IntroductionAtrial fibrillation is the most common sus-

tained cardiac arrhythmia. It is associated with adecrease in cardiac output with a fivefold in-creased risk of stroke and twofold increased mor-tality rate.1–4 Although the control of ventricularresponse is usually the first clinical concern, therestoration and maintenance of sinus rhythmwould be the optimal therapy of the arrhythmiaand could result in improved cardiac performanceand a reduced risk of thromboembolic complica-tions.

The only drugs available for restoring andmaintaining sinus rhythm have been Class IA an-tiarrhythmic agents (quinidine, procainamide,and disopyramide). Their use was limited by thefrequent occurrence of systemic side effects andtheir efficacy in maintaining sinus rhythm did notexceed 50% on a yearly basis.5 Moreover, theirsafety has been questioned since the long-termtreatment with quinidine was found to be associ-ated with an increased mortality compared toplacebo.6

Subsequently, other drugs pertaining toClasses IC and III have gradually gained accep-tance for the chronic prophylaxis of the arrhyth-mia since they were better tolerated (propafenoneand flecainide), more effective (amiodarone), andprobably safer (all of them) than Class IA agents.7

Moreover, a high success rate in acute conversionof the recent onset atrial fibrillation was achievedwith Class IC drugs.8–10

Nevertheless, the existing drugs were far frombeing ideal. Class IC drugs do not seem to be moreeffective than quinidine11 and have a depressanteffect on myocardial contractility and conduction,while amiodarone, which does not have the samedrawbacks, is burdened by a high incidence ofsystemic side effects when used long-term.12

In brief, it is clear that the safety and effec-tiveness of the current antiarrhythmic drugs arelargely suboptimal and that drugs more effectiveand, most important, devoid of systemic and car-diac untoward effects are strongly desirable.

The recent advances in understanding theelectrophysiological basis of the arrhythmia haveidentified the short atrial refractory period associ-ated with atrial fibrillation as the “vulnerable pa-rameter” of the arrhythmia.13 On this basis, in thelast decade, research has focused on the develop-ment of drugs specifically aimed at prolonging re-polarization (the so-called “pure” Class III effect).

A great deal of expectation was placed onthese new compounds because they emerged asbeing virtually devoid of undesirable effects oncardiac contractility, excitability, and conduc-tion,14,15 and this would allow their use even inpatients in whom other antiarrhythmic drugs areprecluded. The first of these novel compounds,ibutilide and dofetilide, are already clinicallyavailable and a number of other ones are goingthrough different stages of preclinical and clinicaldevelopment.

Class III Electrophysiological EffectMost clinical forms of atrial fibrillation are

due to multiple reentrant wavelets with a short ex-citable gap. Since a minimum of four to six reen-trant wavelets are required for the arrhythmia tobe maintained, any intervention decreasing thenumber of wavelets below that critical pointwould terminate the arrhythmia.16

Lengthening of repolarization (Class III effect)can be considered the optimal target for an an-tifibrillatory drug. In fact, the resultant prolonga-tion of the wavelength increases the atrial massnecessary for the reentry and consequently de-creases the number of reentrants circuits that canbe sustained in the atrium. This target can be ob-tained by blocking one or more of the several ionchannels involved in the process of repolariza-tion: the delayed rectifier potassium current, in itsrapid (IKr) or slow (IKs) components, the late in-ward potassium current (Ito), and the voltage-gatedinward rectifying potassium channel (Ik1). Thesame effect can be achieved by increasing the late

REVIEW

New Antiarrhythmic Drugs for the Treatment ofAtrial FibrillationANTONIO CASTRO, LEOPOLDO BIANCONI, and MASSIMO SANTINIFrom the Department of Heart Disease, S. Filippo Neri Hospital, Rome, Italy

PACE, Vol. 25, No. 2 February 2002 249

Address for reprints: Antonio Castro, M.D., Via Pinturicchio99, 00196 Rome, Italy. Fax: 00390633062489; e-mail: antonello.castro6tin.it

Received July 25, 2000; revised October 16, 2000; accepted Jan-uary 15, 2001.

Reprinted with permission fromJOURNAL OF PACING AND CLINICAL ELECTROPHYSIOLOGY , Volume 25, No. 2, February 2002

Copyright © 2002 by Futura Publishing Company, Inc., Armonk, NY 10504-0418.

inward sodium current (INa-s) or by activating thelong-lasting L-type calcium current (ICa(L)).

A peculiar property of several Class III agentsis the so-called “reverse-use dependence,”17

which means their effect is maximal at slow ratesand then progressively diminishes at faster rates.This phenomenon implies two drawbacks: it prob-ably limits the antiarrhythmic efficacy of theseagents during rapid arrhythmias and it predis-poses to the development of torsades de pointes.

