REVIEW

New antiarrhythmic agents for

Anirban Choudhury2 Atrial fibrillation (AF) is the most common sustained encountered in clinical and Gregory YH Lip†1 practice, with an incidence that increases twofold every decade after 55 years of age. †Author for correspondence Despite recent advances in our understanding of the mechanisms of AF, effective treatment †1University Department of Medicine, City Hospital, remains difficult in many patients. Pharmacotherapy remains the mainstay of treatment and Birmingham, B18 7QH, UK includes ventricular rate control as well as restoration and maintenance of sinus rhythm. In Tel.: +44 121 5075080 the light of studies demonstrating safety concerns with class IC agents, class III agents such Fax: +44 121 554 4083 [email protected] as and have become the preferred and most commonly used drugs. 2University Department Unfortunately, a plethora of side effects often limits the long-term use of amiodarone. of Medicine, City Hospital, Thus, there have been many recent developments in antiarrhythmic drug therapy for AF Birmingham, B18 7QH, UK that have gained more interest, particularly with the recent debate over rate versus rhythm Tel.: +44 121 5075080 Fax: +44 121 554 4083 control. It is hoped that the availability of the newer agents will at least provide a greater choice of therapies and improve our management of this common arrhythmia.

Atrial fibrillation (AF) is the most common many existing ones have significant side effects arrhythmia encountered in clinical practice [1]. It and limitations of efficacy. affects 5% of the population above the age of 65 years and 10% above 75 years [2]. AF accounts Pathophysiology of AF: a brief overview for 35% of USA hospitalizations for cardiac The genesis of AF is not entirely clear [5]. Similar to [3]. Its presence increases mortality most cardiac arrhythmias, the basic mechanisms twofold, mostly through stroke and heart failure. can be discussed under three categories. In view of the aging population, AF is likely to be an even greater public health problem. Disorder of impulse generation There have been many recent developments in Enhanced automaticity of atrial myocytes antiarrhythmic drug therapy for AF which have around the pulmonary veins can act as initial gained more interest, particularly with the recent triggers for episodes of paroxysmal AF [6]. Radi- debate over rate versus rhythm control for AF [4]. ofrequency ablation of this focus can therefore Although restoration of sinus rhythm has tradi- result in a ‘cure’ of AF [7]. Indeed, ablation has tionally been the main focus of AF management, been very successful in the selected group of recently published trials have compared the patients where there has been drug intolerance strategy of rate control versus rhythm control as or ineffectiveness and many such patients have the primary aim in the treatment of AF and sug- demonstrated improvement in symptoms and gested that neither may be superior, in relation quality of life following such treatment. to long-term symptoms, quality of life, mortality and morbidity [4]. Disorder of impulse conduction These trials do have some limitations, but During sinus rhythm, the impulse generated based on the combined evidence from the rand- from the sino-atrial node is unidirectional in omized controlled trials, future management for conduction because of the refractoriness of the the majority of AF patients is likely to be cen- preceding myocardium. However, if this impulse tered on rate control and anticoagulation rather encounters an area of refractory myocardium, its Keywords: atrial fibrillation, new than cardioversion, and much of the treatment progression as a wavefront is broken. Following antiarrhythmic agents needs to be individualized [4]. However, rhythm its circuit around this area, the wavefront may control should still be considered in ‘lone’ AF return to its point of origin after the refractory and in those patients who are very symptomatic, period has finished and re-excite the myocar- as well as remaining the target of treatment in dium, thereby setting up a re-entry circuit. In paroxysmal AF. New antiarrhythmic agents chronic AF, multiple re-entrant waves wander Future Drugs Ltd therefore still have some role, especially since over the atria supported by areas of functional

