Address for
Correspondence: Prof. Dr. Johnson Francis, Senior
Consultant Cardiologist, Baby Memorial Hospital, Kozhikode,
Kerala, India, PIN 673017. Email: pulikkottil2002@hotmail.com
Abstract
Ranolazine which has been approved for use an anti-anginal
agent has been shown to have anti-arrhythmic properties both
in experimental and clinical studies. Several case studies
have shown the use of ranolazine in the treatment of atrial
fibrillation, some even as a ‘pill in the pocket’ approach.
MERLIN-TIMI 36, a randomized study of acute coronary syndrome,
showed lower incidence of ventricular arrhythmias in the
ranolazine arm. The most important anti-arrhythmic mechanism
of of ranolazine is thought to be mediated by atrial-selective
inhibition of peak sodium current (INaL) and inhibition of
late INa in both atria and ventricles. The recent
reclassification of anti-arrhythmic agents has designated
drugs with this action in Class Id. There is clinical and
experimental evidence for the potential use of ranolazine in
congenital long QT syndrome 3. The recent RAID trial, a
randomized evaluation of ranolazine in high risk patients with
implantable cardioverter defibrillator and either ischemic or
non-ischemic cardiomyopathy showed a marginally significant
reduction of recurrent ventricular tachycardia and
fibrillation. The potential risk of ranolazine-induced torsade
de pointes in view of mild prolongation of QT interval has not
been well confirmed, with only a single case report suggesting
possible association. But the patient had other confounding
factors including treatment with fluoxetine, amiodarone and
diuretics causing hypokalemia and hypomagnesemia which are
well known to cause torsade de pointes.
Keywords:
ranolazine, antiarrhythmic agent, class Id agent, atrial
fibrillation, ventricular arrhythmias
Introduction
Amiodarone which was initially introduced as an antianginal
agent later became an exclusive anti-arrhythmic agent. The
story of ranolazine seems headed in the same direction.
Ranolazine was approved as an anti-anginal agent for treatment
of chronic stable angina by the US Food and Drug
Administration (FDA) in 2006. Since then there have been case
series and clinical trials documenting an antiarrhythmic role
for ranolazine [1-3]. One study even demonstrated a synergy
between amiodarone analogue dronedarone and ranolazine [3].
Metabolic Efficiency with Ranolazine for Less Ischemia in Non
ST-Elevation Acute Coronary Syndrome Thrombolysis in
Myocardial Infarction 36 (MERLIN-TIMI 36) study which
randomized non-ST-elevation acute coronary syndrome to
ranolazine or placebo found a lower incidence of arrhythmia in
the active treatment arm [4]. A recent paper presenting a
modernized classification of anti-arrhythmic agents has
designated late sodium current inhibitor ranolazine as a Class
Id agent [5].
In this review we evaluate the evidence supporting use of
ranolazine for the treatment of atrial and ventricular
arrhythmias.
Electrophysiological basis of antiarrhythmic effect of
Ranolazine
The electrophysiological basis for the antiarrhythmic effects
of ranolazine was reported even before the FDA approval of
ranolazine as an antianginal agent [6]. This was in spite of
the fact that ranolazine produces modest prolongation of the
QT interval [7], although not resulting in development of
torsade de pointes (TdP). Studies involving canine ventricular
tissue showed that ranolazine has ion channel effects similar
to those observed with chronic amiodarone therapy. Late sodium
current, rectifier currents (IKr and Iks) and calcium currents
were reduced. But the effect of ranolazine on calcium current
is very weak and that would explain the lack of effects on
contractility, atrioventricular nodal conduction and heart
rate. Ranolazine was shown to suppress early after
depolarization (EAD) and transmural dispersion of
repolarization (TDR) [6].
There is a difference between the effect of ranolazine on
atrial and ventricular myocytes. While ranolazine blocks both
peak and late sodium currents in atrial myocytes [8,9], it
predominantly blocks the late sodium current in ventricular
myocytes. Ranolazine has structural similarity to lignocaine
molecule, which is the reason it blocks sodium channels in a
use dependent manner similar to local anaesthetics by
interacting with the local anaesthetic receptor site on the
NaV1.5 channel [10].