The susceptibility to this arrhythmia seemsrelated to a marked dispersion of refractoriness atlow heart rates between the conduction system,where the lengthening of repolarization is maxi-mal, and the rest of the myocardium. This hetero-geneity induces abnormality in the terminal repo-larization (early afterdepolarization), thought tobe responsible for triggering torsades de pointesand to provide an ideal substrate for reentry,thereby promoting the maintenance of the ar-rhythmia.18

The cellular mechanism of reverse-use de-pendence is not completely understood. The mostimportant factor is probably the kinetics of thechannel block (fast or slow channel binding andunbinding rates). In fact, drugs with a rapid onsetof blocking activity may show maximal effectearly at physiological heart rates. By contrast,drugs with slow-onset kinetics would exert theireffect only when it is needed: during the high ac-tivation rates of tachyarrhythmias avoiding therisk of proarrhythmias at physiological heart rates.With offset kinetics the opposite is true; agentsthat unbind rapidly will reduce their blocking ef-fect at the end of a tachyarrhythmia with low sub-sequent risk of torsades de pointes.

Another possibility to explain the “reverse-use dependent effect” is based on the different ki-netics of the two components of the IK channel, IKrand IKs, since their relative contribution to repo-larization depends on cycle length. Experimentalstudies on animals19,20 have demonstrated that IKr

is able to reach steady state and shows maximal ef-fects at physiological heart rates, while IKs is stillincompletely activated. At rapid heart rates, theslowly activating IKs increases its effects and be-comes the major component of the delayed recti-fier potassium current. A drug blocking IKr would,therefore, exert a greater effect at low heart rateswhile the inverse should be the case of a drugblocking IKs.

The clinical experience with the two pureClass III antiarrhythmic agents presently avail-able, dofetilide and ibutilide, has demonstratedthat both agents, differently from Class IC antiar-rhythmic drugs, are more effective in terminatingatrial flutter than atrial fibrillation.21 This is incontrast with the theory of the Sicilian Gambit,

that forecasted a better performance of drugs pro-longing refractory periods in arrhythmias with ashort excitable gap, like atrial fibrillation, and ofdrugs prolonging conduction in arrhythmias witha long excitable gap, as atrial flutter.13 However,this theory is an oversimplification, given that theprevalent effect of a drug on a specific channel ismodified by other properties, one being its depen-dence on stimulation rate.19,20,22 Class 1C drugs,for example, at physiological rates affect only my-ocardial conduction, but due to their rate depen-dent activity at high rates exert a significant effecton the refractory period (postrepolarization refrac-toriness).17,23

In patients with atrial flutter, Guo et al.24 ob-served that ibutilide induces transient beat-to-beatchanges in action potential duration, refractori-ness, and diastolic interval and produces unstableoscillations in the reentrant circuit. These oscilla-tions would tend to close the excitable gap andchange the reentrant circuit from one with a fullyexcitable gap into one where the impulse propa-gates through a partially refractory tissue. Finally,with oscillations between two consecutive cyclelengths, the arriving reentrant impulse collideswith longer refractory isthmus tissues that havenot yet recovered, and therefore, block occurs.

Pure Class III Antiarrhythmic Drugs Acting on aSingle Channel

DofetilideDofetilide selectively inhibits the rapid com-

ponent of the delayed rectifier potassium current(IKr), thus prolonging action potential durationand effective refractory period, in the atria andventricles, without affecting conduction.25,26 Ithas a rapid onset and slow offset kinetics. In hu-mans, dofetilide has been shown to prolong theQT and corrected QT (QTc) intervals in a dose de-pendent way without any effect on PR or QRS in-tervals.27 A reverse use dependent effect has beenobserved, mainly at high plasma concentra-tions.28,29 Dofetilide has no negative inotropic ef-fects, even in patients with markedly reduced leftventricular function.30

Dofetilide is well absorbed with a bioavail-ability . 90% and an elimination half-life fromplasma of about 9 hours (range 7–13 hours).31 Al-most two thirds of the drug are excreted un-changed in the urine, and dose adjustment is nec-essary in patients with impaired renal function.

Eight placebo-controlled studies on its intra-venous use for termination of atrial fibrillation orflutter, including 360 patients, are available (TableI).32–39Overall, its efficacy in terminating the ar-rhythmias was 28% in atrial fibrillation and 66%in atrial flutter with a mean time to conversionvarying between 20 and 50 minutes from the be-

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ginning of infusion. Torsades de pointes appearedin 12 (4.2%) patients, and only one sustained caserequired electrical cardioversion.