2004 © Future Drugs Ltd ISSN 1475-0708 http://www.future-drugs.com Therapy (2004) 1(1), 111–121 111 REVIEW – Lip & Choudhury

conduction block. These waves collide and pacing-induced AF, the initial AF episodes self- divide and maintain the chaotic electrical state terminated but on repeated stimulation, the of chronic AF. episodes became longer in duration until sus- tained AF was established – referred to as ‘AF Combined mechanisms begets AF’ [12]. These include both enhanced automaticity and It is thought that within minutes of rapid abnormal conduction. The role of the autonomic atrial rate, there is intracellular calcium overload, function has also been postulated and forms of AF which decreases the trans-sarcolemmal calcium that are predominantly vagotonic or gradient and hence reduces calcium-induced have been described. In the clinical setting this has activation of the L-type channel, with conse- been less useful, since many patients often have quent reduction in L-type calcium current, ICal. features of both. This phenomenon, termed ‘pseudo-remodeling’, shortens the refractory period [13]. In cases of The remodeling phenomenon persistent atrial tachycardia of longer duration The success rate of cardioversion is higher when (hours to days), there is downregulation of the AF is of short duration and the likelihood of L-type calcium and sarcoplasmic reticular recurrence postcardioversion decreases after a (Ca2+)-ATPase gene [14]; indeed, this is probably few weeks [9–11]. These findings suggest that AF the basis of true electrophysiological remodeling. is a progressive and self-perpetuating disease, When this rapid atrial rate persists even longer which maintains itself via a phenomenon (weeks to months) structural changes take place described as electrical and structural remodeling. (hibernation, fibrosis and fatty degeneration), The hallmark of electrical remodeling is the which can be irreversible [15–17]. shortening of the atrial effective refractory period (AERP) associated with loss of the rate Preventing atrial remodeling with drugs dependency of the AERP. These alterations Prevention of AF recurrence in patients with which appear within minutes to hours of the paroxysmal AF, or the long-term maintenance onset of AF, increase atrial vulnerability and of sinus rhythm after successful cardioversion are self-perpetuating. The classic demonstra- is difficult, with most recurrences occurring tion of this was by Wijffels and coworkers in a within the first 5 days [11]. The increased vul- goat model of AF, who demonstrated that after nerability to recurrence is most likely second- ary to AF-induced atrial electrophysiological Table 1. Data from the VERAF study [21]. remodeling, as described above. The above hypothesis was supported by ani- mal experiments which suggested infusion of 70 significantly reduced electrical Verapamil remodeling [18], whilst (which pro- 60 motes calcium overload) may aggravate this Standard 50 phenomenon [19]. Certainly, there is growing clinical evidence even in humans that pre- 40 treatment with verapamil could reduce the 30 early recurrence of AF after successful cardio- version [11,20,21]. This also seems to be applica- 20 ble for other calcium antagonists, including [11] 10 and dihydropyridines . At the Incidence (% of patients) same time, the lack of benefit from long-term 0 treatment with verapamil strongly supports the ERAF LRAF Sinus hypothesis that recovery from electrical remod- rhythm eling occurs in a few days and after this period, these drugs may only play a marginal role in The effect of administration of standalone verapamil (240 mg/day) from 1 month before to preventing recurrence [20,21] (Figure 1). 1 month after electrical cardioversion (CV) of persistent AF as compared with standard Recent studies suggest AF in the setting of con- therapy (in which no antiarrhythmic agents were used) on ERAF, LRAF and consequent gestive cardiac failure may be mediated through maintenance of sinus rhythm 1 month after CV. Verapamil was significantly more effective in preventing ERAF (p < 0.001) but had no beneficial effect on LRAF. mechanisms that differ from those reported in the AF: Atrial fibrillation; ERAF: Early recurrence of AF (7 days); atrial-tachycardia-induced models [22]. Indeed, LRAF: Late recurrence of AF (8–30 days) atrial dilation and fibrosis seem to play a major

