Review

10.1586/14779072.5.4.707 © 2007 Future Drugs Ltd ISSN 1477-9072 707www.future-drugs.com

New antiarrhythmic treatment of atrial fibrillationGerald V Naccarelli†, Deborah L Wolbrette, Soraya Samii, Javier E Banchs, Erica Penny-Peterson and Mario D Gonzalez

†Author for correspondencePenn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077gnaccarelli@psu.edu

KEYWORDS: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, atrial fibrillation, carvedilol, dronedarone, omega-3 fatty acid, rotigaptide, statins, vernakalant

Antiarrhythmic pharmaceutical development for the treatment of atrial fibrillation (AF) is moving in several directions. The efficacy of existing drugs, such as carvedilol, for rate control and, possibly, suppression of AF, is more appreciated. Efforts are being made to modify existing agents, such as amiodarone, in an attempt to ameliorate safety and adverse effect concerns. This has resulted in promising data from the deiodinated amiodarone analog, dronedarone, and further work with celivarone and ATI-2042. In an attempt to minimize ventricular proarrhythmia, atrial selective drugs, such as intravenous vernakalant, have demonstrated efficacy in terminating AF in addition to promising data in suppression recurrences when used orally. Several other atrial selective drugs are being developed by multiple manufacturers. Other novel therapeutic mechanisms, such as drugs that enhance GAP junction conduction, are being developed to achieve more effective drug therapy than is offered by existing compounds. Finally, nonantiarrhythmic drugs, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, high-mobility group coenzyme A enzyme inhibitors and omega-3 fatty acids/fish oil, appear to have a role in suppressing AF in certain patient subtypes. Future studies will clarify the role of these drugs in treating AF.

Expert Rev. Cardiovasc. Ther. 5(4), 707–714 (2007)

Antiarrhythmic drugs that have proven use-ful in the treatment of atrial fibrillation (AF)include the Class IA sodium channel block-ers quinidine, procainamide and disopyra-mide; the Class IC sodium channel blockersflecainide and propafenone immediaterelease and sustained release; and theClass III agents sotalol, dofetilide and amio-darone [1]. In addition, intravenous ibutilideis effective in the termination of AF. Owingto subjective adverse symptoms and end-organ toxicity, proarrhythmic potential andlack of safety data in structural heart disease,Class IA agents are rarely used and are nolonger included in the current AF guidelines[2]. Class IC drugs have been limited to usein patients with minimal or no structuralheart disease. Sotalol and dofetilide can pro-voke torsade de pointes and amiodarone useis often limited owing to potential end-organ toxicity. Owing to these limitations,more effective and safer antiarrhythmicdrugs for the treatment of AF are required.

In the past, it was believed that an idealantiarrhythmic drug for the treatment of AFshould suppress atrial triggers, prolong atrialrefractory periods in a use-dependent fashion,slow intra-atrial conduction, have atrialselectivity to minimize ventricular proar-rhythmic effects, prolong atrioventricular(AV) nodal refractoriness and slow AV nodalconduction for the purpose of rate control,have a half-life long enough for once-a-dayuse, have a low potential for subjective, end-organ and proarrhythmic side effects, be safein patients with structural heart disease andhave no significant negative inotropic effectsor drug interactions. Although all of theseproperties are important, new mechanisms ofaction, including more atrial selective targets,appear to have promise in the suppression ofAF. Thus, in addition to altering older agents,new antiarrhythmic drugs, with novel thera-peutic mechanisms, are being developed[3–12]. In addition, commonly prescribedmedications, such as angiotensin-converting

CONTENTS

Carvedilol

New antiarrhythmic drugs

Rate control of atrial tachyarrhythmias

GAP junction modulators

Expert commentary

Five-year view

Key issues

References

Affiliations

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enzyme (ACE) inhibitors, angiotensin receptor blockers(ARBs), high-mobility group (HMG) Coenzyme A inhibi-tors and omega-3 fatty acids/fish oil appear to have a role insuppressing AF.

