REVIEW
Europace (2014) 16, 162–173
doi:10.1093/europace/eut274
Pharmacological cardioversion of atrial fibrillation
with vernakalant: evidence in support of the
ESC Guidelines
1
Division of Clinical Sciences, St George’s University of London, London, UK; and 2Medical Writers Group, LLC, New York, USA
Received 2 May 2013; accepted after revision 9 August 2013; online publish-ahead-of-print 9 October 2013
Pharmacological rhythm control (often including electrical or pharmacological cardioversion) is an integral part of therapy for atrial fibrillation
(AF) worldwide. Antiarrhythmic drug strategies would be preferred in many patients provided effective and safe antiarrhythmic agents are
available. Also, pharmacological cardioversion could be the preferred option if the limitations of currently available drugs, such as restriction
to patients without structural heart disease (flecainide and propafenone), risk of torsade de pointes (ibutilide), and slow onset of action
(amiodarone), were overcome. The intravenous formulation of vernakalant (Brinavess, Cardiome) has been approved for pharmacological
cardioversion of recent-onset AF (≤7 days) and early (≤3 days) post-operative AF in the European Union, Iceland, and Norway. Vernakalant
has a high affinity to ion channels specifically involved in repolarization of atrial tissue and has minimal effects in the ventricles and thus, is
thought to have a low proarrhythmic potential. Vernakalant is administered as a 10 min infusion of 3 mg/kg, and if AF persists after 15 min, an
additional dose of 2 mg/kg can be given. The efficacy and safety of the drug has been extensively investigated in randomized controlled trials
against placebo and an active comparator (amiodarone). The placebo-extracted efficacy of vernakalant is 47%. A significant advantage is a
rapid effect, with the median to conversion ranging between 8 and 14 min, with the majority of patients (75 –82%) converting after the first
dose. Vernakalant retained its efficacy in subgroups of patients with associated cardiovascular disease such as hypertension and ischaemic
heart disease, but its benefit may be lower and risk of adverse effects is higher in patients with heart failure. In the post-market reports, cardioversion rates with vernakalant are 65–70%. This review focuses on the role of vernakalant in pharmacological cardioversion for AF.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Antiarrhythmic drugs † Atrial fibrillation † Cardioversion † ESC Guidelines † Pharmacological cardioversion †
Vernakalant
Introduction
Atrial fibrillation (AF) is the most common arrhythmia seen in clinical
practice, with a lifetime risk estimated at one in four in the population
40 years of age and older.1 The epidemiological data suggest that .6
million people in Europe may currently have the arrhythmia, and the
projected number of patients with AF is set at least to double in the
next 40 years.2 – 4
The development of more effective agents to manage patients with
AF is essential.5 While clinical trials have shown no major differences in
outcomes between the two prime treatment strategies for AF (rate
and rhythm control), rhythm control with antiarrhythmic drugs,
ablation, or both remains the preferable treatment in many patients
with recent-onset AF, those who are highly symptomatic, young, and
active individuals, as well as patients seeking symptom relief in addition
to optimal rate control.6 Rhythm control was the first line or preferred
option in 55–67% of patients enroled in epidemiological surveys and
registries worldwide,7 – 9 and was also associated with a lower incidence of progression to permanent AF compared with rate control.10
Pharmacological or electrical cardioversion is an integral part of
rhythm control management.11 Until recently, the choice of antiarrhythmic drugs for pharmacological cardioversion in Europe has
been limited to intravenous formulations of flecainide, propafenone,
and amiodarone, although ibutilide is available in some European
Union countries. A ‘pill-in-the-pocket approach’ with a single oral
loading dose of flecainide or propafenone is limited to highly selected
patients. Vernakalant is a new addition to intravenous antiarrhythmic
drugs available for cardioversion of AF.12
Pharmacological cardioversion
Selection of mode of cardioversion
The current European Society of Cardiology (ESC) Guidelines on AF
recommend that pharmacological cardioversion should be considered
* Corresponding author. Tel: +44 208 725 3414; fax: +44208 725 3416, Email: jcamm@sgul.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com.
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Irene Savelieva 1, Richard Graydon 2, and A. John Camm 1*
163
Pharmacological cardioversion with vernakalant
3943 patients with acute onset AF enroled in 26 countries in
Eastern and Western Europe, South America, and Australia,18 cardioversion was performed in 69% of patients, with pharmacological
cardioversion as first line chosen in 31% of the patients (presented
at the ESC Congress in 2011). In some countries, such as Spain, Italy,
Poland, and Brazil pharmacological cardioversion accounted for a
significant proportion of procedures (up to 40–95%), whereas in
Sweden, Germany, France, and the UK, it was the least preferred
option, with just under 5–15% of patients given an antiarrhythmic
drug for cardioversion.
A recent survey by the European Heart Rhythm Association
(EHRA) of 57 centres—members of the EHRA Electrophysiology
Research Network—has revealed that only 18.8% of sites named
pharmacological cardioversion as their prime strategy, whereas the
majority (68%) preferred electrical cardioversion.19 The presence
and severity of underlying heart disease is likely to have a significant
effect on the mode of cardioversion, mainly because of a limited
choice of antiarrhythmic drugs and associated risks in such patients.
In the EHRA survey, nearly two-thirds of centres opted for pharmacological cardioversion in patients without structural heart disease,
but fewer centres used this method in patients with moderate or
severe cardiovascular pathology.19
Drugs for pharmacological cardioversion
The choice of an antiarrhythmic drug for cardioversion of AF is determined by the underlying heart disease.13 Intravenous formulations of
antiarrhythmic drugs are typically used for cardioversion, mainly
when AF is of short duration (Table 1).11 Propafenone and flecainide
are recommended for cardioversion of recent-onset AF in patients
with no or minimal structural heart disease and are contraindicated
in patients with a history of heart failure, previous myocardial infarction, coronary artery disease, particularly with evidence of transient
myocardial ischaemia, and significant left ventricular hypertrophy.
Both drugs are very effective in acute-onset AF (under 48– 72 h),
with conversion rates as high as 80–90% within 1–2 h after the
start of infusion.20,21 The advantage of propafenone and flecainide
is the possibility of oral administration for cardioversion of AF; the
Table 1 Antiarrhythmic agents for pharmacological cardioversion for AF
Drug
Dose
Efficacy
Time to
conversion
Acute side effects
Hypotension, rapid atrial flutter, and QRS widening
...............................................................................................................................................................................
