• 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.)
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Atrial fibrillation (AF) is characterized by disorganized atrial activity without identifiable P waves on the surface electrocardiogram
(ECG).1 This disorder has been attributed to numerous factors, such as excessive alcohol intake, pericarditis, pulmonary embolism,
changes in autonomic tone, cardiac surgery (coronary artery bypass, valvular), pharmacologic agents, hyperthyroidism, and
numerous cardiac diseases (especially heart failure/ valvular disease).2 AF can be classified according to the duration and frequency of episodes, with the exception of lone AF, a condition that
occurs in the absence of underlying cardiac disease in younger patients. AF that is paroxysmal in onset and offset tends to
be recurrent and of short duration, lasting from a few seconds to 48 hours. Persistent AF may last for >7 days and tends to
be recurrent when an underlying structural cause, such as mitral valve disease, is the dominant pathophysiologic factor. Paroxysmal
and persistent AF become permanent if the patient bypasses cardioversion or if AF lingers despite cardioversion attempts.2
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 periodconduction 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.
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Vaughan Williams class IC anti-arrhythmic agents such as flecainide and propafenone may be proarrhythmic in the presence of
myocardial ischemia, as these agents may cause excessive conduction slowing in ischemic tissue through blockade of sodium
currents.2 Moreover, conversion rates of 80% to 90% with class IC agents do not occur earlier than 8 hours after dosing.
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
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The dominant underlying channels of the ionic currents responsible for generating atrial repolarization differ from the primary
underlying channels of the ionic currents causing ventricular repolarization.7 Kv1.5 channels underlie the ultrarapid delayed rectifier potassium current (IKur), and Kv4.3 channels underlie the transient outward repolarizing potassium current (Ito). The IKur and Ito currents contribute primarily to early atrial repolarization and do not significantly affect ventricular repolarization.
Moreover, an atrial-tissue-specific acetylcholine-activated potassium channel (IKACh) has been demonstrated to shorten phase 2 of the atrial action potential and thereby cause earlier termination of atrial
repolarization. In contrast, the late repolarizing delayed rectifier currents (IKr, IKs), with underlying hERG channels, have a much greater role in ventricular repolarization but contribute less to atrial repolarization.
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 101 mcM, 131 mcM, and 152 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.
PHARMACOKINETICS
The pharmacokinetic profile of vernakalant was studied by Mao et al.10 The investigators obtained 362 plasma vernakalant concentration measurements from 128 patients with AF or atrial flutter.
The majority of patients in the study population (92%) were Caucasian. Male patients comprised 70% of the study population,
and median patient age was 62 years (range, 22–89 y). The median creatinine clearance among study patients was 81 mL/min (range,
31–170 mL/min); 37% of study patients had mild renal impairment (creatinine clearance, 50–79 mL/min), and 12% had moderate
renal impairment (creatinine clearance, 30–49 mL/min). Median serum albumin and serum bilirubin concentrations were 4.1 g/dL
(range, 2.9–5.2 g/dL) and 0.6 mg/dL (range, 0.1–2.1 g/dL), respectively. Patients with heart failure comprised 20% of the
study population.
All patients in this pharmacokinetic study received an initial 3-mg/kg infusion administered over 10 minutes, followed by
a 15-minute assessment period; the majority (70%) of patients then required a second 2-mg/kg infusion administered over 10
minutes. The majority of blood samples were collected within 60 minutes after a vernakalant infusion.
Table 1: Pharmacokinetic profile of IV vernakalant
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The study investigators observed that a 2-compartment model, with rapid first-order elimination from the central compartment,
best characterized the pharmacokinetic profile of vernakalant.10 The calculated pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve [AUC0–∞], and terminal half-life) are highlighted in Table 1.10 The investigators identified gender as a source of variability in the pharmacokinetics of vernakalant, whereas age, renal
impairment, hepatic impairment, comorbid heart failure, and concomitant use of beta-blockers or cytochrome p450 2D6 isoenzyme
inhibitors did not demonstrate a significant effect on the pharmacokinetic profile of this agent. The relationship between
the volume of distribution and gender was described by Vd=46.2e–(0.658•gender) .
CLINICAL TRIALS
Table 2: Combined analysis of ACT 1 and ACT 3 (phase 3 trials of IV vernakalant)
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Acute conversion of AF. The efficacy and safety of IV vernakalant for the acute conversion of AF have been assessed in 2 phase 3 clinical trials,
the Atrial Arrhythmia Conversion Trials 1 and 3 (ACT 1 and ACT 3) (Table 2).11–13 These trials included a total of 575 patients with AF; AF duration among study patients ranged from 3 hours to 45 days. The
mean age of patients in the combined study populations was 62 years. Nearly 70% of patients had an episode of AF ranging from
3 hours to 7 days in duration. Exclusion criteria for the 2 trials included severe heart failure (New York Heart Association
[NYHA] class IV), baseline QT interval >440 msec, heart rate <50 beats per minute (BPM), QRS interval >140 msec, history of
prior cardioversion failure, occurrence of acute coronary syndrome (ACS) within the previous 30 days, and use of IV anti-arrhythmic
drugs (class I or class III [including amiodarone]) within the previous 24 hours. Patients were randomly assigned to receive
placebo or an initial 3-mg/kg dose of IV vernakalant administered over 10 minutes. Assessment for conversion to normal sinus
rhythm took place during the 15-minute postinfusion time period. Patients failing to convert to normal sinus rhythm within
25 minutes after the start of the initial infusion received a 10-minute infusion of vernakalant 2 mg/kg.