CarvedilolCarvedilol possesses dose-related antiadrenergic (β1, β2 and α)effects. In addition, carvedilol has direct membrane-stabilizingactivity (Class IA), prolongs repolarization by blocking potas-sium channels (Class III), and inhibits L-type calcium chan-nels (Class IV) [13]. Carvedilol inhibits several native potas-sium channels responsible for repolarization incardiomyocytes, including the rapidly and slowly activatingcomponents of the delayed rectifier current (IKr and IKs) andthe transient outward current (Ito). The clinical effects ofblocking the potassium channels appear to be small, since QTprolongation and ventricular proarrhythmic activity is notnoted. Carvedilol does not affect the inward rectifier current(IKI), which prolongs the action potential duration and effec-tive refractory period to repeat excitability [13]. Carvedilolslows heart rate and conduction through the AV node.

Several trials suggest that carvedilol is beneficial in treatingAF, which can be explained partially by the drug’s nonadrener-gic effects. In a postcardioversion trial carvedilol had a 14%lower rate of AF relapse compared with bisoprolol over a 1-yearfollow-up period [14]. In a postcardiac surgical trial, AFoccurred in 8% of carvedilol-treated patients, versus 32% ofpatients receiving metoprolol or atenolol, a 75% risk reduction[15]. In a placebo-controlled trial, chronic AF patients were ran-domized to receive carvedilol, amiodarone or no antiarrhyth-mic drug for 6 weeks before and after external transthoraciccardioversion. Successful cardioversion was achieved withcarvedilol and amiodarone pretreatment (87 and 94%, respec-tively) versus no antiarrhythmic prophylaxis (69%). Both thecarvedilol- and amiodarone-treated groups had longer atrialfibrillatory cycle length intervals preconversion, longer atrialeffective refractory periods 5-min postconversion and lower AFrecurrence rates than untreated patients [16]. Although otherβ-blockers have been demonstrated to suppress the recurrenceof AF, carvedilol’s effects on altering atrial effective refractoryperiods is somewhat unique for this class of drugs. Carvedilol,similar to other β-blockers, slows the ventricular response whenused alone or in combination with digoxin [8].

New antiarrhythmic drugsMultiple investigational Class III compounds have targeted vari-ous potassium channels with varying degrees of specificity orbreadth. Some agents have the ability to block other ion chan-nels (BOX 1) [3–12]. Scientists have been able to target blockade ofthe ultrarapid potassium rectifier current (IKur), which existsonly in atrial tissue, thereby affording atrial specificity and theo-retically eliminating the risk of torsade de pointes as a result ofventricular action potential delay. The ability to block the ace-tylcholine-dependent potassium current (IKAch) offers anotheropportunity to specifically target drug effects to the atria.

Investigational antiarrhythmic agents for cardioversion of AFTedisamil

Tedisamil is a Class III agent that slows sinus rate, possessesantianginal and anti-ischemic properties and blocks IKr, Ito, IKs,IKur, potassium ATP current (IKATP) and INa [18]. Tedisamillengthens the atrial and ventricular action potential and theatrial and ventricular effective refractory periods [18]. Tedisamilis currently in Phase III trials to establish an indication for con-version of AF. Hohnloser and colleagues investigated the use oftedisamil versus placebo for treating AF/atrial flutter patientswith onset of less than 48 h [19]. Of the placebo-treated patientswith AF, four out of 46 (9%) converted to sinus rhythm. Treat-ment with tedisamil 0.4 mg/kg converted AF to sinus rhythmin 24 out of 52 patients (46%) and in 24 out of 42 patients(57%) in the 0.6 mg/kg group (p < 0.001 for both tedisamilgroups vs placebo). The conversion to sinus rhythm occurredwith a mean time to conversion of 35 ± 27 min for the0.4 mg/kg dose and 34 ± 21 min for the 0.6 mg/kg dose. Thenumber of patients who remained in sinus rhythm 24 h afterthe dose of tedisamil was also significantly greater in the treatedgroup compared with the placebo group. Tedisamil prolongedthe QTc interval in a dose dependant fashion becoming statisti-cally significant at a dose of 0.6 mg/kg (QTc increased16.9 ± 45.2 from a baseline of 443.1 ms; p = 0.037). At a doseof 0.4 mg/kg, the QTc slightly lengthened (10.8 ± 45.9 ms)but did not reach statistical significance. In the same study,tedisamil’s efficacy in converting atrial flutter to sinus rhythmwas quite low. Tedisamil’s effects on prolonging the QT intervaland case reports of torsade de pointes remain of concern if thisdrug is to become commercially viable.

