Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation

Atrial fibrillation (AF) is a disorder that affects >2 million people in the United States. Firstline antiarrhythmic agents (per American College of Cardiology/American Heart Association/European Society of Cardiology guidelines) that are currently used to treat recent-onset AF work by indiscriminately blocking various ionic channels, thereby inducing a prolonged ventricular action potential duration or possibly inducing ventricular arrhythmias in the presence of myocardial ischemia because of excessive conduction slowing in diseased cardiac tissue. Vernakalant is an atrial-selective, potassium and sodium-channel-blocking agent awaiting FDA approval for the indication of conversion of recent-onset AF to normal sinus rhythm.

Key Points

• Abstract

Atrial fibrillation (AF) is a disorder that affects >2 million people in the United States. First-line antiarrhythmic agents (per American College of Cardiology/American Heart Association/ European Society of Cardiology guidelines) that are currently used to treat recent-onset AF work by indiscriminately blocking various ionic channels, thereby inducing a prolonged ventricular action potential duration or possibly inducing ventricular arrhythmias in the presence of myocardial ischemia because of excessive conduction slowing in diseased cardiac tissue. Vernakalant is an atrial-selective, potassium- and sodium-channel-blocking agent awaiting FDA approval for the indication of conversion of recent-onset AF to normal sinus rhythm. This agent offers a novel mechanism of action for the acute conversion of AF, as it specifically targets the potassium channel underlying the ultrarapid delayed rectifier current that is found only in atrial myocytes, along with other potassium channels. Pivotal phase 3 clinical trials have demonstrated that patients with recent-onset AF (≤7 d) who receive intravenous (IV) vernakalant usually convert to normal sinus rhythm within 10 minutes of administration, with response rates of 51% within 90 minutes. Preliminary results from a single phase 3 clinical trial that enrolled patients with recent-onset AF after cardiac surgery demonstrated a conversion rate of 47%. Unlike the commonly used first-line agents, which have been demonstrated to induce polymorphic ventricular arrhythmias, vernakalant appears to be less proarrhythmic, as it has not been demonstrated to induce torsades de pointes. Comparative studies are needed to determine vernakalant's potential role among the agents used in the treatment of AF. (Formulary. 2007;42:475–483.)

AF is a prevalent disorder in the elderly population; an estimated 70% of patients with AF are aged 65 to 85 years, and ≤8% of people aged >80 years present with this condition.2 Currently, >2 million people in the United States have AF, and as the population ages, this number will likely increase to an estimated 5.6 million by 2050.3,4 Rates of AF occurring after cardiac surgery have been estimated to range from 15% to 40%.5

AF has been associated with an increased long-term risk of stroke; numerous clinical studies have revealed a 2 to 7-fold higher risk of ischemic stroke among patients with nonvalvular AF compared with people without AF.2 Furthermore, the risk of stroke increases with age. The Framingham study demonstrated that the annual stroke risk attributable to AF is increased by a factor of 15 in older (aged 80–89 y) patients compared with younger (aged 50–59 y) patients.2

The electrophysiologic mechanism of AF has not been fully elucidated, but the most commonly proposed mechanism is the multiple reentrant atrial wavelet circuit theory.2 The presence of multiple reentrant wavelet circuits induces loss of mechanical and electrical synchronization of the atria and unpredictable atrioventricular nodal penetration and conduction, which culminates in an irregular ventricular response. A large atrial mass with a short refractory period (unexcitable period following activation) and decreased conduction velocity (wavelength=refractory period×conduction velocity) has a greater chance of sustaining AF, due to the presence of a larger number of wavelets. The anti-arrhythmic agents currently available terminate AF by increasing the wavelength, either by prolonging the refractory period or by slowing conduction velocity, thereby reducing the number of wavelet circuits.2

Recent-onset AF can be terminated through electrical cardioversion, with efficacy rates >90% for patients with shorter episodes of AF (<48 h).2 However, general anesthesia or conscious sedation requirements make this treatment modality an unappealing option for some patients with AF. The recently updated American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) practice guidelines for the management of AF recommend the use of the pharmacologic agents ibutilide, dofetilide, flecainide, or propafenone as first-line agents for the acute conversion of recent-onset AF (duration ≤7 d).2 The ACC/AHA/ ESC guidelines classified amiodarone as a second-line agent for pharmacologic cardioversion because of this agent's highly variable ability to convert recent-onset AF to normal sinus rhythm. However, all of these agents are limited by modest efficacy and/or significant toxicity.

