Atrial fibrillation (AF) is the most common cardiac arrhythmia, having an estimated combined prevalence of 6.8 million in the EU and the US.1,2 It is characterised by unco-ordinated atrial activation followed by the deterioration of mechanical function, which results in disturbances to sinus rhythm and ventricular rate.2 An increased risk of heart failure (HF), thrombo-embolism, cardiomyopathy, a five-fold increased risk of stroke and an approximately two-fold increased risk of mortality have been associated with AF.2,3 AF also represents a major economic burden as it can lead to hospitalisation,1 with 70% of the cost of AF management driven by inpatient care and interventional procedures.4
Antiarrhythmic drugs (AADs) are categorised into four broad categories (I, II, III and IV), based on their dominant electrophysiological properties.5 Pharmacological cardioversion is predominantly performed with Vaughan-Williams class Ia, Ic and III AADs. Class Ic, beta-blockers or class III AADs are commonly used to maintain sinus rhythm. However, the available class Ia, Ic and III AADs have limitations to varying degrees, such as moderate efficacy and proarrhythmic or extra-cardiac toxic effects in patients with structural heart disease.6,7
This article reviews current approaches to the development of new AADs and attempts to address some of the concerns in terms of their development for the management of AF.
Atrial-selective versus non-selective Multichannel-blocking Antiarrhythmic Drugs
There are a number of different approaches in the development of new AADs for the treatment of AF. These approaches include novel non-selective multichannel-blocking drugs and atrial-specific drugs.
Rationale for the Use of Atrial-selective Drugs
It is known that different ionic currents are expressed in the atria than in the ventricles (see Figure 1).8 Atrial-selective drugs only act on these atrial-specific ionic channels, and thus theoretically avoid drug effects (including pro-arrhythmic effects) on the ventricular myocardium. Vernakalant is a novel amino-cyclohexyl ether drug that has relatively atrial-selective blocking activity. It is currently undergoing regulatory review for the indication of converting AF to sinus rhythm. Vernakalant has a unique ion-channel-blocking profile, being capable of blocking IKACh channels, early activating K+ channels (IKur, Ito) and frequencyand voltage-dependent INa channels.9 Such relatively specific blocking activity leads to an atrial-selective action potential duration (APD) and effective refractory period (ERP) prolongation. In addition, the intravenous formulation of vernakalant has exhibited a good safety profile in clinical trials, and no proarrhythmic effects were observed during or up to 90 minutes after drug infusion.10 In the Atrial Arrhythmia Conversion Trials (ACT) I,11 ACT II12 and ACT III13 and the single-arm open-label ACT IV14 trials the conversion rate from acute AF to normal sinus rhythm was significantly higher with an intravenous infusion of vernakalant versus placebo (47.0-51.7% versus 3.6-14%, respectively; p<0.001). The effects of vernakalant were durable up to 24 hours. These data are consistent with the results of the Controlled Randomised Atrial Fibrillation Trial (CRAFT) phase II study in which the conversion rate from acute AF to normal sinus rhythm was 52.9% with vernakalant versus 5.3% for placebo (p=0.0014).15 Importantly, the median time to sinus rhythm conversion was shown to be 11 minutes in the ACT I trial, and such a rapid conversion effect has implications for the clinical use of this drug.11 Vernakalant infusion was associated with QT prolongations, but no cases of torsade de pointes were reported. Vernakalant was also associated with a higher occurrence of moderate to severe hypotension (2.6 versus and 0.6% on placebo). The atrial-selective AVE 0118 blocks the early activating K+ channels (IKur, Ito). Preliminary studies with the agent showed effects on atrial contraction in animal models without proarrhythmic effects on the ventricle.16 Studies on isolated atrial myocardium from patients with AF showed that AVE 0118 enhanced atrial contractility. The positive inotropic effect was atrial-specific and was shown to be due to the changes of the action potential configuration that enhanced Ca2+ entry via reverse mode Na+/Ca2+ exchange.17 The development of the drug has since been stopped.