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The primary efficacy end point was the difference between vernakalant and placebo on the conversion rate of recent-onset AF
(3 h–7 d) to normal sinus rhythm within 90 minutes after initiating therapy. Other efficacy measures included median time
to conversion of AF to normal sinus rhythm, the proportion of patients who remained in normal sinus rhythm at 24-hour and
7-day follow-up, and the proportion of the overall study population (AF duration of 3 h–45 d) achieving normal sinus rhythm
within 90 minutes after the start of the initial infusion.
The combined study results demonstrated that, compared with placebo-treated patients, vernakalant-treated patients with recent-onset
AF exhibited significantly higher conversion rates (51.1% vs 3.8%; OR, 26.7; P<.0001).11–13 Of the vernakalant-treated responders, 78% achieved normal sinus rhythm after a single 3-mg/kg infusion. The median times
to conversion for patients with recent-onset AF and for the overall study population ranged from 10 to 11 minutes. Follow-up
assessments at 24 hours and 7 days demonstrated that normal sinus rhythm persisted in 97.2% and 92.9% of the responders, respectively.
Conversion of AF after cardiac surgery. Preliminary results from ACT 2, a phase 3 clinical trial evaluating the efficacy of IV vernakalant (dosing regimen not specified)
in converting patients (N=190) with AF/atrial flutter to normal sinus rhythm after cardiac surgery, have recently been announced
by vernakalant's manufacturer.14 A significantly higher proportion of patients with AF after cardiac surgery who were treated with IV vernakalant (n=161)
converted to normal sinus rhythm within 90 minutes after initiating drug therapy compared with placebo-treated patients (47%
vs 14%; P=.0001). Median time to conversion approached 12 minutes for the vernakalant treatment group responders. None of the vernakalant-treated
patients experienced torsades de pointes.
ADVERSE EVENTS
Formulary considerations
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Data from ACT 1 and ACT 3 indicate that vernakalant is well tolerated. Dysgeusia (28.3%), sneezing (17.1%), and paresthesia
(10.9%) represent the 3 most commonly reported adverse events.11–13 Of note, none of the patients treated with vernakalant in ACT 1, ACT 2, or ACT 3 experienced torsades de pointes.11–14 One vernakalant-treated patient with comorbid aortic stenosis experienced ventricular fibrillation during the 30-day follow-up
period. The safety of vernakalant in patients with severe heart failure (NYHA class IV), bradycardia, recent (within the previous
30 d) history of ACS, recent (within the previous 24 h) use of IV antiarrhythmics, or elevated baseline QT intervals (>440
msec) has yet to be determined, as these subsets of patients were excluded from phase 3 clinical trials.
DRUG INTERACTIONS
ACT 1 and ACT 3 included a limited number of patients who concurrently took vernakalant and digoxin (combined, n=30) or who
received concomitant class I antiarrhythmics (combined, n=25), sotalol (a class III antiarrhythmic agent that is approved
by FDA for use in maintaining a normal sinus rhythm) (combined, n=28), or other class III antiarrhythmics (combined, n=16).12 Coadministration of digoxin, class I antiarrhythmics, or class III antiarrhythmics was associated with conversion rates
of 20%, 20%, and 38%, respectively (P value not significant vs no concomitant drug). Of note, concomitant use of sotalol was associated with a somewhat higher conversion
rate (64%) versus no sotalol (P value not significant). Further studies with a larger number of patients receiving vernakalant and concomitant antiarrhythmic
agents or digoxin are warranted to determine the effect of concomitant drug use on conversion rates to normal sinus rhythm.
DOSING AND ADMINISTRATION
The dosing regimen that will be recommended if FDA approves vernakalant has not yet been established. ACT 1 and ACT 3 demonstrated
the efficacy of initial IV doses of vernakalant 3 mg/kg infused over 10 minutes, followed by an IV dose of 2 mg/kg if recent-onset
AF persisted during the 15-minute postinfusion, drug-free period. The potential dosing regimen of IV vernakalant for the acute
conversion of AF after cardiac surgery is unknown, as the data have not yet been published.
Ms Dia and Mr Rathbun is PharmD candidate at the University of the Pacific School of Pharmacy, Stockton, California. Dr Song is an associate professor of pharmacy practice at the University of the Pacific School of Pharmacy and is the pharmacy practice
residency coordinator, Department of Pharmacy Services, Santa Clara Valley Medical Center, San Jose, California.
Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.
In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics
committee members. The column is coordinated by Robert A. Quercia, MS, RPh, clinical manager and director of Drug Information, Department of Pharmacy Services, Hartford Hospital, Hartford, Conn, and
adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and
Outcomes Studies Group, Hartford Hospital.
EDITORS' NOTE:
The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental
or newly approved drug therapies, articles include information published or presented and available to the author up until
the time of the manuscript submission.
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Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines
(Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in collaboration
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9. Fedida D, Orth PMR, Hesketh JC, Ezrin AM. The role of late I Na and antiarrhythmic drugs in EAD formation and termination in Purkinje fibers. J Cardiovasc Electrophysiol. 2006;17(suppl 1):S71–S78.
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12. Stiell I, Roy D, Pratt C, et al. Vernakalant hydrochloride injection (RSD1235) effectively converts acute atrial fibrillation
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