Flecainide
200–300 mg p.o. stat
2 mg/kg i.v. over 10 min
450–600 mg p.o. stat
2 mg/kg i.v. over 10 min
150 mg i.v. bolus, or 5 mg/kg i.v.
over 1 h
59–92%
57–91%
51–82%
56–83%
34–69% (bolus)
55–95%
(bolus + infusion)
2 –4 h (max 8 h)
2h
2 –4 h (max 8 h)
1 –2 h
6 –24 h
Hypotension, rapid atrial flutter, and QRS widening
Ibutilide
1 mg i.v. over 10 min, repeat if
necessary
44–51%
90 min
QT prolongation, torsade de pointes, and bradycardia
Vernakalant
3 mg/kg i.v. over 10 min, repeat
2 mg/kg i.v. if necessary
51–70%
90 min (median
8 –14 min)
Hypotension (especially in heart failure), QT
prolongation (low risk of torsade de pointes)
Propafenone
Amiodarone
AF, atrial fibrillation i.v., intravenous; p.o., per os.
a
For i.v. formulation.
Modified from: Camm AJ et al. 11
Hypotension, bradycardia, QT prolongation
(low risk of torsade de pointes), and phlebitis
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in patients, who can tolerate their arrhythmia without significant
haemodynamic compromise.13 The choice between electrical and
pharmacological cardioversion in haemodynamically stable patients
depends on several considerations, with the duration of AF
episode being the key element to this decision.11 Pharmacological cardioversion usually is most effective if initiated within a week after the
onset of the arrhythmia, in which case restoration of sinus rhythm
can be achieved in 50–70% of patients, but the success rate decreases
significantly as AF persists beyond this limit. The likelihood of spontaneous conversion varies greatly.14 Systematic analysis of placebocontrolled studies of pharmacological cardioversion for AF has
shown that among patients with AF of ,24 h, 66% spontaneously
converted to sinus rhythm compared with only 17% of those with
the arrhythmia of longer duration (odds ratio 1.8).15
No need for general anaesthesia or conscious sedation and fasting,
intuitively lower risk of immediate recurrence of AF, and arguably,
lower psychological impact on some patients, are clear advantages
of pharmacological cardioversion. The major limitations are the relatively unpredictable outcomes of treatment, a generally lower efficacy compared with electrical cardioversion, and thus a potentially
longer hospital stay, as well as restricted drug choice because of
underlying heart disease, risk of proarrhythmia, potential drug interactions including pretreatment with other antiarrhythmic drugs, and
country-specific drug availability and prescribing recommendations.
In the EuroHeart Survey of AF, pharmacological, as opposed to
electrical, cardioversion was most commonly chosen if a patient
developed their first episode of AF, had a history of paroxysmal AF,
and a short overall duration of the arrhythmia.16 Sinus rhythm at
24 h was achieved in 71 and 75% of the patients, respectively, after
intravenous and oral drug administration. The success rates were significantly lower in patients with AF ≥ 48 h compared with AF , 48 h
(54–67 vs. 80 –87%). Other surveys reported the need to switch to
electrical cardioversion in up to 38.6% of patients primarily undergoing pharmacological cardioversion.17
The selection of mode of cardioversion is subject to wide geographical variations and local practices. Thus, in the International
Registry on Cardioversion for Atrial Fibrillation (RHYTHM-AF) of
164
‘Pill-in-the-pocket’ strategy
Proponents of cardioversion with oral medication cite multiple randomized controlled trials, which successfully used single dose oral
loading regimens of propafenone and flecainide, for pharmacological
cardioversion of recent-onset AF.23,24,28 Typically, single doses of
propafenone 450 –600 mg or flecainide 200 –300 mg have been
administered, with success rates ranging from 56 to 83%, and 57–
91%, respectively.23,24 The conversion times were in the order of
2 –4 h. Reversible QRS complex widening, transient hypotension,
arrhythmias, left ventricular dysfunction, and mild non-cardiac side
effects have been reported. Organization of AF into atrial flutter
occurs in 2.5 –20% of patients (5–7% on average).22 In patients
without structural heart disease, single oral doses of propafenone
and flecainide are safe and effective; however, patients with substantial structural heart disease were excluded from most of the trials.
Self-administration of flecainide or propafenone to terminate AF in
an out-of-hospital setting has been referred to as a ‘pill-in-the-pocket’
approach. In patients with no or minimal structural heart disease and
relatively infrequent (,12 per year), paroxysms of AF of distinct
onset which, although symptomatic, do not cause significant haemodynamic compromise (e.g. hypotension), a loading single dose of
either drug can be used for expedient cardioversion.29 The efficacy
and safety of ‘pill-in-the-pocket’ therapy with flecainide and propafenone in an out-of-hospital setting was tested in 210 patients.30 Of 618
total episodes of AF, treatment was successful in 534 (94%), and the
mean time to resolution of symptoms was 2 h. Adverse effects
included 1 case of atrial flutter at a rapid ventricular rate and noncardiac side effects in 11 patients. However, the experience with
this strategy is limited, neither propafenone nor flecainide is licensed
for patients to use for self-treating single attacks, and it is mandatory
that the efficacy and safety of this strategy is first tested in-hospital.
Drug-induced cardioversion during
long-term therapy
Occasionally, antiarrhythmic drugs given as a pre-treatment for electrical cardioversion in patients with persistent AF may facilitate ‘spontaneous’ restoration of sinus rhythm. This should not be confused
with a ‘pill-in-the-pocket’ approach where a single loading dose of
the drug is utilized. More than half the centres in the EHRA Electrophysiology Research Network have reported routine pre-treatment
with antiarrhythmic drugs to improve outcome of electrical cardioversion.19 In the SAFE-T (Sotalol Amiodarone Atrial Fibrillation Efficacy Trial), 24.2 and 27.1% of patients with persistent AF treated with
sotalol or amiodarone, respectively, converted to sinus rhythm
within 28 days, compared with 0.8% on placebo.31 Similarly, a
subset of patients with AF randomized to dofetilide in the mortality
DIAMOND (Danish Investigations of Arrhythmia and Mortality
ON Dofetilide) studies in patients with congestive heart failure
(DIAMOND-CHF) or myocardial infarction with left ventricular dysfunction (DIAMOND-MI), were more likely to convert to sinus
rhythm compared with placebo (44 vs. 14%).32 However, in specific
cardioversion studies, dofetilide at 1000 mg daily demonstrated a
modest 30% efficacy compared with 1.2% of spontaneous conversion on placebo.33 Because of its clear torsadogenic potential, it is
mandatory that dofetilide is initiated in hospital and patients are monitored for at least 3 days. The drug is not widely available in Europe.