Rationale for the Use of Non-selective Multichannel-blocking Drugs
Non-selective multichannel-blocking drugs act to inhibit not only the ionic channels in the atria but also other specific and non-specific channels. Such activity may provide additional benefits compared with atrial-specific drugs, i.e. beta-receptor blockade. The most widely used non-selective multichannel-blocking drug is the class III amiodarone. It is a highly effective treatment for AF but is associated with several adverse events, especially extra-cardiac toxicities.6 More recently, a novel orally administered non-selective multichannelblocking drug, dronedarone, has been developed. Dronedarone has recently been approved by the US Food and Drug Administration (FDA) for reducing the risk of cardiovascular hospitalisation in patients with paroxysmal/ persistent AF or atrial flutter (AFL). This group of patients are required to have had a recent episode of AF/AFL, to have associated cardiovascular risk factors and to be in sinus rhythm or to be scheduled for cardioversion. Dronedarone is contraindicated in patients with New York Heart Association (NYHA) class IV HF or NYHA class II-III HF with a recent decompensation requiring hospitalisation or referral to a specialised HF clinic. In the EU, dronedarone is indicated in clinically stable adult patients with a history of or current non-permanent AF to prevent recurrence of AF or to lower the ventricular rate. Like amiodarone, dronedarone can block Na+, Ca+ and multiple K+ channels to produce a sympatholytic blockade.18 Dronedarone is a structurally modified version of amiodarone, and these structural changes offer the former some advantages. The presence of a methane-sulfonyl group to amiodarone results in lowering of dronedarone's lipophilicity and, consequently, a reduction in its half-life.19 This helps reduce the toxic effects of long-term dronedarone administration. The addition of the methane-sulfonyl group and the removal of iodine from amiodarone leads to a reduction in the risk of thyroid-related effects and pulmonary fibrosis.19,20 While amiodarone has been shown to enhance the anticoagulant effects of warfarin, resulting in an increased haemorrhagic risk,21-23 no dronedarone-warfarin interactions have been noted. Dronedarone has also been shown to have rhythm- and rate-controlling effects in randomised controlled trials of patients with AF or AFL.
In the US-based American-Australian-African Trial with Dronedarone in Atrial Fibrillation/Flutter Patients for the Maintenance of. Sinus Rhythym (ADONIS) study, the median time to recurrence of AF or AFL increased significantly (x2.67) from 59 days on placebo to 158 days with dronedarone (p=0.002).20 Additionally, the mean ventricular rate at first AF recurrence reduced from 116.6 on placebo to 104.6 with dronedarone (p<0.001). In the European Trial In Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) study, the time to a recurrence of AF increased significantly (x2.34) from 41 days on placebo to 96 days on dronedarone (p=0.01), while the mean ventricular rate at first AF recurrence was 117.5 beats per minute on placebo compared with 102.3 beats per minute on dronedarone (p<0.001).20
While dronedarone has shown rhythm- and rate-controlling effects, safety concerns were raised by the randomised controlled Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial.24 This trial accrued patients with recently decompensated HF (but without AF) requiring recent hospitalisation or referral to a specialised HF clinic for worsening symptoms. At a median follow-up of two months, there were significantly more deaths in the dronedarone treatment group versus the placebotreated group (25 versus 12, respectively; p=0.03). These observations led to the trial being prematurely stopped. The large randomised controlled ATHENA trial evaluated the efficacy of dronedarone versus placebo, on top of standard treatment, in preventing cardiovascular hospitalisation or death.25,26 The trial accrued 4,628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. In addition, patients were either ÔëÑ75 years of age or >70 years of age with at least one risk factor for death. At a mean follow-up of 21±5 months, there was a significant reduction in the time to first event of cardiovascular hospitalisation or death in the dronedarone-treated group versus the placebo-treated group (31.9 versus 39.4%, respectively; p<0.001). The reduction in cardiovascular hospitalisations and mortality in the dronedarone group was driven by a subtantial reduction of AF-related hopitalisations, but other causes for CV admissions were also reduced. These data are consistent with a post hoc analysis from the ADONIS and EURIDIS trials, which accrued patients with AF or AFL. The results of this analysis showed that there were fewer hospitalisations due to cardiovascular causes or deaths in the dronedarone-treated group compared with the placebo-treated group (22.8 versus 30.9%, respectively; p=0.01).20 Furthermore, a post hoc analysis of the pivotal ATHENA study has shown dronedarone to significantly reduce the risk of stroke in patients with AF. The risk reduction was from 1.8 to 1.2% per year (p=0.027). This is a novel finding as there is no previous evidence linking AADs to a reduction in the risk of stroke in AF patients. These data, showing improvements in clinical outcomes suggest that novel multichannel-blocking AADs are still very relevant in the treatment of AF. The atrial-selective strategy is still promising, but it should be noted that the expression of atrial ionic channels is different in the re-modelled atrium versus in the normal healthy atria; consequently, atrial-specific drugs may have reduced efficacy.27,28
Influence of Rate versus Rhythm Control Trials on Antiarrhythmic Drug Development
