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Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting millions of people worldwide, and its prevalence is expected to increase owing to factors such as the growing aged population1. Its effects range from symptoms such as breathlessness and chest pain to potentially fatal complications such as stroke1,2.

To reduce the risk of stroke, patients with AF are often treated with anticoagulants and with drugs that control heart rate, such as β-adrenoceptor antagonists1,2. Restoration and maintenance of sinus rhythm is also a major approach for the management of AF1,2. However, established drugs for achieving this goal are limited by either modest efficacy and/or side effects, such as life-threatening ventricular pro-arrhythmias or severe extracardiac toxicities1,2. For example, amiodarone, which is generally considered to be the most effective drug for the treatment of AF and has low pro-arrhythmic potential, is associated with serious systemic side effects1. In 2009, a derivative of amiodarone that was developed with the aim of overcoming these limitations, dronedarone (Multaq; Sanofi–Aventis), was approved for AF, although it might not be as effective as amiodarone in maintaining sinus rhythm1,2.

Basis of discovery

Many drugs used for the treatment of AF affect ion channels in both atrial and ventricular tissue, and this lack of selectivity means that they are associated with a risk of ventricular pro-arrhythmias1. Vernakalant was discovered through a search for atrial-selective agents in a canine model of AF1,3.

Drug properties

Vernakalant (Fig. 1) is an anti-arrhythmic agent that affects cardiac Na+ and K+ currents, including the atrial-selective currents IKur and IK,ACh (Refs 4, 5, 6). In animal models of AF and in initial clinical studies, vernakalant significantly prolonged the atrial refractory period without significantly affecting ventricular refractoriness4,5,6.

Figure 1
figure 1

Structure of vernakalant.

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Clinical data

The efficacy and safety of vernakalant for the treatment of patients with AF has been assessed in three randomized, double-blind, placebo-controlled studies (known as ACT I, ACT II and ACT III) and in an active comparator trial versus intravenous amiodarone (known as AVRO)6,7,8. In all of these studies, vernakalant was administered by a 10 minute intravenous infusion at a dose of 3 mg per kg followed by a second 10 minute infusion at a dose of 2 mg per kg 15 minutes later if AF had not been terminated6,7,8.

The ACT I and ACT III trials investigated vernakalant in the treatment of patients with sustained AF (duration >3 hours, but not more than 45 days)6,7. The primary end point in both trials was the proportion of patients with short-duration AF (3 hours to 7 days) who had treatment-induced conversion of AF to sinus rhythm (cardioversion) for at least 1 minute within 90 minutes of treatment infusion6,7. A secondary efficacy end point was conversion of AF in patients with longer-duration AF (>7 days and ≤45 days)6,7.

Treatment with vernakalant effectively converted AF to sinus rhythm compared with placebo6,7. The primary end point was met in 74 out of 145 (51.0%) of patients receiving vernakalant compared with 3 out of 75 (4.0%) of patients receiving placebo in the ACT I study6,7, and in 44 out of 86 (51.2%) of patients receiving vernakalant compared with 3 out of 84 (3.6%) of patients receiving placebo in the ACT III study6. Conversion of AF to sinus rhythm occurred rapidly (the median time to conversion in responders was 10 minutes from the start of the first infusion) and sinus rhythm was maintained over 24 hours (97%)6. Vernakalant provided relief of the symptoms of AF consistent with conversion to sinus rhythm6.

No significant differences in safety or effectiveness were observed based on age, gender, use of rate-control drugs, use of anti-arrhythmic drugs, use of the anticoagulant warfarin, history of ischaemic heart disease or renal impairment6. Assessment of the conversion of AF in patients with longer-duration AF in a total of 185 patients did not show statistically significant differences between vernakalant and placebo6.

