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Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity?

Bramah N. Singh^1,2,* and Etienne Aliot³

¹ Department of Cardiology, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA
² David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
³ Centre Hospitalier Universitaire de Nancy, Hôpital de Brabois, Vandoeuvre lès Nancy, France

^* Corresponding author. Tel: +1 310 268 36 46; fax: +1 310 473 07 24. E-mail address: b.singh{at}ucla.edu or bramah.singh{at}va.gov

	Abstract

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
The morbidity and mortality associated with atrial fibrillation (AF), the most frequent cardiac arrhythmia, remain substantial. The efficacy and safety of current antiarrhythmic drugs continue to be less than optimal. The development of newer antiarrhythmic drugs has recently been made possible through a greater understanding of the pathophysiology of AF and knowledge of atrial electrophysiology relative to the properties of the congeners of known antiarrhythmic agents. Highly specific atrially acting drugs are currently being explored, their major merit concerning safety. In contrast, their role may be somewhat limited in view of the electrophysiological complexity of AF as an arrhythmia. The data suggest that complex antiarrhythmic agents with a multiplicity of actions may be preferable, although currently there are few data on the precise effectiveness of atrial-specific agents in maintaining sinus rhythm in AF. It is of interest that combining antiarrhythmic and non-antiarrhythmic agents, such as anti-inflammatory or antioxidant drugs, may increase the effectiveness of antifibrillatory actions in patients with AF, although these data have been obtained in uncontrolled, small or retrospective studies. Thus, at present, it is not certain whether it is preferable to target single antiarrhythmic drugs with antiadrenergic properties or to combine ‘purely’ antiarrhythmic drugs with other drugs devoid of anti-adrenergic effects. Controlled clinical trials are required to precisely define the effectiveness of single agents vs. various combinations of agents in maintaining sinus rhythm in patients with AF.

Key Words: Antiarrhythmic drug • Atrial fibrillation • Atrial selectivity • Cardioversion • Sinus rhythm

	Introduction

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Atrial fibrillation (AF) is the most common cardiac arrhythmia, with an estimated prevalence of 0.4–1% in the general population, increasing with age to 8% in patients older than 80 years.¹ The morbidity and mortality associated with AF are substantial. Owing to the deterioration of atrial mechanical function, patients with AF present a high risk of thrombo-embolism. AF also accounts for a third of all hospitalizations for cardiac rhythm disturbances,¹ is responsible for up to 15% of all strokes,² and is associated with an odds ratio for death of 1.5 for men and 1.9 for women.³

In general, AF is a recurrent, persistent, or chronic disorder. The management of patients with AF involves two main treatment strategies, not mutually exclusive, i.e. rhythm control and rate control. The rhythm control strategy aims to restore and maintain normal sinus rhythm, whereas the objective of rate control is to control ventricular rate. In both approaches, the critical issue is the prevention of thrombo-embolism by adequate and sustained anticoagulation and all patients at risk should be anticoagulated in the absence of any contraindication. AF may often be self-terminating (paroxysmal AF), but in persistent AF, sinus rhythm must be restored either by electrical or pharmacological conversion or by electrophysiological or surgical intervention. However, as the rate of AF recurrence is high, most patients, whether presenting paroxysmal or persistent AF, eventually need continuous antiarrhythmic drug treatment to maintain sinus rhythm, suppress symptoms, and improve exercise capacity, quality of life, and haemodynamic function. Restoration and maintenance of SR may also prevent tachycardia-induced cardiomyopathy.¹

	Currently available antiarrhythmics

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Antiarrhythmic drugs are generally classified into four categories on the basis of their mode of action: blockade of sodium (class I), potassium (class III), or calcium (class IV) channels or inhibition of sympathetic stimulation (class II). Currently, the drugs primarily used for rhythm control are class Ic and III drugs.⁴ Class II and IV agents are more commonly used for rate control, because of their atrioventricular node-blocking properties. These agents generally also exert antiarrhythmic actions, but in restricted contexts.

Available antiarrhythmic drugs, particularly those used to control AF, are not optimal with respect to either long-term efficacy or safety.⁴ For example, it is rarely possible to maintain sinus rhythm by drug therapy in more than 50% of patients over the first year following conversion of AF to normal rhythm. In terms of safety, the major concern in the use of antiarrhythmic agents is the occurrence of proarrhythmia, which may sometimes be fatal. Owing to their proarrhythmic effects, class 1c agents (propafenone and flecainide for AF) cannot be used safely in patients with ischaemic heart disease, especially those who have experienced myocardial infarction, or in those with other serious cardiac diseases associated with a low ejection fraction.

