ricard et al33 demonstrated that for AF of less

than 24 hours of duration, energies equal or less

than 200 J were successful in 98% of patients. For

AF of over 48 hours of duration, the energy

requirements were higher. The authors per-

formed a prospective randomized study evaluat-

ing 3 different initial energies (100, 200, and360 J) for elective cardioversion of persistent AF

using monophasic defibrillators.34 The study

included 64 patients with persistent AF of over

48 hours of duration. The initial success rate was

14% with 100 J, 39% with 200 J, and 95% with

360 J ( P b .0001). Furthermore, when the

patients were started at the lower energy levels,

they ultimately received a higher total energy andhigher number of shocks, whereas no adverse

effects were seen when a high initial energy was

used (Fig 2).34 For conversion of atrial flutter,

Pinski et al35 demonstrated that 100 J of energy

achieved an 85% conversion rate vs a 70%

conversion rate when only 50 J were used.

Recent studies have confirmed the superiority

of biphasic over monophasic shocks for cardio-

version of AF.22 In a prospective randomized

study, Mittal et al22 demonstrated the superiority

of the rectilinear biphasic waveform overdamped sinusoidal monophasic waveform for

elective cardioversion of AF. The conversion

efficacy of the biphasic shocks was markedly

superior to monophasic shocks at all energy

levels in their study (Fig 3).22 One important

aspect of this type of waveform is that it

compensates for transthoracic impedance by

maintaining a constant current during the firstphase of defibrillation. Therefore, the superiority

of biphasic over monophasic waveforms was

more dramatic in those with high transthoracic

impedances (N70 X), who are, therefore, less


likely to convert with monophasic shocks

(Fig 3).22 Page et al compared a damped

sinusoidal monophasic waveform to a truncatedexponential biphasic waveform. Patients under-

went a step-up protocol, where they received up

to 5 shocks, 100, 150, 200, and 200 J of biphasic

or 360 J of monophasic, and a final crossover

shock at the maximum output of the alternate

Fig 2. When performing elective cardioversion ofpersistent AF using monophasic defibrillators, com-pared with 100 or 200 J, the higher level (360 J)resulted in higher success rate (A), fewer number ofshocks (B), and less total energy (C). *P VVVVVVVVVVVVVVV____ .0001;+P = .05.35

Fig 3. Arrhythmia-free survival after electrical cardio-version in-patients with persistent AF. The lowercurve represents outcome after a single shock whenno prophylactic drug therapy was given. The uppercurve depicts the outcome with repeated electricalcardioversions in conjunction with AAD prophylaxis.Abbreviations: ECV indicates electrical cardioversion;SR, sinus rhythm.114

waveform. At the first 3 energy levels, the

biphasic waveform was dramatically superior to

the monophasic waveform (60% vs 22% at 100 J,

77% vs 44% at 150 J, and 90% vs 53% at 200 J).

Furthermore, the patients receiving biphasic

shocks required fewer shocks and experienced

significantly less dermal injury.Therefore, for cardioversion of patients with

persistent AF, it is recommended that an initial

energy of 200 J be selected when biphasic

waveform defibrillators are used. In patients with

AF of less than 24 hours of duration, 100 J will be

appropriate for most patients. If monophasic

waveform defibrillators are used, higher initial

cardioversion energy should be selected (300-360 J). For patients undergoing cardioversion for

atrial flutter, the optimal initial energy selection

is 100 J if monophasic or 25 J if biphasic wave-

form defibrillators.

Clinical Aspects

Cardioversion is performed with the patient

having fasted and under adequate general anes-


thesia to avoid pain related to delivery of the

electrical shock. Short-acting anesthetic drugs or

agents that produce conscious sedation arepreferred; because cardioversion patients should

recover rapidly after the procedure, they usually

do not require overnight hospitalization.36

Efficacy

Successful cardioversion of AF may occur 70% to

90% of the time.37,38 This variability is explained

in part by differences in patient characteristics

and in part by the definition of success. Success

can be defined as maintenance of sinus rhythm

immediately after cardioversion or for several

days to months later. Older studies estimated

successful cardioversion in a patient populationthat included a large number of patients with

rheumatic heart disease. Over the past few

decades the incidence of the above disease has

decreased, where as the incidence of alone AF

has remained constant. Hence it is difficult to

compare recent and older data on the outcome of

cardioversion. In a large consecutive series of

patients undergoing cardioversion of AF, 24%were classified as having ischemic heart disease,

24% rheumatic valvular disease, 15% lone AF,

11% hypertension, 10% cardiomyopathy, 8%

nonrheumatic valvular disease, 6% congenital

heart disease, and 2% treated hyperthyroidism.37

Seventy percent of the patients were in sinus

rhythm 24 hours after cardioversion. Multivari-

ate analysis revealed that short duration of AF,presence of atrial flutter, and younger ages were

independent predictors of success, whereas left

atrial enlargement, underlying heart disease,

and cardiomegaly predicted failure.

Eighty-six percent of the patients converted to

sinus rhythm and remained in sinus rhythm for 3

days after the procedure; this increased to 94%

when the procedure was repeated during treat-ment with quinidine or disopyramide after an

initial failure to convert the rhythm. Only 23% of

the patients remained in sinus rhythm after 1 year

and 16% after 2 years; in those who relapsed,

repeated cardioversion with antiarrhythmic

medication resulted in sinus rhythm in 40%

and 33% after 1 and 2 years, respectively. For

patients who relapsed again, a third cardiover-sion resulted in sinus rhythm in 54% at 1 year

and 41% at 2 years.39 Concomitant antiarrhyth-

mic drug therapy can help reduce the rate of

relapse from a successful cardioversion. Success-

ful conversion may be achieved with adjunctivestrategies, which may include alternative elec-

trode positions, concomitant administration of

intravenous ibutilide, and delivery of higher

energy with the use of 2 defibrillators (see

below). External cardioversion with a biphasic

shock waveform in many instances has reduced

the need for these adjunctive maneuvers.

Early or Immediate Recurrence of AF (ERAF

and IRAF)

Early recurrence of AF (ERAF) is defined as a

relapse of AF within a few hours to days aftersuccessful cardioversion for at least 2 sinus

beats.39 Immediate recurrence of AF (IRAF) is

the recurrence of AF within a few minutes after

restoration of sinus rhythm.40

Incidence

Early recurrence of atrial fibrillation is a fairly

common phenomenon with an incidence rang-

ing from 12% to 26% with either internal or

external cardioversion.39 Some authors report an

incidence up to 44% in patients with recurrent,

drug-resistant, symptomatic AF after cardiover-sion shocks delivered by permanently implanted

rhythm management systems.41

Putative mechanisms for ERAF initiation

include atrial premature depolarization (APDs)

with decreasing coupling intervals or a burst of

pulmonary vein tachycardia rather than a single

premature depolarization.42

Management of ERAF

Early recurrence of atrial fibrillation is a

major cause of failure in cardioversion andcould be prevented with an increase of shock

energy or combination of pharmacological

agents. Early recurrence of atrial fibrillation

initiated by pulmonary vein (PV) tachycardia

can be effectively abolished by PV isolation.39

Alternative Techniques

Internal or Transvenous Cardioversion

A technique for delivering high-energy (200-

300 J) direct current internally for cardioversion


of AF was introduced by Levy et al43,44 using a

right atrial catheter and a backplate. In a

randomized trial, internal cardioversion wassuperior to external countershock, particularly

in obese patients and patients with chronic

obstructive lung disease, but the frequency of

recurrence of AF over the long term did not

differ between the 2 methods. A monophasic

shock waveform was used for external cardio-

version in the study; use of a biphasic waveform

would likely necessitate internal cardioversionconsiderably less frequently.

Other techniques for internal cardioversion

apply low-energy (less than 20 J) shocks via a

large-surface cathodal electrode in the right

atrium and an anode in the coronary sinus or

left pulmonary artery.45,46 These techniques

have been successful for restoration of sinus

rhythm in 70% to 90% of mixed cohorts,including those who did not respond to external

cardioversion.51-53 Low-energy internal cardio-

version does not require general anesthesia but

is performed under sedation. Internal cardio-

version can also be performed through im-

planted defibrillators.

Cardioversion Via Devices

Technological advances in implantable cardio-

verter defibrillators (ICDs) have provided a

variety of programmable parameter therapies

that could be used to electrically cardiovert AF

through the ICD. In a prospective study of

96 patients with an ICD having atrial tachy-

therapies including cardioversion for AF, most

patients had less psychosocial distress, greaterquality of life, and lower AF symptom burden.47

Another study by Gold et al48 evaluated the

safety and efficacy of dual-chamber implantable

ICD to detect and treat atrial tachyarrhythmias

in patients with drug-refractory AF in

144 patients. The dual-chamber ICDs were

found to be safe and well tolerated in patients

with drug-refractory symptomatic atrial tachyar-rhythmias including AF in several studies.