Recently, ranolazine, an antianginal agent, which selectively inhibits
the late INa current, the rapidly activating component of the delayed
rectifier (IKr), and the late ICaL, with a preferential effect at the atrial
level,34 has demonstrated a promising antiarrhythmic potential including patients with structural heart disease.35,36
Vernakalant for pharmacological
cardioversion of atrial fibrillation
Limitations of available antiarrhythmic drugs have stimulated research into new antifibrillatory agents with enhanced efficacy, incorporating optimal multichannel blocking profiles, such as inhibition of
atrial-specific currents such as IKACh and IKur, and atrial-selective Na+channel blockade.12 To this end, the unique pharmacological profile
of vernakalant addresses many problems of existing antifibrillatory
drugs by selectively targeting ion channels that are expressed primarily in atrial cardiomyocytes and provides rapid, effective treatment for
acute onset AF.
Electrophysiological effects of vernakalant
Vernakalant, a pyrrolidine compound, rapidly terminates AF through
blocking of potassium and sodium ion channels in all phases of the
atrial action potential (Figure 1, Table 2).37,38
Inhibition of potassium currents
By targeting potassium channels Kv1.5, which carry the ultra-rapid
delayed rectifier potassium current (IKur) and exist primarily in
atrial cardiomyocytes, vernakalant produces atrial-specific prolongation of the effective refractory period. Since the drug blocks Kv1.5
channels in the open state, it is effective at fast atrial rates associated
with AF. Other targets include the acetylcholine-activated IKACh
current, which is also exclusive to the atria, the transient outward
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conversion rates are comparable with those achieved with intravenous formulations, although the effect is expectedly delayed to 2–4 h
(up to 8 h).22 – 24
Ibutilide is only modestly effective for conversion of AF (as it is
more effective in converting atrial flutter), but may be used in patients
with moderate structural heart disease, apart from heart failure, and
its use is limited by a sizeable risk of torsade de pointes (up to 4%).25
Cardioversion with amiodarone is delayed by 8–24 h and its efficacy
has not proven superior to other antiarrhythmic drugs,26,27 but it is
the only agent which is recommended in patients with significant
structural heart disease, particularly left ventricular systolic dysfunction and heart failure. In the presence of fast AF, amiodarone offers
the benefit of atrioventricular (AV) blockade. Intravenous procainamide is available in some countries, but is no longer used routinely for
cardioversion of AF.
The efficacy of antiarrhythmic drugs varied across the studies
(Table 1), but usually is the greatest for AF of short duration (≤48–
72 h). Intravenous amiodarone was the most commonly used drug
for pharmacological cardioversion in the EuroHeart Survey (63%) followed by oral flecainide or propafenone (30%)16 and in the recent
EHRA survey, particularly in patients with underlying heart disease
(50%).17 In the RHYTHM-AF registry, amiodarone was chosen for
pharmacological cardioversion in 54% of cases, followed by flecainide
and propafenone (31 and 15%, respectively).
I. Savelieva et al.
165
Pharmacological cardioversion with vernakalant
Ito
INa
0 mV
Late INa
IKur
IKr
IKs
IKACh
0
100
200
300
400
ms
Figure 1 Ion currents blocked by vernakalant.
Table 2 Potency of sodium and potassium current block
by vernakalant
Current
IC50, mcMol
................................................................................
Peak INa, voltage-dependent
31– 107
Peak INa, frequency-dependent
9 –43
Late INa
Ito
14
5 –30
IKur
3 –13
IKAch
IKr
10
7 –21
IKs
.100
IK1
.100
IC, half maximal inhibitory concentration.
Modified from: http://www.fda.gov/ohrms/dockets/ac/07/briefing/
2007-4327b1-01-astellas-backgrounder.pdf.
Pharmacokinetics and pharmacodynamics
current Ito, and the rapid component of the delayed rectifier IKr. The
contribution of Ito to the action potential is greater in the atria than
the ventricles. The potency of vernakalant to block the human
ether-à-go-go-related gene channels, which carry a rapid delayed rectifier potassium current (IKr), is 30- to 100-fold lower than that of flecainide and propafenone, and 1000-fold lower potency than that of
ibutilide and dofetilide, which may explain the lack of significant QT
interval prolongation and low risk of torsade de pointes.38 Vernakalant has little effect on other currents involved in ventricular repolarization, such as the slow component of the delayed rectifier IKs and
the inward rectifier IK1 currents.
Inhibition of sodium currents
Vernakalant inhibits both the peak and late components of the Na+
current (INa). At the ventricular level, block of late INa opposes the
prolonging effect of IKr inhibition. The drug binds to Na+-channel
Nav1.5 a-subunits, and blocks the channels in a mechanism that
Vernakalant is metabolized in the liver by cytochrome P450 CYP 2D6
and has an elimination half-life of 3 h, which was prolonged up to
8.5 h in poor metabolizers.38,45 Mean plasma concentrations peak
at the end of the 10 min infusion and decrease sharply following
the end of infusion. No dose adjustment for age, gender, and renal
function is required. Vernakalant is a moderate competitive inhibitor
of CYP2D6, but showed no significant effect on CYP3A4 and
P-glycoprotein and given its rapid distribution and short half-life is
unlikely to cause any major drug–drug interactions.
Administration of vernakalant
Vernakalant is administered by intravenous infusion, initially at 3 mg/
kg over a 10 min period. If the sinus rhythm is not restored within
15 min following the end of the first infusion, a second 10 min infusion
of 2 mg/kg can be administered.46 If conversion to sinus rhythm
occurs during either infusion, the full 10 min infusion should be
completed.
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IK1
varies with heart rate and membrane potential (frequency- and
voltage-dependent block). At normal heart rates, block of Nav1.5
by vernakalant does not produce any significant electrophysiological
effect because of its rapid unbinding kinetics. As heart rate increases,
the affinity of vernakalant for the activated Na+ channel becomes
greater, which is unique among antiarrhythmic drugs.
