Drug Update

40 Cardiology Review | Vol 25 No 12 | December 2008

A trial fi brillation (AF) is the most common sustained cardiac arrhythmia, occur-

ring in over 2% of the general popu-lation.1 Its incidence increases with advanced age, and more than 9% of octogenarians have this disor-der.2 AF presentations are also be-ing encountered more frequently in emergency departments, with sub-sequent hospital admission rates ap-proaching 60%.2 The effect of AF on health care resources is a grow-ing concern, and a streamlined,effi cacious, and safe approach totreating AF patients is greatly needed.

Currently, there are 2 strategies for managing AF: (1) attempting to maintain the patient in sinus rhythm or (2) controlling the ventricular response rate. Older and asymp-tomatic patients generally receive rate-control treatments, while con-version to sinus rhythm may be the preferred initial approach in active, symptomatic, or younger patients.1 In this latter group of patients and in cases where the strategy is not clear, variable effi cacy and exten-sive side effects limit the usefulness of currently available antiarrhyth-

mic medications. Newer drugs are being developed and will ideally provide a safer and more effective option to combat AF.

In December 2007, the US Food and Drug Administration (FDA) Cardiovascular and Re-nal Drugs Advisory Committee evaluated 2 new antiarrhythmic medications, both intended for the rapid conversion of AF. The group unanimously voted against approv-ing intravenous tedisamil, while voting 6 to 2 in favor of approving vernakalant (Kynapid). Although these drugs are both novel class III antiarrhythmics, the FDA voted to approve vernakalant based on what the committee viewed as signifi cant differences in safety profi les and in patient populations studied (appli-cability to the US market); thus, it is possible that vernakalant will be the fi rst new antiarrhythmic medi-cation to hit the US market in almosta decade.

Pharmacology of AF converting medications

The currently evaluated anti-arrhythmic agents for the conver-sion of AF to normal sinus rhythm

include Vaughn Williams class Ia, class Ic, and class III antiarrhyth-mics. Class Ia (procainamide [Pron-estyl], quinidine [Quinaglute]) and class Ic (fl ecainide [Tambocor], propafenone [Rhthmol]) agents interrupt AF by blocking the in-ward sodium current (INa) to reduce conduction velocity.3 Class Ic agents also demonstrate rate-dependent inhibition, resulting in an increase in effi cacy when the atrial depolarization rate is high. This is different from class III agents, such as amiodarone (Cord-arone) and ibutilide (Corvert), which inhibit the rapidly and ultra-rapidly activating potassium cur-rents, IKr and IKur, respectively.4 This increases the action potential duration, enhances refractoriness, and increases the length of reen-trant wavelengths that are respon-sible for sustaining AF, ultimately terminating the arrhythmia. While all currently available antiarrhyth-mic agents are atrial repolarization delaying agents (ARDAs), they do not increase the atrial conduction velocity. Vernakalant is also re-ferred to as an ARDA, but is ac-tually considered a multichannel

Vernakalant: Expanding the antiarrhythmic vernacularSteven P. Dunn, PharmD • Tracy E. Macaulay, PharmD

From the department of pharmacy practice and science, University of Kentucky College of Pharmacy, UKHealthCare, department of pharmacy services, University of Kentucky, Gill Heart Institute, Lexington, KY.

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December 2008 | Vol 25 No 12 | Cardiology Review 41

blocker with varying pharmaco-logic effects.

Like other class III antiar-rhythmic medications, IKur is the main target of vernakalant, but its mechanism of action also involves blockade of transient outward cur-rents and sodium ion channels.5

The selectivity for IKur compared with IKs, IKr, and INa blockade may impart atrial selectivity and less proarrhythmia across all heart rates compared with other anti-arrhythmic medications.4

PharmacokineticsThe published literature is

scarce with regard to the phar-macokinetics, pharmacodynamics, and drug interactions of vernakal-ant, but small phase 2 trials have shed some light on these issues. Vernakalant has demonstrated lin-ear pharmacokinetics in the dos-age range of 0.1 to 5 mg/kg. The oral bioavailability of this agent is estimated to be 20%. Vernaka-lant follows a two-compartment pharmacokinetic model, achiev-ing nearly complete distribution within 30 minutes and undergo-ing rapid fi rst-order eliminations (t1/2 = 3-6 minutes).3 A study by Moe and colleagues found that af-ter a single dose, maximum plas-ma concentrations ranged from 0.08 to 4 mcg/mL, and the area under the curve was approximately 12 mcg(h)/mL.6

Vernakalant is hepatically me-tabolized by cytochrome P4502D6 (CYP4502D6) and has an estimat-ed elimination half-life of 2 to 3

hours. The plasma concentration of vernakalant may be increased in patients who are poor metaboliz-ers or in those taking concomitant inhibitors of the 2D6 isoenzyme. Although evaluation samples have been small, age, renal impair-ment, hepatic insuffi ciency, and heart failure did not demonstrate a signifi cant effect on the pharma-cokinetic profi le. Comparison of these parameters as well as others between vernakalant and other medications used for cardioversion are included in the Table.

