A phase iii superiority study of vernakalant vs

A Phase III Superiority Study of Vernakalant vs Amiodarone in

Subjects With Recent Onset Atrial Fibrillation (AVRO)

2010Journal Club

Dr Ihab Suliman

Purpose The primary objective of the study is to

demonstrate the superiority of vernakalant injection over amiodarone injection in the conversion of atrial fibrillation (AF) to sinus rhythm (SR) within 90 minutes of the start of drug administration.

The secondary objective is to compare the safety of vernakalant to amiodarone.

Vernakalant is a novel, atrium-selective, early-activating K+ and frequency-dependent Na+ channel blocker whose antiarrhythmic efficacy in AF was established in the atrial arrhythmia conversion trial (ACT) I – a Phase III, double-blind placebo-controlled trial

This study demonstrated a highly significant difference in the rate of successful cardioversion in those treated with vernakalant when compared with placebo (51.7 vs 4%, p ≤ 0.001). In those with recent onset of AF, the median time to conversion was 11 min. ACT III produced similar results in a further 276 patients

ACT II Trial Post Cardiac Surgery The recently published ACT II trial adds to

the previously published data, confirming efficacy and safety for vernakalant’s use in managing AF between 24 h and 7 days after cardiac surgery. In this second trial, similar results were obtained, with 47% of patients reverting to sinus rhythm at 90 min compared with 14% with placebo (p ≤ 0.001).

Vernakalant Injection

Indication: Vernakalant injection is indicated for the rapid conversion of atrial fibrillation of ≤ 7 days duration to sinus rhythm.

Dosage and Administration: The initial infusion of vernakalant injection is 3 mg/kg infused over 10 minutes. If conversion to sinus rhythm does not occur within 15 minutes after the end of the initial infusion, a second 10-minute infusion of 2 mg/kg may be administered.

Primary Outcome Measures: Proportion of subjects with conversion of

atrial fibrillation to sinus rhythm within 90 minutes after the start of infusion.

Assigned Interventions  Vernakalant Injection10-minute infusion of 3

mg/kg vernakalant injection followed by a 15-minute observation period, followed by an additional 10-minute infusion of 2 mg/kg of vernakalant if required (if the subject is still in AF).

 Amiodarone Injection:60-minute infusion of 5 mg/kg amiodarone followed by a maintenance infusion of 50 mg amiodarone over an additional 60 minutes (equivalent to approximately 15 mg/kg over 24 hrs).

Key Inclusion Criteria Have symptomatic AF of 3 to 48 hours duration at

baseline. Be eligible for cardioversion. Have adequate anticoagulation therapy for

cardioversion in accordance with standard of practice as recommended by ACC/AHA/ESC guidelines

Be hemodynamically stable and have systolic blood pressure (BP) above 100 mmHg and less than 160 mmHg and diastolic BP less than 95 mmHg at screening and baseline.

: Key Exclusion Criteria Known or suspected prolonged QT or uncorrected

QT interval of >440 msec as measured at screening on a 12 lead ECG, familial long QT syndrome, or previous torsades de pointes, ventricular fibrillation; or sustained ventricular tachycardia (VT).

Symptomatic bradycardia, sick sinus syndrome, or ventricular rate less than 50 beats per minute (bpm) as documented by 12-lead ECG at screening.

A QRS interval >140 msec.

Key Exclusion Criteria Atrial flutter. Significant valvular stenosis, hypertrophic

obstructive cardiomyopathy, restrictive cardiomyopathy or constrictive pericarditis.

Documented previous episodes of second or third degree atrioventricular (AV) block.

Had a myocardial infarction (MI), acute coronary syndrome or cardiac surgery within 30 days prior to entry into the study.

Uncorrected electrolyte imbalance of serum potassium or magnesium. Both K+ and Mg2+ must be corrected prior to dosing.

Results The primary endpoint of conversion to sinus

rhythm within 90 minutes was met in 52% of patients receiving vernakalant infusions vs 5.2% of those receiving amiodarone infusions.

Among those responding to vernakalant, the median time to conversion was 11 minutes. In addition a higher proportion of patients receiving vernakalant were free of AF symptoms at 90minutes compared with patients receiving amiodarone infusions (53.4% vs 32.8%).

Safety There were no cases of Torsades de pointes,

VF, and polymorphic or sustained VT.

The conclusion of this study was that intravenous vernakalant was superior to intravenous amiodarone for the acute conversion of AF and the relief of symptoms due to acute AF.