112 Therapy (2004) 1(1) New antiarrhythmic agents for AF – REVIEW

role in this setting and the observed changes in as the possible synergistic effect in combination AERP are opposite to that seen in the tachycardia with antiarrhythmic drugs. model, that is an increased AERP [22]. These changes may be prevented by treatment with the Classification of AF & current angiotensin-converting enzyme (ACE) inhibitors management approaches [23] or angiotensin II blockers – the bene- Various terminologies are used to describe differ- ficial effects of these groups of drugs have also ent subtypes of AF – acute, paroxysmal, recur- been noted in the atrial tachycardia model [24]. For rent, persistent and permanent. The term example, the results of the first prospective and chronic AF is often loosely used to encompass all randomized trial conducted in humans [25] the subtypes of AF, other than acute AF. Lack of showed that adding the angiotensin II receptor uniformity of these terms often results in diffi- antagonist, irbesartan, to amiodarone was more culties in comparing studies on AF, effectiveness effective in maintaining sinus rhythm after suc- of treatments or therapeutic strategies. cessful cardioversion of AF, when compared with ‘Acute AF’ usually occurs in context of a pre- amiodarone alone. In this study, irbesartan cipitating illness, such as myocardial infarction, reduced both the immediate (1 h) and subacute thyrotoxicosis, chest infection, or secondary to recurrence (first few weeks) of AF. positive chronotrophic agents as often seen in The mechanisms underlying the beneficial the critical care setting. It is important for the effects of renin–angiotensin system blockade clinician to ascertain whether an incident of AF (with the ACE inhibitors and angiotensin II is the very first episode i.e., the initial event and receptor blockers) remain speculative but may be whether it is symptomatic or not, self-terminat- related to one of the following mechanisms: ing or not, in order to formulate a long-term • Decreased atrial stretch management plan. Treatment of the underlying • Reduction of left ventricular end-diastolic cause is usually sufficient to restore sinus pressure rhythm but if the AF causes hemodynamic compromise then electrical cardioversion may • Prevention and regression of atrial fibrosis be required, or rate control may be needed in • Modulation of autonomic balance the acute setting using β-blockers, rate-limiting • Prevention of ion current alterations with blockers (although it should subsequent reversal of atrial remodeling be noted that some of these are also negative • Reduction of blood pressure ionotropes) or amiodarone. Class I agents are Further randomized prospective trials are usually avoided because of the risk of provok- needed to establish the actual role of verapamil ing serious ventricular arrhythmias or acute and renin–angiotensin blockade (and their com- heart failure. Digoxin, although positively bination) in preventing recurrence of AF, as well ionotropic and rate-limiting, is not the best

Table 1. Antiarrhythmic drugs to restore sinus rhythm in atrial fibrillation. Drug Route Time to efficacy Efficacy (%) Side effects (%) Intravenous <4 h 43–89 0–17 Oral <5 h 72–86 10–14 Disopyramide Intravenous <8 h 55–86 7 Quinidine Oral <24 h 59–92 3–46 Flecainide Intravenous <2 h 65–96 7–31 Oral <5 h 78–95 21–23 Amiodarone Intravenous <12 h 25–89 7–27 Sotalol Intravenous <4 h 31–85 10–20 Ibutilide Intravenous <90 min 18–48 4 Dofetilide iIntravenous <2 h 30–35 3–8 Oral <36 h 6–18 Different classes of antiarrhythmic agents appear to yield similar results. However, certain factors must be taken into account if one is to compare and evaluate the real differences between these drugs, namely, the route of administration, the ‘time to efficacy’, incidence of adverse events, the duration of AF, underlying clinical condition, left ventricular function, the presence or absence of any organic heart disease and finally the placebo effect (which is consistently around 50% at 12–24 h in durations of AF of 48 h or less).