In this context, the properties of class 1a and class III agents are of major importance in view of the nature of their most prominent cardiac side effect, i.e. torsade de pointes (TdP). The major effect of class 1a agents (e.g. quinidine, procainamide, and disopyramide) is inhibition of sodium channels, but they also significantly block I_kr, the basis for the development of TdP as a proarrhythmic reaction. In contrast, I_kr blockade has been found to exert what has come to be recognized as the class III action⁵ in the ventricular as well as the atrial myocardium. However, beyond a certain range of doses and serum concentrations, proarrhythmic reactions (TdP) are likely to occur. The major class III agents, dl-sotalol, d-sotalol, dofetilide, and ibutilide, increase the risk of TdP, although being effective drugs for the control of AF. Amiodarone, classified as a class III agent for over 30 years,⁶ is a highly effective agent for the control of AF,⁷ as well as ventricular tachycardia or ventricular fibrillation (VT/VF),⁸ yet despite markedly blocking the I_kr and prolonging the QT interval,⁶ it rarely induces proarrhythmic reactions. Clearly, the deleterious effect of I_kr blockade is negated by the other properties of the compound to the extent that the drug does not induce TdP and may even exert an anti-torsadogenic effect.⁹

The major shortcoming of amiodarone as an antiarrhythmic agent is its variegated spectrum of adverse reactions, particularly altered thyroid function, pulmonary toxicity (which may sometimes be fatal), and peripheral neuropathy. Thus, there is a need for more effective and safer antiarrhythmic regimens for the control of cardiac arrhythmias. The major focus is on AF,¹⁰ for which the ideal pharmacological therapy still remains to be developed. The search for and development of newer compounds is therefore now an active scene.

	Newer antiarrhythmic drugs

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
The ideal characteristics of a new antiarrhythmic drug are listed in Table 1. The search for such a compound is likely to continue, but available data do not suggest rapid development of a single agent with the requisite effectiveness as well as freedom from serious adverse reactions. It is therefore worth considering the critical issues concerning combination of the newer antiarrhythmic compounds in development with other treatments.

View this table: [in this window] [in a new window]   Table 1 Ideal characteristics of a new antiarrhythmic drug

 

• Is the effectiveness of maintaining sinus rhythm in patients with AF augmented meaningfully by combining the drug with other antifibrillatory drugs differing in their mode of action?
  
• Could the efficacy of antifibrillatory drugs be meaningfully enhanced by other antifibrillatory agents or by non-antifibrillatory compounds?
  
• Could TdP induced by class III antiarrhythmic drugs be prevented by the administration of other cardioactive drugs?
  
• Is atrioventricular delay desirable as an integral component of any antifibrillatory agent intended for the treatment of AF?
  

Aspects of these pharmcodynamic properties of antiarrhythmic agents will be discussed in this review.

Currently, three categories of antiarrhythmic drugs are under investigation: (i) atrial-selective agents with simple ion-channel-blocking properties; (ii) de-iodinated amiodarone congeners with multi-channel-blocking properties; and (iii) other agents with non-selective ion-channel-blocking properties (Table 2). As indicated earlier, the first group may be critical with respect to avoiding the serious ventricular proarrhythmic effect of most current antiarrhythmic drugs. The second group includes newer drugs, similar to amiodarone, that are primarily class III agents (i.e. delay repolarization by blocking outward potassium channels), but, importantly, also block multiple other ion channels. The expectation is that such amiodarone congeners might retain the efficacy of the parent compound, although not inducing its well-known adverse reactions.

View this table: [in this window] [in a new window]   Table 2 New antiarrhythmic drugs

 

	Atrial-selective antiarrhythmic drugs

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
This subclass of antiarrhythmic agents has been developed recently to overcome the consequences of proarrhythmic reactions of ventricular origin. The atrial selectivity of these agents is designed to prevent the development of VT or VF and, in particular, the genesis of TdP resulting from the QT interval prolongation induced by many currently available class III agents. Thus, atrial-selective agents should ideally be devoid of significant Na-channel-blocking or QT lengthening properties in the ventricular tissues, including the Purkinje fibres.

The development of antiarrhythmic drugs with selective channel-blocking profiles⁴ has recently been made possible through a greater understanding of the pathophysiology of AF.¹⁰ For example, the finding that the ultra-rapid delayed rectifier (I_Kur) current exists in the atria, but not in ventricular tissues, has offered the prospect of developing atrial-selective drugs devoid of ventricular proarrhythmic toxicity for the treatment of patients with AF. These so-called atrial-selective agents include I_Kur blockers, atrial-selective sodium-channel blockers, muscarinic M₂-receptor blockers, and 5-HT₄ receptor antagonists.

Vernakalant (RSD1235; Cardiome, Canada; Astellas Pharma, USA) is a frequency-dependent sodium and early-activating potassium channel blocker¹¹ (Table 2). This agent was synthesized as an atrial-selective compound intended for both acute restoration of sinus rhythm in patients with AF, using the intravenous formulation, and long-term maintenance of sinus rhythm, using an oral formulation. When compared with placebo, intravenous vernakalant appears to be both effective and safe for acute conversion in patients with AF.^12,13 However, its efficacy in patients with atrial flutter is uncertain. An oral formulation of vernakalant is under development for the long-term maintenance of normal sinus rhythm following cardioversion.