Differences in membrane potential between atrial and ventricular
cardiomyocytes are in part responsible for the specificity of blockade
demonstrated with vernakalant. The potency of vernakalant to block
the Na+ channels increases in parallel with the level of depolarization. In the presence of fast atrial rates associated with AF, the
resting membrane potential of atrial cells is more depolarized than
ventricular cells, resulting in an increased number of Na+ channels
in the inactivated state in the atria, thereby reducing the Na+channel reserve and facilitating a greater inhibiting effect of vernakalant in the atria.39 This may account for the apparently paradoxical
atrial selectivity of INa block in rapidly activating and partially depolarized atrial tissue. Furthermore, rapid unbinding kinetics of vernakalant may be beneficial at high activation rates. Prolongation of the
effective refractory period without change of the duration of the
action potential, inducing post-repolarization refractoriness, is an
additional atrial-specific feature of INa current blockade.
Presently, it remains unclear whether the atrial-selective antifibrillatory effectiveness of vernakalant is primarily due to inhibition of the
IKur or INa current. Possibly resulting from the electrical and structural
remodelling of AF, ‘pure’ IKur blockade with selective agents, prolongs
action potential duration in the presence of AF, while it actually shortens the action potential in sinus rhythm.40 In persistent AF, IKur channels are downregulated and their influence on atrial repolarization
is reduced.41 Therefore, concomitant inhibition of INa may account
for the observation that some IKur blockers, such as vernakalant,
are able to convert AF to sinus rhythm.42,43 It is also possible that
the ability of vernakalant to suppress delayed afterdepolarizations
by reducing intracellular calcium overload, probably secondary to
late INa block, can contribute to its antifibrillatory properties.44
166
Efficacy of vernakalant
Active comparator studies
In the AVRO (Active-controlled, superiority study of Vernakalant
versus amiodarone in Recent Onset atrial fibrillation) requested by
European Medicines Agency (EMA), sinus rhythm was restored
within 90 min in 51.7% of patients with AF of 3– 48 h treated with vernakalant compared with 5.2% treated with amiodarone (P , 0.0001),
and at 4 h (54.4 vs. 22.6%; P , 0.0001).51 A significantly higher proportion of patients, who received vernakalant, were ready for discharge at 2 h (37 vs. 9.5%).
Two small (36 and 32 patients, respectively) sequential nonrandomized studies from a single centre have demonstrated the advantage of vernakalant to rapidly convert recent-onset (,48 h) AF
compared with a single oral dose of flecainide (300 mg)54 or propafenone (600 mg)55 in patients without structural heart disease
(Figure 3). In the vernakalant cohort, 86 –93% of patients were in
sinus rhythm at 2 h; in the flecainide and propafenone cohorts, 78%
of patients were in sinus rhythm at 8 h. Time to conversion was 9–
10 min on vernakalant and 163–166 min on flecainide or propafenone. More patients in the flecainide or propafenone group required
electrical cardioversion (20 –22 vs. 7%). Patients treated with vernakalant had a 43% shorter hospital stay. Serious adverse events were
rare in all cohorts, but substantially more patients who received vernakalant reported non-serious side effects.
Subgroup and meta-analyses
In the pooled analysis, vernakalant was 8.4 times more likely to
convert AF to sinus rhythm than placebo or amiodarone (95% confidence interval (CI), 4.4 –16.3), without excess risk of serious
adverse events (risk ratio, 0.91; 95% CI, 0.6 –1.36).56 In another
meta-analysis which looked specifically at rapid conversion of AF to
sinus rhythm using Bayesian mixed-treatment comparisons, vernakalant also compared favourably with older antiarrhythmic agents.57 Specifically, conversion rates at 2 h with intravenous formulations of the
drugs were 52% on vernakalant, 16% on amiodarone, 51% on propafenone, and 64% on flecainide compared with 12% on placebo. Over 95%
of patients, who converted to sinus rhythm after receiving vernakalant,
remained in sinus rhythm at 24 h.53
The subgroup analysis in 274 patients with ischaemic heart disease
(41% with previous myocardial infarction) enroled in ACT I– IV trials,
revealed no increased risk of serious adverse events associated with
vernakalant compared with their counterparts without ischaemic
heart disease (Figure 2)58 There were no drug-related cases of
torsade de pointes, ventricular fibrillation, or death in the subgroup
with ischaemic heart disease, and the placebo-extracted efficacy of
vernakalant was comparable (45.7 vs. 47.3% ischaemic vs. nonischaemic). However, there was a trend towards a reduced benefit
in patients with heart failure.
Real-world experience with vernakalant
There is accumulating, albeit still limited evidence from national registries, for the use of vernakalant in unselected patient populations
(Figure 3). In the observational study from a single centre in
Malmö, Sweden, where the drug has been used since 2011, 70% of
251 patients treated with vernakalant in the emergency department
converted to sinus rhythm within 2 h after the start of infusion, with
the median time to conversion of 11 min (Juul-Möller et al. Eur J
Cardiovasc Med 2013, in press). Hypertension was the prevalent diagnosis, and few patients (10%) had structural heart disease. The
conversion rates were higher in patients with AF duration ,10 h
compared with AF lasting for .10 h (76 vs. 66%). The incidence of
adverse events was low, with transient hypotension and bradycardia
occurring in 5 (1.4%) of patients, mainly due to sinus pauses (2–12 s)
following conversion which required atropine injection in one
patient. There were no ventricular arrhythmias or torsade de
pointes tachycardia. Patients who did not respond to vernakalant
(n ¼ 91) had electrical cardioversion. The preliminary results from
Kuopio University Hospital presented at the ESC Congress in 2013
reported a similar ‘real-world’ success rates for cardioversion with
vernalalant of 65– 70%.
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Pivotal placebo-controlled studies
The clinical efficacy of vernakalant was investigated in one dose finding,
three medium-size randomized placebo-controlled phase III clinical
studies, one randomized clinical trial with amiodarone as an active
comparator, and a phase IV open-label study (Table 3 and
Figure 2).47 – 52 Atrial arrhythmia Conversion Trial (ACT) I and III
were randomized, placebo-controlled, double-blind trials involving,
respectively, 336 and 262 patients with AF of 3 h to 45 days, who
were further stratified according to duration of AF between 3 h to 7
days and 8–45 days.48,49 Patients enroled in the vernakalant studies
were primarily men (68%) with a mean age of 63 years (range 22–
94), with approximately half the patients over 65 years. The prevalent
diagnosis was hypertension (40%) and a smaller proportion (10–
20%) had ischaemic heart disease (6–10% with previous myocardial infarction) or heart failure (15–20%). In phase III and IV studies, vernakalant was administered as a 10 min infusion of 3 mg/kg and if AF persisted
after 15 min, a second infusion of 2 mg/kg was given. The primary endpoint was the proportion of patients with AF of 3 h to 7 days, who converted to sinus rhythm (for at least 1 min) within 90 min after the start
of infusion.