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drug to use in acute AF because of its slow Established or permanent AF refers to those onset of action and its reduced rate-limiting patients in whom AF has been present for a long effect in the presence of sympathetic overdrive. time and in whom cardioversion has not been It should also be noted that digoxin use may be indicated, or one or more attempts have failed to associated with increased mortality in the restore sinus rhythm. Established AF or perma- setting of acute myocardial infarction [26]. nent AF may be the first presentation of a non- Episodes of paroxysmal AF usually self-termi- self-terminating arrhythmia or be preceded by nate within 48 h and, by definition, in fewer recurrent self-terminating episodes. In these than 7 days. If the patient has had two or more patients, the main aim is rate control and anti- episodes, AF is said to be recurrent. The aim of thrombotic therapy. This is generally achieved management in this group of patients is reduc- with class IV agents (diltiazem, verapamil), class tion in frequency and duration of paroxysms of II agents (β−blockers) or digoxin. Amiodarone AF and maintenance of sinus rhythm. Class IC may have a role to play, particularly in patients drugs ( [Tambocor®, 3M Pharmaceuti- with AF and congestive cardiac failure. Mono- cals, MN, USA], propafenone [Rythmol®, therapy is often found to be inadequate in 24 h Abbott Laboratories, CA, USA]) administered and exercise-induced heart rate control, whereas orally or intravenously represent the first-choice combination therapy (e.g., digoxin plus β- therapy in patients with no organic heart disease blocker or rate-limiting calcium antagonist [37]) [27–30]. However, in the presence of heart failure, should be considered as it may be useful not only ischemic heart disease or after coronary artery in achieving satisfactory ventricular rate but also bypass surgery, this group of drugs is associated in reducing the dosage of individual drugs and, with increased mortality [31] and amiodarone is consequently, dose-dependent side effects. the preferred drug (Table 1). In summary, the goals of management in AF When an episode of AF has lasted longer should be tailored both to the patient and the than 7 days, it is designated as ‘persistent’. The type of AF. Careful definition of the subtype of timeframe of 7 days, although arbitrary, repre- AF and patient characteristics help define sents the limit beyond which spontaneous car- management goals and the right antiarrhyth- dioversion is unlikely to occur. Electrical cardi- mic drug choice. Despite recent advances in oversion (preferably with a biphasic our understanding of the pathophysiology of defibrillator) currently plays a major role [32]. AF, effective treatment still remains difficult in However, maintenance of sinus rhythm can be many patients. In view of the limited role of difficult with a recurrence rate of 50–60% at nonpharmacological agents, drug therapy 6–12 months [33–36]. Concurrent treatment remains the mainstay of treatment. The limita- with antiarrhythmic agents may increase the tions in current treatments leave the door open success rate (Table 2). However, given the evi- for the development of new antiarrhythmics dence from the recent rate versus rhythm tri- with improved efficacy, safety and favorable als, future management of the majority of side-effect profile. these patients is likely to be centered on rate control and anticoagulation, rather than an New antiarrhythmic agents aggressive cardioversion policy for all patients The main emphasis in research and develop- with AF. ment has been on agents that would be used for cardioversion or maintenance of sinus rhythm. Table 2. Maintaining sinus rhythm after Thus, class I and III agents that prolong the electrical cardioversion. refractory period and thus prevent re-entry have been researched the most. Their mechanism of Drug Sinus rhythm (%) action and development can be discussed 6 months 12 months according to whether they are class I or III Propafenone 40 – agents, combination agents, modification of 44-50 54 existing agents or de novo agents (Table 3). 27–58 23–51 Drugs with class IC action Flecainide – 34–42 The current role of IC agents has been largely lim- Amiodarone 75 50–73 ited to patients with paroxysmal AF and to facili- Sotalol 44–50 37–46 tate electrical cardioversion in persistent AF, pro- 71 66 vided there is no history of ischemic heart disease

114 Therapy (2004) 1(1) New antiarrhythmic agents for AF – REVIEW

Table 3. Mechanism of action of new antiarrhythmic drugs. Class Mechanism of action Route of adminstration I Pure Na Oral

Dofetilide Blocks Ikr Oral/Intravenous

III Blocks Ikr, stimulates INa Intravenous

Azilimide Blocks Ikr, IKs Oral Tedisamil Intravenous Blocks Ikr, IKTo, IK ATP

Multichannel blocker Ersentilide Blocks IKr and b1 Intravenous and oral

Dronedarone Blocks INa, ICa, IL, IKr, IKs and IK1 Oral SD3212 Intravenous Blocks INa, IK, ICa