Khaddaha et al49 looked at the safety and

efficacy of termination of AF with cardioversion

through implanted dual-chamber ICDs. The

study showed that ICDs could be effectively

used for cardioversion of AF in place of

transthoracic defibrillators.

Esophageal Cardioversion

Lukoshevichiute50 proposed a method where

cardioversion was performed through an esoph-

ageal electrode in 277 patients 296 times for

different cardiac arrhythmias. Paroxysmal AF

and flutter of the atria, and paroxysmal tachy-

cardia were terminated in all cases, chronic AFin 92%, and chronic atrial flutter in 94% of

cases. In the group of patients where transtho-

racic cardioversion was ineffective, sinus

rhythm was restored in 77% of cases with AF

and 84% of cases with irregular atrial flutter

when one of the electrodes was introduced into

the esophagus. The mean defibrillating voltage

in transesophageal cardioversion for chronic AFwas 54% lower than that in transthoracic

cardioversion. The design of the esophageal

electrode provides for continuous recording of

the ECG for the purpose of determining the

optimum position of the electrode and identi-

fying the character of disorders that initiate the

cardiac rhythm.

Chemical Cardioversion

To understand the effects of AADs on AF

termination, one must consider changes in atrial

electrophysiology because of tachycardia- in-duced remodeling and theoretical concepts that

explain the effects of antiarrhythmics.

The most widely accepted proposed theory of

AF mechanism was elucidated by Moe51 as early

as 1962. It postulated that AF perpetuation is

based on the continuous propagation of multiple

wavelets wandering throughout the atria. In

1985, mapping of experimentally induced AF incanine hearts provided the first evidence sup-

porting Moe’s multiple wavelet hypotheses.52 An

important component of this theoretical frame-

work is the concept of the bwavelength of

reentryQ, as developed by Allessie et al.52,53 The

average size of reentry pathways during AF is

dependent on atrial wavelength. The wavelength

is the distance traveled by the electrical impulsein one reentrant cycle, which is the product of the

refractory period and the conduction velocity.

Long wavelengths are associated with larger and

fewer wave fronts, whereas short wavelengths

result in a greater number of smaller circuits. If

the path length of the potential circuit is smaller


than the wavelength, the impulse will traverse the

circuit and return to its starting point in a time

shorter than the refractory period, forcing it toimpinge on still-refractory tissue and die out.

Thus, the wavelength is the shortest path length

that can sustain reentry.

Atrial fibrillation creates an atrial substrate

that facilitates its own persistence and induces a

number of electrophysiological, structural, and

mechanical changes. The electrophysiological

changes occur early in AF and are due toreduction in L-type calcium currents (ICa,L).54,55

They lead to shortened effective refractory

period (ERP) and reduced wavelength, ulti-

mately promoting reentry.56 Fig 457 summarizes

key features of AF-induced remodeling and puts

changes in ERP in perspective with the likeli-

hood of spontaneous or pharmacological cardi-

oversion and the risk of AF relapse.Chemical cardioversion is often used to convert

paroxysmal AF of recent onset (b48 hours of du-

ration). Many clinical trials have shown efficacy

of classes I and III AADs for this purpose. When

compared to placebo, class I and III drugs shorten

the time to conversion and increase the number of

patients who convert acutely (within 30-60 min-

utes) or subacutely (within a few hours to days).The most important agents with proven efficacy

include amiodarone, dofetilide, flecainide, ibuti-

lide, propafenone, and quinidine. The less effec-

Fig 4. This figure schematically demonstrates theinterlude between shortening of the ERP as a keyfeature of AF-induced remodeling and the probabilitythat an AF episode may end spontaneously. Pharma-cological cardioversion with class I agents is readilypossible within a time frame of hours to a few days,with decreasing efficacy after prolonged periods ofAF. The risk of an AF relapse increases conversely.58

tive agents include b-blockers, calcium channel

antagonists (verapamil and diltiazem), digoxin,

disopyramide, procainamide, and sotalol.The clinical reasons for restoration and

maintenance of sinus rhythm in patients with

AF include relief of symptoms (eg, palpitations,

fatigue, and dyspnea) and prevention of tachy-

cardia-induced myocardial remodeling and

heart failure. There are number of considera-

tions that need to be taken into account when

evaluating the potential of a drug to cardiovertAF to sinus rhythm: the conversion rate and

time, the route of drug administration, the

duration of arrhythmic episode, and the history

of structural heart disease.

In patients with structural heart disease, such

as coronary artery disease, congestive heart

failure administration of class I drugs is contra-

indicated because of increased risk of ventricularproarrhythmia.59,60 Paroxysmal AF will convert

earlier after initiation of the therapy than

persistent AF. Class IC drugs are more effective

in converting shorter duration of AF. If the

arrhythmia episode is of shorter than 24 hours of

duration, then the conversion rate can be as high

as 90% with intravenous administration of

flecainide or propafenone. If the arrhythmicepisode is of longer duration, days to weeks,

the same drugs are less efficacious in converting

AF to normal sinus rhythm (NSR). Class III

agents are less effective than class IC agents in

cardioverting shorter duration of AF but are

more efficacious in cardioverting AF of longer

duration.61

Mechanisms of AF Termination

Mapping studies have shown that during AF,

multiple wavelets are propagating through the

atria.67 -70 Some studies have suggested that one

antifibrillatory action of antifibrillatory drugs is

based on a prolongation of the atrial wave-

length.70-72 When the wavelength during AF gets

longer, the average number of multiple wave-

lets decreases, and the statistical chance that AF

will terminate increases. From a theoretical

point of view, the effect of sodium channel

blocking agents is less compatible with the

classic multiple wavelet theory. These agents

are effective in terminating AF, but they should

rather promote AF because of reduced avail-


ability of sodium channels and decreased wave-

lengths. Contrary to these predictions, flecainide

and propafenone are safe and effective drugs for

conversion of paroxysmal AF to sinus rhythm,

although ineffective for atrial flutter.62 - 72

Excitation of atria in AF can also be viewed as

spiral waves with rotors that wander through the

atria with a gradient of excitability that makes

activation in the center of rotor slower than in the

periphery.63 With the sodium channel blockingagent, atrial excitability is reduced and the rotor is

no longer able to turn in a small radius. With

increasing radius, it loses its ability to maintain

itself, which ultimately results in conversion of

AF to sinus rhythm.64 Kawase et al65 demonstrat-

ed this concept by using a pure sodium channel

blocker, pilsicainide, and noted an increase in the

excitable gap and an enlarged core of the motherrotor that may lead to AF termination.

It is still unclear why class I agents are

effective in recent-onset AF, whereas persistent

or permanent AF remains resistant to these

agents. Most likely, prolonged AF has remodel-

ing as a prominent feature.

Class III agents act by lengthening the action

potential and hence the ERP. Antiarrhythmicagents that prolong ERP are effective agents for

pharmacological cardioversion of AF. As a

consequence of wavelength prolongation, multi-

ple wavelets are unable to coexist simultaneously

in the atria.

Fig 5. Reversion of AF with antiarrhythmic drugs isrelated to arrhythmia duration. In a study comparing 2doses of intravenous ibutilide with intravenous sotalolfor acute reversion of AF, the rate of successfulreversion was inversely related to the duration of theantiarrhythmia before therapy.66

Antiarrhythmic Drugs With Proven Efficacy

Ibutilide

Ibutilide was the first of the bpureQ class III

antiarrhythmic agents to be approved by the

Food and Drug Administration for the termina-

tion of AF and atrial flutter. Ibutilide prolongs

repolarization of cardiac tissue by prolonging the

action potential duration and ERP in both atrial

and ventricular cardiac tissue.

In vitro studies of its electrophysiologicaleffects suggest that the antiarrhythmic action of

ibutilide may result at least in part from

activation of a slow, predominantly sodium,

inward current at very low concentrations, and/

or from inhibition of the rapidly activating

component of the potassium channel involved

in repolarization of cardiac cells (ie, the rapidly

activated component of the delayed rectifier

potassium current IKr) at higher concentrations.

Like other class III antiarrhythmics, effects oncardiac repolarization can result in proarrhyth-

mic effects (ie, torsade de pointes).

Ibutilide is effective for the acute termination

of AF and atrial flutter, and as with other agents,

its efficacy is greater when the arrhythmia is of

shorter duration (see Fig 5).66 Because there is

no oral preparation of ibutilide, it is only useful

for reversion and has no role for long-termprevention of these arrhythmias.