In two comparative studies,37,39 dofetilidewas significantly more effective for conversion ofatrial fibrillation/flutter than amiodarone and pro-cainamide. Incomplete data are reported on the ef-fect of arrhythmia duration on the outcome oftherapy, but the drug is possibly more effective inarrhythmias of shorter duration.38

The efficacy and safety of oral dofetilide inpatients with chronic paroxysmal or persistentatrial fibrillation were examined in three double-blind, placebo-controlled multicenter studies(Table II).

In the symptomatic atrial fibrillation inves-tigative research on dofetilide (SAFIRE-D)study,40 325 patients with persistent atrial fibrilla-tion, 67% with structural heart disease and 40%with cardiac insufficiency, were allocated to re-ceive one of three doses of dofetilide (125, 250,

and 500 mcg twice daily) or placebo. By day 3, si-nus rhythm was obtained in 32% of the patientson dofetilide versus 1% of those on placebo (P ,0.001). The patients who did not convert wereelectrically cardioverted and those in whom sinusrhythm was obtained were followed for 1 year. Si-nus rhythm was still present at 6 months and 1year, respectively, in 62% and 58% of the patientstreated with the highest dose of the drug, and in36% and 25% of those on placebo (P , 0.005). Thedrug was well tolerated and the incidence of tor-sades de pointes was 0.6%.

In the European and Australian MulticenterEvaluation Research of Atrial FibrillationDofetilide (EMERALD) study,41 including 535 pa-tients with persistent atrial fibrillation or flutter,the same three doses of dofetilide (125, 250, and500 mcg twice daily) were randomly comparedwith sotalol 160 mg/bid and placebo. Dofetiliderestored sinus rhythm in more patients than so-talol in a dose dependent manner (up to 29% with

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PACE, Vol. 25, No. 2 February 2002 251

Table I.

Summary of the Results of the Published Trials of Intravenous Dofetilide in Atrial Fibrillation

ConvertedPatients/ Total (%)

Author, Year Dofetilide Atrial Atrial NSVT/Total TdP/Total DC ShockPublished Dosage Fibrillation Flutter (%) (%) (%)

Suttorp 199232 2.5–8 mcg/kg 10/19 (53) 4/5 (80) 0/24 (0) 0/24 (0) 0/24 (0)Crjins 199433 4–8 mcg/kg 7/10 (70) 0/10 (0) 0/10 (0) 0/10 (0)Sedgwick 199534 8–12 mcg/kg 4/15 (27) 0/15 (0) 2/15 (13.3) Not reportedFrost 199735 4–8 mcg/kg 26/65 (40) 3/65 (4.5)* 0/65 (0) 0/65 (0)Falk 199736 4–8 mcg/kg 7/50 (14) 6/11 (54) 2/61 (3.2) 2/61 (3.2) 0/61 (0)Bianconi 200037 8 mcg/kg 8/36 (22) 9/12 (75) 2/48 (4.2) 4/48 (8.3) 1/48 (2.1)Norgaard 19993 8 8 mcg/kg 13/55 (24) 7/11 (64) 2/67 (3) 0/67 (0)Green 19973 9 8 mcg/kg 15/53 (28) 4/8 (50) 2/61 (3.2) 4/61 (6.5)Total trials 83/293 (28) 38/57 (66) 9/284 (3.1) 12/284 (4.2) 1/208 (0.5)

* 3 patients had atrial flutter. NSVT 5 nonsustained ventricular tachycardia; TdP 5 torsades de pointes; DC shock 5 torsade depointes requiring direct current shock.

Table II.

Maintenance of Sinus Rhythm at 12 Months with Oral Dofetilide. Summary of Available Trials

Dofetilide N8/Total (%) Dosage

Studies, Year 125 mg 250 mg 500 mg Placebo Sotalol TdPPublished bid bid bid N8/Total (%) N8/Total (%) N8 (%)

EMERALD 19984 1 42/107 (40) 56/108 (52) 70/106 (66) 22/107 (21) 54/107 (49) 3 (0.75)DIAMOND CHF 199943 119/190 (62) 69/201 (34) Not reportedSAFIRE D 200040 24/60 (40) 23/61 (37) 35/61 (58) 17/68 (25) 3 (0.8)

TdP 5 torsades de pointes.