SafetyRecent evaluations of antiar-

rhythmic drug safety for drug de-sign and regulatory approval have focused on the potential of the agent to prolong ventricular repo-larization time and induce torsade de pointes. Vernakalant was not thought likely to cause ventricular arrhythmias, as the IKur receptor has only been identifi ed in atrial tis-sue.7,8 Early clinical investigations did not demonstrate drug-induced QT prolongation with vernakal-

ant and even found it protective against clofi lium-induced torsade de pointes in one animal model.9

Larger evaluations of the safe-ty and effi cacy of vernakalant were performed in the 4 phase 3 ACT (Atrial Arrhythmia Conversion Trial) trials. To date, data from ACT 1, 2, and 3 have been pre-sented at major meetings, but the only published, peer-reviewed trial was ACT 1. ACT 4 is an open-label safety trial evaluating vernakalant for new-onset AF. The trial aims to corroborate clinical safety data ob-tained thus far. Enrollment in ACT 4 is complete, and data from the trial were used in the submission to the FDA. In ACT 1, no patients ex-perienced torsade de pointes with-in the fi rst 24 hours of infusion.10

In addition, no signifi cant differ-ence was detected in QRS or QTc intervals relative to patients receiv-ing placebo. Pooled data from all 4 ACT trials indicated that the in-cidence of ventricular arrhythmia observed on continuous electro-cardiographic monitoring within the fi rst 24 hours of infusion was 16.5% in patients receiving pla-cebo (n = 315), 12.9% in patients receiving 1 dose of vernakalant (n = 241), and 12.3% in patients receiving 2 doses of vernakalant (n = 496).11 In all phase 2 and 3 trials conducted, only 1 patient receiving vernakalant experienced torsade de pointes, but this inci-dence was thought to result from previous administration of ibutilide (Corvert).11

While vernakalant does not

Vernakalant follows a two-compartment

pharmacokinetic model, achieving nearly complete

distribution within 30 minutes and undergoing rapid

fi rst-order eliminations.

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Drug Update

42 Cardiology Review | Vol 25 No 12 | December 2008

appear to prolong the QT inter-val or cause excess ventricular ar-rhythmias, a number of adverse events were identifi ed in clinical trials. In a pooled analysis of all phase 2 and 3 trials, hypotensive adverse events within 2 hours of dosing were increased in patients receiving vernakalant compared with placebo (5.4% vs 1.0%).11 Hy-

potensive events did not appear to persist beyond 2 hours. The most frequently reported adverse events in patients receiving vernakalant were dysgeusia (20.4%), sneezing (15.0%), paresthesia (8.8%), and nausea (6.5%).11 Bradycardia and atrioventricular block were also observed more frequently in those receiving vernakalant compared

with placebo,11 but this could be a result of more successful conver-sion to sinus rhythm in the pres-ence of rate-controlling agents.

Of note, while some patients with systolic dysfunction were represented in phase 3 trials, more severely ill and hemodynamically unstable individuals who may re-quire electrical cardioversion for

Table. Comparison of antiarrhythmic medications for cardioversion of atrial fi brillation.

Parameter Amiodarone Dronedarone Flecainide Ibutilide Vernakalant

Mechanism of action

Beta-receptor blocker, K+ channel blocker,

Na+ channel blocker, Ca+ channel blocker

Beta-receptor blocker, alpha-receptor

blocker, K+ channel blocker, Na+ channel blocker, Ca+ channel

blocker

Slow Na+ channel blocker

Beta-receptor blocker and agonist,

alpha-receptor blocker and agonist, K+ channel blocker

K+ channel blocker, Na+ channel

blocker, with atrial selectivity

Oral bioavailability

~50%15%-20%

(increased 2-fold with food)

70%-95% (may be decreased

with antacids)Not available ~20%

Volume of distribution

~60 L/kg ~12 L/kg 4.9-10 L/kg 9-13 L/kg Unknown

Route of elimination

Metabolized by CYP3A4 and 2C8; an inhibitor of CYP3A4, CYP1A2, CYP2C9, and CYP2D6