There have been a few studies in which

ibutilide was administered to patients with sus-

tained AF.75 -78 In a dose-response study, there

was an association between the reversion rate and

the dose administered67: 10%, 35%, 32%, and

40% for 0.005, 0.010, 0.015, and 0.025 mg/kg of

ibutilide, respectively. In another report, restora-tion of sinus rhythm was much more common

with ibutilide than placebo (31% vs 2%).68

Ibutilide has also been compared to other

agents. One report of 251 patients with AF found

that ibutilide was more effective than sotalol for

acute reversion (Fig 5).66 Reversion was attained

in 43% of patients treated with 2 mg of ibutilide vs

only 11% in those treated with intravenous sotalol

(1.5 mg/kg) ( P b .0001). Ibutilide has also been

compared to procainamide (up to 1200 mg IV).69


In one report, there was a substantially higher

reversion rate with ibutilide (51% vs 21%).70

Although the reversion rate with ibutilide is

higher than with placebo, it is still relatively low.

The drug is more effective when given as

pretreatment before electrical cardioversion. As

an example, one study randomized 100 patients

to cardioversion with or without pretreatment

with 1 mg of ibutilide; the rate of conversion was

higher in those pretreated with ibutilide (100%

vs 72% without pretreatment), and all patients in

whom cardioversion alone failed had sinus

rhythm restored when cardioversion was repeat-

ed after ibutilide therapy.71

Amiodarone

Data on amiodarone are complex because the

drug may be given intravenously, orally, or

sequentially. The drug is modestly effective for

pharmacological cardioversion of recent-onset

AF.72 but acts less rapidly and probably less

effectively than other agents. The conversion rate

in patients with AF for longer than 7 days is

limited, however, and restoration of sinusrhythm may not occur for days or weeks.

Amiodarone is also effective for controlling the

rate of ventricular response to AF.

Several studies have evaluated intravenous

administration of amiodarone for conversion of

AF to sinus rhythm, according to a recent

metaanalysis73 in which 10 randomized con-

trolled trials were included. Three studies com-pared amiodarone with class IC drugs as well as

with placebo. Six studies compared amiodarone

with placebo. Three of these were single blind,

2 were double blind, and the design of the sixth

was not stated.

For return of sinus rhythm, amiodarone showed

greater efficiency compared with placebo at 6 to

8 hours (RR 1.2) and at 24 hours (RR 1.4). Thedrug showed no efficacy at 1 to 2 hours. Class IC

drugs were more effective than amiodarone at 1 to

2 hours (RR 0.35), at 3 to 5 hours (RR 0.44), and

at 6 to 8 hours (RR 0.57). However, both drugs

were equally effective at 24 hours. Similarly, the

incidence and quality of side effects were compa-

rable except for the occurrence of flutter with 1:1

AV conduction, which was observed in 3 patientson flecainide but not in any of the amiodarone-

treated patients.

On the basis of the above data, amiodarone

appears to be less effective than class IC drugs for

the pharmacological cardioversion of AF. Thecomplex pharmacokinetic and pharmacodynamic

profile of amiodarone seems to be responsible for

its somewhat delayed onset of action. Adverse

effects of amiodarone include bradycardia, hypo-

tension, visual disturbances, nausea, and consti-

pation after oral administration and phlebitis after

peripheral intravenous administration.83 - 94

Flecainide and Propafenone

Flecainide and propafenone are class IC AADs

that have been extensively studied for the phar-macological conversion of AF. In patients with

short-lasting recent-onset AF, these drugs restore

sinus rhythm in up to 90% of treatment attempts.

In most studies, flecainide has been administered

as a short bolus infusion at doses of 1 to 2 mg/kg.

There are only limited data in the literature about

effectiveness of single oral doses of flecainide for

pharmacological cardioversion. Alp et al74

designed the first double-blind randomized trial

to compare intravenous and oral routes of

flecainide loading for cardioversion of acute AF.

In this study, 79 patients were randomized to

intravenous or large oral dose of flecainide:

flecainide, 2 mg/kg (maximum, 150 mg) and oral

placebo solution; or placebo and oral flecainide, 4

mg/kg (maximum, 300 mg) as a solution. Thedose of oral flecainide was twice that of the

intravenous dose: this was calculated from

pharmacokinetic data on flecainide absorption

to obtain similar therapeutic peak plasma

concentrations.75 - 76 Intravenous flecainide re-

stored sinus rhythm more quickly than oral

flecainide (52 vs 110 minutes). However, there

was no significant difference between the2 routes of treatment in the proportions of

patients cardioverted by 2 and 8 hours. At

present, the intravenous preparation of flecai-

nide is not available in the United States.

Unlike flecainide, propafenone has been

studied in several trials in its oral form.86- 90

In one study, 240 hospitalized patients with AF

of less than 8 days of duration were randomizedto propafenone (one 600-mg oral dose) or

placebo. The conversion rate with propafenone

was 45% at 3 hours and 76% at 8 hours

compared with 18% and 37% in control


patients. The mean time for conversion to sinus

rhythm within 8 hours was similar for prop-

afenone and for placebo. The rate of spontane-ous conversion to sinus rhythm was higher in

patients without structural heart disease; this

finding has important implications for the

assessment of drug effectiveness in recent-onset

AF. However, patients with documented con-

duction disturbances, recent myocardial infarc-

tion, or congestive heart failure were excluded

from the study.The efficacy and safety of the single-dose oral

loading regimen of propafenone for pharmaco-

logical cardioversion of recent-onset AF was

evaluated by analyzing the trials on the subject

identified through a comprehensive literature

search.86- 97 Most of the trials used a single dose

of 600 mg for oral loading. The success rates

ranged from 56% to 83%, depending on theduration of AF and follow-up after drug admin-

istration.77 The single-dose oral loading regimen

of propafenone was significantly more efficacious

than placebo in the first 8 hours after administra-

tion, but not at 24 hours. The same study also

demonstrated that the oral propafenone regimen

was as efficacious as the single-dose oral loading

regimen of flecainide but was superior to those ofquinidine and amiodarone. The adverse effects

reported were transient arrhythmia, reversible

QRS-complex widening, transient hypotension,

and mild noncardiac side effects. The transient

arrhythmias were chiefly at the time of conversion

and included appearance of atrial flutter, brady-

cardia, pauses, and junctional rhythm. No life-

threatening proarrhythmic adverse effects werereported. Because of its high rate of effectiveness,

a relatively rapid effect within 2 to 3 hours and the

simplicity of administration, the single oral

loading dose of propafenone was considered to

be among the first-line treatments used for

conversion of recent-onset AF. On the basis of

this study, the concept of bpill-in-the-pocket

approachQ emerged.In a recent study,78 a single dose of 200 to

300 mg of flecainide or 450 to 600 mg of

propafenone was administered in the hospital to

268 patients with symptomatic AF less than 48

hours who had an ejection fraction greater than

50% and a history of less than 12 episodes per

year. If conversion to sinus rhythm occurred in

less than 6 hours, the patient was instructed to

self-administer the drug whenever AF recurred.

The outpatient pill-in-the-pocket approach was

used in 210 patients (mean age, 59 years).During a mean of 15 months of follow-up,

618 episodes of AF occurred in 165 patients.

Ninety-four percent of episodes resolved within

6 hours. An adverse drug effect or side effect

occurred in 7% of patients. The number of

hospitalizations per month during follow-up was

1.6, compared with 15 in the year before study

entry. The pill-in-the-pocket is effective and welltolerated in selected patients with symptomatic

AF and normal left ventricular function.

According to the present evidence derived from

clinical trials, good candidates for the pill-in-the-

pocket approach can clearly recognize when

episodes start and stop, have normal left ventric-

ular function, and have episodes that last longer

than l to 2 hours and occur less than l to 2 times amonth. The safety of the pill-in-the-pocket ap-

proach can be improved by having the patient

take 20 to 40 mg of propranolol along with

the flecainide or propafenone. A short-acting

b-blocker is also helpful in lowering the ventric-

ular rate and improving symptoms before cardi-

oversion. Because patients with symptomatic AF

also may have asymptomatic AF, therapeuticanticoagulation with warfarin is appropriate in

patients with risk factors for stroke.

Dofetilide

Dofetilide, a class III antiarrhythmic agent, is a

methanesulfonamide derivative that is structur-

ally related to sotalol. Dofetilide exhibits elec-

trophysiological effects characteristic of class III

antiarrhythmic agents (eg, prolongs repolariza-

tion and refractoriness without affecting cardiac

conduction velocity and sinus node function).However, unlike ibutilide and sotalol, dofetilide

has no effect on sodium channels (associated

with class I antiarrhythmic agents) or adrenergic

receptors at clinically relevant concentrations.

Dofetilide prolongs the action potential dura-

tion and the ERP in both atrial and ventricular

cardiac tissue, principally because of delayed

repolarization. The antiarrhythmic action ofdofetilide results from selective inhibition of

the rapidly activating component of the potassi-

um channel involved in repolarization of cardiac

cells (ie, the rapidly activated component of the


delayed rectifier potassium current IKr). Like

other class III antiarrhythmics, effects on cardi-

ac repolarization induced by the drug can resultin proarrhythmic effects (principally torsade

de pointes).