In both trials, vernakalant was significantly more effective than
placebo in converting AF (51.7 vs. 4%, P , 0.001, and 51.2 vs. 3.6%,
P , 0.0001, respectively). The placebo-extracted efficacy was
47.3%.53 Patients with AF ≤ 48 h demonstrated the highest rate of
conversion (62.1 vs. 4.9% on placebo, P , 0.001). The median time
to conversion was 11 and 8 min in the ACT I and ACT III study, respectively, and the majority of patients (76 and 81.8%) converted
after the first dose. These results were complemented by the openlabel ACT IV study in which vernakalant restored sinus rhythm in
50.9% within 14 min after the start of infusion.50
The ACT II study assessed the efficacy of vernakalant for
cardioversion of AF which occurred 24 h and 7 days following valvular or coronary artery bypass surgery.52 A total of 160 patients
received either placebo or vernakalant 3 mg/kg followed by a
second infusion of 2 mg/kg if AF persisted during a 15 min observation
period. In ACT II, 47% patients in the vernakalant group and 14% in the
placebo group converted to normal sinus rhythm within 90 min of the
start of treatment (P , 0.001), with a median conversion time of
12 min; 75% patients converted after the first dose.
I. Savelieva et al.
Design
Number of patients
Age, years
AF duration
Underlying heart disease
CRAFT47
Double-blind, step-dose,
placebo-controlled,
phase II
Vernakalant 2 + 3 mg/kg: 60.8
Vernakalant 0.5 + 1 mg/kg: 67.4
Placebo: 64
AF 3– 72 h
(mean, 11.5– 19.5 h)
Hypertension, 57%
diabetes, 23%
ACT I48
Double-blind,
placebo-controlled,
phase III
56
Vernakalant 2 + 3 mg/kg: n ¼ 18
Vernakalant 0.5 + 1 mg/kg: n ¼ 18
Placebo: n ¼ 20
336
Vernakalant: n ¼ 221
Placebo: n ¼ 115
Vernakalant: 62.3 + 13.7
Placebo: 61.5 + 11.3
Hypertension, 42.5%
ischaemic heart disease, 20.2%
myocardial infarction, 9.8%
heart failure, 14.9%
diabetes, 8%
ACT II52
Double-blind,
placebo-controlled,
phase III
160 (atrial flutter, n ¼ 10)
Vernakalant: 106
Placebo: 54
Vernakalant: 68.3 + 7.7
Placebo: 67.8 + 6.4
AF 3 h to 45 days
(median, 41.8 –59.1 h)
AF 3 h to 7 days (median,
28.2– 28.4 h): n ¼ 220
AF 8– 45 days (median,
19.4– 25.5 days): n ¼ 116
AF 3– 72 h occurring between 24 h
and 7 days after cardiac surgery
ACT III49
Double-blind,
placebo-controlled
phase III
262
ACT IV50
Open-label, phase IV
167
AF 3 h to 7 days:
Vernakalant: 60 + 16
Placebo: 60 + 15
AF 8– 45 days:
Vernakalant: 65 + 11
Placebo: 66+ 10
63 + 13
AVRO51
Double-blind,
active-controlled
(i.v. amiodarone),
phase III
232
Vernakalant: n ¼ 116
Amiodarone: n ¼ 116
Vernakalant: 63.1 + 10.8
Placebo: 62.2 + 11.6
Scene 259
Double-blind, controlled,
phase II/III
54
Vernakalant: n ¼ 39
Placebo: n ¼ 15
Vernakalant: 67 + 11
Placebo: 69 + 11
Atrial flutter 3 h to 45 days
(mean, 98– 178 h)
Study
Primary endpoint
Conversion to sinus rhythm vs.
placebo or control
Time to conversion (median)
on vernakalant, minutes
Other efficacy outcomes
.............................................................................................................................................................................................................................................
AF 3 h to 45 days
AF 3 h to 7 days: n ¼ 170
AF 8– 45 days: n ¼ 9
Atrial flutter: n ¼ 23
AF 3 h to 45 days (median, 38.5 h)
AF 3 h to 7 days: n ¼ 170
AF 8– 45 days: n ¼ 69
AF 3– 48 h (median, 17.7 h)
CABG, 67%; valvular surgery,
23.6%; combined, 9.3%
hypertension, 69.5%
ischaemic heart disease, 80%
heart failure, 31.6%
Hypertension, 43.9%
ischaemic heart disease, 11.8%
myocardial infarction, 6.5%
heart failure, 19.8%
diabetes, 8.4%
Hypertension, 44%
ischaemic heart disease, 8%
heart failure, 11%
Hypertension, 71.6%
structural heart disease, 34.9%
ischaemic heart disease, 22.4%
myocardial infarction, 8.2%
heart failure, 19.8%
NYHA I, 19.8%
NYHA II, 54.3%
valvular heart disease, 6.9%
–
Safety and adverse effects on
vernakalant vs. placebo or
control
.............................................................................................................................................................................................................................................
CRAFT47
Proportion of patients
converted to SR during
infusion or within 30 min
after the last infusion
61% (vernakalant 2 + 3 mg) vs. 5%,
P , 0.001
14
Conversion rate for vernakalant
0.5 + 1 mg/kg:
11%
Cardiac events (SAE, VAE, and
bradycardia): 16.7% and
22.2% on vernakalant 2 + 3 mg/kg
and 0.5 + 1 mg/kg,
167
Continued
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Study
Pharmacological cardioversion with vernakalant
Table 3 Summary of clinical studies of vernakalant in atrial fibrillation/flutter
168
Table 3 Continued
Study
Design
Number of patients
Age, years
AF duration
Underlying heart disease
.............................................................................................................................................................................................................................................