Important mechanism by which ranolazine exerts its
anti-arrhythmic effect on the ventricles is by the inhibition
of late sodium current. This in turn reduces the sodium
dependent intracellular calcium overload which contributes to
suppression of afterdepolarization activity [11].
Ranolazine in atrial fibrillation
One of the earliest reports of the role of ranolazine in
atrial fibrillation (AF) was a case series published in 2008
[1]. Murdock DK et al. used it in 7 patients who developed AF
within hours to days of ablation and / or failure of other
anti-arrhythmic agents. Four of them had no recurrence of AF
while on ranolazine, two did not respond and one had a delayed
recurrence. The same group of authors reported a “Pill in the
pocket” approach to AF using ranolazine the next year [2].
Thirteen of their 18 patients converted to sinus rhythm
without any proarrhythmic effects following a single dose of
2000 mg. All but one of their patients had some form of
structural heart disease and all but 2 had left atrial
enlargement. The 72% conversion rate was comparable to other
reported protocols for “pill in the pocket” approach.
Ranolazine-induced inhibition of peak INa in the atria,
reduces atrial excitability and effective refractory period.
This prevents rapid activation of the atria in AF. The
blockade of IKr by ranolazine delays atrial repolarization
thus abbreviating the diastolic interval. It is during
the diastolic interval that much of the recovery of the sodium
channel from drug block occurs. As a result recovery of
the sodium channel from ranolazine block is impaired,
resulting in greater accumulation of block and reduction of
INa. The maintenance of a diastolic interval in the ventricle,
even at rapid rapids of activation, accounts for the lesser
effect of ranolazine in the ventricles when compared with the
atria. Block of both peak and late sodium current by
ranolazine in the atria reduces intracellular calcium activity
which in turn suppresses afterdepolarization-mediated triggers
of AF [11].
A recent systematic review of the role of ranolazine in the
treatment and prevention of AF found a modest beneficial
effect of ranolazine for prevention or treatment of atrial
fibrillation [12].
Enhancement of effect of amiodarone on AF by ranolazine
Ranolazine added to intravenous amiodarone was found to
enhance the efficacy of the latter in converting recent onset
AF [13]. 121 patients with recent onset AF received either
amiodarone infusion alone or amiodarone infusion and a single
oral dose of ranolazine 1500 mg. Conversion rate at 24 hours
was higher in those who received ranolazine (87% vs 70%,
P=0.024). Time to conversion was also shorter in those who
received ranolazine along with amiodarone (10.2 ± 3.3 vs. 13.3
± 4.1 h; P = 0.001). In a subgroup analysis, they noted that
those with left atrial diameter above 46 mm responded to the
combination (81% vs. 54%; P = 0.02), while there was no
difference between the two groups in those with left atrial
diameter of 46 mm or lower (P=0.77). This study confirmed the
findings of an earlier pilot study involving 51 patients from
the same center [14].
Another single blinded randomized trial evaluated the effect
of ranolazine on post-operative AF after coronary artery
bypass graft surgery [15]. 375 mg twice daily of ranolazine
was added to intravenous amiodarone (study group) and compared
with intravenous amiodarone alone (control group). Though this
was a small study with a total of only 41 patients, it could
document a significantly faster conversion of post-operative
AF (19.9 ± 3.2 vs 37.2 ± 3.9 hours, P < 0.001) when
ranolazine was combined with intravenous amiodarone.