Novel antiarrhythmics Piboserod (SB207266) 5HT4 antagonist, blocks Ikr Oral RSD1235 Blocks atrial potassium (Kv1.5) Intravenous and oral CVT-2759, CVT-510, SHA-040 and Intravenous Partial to A1- receptor

or heart failure. Thus, the current aim is to duration (and hence of QT interval). Initial tri- develop pure class IC agents without a significant als using dofetilide and ibutilide have shown negative inotropic action. promising results in their role in attaining and One such agent is pilsicainide (Sunrythm®, maintaining sinus rhythm. Suntory Limited), which has been shown to Dofetilide is a pure class III agent that selec- block sodium channels without any significant tively blocks Ikr and has been licensed in the action on Ca2+ or K+ channels [38]. In patients USA for maintenance of sinus rhythm. Its with recent onset AF, a single oral dose of pil- pharmacological profile includes a linear dose– sicainide (150 mg) achieved cardioversion to plasma concentration relationship and also a sinus rhythm in 45% of patients within linear plasma concentration–QTc effect. The 90 min, compared with 8.6% in the placebo blockade by dofetilide of Ikr increases with arm [39]. In the setting of chronic AF (average hypokalemia causing a disproportionate duration of 22 months) treatment with 150 mg increase in the duration of and once daily of oral pilsicainide for 4 weeks the QTc. Thus, the correction of hypokalemia achieved pharmacological cardioversion in and hypomagnesaemia is of crucial importance 21%. Of the remaining, 69% were successfully in preventing and treating QT prolongation cardioverted electrically after 4 weeks of pre- and torsade de pointes (3–4%). Conversely, treatment. Pilsicainide was also found to be hyperkalemia blunts its effect [41], suggesting reasonably successful in maintaining sinus the possibility of reduced efficacy after acute rhythm in this subgroup of patients (34% after coronary occlusion or during rapid heart rates, 2years) [40]. Potential side effects include AV when local cardiac tissue hyperkalemia may dissociation and QTc prolongation, especially occur. It also exhibits reverse use-dependence, in association with dehydration or renal dis- that is, its effects decrease with increasing heart ease, as the drug is actively secreted by the rate. This results from the rate induced proximal convoluted tubule. enhancement of other repolarizing ionic cur- rents (principally Iks) and the accumulation of Drugs with class III action K+ in the intracellular clefts. The terminal phase of repolarization of an action Dofetilide has been shown to be moderately potential is mediated by outward delayed rectifier effective in cardioverting persistent AF (both + K currents, Ik. This can be separated pharmaco- orally and intravenously) and significantly effec- logically into two components: a rapidly acting tive in maintaining sinus rhythm after pharmaco- component Ikr and a slower component Iks. logical and electrical cardioversion. Data from the Dofetilide (Tikosyn®, Pfizer), ibutilide (Cor- European and Australian Multicenter Evaluative vert®, Pharmacia & Upjohn), tedisamil® Research on Atrial Fibrillation Dofetilide (Solvay pharmaceuticals), E4031, D-sotalol (EMERALD) [42] and the Symptomatic Atrial and are Ik-blockers and thus pro- Fibrillation Investigative Research on Dofetilide duce only prolongation of action potential (SAFIRE-D) [43] trials demonstrated a conversion