Vernakalant hydrochloride (RSD1235)

Vernakalant hydrochloride (RSD1235) is an atrial selective(IKACh, IKur) potassium channel blocker with little effect onventricular repolarization and a frequency- and voltage-dependent, INa-blocking activity [20,21]. Intravenously, thedrug has a very short half-life and is metabolized primarily bythe CYP2D6 system.

In the CRAFT trial, the drug was shown to have a dose-related ability to terminate AF [22]. Patients (n = 56) with AF of3–72 h duration were treated with RSD-1 (0.5 mg/kg followedby 1 mg/kg; n = 18) versus RSD-2 (2 mg/kg followed by3 mg/kg; n = 18) versus placebo (n = 20). The RSD-2 groupwas superior to placebo for termination of AF (61 vs 5%;p < 0.0005), patients in sinus rhythm at 30 min (56 vs 5%;p < 0.001) and 1 h (53 vs 5%; p = 0.0014) and median time toconversion (14 vs 162 min, p = 0.016). No serious adverseevents, including torsade de pointes, were noted.

Similar efficacy data have been reported in a larger group ofpatients in the Atrial Arrhythmia Conversion Trial (ACT)-1(416 patients) [23] and ACT-3 (276 patients) [24]. In both stud-ies, intravenous vernakalant was useful in converting AF tosinus rhythm if the AF was 3 h to 7 days in duration but muchless useful if AF persisted from 8–45 days in duration. InACT-1, only one out of 39, and in ACT-3, 7% of atrial flutter

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patients converted to sinus rhythm when intravenous vernaka-lant was given. The ACT-2 trial is ongoing to determine theefficacy and safety of intravenous vernakalant in the conversionof AF postvalvular and coronary bypass graft surgery. ACT-4 isan open-label study to assess the safety of vernakalant in120 AF patients.

The most common noncardiac side effects noted with intra-venous vernakalant is dysgeusia, paresthesia, nausea, cough,pruritus and sneezing. Advantages of intravenous vernakalantcompared with ibutilide is that torsade de pointes has notbeen reported, to date, with intravenous vernakalant. Further-more, different than ibutilide studies, intravenous vernakalantstudies included patients who had AF recurrences on oralantiarrhythmic agents.

At this time, vernakalant holds the most promise as the nextantiarrhythmic to receive commercial approval for the intra-venous termination of recent onset AF with a high safety pro-file. Intravenous vernakalant has been submitted to the USFDA for consideration of market approval in the USA.

In follow-up to the previously mentioned intravenous for-mulation, a sustained-release oral preparation of vernakalanthas been developed. A Phase IIa trial demonstrated that oralvernakalant at 300 and 600 mg twice daily was superior toplacebo in maintaining sinus rhythm after cardioversion ofpersistent AF over a 28-day treatment [25]. In the placebogroup, 57% of patients had AF recurrence compared with39% in the vernakalant 300 mg twice-daily group (p = 0.048)and 39% in the 600 mg twice-daily group (p = 0.06). Furtherdose-ranging studies are planned.

AZD7009

In a sterile pericarditis model, AZD7009, which blocks IKur, IKrand INa, prolonged arrhythmia cycle length (p < 0.001) beforeterminating 23 out of 23 episodes of AF/flutter [26]. Arrhythmiareinduction failed in 19 out of 20 attempted. The drug demon-strated some atrial selectivity since the atrial effective refractoryperiod (AERP) increased 33%, while the ventricular effectiverefractory period (VERP) increased 17% (p < 0.001 vs AERP)and the QT 9% (18 ± 2 ms). In addition atrial conduction timeincreased (p < 0.001) but ventricular conduction time wasunchanged. Phase II studies have demonstrated that intrave-nous AZD7009 was superior (50% conversion rate) to placebo(0% conversion rate) in converting persistent AF (2–90 days)to sinus rhythm [27]. Recent onset AF of less than 30 days hadan 82% conversion rate with intravenous AZD7009 [27]. Thepotential for AZD7009 to prolong the QT interval and possi-bly cause torsade-de-pointes may limit further commercialdevelopment of this specific compound.