Proportion of patients
converted to SR within
90 min of drug initiation in
AF 3 h to 7 days
51.7 vs. 4%,
P , 0.001
11
76% converted after a single dose
Conversion rates for patients with AF
48 h: 62.1 vs. 4.9%, P , 0.001;
with AF . 7 days: 7.9 vs. 0%,
P ¼ 0.09
ACT II52
Proportion of patients
converted to SR within
90 min of drug initiation in
AF 3 h to 7 days
47 vs. 14%,
P , 0.001
12
75% converted after a single dose
Patients with flutter converted to SR:
0/6 vs. 1/4
ACT III49
Proportion of patients
converted to SR within
90 min of drug initiation in
AF 3 h to 7 days
51.2 vs. 3.6%, P , 0.001
8
81.8% converted after a single dose
Conversion rates for patients with
AF . 7 days: 9 vs. 3%, P ¼ 0.33;
with flutter: 7.1% (1/14) vs. 0% (0/9)
ACT IV50
Proportion of patients
converted to SR within
90 min of drug initiation in
AF 3 h to 7 days
50.9%
14
Conversion rates for patients with
AF ≤ 48 h: 57.9%;
with AF . 7 days: 11.6%
AVRO51
Proportion of patients
converted to SR within
90 min of drug initiation
51.7 vs. 5.2%, P , 0.0001
11
Reduction in symptoms at 2 h
reported by 53.4% patients in the
vernakalant group vs. 32.8% in the
amiodarone group, P ¼ 0.0012
Scene 259
Proportion of patients
converted to SR within
90 min of drug initiation
3 vs. 0%, P ¼ 0.45
–
–
I. Savelieva et al.
ACT, Atrial arrhythmia Conversion trial; AF, atrial fibrillation; AVRO, a prospective, randomized, double-blind, Active-controlled, superiority study of Vernakalant versus amiodarone in Recent Onset atrial fibrillation; CABG, coronary artery bypass
grafting; CRAFT, Controlled Randomized Atrial Fibrillation Trial; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association; SAE, serious adverse event; SR, sinus rhythm; TdP, torsade de pointes; VAE, ventricular arrhythmia
event; VT, ventricular tachycardia.
In the dose-finding CRAFT study, two doses of vernakalant were used: 0.5 mg/kg 10 min bolus followed by 1 mg/kg bolus or 2 mg/kg 10 min bolus followed by 3 mg/kg bolus if AF was present 30 min after the first infusion. In the subsequent ACT I –IV,
AVRO, and Scene 2 studies, a 10 min infusion of 3 mg/kg was given followed by a 2 mg/kg bolus if AF did not terminate within 15 min after the first infusion.
a
No reports of torsade de pointes within 24 h of treatment; three cases of torsade de pointes 32 h, 16, and 17 days after vernakalant infusion (drug-unrelated).
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ACT I48
respectively, vs. 35% on placebo
No difference in QTc
SAE within 30 days: 13.1 vs. 18.3%
Any VAE within 24 h: 17.4 vs. 9%
NSVT: 6.3 vs. 14.8%, no TdPa
OTc . 500 ms: 24 vs. 15% (after
the first infusion)
and 11 vs. 14% (at 90 min)
SAE within 24 h: 9.3 vs. 11.1%
AE: 38.3 vs. 31.5%
Any VAE: 17.8 vs. 16.7%, no TdP
QTc . 500 ms: 18 vs. 7% (after the
first infusion)
and 7 vs. 10% (at 90 min)
SAE within 24 h: 2.2 vs. 4.6%
SAE within 30 days: 10.4 vs. 13%
Any VT: 11.9 vs. 10%, no TdP
1 death within 24 h in a patient with
severe aortic stenosis
QTc prolongation by 20–25 ms
after each infusion at
10 and 35 min
SAE at 0 –2 h: 3%, at 2– 24 h: 2.1%
Drug discontinuation: 4.2%
Any VAE at 0– 2 h: 5.1%, at 2– 24 h:
6.4%, no TdP
Non-SAE: 63.6%
SAE at 0 –2 h: 2.6 vs. 0.9%, at 2 –24 h:
1.7 vs. 0.9%
Any adverse event at 0– 2 h: 27.6 vs.
8.6%, at 2– 24 h: 18.1 vs. 12.9%
No TdP
SAE: 18 vs. 27%
Any adverse event: 87 vs. 73%
1 TdP after ibutilide infusion (2 h
after vernakalat infusion)
169
Pharmacological cardioversion with vernakalant
Vernakalant
60
52.9
51.2
51
50.9
Placebo / Amiodarone
52
Patients, %
51.8
50.9
47
50
45.7
40
30
20
14
10
5.3
4
11.8
5.8
5.7
3.6
0
0
ACT I
ACT III
ACT IV
AVRO
ACT II
Pooled Subgroup Conversion
analysis with IHD within 2 h*
Figure 2 Proportion of patients who converted to sinus rhythm on vernakalant compared with placebo or active control. IHD, ischaemic heart
disease. *Placebo conversion rates including historical data (13 studies, 583 patients).
Patients, %
Vernakalant
100
90
80
70
60
50
40
30
20
10
0
93
Comparator
87
86
78
70
65
33.3
10
Conde et al. - Conde et al. - Conde et al. - Malmo
Flecainide* Propafenone Amiodarone
AVRO trial51 and a smaller sequential series. In the AVRO study,
53.4% of patients in the vernakalant group reported symptom relief
at 2 h after the start of treatment compared with 32.8% in the
amiodarone group.51 Consequently, there was an improvement of
12 points the EQ-5D questionnaire among patients who received
vernakalant and only 5 points in those who received oral flecainide
or propafenone for cardioversion.61
Clinical safety
Kuopio
Figure 3 Efficacy of vernakalant for cardioversion of atrial fibrillation in non-randomized studies and registries.
* Conversion rates for vernakalant at 2 h, for flecainide at 8 h.