The relative benefits of a rate-controlling strategy versus a rhythmcontrolling strategy is a subject of much debate, especially as several key trials failed to show survival benefits for rhythm control strategies for AF compared with rate control. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM),29 Pharmacologic Intervention in Atrial Fibrillation (PIAF),30 Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study (RACE),31 Strategies of Treatment of Atrial Fibrillation (STAF)32 and How to Treat Chronic Atrial Fibrillation (HOT CAFE)33 trials showed no significant difference in mortality, major bleeding and thrombo-embolic events between rhythm control and rate control strategies in patients with AF. Notably, the pivotal AFFIRM study, which enrolled just over 4,000 AF patients with a high risk of stroke or death, showed the incidence of all-cause death to be similar in the rhythm control versus rate control groups (23.8 versus 21.3%, respectively; p=0.08).29 The AFFIRM investigator remarked that management of AF with the rate control strategy may offer potential advantages such as a lower risk of adverse drug effects, including bradycardia, gastrointestinal events and pulmonary events. A meta-analysis of these five rate versus rhythm control trials have shown no significant difference in all-cause mortality or in ischaemic stroke incidence between the two groups (p=0.09 and p=0.30, respectively).34 The recent AF-CHF trial evaluated the rhythm versus rate control strategies in congestive HF patients who had left ventricular ejection fraction Ôëñ35% and a documented recent episode of atrial fibrillation.35 Over a treatment period of 60 months, there was no significant difference in the survival rate (% death from cardiovascular causes) of the patients in the two groups (see Figure 2). The results of these recent rate versus rhythm control trials have the potential to influence the development of new AADs, particularly from a regulatory standpoint, with rhythm-controlling drugs coming under increased scrutiny. Novel agents will need to demonstrate both effective suppression of AF symptomology and improved side effect profiles. While rhythm-controlling drugs have proven benefits, especially in terms of symptomatic relief in AF, a rate control plus anticoagulation strategy may be perceived to be a more suitable option for many patients. However, the development of AADs should continue to focus on both strategies.
Outcome Measures for New Antiarrhythmic Drug Trials
The outcome measures used in trials of new AADs should be able to demonstrate the ability of a drug to prevent the burden of AF-related morbidity and mortality and be associated with a good safety profile. The choice of ideal outcome measures in AAD trials should be largely based on the requirements of the regulatory agencies; such measures would be able to demonstrate a drug's safety and efficacy and their superiority over currently available drugs, thereby facilitating regulatory approval. Members of the FDA's Cardiovascular and Renal Drugs Advisory Committee have indicated that the prevention of AF recurrence is still a valid end-point and that symptom reduction is still desirable.36 However, the ability to prevent AF recurrence alone may be insufficient in the bid to gain approval. Safety is of primary importance; this is where the problem often arises with AADs as these agents have been shown to be associated with severe adverse effects.6,7 Therefore, it is of the utmost important for trials to demonstrate the safety of new AADs. If a trial is further able to demonstrate improvements in clinical outcome with a novel drug and also correlate the prevention of AF recurrence (a surrogate end-point) with improvement in clinical outcomes, the drug will have a higher possibility of gaining regulatory approval. For instance, in the previously mentioned ATHENA trial, dronedarone use prolonged the time to a first event of cardiovascular hospitalisation or death; this duration was positively correlated with the prevention of arrhythmia. This study also identified a subset of patients with AF in whom such outcome data (time to first event of cardiovascular hospitalisation or death) may be very relevant. Based on this, it is likely that future trials of AADs will use the same hard end-points as the ATHENA study to evaluate the efficacy and safety of the drugs in different populations. This would provide an opportunity to identify the patient population that would benefit the most from the drug, which would then have a good chance of gaining approval for that specific patient population.
Issues in Pharmacological Cardioversion
Cardioversion of AF is the process of restoring sinus rhythm, and often involves electrical cardioversion (direct-current cardioversion). Electrical cardioversion has shown a high acute success rate (90%) in selected patients.37 Nevertheless, it is an expensive and complex procedure, often requiring specialists to carry out general anaesthesia or sedation during the procedure. The alternative is pharmacological cardioversion with AADs. There are few controlled studies comparing pharmacological cardioversion with direct-current cardioversion. One of the few published studies showed that the efficacy of the initial attempt for cardioversion was similar with pharmacological or electrical cardioversion.38 However, anecdotally, many clinicians prefer having the pharmacological option, especially for rapid conversion. Additionally, the strategy of pre-treatment with an AAD before direct-current cardioversion has been demonstrated to be more beneficial than electrical cardioversion alone. The combination therapy strategy may be more effective in lowering the threshold of cardioversion, in restoring normal sinus rhythm and in preventing the recurrence of AF versus electrical cardioversion alone.2 New AADs that offer a short duration of observation after infusion for cardioversion would also be preferable.