500 mg bid vs 6% with sotalol, P , 0.05). At 12months, the probability of maintaining sinusrhythm were, respectively, 40%, 52%, and 66%for the increasing doses of dofetilide and 21% inthe placebo group. However, dofetilide was signif-icantly better than sotalol only at a high dosage(500 mg bid). Three (0.75%) cases of torsades depointes (one requiring cardioversion) occurred ondofetilide within the first 3 days and one unex-pected death on day 5 was reported. However, theall-cause 1-year mortality for patients ondofetilide and placebo was similar, 1.5% and2.2%, respectively (RR 5 0.69, 95% confidenceinterval [CI]: 0.17–2.75).42

In the DIAMOND-CHF, a mortality study con-ducted on 1,510 patients with heart failure, pa-tients with atrial fibrillation at baseline (n 5 391)had more frequent spontaneous cardioversionwith dofetilide (12% at 1 month and 44% at 1year) than with placebo (respectively, 1% and13%) (P , 0.001). Once cardioversion had oc-curred by pharmacologic or electrical means, thelikelihood of sinus rhythm maintenance was sig-nificantly higher in the dofetilide group than inthe placebo group (62 vs 34% at 24 months, P ,0.01).43

In the overall population of the DIAMOND-CHF study, and in a second similar trial on 1,510patients with left ventricular dysfunction and re-cent myocardial infarction,44 mortality rates at 1-year follow-up were 27% and 22%, respectively,without any significant difference between thedofetilide and placebo arms. In the DIAMOND-CHF study, torsades de pointes were recorded in25 (3.3%) cases, mostly (76%) during the first 3days of treatment. Of these episodes, 15 requiredelectrical cardioversion and 2 resulted in death.43

In conclusion, intravenous dofetilide hasbeen shown to be highly effective in cardioversionof atrial flutter, while its efficacy for conversion ofatrial fibrillation is low. Oral dofetilide is effectivein converting persistent atrial fibrillation or flutterand in maintaining sinus rhythm thereafter. It hasno adverse effects on survival even in patientswith cardiac insufficiency or previous myocardialinfarction. The only serious drawback is torsadesde pointes, that generally occurs within 30–50minutes from the start of intravenous infusion,and within the first 3 days of oral therapy. The riskof developing this tachyarrhythmia seems higherin women (by three- to fourfold), in patients withheart failure, and in those with impaired renalfunction. Dose adjustment based on renal functionand monitoring of QT interval during the firstdays of therapy are critical to reduce this risk.45

Therapy must thus be initiated during a strict inhospital observation for 3 days. Dofetilide was re-cently approved for use in the United States for

prevention of atrial fibrillation recurrence aftercardioversion.

Other DrugsAlmokalant, sematilide, and E-4031, like

dofetilide, selectively block IKr with a rapid initialphase and a slow recovery.12 Studies in animalsand humans showed that all drugs prolong the QTinterval, the atrial, and the ventricular effective re-fractory periods, the latter in a reverse use depen-dent fashion.46–49

Intravenous almokalant in dogs producedmore delay and inhomogeneity in repolarizationthan D-sotalol, and was associated with a high in-cidence of torsades de pointes.50

In a recent prospective study,51 almokalant(total dose up to 25 6 4 mg) was infused in 100 pa-tients with long-standing atrial fibrillation/flutter.The conversion rate was 32% and the time to con-version was 3.5 6 2.2 hours. Four patients devel-oped torsades de pointes.

No clinical investigations concerning atrialfibrillation have been published on E-4031 and se-matilide.

Given the suboptimal safety profile of pure IKr

blockers and the recent introduction on the mar-ket of dofetilide (a close related drug), it seems un-likely that any of these drugs will undergo a moreadvanced phase of clinical investigation.

Pure Class III Antiarrhythmic Drugs Acting onMultiple Channels

Sotalol

Sotalol is a drug that has been available in Eu-rope for more than 20 years for intravenous andoral use. It has been recently approved in theUnited States, in the oral form, for the treatment ofatrial fibrillation.

This drug is a racemic mixture of D- and L-isomers, exerting nonselective beta-blocking andClass III antiarrhythmic activities.52–54 D- and L-isomers block IKr

55 with a reverse-use dependentbehavior,56 and they induce a smaller decrease inthe inward rectifier current (IK1),57 while the beta-blocking effect is almost exclusively due to the L-isomer.54,58 The beta-blocking action appears andreaches it maximum at lower concentrations thanthe Class III effect.53 Both are dose related. Clini-cally, sotalol slightly prolongs PR and QT inter-vals and decreases heart rate.59 Its negative in-otropic effect appears to be modest,60,61 possiblybecause b-blockade is partially counterbalancedby the Class III effect. However, in patients withmoderate left ventricular dysfunction (mean leftventricular ejection fraction [LVEF] 0.37), it de-creased cardiac index (by 24%) and increased sys-temic vascular resistance (by 25%) and pul-monary capillary wedge pressure (by 84%).62

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After oral administration, the drug is nearlycompletely absorbed with a bioavailability of100% and 0% binding to plasma proteins. It doesnot undergo hepatic metabolism and it is almostentirely eliminated by the kidney. Sotalol does notshow any significant pharmacokinetic interactionwith other drugs.63,64

The clinical development of D-sotalol (a com-pound devoid of beta-blocking activity) was aban-doned after the drug was found to increase mor-tality (5.0 vs 3.1% at 5 months, P , 0.006) in thelarge SWORD trial,65 including 3,121 patientswith recent myocardial infarction and left ventric-ular dysfunction.