Hepatically metabolized by

CYP3A4

Hepatically metabolized,

81%-90% renally eliminated

Hepatic metabolism via oxidation,

80% excreted in urine and 20% in feces

Hepatically metabolized by

CYP2D6

Half-life 26-107 days 24 hours 7-22 hours 2-12 hours 2-3 hours

Adverse drug effects

Pulmonary fi brosis, acute lung injury,

thyroid dysfunction, corneal deposits,

hepatitis, bradycardia, hypotension, skin

discoloration

Nausea, vomiting, diarrhea, QT prolongation

Torsade de pointes, rash, uticaria,

nausea, arthralgias, dizziness, headache,

fatigue, tremor, heart failure

Bradyarrhythmias, palpitations, head-

ache, torsade de pointes, ventricular

arrhythmias

Dysgeusias, sneezing,

paresthesia, and nausea

Dose

Atrial: 150 mg intravenous bolus, then continuous infusion or oral dosing to a total of 6-10 g load followed by

200 mg once daily

400 mg twice daily

Contraindicated in patients with New

York Heart Association class IV heart failure

200-600 mg orally

Contraindicated in patients with

structural heart disease

Patients >60 kg: 1 mg intravenous over 10 minutes, may repeat once

Patient <60 kg:

0.01 mg/kg

Intravenous: 2 mg/kg over 10

minutes, followed by 3 mg/kg

10 minutes later

Oral: under investigation

FDA-approved indications

Life-threatening ventricular arrhythmias

Approval pending

Paroxysmal atrial fi brillation, atrial fl utter,

supraventricular tachycardia,

life-threatening ventricular tachycardia

Recent-onset atrial fi brillation or atrial

fl utterApproval pending

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December 2008 | Vol 25 No 12 | Cardiology Review 43

atrial arrhythmias were not includ-ed. These and other acutely ill pop-ulations require further study to confi rm the effi cacy and safety of vernakalant in this setting. Patients with QT prolongation at baseline were also excluded from all study populations.11

Effi cacy Vernakalant has shown consis-

tent effi cacy in achieving chemical cardioversion of AF. In a phase 2,dose-ranging trial conducted by Roy and colleagues, the high-est dose of vernakalant studied (2 mg/kg, followed by 3 mg/kg if necessary) was more effective 30 minutes after infusion than placebo in the cardioversion of recent-onset AF (61% vs 5%, P <.0005).12

In the ACT 1 trial, which was the fi rst phase 3 investigation, the effi cacy of vernakalant (3 mg/kg, followed by 2 mg/kg if necessary) in the cardioversion of AF was con-fi rmed in a larger group of patients (n = 336).10 In the primary effi cacy analysis, 75 of the 145 vernakal-ant patients in the short-duration (3 hours to 7 days) AF group con-verted to sinus rhythm within 90 minutes compared with 3 of the 75 placebo patients (P <.001). Those

with long-duration (8-45 dayspost-onset) AF, however, had less success with chemical cardiover-sion, and vernakalant failed to demonstrate statistical superior-ity over placebo (7.9% vs 0%, P = .09). ACT 2 demonstrated the effectiveness of vernakalant in pa-tients developing AF shortly after cardiothoracic surgery (coronary artery bypass grafting or valve re-placement), with 47% of patients receiving the study drug converting to sinus rhythm after 90 minutes compared with 14% in the placebo group (P = .0001).13 ACT 3 simi-larly confi rmed the effectiveness of vernakalant in patients with recent-onset AF (3 hours to 7 days), with 51% of patients converting compared with 4% of patients re-ceiving placebo (P <.001).11,14 A pooled analysis of both ACT 1 and ACT 3 patients (n = 390) demon-strated that vernakalant was sig-nifi cantly effective in converting patients with recent-onset AF over placebo.11 Importantly, however, vernakalant was not statistically superior to placebo in converting a cohort of patients with longer duration AF.11

Ongoing trials Although vernakalant has

been recommended for approval by the FDA, additional clinical trials will be important to further defi ne its role in practice. One currently ongoing trial is a head-to-head comparison of vernakalant versus amiodarone in the cardioversion of recent-onset AF (ClinialTrials.gov

identifi er: NCT00668759). Patients are being actively enrolled and the trial is expected to complete enroll-ment this December.

Clinical implicationsVernakalant is likely to be a

promising addition to the antiar-rhythmic armamentarium. As one of a new generation of antiarrhyth-mic agents that has been designed with improved safety as a principal objective, vernakalant will hope-fully provide a therapeutic target that is effi cacious and without the risk of inducing QT prolongation and torsade de pointes, which have plagued antiarrhythmic drug ther-apy in the past. As an intravenous formulation, vernakalant seems likely to overtake other medica-tions for acute cardioversion, such as ibutilide and amiodarone, based on its safety profi le alone.

Nevertheless, questions and concerns surrounding the use of vernakalant in the “real world” re-main. The most likely application of the intravenous formulation is for recent-onset AF in hospital-ized patients necessitating conver-

Vernakalant has shown consistent effi cacy in achieving chemical cardioversion of AF.

