|Home | About | Journals | Submit | Contact Us | Français|
Atrial fibrillation (AF) is a growing clinical problem that is associated with increased morbidity and mortality rates. There are two principal options for the management of AF: rate and rhythm control. The rhythm control strategy aims to maintain sinus rhythm, or to restore rhythm when required, using antiarrhythmic drugs (AADs), catheter ablation, electrical cardioversion, or surgical techniques. AADs are also used to maintain sinus rhythm following catheter ablation or cardioversion. Rate control, in which fibrillation remains in the atrium, is focused on preventing the detrimental effects of rapid activation of the atria on the ventricles. Such effects include the development of cardiomyopathy and heart failure (HF). Depending on their CHADS (congestive HF, hypertension, age, diabetes mellitus, and prior stroke or transient ischemic attack) score, patients undergoing rate or rhythm control may require anticoagulation therapy to reduce the risk of stroke.
Data from multicenter, randomized, prospective clinical trials suggest that rhythm control strategies with currently available AADs are not superior to rate control strategies in terms of survival rates (for a review see ). A common interpretation of these data is that the adverse effects of using AADs, secondary to extra-cardiac toxicity and ventricular proarrhythmia, exceed the benefit derived from their limited capability to maintain sinus rhythm . However, AF patients with maintained sinus rhythm (with or without AADs) have a better survival rate and quality of life than those in whom AF persists [2,3]. Although the use and efficacy of catheter ablation-based approaches in AF treatment have increased significantly over the past decade, pharmacological agents remain the first-line therapy for rhythm management of AF . It has been speculated that rhythm control using AADs would be preferable for the treatment of most AF patients if safer and more effective AADs were available [1,5].
Most AADs in current clinical use, and those that are under development, exert their anti-AF actions exclusively or primarily via modulation of cardiac ion-channel activity. However, AF is commonly associated with both atrial electrical and structural abnormalities as well as with a number of, often overlapping, intracardiac and extra-cardiac diseases (including HF, hypertension, coronary artery disease, and myocardial infarction). These abnormalities and diseases may significantly modulate the safety and anti-AF efficacy of AAD therapy. Therefore, development of anti-AF agents is focused on alteration of ion-channel activity and targeting upstream intracardiac and extracardiac, non-electrical factors that promote AF (Figure 1). Investigational approaches for pharmacological AF treatments that alter gap junctions or intracellular calcium activity have yielded some positive data but these agents remain far from clinical testing .
Currently available agents used in the management of AF act to increase the effective refractory period (ERP). They fulfill this function by prolonging action potential duration (APD) via inhibition of the rapidly activating delayed rectifier potassium current (IKr; e.g. D-sotalol or dofetilide), by reducing excitability via inhibition of peak sodium current (INa; e.g. flecainide or propafenone), or by both of these mechanisms via inhibition of multiple ion channels (potassium, sodium, and calcium channels; e.g. amiodarone and dronedarone). Important limitations of these agents are the risks of severe ventricular arrhythmias, extra-cardiac toxicity, or pre-existing cardiac disease progression [4,7]. These adverse effects tend to occur in AF patients with a structurally compromised heart.
The search for new AADs for AF has largely been focused on the delineation of atrial-specific or -selective agents and on improvement of “old” AADs (Figure 1). Atrial-selective strategies for AF treatment are designed to prevent or reduce the risk of ventricular proarrhythmia . Atrial-specific targets are exclusively (or almost exclusively) present in the atria and include the ultrarapid IKr (IKur), the conventional acetylcholine-regulated inward IKr (IK-ACh), and the constitutively active IK-Ach (CA IK-Ach), which does not require acetylcholine or muscarinic receptors for activation .
IKur is among the most well-investigated ion current and, until recently, was widely considered to be the most promising target for AADs in the treatment of AF . However, available data suggest that blockade of IKur alone is unlikely to be sufficient for effective suppression of AF (for reviews see [6,10]). Indeed, inhibition of IKur may actually promote AF in non-remodeled atria . Of note, the contribution of IKur to AF may be relatively small as IKur density is reduced with acceleration of the rate of atrial activation . IKur density had also been found to be reduced in cells isolated from the atria of patients with chronic AF .
Blockade of IK-ACh may be a useful strategy for managing clinical cases of vagally mediated AF. Interestingly, CA IK-ACh is only marginally present in healthy, non-fibrillating atria and is significantly increased in persistent or chronically fibrillating atria; thus, CA IK-ACh is an atrial-specific and pathology-specific target for AF treatment [9,14]. CA IK-ACh could be a favorable target for safe AF treatment if it can be inhibited independently of conventional IK-ACh channels that are present in many organs other than the heart (e.g. in the central nervous system). However, there is no selective CA IK-ACh blocker available at present.
Atrial-selective ion-channel targets are channels that are present in both chambers of the heart, but whose inhibition produces greater effects in the atria than in the ventricles. These channels include INa and IKr. INa inhibitors – including ranolazine, AZD7009, and amiodarone (for chronic treatment) – are able to produce atrial-selective depression of INa and INa-dependent parameters and effectively suppress AF in the canine heart at concentrations that cause little to no electrophysiological changes in the ventricles [6,10,15–17]. Atrial-selective IKr blockers produce a greater prolongation of APD and ERP in the atria than in the ventricles at normal activation rates [10,16,18]. Of note, all atrial-selective INa blockers identified to date also inhibit IKr and preferentially prolong APD in atria. APD prolongation in the atria has been shown to potentiate the development of a “use-dependent block” of INa [10,15,16]. Atrial-selective INa blockers effectively suppress AF in both experimental models and in clinical practice [19,20]. The degree to which the clinical effectiveness of these multiple-ion-channel blockers depends on their potency in depressing INa remains to be elucidated.