AVE-0018

AVE-0118 is a biphenyl derivative that blocks the atrial delayedrectifier current (IKur), IKACh and Ito and, thus, has little electro-physiologic effect on ventricular tissue. Basic studies demon-strate that it prolongs the AERP, even after atrial remodelinghas occurred from persistent AF [28]. In a goat model, AVE-0118 has been shown to be a positive atrial inotropic agent [29].In animal models, AVE0118 successfully converted 63% in apersistent AF model. In humans, conversion of recent onset AFhas been achieved but the results are more disappointing in AFof longer duration.

New multichannel amiodarone analog antiarrhymic agentsDronedarone (SR33589)

Dronedarone is an amiodarone-like compound without theiodine moiety [30–32]. To date, thyroid, pulmonary or hepaticend-organ toxicity have not been reported. Electrophysiologi-cally, dronedarone blocks IKr, IKs, Ito and fast sodium and cal-cium channels [33]. Dronedarone prolongs the action potentialduration in the atria and ventricles with no significant reverse-usedependence [34]. Other electrophysiologic effects similar to amio-darone include α, β and muscarinic blocking effects. Dronedar-one appears to slow sinus rates less than amiodarone but prolongsAV nodal refractory periods and, thus, is useful as a rate-controlagent. Similar to amiodarone, dronedarone increases the QT

Box 1. Investigational antiarrhythmic drugs (mechanisms of action).

Multichannel, atrial selective blockers and modification of existing compounds

• Amiodarone analogs:

–Dronedarone (IKr, IKs, β1, ICa, Ito, INa)

–Celivarone (IKr, IKs, β1, ICa, Ito, INa)

–ATI-2042 (IKr, IKs, β1, ICa, Ito, INa)

• Atrial Selective

–RSD1235 (IKur, Ito, INa,IKAch)

–AZD7009 (atrial repolarization delay)

–AVE-0118 (IKur, Ito)

• Class III

–Tedisamil (IKr, Ito, IKATP, INa, IKur)

• Adenosine A1 Agonists

–Tecadenoson (CVT-510)

–Selodenoson (DTI0009)

Novel mechanisms of action

• Rotigaptide (connexin modulator)

• GsMtx4 (stretch receptor antagonist)

Others

• Angiotensin-converting enzyme inhibitors

• Angiotensin receptor blockers

• High-mobility group coenzyme A reductase inhibitors

• Omega-3 fatty acids

• Corticosteroids

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interval but torsade de pointes has not yet been reported, possiblydue to the fact that dronedarone reduces the transmural disper-sion of ventricular refractoriness and protects from Class IIIantiarrhythmic-induced early after depolarizations [35–37].

Dronedarone has a half-life of 27–31 h with steady statebeing achieved within 7–10 days [30,31]. It is metabolized pri-marily by CYP3A4 and is both an inhibitor and substrate ofthe enzyme. The N-debutyl metabolite exhibits a third to atenth of the pharmacodynamic activity of the parent com-pound. Similar to amiodarone, dronedarone causes increases inthe levels of simvastatin and digoxin. However, no significantdronedarone-warfarin interaction has been noted.