There are many placebo-controlled studies on

dofetilide’s intravenous use for termination of

AF or flutter. Overall, its efficacy in terminating

the arrhythmias was 28% in AF and 66% in

flutter with a mean time of conversion between

20 and 50 minutes from the beginning ofinfusion. Torsade de pointes was observed in

4.2% of patients.

The efficacy and safety of oral dofetilide in

patients with chronic paroxysmal or persistent

AF were examined in 3 double-blind, placebo-

controlled multicenter studies—EMERALD

(1998),79 DIAMOND-CHF (1999),80 and

SAFIRE-D (2000).81

In the European and Australian Multicenter

Evaluation Research of Atrial fibrillation Dofe-

tilide (EMERALD) study, which included

535 patients with persistent AF or flutter, 3

doses of dofetilide (125, 250, and 500 lg BID)

were randomly compared with sotalol 160 mg

BID and placebo.82 The reversion rate in

patients with AF with dofetilide was doserelated; pharmacological reversion with doses

of 125, 250, and 500 lg BID occurred in 6%,

11%, and 29%, respectively, compared with 5%

with sotalol.

In the Symptomatic Atrial Fibrillation Inves-

tigative Research on Dofetilide (SAFIRE-D)

study, 325 patients with persistent AF, 67%

with structural heart disease, and 40% withcardiac insufficiency were allocated to receive

1 of 3 doses of dofetilide (125, 250, and 500 lg

twice daily) or placebo.83 By day 3, sinus rhythm

was obtained in 32% of the patients on dofetilide

vs 1% of those on placebo ( P b .001).

A placebo-controlled trial evaluated the safety

and efficacy of a single bolus of intravenous

dofetilide (4 or 8 lg/kg) for the termination ofsustained AF or flutter in 91 patients.84 Dofe-

tilide terminated the arrhythmia in 31% of

patients receiving 8 lg/kg and 13% of those

receiving 4 lg/kg, compared with no conver-

sion with placebo ( P b .01). Although the

number of patients with atrial flutter was small,

this group had a greater response to dofetilide

than those with AF (54% vs 15%, P b .001).

Another controlled trial of 96 patients found

that intravenous dofetilide (8 lg/kg) was more

effective than placebo for the reversion of AF(24% vs 4%) and flutter (64% vs 0%).85 Torsade

de pointes occurred in 3% of patients receiving

dofetilide. In a third controlled trial of 98

patients with AF after coronary artery bypass

surgery, the reversion rate with intravenous

dofetilide at a dose of 4 and 8 lg/kg was not

significantly different from placebo (36%, 44%,

and 24%, respectively).86

In conclusion, intravenous dofetilide is cur-

rently not available in the United States for

cardioversion. Oral dofetilide is effective in

converting persistent AF or flutter and in

maintaining sinus rhythm thereafter. It has no

adverse effect on survival even in patients with

cardiac insufficiency or previous myocardial

infarction. The only serious drawback is torsade

de pointes that generally occur within 30 to 50

minutes from the start of intravenous infusion,

and within the first 3 days of oral therapy. The

risk of developing this tachyarrhythmia seems

higher in women (by three- to fourfold), in

patients with heart failure, and in those with

impaired renal function. Dose adjustment based

on renal function and monitoring of QT interval

during the first days of therapy are critical to

reduce this risk.87 Therapy must, thus, be

initiated during a strict in-hospital observation

for 3 days.

Quinidine

Quinidine, a class IA antiarrhythmic agent, hasbeen commercially available in the United

States for many years for the treatment of

supraventricular and ventricular arrhythmias.

Quinidine, given in a cumulative dose of up

to 1000 to 1200 mg, has been shown to

cardiovert 60% to 80% of patients with recent-

onset AF. It was more effective than sotalol, and

in some studies, it was as effective as intrave-nous amiodarone for conversion of persistent

AF (47%). The effect usually occurs within

12 hours of treatment. To reduce the risk of

1:1 AV conduction during organization of AF

into flutter, quinidine should be administered

in conjunction with AV node blocking agents,

such as b-blockers or nondihydropyridine cal-

cium antagonists. The combination of quinidine


and digoxin is not recommended, because it is

associated with lower conversion rate. Because

of its poor safety tolerance profile, quinidine isnot used enthusiastically for acute cardioversion

of atrial tachyarrhythmias.

New Agents for Pharmacological Cardioversion

Azimilide

Azimilide is a new agent that has not yet been

approved by the Food and Drug Administration.

It blocks both the rapid (IKr) and slow (IKs)

components of the delayed rectifier potassium

current. This means that the drug has little or no

reverse use dependency, the implication beingthat it possesses antiarrhythmic activity even at

faster heart rates. Several clinical studies have

demonstrated the safety and efficacy of azimilide

in the management of ventricular as well as

supraventricular arrhythmias.

Azimilide was compared to placebo in the

Azimilide Postinfarction Survival Evaluation

(ALIVE) trial.88 Compared to placebo, azimilidewas significantly better at converting baseline AF

to normal sinus rhythm. Azimilide was also

better in preventing AF throughout the study.

Pritchett et al89 assessed effectiveness of

azimilide at 3 different doses of 50, 100, and

125 mg and compared them to placebo in

patients with symptomatic AF. A total of

384 patients with a history of AF, flutter, orboth were randomly assigned to receive once

daily doses of placebo or azimilide; recurrent

symptomatic arrhythmias were documented

using transtelephonic ECG recording. Higher

doses of azimilide (100 and 125 mg) were

associated with better efficacy in the compar-

ison of individual dose groups with the

placebo group measured during the efficacyperiod. This randomized clinical trial demon-

strated that azimilide is an effective AAD to

reduce the frequency of symptomatic arrhyth-

mia recurrences in patients with AF, flutter, or

both, and it demonstrated the effective dose

range for azimilide.

Tedisamil

Tedisamil is a bradycardic and antianginal agent

possessing Vaughan Williams class III antiar-

rhythmic activity and has been reported to block

several potassium currents including the delayed

rectifier current (IK),90,91 the calcium-activated

potassium current (IK,Ca),92,93 the adenosinetriphosphate (ATP)–gated potassium channel

(IK,ATP),94,95 as well as the transient outward

current (Ito).100 -103 In addition, at higher con-

centrations, tedisamil inhibits the rapid inward

sodium current (INa),96 as well as the chloride

channel (ICl).97 After extensive experimental

studies with this compound, tedisamil is cur-

rently being investigated for acute termination of

AF and flutter.98,99

Trecetilide

Trecetilide, a congener of ibutilide, is being

evaluated in both intravenous and oral prepara-

tions for the termination and prevention of AFand flutter. In addition to blocking IKr, it seems

to prolong repolarization through other mecha-

nisms that are still being delineated.100,101 It also

significantly prolongs the action potential in

animals and repolarization in humans without

exerting other electrophysiological effects.111 -113

Ambasilide

Ambasilide (LU 47110) is a new class III AAD

with a unique profile of action in mammals. It

is reported to be a nonselective blocker of both

components of the delayed rectifier of potassi-

um current, and of several other repolarizingpotassium currents including Ito, Icur, IKach, and

IK.102 Ambasilide has been shown to block fast

sodium channels at high rates with rapid offset

kinetics. In a canine model of AF, ambisilide

and dl-sotalol were compared for efficacy.

Ambisilide terminated the arrhythmia in 100%

of cases and prevented its induction in 83%. By

contrast, sotalol interrupted AF in 12% ofanimals and prevented its induction in none

of them. This drug has recently entered phase

III trials.

Dronaderone

Dronedarone is an experimental agent that

has multiple electrophysiological actions, inclu-

ding all 4 Vaughan Williams class effects.103 It has

a similar structure to amiodarone; however, it

does not have the iodine moiety of amiodarone;

therefore, there may have lesser side effects. It has


been shown to have antiadrenergic effects104,105

and to prolong atrial and ventricular refractory

periods, atrioventricular node conduction, and

the paced QRS complex106; these effects are

consistent with class I drug-induced slowing of

ventricular conduction.

RSD1235

RSD1235, a novel compound, is a mixed fre-

quency-dependent Na+ and atria-preferential

K+ channel blocker. Its properties exhibitelectrophysiological specificity for atrial tissue

in therapeutically relevant doses.107 It acts by

blocking repolarizing ion channels (Ito, IKur) and

the frequency-dependent cardiac INa channel at

high concentrations and is associated with

increases in the APD and ERP in atrial myo-

cardium, seemingly independent of cardiac

frequency. The drug does not block IKr inventricular tissue; hence, there is no increase

in the QT interval. It is a prototype of an atrial-

specific compound. In animal models of AF,

RSD1235 is effective in terminating and pre-

venting relapse of AF. In several preclinical

studies, RSD1235 has been shown to selectively

prolong atrial refractory periods without signif-

icant effects on ventricular refractoriness or QTintervals.108 Recently, a phase II dose-finding

study demonstrated that the upper dose of

RSD1235 (2 + 3 mg/kg) rapidly and effectively

terminated AF compared with lower dose of

RSD1235 and placebo.109 RSD1235 appears to

be a potential alternative to existing chemical

and electrical cardioversion for rapid termina-

tion of AF.