With the exception of IKr blockers such as dofetilide, currently available AADs showing anti-AF efficacy (e.g. amiodarone, dronedarone, flecainide, propafenone, and quinidine) and promising investigational AADs (e.g. vernakalant and ranolazine) all inhibit multiple ion channels. Among these multiple-ion-channel blockers, those that inhibit INa and exhibit rapid dissociation kinetics (e.g. amiodarone, dronedarone, vernakalant, and ranolazine) rarely, if ever, induce ventricular proarrhythmia. In contrast, AADs that inhibit INa and exhibit slow dissociation kinetics (e.g. propafenone and flecainide) are capable of inducing ventricular proarrhythmia and are contraindicated in patients with a structurally compromised heart and in those with acute coronary syndromes. Another important side-effect of AF therapy with slow INa blockers is the induction of atrial flutter with 1:1 atrioventricular conduction. Of note, rapidly dissociating INa blockers tend to be atrial-selective, whereas slowly dissociating INa blockers are not .
Vernakalant appears to be the most advanced anti-AF AAD awaiting US Food and Drug Administration (FDA) approval. Indications for vernakalant use may be acute cardioversion of paroxysmal AF and rapid termination of post-operative AF [21,22]. The success rate of vernakalant in treating acute cardioversion of paroxysmal AF (of <7 day duration) is approximately 50% .
The long-term adverse effects, both arrhythmic and non-arrhythmic, of AADs are often difficult to predict [7,23]. Clinical experience indicates that an optimal long-term risk:benefit ratio is best achieved with multiple-ion-channel blockers that inhibit INa with rapid dissociation kinetics and inhibit IKr (for reviews see [6,10,24]). However, it is not the case that “one size fits all” with multiple-ion-channel blockers. For example, dronedarone, while generally a safe AAD, may increase mortality rates in patients with pre-existing advanced HF .
Atrial structural remodeling is often involved in the development and maintenance of AF. Upstream therapies are those that target structural remodeling in the atria, factors that promote such remodeling, or both . Studies designed to investigate the direct or indirect mitigation of atrial structural remodeling and precipitating factors using agents such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ω-3 polyunsaturated fatty acids, and statins have yielded variable results [6,25,26]. The precise value of upstream therapy in the treatment of AF can vary substantially with different AF pathologies. Most of the current clinical data on upstream AF therapy are derived from observational studies that were not sufficiently powered; thus, practical clinical applicability of the upstream therapies remains to be determined. Interestingly, because atria develop structural remodeling to a greater extent than ventricles, structural remodeling is a potential atrial-selective target for upstream therapy of AF .
The ultimate goal of pharmacological therapy for AF, as with any therapy, is to improve patient morbidities and reduce mortality rates. Although morbidities of AF patients (e.g. hospitalization) can be significantly improved using AADs [3,28], to date, all placebo-controlled, large, randomized clinical trials evaluating the efficacy of anti-AF AADs in improving all-cause mortality rates have yielded either negative or neutral outcomes [4,28–30].
Amiodarone remains the most effective AAD for the long-term maintenance of sinus rhythm, but such long-term use is often associated with organ toxicity . Dronedarone, a non-iodinated benzofurane derivative of amiodarone, has a better safety profile but poorer clinical anti-AF efficacy compared with amiodarone [31,32]. Dronedarone was approved by the US FDA in 2009 based on its effectiveness in reducing the incidence of cardiovascular (CV)-related hospitalization of AF patients without severe HF. ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg Twice Daily for the Prevention of CV Hospitalization or Death from Any Cause in Patients with AF/Atrial Flutter) demonstrated a significant reduction in the primary endpoint (CV-related hospitalization and mortality) in AF patients who were treated with dronedarone compared with patients who received placebo . This outcome is likely due to the ability of dronedarone to reduce the incidence of stroke, the rate of ventricular activation, and the incidence of CV events in patients with AF [28,30,33]. Considering the modest long-term anti-AF effects of dronedarone [30–32,34], the available evidence suggests that AF suppression may not have a major role in the reduction of the number of CV-related hospitalizations. Owing to the unique endpoint of the ATHENA trial, it is yet to be determined whether dronedarone is superior to the other anti-AF AADs in reaching this composite endpoint.
Future development of AADs for rhythm control in the management of AF must take into consideration the balance between efficacy and safety. Multiple-ion-channel blockers that inhibit both INa (with rapid dissociation kinetics) and IKr appear to be optimal for the long-term management of AF. Pharmacological strategies that aim to ameliorate both electrical and structural substrates and triggers are likely to be most successful in the improvement of morbidity and mortality rates in AF patients.
Disclosures: Dr Antzelevitch is a consultant and has received grant support from AstraZeneca, Gilead Sciences, and the US National Heart, Lung, and Blood Institute. Dr Burashnikov has no relevant financial interests to disclose.