AVE0118 (Sanofi-Aventis, France) is an atrial-selective potassium channel blocker, inhibiting the ultra-rapid component of the delayed rectifier (I_kur), which is only present in the atria, and the transient outward current (I_to), which is found in much higher density in the atria. In animals, AVE0118 prolonged atrial refractoriness, notably in electrically remodelled atria, prolonged atrial wavelength in a dose-dependent fashion, reduced the inducibility of AF, and acutely converted persistent AF to sinus rhythm without altering the QT interval.¹⁴.

AZD7009 (AstraZeneca, UK) is a mixed ion-channel blocker blocking the delayed rectifying potassium current (I_Kr), the sodium current (I_Na), and the ultra-rapid delayed rectifying potassium current (I_Kur), with electrophysiological effects predominantly on atrial tissue.¹⁵ Both an intravenous formulation for acute conversion and an oral formulation for long-term treatment of AF are being developed and are now in phase II trials.

The clinical merits and limitations of the so-called atrial-selective agents in the control of AF are worth examining. From the known properties of vernakalant (RSD1235), one of the first of such compounds to be tested in clinical trials, it is certain that the drug is effective in the conversion of AF to sinus rhythm when administered intravenously.^11,12 On the contrary, it is not clear how an atrial-selective compound might act in other clinical settings, nor is it yet known how effective such a compound might be for maintaining sinus rhythm in patients with AF. Furthermore, vernakalant does not appear to impede atrioventricular conduction and, therefore, the addition of a rate-controlling agent during AF recurrences may become imperative. At this early stage of development of atrial-selective compounds, the precise role of these agents in the control of AF remains to be defined. However, if they are found to be consistently effective in maintaining sinus rhythm in the long-term, they could play a significant therapeutic role by augmenting the activity of a wide range of antifibrillatory agents, particularly amiodarone congeners. These latter compounds appear to be devoid of major proarrhythmic reactions, particularly TdP, and are also effective in slowing ventricular rate should sinus rhythm relapse to AF.

	Amiodarone congeners

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Both amiodarone and sotalol were synthesized as antianginal agents in 1962, but their unique electrophysiological properties were not elucidated until 1970¹⁶ and they were not introduced as antiarrhythmic agents until a decade later. They formed the basis for the concept of controlling both atrial and ventricular arrhythmias by lengthening the action potential duration (APD) and the refractory period in myocardial cells. Over 40 years later, amiodarone and sotalol remain the two leading antiarrhythmic agents for the control of arrhythmias, especially AF. Amiodarone is of particular interest in view of the complexity of its electropharmacological properties and its effectiveness in maintaining sinus rhythm, balanced against its unique combination of adverse reactions. The iodine moiety of amiodarone has been linked to many of its non-cardiac adverse effects, including pulmonary fibrosis (rarely fatal) and hypo- and hyper-thyroidism, as well as neuropathy, dermatological disorders, and hepatic toxicity. In contrast, amiodarone exerts a multiplicity of cardiac effects in the atria and ventricles, the most prominent being its striking and unique antifibrillatory actions in the control of cardiac arrhythmias, particularly AF.

Any mechanistic explanation of amiodarone's efficacy must encompass the multiplicity of variegated electropharmacological and pharmacodynamic actions, an understanding of which is critical for the development of clinically desirable congeners of the compound. The most significant of these include the following:

1. an unusually high degree of antiarrhythmic efficacy, particularly in the case of AF^7,17,18;
   
2. a very low proclivity to induce proarrhythmic reactions despite its significant class 1 actions and its marked tendency to prolong QT/QTc^19,20;
   
3. a powerful suppressant effect on premature ventricular contraction with a low efficacy in preventing VT/VF induced by programmed electrical stimulation²¹;
   
4. a striking difference between the acute and chronic pharmacological and therapeutic effects not readily accounted for by differences in plasma, tissue, or membrane levels of the drug²²;
   
5. an exceedingly long and variable plasma elimination half-life and an even longer therapeutic half-life, with a slow onset and offset of electrophysiological and therapeutic actions²²;
   
6. a propensity to induce marked bradycardia by its anti-adrenergic actions, without competitively blocking beta-adrenoceptors²²;
   
7. the virtual absence of negative inotropic effects, resulting in a potential to induce sustained increases in left ventricular ejection fraction, despite its reasonably potent class I actions²³;
   
8. electrophysiological effects closely resembling those present in hypothyroidism on the one hand and those induced by ranolazine on the other hand²⁴;
   
9. consistent reduction in the heterogeneity of myocardial refractoriness²⁵;
   
10. reduction of ventricular rate in AF because of its calcium channel-blocking effects and non-specific antiadrenergic actions.¹⁸
    

The above considerations undoubtedly created the background for the conception and development of amiodarone congeners designed to obviate, in particular, the development of thyroid dysfunction and pulmonary fibrosis. Dronedarone (Sanofi-Aventis) is a non-iodinated amiodarone benzofurane,^26,27 with many antiarrhythmic properties corresponding to those of amiodarone. Dronedarone inhibits sodium, potassium, and calcium currents, including the rapid delayed rectifier and acetylcholine-activated potassium currents and the L-type calcium current. Moreover, it is an antagonist of both alpha- and beta-adrenoreceptors. The ion-channel profile of the compound is compared with that of the parent compound in Table 2.

