BRINAVESS™
In September 2010, Merck (known as MSD outside the United States and Canada) and Cardiome announced that the intravenous (IV) formulation of BRINAVESS™ (vernakalant) has been granted marketing approval in the European Union (EU), Iceland and Norway for the rapid conversion of recent onset atrial fibrillation (AF) to sinus rhythm in adults: for non-surgery patients with AF of seven days or less and for post-cardiac surgery patients with AF of three days or less.
BRINAVESS acts preferentially in the atria and is the first product in a new class of pharmacologic agents for cardioversion of AF to launch in the EU.
Information on the clinical program for BRINAVESS
The approval of BRINAVESS is based on the results of three randomized, double-blind, placebo controlled studies (ACT I, ACT II, and ACT III) and an active comparator trial (AVRO).
In ACT I and III, the efficacy of BRINAVESS at converting patients from AF to sinus rhythm for a minimum duration of one minute with 90 minutes of initiating therapy was evaluated in 390 haemodynamically stable adult patients with short duration AF (3 hours to 7 days) versus placebo. In ACT I, vernakalant cardioverted 51.0 percent of patients versus 4.0 percent of patients taking placebo (n=74 and 3, respectively; p<0.0001). In ACT III, vernakalant cardioverted 51.2 percent of patients versus 3.6 percent of patients taking placebo (n=44 and 3, respectively; p<0.0001). Conversion of AF to sinus rhythm occurred rapidly; in responders, the median time to conversion was 10 minutes from start of first infusion, based on pooled results from the ACT I and ACT III studies.
The efficacy of BRINAVESS was also studied in ACT II in 150 patients with sustained AF (3 hours to 72 hours duration) that occurred between 24 hours and 7 days post coronary artery bypass graft and/or valvular surgery. Treatment with BRINAVESS effectively converted 47.0 percent of patients from AF to sinus rhythm versus 14.0 percent placebo (p=0.0001).
In the AVRO (Active-Controlled, Multi-Center Study of Vernakalant Injection versus Amiodarone in Subjects with Recent Onset Atrial Fibrillation) study, BRINAVESS was demonstrated to be significantly faster than amiodarone IV in converting AF patients to sinus rhythm. In the trial, BRINAVESS was studied in 116 patients with AF (3 hours to 48 hours) versus 116 patients on amiodarone. The amiodarone infusion was given over two hours (i.e., one hour loading dose of 5 mg/kg, followed by one hour maintenance infusion of 50 mg) with the objective to compare rapid conversion to sinus rhythm. The primary endpoint was the proportion of patients that achieved sinus rhythm for a minimum duration of one minute within 90 minutes of the first exposure of the study drug. In this study, treatment with BRINAVESS converted 51.7 percent of patients to sinus rhythm at 90 minutes versus 5.2 percent with amiodarone.
Important Safety Information for BRINAVESS
BRINAVESS is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. BRINAVESS also is contraindicated in patients with severe aortic stenosis, systolic blood pressure <100 mm Hg, and heart failure class NYHA III and NYHA IV. Furthermore, BRINAVESS is contraindicated in patients with prolonged QT at baseline (uncorrected >440 msec), severe bradycardia, sinus node dysfunction, or second-degree or third-degree heart block in the absence of a pacemaker. BRINAVESS is also contraindictated in patients who use intravenous rhythm control antiarrhythmics (class I and class III) within four hours prior to administration of BRINAVESS and patients with acute coronary syndrome (including myocardial infarction) within the last 30 days.
Patients should be observed with assessment of vital signs and continuous cardiac rhythm monitoring during and after administration of BRINAVESS, until clinical and ECG parameters have stabilized.
Hypotension can occur in a small number of patients (vernakalant 7.6%, placebo 5.1%). Hypotension typically occurs early, either during the infusion or early after the end of the infusion, and can usually be corrected by standard supportive measures. Patients with congestive heart failure (CHF) have been identified as a population at higher risk for hypotension.
Patients with a history of CHF showed a higher incidence of ventricular arrhythmia in the first two hours post dose (7.3% for BRINAVESS compared to 1.6% for placebo). These arrhythmias typically presented as asymptomatic, monomorphic, non-sustained
(average 3 to 4 beats) ventricular tachycardias. By contrast, ventricular arrhythmias were reported with similar frequencies in patients without a history of CHF who were treated with either BRINAVESS or placebo (3.2% for BRINAVESS vs 3.6% for placebo).
In patients with valvular heart disease, there was a higher incidence of ventricular arrhythmia events in patients on BRINAVESS. These patients should be monitored closely.
As a precautionary measure, it is preferable to avoid the use of BRINAVESS during pregnancy. It is unknown whether vernakalant/metabolites are excreted in human milk. Caution should be exercised when used in breast-feeding women.
In clinical studies, the most commonly reported adverse reactions (>5%) seen in the first 24 hours after receiving BRINAVESS were dysgeusia (taste disturbance) (20.1%), sneezing (14.6%), and paraesthesia (9.7%).
Clinically significant adverse reactions observed in clinical trials included hypotension and ventricular arrhythmia.