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to sinus rhythm of 30% of patients with long- Ibutilide is also effective as an adjunct to lasting AF with a dose of 500 µg orally twice direct current (DC) cardioversion, when pre- daily for 3 days. Oral dofetilide also appears to be treatment with 1mg ibutilide was associated significantly effective in maintaining sinus with a 100% success rate, as opposed to 72% rhythm, with 71 and 60% of the patients remain- with DC cardioversion alone [47]. Interestingly, ing in sinus rhythm after 6 months and 1 year all patients who initially failed DC cardiover- respectively. In the EMERALD trial, dofetilide sion were subsequently successfully cardio- achieved significantly higher conversion as well as verted with ibutilide and DC cardioversion. maintenance of sinus rhythm, when compared Ibutilide was also found to significantly reduce with sotalol (Betapace®, Bristol Myers Squibb). the mean energy requirement for cardioversion Even in patients with symptomatic heart failure from 228–166 J. Even in patients who were and left ventricular dysfunction dofetilide was chronically on amiodarone, the addition of found to be significantly better than placebo at 2 mg of ibutilide intravenously resulted in car- maintaining sinus rhythm (p < 0.0001) and dioversion of 54% of the patients with atrial reducing risk of hospitalization from heart failure flutter and 36% of those with AF [48]. Of the [44]. Although no mortality difference was remaining, 90% had successful electrical cardi- observed between the two groups, treatment was oversion. This suggests that combination ther- initiated with 3 days of intensive cardiac moni- apy may be a useful method for achieving car- toring and dose-adjustment and most cases of dioversion for patients with chronic AF, torsade de pointes occurred during this period. A particularly in adjunction with direct current number of potential interactions with commonly cardioversion (DCC) and in those with nega- used drugs have also been described – verapamil tive response to monotherapy. However, given (increases oral absorption), cimetidine (inhibits the current trend towards rate control and anti- renal excretion), (Nizoral®, Janssen coagulation in persistent and chronic AF and Cilag, reduces hepatic excretion), diuretics (by the fact that alternative drugs are available to causing hypokalemia). Thus, the safety of initiat- terminate recent onset AF, the risks and bene- ing dofetilide in the community is questionable. fits of ibutilide administration should be care- Dose adjustment according to the length of the fully considered for each patient to minimize QTc interval and creatinine clearance (when pro-arrhythmic adverse events. GFR < 60ml/min) along with correction of The option of safe but effective arrhythmic hypokalemia reduces the risk of this potentially drugs in the setting of coronary artery disease life-threatening arrhythmia. and left ventricular dysfunction is pretty lim- On the other hand, studies with ibutilide ited. Tedisamil, another class III agent is under- (Corvert®, Pharmacia & Upjohn) have focused going development with a potential to occupy in its ability to achieve cardioversion – which this niche. As an effect of its multi-channel- appears greater than dofetilide (Tikosyn®, Pfizer) blocking properties (Table 3), tedisamil produces – rather than maintenance of sinus rhythm, as bradycardia, prolongs the action potential in the drug is available only in an intravenous form both the atria and ventricle and increases the [45,46], in view of its high first-pass metabolism. ventricular refractory period [49]. Another This drug has been licensed in the USA for the major advantage is the lack of negative ino- acute termination of both atrial fibrillation and tropic action. Though tedisamil has been atrial flutter but is unavailable in the UK. Ibuti- shown to be effective in a dose-dependent fash- lide is predominantly an Ikr-blocker, thereby pro- ion in increasing angina threshold and reducing longing atrial and ventricular refractoriness and the frequency of angina, it also exhibits reverse action potential duration, but also activates a dose-dependence, thus limiting its efficacy with slow inward sodium current. In view of the rela- exercise and rendering β-blockers superior [50]. tively high incidence of torsade de pointes (3– In animal studies, tedisamil has been shown to 4%) it should be used with caution in a moni- be effective in preventing and reversing ven- tored setting. QT prolongation is dose-depend- tricular arrhythmia in the ischemic setting [51]. ent, maximal at the end of the infusion and In a recently concluded Phase II trial in return to baseline within 2–4 h following infu- patients with symptomatic AF or atrial flutter, sion (elimination half-life 3–6 h). The incidence tedisamil dose-dependently converted patients of torsade de pointes can be further reduced by to sinus rhythm [52]. There was also a dose- strict maintenance of potassium and dependent increase in QT, a slight increase in levels within normal limits. blood pressure and a decrease in heart rate.