In an animal model of ischaemia- and reperfusion-induced arrhythmias, dronedarone was more potent than amiodarone in inhibiting arrhythmias.²⁸ When compared with amiodarone, dronedarone has a shorter half-life, can be loaded more rapidly, and may accumulate less in the tissues. In a dose-ranging trial in 199 patients,²⁹ the median time to AF relapse within a 6-month follow-up was 60 days on dronedarone 800 mg daily vs. 5 days in the placebo group (relative risk reduction 55% [95% Cl, 28 to 72%] P = 0.001). Higher doses (1200 and 1600 mg daily) were no more effective and were poorly tolerated, notably in terms of gastrointestinal side effects. Importantly, no thyroid, ocular or pulmonary toxicity, and no proarrhythmia were reported at any dose in this study. In the pooled analysis of the results from two international phase III trials of dronedarone in the maintenance of sinus rhythm in 1250 patients with either paroxysmal (70%) or persistent AF (EURIDIS and ADONIS), first-year data showed that, compared with placebo (two to one randomization), the time to AF recurrence was 2.3–2.7 times longer after treatment with dronedarone 400 mg twice daily.³⁰ Of particular importance is the fact that dronedarone significantly decreased the ventricular response during AF recurrences. Safety data were promising, but it should be noted that patients with advanced heart failure were excluded from the EURIDIS and ADONIS trials. The ATHENA clinical trial is ongoing in patients with AF at high cardiovascular risk.

SSR149744C (Sanofi-Aventis) is another new non-iodinated amiodarone derivative that exhibits electrophysiological and haemodynamic properties characteristic of dronedarone.³¹ Clinical trials are ongoing. ATI-2042 (Aryx, USA) is another amiodarone congener in which iodination is retained. This congener is being studied in a phase II trial. There is much evidence that amiodarone is a desirable developmental model for the creation of newer antiarrhythmic compounds. Figure 1 shows the similarities and differences in the properties of amiodarone and dronedarone. Of particular importance is the fact that the change in the molecular structure in the case of dronedarone led to the loss of unwanted thyroid and pulmonary effects, but the electrophysiological properties of the parent compound were retained. In addition, the non-specific anti-adrenergic and calcium-channel-blocking actions of dronedarone confer a potential for ventricular rate control in AF recurrences.

View larger version (63K): [in this window] [in a new window] [Download PowerPoint slide]   Figure 1 Comparison of some major pharmacodynamic properties of dronedarone and amiodarone. Both drugs are effective in the control of atrial fibrillation and flutter. Compared with amiodarone, dronedarone does not affect thyroid function nor does it induce pulmonary fibrosis. It has a much shorter half-life.

 

	Amiodarone congeners and proarrhythmic actions

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Compelling data have been reported, suggesting that amiodarone is a compound that consistently increases the QT interval on the surface ECG and reduces heart rate almost to the same level to that observed with sotalol. Nevertheless, in placebo-controlled, blinded trials involving 4000 patients, it did not appear to induce TdP, despite the major increases in the QT intervals.^19,20 There are increasing data indicating that amiodarone and its congeners, e.g. dronedarone and ranolazine, have the potential to variably increase ventricular repolarization by ionic mechanisms such that they are unlikely to provoke the early depolarizations produced by I_kr blockers and therefore have a lower risk of inducing TdP. Unlike most other class III agents such as dofetilide, d-sotalol, l-sotalol, amiodarone lengthens the APD in the ventricular myocardium. This effect is more evident in the epicardium and endocardium than in the mid-myocardial cells, in which the APD may even be shortened by the drug. The effects of chronic administration of amiodarone on the APD in epicardial, endocardial, and M cells relative to the alterations in the late I_Na, I_Ca, I_Kr, and I_Ks^32,33 have been studied.

This differential electrophysiological effect has two consequences. First, there will be less risk of generation of early after-depolarizations (the precursor of TdP) and secondly, the homogeneity of the myocardium will be increased, potentially reducing the likelihood of VT. A similar differential effect has been shown in the Purkinje fibres. This differential effect of drugs such as amiodarone, dronedarone, and ranolazine underlies the characteristic that rather than inducing TdP, they may be neutral in this respect or may even be anti-torsadogenic.^32,33 As an example, in a study of approximately 70 patients with AF receiving chronic amiodarone therapy, the intravenous administration of ibutilide resulted in only one very short-lived and self-terminating case of TdP,³⁴ in contrast to an expected incidence of this event of 5–6%.

