Effects of vernakalant and flecainide on atrial contractility in patients with atrial fibrillation

Pharmacological cardioversion has the advantage of not requiring sedation or
anaesthesia.[1] Unfortunately, many of current available anti-arrhythmic drugs
have potential proarrhythmic and negative inotropic effects and may be
contraindicated in certain patient groups such as postoperative patients. [2]
Vernakalant is a relatively new anti-arrhythmic drug (AAD) for rapid conversion
of recent-onset atrial fibrillation to sinus rhythm. Vernakalant is a
multi-channel blocker which acts preferentially in the atrial ion channels. In
this way it has minimal ventricular effects and consequently has a lower risk
of potentially dangerous arrhythmia*s compared to other anti-arrhythmic
drugs.[3, 4] Vernakalant exerts its anti-arrhythmic activity by means of
frequency-dependent blockade of cardiac sodium channels as well as blockade of
early-activating potassium channels important in atrial repolarization. The
blockade of these channels results in a prolongation of the atrial refractory
period and increase of the atrial action potential duration.[4-6] During atrial
fibrillation there is a higher frequency. Thus, the frequency-dependent
blockade results in an increased block of sodium channels during the
fibrillation resulting in a higher effectiveness of the treatment.[5]
Vernakalant has a half-life of about 3 hours.[7] The conversion rate in
patients presenting with AF with short duration (< 48 hours) varies between
52-59% with a time to conversion varying between 11-14 minutes. [3, 8-10]
The incidence of serious adverse events is low in patients using vernakalant.
The described adverse events (AE*s) were of minor clinical significance.
Compared to other anti-arrhythmic drugs it has no clinically significant
proarrhythmic risk. No cases of torsades de pointes, sustained ventricular
tachycardia or ventricular fibrillation were described. [3, 10]
Studies have shown that recovery of atrial contraction is delayed in patients
undergoing direct current cardioversion compared to patients undergoing
pharmacological cardioversion.[11, 12] We could recently demonstrate that
blockade of the ultra-rapid delayed rectifier current IKur can acutely restore
atrial contractility after spontaneous cardioversion of AF in goats.[13] This
effect was caused by elevation of the atrial plateau potential which enhances
Ca2+ influx in atrial myocytes by reverse mode Na/Ca exchange.[14] We
hypothesize that vernakalant, the only clinical available IKur blocker so far,
enhances atrial contractility after cardioversion of AF. Enhanced atrial
contractility after cardioversion of AF might reduce thromboembolic risks and
improve hemodynamics after cardioversion of AF.
Assessment of the effect of vernakalant on atrial contractility after
cardioversion requires the presence of sinus rhythm. As atrial contractility
after vernakalant administratrion cannot be compared to predrug values (before
exposure to vernakalant the patients are in AF), the effect of vernakalant
needs to be compared to a control compound with comparable effects with the
exception of the IKur block. Flecainide is widely used for cardioversion of AF,
blocks (as vernakalant) sodium channels, and lacks IKur blocking properties.
Thus, the goal of our study is to compare the atrial contractility of patients
who are treated with vernakalant i.v. to patients who are treated with
flecainide i.v.

Primary Objective: to compare the atrial contractility by means of
echocardiography between patients receiving flecainide and vernakalant i.v.
after conversion to sinus rhythm
Secondary Objective(s):
2a. To compare the conversion rate of AF between patients receiving flecainide
and
vernakalant i.v.
2b. To compare the recurrence rate of AF four weeks after successful
cardioversion between
patients receiving flecainide and vernakalant i.v.

This is an observational pilot study to compare the atrial contractility after
pharmacological conversion in patients receiving vernakalant or flecainide. The
patients are included at our first heart aid department where AF is diagnosed.
When the treating cardiologist decides to apply pharmacological cardioversion,
the patient will be asked to participate. After obtaining informed consent, the
patient will be randomized to receive flecainide or vernakalant intravenously.
Patients randomized to vernakalant will receive a 10-minute infusion of 3 mg/kg
vernakalant, followed by a 15 minute observation period. If the patient is
still in atrial fibrillation, an additional 10-minute infusion of 2 mg/kg
vernakalant will be given. Patients randomized to flecainide received a
10-minute infusion of 2 mg/kg (maximal 150 mg) flecainide. If the patient is
still in AF 1 hour after the infusion, electrical cardioversion will be
performed according to protocol. If conversion to sinus rhythm occurs within 60
minutes after start of the infusion, one of the secondary endpoints (2a) will
be reached. The time point of conversion to sustained (> 1 minute) sinus rhythm
will be noted. An echocardiography evaluating the atrial contractility (primary
endpoint, 1) will be performed during sinus rhythm, this can be after
pharmacological, electrical or spontaneous cardioversion. This is not part of
the regular therapy. All baseline characteristics and echocardiographic
measurements will be noted in a case record form. These include demographic
characteristics, medical history, use of anti-arrhythmic drugs, previous rhythm
control, data on electrocardiogram and echocardiogram. Patients will be
continuously monitored for at least 1-4 hours after ending the intravenous
treatment. Four weeks after the cardioversion patients will visit the
outpatient clinic by their own cardiologist for follow-up. This is part of the
regular treatment. During this visit we will evaluate the heart rhythm by
electrocardiography (2b). We will also perform a second echocardiography,
determining the same parameters as the first echocardiography. This is not part
of the regular treatment. See figure with study flow chart and numbered
objectives.

Administration of vernakalant or flecainide

During this study two extra echocardiographies will be performed. Both during
regular visits, meaning that there is no extra visit necessary. There are no
risks related to an echocardiography.