Intravenous sotalol (1–1.5 mg/kg) was not dis-similar from placebo for rapid conversion of 48patients with acute atrial fibrillation/flutter (11 vs14% conversion, respectively), though it was ef-fective in reducing ventricular response.66 In arandomized study including 306 patients, it wasinferior to two doses of ibutilide (1 or 2 mg) in con-verting acute or persistent atrial fibrillation (re-spectively 11%, 20%, and 44% efficacy) or atrialflutter (respectively 19%, 56% and 70% effi-cacy).67 It was also less effective than intravenousflecainide (both drugs administered intravenouslyat a dose of 1.5 mg/Kg) in 106 patients with recent-onset duration atrial fibrillation (conversion rateat 2 hours 23 vs 52%).68

Oral sotalol has been widely studied for theprevention of atrial fibrillation recurrences (TableIII).

The drug, at three different doses of 80, 120,and 180 mg bid, was compared to placebo in 253patients with documented atrial fibrillation/flut-ter who were in sinus rhythm at randomization.At 12-month follow-up, the median time to recur-rence were 27 days for placebo and 106, 229, and175 days, respectively, for the increasing doses ofsotalol (P , 0.05 for the two higher drug doses ver-

sus placebo).69 There were no deaths or torsadesde pointes.

After cardioversion of persistent atrial fibril-lation, sotalol resulted similar to sustained releasequinidine in maintaining sinus rhythm at 6months (respectively 52 vs 48%), but was bettertolerated (withdrawal rate 11 vs 26%).70

Reimold et al.71 compared sotalol topropafenone in 99 patients with paroxysmal orpersistent atrial fibrillation, all in sinus rhythm atthe beginning of the study. Maintenance of sinusrhythm in the follow-up and side effects (12% so-talol and 8% propafenone) were similar with thetwo drugs. Two patients in the sotalol group diedsuddenly. In one of them torsades de pointes dur-ing hypokalemia in the setting of diarrhea wasdocumented.

Lee et al.72 found sotalol and propafenoneequally effective and safe in 79 patients withparoxysmal atrial fibrillation. The drugs obtaineda . 75% decrease of the arrhythmic symptomaticattacks, respectively, in 73% and 79% of the pa-tients (P 5 NS) with a similar incidence of intol-erable adverse effects (10 vs 5%, P 5 NS).

Carunchio et al.73 compared sotalol with fle-cainide and placebo in 66 patients with paroxys-mal atrial fibrillation and found 60%, 70%, and27%, respectively, of the patients arrhythmia-freeat 12 months. The drugs were equally tolerated.

Recently, sotalol was compared with propa-fenone and amiodarone in a multicenter trial in-cluding 403 patients with paroxysmal or car-dioverted persistent atrial fibrillation. After amean 16-month follow-up, recurrence of the ar-rhythmia was documented in 63% of the patientson sotalol or propafenone and 35% in those onamiodarone (P , 0.01). However, there was atrend toward a better tolerance of the drug with so-talol or propafenone than with amiodarone (P 50.06).74

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Table III.

Summary of the Results of the Published Trials of Oral d/l Sotalol in the Prevention of AtrialFibrillation

Author, Year Sotalol Number of Patients in NSVT TdPPublished Dosage (mg) Sinus Rhythm/ Total (%) (%) (%)

Benditt 19996 9 160, 240, 320 72/184 (39) 4 (2) 0Juul-Moller 199070 240 52/98 (51) 0 1/98 (1)Reimold 199371 240 20/50 (40) 3 (6) 1/50 (2)Lee 199772 240 26/34 (76) 0 0Carunchio 199573 240 10/20 (60) 0 0Roy 20007 4 320 39/101 (39) 1 (0.9) 0Total trials 219/487 (51) 8 (1.6) 2 (0.4)

NSVT 5 nonsustained ventricular tachycardia; TdP 5 torsades de pointest.

Oral sotalol, administered perioperatively,was found to be useful for the prevention of atrialfibrillation that frequently appears after cardiacsurgery. In several trials the arrhythmia occur-rence was decreased by 50–75% compared toplacebo.75–77

The adverse effect profile of sotalol is relatedto its beta-blocking activity and propensity to in-duce torsades de pointes. This risk is dose relatedand is higher in patients treated for ventricular ar-rhythmias. There is a 1.9% incidence of seriousproarrhythmia in the database of patients treatedfor supraventricular arrhythmias, including a1.3% occurrence of torsades de pointes.78

In summary, racemic sotalol appears usefulfor prevention of atrial fibrillation recurrenceswith an efficacy that is similar to Class I antiar-rhythmic agents and inferior to amiodarone. Itshares the contraindications of the other b-block-ers (sinus node and atrioventricular node dys-function, bronchial asthma, congestive heart fail-ure). Care should be taken in correcting and/oravoiding electrolyte imbalance (primarily hy-pokalemia and hypomagnesemia) and in adaptingthe dose to renal function. Given that adverseevents occur usually at the beginning of drug ad-ministration, a few days hospitalization is recom-mended at the beginning of therapy.