In the Dose Adjustment For Normal Eating (DAFNE)trial, dronedarone 400 mg administered twice daily wassuperior to placebo in preventing recurrent AF. The mediantime to recurrence was 59.9 days in the dronedarone groupcompared with 5.3 days in the placebo group (p < 0.05;RR = 0.45; confidence interval [CI]: 0.28–0.72). Higherdoses (800 and 1600 mg twice daily) of dronedarone wereineffective and associated with a higher incidence of gastro-intestinal subjective adverse effects [38]. The American-Afri-can Trial with Dronedarone in AF or Flutter for the Mainte-nance of Sinus Rhythm (ADONIS) and Eurropean Trial InAF or Atrial Flutter Patients Receiving Dronedarone for theMaintenance of Sinus Rhythm (EURIDIS) both demon-strated that dronedarone significantly (p < 0.05) suppressesrecurrent AF at a dose of 400 mg twice daily [39]. InEURIDIS, the median time to first arrhythmia recurrencewas 2.3-times longer in the dronedarone group with a 22%reduction in AF/flutter recurrences compared with placebo.In ADONIS, the median time to arrhythmia recurrence wasalmost three-times longer and there was a 28% reduction ofAF/flutter recurrences compared with the placebo arm of thestudy. Data from these trials and the Efficacy and safety ofDronedarone for the Control of Ventricular Rate (ERATO)trial demonstrate that dronedarone, similar to amiodarone,has the ability to statistically slow the ventricular response ifAF/flutter recurs [40].

The Antiarrhythmic Trial with Dronedarone in Moderate toSevere Congestive Heart Failure Evaluating Morbidity Decrease(ANDROMEDA), studying the safety of dronedarone inpatients with severe left ventricular dysfunction, was prema-turely terminated due to a higher mortality in the antiarrhyth-mic treated arm of the study [30,31]. This adverse effect may besecondary to the withdrawal of ACE inhibitors and ARBs giventhe fact that dronedarone increases the tubular secretion of cre-atinine with no effect on creatinine clearance [41]. The primaryefficacy objective: of this study was the reduction of deathsfrom any cause or hospitalizations for worsening heart failure inpatients with moderate-to-severe chronic heart failure and leftventricular dysfunction, over a minimum period of 12 monthscompared with placebo.

A large placebo-controlled trial, Athletes Targeting HealthyExercise And Nutrition Alternatives (ATHENA), has completedenrollment of over 4500 patients with a primary composite end

point of reducing mortality and hospitalizations. This end pointis based on a combined retrospective analysis of ADONIS andEURIDIS that demonstrated a favorable trend for this endpoint in the dronedarone-treated subgroup [42]. The result ofthis trial, in patients with risk factors of stroke, will determine ifthe FDA will approve dronedarone.

Other amiodarone analog compounds (celivarone, ATI-2042)The same sponsor is studying a next-generation, once-a-daynoniodinated multichannel blocker, celivarone(SSR149744C), with similar electrophysiological effects todronedarone [42]. An early Phase II human trial with oral celi-varone reported no dose effect (50, 100, 200 and 300 mg aday) in preventing the recurrence of persistent AF postcardio-version [42]. The 50 mg daily dose had a recurrence rate of52.1% at 3 months compared with 67.1% for placebo patients(p = 0.055). No torsade de pointes was reported in this study[42]. Another sponsor is starting human Phase II trials withanother amiodarone-like compound, ATI-2042 [12].

Rate control of atrial tachyarrhythmiasTecadenoson & selodonosonDue to their AV nodal blocking properties, new long actingadenosine analogs are being studied for rate control of AF. Tec-adenoson is an adenosine analog with selective A1 receptoragonist activity and, thus, a role in slowing the ventricularresponse by slowing conduction at the AV node level. Tecade-noson avoids hypotension and bronchoconstriction that is asso-ciated with stimulation of the A2 receptor, and is commonlyexperienced with intravenous administration of adenosine. Tec-adenoson Phase III trials have demonstrated efficacy in thetreatment of paroxysmal supraventricular tachycardia [43].Enrollment continues in trials to examine tecadenoson as anagent for ventricular rate control in AF.

DTI-0009 (selodonoson) is an adenosine A1 receptor antag-onist that has a longer half-life (150 min) than tecodenosonand is now undergoing clinical studies.