	Other antiarrhythmic drugs

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Azimilide (Procter & Gamble, USA) is a selective class III antiarrhythmic drug that blocks both the rapid (I_Kr) and the slow (I_Ks) components of the delayed rectifier potassium channel.³⁵ Azimilide prolongs cardiac APD and refractory periods in both the atria and the ventricles. Its long half-life (up to 4 days) allows once-daily dosing and limits major fluctuations in blood concentrations. Several randomized placebo-controlled clinical trials have demonstrated the efficacy of azimilide in prolonging the symptom-free interval in patients with AF or atrial flutter.^36–39 In a meta-analysis, both 100 mg and 125 mg doses of azimilide demonstrated greater efficacy when compared with placebo in prolonging the symptomatic arrhythmia-free interval.³⁷ However, the precise effects of the drug with respect to maintaining sinus rhythm remain unclear. Nevertheless, in a double-blind, placebo-controlled study in patients with implantable cardioverter-defibrillators (ICD), azimilide significantly reduced the recurrence of VT or VF terminated by ICD shocks or anti-tachycardia pacing.⁴⁰

Tedisamil (Solvay Pharmaceuticals, Belgium), an antianginal agent, possesses multiple ion-channel effects, including blockade of the transient outward current, I_to, in addition to I_Kr, I_Ks, I_Kur, I_K-ATP, and even I_Na.^41–43 The drug also causes reverse, rate-dependent QT interval prolongation. In a multi-centre, double-blind, randomized, placebo-controlled study in 175 patients with symptomatic recent onset AF or atrial flutter, 41 and 51% of patients receiving intravenous tedisamil (0.4 or 0.6 mg/kg) converted to sinus rhythm with an average time to conversion of 35 min.⁴⁴ There were two instances (1.8%) of possible proarrhythmia. Other studies have also raised possible safety concerns about tedisamil's proarrhythmic effects, leading to temporary interruption of clinical trials.

Rotigaptide (ZP123, Zealand Pharma, Denmark) is a specific gap-junction-modifying drug. Gap junctions are specialized pores that ensure the coordinated cell-to-cell transmission of electrical impulses, essential for synchronized contraction.⁴⁵ Gap-junction modulation with rotigaptide reduced AF vulnerability to a level similar to that of control animals in a canine mitral regurgitation model of AF. However, it did not affect AF vulnerability in a canine heart failure model. Gap-junction modulation may present a novel therapeutic target in some forms of AF currently being studied in a phase II trial on rotigaptide.

Finally, recent data indicate that serotonin 5-HT₄ receptor antagonists could be promising drugs in patients with AF, on the basis that infusion of serotonin induces sinus tachycardia and other atrial tachyarrhythmias including AF. Furthermore, the atrial-specific 5-HT₄ receptor subtype is present in the atria but not in the ventricles, allowing the possibility to pharmacologically target this hormonal pathway without potentially inducing ventricular adverse effects. Serotonin 5-HT₄ receptor antagonists, currently in development, include RS-100302, SB 207266 (GlaxoSmithKline, UK) and CVT-150.⁴

	Pharmacological improvement of maintenance of sinus rhythm in atrial fibrillation by combination therapy

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
It is widely recognized that over 50% of patients with AF restored to sinus rhythm experience relapse at 1 year while taking currently available antifibrillatory drugs, with the sole exception of amiodarone. The uniqueness of amiodarone in this respect is not well understood.²² However, its superior effectiveness in maintaining sinus rhythm may be attributable at least in part to the multiplicity of its discrete pharmacodynamic effects. In this respect, the properties of amiodarone clearly extend beyond the relatively narrow confines of the antiarrhythmic drug classification.

In recent years, the question has arisen whether it might be possible to augment the antiarrhythmic effectiveness of agents used for maintaining sinus rhythm in patients with AF by combination therapy. This concept is not entirely new and overall experience with antiarrythmic drug combinations has been small, uncontrolled, non-systematic, and sporadic.⁴⁶ However, some aspects of the rationale for the use of single agents vs. combination therapy in maintaining sinus rhythm in patients with AF were examined a number of years ago.⁴⁷ In the event, it appears that the scope of combination therapy is somewhat broader than originally conceived. Several objectives of antiarhythmic drug combinations may be defined, the primary objective being better maintenance of sinus rhythm. The possibility of counteracting the proarrhythmic effects of antiarrhythmic agents is also of growing importance, a topic discussed briefly above.