116 Therapy (2004) 1(1) New antiarrhythmic agents for AF – REVIEW

The dual antiarrhythmic and anti-ischemic Drugs with more than one class action properties of tedisamil, without negative inotro- Ikr blockade is ineffective in preventing ventricular pism, make it an attractive novel agent for use in fibrillation elicited by the interaction between AF with coexisting ischemia. Concerns over a acute myocardial ischemia and elevated sympa- coexisting increase in vascular resistance mean thetic activity. This depends in part on the fact that that further evaluation is required in patients sympathetic activity offsets more than 50% of the with left ventricular dysfunction to avoid the action potential prolonging effect of Ikr blockade. risk of decompensation of heart failure. Further- Ersentilide, which has a combined action Ikr more, the development of oral formulation and and weak β-adrenergic blockade, represents an evaluation of the optimal dosage is essential for effective and safe option to overcome this prob- continuing therapy in the community. lem. In one canine study, ersentilide seems to One of the major limiting factors of Ikr- prevent ventricular fibrillation in the post myo- blockers has been reverse dose-dependence, cardial infarction setting [58]. Further work is due to offsetting of Ikr and enhancement of ongoing, regarding its potential role in AF and other ionic currents, principally Iks. This led to ischemic heart disease patients. Success of com- the development of , another class III bination therapy in some trials have lead to fur- agent which was designed to specifically block ther research in an effort to develop drugs with Iks, however there is evidence to suggest that it multiple class actions. One such drug is also blocks Ikr [53]. In the canine model, azimi- SD3212, with class I, III and IV actions and in a lide has been shown to be superior to dofeti- rabbit model appeared to raise the threshold of lide in terminating acute AF and unlike the AF by its combined actions [59]. latter, its effects on effective refractory period (ERP) were rate-independent [54]. In patients Modification of existing drugs with paroxysmal atrial fibrillation (PAF), azi- The long-term use of amiodarone, probably the milide has been found to significantly most effective antiarrhythmic available, is largely lengthen the arrhythmia free interval com- limited by its wide spectrum of side effects, some pared with placebo [55]. Subgroup analysis of which are due to its iodine base. , reveal increased efficacy in patients with a benzofurane derivative without iodine substitu- ischemic heart disease and congestive heart ents shares similar electrophysiological properties failure. The azimilide postinfarct survival eval- with amiodarone [60] (Table 3). A recent Phase II uation (ALIVE) study demonstrated that azi- study has suggested 800 mg once daily as the safe milide had neither beneficial nor adverse and effective dose for preventing AF relapses fol- effects on reducing all-cause mortality in lowing cardioversion [61]. There was no evidence patients who had had a recent myocardial inf- of thyroid, ocular or pulmonary toxicity during arction [56]. Twice the number of patients in the 6 month follow-up period. Nonetheless, fur- the placebo group developed AF compared ther studies are needed to further delineate the with the treatment group but the numbers antiarrhythmic and safety profile of this drug. were small (19 and 8 respectively). The safety of azilimide in high-risk patients has been fur- Novel antiarrhythmics ther demonstrated by Singer and colleagues [57] Serotonin receptor antagonists who found that azimilide decreases recurrent Serotonin (5HT) is known to exert positive ventricular tachyarrhythmias in patients with chronotropic and inotropic effects on the implantable cardioverter defibrillators (hazard human atria [62]. Hence, it has been postulated ratio = 0.31, p = 0.0001). Furthermore, its that serotonin can induce supraventricular excellent oral absorption, long half-life of arrhythmias [63] and thus the blockade of the 110 h, lack of need for dose alteration in renal 5HT4 receptors expressed on the atria would and hepatic dysfunction and the absence of suppress these arrhythmias. Accordingly a 5HT4 any major drug interaction makes azimilide an , SB207266 (piboserod), has interesting proposition. Adverse effects are in been developed as a potential new treatment for the form of a small risk of torsade de pointes AF and is currently undergoing Phase II trials. and rarely, neutropenia. Another nonselective class III agent, ambasil- Atrial selective antiarrhythmic agents ide, has shown similar effects to sotalol in experi- Due to the nonselective action of currently availa- mental studies on dogs but no conclusive clinical ble drugs on both the atria and ventricle, signifi- studies have been evaluated in humans. cant adverse effects in the form of myocardial www.future-drugs.com 117 REVIEW – Lip & Choudhury