GAP junction modulatorsRotigaptideAs our understanding of the wide range of etiologies for AFonset improves, scientists have begun to develop antiarrhyth-mic agents with entirely new mechanisms of action. GAPjunction (connexin) modulators, such as rotigaptide (ZP123,GAP, 486), offer promise for the treatment of AF [44–46]. Lossof cell contact is important for the genesis of atrial arrhyth-mias. Thus, conduction slowing and GAP junction uncou-pling may be substrates for AF. Mutations in GJA5, the geneencoding connexin 40, may predispose impairment of GAPjunction assembly or uncoupling in certain predisposedpatients [47]. Thus, restoration of intercellular conductionmay prevent atrial conduction slowing in certain pathologicstates. This compound has demonstrated this favorable effectin a rat model of metabolically stress-induced changes. Roti-gaptide has been demonstrated to reduce AF vulnerability in

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a canine model of chronic mitral regurgitation (dilatedcardiomyopathy model) but not in a ventricular tachypacingmodel that results in atrial fibrosis [44]. This drug recentlyreduced AF in a canine model of atrial ischemia [46]. Whichpatients will benefit from such an approach is not known atthis time.

Angiotensin-converting enzymes & ARBsElevations of ACE and especially angiotensin II can provokeAF by adversely effecting electrical and structural remodelingin congestive heart failure [48]. Data exist from multiple stud-ies that ACE inhibitors [49–52] and ARBs [52–54] are useful forthe suppression of AF. Candesartan has been shown todecrease the duration of (p <0.05) and percent of atrial fibro-sis in an atrial paced canine model (p < 0.001) [55]. These datasuggest that angiotensin II receptor blockade can prevent thepromotion of AF by suppressing the development of structuralremodeling. The addition of enalapril [51] or irbesartan [53] toamiodarone has been demonstrated to statistically reduce therecurrence of AF postconversion of persistent AF comparedwith amiodarone alone. In a substudy of the Losartan Inter-vention For End Point (LIFE) trial [54], losartan reduced AF(HR 0.67; p < 0.001) in 342 hypertensive patients with leftventricular hypertrophy and AF compared with atenolol, inspite of equal blood pressure control with both agents. Morerecent data from AFFIRM suggest these drugs may be partic-ularly useful as antiarrhythmic agents in patients with signifi-cant heart failure [52]. The Atrial Fibrillation ClopidogrelTrial with Irbesartan for Prevention of Vascular Events(ACTIVE)-I trial is studying high-risk stroke patients withAF, to determine if irbesartan will decrease AF recurrencesand left atrial size, and limit the progression of paroxysmal topersistent AF [56].

HMG coenzyme A reductase inhibitors (statins)In addition to their use as lipid-lowering agents, statins havebeen demonstrated to reduce the development of AF in449 coronary artery disease patients by 51% over a 5-year fol-low-up period [57]. Ozadyin and colleagues demonstrated that10-mg atorvastatin daily decreased the recurrence of persist-ent AF postconversion (RR 0.23; CI: 0.64–0.82; p = 0.01)[58]. These data are similar to that reported by Siu and col-leagues who retrospectively reported that statins decreasedrecurrences of AF after direct current cardioversion [59]. In theAtorvastatin for Reduction of Myocardial Dysrhythmia AfterCardiac Surgery (ARMYDA)-3 study, atorvastatin signifi-cantly reduced the incidence of AF postcardiac surgery to35% compared with placebo recurrence rate of 57%(p = 0.0003) [60]. Whether statins reduce AF through an anti-inflammatory mechanism remains speculative. In ARMYDA-3,peak C-reactive protein levels were lower in patients that didnot have AF recurrence (p =0.01); irrespective of randomiza-tion assignment. Another study suggested that statins mightdecrease post-coronary artery bypass graft (CABG) AF byaltering extracellular matrix remodeling [61].

Omega-3 fatty acidsOmega-3 fatty acids/fish oil has multiple basic electrophysio-logical effects [62–65]. Eicosapentaenoic acid (EPA) prolongsthe QTc in a Langendorff rabbit model. Fish oils block theL-type calcium channels. EPA and docosahexaenoic acid(DHA) suppress sodium channels in cardiomyocytes andDHA slows sodium channel dependent longitudinal conduc-tion in a perfused heart model. Both DHA and EPA raise thethreshold to elicit an extrasystole. Mozzaferian and colleaguesreported that the consumption of tuna or other broiled/bakedfish lowered AF by 31% if intake was greater than or equal tofive-times per week compared with less than once per month(p = 0.004) [66]. In humans, fish oils slow heart rate, increasethe PR and decrease the likelihood of a prolonged QTc [67].Prospective randomized data exist that state that omega-3fatty acids significantly reduce the occurrence of post-CABGAF from 33% in placebo patients to 15% in the treated group(p =0.013) [68]. In patients with pacemakers, fish oils signifi-cantly reduced AF episodes by 59% (p = 0.037) and AF bur-den by 67% (p = 0.029) [69]. Recently, the Rotterdam studyreported that intake of EPA and DHA and the consumptionof fish in a population-based study were not associated withthe prevention of the development of AF [70].