The Role of Antiarrhythmic Drugs in a World of Curative Ablation Therapy
Atrioventricular (AV) nodal ablation, coupled with pacing, is a highly effective non-pharmacological option for rate control in select patients,39 but is typically recommended as second-line treatment after drug therapy. Similarly, left atrial (LA) ablation for rhythm control is second-line treatment after AADs.2 Catheter-directed ablation techniques and strategies have evolved in recent years to include pulmonary vein isolation (PVI) and linear ablation.40-42 However, there are limited available studies for catheter ablation strategies.2 The predicted prevalence of AF in the US is expected to be as high as nearly 16 million by 2050 (see Figure 3).43 Such a high prevalence would present a substantial increase in the demand for these procedures as they are already becoming more commonplace. However, this is problematic as ablation procedures can only becarried out at specialised centres by skilled professionals.
The current lack of scientific data demonstrating long-term efficacy ofablation in preventing AF suggests that there is still very much a need to develop novel AADs. Pharmacological therapy provides options for multiple indications, including elderly patients and those who are failed or have undergone a partially effective ablation, as well as those for whom AF ablation is not accessible. Additionally, AADs may be more cost-effective as the annual cost of medical therapy has been shown to be lower than catheter ablation in patients with permanent AF (US$4,176-5,060 versus US$16,278-21,294, respectively).44 The use of ablation is now being extensively surveyed and data will become available providing information on the rate of AF recurrence associated with ablation techniques. Hybrid therapeutic strategies involving pharmacotherapy with AADs plus ablation may be an attractive option as it could allow effective rate control and prevention of AF recurrence, and may also reduce the economic burden of disease management, particularly due to a reduction in the need for ablations. Such a strategy is a key area for further research.
Conclusions
Regulatory considerations for new drug applications for new AADs may include the expectation of a positive placebo-controlled clinical outcome trial similar to ATHENA. If this occurs, it is possible that sponsors of novel AF therapies may be dissuaded from continuing drug development. However, if clinical outcome is not required, agencies may still require evidence of unequivocal safety; this would require enrolment of thousands of patients in an expensive and lengthy non-inferiority trial. Another potential hurdle could be that performing placebo-controlled clinical outcome trials, as was the case with ATHENA, may be deemed unethical, and regulatory agencies may instead insist on a positive control (i.e. dronedarone) trial. Thus, unknown regulatory challenges may present obstacles in the development of promising novel therapies for AF. If the bar is sufficiently raised and includes the expectation of a positive placebocontrolled clinical outcome trial similar to that of ATHENA, it is possible that sponsors of novel AF therapies may be dissuaded from continuing drug development. However, if clinical outcome is not required, agencies may still require evidence of unequivocal safety; this would require enrolment of thousands of patients in an expensive and lengthy non-inferiority trial. Another potential hurdle could be that performing placebo-controlled clinical outcome trials, as took place in the ATHENA study, may be deemed unethical, and regulatory agencies may instead insist on a positive control (i.e. dronedarone) trial. Thus, unknown regulatory challenges may present obstacles in the development of promising novel therapies for AF.
The current strategies for the development of new AADs include drugs with atrial-selective or novel non-selective multichannelblocking mechanisms. In the future, atrial-selective drugs will need to demonstrate equivalent or superior safety and efficacy to the non-selective multichannel-blocking approach, especially in light of the approval of dronedarone, a novel multichannel-blocking drug. There is also the question of whether there is a need to continue to develop new AADs in the age of direct-current cardioconversion, potential curative procedures with ablation and the results of the major rate versus rhythm trials. An immediate impact is that there will be an increased impetus on the demonstration of safety and efficacy of new agents over current options. Desirable end-points for future clinical trials of new AADs include symptom reduction, correlation of AF recurrence prevention with improvement in clinical outcomes and efficacy and safety in different patient populations. Novel pharmacological agents with improved safety profiles and demonstrated efficacy will continue to have a place in the management of AF. Pharmacotherapy offers more choices for both clinicians and patients, both as primary therapy and as adjunctive or complementary options in clinical settings.