The ACT II trial investigated the effect of vernakalant in 150 patients with sustained AF (3–72 hours duration) that occurred between 24 hours and 7 days after coronary artery bypass graft and/or valvular surgery6,8. The primary end point was the conversion to sinus rhythm within 90 minutes of dosing, which was achieved in 47 out of 100 (47%) patients who received vernakalant compared with 7 out of 50 (14%) patients who received placebo6,8. The median time to conversion was 12 minutes from the start of treatment infusion6.

In the AVRO trial, vernakalant was compared with intravenous amiodarone (administered over 2 hours) in 116 patients with recent-onset AF (3–48 hours)6. The primary end point was the proportion of patients who achieved sinus rhythm at 90 minutes after initiating treatment6. Treatment with vernakalant converted 51.7% of patients to sinus rhythm at 90 minutes compared with 5.2% of patients treated with amiodarone6.

Indications

Vernakalant is approved by the European Commission for the rapid conversion of recent-onset AF (≤7 days duration for non-surgery patients, and ≤3 days duration for post-cardiac surgery patients) to sinus rhythm in adults6.

Analysis | Atrial fibrillation

Analysing clinical issues in the treatment of AF is Dobromir Dobrev, M.D., Professor and Chair, Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Germany.

Current pharmacotherapy for AF has major limitations, including moderate efficacy and unpredictable risks of life-threatening pro-arrhythmia with anti-arrhythmic drugs, and bleeding complications with anticoagulants1. Non-pharmacological (ablation) approaches have improved, but still have safety and efficacy limitations, and are not applicable for a substantial proportion of the AF patient population.

These considerations and the growing importance of AF as a clinical problem have fostered efforts to develop anti-arrhythmic drugs with improved efficacy and safety profiles, focusing on favourable multichannel-blocking profiles, atrial-specific currents such as IK,ACh and IKur, and atrial-selective Na+-channel blockade. Molecular modification of the highly effective multichannel-blocker amiodarone to improve safety and tolerability led to dronedarone, which is the first anti-arrhythmic drug that reduces cardiovascular mortality and hospitalization of patients with AF2. However, dronedarone was approved for the suppression of AF, but not for the reduction of cardiovascular mortality in patients with AF.

Vernakalant is the first atrial-selective drug to reach the market. Atrial-selectivity of vernakalant is achieved by inhibiting IK,ACh and IKur and by exploiting state-selective rapidly unbinding Na+ channel-inhibitory properties that produce stronger effects on atrial than ventricular action potentials, especially during rapid rhythms like AF. Consequently, vernakalant is associated with a low pro-arrhythmic risk for ventricular tachyarrhythmias. Owing to its very short half-life, vernakalant has primarily been used intravenously for termination of recent-onset AF, but a longer-acting slow-release oral formulation is in clinical trials.

The efficacy of vernakalant for acute AF termination seems comparable with other available compounds9, although comparative studies have not been conducted. Although the AVRO trial compared intravenous vernakalant with amiodarone in recent-onset AF6, amiodarone is less suitable for acute AF cardioversion10 because of its slow (up to 24 hour) onset of action, and thus is not the most appropriate comparator when assessing the short-term (90 minutes) success rate of pharmacological cardioversion. Head-to-head trials with intravenous flecainide (not available in North America) are needed to validate the superiority of vernakalant for acute AF cardioversion in the different patient populations. Of note, vernakalant has a substantially lower AF conversion rate in congestive heart failure (26.9%) than in haemodynamically stable patients (54.1%)6,7,8, suggesting that vernakalant is safe but less effective in patients with structural heart disease. Vernakalant was also not found to be effective in converting typical primary atrial flutter to sinus rhythm6, and so cannot replace established drugs used for the acute termination of atrial flutter, such as ibutilide and dofetilide. Finally, the clinical value of vernakalant for prevention of AF recurrence requires further large-scale trials with suitable AF patient populations.

Overall, given the atrial selectivity and different safety profile of vernakalant, it provides an important addition to the options for anti-arrhythmic pharmacotherapy, with the potential to change the algorithm for acute AF cardioversion.