New Antiarrhythmic Agents for Atrial Fibrillation

REVIEW New antiarrhythmic agents for atrial fibrillation Anirban Choudhury2 Atrial fibrillation (AF) is the most common sustained arrhythmia 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 sotalol and amiodarone 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 arrhythmias [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 sustained 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 adrenergic 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 verapamil significantly reduced electrical Verapamil remodeling [18], whilst digoxin (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 cardioversion [11,20,21]. This also seems to be applica- 20 ble for other calcium antagonists, including [11] 10 diltiazem 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 receptor 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

Load more