Atrial flutter and atrial fibrillation of >7 days
Vernakalant was ineffective in converting typical atrial flutter49,52,59
and AF of .7 days.47 – 49 For atrial flutter, cardioversion rates for vernakalant and placebo were, respectively, 3 and 0%,59 and for AF of .7
days, 6.5 and 1.3%.53 Conversion of AF to atrial flutter was observed
in 8.6 –12.7% of patients treated with vernakalant, one-third of whom
subsequently converted to sinus rhythm, suggesting that atrial flutter
may be a transitional rhythm prior to conversion.48,49,51 Unlike with
flecainide and propafenone, there is probably low risk of developing
atrial flutter with 1 : 1 AV conduction due to the electrophysiological
properties of vernakalant to prolong the atrial flutter cycle length and
AV nodal refractoriness.60
Patient perception of treatment
In the Malmö registry, among patients successfully treated with vernakalant, 72% would prefer this treatment in the case of recurrence,
whereas among non-responders to vernakalant only 61% would
prefer electrical cardioversion. This is in line with a significantly
greater improvement in symptoms and perception of health in the
The pooled safety data included 773 patients receiving vernakalant
and 335 receiving placebo enrolled in the ACT I–IV; CRAFT, and
Scene 2 atrial flutter studies.46,53 In general, vernakalant was welltolerated and was not associated with increased rates of clinically
relevant adverse and serious adverse events compared with
placebo or amiodarone. The most common side effects of vernakalant were taste alterations (20 –30%), sneezing (10 –20%), paraesthesia (8%), and nausea (6%), which are secondary to the effect of
vernakalant on Na+ channels in the central nervous system. These
usually resolved within 5–15 min.38,53
Total serious adverse events in the first 24 h were reported at
similar rates for vernakalant and placebo (4.1 vs. 3.9%).38 Drug-related
serious adverse events or other significant events related to medication administration occurred in 2.1% of patients who received vernakalant, as compared with 0.3% among those receiving placebo.53
Transient hypotension occurred in about 5–7% of patients treated
with vernakalant, with the blood pressure restoring to baseline after
15 –20 min; as a serious adverse event, hypotension was reported
in 1.2% compared with 0.3% on placebo (Table 4).38 Hypotension
within the first 2 h was most common in patients with heart failure
(16.1%), who were probably more sensitive to the potential negative
inotropic effect of the Na+-channel blockade.53
Bradycardia was more common with vernakalant than placebo
[(5.4 vs. 3.8% at 2 h)53 and (3.4 vs. 2.1% at 24 h38)], but seldom led
to drug discontinuation and was associated with AF termination
rather than an intrinsic property of the drug. Vernakalant produced
no significant effect on ventricular rates during AF.
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CRAFT
170
I. Savelieva et al.
There was no excess in ventricular arrhythmia events compared
with placebo (5.3 vs. 6.3% at 2 h and 12.5 vs. 16.5%, at 24 h after
the start of treatment).38 The incidence of non-sustained monomorphic tachycardia within the first 2 h was 2.3% following vernakalant infusion and 1.6% on placebo. However, in patients with heart
failure, non-sustained ventricular arrhythmias occurred more often
on treatment (7.3 vs. 1.6% on placebo at 2 h).53 Clinically significant
ventricular arrhythmias occurred within 2 h after vernakalant administration in five patients (none on placebo), three of which had heart
failure. Similarly, patients with valvular heart disease more often
experienced ventricular arrhythmias.
Vernakalant prolonged the QRS complex and QTc interval by 8
and 20– 25 ms, respectively. Torsade de pointes occurred in four
patients with three occurring in the vernakalant group, two of
which were deemed unrelated to the drug. There was one case of
torsade de pointes within 24 h of treatment with vernakalant (2 h
20 min after the start of vernakalant infusion) in a patient who was
given ibutilide after vernakalant failed to convert AF. This led to a
contraindication for vernakalant administration within 4 h of class I
and III antiarrhythmic drugs.
In patients with post-operative AF in the ACT II study, the incidence of serious adverse events in the vernakalant group was 9.3%
compared with 11.1% in the placebo group.52 Bradycardia and hypotension occurred more often after vernakalant infusion.
In the AVRO study, the incidence of serious adverse events at 2 and
2–24 h was 2.6 vs. 0.9% and 1.7 vs. 0.9% in patients treated with vernakalant compared with amiodarone.51 In the pooled analysis of five
studies, the overall incidence of serious adverse events was virtually
identical in the vernakalant and comparator groups (10.5 vs. 10.4%;
risk ratio, 0.91; 95% CIs, 0.60 –1.36; P ¼ 0.64).51
A total of five deaths were reported in the vernakalant programme,
with one considered possibly related to drug administration. The
individual was a 64-year-old man with a history of critical aortic
stenosis (ordinarily an exclusion criterion), heart failure New York
Heart Association (NYHA) class II, left ventricular hypertrophy,
an ejection fraction of 40%, who presented with acute coronary
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Figure 4 Choice of cardioversion mode and an antiarrhythmic agent for pharmacological cardioversion of AF. ACS, acute coronary syndrome; AF,
atrial fibrillation; CAD, coronary artery disease; HF, heart failure; HCM, hypertrophic (obstructive) cardiomyopathy; LVH, left ventricular hypertrophy. aIbutilide should not be given when significant left ventricular hypertrophy (≥1.4 cm) is present. bVernakalant should not be given in moderate or severe heart failure, aortic stenosis, ACS, or hypotension. Caution in mild heart failure. c‘Pill-in-the-pocket’ technique—preliminary
assessment in a medically safe environment and then used by the patient in the ambulatory setting. dRanolazine is not currently approved for use
in AF and definitive trials have not been reported. Dashed line, agent is not included in the ESC Guidelines. Modified from: Camm AJ et al. 62
171
Pharmacological cardioversion with vernakalant
Table 4 Cardiovascular adverse effects and precautions
for the use of vernakalant
Incidence and warnings
Hypotension
Vernakalant vs. placebo: 7.6 vs. 5.1% at 2 h, 5.8 vs.
3.6% at 24 h, severe 1.2 vs. 0.3%
Usually transient (15– 20 min)
Greater risk in patients with heart failure than
without (16.1 vs. 4.7% within the first 2 h)
Do not use if systolic blood pressure
,100 mmHg
Ventricular
arrhythmias
5.3 vs. 6.3% at 2 h, clinically significant 0.6 vs. 0%
Patients with heart failure had higher incidence of
ventricular arrhythmias (7.3 vs. 1.6% within the
first 2 h)
No drug-related torsadesa
Bradycardia
5.4 vs. 3.8% at 2 h, clinically significant (1.3 vs. 0%)
Predominantly at the time of conversion to sinus
rhythm
Responded well to vernakalant discontinuation
and/or administration of atropine
................................................................................