Ibutilide

Ibutilide was the first of the pure Class III an-tiarrhythmic agents to be approved in the United

States for intravenous use in the acute terminationof atrial flutter and fibrillation.

The drug increases the atrial effective refrac-tory period at all pacing cycle lengths without sig-nificant reverse use dependent effect, and pro-duces a dose dependent prolongation of the QTinterval by activation of INa-s and IKr blockade.79–81

It is not available for oral use because of extensivefirst-pass hepatic metabolism.

The elimination half-life is variable andranges from 2 to 12 hours with a mean of 6hours.82 The effective intravenous dosage is 1–2mg.

The available placebo-controlled clinical tri-als (Table IV) demonstrated that intravenous ibu-tilide is superior to placebo in terminating atrialfibrillation and flutter, with most patients con-verting within 30 minutes from the start of druginfusion. Like dofetilide, the drug was more effec-tive in interrupting atrial flutter (mean successrate 64%) than atrial fibrillation (mean successrate 33%).67,83–87

Two studies compared its efficacy with otherdrugs in terminating atrial fibrillation or flutter.Ibutilide was found to be significantly superior tointravenous administration of sotalol (respec-tively 33 vs 11% in atrial fibrillation and 64 vs19% in atrial flutter)67 or procainamide (respec-tively 51 vs 20% in atrial fibrillation and 76 vs12% in atrial flutter).86

The effect of ibutilide on atrial defibrillationthreshold is interesting. In a placebo-controlled

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Table IV.

Summary of the Results of the Published Trials of Intravenous Ibutilide in Atrial Fibrillation

Number of ConvertedPatients/Total (%)

Author, Year Ibutilide Atrial Atrial TdP/Total DCPublished Dosage Fibrillation Flutter NSVT/Total (%) Shock

Stambler 19968 3 1 mg/10 min 1 25/81 (31) 50/80 (63) 7/180 (3.9) 15/180 (8.3) 3 (1.7)0.5– 1 mg/10 min

Ellenbogen 199684 0.015–0.025 23/78 (29) 30/79 (38) Not reported 6/157 (3.8) 4 (2.5)mg/Kg/10 min

Abi-Mansour 199885 1 mg/10 min 1 46/164 (28) 27/45 (61) 8/219 (3.6) 14/219 (6.4) 4 (1.9)1 mg/10 min

Volgman 19988 6 1 mg/10 min 1 22/43 (51) 13/17 (76) 1/60 (1.7) 1/60 (1.7) 1 (1.7)1 mg/10 min

Vos 199967 1–2 mg/10 min 55/169 (33) 23/36 (64) 13/211 (6.2) 2/211 (0.9) 1 (0.5)Vanderlugt 199987 0.25–0.50–1 54/141 (38) 50/77 (65) 10/218 (4,6) 4/218 (1.9) 2 (0.9)

mg/kg/10 minTotal trials 225/676 (33) 193/334 (58) 39/888 (4.3) 42/1045 (4) 15/1045 (1.4)

NSVT 5 nonsustained ventricular tachycardia; TdP 5 torsades de pointes; DC shock 5 torsade de pointes requiring direct currentshock.

study, drug administration before transthoraciccardioversion significantly improved the successrate of the procedure, while lowering the energyrequirement for defibrillation by approximately30%.88 Moreover, in all the patients in the placebogroup in whom the transthoracic cardioversionfailed, conversion to sinus rhythm was achievedwhen the cardioversion was repeated after ibu-tilide administration.

Considering the overall studies on intra-venous ibutilide administration, the cardiovascu-lar adverse effects were rare and not different fromthose experienced with placebo.89 The incidenceof torsades de pointes was 3.5% including 1.5% ofpatients in whom the arrhythmia was sustainedand required electrical cardioversion. In almost allcases, the arrhythmia occurred within 40 minutesfrom the start of the ibutilide infusion. It was morelikely to occur in women and in the presence ofheart failure, or sinus bradycardia.

In summary, (1) ibutilide is effective and su-perior to the other available antiarrhythmic agentsin terminating atrial flutter, even in the persistentform; (2) its efficacy in terminating atrial fibrilla-tion is low, and in the cases of acute arrhythmia, itseems lower than that of Class IC drugs; (3) theatrial defibrillation threshold is significantly de-creased with resultant facilitation of external elec-trical cardioversion in resistant cases; and (4) thelow but significant incidence of potentially lethaltorsades de pointes mandates its use by personnelexperienced with resuscitation maneuvers.