Although vernakalant has been recommended for

approval by the FDA, additional clinical trials will

be important to further defi ne its role in practice.

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44 Cardiology Review | Vol 25 No 12 | December 2008

sion for a perceived hemodynamic benefi t or in cases where there is an inability to control ventricu-lar response rate. Patients such as these are likely to be acutely ill from heart failure, myocardial in-farction, or other severe illnesses, and although they are the most likely candidates to receive the drug in practice, they were not adequately represented in the clini-cal trials leading to vernakalant’s approval. Vernakalant also has not been shown to be effective if

the duration of AF is greater than 7 days.

Overall, vernakalant seems to be both effi cacious and safe in its ability to convert AF to si-

nus rhythm; however, the general lack of benefi t of rhythm control strategies in major clinical trials may limit widespread use as more practitioners pursue equally viable rate-control options.15,16 While im-proved safety of newer generation antiarrhythmic agents may lead to additional investigation in the future, vernakalant should at the very least be considered a safer way to convert a patient to sinus rhythm than traditional antiarrhythmic therapy. •

References

1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fi brillation—executive summary: a report of the American College of Cardiology/American Heart Associa-tion Task Force on Practice Guidelines and the European Society of Cardiol-ogy Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Pa-tients With Atrial Fibrillation) [pub-lished correction in J Am Coll Cardiol. 2007;50(6):562]. J Am Coll Cardiol. 2006;48(4):854-906.

2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fi brilla-tion in adults: national implications for rhythm management and stroke pre-vention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285(18):2370-2375.

3. Cheng JW. Vernakalant in the manage-ment of atrial fi brillation. Ann Phar-macother. 2008;42(4):533-542.

4. Naccarelli GV, Wolbrette DL, Samii S, et al. Vernakalant: pharmacology, electrophysiology, safety and effi cacy.Drugs Today (Barc). 2008;44(5):325-329.

5. Cardiome Pharma Corp. Vernakalant(oral). http://www.cardiome.com/VernakalantOral.php. Accessed Sep-tember 11, 2008.

6. Mao ZL, Wheeler JJ, Clohs L, Beatch

GN, Keirns J. Pharmacokinetics of the novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injec-tion (RSD1235): infl uence of CYP2D6 expression and other factors. J Clin Pharmacol. 2008 Oct 16. [Epub ahead of print]

7. Fedida D, Orth PM, Chen JY, et al. The mechanism of atrial antiarrhyth-mic action of RSD1235. J Cardiovasc Electrophysiol. 2005;16(11):1227-1238.

8. Fedida D, Wible B, Wang Z, et al. Identity of a novel delayed recti-fi er current from human heart with a cloned K+ channel current. Circ Res. 1993;73(1):210-216.

9. Orth PM, Hesketh JC, Mak CK, et al. RSD1235 blocks late INa and suppresses early after depolariza-tions and torsades de pointes induced by class III agents. Cardiovasc Res. 2006;70(3):486-496.

10. Roy D, Pratt CM, Torp-Pedersen C, et al; Atrial Arrhythmia Conversion Trial Investigators. Vernakalant hydro-chloride for rapid conversion of atrial fi brillation: a phase 3, randomized, placebo-controlled trial. Circulation. 2008;117(12):1518-1525.

11. Astellas Pharma US, Inc. Briefi ng ma-terials for the cardiovascular and renal drugs advisory committee: December 11, 2007. KYNAPIDTM (vernakalanthydrochloride injection), NDA 22-034.http://www.fda.gov/ohrms/dockets/

ac/07/briefing/2007-4327b1-01-astellas-backgrounder.pdf. Accessed Sept-ember 30, 2008.

12. Roy D, Rowe BH, Stiell IG, et al; CRAFT Investigators. A randomized, controlled trial of RSD1235, a novel antiarrhythmic agent, in the treat-ment of recent onset atrial fi brillation. J Am Coll Cardiol. 2004;44(12):2355-2361.

13. Kowey PR, Roy D, Pratt CM, et al. Effi cacy and safety of vernakalant hydrochloride injection for the treat-ment of atrial fi brillation after valvu-lar or coronary artery bypass surgery. Circulation. 2007;116:II636-II637.

14. Stiell IG, Roy D, Pratt CM, et al. RSD1235 effectively converts acute atrial fi brillation to sinus rhythm inde-pendent of background use of oral rate or rhythm-control medications. Ann Emerg Med. 2006;48(suppl):S46.

15. Roy D, Talajic M, Nattel S, et al; Atri-al Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fi brilla-tion and heart failure. N Engl J Med. 2008;358(25):2667-2677.

16. Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fi brillation. N Engl J Med. 2002;347(23):1825-1833.

Vernakalant has not been shown to be effective

if the duration of AF isgreater than 7 days.

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