It was recently shown that sinus rhythm achieved after conversion of AF may be meaningfully prolonged by certain non-antiarrhythmic agents, such as angiotensin-converting enzyme (ACE)-inhibitors, corticosteroids, aldosterone antagonists, statins, and omega-3PUFA (Table 3). For example, the rate of AF recurrence was lower when amiodarone was combined with ACE-inhibitors than with amiodarone alone.⁴⁸ Madrid et al.⁴⁹ compared two groups of patients who had experienced one episode of AF for > 7 days. After conversion, the first group of patients was treated with amiodarone alone (400 mg/day) and the second group with amiodarone and irbesartan (150–300 mg/day) combined. The primary endpoint of the study was the time to recurrence of AF. Out of a total of 186 patients, 154 were available for intention-to-treat-analysis. During the follow-up (median time 254 days), Kaplan–Meier analysis showed that patients treated with irbesartan against a background of amiodarone treatment had a greater probability of remaining free of AF (79.52 vs. 55.91%, P = 0.007).

View this table: [in this window] [in a new window]   Table 3 Conventionally non-antiarrhythmic agents with antiarrhythmic properties

 
Pedersen et al.⁴⁸ investigated the effect of trandolapril on the incidence of AF in patients with ischaemic heart disease associated with impaired left ventricular function. This study comprised a retrospective analysis of data from a large placebo-controlled trial (n = 1577), in which a total of 64 patients developed AF during a follow-up of 2–4 years. Significantly more patients on placebo developed AF (n = 42; 5.3%) than those on trandolapril (n = 22; 2.8%; P = 0.05). Although these and other data are clearly promising, they were not derived from prospective, blinded, and controlled clinical trials, which are mandatory for defining the role of this multitude of compounds in the treatment of AF. It should be emphasized that both beta-blockers and ACE-inhibitors exert significant effects on the long-term maintenance of sinus rhythm in patients with AF. Their concomitant use in a combination regimen is not excluded.⁵⁰ Beta-blockers and ACE-inhibitors can be combined with long-term amiodarone therapy to prolong the duration of sinus rhythm after cardioversion in a large percentage of patients with AF. However, it should be emphasized that beta-blockers are superior antifibrillatory drugs for the control of a wide spectrum of ventricular and supraventricular arrhythmias.^51–53 Furthermore, they confer a mortality benefit and freedom from proarrhythmic actions, although in the elderly, they may precipitate the need for implantation of a pacemaker because of the additive anti-adrenergic effects of beta-blockade and amiodarone.

	Conclusions

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 
Cardioversion and maintenance of sinus rhythm in patients with AF remain a therapeutic challenge. Currently available antiarrhythmic agents have two limitations. In the first instance, many of them have limited effectiveness in patients with AF. Furthermore, although some of these agents are reasonably effective in maintaining sinus rhythm, their side effects preclude their continuous long-term optimal use in clinical practice. The most promising of the newer antiarrhythmic drugs include atrial-selective agents (e.g. vernakalant) and agents with multiple channel-blocking properties (e.g. dronedarone), the latter allowing the simultaneous control of rate and rhythm, as in the case of amiodarone. Although the ideal antiarrhythmic agent remains elusive, the newer drugs discussed in this review may offer safety as well as effectiveness in the control of AF, especially in the context of rational and judicious combination therapy. These newer antiarrhythmic agents may also pave the way to the development of further novel compounds.

Conflict of interest: none declared.

	References

Top Abstract Introduction Currently available... Newer antiarrhythmic drugs Atrial-selective antiarrhythmic... Amiodarone congeners Amiodarone congeners and... Other antiarrhythmic drugs Pharmacological improvement of... Conclusions References

 

1. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey J-Y, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc J-J, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, ACC/AHA Task Force Members ESC Committee for Practice Guidelines. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation (2006) 114:e257–e354.[Free Full Text]
2. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke (2001) 32:803–808.[Free Full Text]
3. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation (1998) 98:946–952.[Abstract/Free Full Text]
4. Goldstein RN, Stambler BS. New antiarrhythmic drugs for prevention of atrial fibrillation. Prog Cardiovasc Dis (2005) 48:193–208.[CrossRef][Web of Science][Medline]
5. Singh BN. The coming of age of the class III antiarrhythmic principle: retrospective and future trends. Am J Cardiol (1996) 78(Suppl. 4A):17–27.[Web of Science][Medline]
6. Singh BN. Amiodarone: a multifaceted antiarrhythmic drug. Curr Cardiol Rep (2006) 8:349–355.[CrossRef][Medline]
7. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD, Raisch DW, Ezekowitz MD, Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med (2005) 352:1861–1872.[Abstract/Free Full Text]
8. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med (2002) 346:884–890.[Abstract/Free Full Text]
9. Sicouri S, Moro S, Litovsky S, Elizari MV, Antzelevitch C. Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart. J Cardiovasc Electrophysiol (1997) 8:1269–1279.[Web of Science][Medline]
10. Nattel S. Therapeutic implications of atrial fibrillation mechanisms: can mechanistic insights be used to improve AF management? Cardiovasc Res (2002) 54:347–360.[Abstract/Free Full Text]
11. Fedida D, Orth PM, Chen JY, Lin S, Plouvier B, Jung G, Ezrin AM, Beatch GN. The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol (2005) 16:1227–1238.[CrossRef][Web of Science][Medline]
12. Roy D, Rowe BH, Stiell IG, Coutu B, Ip JH, Phaneuf D, Lee J, Vidaillet H, Dickinson G, Grant S, Ezrin AM, Beatch GN, CRAFT Investigators. A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent-onset atrial fibrillation. J Am Coll Cardiol (2004) 44:2355–2361.[Abstract/Free Full Text]
13. ACT 1: Atrial Arrhythmia Conversion Trial 1—a new antiarrhythmic agent. http://www.medscape.com/viewarticle/504950.
14. Blaauw Y, Gögelein H, Tieleman RG, van Hunnik A, Schotten U, Allessie MA. ‘Early’ class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodelled atria of the goat. Circulation (2004) 110:1717–1724.[Abstract/Free Full Text]
15. Goldstein RN, Christian C, Carlson L, Waldo AL. AZD7009: a new antiarrhythmic drug with predominant effects on the atria effectively terminates and prevents re-induction of atrial fibrillation and flutter in the sterile pericarditis model. J Cardiovasc Electrophysiol (2004) 15:1444–1450.[CrossRef][Web of Science][Medline]
16. Singh BN, Vaughan Williams EM. The effect of amiodarone: a new anti-anginal drug, on cardiac muscle. Br J Pharmacol (1970) 39:657–668.[Web of Science][Medline]
17. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, Kus T, Lambert J, Dubuc M, Gagné P, Nattel S, Thibault B. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med (2000) 342:913–920.[Abstract/Free Full Text]
18. Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, Singh SN. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT). Circulation (1998) 98:2574–2579.[Abstract/Free Full Text]
19. Hohnloser S, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects: a review with special reference to torsades de pointes tachycardia. Ann Intern Med (1994) 121:529–537.[Abstract/Free Full Text]
20. Hohnloser S, Singh BN. Proarrhythmia with class III antiarrhythmic drugs. Definition, electrophysiologic mechanism, incidence, predisposing factors, and clinical implications. J Electrophysiol (1995) 6:920–936.[CrossRef]
21. Singh BN. Rise and fall of guided antiarrhythmic therapy for ventricular tachycardia and fibrillation. J Cardiovasc Pharmacol Ther (1996) 1:89–94.[Free Full Text]
22. Singh BN. Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent. Am J Cardiol (1996) 78:41–53.[Web of Science][Medline]
23. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmias. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med (1995) 333:77–82.[Abstract/Free Full Text]
24. Singh BN. Amiodarone and homogeneity of ventricular repolarization and refractoriness. J Cardiovasc Pharmacol Ther (1996) 1:265–270.[Free Full Text]
25. Sun W, Sarma JSM, Singh BN. Electrophysiological effects of dronedarone (SR33589), a non-iodinated benzofuran derivative in the rabbit heart. Comparison with amiodarone. Circulation (1999) 100:2276–2283.[Abstract/Free Full Text]
26. Sun W, Sarma JSM, Singh BN. Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone. J Cardiovasc Pharmacol (2002) 39:677–684.[CrossRef][Web of Science][Medline]
27. Rochetti M, Bertrand JP, Nisato D, et al. Cellular electrophysiological study of dronedarone, a new amiodarone-like agent, in guinea pig sino-atrial node. Arch Pharmacol (1998) 358:R617.
28. Rochetaing A, Barbe C, Kreher P. Beneficial effects of amiodarone and dronedarone (SR33589b), when applied during low-flow ischemia, on arrhythmia and functional parameters assessed during reperfusion in isolated rat hearts. J Cardiovasc Pharmacol (2001) 38:500–511.[CrossRef][Web of Science][Medline]
29. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J (2003) 24:1481–1487.[Abstract/Free Full Text]