Refractory Case Management

Fortunately, if one adheres to appropriate tech-

nique, especially with the use of biphasic wave-

forms, failure to cardiovert is uncommon.

Nevertheless, in rare patients in whom standardcardioversion is not successful, additional

options must be pursued. There are 2 potential

negative outcomes from cardioversion that are

important to recognize and distinguish. First,

there is shock failure, where no sinus beats are

identified. Second, there is IRAF and ERAF,

where sinus rhythm is restored, but AF recurs

anytime from the first minute (IRAF) to hours to

days (ERAF). Rossi et al reported an average of

16% incidence of recurrent AF within 1 minute

of cardioversion.110 Therefore, a continuousECG recording should be available during

cardioversion for careful inspection of the post-

cardioversion rhythm, because different strate-

gies are required for these 2 different negative

outcomes.

For overcoming shock failure, Saliba et al111

reported the rapid sequential use of 2 defibrilla-

tors with 720 J of total energy in a group ofpatients with large body habitus (mean weight

was 117 kg) who previously had failed to convert

with the standard technique. They used 2 sets of

patch electrodes in the anterior-posterior posi-

tion next to each other, and a single operator

delivered the energy simultaneously. By using

this technique, they successfully restored normal

sinus rhythm in 46 of 55 (84%) of thesepreviously refractory patients, with no signifi-

cant complications.

Drug-facilitated cardioversion, which is a

combination of pharmacological therapy for

atrial remodeling along with electrical cardio-

version, has been shown to be effective in

refractory cases. This is discussed in detail in

an earlier section.Internal cardioversion can also be an effective

alternative for highly resistant cases of AF. Other

than its role in patients already undergoing

electrophysiologic study, internal cardioversion

appears to be most useful in individuals refrac-

tory to standard transthoracic cardioversion. In a

study of 55 patients with AF refractory to

external cardioversion, Gasparini et al112

reported successful internal cardioversion in

95% of these subjects without complications.

Although 31% suffered recurrence of AF within

1 week, 40% of the population remained in sinus

rhythm after a mean follow-up of 18 months.

Similarly, reports have demonstrated an effective

role for internal cardioversion in extremely

obese patients.Higher energy direct current shock applica-

tion using a double external defibrillator is an

effective and safe method for the cardioversion of

refractory AF. Kabukca et al113 showed that this

method restored sinus rhythm in patients with

concomitant structural heart disease, even

though single maximum strength external defi-

brillator had failed to restore sinus rhythm. This


technique should be performed before internal

atrial cardioversion.

Anticoagulation for Cardioversionin AF

In patients who undergo cardioversion without

receiving anticoagulation, the risk of embolic

events has been reported to be as high as 6%.

This is likely the result of postcardioversion

atrial stunning, which is a delay in resumption

of atrial mechanical function despite organizedelectrical activity. It is, therefore, general

practice that patients receive anticoagulation

for at least 3 weeks before cardioversion and

continue it for 4 weeks postprocedure, unless

the arrhythmia duration is known to be less

than 48 hours.114 Such a strategy decreases the

overall risk of stroke to less than 1% (range,

0.5% to 0.8%). When transesophageal echocar-diography is used to guide cardioversion, the

risk is similarly low, provided that anticoagu-

lation is maintained during the cardioversion

and at least 4 weeks afterward.115

Special Circumstances

Cardioversion in Pregnancy

Electrical cardioversion is safe during pregnan-

cy.116 Numerous reports have suggested that

even repeat shocks (up to 400 J) have been safe

in pregnancy. It appears to be safe becauseamount of energy reaching the fetus is small

and because the small fetal heart has a high VF

threshold.117 Isolated instances of fetal distress

have been reported; hence, close fetal monitor-

ing is recommended. Chemical cardioversion is

the less preferred alternative to electrical

cardioversion because of the inherent risks to

the fetus.118

Cardioversion in the Pediatric Population

Atrial tachyarrhythmias are unusual in theyoung, other than in the situations after cardiac

surgery/cardiac transplantation for congenital

heart diseases. Guidelines for electrical cardio-

version in the pediatric population are similar to

adults. It is recommended to start initial cardi-

oversion with lower energies.119

Risks and Complications

Electrical Cardioversion

The risks of electrical cardioversion are mainly

related to embolic events and cardiac arrhythmias.

Embolism

Thromboembolic events have been reported in

between 1% and 7% of patients who did not

receive prophylactic anticoagulation before car-

dioversion of AF.120,121 Prophylactic antithrom-

botic therapy is discussed above.

Arrhythmias

Various benign arrhythmias may arise after

cardioversion of AF, which commonly subside

spontaneously, especially ventricular and sup-

raventricular premature beats, bradycardia, and

short periods of sinus arrest.122 Electrolyte

imbalances or digitalis intoxication may precip-itate other dangerous arrhythmias, such as

ventricular tachycardia and fibrillation.123,124

Cardioversion is contraindicated in cases if

digitalis toxicity because the ventricular

tachyarrythmias that are provoked may be

difficult to terminate. Digitalis need not be

discontinued before cardioversion since, a se-

rum digitalis level in the therapeutic range doesnot exclude clinical toxicity but, may not

precipitate malignant ventricular arrhythmias

during cardioversion.125

In some instances (for example, long stand-

ing AF), cardioversion unmasks underlying

sinus node dysfunction, which could be her-

alded by a slow ventricular response in the

absence of drugs. The patient should beevaluated before cardioversion with these issues

in mind to avoid symptomatic bradycardia.126

When sinus rate is extremely slow or there is

evidence of high grade atrioventricular block, a

transvenous or transcutaneous pacemaker may

be needed temporarily.

Myocardial Injury

There is a wide margin of safety between the

energy required for cardioversion of AF and that

associated with clinically relevant myocardial

depression.127,128 However, transient ST-segment


elevation without clinical symptoms, may appear

on the ECG after cardioversion129,130 and blood

levels of creatine kinase may rise. In a study of72 elective cardioversion attempts involving an

average energy greater than 400 J (range, 50 to

1280 J), serum troponin-T and -I levels did not

rise significantly. There was a small increase in

creatine kinase-MB mass levels above the propor-

tion attributable to skeletal muscle trauma in 10%

of patients, and this was related to the energy

delivered.130 Direct-current cardioversion doesnot cause clinically significant myocardial damage.

Dermal Injury

Skin injury is common and usually outlines theborders of the defibrillation electrodes. Pagan-

Carlo et al131 described the nature of these

lesions, often referred to as burns. They

performed biopsies on 30 patients who suffered

thermal injury after elective cardioversion of AF

and flutter and compared them to biopsies

obtained from 2 healthy subjects. They demon-

strated variable degrees of epidermal necrosisand confirmed the lesions to be consistent with

first-degree burns, although they also found

variable numbers of neutrophils and eosino-

phils, suggesting a possible hypersensitivity

reaction component. Page et al132 reported

a reduction in the incidence of symptomatic

skin burns by more than half with the use of

biphasic defibrillators compared with mono-phasic defibrillators.

Internal Cardioversion

Internal cardioversion is not without limitation.The invasive nature of the procedure, require-

ment for fluoroscopic guidance of catheter

placement, and the prolonged postprocedure

observation make the approach substantially

more expensive than standard external cardio-

version. Furthermore, anticoagulation must be

terminated before the procedure, necessitating

the use of heparin in the periprocedure period tolimit the risk of periconversion stroke. Finally,

Verdino et al133 observed that of 20 patients

referred for internal cardioversion, 16 were

converted to sinus rhythm successfully with an

additional attempt at external cardioversion

employing careful electrode placement and the

use of significant chest wall pressure, suggesting

that internal cardioversion is needed for only a

small minority of patients.

References

1. Joglar AJ, Schwarzberg RJ: EP lab Digest 3:1-3,

2003

2. Wyse DG, Waldo AL, DiMarco JP, et al: A comparison

of rate control and rhythm control in patients withatrial fibrillation. N Engl J Med 347:18525-18533,

2002

3. Carl L, et al: Enige neue Versuche uber Herzbewe-

gung. Zeitschrift Rationelle Medizin 9:107-144, 18504. Fye WB: Ventricular fibrillation and defibrillation:

Historical perspectives with emphasis on the con-

tributions of John McWilliam, Carl Wiggers andWilliam K. Circulation 71:858-865, 1985

5. Prevost JL, Batelli F, et al: La Mort Par Les

Descharges Electriques. J Physiol 1085-1100, 1899

6. Borys S: Brief history of cardiac arrhythmias sincethe end of the nineteenth century. J Cardiovasc

Electrophysiol 15:101-104, 2004

7. Beck CS, et al: Ventricular defibrillation of long

duration abolished by electrical shock. JAMA 135:985-988, 1947

8. Berndt L, et al: Historical perspectives on interven-

tional electrophysiology. J Interv Card Electrophy-

siol 9:75-83, 20039. Lown B, et al: Cardioversion of atrial fibrillation.