Dofetilide and ibutilide, the prototypical class III antiarrhythmic agents, exert their anti-arrhythmic effects through blockade of the delayed rectifier potassium currents; cardiac refractoriness is enhanced by this blockade.2 However, delayed rectifier potassium current blockade may also prolong ventricular repolarization, and thereby cause QT-interval prolongation. Dofetilide has a delayed onset of action, with conversion times in patients with AF ranging from 24 to 36 hours. Moreover, response rates with this agent rarely exceed 30%, and the risk of torsades de pointes ranges from 0.8% to 3.3%. To minimize the risk of the development of torsades de pointes, the manufacturer of dofetilide has mandated that patients treated with this agent undergo a 3-day hospitalization in a facility where trained physicians can conduct appropriate ECG monitoring. Ibutilide has the quickest onset of action, with time to conversion approaching 23 minutes, but torsades de pointes has been demonstrated to occur in approximately 4% of ibutilide-treated patients, with an even higher rate observed in patients with AF after cardiac surgery and with decreased left ventricular ejection fractions.2

Consequently, investigative efforts have been directed towards developing antiarrhythmic agents that provide atrial antiarrhythmic effects without inducing ventricular arrhythmia. More effective agents are also needed for patients who experience AF after cardiac surgery; despite the availability of beta-blockers and amiodarone for use in preventing the development of atrial arrhythmias in these patients, a substantial number will experience such arrhythmias and hence will be at increased risk for cerebrovascular accidents.5

Investigation into potential therapies for AF has led to the development of vernakalant (RSD1235), a novel antiarrhythmic agent that targets multiple ionic channels, some of which are only found in the atria. In December 2006, Astellas/Cardiome submitted a revised NDA to FDA to seek approval for the use of intravenous (IV) vernakalant for acute conversion of AF to normal sinus rhythm.6

CHEMISTRY AND PHARMACOLOGY

Vernakalant, 3-pyrrolidinol, 1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy] cyclohexyl]-, hydrochloride (3R)-, is a chemical entity that has been demonstrated to block multiple ionic channels in various atrial tissue models.7–9

Data from recently published electro-physiology studies have led to a more complete understanding of the significant differences in the currents underlying atrial and ventricular action potentials.7–9 In normal atrial and ventricular cells, the action potential upstroke (phase 0) is generated by a sodium current. Depolarization to the threshold voltage results in opening of the activation gates of underlying sodium channels, followed by inactivation (closure of gates) of the sodium channels. The rapid repolarization (phase 1), plateau (phase 2), and late/final repolarization (phase 3) reflect the turning off of most of the sodium current, the waxing and waning of the calcium current, the gradual development of a repolarization potassium current, and the termination of sodium-/calcium-channel inactivation. Phase 4 of the action potential represents the resting potential of the atria and ventricles of the heart.7

Preliminary in vitro studies have demonstrated that vernakalant displays numerous characteristics of an ideal antiarrhythmic agent, as demonstrated by its predilection for blocking atrial-specific potassium channels and its rate and voltage-dependent sodium-channel blockade.7–9 Fedida et al7 elucidated vernakalant's mechanism of action by examining the inhibitory effects of this drug on sodium channels (Nav1.5) of human embryonic kidney (HEK) cells in the presence of escalating rates and varying depolarizing pulses; the investigators also analyzed the potency of Kv1.5, Kv4.3, IKACh, and hERG blockade in HEK cells. The concentrations producing half-maximal inhibition (IC50) served as markers of ionic channel blockade in this study.

Vernakalant clearly displayed rate-dependent Nav1.5 blockade, as demonstrated by a 3 to 4-fold lower IC50 at 20 Hz compared with the IC50 yielded at 1 Hz (holding potentials between –100 and –80 mV).7 The rate-dependent inhibitory actions of vernakalant reflected the quick onset of drug action as an activated sodium-channel-blocking agent, a potentially desirable property for an antiarrhythmic agent. Moreover, rapid recovery from vernakalant- induced blockage of sodium currents occurred as the rate decreased from 10 Hz to 1 Hz, a change thought to reflect the progression from tachyarrhythmia to normal sinus rhythm. A rapid offset of antiarrhythmic blockade of Nav1.5 may translate to reversal of this phenomenon within a few beats after termination of AF.

Fedida et al7 also observed vernakalant's voltage-dependent properties; as HEK cells underwent resting membrane potential depolarization from –120 mV to –60 mV, a >3-fold increase in potency of Nav1.5 occurred. The clinical significance of the voltage-dependent properties of vernakalant may be the further enhancement of atrial selectivity of this agent, as the resting potential of normal atria is approximately 10 mV positive to that of the ventricle. Moreover, during an AF episode, repolarization failure may result in an even greater difference between the resting potentials of the atria and ventricle, thereby increasing the pathologic selectivity of Nav1.5 blockade by vernakalant.

Additionally, Fedida et al7 demonstrated that vernakalant induced potent blockade of atrial-selective potassium channels, with IC50 values of 10±1 mcM, 13±1 mcM, and 15±2 mcM for IKACh, Kv1.5, and Ito, respectively. Blockade of these atrial-selective potassium channels enhances atrial refractoriness through prolongation of action potential duration and may thus increase the wavelength of reentrant circuits, culminating in termination of abnormal atrial electrical activity. Vernakalant was also demonstrated to induce minor blockade of hERG channels, with an IC50 of 21 mcM, a 30 to 100-fold higher value than the values reported with the antiarrhythmic agents flecainide and propafenone.