AzimilideAzimilide is currently under review for ap-

proval for the control of atrial fibrillation. Its elec-tropharmacologic and antifibrillatory actions inexperimental animals are well established.90,91

Based on early research,92 azimilide was initiallythought to be a highly selective IKs blocker. Subse-quent studies indicated that azimilide actuallyblocks a variety of other currents, including IKr,ICa, and INa.

93,94

The drug increases the atrial effective refrac-tory period in a frequency independent fashion,and it does not significantly alter conduction ve-locity.95 In healthy volunteers, oral azimilide indoses up 200 mg/day was well tolerated and pro-duced dose dependent lengthening of the QT in-terval (maximum 32% at the highest single dosageof 8 mg/kg) without modification of the PR andQRS intervals.91

Azimilide is completely absorbed by the gut,with peak blood concentrations occurring approx-imately 7 hours after administration.91 It is 94%bound to plasma proteins96 and it is metabolizedby the liver97 with a terminal elimination half-life

of about 4–5 days.96 The drug plasma concentra-tions are dose related in a linear manner.91

Various studies testing the drug in differentarrhythmic animal models yielded encouragingresults. In dogs, intravenous azimilide was supe-rior to intravenous dofetilide in terminating va-gally induced atrial fibrillation (success rate 93 vs50%).95 The drug induced lengthening of atrial re-fractory period was rate independent for azim-ilide, while it showed a reverse use dependent ef-fect with dofetilide. In dogs, azimilide and E4031(a pure IKr blocker) prolonged atrial refractory pe-riods even after 14 days of rapid atrial pacing.However, the preserved effect on refractory periodprolongation was accompanied by atrial fibrilla-tion prevention by azimilide, but not by E4031.98

In canine atrial flutter models, ibutilide ter-minated atrial flutter in all the cases.99,100

The clinical safety and efficacy of azimilideon humans are currently being evaluated in theAzimilide Supraventricular Arrhythmia Program(ASAP). The preliminary reports have given con-trasting results.

In a randomized, dose-ranging trial on 384 pa-tients with paroxysmal atrial fibrillation or flutter,three doses of azimilide (50, 100, or 125 mg) werecompared to placebo. The hazard ratios for ar-rhythmia recurrence improved across doses: 50mg 1.17 (95% CI: 0.83–1.66), 100 mg 1.37 (95% CI:0.96–1.98), 125 mg 1.83 (95% CI: 1.24–2.70). Thedrug was significantly effective only at its higherdosage (125 mg/day), that significantly prolongedthe time to the first arrhythmia recurrence respectto placebo (130 vs 17 days, P , 0.002).101 Simi-larly, the drug (100 mg/bid) was superior toplacebo in 133 patients with supraventricularparoxysmal tachycardia (RR 5 2.35, 95% CI:1.18–4.68, P 5 0.015).102 On the contrary, in athird study including 682 patients with paroxys-mal supraventricular tachycardia, atrial fibrilla-tion, and atrial flutter, a dose of 125 mg/bid of az-imilide failed to show any significant differencefrom placebo.103

Azimilide tolerability is excellent. Cumula-tive data from 906 patients treated because ofsupraventricular arrhythmias, using daily dosesbetween 35 and 125 mg, showed a low (0.55%) in-cidence of torsades de pointes104 and the adverseeffects and total mortality were not different fromplacebo.105 Indeed, azimilide 125 mg/bid was re-ported to lower the incidence of fatigue and dysp-nea compared to placebo.103

A mortality study, the Azimilide Post-InfarctSurvival Evaluation (ALIVE) trial, is currently un-der way in patients with a recent myocardial in-farction at high risk for arrhythmic sudden cardiacdeath.106

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TedisamilTedisamil is a new compound that blocks the

delayed rectifier current of potassium (IKr), the tran-sient outward current (Ito) channels, and probably,the adenosine triphosphate (ATP) dependentpotassium channels (IKATP).107–109 In animal mod-els, the drug increases the effective refractory peri-ods, reduces the inducibility of ventricular tach-yarrhythmias, and does not affect myocardialcontractility.107,110 In isolated human myocardialfibers, tedisamil lengthens the action potential du-ration more in atrial (1 29%) than in ventricular (1 13%) muscle.111 Its lengthening effect onmonophasic action potential and refractory periodsin the atrium is decreased by increasing atrial pac-ing rates, indicating a reverse use dependent effect.