N Engl J Med 269:325-331, 1963

10. Lown B, Amarasingham R, Neuman J, et al: Newmethod for treating cardiac arrhythmias; Use of

synchronized capacitor discharge. JAMA 182:

548-555, 1962

11. Alexander S: The new era of cardioversion. JAMA256:628-629, 1986

12. Silverman ME: History and personal observations of

electrical cardioversion of atrial fibrillation. Am J

Cardiol 94:751-752, 200413. Hou CJ, Chang-Sing P, Flynn E, et al: Determination

of ventricular vulnerable period and ventricular

fibrillation threshold by use of T-wave shocks inpatients undergoing implantation of cardioverter/

defibrillators. Circulation 92:2558-2564, 1995

14. Mower MM, Mirowski M, Spear JF, et al: Patterns of

ventricular activity during catheter defibrillation.Circulation 49:858-861, 1974

15. Zipes DP, Fischer J, King RM: Termination of

ventricular fibrillation in dogs by depolarizing a

critical amount of myocardium. Am J Cardiol36:37-44, 1975

16. Witkowski FX, Penkoske PA, Plonsey R: Mecha-

nism of cardiac defibrillation in open-chest dogs

with unipolar DC-coupled simultaneous activationand shock potential recordings. Circulation 82:

244-260, 1990

17. Chen PS, Fischer J, King RM, et al: Mechanism ofcardiac defibrillation: A different point of view.

Circulation 84:913, 1991


18. Witkowski FX, Kerber RE: Currently known mecha-nisms underlying direct current external and internal

cardiac defibrillation. J Cardiovasc Electrophysiol

2:562, 1991

19. Chen PS, Wolf PD, Ideker RE: Mechanism of cardiacdefibrillation: A different point of view. Circulation

84:913-919, 1991

20. Chen PS, Shibata N, Dixon EG, et al: Compar-

ison of the defibrillation threshold and the upperlimit of ventricular vulnerability. Circulation 73:

1022-1028, 1986

21. Huang J, KenKnight BH, Walcott GP, et al: Effectsof transvenous electrode polarity and waveform

duration on the relationship between defibrillation

threshold and upper limit of vulnerability. Circula-

tion 96:1351-1359, 199722. Mittal S, Ayati S, Stein KM, et al: Transthoracic

cardioversion of atrial fibrillation. Comparison of

rectilinear biphasic versus damped sine wave mono-

phasic shocks. Circulation 101:1282-1287, 200023. Dalzell GW, Cunningham SR, Anderson, et al:

Electrode pad size, transthoracic impedance and

success of external ventricular defibrillation.

Am J Cardiol 64:741-744, 198924. Connell PN, Ewy GA, Dahl CF, et al: Transthoracic

impedance to defibrillator discharge: Effect of

electrode size and electrode-chest wall interface.J Electrocardiol 6:313-316, 1973

25. Lown B, et al: Cardioversion of atrial fibrillation: A

report on the treatment of 65 episodes in 50 patients.

N Engl J Med 269:325-331, 196326. Botto GL, Politi A, Bonini W, et al: External

cardioversion of atrial fibrillation: Role of paddle

position on technical efficacy and energy require-

ments. Heart 82:726-730, 199927. Dahl CF, Ewy GA, Warner ED, et al: Myocardial

necrosis from direct current countershock: Effect

of paddle electrode size and time intervalbetween discharges. Circulation 50:956 - 961,

1974

28. Jose AJ, Joglar MD, Robert CK: Electricalcardioversion of atrial fibrillation. Cardiol Clin 22:

314-317, 2004

29. Jones J, Swartz J, Jones RE, et al: Increasingfibrillation duration enhances relative asymmetrical

biphasic versus monophasic defibrillator waveform

efficacy. Circ Res 67:376-384, 1990

30. Fain E, Sweeney MB, Franz MR: Improved internaldefibrillation efficacy with a biphasic waveform.

Am Heart J 117:358-364, 1989

31. Wyse DG, Wyse DG, Kavanagh KM, et al: Compar-

ison of biphasic and monophasic shocks for defi-bril lation using a nonthoracotomy system.

Am Cardiol 71:197-202, 1993

32. Takata TS, Page RL, Joglar JA: Automated externaldefibrillators: Technical considerations and clinical

promise. Ann Intern Med 135:990-998, 2001

33. Ricard P, Levy S, Trigano J, et al: Prospective

assessment of the minimum energy needed forexternal electrical cardioversion of atrial fibrillation.

Am J Cardiol 79:815-816, 1997

34. Joglar JA, Hamdan MH, Ramaswamy KR, et al:Initial energy for elective external cardioversion

of persistent atrial fibrillation. Am J Cardiol 86:

348-350, 2000

35. Pinski SL, Sgarbossa EB, Ching E, et al: Acomparison of 50 J versus 100 J shocks for direct

current cardioversion of atrial flutter. Am Heart J

137:439-442, 1999

36. Lesser MF: Safety and efficacy of in-office cardio-

version for treatment of supraventricular arrhyth-

mias. Am J Cardiol 66:1267-1268, 1990

37. Van Gelder IC, Crijns HJ, Van Gilst WH, et al:

Prediction of uneventful cardioversion and mainte-

nance of sinus rhythm from direct-current electrical

cardioversion of chronic atrial fibrillation and flutter.Am J Cardiol 68:41-46, 1991

38. Sodermark T, Jonsson B, Olsson A, et al: Effect of

quinidine on maintaining sinus rhythm after conver-sion of atrial fibrillation or flutter: A multicentre study

from Stockholm. Br Heart J 37:486-492, 1975

39. Stephanos S, Jung J, Buob A, et al: Incidence and

management of early recurrent atrial fibrillation(ERAF) after transthoracic electrical cardioversion.

Europace 6:15-20, 2004

40. Chugh A, Ozaydin M, Scharf C, et al: Mechanism of

immediate recurrences of atrial fibrillation afterrestoration of sinus rhythm. Pacing Clin Electro-

physiol 1:77-78, 2004

41. Schwartzman D, Musley SK, Swerdlow C, et al:Early recurrence of atrial fibrillation after am-

bulatory shock conversion. J Am Coll Cardiol 3:

93-99, 2002

42. Frick M, Frykman V, Jensen-Urstad M, et al: Factorspredicting success rate and recurrence of atrial

fibrillation after first electrical cardioversion in

patients with persistent atrial fibrillation. Clin Cardiol

3:238-244, 200143. Levy S, Lacombe P, Cointe R, et al: High energy

transcatheter cardioversion of chronic atrial fibrilla-

tion. J Am Coll Cardiol 12:514-518, 198844. Levy S, Lauribe P, Dolla E, et al: A randomized

comparison of external and internal cardiover-

sion of chronic atrial fibrillation. Circulation 86:

1415-1420, 199245. Murgatroyd FD, Slade AK, Sopher SM, et al:

Efficacy and tolerability of transvenous low energy

cardioversion of paroxysmal atrial fibrillation in

humans. J Am Coll Cardiol 25:1347-1353, 199546. Alt E, Schmitt C, Ammer R, et al: Initial experience

with intracardiac atrial defibrillation in patients with

chronic atrial fibrillation. Pacing Clin Electrophysiol

17:1067-1078, 199447. Burns JL, Sears SF, Sotile R, et al: Do patients

accept implantable atrial defibrillation therapy?

Results from the Patient Atrial Shock Survey ofAcceptance and Tolerance (PASSAT) Study.

J Cardiovasc Electrophysiol 15:286-291, 2004

48. Gold MR, Sulke N, Schwartzman DS, et al: Clinical

experience with a dual-chamber implantable cardi-overter defibrillator to treat atrial tachyarrhythmias.

J Cardiovasc Electrophysiol 12:1247-1253, 2001


49. Khaddaha R, Narula DD, Fefer F, et al: Atrialdefibrillation using the conventional implantable

cardioverter defibrillator. J Am Coll Cardiol 33:

146A, 1999

50. Lukoshevichiute AI: Use of esophageal electriccountershock. Kardiologiia 18:12-20, 1978

51. Moe G: On the multiple wavelet hypothesis of

atrial fibrillation. Arch Int Pharmacodyn Ther 140:

183-188, 196252. Allessie MA, Lammers WJ, Bonke FI, et al: Exper-

imental evaluation of Moe’s multiple wavelet hy-

pothesis of AF. Cardiac arrhythmias. Grune andStratton, 1985, pp 265-270

53. Allessie MA, Bonke FI, Schopman FJ: Circus

movement in rabbit atrial muscle as a mechanism

of tachycardia. III. The bleading circleQ concept: Anew model of circus movement in cardiac tissue

without the involvement of an anatomical obstacle.