depression and torsade de pointes are often 10 µmol its action on the AV node reaches a pla- encountered. RSD-1235 is a novel, mixed ion teau thus reducing the risk of heart block but at channel antagonist that selectively blocks the these concentrations it causes mild coronary atrial potassium (Kv1.5) and sodium channels in vasodilation [68] which is most likely to be benefi- a dose-dependent fashion, thus prolonging the cial in patients with a background of IHD. atrial refractory period without significantly Another A1 partial agonist, CVT-510, has been affecting the ventricular refractory period [64–66]. found to slow AV nodal conduction at least equiv- A recently completed Phase II trial showed high alent to diltiazem, but without causing the negative dose RSD-1235 significantly terminated recent inotropic, vasodilatory and hypotensive effects onset AF within 30 min of dosing (61% conver- associated with diltiazem [70]. sion compared with 5% for placebo) [67]. In addi- In summary, partial of A1 receptors tion, 10 of the 11 patients remained in sinus have the therapeutic potential for treating rhythm after 24 h. The availability of an oral supraventricular tachycardias (SVTs) that incor- preparation, rapid onset of action (75% oral bioa- porate the sinus node or AV node as part of the vailability within 15–30 min) and relatively short arrhythmia circuit, unmasking atrial tachyar- half-life of 2 h, makes it an attractive agent for use rhythmias or ventricular pre-excitation and for in the acute termination of AF with the potential ventricular rate control in permanent AF. for being used in prehospital settings. The cur- rently ongoing Phase III trials would further Outlook & conclusions clarify the safety and efficacy of this drug. Despite recent advances in our understanding of the mechanisms of AF, effective treatment Adenosine receptor agonists remains difficult in many patients. Pharmaco- Adenosine produces acute inhibition of sinus therapy remains the mainstay of treatment and node and AV nodal function. This profound includes control of ventricular rate as well as res- but short lived electrophysiologic effect is toration and maintenance of sinus rhythm. exerted via adenosine A1 receptors [68] which Of the new antiarrhythmics, ibutilide seems to are maximally concentrated around the AV have the most to offer for cardioversion to sinus node with some representation in the atria and rhythm, especially as adjunct to DC cardioversion minimal expression on the ventricular myocar- in the setting of recent-onset AF and as part of dium. This receptor distribution explains the combination therapy in chronic AF. However, as lack of negative inotropic effect of adenosine. the drug is administered intravenously and the risk Potent ‘complete’ agonists of A1 receptors are of pro-arrhythmia is greatest shortly after adminis- limited by their causation of high-grade AV block, tration, it should be used in a closely monitored profound bradycardia, atrial fibrillation (shortens setting. The new class I agent, pilsicainide may atrial effective refractory period) and vasodilation prove as effective as ibutilide in achieving cardio- (adenosine 2A receptors) [69]. However, experi- version but some concern will still remain about ments on guinea-pig heart have shown CVT-2759 using this group of drugs in patients known or sus- (a partial agonist of A1 receptors) to selectively pro- pected to have ischemic heart disease. On the long cardiac AV nodal conduction time while caus- other hand, dofetilide shows some promise as an ing minimal sinus bradycardia, shortening of the agent for maintaining sinus rhythm, although in duration of the atrial monophasic action potential, view of the frequency of QTc prolongation and or coronary vasodilation. At concentrations above torsade de pointes early in the treatment, its initia- tion in the community might be problematic. HIghlights Despite limited clinical data, both azimilide and dronedarone seem to have the potential to play a • Despite recent advances in our understanding of the pathophysiology of role in the long-term maintenance of sinus rhythm atrial fibrillation, effective treatment remains difficult in many patients. in patients with AF. • Currently available drugs are reasonably effective in converting paroxysmal Thus, the potential of new antiarrhythmic atrial fibrillation into sinus rhythm and in enhancing the electrical effects of cardioversion. drugs to improve our management of AF and • The current choice of antiarrhythmic drugs is limited in patients with atrial flutter poses exciting new possibilities. structural heart disease, ischemic heart disease and left ventricular However, their uptake in clinical practice will dysfunction. depend not only on their efficacy as antiarrhyth- • These limitations in current treatments leaves the door open for newer mic agents but also on their safety in acutely ter- antiarrhythmic agents with improved efficacy, safety and side effect minating AF and in long-term maintenance of profile. sinus rhythm in the community.

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