Atrial flutter
As a transitional rhythm in 8.6– 12.7%, as an
adverse event in 1– 30% of patients with atrial
flutter converted to sinus rhythm
Electrical cardioversion for the remaining
patients
No 1 : 1 AV conduction
ECG intervals
QTc increased by 20– 25 ms
QRS increased by 8 ms
Do not use if baseline QT . 440 ms
Concomitant
therapy
76% received b-blockers, calcium antagonists,
or digoxin
24% class I and III antiarrhythmic drugs
No difference in conversion rates and adverse
effects, but data are limited (use with caution)
Prophylactic antiarrhythmic drug therapy can be
resumed 2 h after infusion of vernakalant
a
Defined as an event occurring within 24 h after treatment; one episode of torsade
de pointes immediately after infusion of ibutilide (2 h 20 min after initialization of
vernakalant infusion).
syndrome and AF. He was first given metoprolol, but became
haemodynamically unstable. After stabilization with intravenous
fluid, he received two infusions of vernakalant leading to exacerbation of hypotension, myocardial ischaemia, and a fatal ventricular arrhythmia. One patient who failed to respond to a single vernakalant
infusion developed cardiogenic shock several hours after electrical
cardioversion, but survived and was later diagnosed with
tachycardia-induced cardiomyopathy. This further underscores the
importance of stable haemodynamics and the absence of advanced
heart failure when considering vernakalant for cardioversion of AF.
Summary of therapeutic
indications and contraindications
At the time of this review, vernakalant is approved under the brand
name Brinavess by the EMA, but is still under investigation for approval by the US Food and Drug Administration.
Given its rapid antiarrhythmic effect with 50% of patients converting within 90 min after the start of treatment and a median time to
conversion of 8– 14 min, vernakalant is indicated in cardioversion
of patients with AF ≤ 7 days and for cardioversion of early (≤3
days) post-operative AF.46
In the 2012 focused update of the ESC Guidelines on management
of AF, vernakalant was granted a class I indication with a level of evidence A for cardioversion of AF with structurally normal heart or
minimal heart disease and a class IIb recommendation with a level
of evidence B for cardioversion of patients with moderate structural
heart disease.62 Figure 3 shows the updated flowchart of choice of an
antiarrhythmic agent incorporating vernakalant.
Contraindications and precautions
Vernakalant should be used with caution in patients with NYHA class
I and II heart failure (who should be haemodynamically stable),
because of increased risk of hypotension and non-sustained ventricular arrhythmias in these patients. It is contraindicated in the presence
of hypotension ,100 mmHg, recent (,30 days) acute coronary
syndrome, NYHA class III and IV heart failure, severe aortic stenosis,
and QT interval prolongation (uncorrected QT at baseline
.440 ms), severe bradycardia and a history of second or third
degree AV block in the absence of a pacemaker, and in conjunction
with intravenous class I and III antiarrhythmic drugs administered
within 4 h.46 Vernakalant has not been evaluated in clinically significant valvular stenosis, hypertrophic obstructive cardiomyopathy,
or previously documented left ventricular ejection fraction ≤35%.
As clinical trial experience for these conditions is limited, vernakalant
is not recommended in these patients. Patients with valvular heart
disease should be monitored closely.
Patients must be adequately hydrated prior to pharmacological
cardioversion, a key clinical precaution that can be viewed as essential
to avoiding hypotension. Heart rhythm should be monitored continuously during administration of vernakalant for 2 h from the
start of the infusion, and frequent blood pressure measurements
are required during and for at least 15 min following the end of infusion. Vernakalant should be stopped if clinically significant bradycardia (e.g. symptomatic or heart rate ,40 b.p.m. or sinus pauses ≥5 s)
or hypotension (e.g. symptomatic or ,85 mmHg) develop during
the infusion.49 – 52 Other criteria for discontinuation include QRS
widening by .50% or new bundle branch block, QTc prolongation
by 25% from baseline or to .550 ms, and complete heart block. If
these events occur during the first infusion, subsequent dosing
should be suspended.
The incidence of conversion of AF to atrial flutter following vernakalant infusion was higher in patients who received class I antiarrhythmic drugs. If atrial flutter is observed secondary to treatment,
continued infusion should be considered as there was a 30% probability of converting to sinus rhythm.
Vernakalant should not be used after administration of other intravenous antiarrhythmic drugs within the previous 4 h (and preferably
avoided up to 24 h),54 and these agents should not be given within 4 h
after vernakalant infusion. Although background prophylactic antiarrhythmic drug therapy was allowed in clinical trials, the proportion of
patients was relatively low, and vernakalant should be used with
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Adverse effect
Therapeutic indications
172
caution in such patients, due to lack of data. Resumption or initiation
of oral maintenance antiarrhythmic therapy can be considered 2 h
following therapy with vernakalant.
Electrical cardioversion may be considered for patients who do
not respond to therapy. There was no increased risk of arrhythmias,
bradycardia, or hypotension associated with pre-treatment with vernakalant, but there is no clinical experience with electrical cardioversion within 2 h of vernakalant dosing.
I. Savelieva et al.
3.
4.
5.
6.
Current and future developments
8.
9.
10.
11.
12.
13.
14.
Conclusion
The rising incidence of AF has driven research to identify novel therapeutic options. Vernakalant is the first atrial-specific antiarrhythmic
drug developed for pharmacological cardioversion of recent-onset
AF. Vernakalant has been shown to be more effective than placebo
and amiodarone, but more comparisons with existing agents are
required. The main advantage of vernakalant is rapid conversion of
AF, which potentially reduces atrial remodelling. It can be used,
unlike flecainide or propafenone, in patients with little or no underlying cardiovascular disease and in patients with moderate disease,
such as stable coronary and hypertensive heart disease. The extensive development programme of this drug provided strong evidence
to support recent recommendations in the updated ESC Guidelines
for management of patients with AF.
15.
Conflict of interest: I.S. is an advisor/speaker/investigator for Astellas,
Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Menarini,
Merck, Mitsubishi Pharma, Pfizer, Servier, and Sanofi. R.G. was
supported by an unrestricted grant from Merck & Co. A.J.C. is an
advisor/speaker/investigator for Astra Zeneca, Bayer, Biotronic,
Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi,
Medtronic, Menarini, Merck, Novartis, Pfizer, Sanofi, Servier, St Jude
Medical, and Xention.
20.
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