If efficacious, possible mechanisms for omega-3 fattyacids/fish oil to suppress AF include direct electrophysiologicaleffects, anti-inflammatory effects, slowing the progression ofcoronary artery disease or other structural, metabolic or auto-nomic effects that are poorly understood at this time. Anongoing prospective, randomized, placebo-controlled trial iscurrently ongoing with a commercially concentrated n-3 fattyacid to determine if this form of omega-3 fatty acids/fish oil iseffective in the suppression of AF.

Expert commentaryUntil some of the investigational antiarrhythmic drugs for AFbecome available, treatment of AF should follow the currentpublished guidelines [2]. These guidelines suggest proper anti-coagulation of patients at high risk for thromboembolic events,appropriate rate control and antiarrhythmic drugs chosen basedon the absence or presence of structural heart disease. Catheterablation procedures with isolation of the pulmonary veinsshould continue to be performed in appropriate patients. Asnew antiarrhyhmic drugs become commercially available, theywill be appropriately positioned into the guidelines and clinicalpractice based on their overall safety and efficacy. The use ofACE inhibitors and ARBs should be encouraged in patientswith AF associated with hypertension and in those with leftventricular dysfunction. In AF patients with hyperlipidemia orcoronary artery disease, the use of statins or omega-3 fattyacids/fish oil may have some therapeutic advantage.

Five-year viewHopefully, oral dronedarone and intravenous and oral vernakalantwill be commercially available within a 5-year timeframe. Furtherstudies with other multichannel blockers, such as celivarone and

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ATI-2042, and atrial selective drugs will determine their commer-cial viability. The results of the current prospective trial will deter-mine if fish oils will be used as monotherapy. The ACTIVE-Istudy will help us understand the role of renin–angiotensin block-ade in suppressing AF. It is likely that combination therapy ofomega-3 fatty acids/fish oil, statins, ACE inhibitors and ARBs

with channel blocking antiarrhythmic agents will be studied morefully. Specific subtypes of patients that benefit from anti-inflam-matory and GAP junction facilitating drugs will help us betterselect patients that will respond to such therapies. In the mean-time, rate-control drugs and AF ablation will compete with thesenovel approaches.

Key issues

• There is a need for new antiarrhythmic drugs for the treatment of atrial fibrillation (AF) since current agents have limited efficacy and significant adverse effects.

• Several trials suggest that carvedilol has benefit in treating AF that can be partially explained by the drug’s nonadrenergic effects.

• Intravenous vernakalant is useful in terminating recent-onset persistent AF with a good proarrhythmic profile and promising efficacy as an oral drug.

• Dronedarone is useful in the maintenance of sinus rhythm and as a rate control drug without some of the end-organ toxicity of amiodarone.

• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been demonstrated to suppress AF, especially in patients with left ventricular dysfunction.

• Statins and omega-3 fatty acids have both been shown to suppress AF in patients with coronary artery disease and in the postcardiac surgical setting.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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•• Comprehensive review of dronedarone.

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Affiliations

• Gerald V Naccarelli, MD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077gnaccarelli@psu.edu

• Deborah L Wolbrette, MD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077dwolbrette@psu.edu

• Soraya Samii, MD PhD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077ssamii@hmc.psu.edu

• Javier E Banchs, MD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077jbanchs@psu.edu

• Erica Penny-Peterson, MD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077epennypeterson@psu.edu

• Mario D Gonzalez, MD

Penn State University Heart and Vascular Institute, The Electrophysiology Program, Penn State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Dr., Room H 1.511, Hershey, PA 17033, USATel.: +1 717 531 3907Fax: +1 717 531 4077mgonzalez@hmc.psu.edu