In humans, tedisamil reduces heart rate andprolongs QT without affecting QRS and QT inter-vals.112,113 Intravenously, the drug exerts antiis-chemic effects similar to esmolol and superior togallopamil.114 In a recent clinical study involving203 patients with stable angina, three doses of thedrug (50, 100, and 150 mg), compared to placebo,led to a dose dependent decrease of anginal at-tacks and electrocardiographic signs of exerciseinduced ischemia and an increase of the exercisecapacity. The highest dose of the drug, however,was associated with a pronounced incidence of di-arrhea.115

At the moment, clinical studies on atrial fib-rillation are lacking.

DronedaroneDronedarone is a noniodinated derivative of

amiodarone that has similar multiple actions (allfour Vaughan-Williams classes) on the cardiacmyocytes membrane.116 In fact, in animal modelsit demonstrated antiadrenergic effects,117,118 itprolonged atrioventricular nodal conduction, theduration of paced QRS interval, and the atrial andventricular refractory periods.119,120 A reverse usedependent effect of the drug on effective refractoryperiods was found in atrial and ventricular my-ocardium, but a still significant effect was foundeven at high rates.119,120

The effects of the drug on repolarization areinfluenced by the route of administration. In con-trast with oral treatment, intravenous droned-arone shortens ventricular repolarization. More-over, similarly to amiodarone, it was shown toinduce a homogenization of repolarization and tosuppress torsades de pointes induced byalmokalant.50 In rats after myocardial infarction, itdecreased premature ventricular beats and had noproarrhythmic effects.121

The drug is presently under development fororal and intravenous use in the treatment of atrialfibrillation and flutter.

AmbasilideAmbasilide is a new antiarrhythmic agent re-

ported to be a nonselective blocker of both com-ponents (IKr and IKs) of the delayed rectifier potas-sium current and of several other repolarizingpotassium currents (Ito,IK1,IKAch, and IKur).122–126

Recently, it was also shown to block the fastsodium channels at high rates with fast kinetics(Class IB action).127

Several studies in animals and in humanatrial myocytes have shown that the drug length-ens the atrial effective refractory period and actionpotential duration in a concentration dependentmanner without any significant reverse use de-pendent effect.122,123,126–128

In a dog model of sustained vagotonic atrialfibrillation, equal loading and maintenance infu-sion doses of intravenous ambasilide and sotalolwere compared. Ambasilide terminated the ar-rhythmia in 100% of the cases and prevented itsinduction in 83% of the cases, while sotalol inter-rupted atrial fibrillation in 12% of the animals andprevented its induction in none of them (P ,0.02).129

The drug has now entered phase III clinicaltrials.

ConclusionThe treatment of atrial fibrillation and atrial

flutter with conventional drugs is far from satis-factory. The new “pure” Class III antiarrhythmicagents were expected to better fulfill our need foran “ideal drug,” owing to their specific action onrefractoriness and lack of action on cardiac ex-citability, conduction, and contractility. Al-though they have proven not to be wonder drugs,the new and available pure Class III drugs mayhave their place in the treatment of these arrhyth-mias. Specifically, intravenous ibutilide can beused for rapid interruption of acute atrial fibrilla-tion where other drugs are contraindicated (e.g.,in patients with heart failure or with alterationsin excitability or conduction). It can also be con-sidered the first choice drug for the conversion ofatrial flutter. Dofetilide, given the risk of torsadesde pointes, should be presently considered a sec-ond line drug for long-term prevention of atrialfibrillation, to be used only in cases where otherdrugs have failed or are contraindicated. Sotalolmay find its place, aside Class I drugs and amio-darone, for prevention of atrial fibrillation/flutterrecurrence.

Recently, experimental and clinical studieshave shown that the main problem of these drugs,probably accounting for their limited efficacy andthe propensity to promote torsades de pointes,may be related to their reverse use dependent be-havior. New drugs targeting channels different

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from IKr are being developed to overcome thesedrawbacks and obtain a more favorable electro-physiological profile.

Block of the slow component of the inwardrectifying current (IKs), a current whose contribu-tion to repolarization seems to become predomi-nant at high activation rates, should improve effi-cacy at the high rates of atrial fibrillation andreduce the risk of torsades de pointes at the lowerventricular rates.

Another possibility is to find drugs specifi-cally targeting ion channels present in human

atrium but not in the ventricle. This is the casewith ultrarapid potassium rectifier (IKur)130 andacetylcholine-sensitive potassium channels(IKAch)131 whose blockade would prolong repolar-ization only at the atrial level (opposing atrial fib-rillation) but avoid the risk of ventricular arrhyth-mias. Finally, new drugs, like dronedarone, ade-iodinated molecule derived from amiodarone,that are able to block multiple channels are hope-fully expected to share the good efficacy profile ofthe parent drug without the side effects due to theiodine molecule.

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