Circ Res 41:9-18, 1977

54. Rensma PL, Allessie MA, Lammers WJ, et al: Lengthof excitation wave and susceptibility to reentrant

atrial arrhythmias in normal conscious dogs. Circ

Res 62:395-410, 1988

55. Yue L, Feng J, Gaspo R, et al: Ionic remodelingunderlying action potential changes in a canine

model of atrial fibrillation. Circ Res 81:512-525, 1997

56. Bosch RF, Scherer CR, Rub N, et al: Molecularmechanisms of early electrical remodeling: Tran-

scriptional down regulation of ion channel subunits

reduces I(Ca,L) and I(to) in rapid atrial pacing in

rabbits. J Am Coll Cardiol 41:858-869, 200357. Nattel S, et al: New ideas about atrial fibrillation 50

years on. Nature 415:219-226, 2002

58. Ehrlich J, Kowey P, Nacarelli A, et al: Pharmacological

cardioversion of atrial fibrillation. 182, 2005 (chap 9)59. Echt DS, Liebson PR, Mitchell LB, et al: Mortality

and morbidity in patients receiving encainide, fle-

cainide, or placebo. The cardiac arrhythmia sup-pression trial. N Engl J Med 324:781-788, 1991

60. Coplen SE, Antman EM, Berlin JA, et al: Efficacy

and safety of quinidine therapy for maintenance

of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation

82:1106-1116, 1990

61. Reisinger J, Gatterer E, Heinze G, et al: Prospective

comparison of flecainide versus sotalol for immedi-ate cardioversion of atrial fibrillation. Am J Cardiol

81:1450-1454, 1998

62. Suttorp MJ, Kingma JH, Lie-A-Huen L, et al: Intra-venous flecainide versus verapamil for acute con-

version of paroxysmal atrial fibrillation or flutter to

sinus rhythm. Am J Cardiol 63:693-696, 1989

63. Jalife J, Berenfeld O, Mansour M: Mother rotors andfibrillatory conduction: A mechanism of atrial fibril-

lation. Cardiovasc Res 54:204-216, 2002

64. Kneller J, Leon J, Nattel S: How do class I anti-

arrhythmic drugs terminate atrial fibrillation? A quan-titative analysis based on a realistic ionic model.

Circulation 104:ab5, 2001

65. Kawase A, Takanori I, Kazuo N, et al: Widening of

the excitable gap and enlargement of the core of

reentry during atrial fibrillation with a pure sodiumchannel blocker in canine atria. Circulation 107:

905-910, 2003

66. Vos MA, Golitsyn SR, Stangl K, et al: Superiority of

ibutilide (a new class III agent) over DL-sotalol inconverting atrial flutter and atrial fibrillation. Heart

79:568-575, 1998

67. Ellenbogen KA, Stambler BS, Wood MA, et al:

Efficacy of intravenous ibutilide for rapid terminationof atrial fibrillation and atrial flutter: A dose-response

study. J Am Coll Cardiol 28:130-136, 1996

68. Stambler BS, Wood MA, Ellenbogen KA, et al:Efficacy and safety of repeated intravenous doses

of ibutilide for rapid conversion of atrial flutter or

fibrillation. Circulation 94:1613-1621, 1996

69. Stambler BS, Wood MA, Ellenbogen KA: Antiar-rhythmic actions of intravenous ibutilide com-

pared with procainamide during human atrial

flutter and fibrillation: Electrophysiologic determi-

nants of enhanced conversion efficacy. Circulation96:4298-4300, 1997

70. Volgman AS, Carberry PA, Stambler B, et al:

Conversion efficacy and safety of intravenous

ibutilide compared with intravenous procainamidein patients with atrial flutter or fibrillation. J Am Coll

Cardiol 31:1414-1418, 1998

71. Oral H, Souza JJ, Michaud GF, et al: Facilitatingtransthoracic cardioversion of atrial fibrillation

with ibutilide pretreatment. N Engl J Med 340:

1849-1852, 1999

72. Galve E, Rius T, Ballester R, et al: Intravenousamiodarone in treatment of recent-onset atrial

fibrillation: Results of a randomized, controlled

study. J Am Coll Cardiol 27:1079-1082, 1996

73. Chevalier P, Durand-Dubief A, Burri H, et al: Amio-darone versus placebo and classic drugs for

cardioversion of recent-onset atrial fibrillation: A

meta-analysis. J Am Coll Cardiol 41:255-262, 200374. Alp NJ, Bell JA, Shahi M: Randomised double blind

trial of oral versus intravenous flecainide for the

cardioversion of acute atrial fibrillation. Heart

84:37-40, 200075. Lie-A-Huen L, Proost JH, Kingma JH, et al: Absorp-

tion kinetics of oral and rectal flecainide in healthy

subjects. Eur J Clin Pharmacol 38:595-598, 1990

76. Hage K, Buhl K, Fischer C, et al: Estimation ofthe absolute bioavailability of flecainide using

stable isotope technique. Eur J Clin Pharmacol

48:51-55, 199577. Khan IA, Khan IA, Mehta NJ, et al: Single oral

loading dose of propafenone for pharmacological

cardioversion of recent-onset atrial fibrillation. J Am

Coll Cardiol 37:542-547, 200178. Alboni P, Botto GL, Baldi N, et al: Outpatient

treatment of recent-onset atrial fibrillation with the

bpill-in-the-pocketQ approach. N Engl J Med

351:2384-2391, 200479. Greenbaum R, Campbell TJ, Charmer KS, et al:

Conversion of atrial fibrillation and Maintenance of

sinus rhythm by dofetilide. The EMERALD study.

Circulation 98:I -633, 1998


80. Torp-Pedersen C, Moller M, Bloch-Thomsen PE,et al: Dofetilide in patients with congestive heart

failure and left ventricular dysfunction. Danish Inves-

tigations of Arrhythmia and Mortality on Dofetilide

Study Group. N Engl J Med 341:857-865, 199981. Singh S, et al: Efficacy and safety of oral dofetilide in

converting to and maintaining sinus rhythm in

patients with chronic atrial fibrillation or atrial flutter:

The Symptomatic Atrial Fibrillation InvestigativeResearch on Dofetilide (SAFIRE-D) study. Circula-

tion 102:2385-2390, 2000

82. Greenbaum R, et al: Conversion of atrial fibrillationand Maintenance of sinus rhythm by dofetilide.

Circulation 98:I-633, 1998 (Suppl I)

83. Singh S, Zoble RG, Yellen L, et al: Efficacy and

safety of oral dofetilide in converting to andmaintaining sinus rhythm in patients with chron-

ic atrial fibrillation or atrial flutter: The Symp-

tomatic Atrial Fibrillation Investigative Research

on Dofetilide (SAFIRE-D) study. Circulation 102:2385-2390, 2000

84. Falk RH, Pollak A, Singh SN, et al: Intravenous

dofetilide, a class III antiarrhythmic agent, for the

termination of sustained atrial fibrillation or flutter.Intravenous dofetilide investigators. J Am Coll

Cardiol 29:385-390, 1997

85. Norgaard BL, Wachtell K, Christensen PD, et al:Efficacy and safety of intravenously administered

dofetilide in acute termination of atrial fibrillation

and flutter: A multicenter, randomized, double-

blind, placebo-controlled trial. Am Heart J 137:1062-1069, 1999

86. Frost L, Mortensen PE, Tingleff J, et al: Efficacy and

safety of dofetilide, a new class III antiarrhythmic

agent, in acute termination of atrial fibrillation orflutter after coronary artery bypass surgery. Int J

Cardiol 58:135-140, 1997

87. Pratt CM, Ruskin JN, Friedrieck T: Dofetilide usein atrial fibrillation: A treatment strategy to mini-

mize proarrhythmic risk. J Am Coll Cardiol 35:

154A, 2000 (Suppl A)

88. Pratt CM, Singh SN, Al-Khalidi HR, et al: Theefficacy of azimilide in the treatment of atrial

fibrillation in the presence of left ventricular systolic

dysfunction. J Am Coll Cardiol 43:1211-1216, 2004

89. Pritchett EL, Page RL, Connolly SJ, et al: Antiar-rhythmic effects of azimilide in atrial fibrillation:

Efficacy and dose-response. Azimilide Supraven-

tricular Arrhythmia Program 3 (SVA-3) Investigators.J Am Coll Cardiol 36:794-802, 2000

90. Dukes ID, Cleemann L, Morad M: Tedisamil blocks

the transient and delayed rectifier K+ currents in

mammalian cardiac and glial cells. J Pharmacol ExpTher 254:560-569, 1990

91. Pfrunder D, Kreye VA: Tedisamil inhibits the

delayed rectifier K+ current in single smooth

muscle cells of the guinea-pig portal vein. PflugersArch 421:22-25, 1992

92. McLarnon JG, et al: Tedisamil blocks a calcium-

dependent potassium channel in cultured moto-

neurons. Neurosci Lett 144:185-188, 1992

93. Pfrunder D, Kreye VA: Tedisamil blocks singlelarge-conductance Ca(2+)-activated K+ channels

in membrane patches from smooth muscle cells

of the guinea-pig portal vein. Pflugers Arch 418:

308-402, 199194. Faivre J, Rouanet S, Bril A: Tedisamil inhibition of

ATP-sensitive K+ channels in adult rat ventricular

cells. J Mol Cell Cardiol 24:S40, 1992

95. Chi L, Park JL, Friedrichs GS, et al: Effects oftedisamil (KC-8857) on cardiac electrophysiology

and ventricular fibrillation in the rabbit isolated heart.

