A Phase III Superiority Study of Vernakalant vs. Amiodarone in Subjects With Recent Onset Atrial Fibrillation - AVRO

Jan 10, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Cardiome Pharma Corporation (Vancouver, British Columbia, Canada)
Date Published:
01/01/2011
Date Updated:
01/10/2011
Original Posted Date:
01/10/2011
References

Description:

Currently, ibutilide is the only agent that is Food and Drug Administration (FDA) approved for acute conversion of atrial fibrillation (AF). Other agents that are frequently used, such as amiodarone, are associated with modest efficacy, and frequent side effects. Vernakalant hydrochloride is a newer agent, which showed promising results in a placebo-controlled phase II and III trial. The goal of this trial was to compare the safety and efficacy of vernakalant versus amiodarone in acute conversion of AF.

Hypothesis:

Vernakalant would be superior to amiodarone in the acute conversion of AF to normal sinus rhythm (NSR).

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patient Populations:

  • Age 18-85 years
  • Symptomatic recent-onset AF (duration of 3-48 hours), who were eligible for cardioversion
  • Hemodynamically stable (systolic blood pressure >100 but <160 mm Hg, and diastolic blood pressure <95 mm Hg)
  • On adequate anticoagulation therapy (if recommended by American College of Cardiology/American Heart Association/European Society of Cardiology guidelines)

    Number of enrollees: 254
    Duration of follow-up: 7 days
    Mean patient age: 62.7 years
    Percentage female: 37%
    Ejection fraction: 58.5%
    NYHA class: I (45.7%), II (54.3%)

Exclusions:

  • Uncorrected QT interval >440 ms
  • Familial long QT syndrome
  • Previous TdP, ventricular fibrillation, or sustained VT
  • Symptomatic bradycardia, known sick sinus syndrome, or ventricular rate <50 bpm
  • QRS interval >140 ms
  • Pacemaker
  • Atrial flutter
  • Atrial thrombus
  • Unstable congestive heart failure, New York Heart Association class IV heart failure, or heart failure requiring inotropes
  • Myocardial infarction, acute coronary syndrome, or cardiac surgery within 30 days prior to enrollment
  • Cerebrovascular accident within 3 months prior to enrollment
  • Atrioventricular block
  • Valvular stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or constrictive pericarditis
  • End-stage disease states
  • Previously failed electrical cardioversion, secondary causes of AF, uncorrected electrolyte imbalance, digoxin toxicity, contraindications to amiodarone, or previous exposure to vernakalant

Primary Endpoints:

  • Proportion of patients with conversion of AF to NSR within 90 minutes of first exposure to study drug and for a minimum duration of 1 minute

Secondary Endpoints:

  • Time to conversion of AF to SR within the first 90 minutes after the start of infusion
  • Proportion of patients exhibiting no AF symptoms at 90 minutes
  • Change in EQ-5D quality-of-life assessment visual analog scale (VAS; 15) from screening to hour 2

Drug/Procedures Used:

Patients randomized to vernakalant received a 10-minute infusion of 3 mg/kg vernakalant in one infusion line, followed by a 15-minute observation period and an additional 10-minute infusion of 2 mg/kg vernakalant if still in AF. To maintain blinding, a 60-minute infusion of placebo (5% dextrose in water) was administered in a second infusion line, followed by a maintenance infusion of placebo for an additional 60 minutes. Patients randomized to amiodarone received a 60-minute infusion of 5 mg/kg amiodarone in one infusion line, followed by a maintenance infusion of 50 mg amiodarone over an additional 60 minutes (equivalent to approximately 15 mg/kg over 24 hours). To maintain blinding, these patients received a 10-minute infusion of placebo (normal saline) in a second infusion line, followed by a 15-minute observation period and a second 10-minute infusion of placebo if still in AF.

Concomitant Medications:

Beta-blockers (59.9%), digitalis (6.9%), calcium channel blockers (6.0%), any rate control (64.2%)

Principal Findings:

A total of 232 patients were randomized, 116 to vernakalant and 116 to amiodarone. Baseline characteristics were fairly similar between the two arms. About 72% of patients had hypertension, and 35% had evidence of structural heart disease, including valvular heart disease in about 7%. The mean left atrial (LA) diameter was about 4.1 cm, with only 5% having an LA diameter >5 cm. About 29% of patients had never had AF before, and the median duration of AF was about 18 hours; in about 60% of patients, the median duration of AF was ≤24 hours.

Efficacy: The primary endpoint of acute conversion to NSR within 90 minutes of exposure to the drug was significantly higher in the vernakalant arm compared with the amiodarone arm (51.7% vs. 5.2%, relative risk [RR] 10.0, 95% confidence interval [CI] 4.5-22.0, p < 0.0001). Of the patients that responded to vernakalant, the median time to conversion was 11 minutes. Quality-of-life measures were also higher in the vernakalant arm. Of the patients converting within 90 minutes, 59 of 60 patients in the vernakalant arm (98.3%) and 6 of 6 patients in the amiodarone arm (100%) stayed in NSR at 4 hours. About 37% of patients in the vernakalant arm, as compared with 9.5% of patients in the amiodarone arm, were ready for discharge at 2 hours (p < 0.0001).

Safety: Any treatment-emergent adverse event (any adverse event that began or worsened following the start of study drug infusion) was more common in the vernakalant arm at both 0-2 hours (27.6% vs. 8.6%) and 2-24 hours (18.1% vs. 12.9%). The most common adverse events with vernakalant were dysgeusia (6.9%) and sneezing (3.4%); 3 patients discontinued vernakalant due to treatment-related adverse effects. The incidence of atrial flutter was significantly higher in the vernakalant arm within 4 hours post-dose (8.6% vs. 0.9%). One death was noted in the vernakalant arm, with none in the amiodarone arm; one episode of nonsustained ventricular tachycardia (VT) was also noted in the vernakalant arm. There were no cases of torsades de pointes (TdP), ventricular fibrillation, or polymorphic or sustained VT in either group.

Interpretation:

The results of this phase III trial demonstrate that vernakalant is superior to amiodarone for acute conversion of AF to NSR, with more than 50% of patients treated with vernakalant converting to NSR, although the incidence of short-term adverse events was higher with vernakalant. Proarrhythmic events were rare, except for atrial flutter (about 9%).

Vernakalant hydrochloride is a new atrial-selective, early-activating K+ (IKur) and frequency-dependent Na+ channel blocker, and may be a novel alternative to currently used agents for acute conversion of AF to sinus rhythm, especially if it is of relatively short duration (ibutilide being the only FDA approved drug for this indication). Further studies will need to clarify the role of vernakalant in patient subsets who were excluded from this study (acute decompensated heart failure or acute coronary syndromes, hypertrophic cardiomyopathy, history of ventricular arrhythmias, or baseline QT intervals >440 ms), who have a high propensity of developing AF, as well a head-to-head comparison between vernakalant and ibutilide, since both of them seem to have comparable rates of conversion of recent-onset AF to NSR.

References:

Camm AJ, Capucci A, Hohnloser SH, et al., on behalf of the AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol 2011;57:313-321.

Keywords: Risk, Acute Coronary Syndrome, Follow-Up Studies, Cardiomyopathy, Hypertrophic, Ventricular Fibrillation, Electric Countershock, Torsades de Pointes, United States Food and Drug Administration, Sneezing, Dysgeusia, Heart Failure, Pyrrolidines, Atrial Fibrillation, Confidence Intervals, Hypertension, Sulfonamides, Atrial Flutter


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