30. Singh BN, Connolly SJ, Crijns HJGM, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH, for the EURIDIS ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med (2007) 357:987–989.[Abstract/Free Full Text]
31. Gautier P, Serre M, Cosnier-Pucheu S, Djandjighian L, Roccon A, Herbert JM, Nisato D. In vivo and in vitro antiarrhythmic effects of SSR149744C in animal models of atrial fibrillation and ventricular arrhythmias. J Cardiovasc Pharmacol (2005) 45:125–135.[CrossRef][Web of Science][Medline]
32. Singh BN, Wadhani N. Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. J Cardiovasc Pharmacol Ther (2004) 9(Suppl. 1):S85–S97.[Abstract/Free Full Text]
33. Antzelevitch C, Bellardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A, Diego JM, Fish JM, Cordeiro JM, Goodrow RJ, Scornik F, Perez G. Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther (2004) 9(Suppl. 1):S65–S83.[Abstract/Free Full Text]
34. Glatter K, Yang Y, Chatterjee K, Modin G, Cheng J, Kayser S, Scheinman MM. Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation (2001) 103:253–257.[Abstract/Free Full Text]
35. VerNooy RA, Mangrum JM. Azimilide, a novel oral class III antiarrhythmic for both supraventricular and ventricular arrhythmias. Curr Drug Targets Cardiovasc Haematol Disord (2005) 5:75–84.[CrossRef][Medline]
36. Page RL, Connolly SJ, Wilkinson WE, Marcello SR, Schnell DJ, Pritchett EL, Azimilide Supraventricular Arrhythmia Program (ASAP) Investigators. Antiarrhythmic effects of azimilide in paroxysmal supraventricular tachycardia: efficacy and dose–response. Am Heart J (2002) 143:643–649.[CrossRef][Web of Science][Medline]
37. Connolly SJ, Schnell DJ, Page RL, Wilkinson WE, Marcello SR, Pritchett EL. Dose response relations of azimilide in the management of symptomatic, recurrent, atrial fibrillation. Am J Cardiol (2001) 88:974–979.[CrossRef][Web of Science][Medline]
38. Pritchett EL, Page RL, Connolly SJ, Marcello SR, Schnell DJ, Wilkinson WE. Antiarrhythmic effects of azimilide in atrial fibrillation: efficacy and dose–response. Azimilide supraventricular arrhythmia program 3 (SVA-3) Investigators. J Am Coll Cardiol (2000) 36:794–802.[Abstract/Free Full Text]
39. Pratt CM, Singh SN, Al-Khalidi HR, Brum JM, Holroyde MJ, Marcello SR, Schwartz PJ, Camm AJ, ALIVE Investigators. The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: Results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. J Am Coll Cardiol (2004) 43:1211–1216.[Abstract/Free Full Text]
40. Dorian P, Borggrefe M, Al-Khalidi HR, Hohnloser SH, Brum JM, Tatla DS, Brachmann J, Myerburg RJ, Cannom DS, van der Laan M, Holroyde MJ, Singer I, Pratt CM. SHock Inhibition Evaluation with AzimiLiDe (SHIELD) Investigators. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation (2004) 110:3646–3654.[Abstract/Free Full Text]
41. Dukes ID, Morad M. Tedisamil inactivates transient outward K + current in rat ventricular myocytes. Am J Physiol (1989) 257:H1746–H1749.[Web of Science][Medline]
42. Dukes ID, Cleemann L, Morad M. Tedisamil blocks the transient and delayed rectifier K⁺ currents in mammalian cardiac and glial cells. J Pharmacol Exp Ther (1990) 254:560–569.[Abstract/Free Full Text]
43. Jost N, Virág L, Hála O, Varró A, Thormählen D, Papp JG. Effect of the antifibrillatory compound tedisamil (KC-8857) on transmembrane currents in mammalian ventricular myocytes. Curr Med Chem (2004) 11:3219–3228.[Web of Science][Medline]
44. Hohnloser SH, Dorian P, Straub M, Beckmann K, Kowey P. Safety and efficacy of intravenously administered tedisamil for rapid conversion of recent-onset atrial fibrillation atrial flutter. J Am Coll Cardiol (2004) 44:99–104.[Abstract/Free Full Text]
45. Guerra JM, Everett TH, Lee KW, Wilson E, Olgin JE. Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation (2006) 114:110–118.[Abstract/Free Full Text]
46. Singh BN, Doshi S. Maintaining sinus rhythm in atrial fibrillation by drug therapy: single agents or combinations? J Cardiovasc Pharmacol Ther (2000) 5:139–142.[Medline]
47. Altamirano J, Gallik DM, Singh BN. Controlling paroxysmal atrial fibrillation by a combination of amiodarone and flecainide: description of a case with 15-year follow-up. J Cardiovasc Pharmacol Ther (1996) 1:333–338.[Abstract/Free Full Text]
48. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolopril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation (1999) 100:376–380.[Abstract/Free Full Text]
49. Madrid AH, Bueno MG, Rebollo JM, Marín I, Peña G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation (2002) 106:331–336.[Abstract/Free Full Text]
50. Singh JP, Larson MG, Levy D, Evans JC, Tsuji H, Benjamin EJ. Is baseline autonomic tone associated with new onset atrial fibrillation? Insights from the Framingham heart study. Ann Noninvasive Electrocardiol (2004) 9:215–220.[CrossRef][Web of Science][Medline]
51. Kennedy HL, Brooks MM, Barker AH, Bergstrand R, Huther ML, Beanlands DS, Bigger JT, Goldstein S, for the CAST Investigators. Beta-blocker therapy in the cardiac arrhythmia suppression trial. Am J Cardiol (1994) 74:674–680.[CrossRef][Web of Science][Medline]
52. Singh BN. Beta-adrenergic blockers as antiarrhythmic antifibrillatory compounds: an overview. J Cardiovasc Pharmacol Ther (2005) 10(Suppl. 1):S3–S14.[Abstract/Free Full Text]
53. Andrews M, Nelson BP. Atrial fibrillation. Mt Sinai J Med (2006) 73:482–492.[Medline]

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