Br J Pharmacol 117:1261-1269, 199696. Dukes ID, Morad M: Tedisamil inactivates transient

outward K+ current in rat ventricular myocytes.

Am J Physiol 257:1746-1749, 1989

97. Faivre J, Rouanet S, Bril A: Comparative effects ofglibenclamide, tedisamil, dofetilide, E-4031 and

BRL-32872 on protein kinase A–activated chloride

current in guinea pig ventricular myocytes. J Car-

diovasc Pharmacol 31:551-557, 198898. Bargheer K, Bode F, Klein HU: Prolongation of

monophasic action potential duration and the re-

fractory period in the human heart by tedisamil, a

new potassium-blocking agent. Eur Heart J15:1409-1414, 1994

99. Wettwer E, Himmel HM, Amos GJ, et al: Mechanism

of block by tedisamil of transient outward current inhuman ventricular subepicardial myocytes. Br J

Pharmacol 125:659-666, 1998

100. Hester J, Gibson JK, Buchanan LV, et al:

Progress toward the development of a safeand effective agent for treating reentrant cardiac

arrhythmias: Synthesis and evaluation of ibutilide

analogues with enhanced metabolic stability and

diminished proarrhythmic potential. J Med Chem44:1099-1115, 2001

101. Buist S, Hsu CY, Walters RR: Sensitive determina-

tion of a new antiarrhythmic agent, trecetilide, inplasma by high-performance liquid chromatography

with fluorescence detection. J Chromatogr

828:259-265, 1998

102. Castro, Bianconi L, Santini M: New antiarrhythmicdrugs for the treatment of atrial fibrillation. Pacing

Clin Electrophysiol 25:249-259, 2002

103. Manning AS, Bruyninckx C, Ramboux J, et al: A

new amiodarone-like agent: Effect on ischemia andreperfusion induced arrhythmias in anesthetized

rats. J Cardiovasc Pharmacol 26:453-461, 1995

104. Chatelain P, Meysmans L, Matteazzi JR, et al:Interaction of the antiarrhythmic agents SR 33589

and amiodarone with the beta-adrenoceptor and

adenylate cyclase in rat heart. Brit J Pharmacol

116:1949-1956, 1995105. Hodeige D, Heyndrickx JP, Chatelain P, et al: A new

amiodarone like antiarrhythmic agent: Anti-adreno-

ceptor activity in anesthetized and conscious dogs.

Eur J Pharmacol 279:25-32, 1995106. Manning A, Thisse V, Hodeige D, et al: A new

amiodarone like antiarrhythmic agent: Electrophys-

iological effects in anesthetized dogs. J Cardiovasc

Pharmacol 25:252-261, 1995


107. Beatch GN, Lin SP, Hesketh JC, et al: Electrophys-iological mechanism of RSD1235, a new atrial

fibrillation converting drug. Circulation 108:IV85,

2002 (Suppl IV)

108. Beatch GN, Shinagawa K, Johnson B: RSD1235selectively prolongs atrial refractoriness and ter-

minates AF in dogs with electrically remodeled

atria. Pacing Clin Electrophysiol 25:698-699, 2002

109. Roy, Rowe BH, Stiell IG, et al: A randomized,controlled trial of RSD1235, a novel anti-arrhythmic

agent, in the treatment of recent onset atrial fibrilla-

tion. J Am Coll Cardiol 44:2355-2361, 2004110. Jose AJ, Richard LP: Early recurrence of atrial

fibrillation. J Cardiovasc Electrophysiol 15:898-900,

2004

111. Saliba W, Juratli N, Chung MK, et al: Higher energysynchronized external direct current cardioversion

for refractory atrial fibrillation. J Am Coll Cardiol

34:2031-2034, 1999

112. Gasparini G, Bonso A, Themistoclakis S, et al:Low-energy internal cardioversion in patients with

long-lasting atrial fibrillation refractory to external

electrical cardioversion: Results and long-term fol-

low-up. Europace 3:90-95, 2001113. Kabukca M, Demircioglu F, Yanik E, et al: Simulta-

neous double external DC shock technique for

refractory atrial fibrillation in concomitant heartdisease. Jpn Heart J 45:929-936, 2004

114. Van Gelder IC, Crijns HJ, Tieleman RG, et al:

Chronic atrial fibrillation: Success of serial cardio-

version therapy and safety of oral anticoagulation.Arch Intern Med 156:2585-2592, 1996

115. Fuster V, Ryden LE, Asinger RW, et al: ACC/AHA/

ESC Guidelines for the management of patients with

atrial fibrillation. J Am Coll Cardiol 38:1266-1299,2001

116. Barnes EJ, Eben F, Patterson D: Direct current

cardioversion during pregnancy should be per-formed with facilities available for fetal monitoring

and emergency caesarean section. BJOG 109:

1406-1407, 2002

117. Deborah W: Treatment of arrhythmias during preg-nancy. Curr Womens Health Rep 3:135-139, 2003

118. Sacchetti A, Moyer V, Baricella R, et al: Primary

cardiac arrhythmias in children. Pediatr Emerg Care

15:95-98, 1999119. Radford ADJ, Izukawa T: Atrial fibrillation in children.

Pediatrics 59:250-256, 1977

120. Bjerkelund CJ, Orning OM: The efficacy of antico-agulant therapy in preventing embolism related to

DC electrical conversion of atrial fibrillation. Am JCardiol 23:208-216, 1969

121. Arnold AZ, Mick MJ, Mazurek RP, et al: Role of

prophylactic anticoagulation for direct current car-

dioversion in patients with atrial fibrillation or atrialflutter. J Am Coll Cardiol 19:851-855, 1992

122. Rabbino MD, et al: Complications and limitations of

direct current countershock. JAMA 190:417-420,

1964123. Lown B, Likoff W, Dreifus LS: Cardioversion and

digitalis drugs: Changed threshold to electric shock

in digitalized animals. Circ Res 17:519-531, 1965124. Aberg H, Cullhed I: Direct current countershock

complications. Acta Med Scand 183:415-421, 1968

125. Ditchey RV, Karliner JS: Safety of electrical cardio-

version in patients without digitalis toxicity. AnnIntern Med 95:676-679, 1981

126. Mancini GB, Goldberger AL: Cardioversion of atrial

fibrillation: Consideration of embolization, anticoa-

gulation, prophylactic pacemaker, and long-termsuccess. Am Heart J 104:617-621, 1982

127. Lipkin DP, Frenneaux M, Stewart R, et al: Delayed

improvement in exercise capacity after cardiover-

sion of atrial fibrillation to sinus rhythm. Br Heart J59:572-577, 1988

128. Patton JN, Allen JD, Pantridge JF: The effects of

shock energy, propranolol, and verapamil on cardi-ac damage caused by transthoracic countercheck.

Circulation 69:357-368, 1984

129. Van Gelder IC, Crijns HJ, Van der LA, et al: Incidence

and clinical significance of ST segment elevationafter electrical cardioversion of atrial fibrillation and

atrial flutter. Am Heart J 121:51-56, 1991

130. Ehsani A, Ewy GA, Sobel BE: Effects of electri-

cal countershock on serum creatine phospho-kinase (CPK) isoenzyme activity. Am J Cardiol 37:

12-18, 1976

131. Pagan-Carlo, Stone MS, Kerber RE: Nature anddeterminants of skin burns after transthoracic car-

dioversion. Am J Cardiol 79:689-691, 1997

132. Page RL, Kerber RE, Russell JK, et al: Biphasic

versus monophasic shock waveform for conversionof atrial fibrillation: The results of an international

randomized, double-blind multicenter trial. J Am

Coll Cardiol 39:1956-1963, 2002

133. Verdino, Teuteberg JJ, Burke MC, et al: Successfulcardioversion of atrial fibrillation in-patients referred

to an electrophysiologist for internal cardioversion.

Clin Cardiol 24:500-502, 2001

Documents

Cardioversion of Atrial Fibrillation