Synergy between ranolazine and dronedarone in AF
A Study to Evaluate the Effect of Ranolazine and Dronedarone
When Given Alone and in Combination in Patients with
Paroxysmal Atrial Fibrillation (HARMONY Trial) [3] showed a
synergy between the anti-arrhythmic actions of ranolazine and
dronedarone. 750 mg twice daily or ranolazine was tested with
150 mg twice daily and 225 mg twice daily of dronedarone in
134 patients with paroxysmal atrial fibrillation (AF) and
implanted pacemakers. The AF burden was continuously assessed
by the pacemaker electrogram recordings. It was noted that
neither placebo nor either of the two drugs alone reduced the
AF burden significantly. The higher dose combination reduced
AF burden by 59% compared to placebo while the lower dose
combination reduced AF burden by 43%. The combinations were
well tolerated by the participants. Lower doses of dronedarone
were chosen in this study to reduce its negative ionotropic
effect.
The experimental basis for HARMONY trial was provided by a
previous canine study involving isolated canine coronary
perfused atrial and ventricular preparations [16]. In that
study, it was shown that low concentrations of ranolazine
which had weak suppression of AF independently, had a potent
synergistic effect on combination. While the drugs
independently could only prevent induction of AF in 17% and
29% respectively, the combination could prevent induction of
AF in 90% of the preparations studied.
Role of ranolazine in congenital long QT syndrome type 3
It is well known that ranolazine inhibits late sodium current
[6]. Congenital long QT syndrome type 3 (LQT3) is due to
excessive late sodium current during phase 3 of the action
potential, secondary to a mutation in the cardiac sodium
channel gene SCN5A [17]. Hence the role of ranolazine in LQT3
was studied in experimental and clinical settings [18]. In the
clinical arm of the trial involving 8 patients evaluated over
22.8 +/- 12.8 months, ranolazine was found to shorten the
corrected QT interval (QTc) from 509+/-41 to 451+/-26 ms
(P+0.012). QTc abbreviation was less prominent during extreme
nocturnal bradycardia. This study was prompted by a previous
short-term study involving 5 patients with LQT3, which had
shown abbreviation of QTc by 26+/- 3 ms following an 8-hour
intravenous infusion of ranolazine [19]. The added advantage
noted with ranolazine treatment for LQT3 was that none of the
patients developed ECG pattern suggestive of Brugada syndrome.
Earlier it had been reported that patients with LQT3 treated
with sodium channel blockers can develop Brugada syndrome
[20]. One important limitation noted in the report on
ranolazine for LQT3 [18] was that there was only one case with
documented TdP in this series. Hence the role of ranolazine in
preventing arrhythmias in LQT3 could not be documented.
Moreover, QTc values above 500 ms were noted during extreme
nocturnal bradycardia even while on treatment with ranolazine.
These values are usually associated with TdP, though no TdP
occurred during the study period.
Can ranolazine cause TdP?
Mild QT prolongation produced by ranolazine is due to its
effect to inhibit the rapidly activating component of the
delayed rectifier potassium current (IKr), encoded by the
human ether-a-go-go-related gene (hERG) [21]. The protective
effect of ranolazine against TdP is thought to be the potent
inhibition of late sodium current which opposes the
prolongation of action potential and increase in transmural
dispersion of repolarization induced by IKr block [22].
Another reason proposed is that the kinetics of both blocking
and unblocking of the channel by ranolazine is rapid [21].
This is in contrast with the slow kinetics of dofetilide for
unblocking of the IKr channels.
Romero J et al [23] in a retrospective analysis of 2735
patients with prolonged QTc found 7 cases of QTc prolongation
and 3 cases of TdP associated with ranolazine, which was found
to be significant in univariate and multivariate analysis. But
they mentioned in the limitations of their study that it is
difficult to make meaningful conclusions due to the small
number of patients who took this medication in their study.
Moreover, their discussion was mostly focussed on methadone,
which was highlighted in the title of the article.
One case of TdP with potential role for ranolazine as a
contributing agent has been reported by Liu et al [24]. This
elderly female was on multiple drugs including fluoxetine,
amiodarone and diuretics. Ranolazine 500 mg daily was added
for refractory angina. She developed multiple episodes of TdP
while in hospital. An absolute causal role for ranolazine
cannot be confirmed as she was on diuretics causing
hypokalemia and hypomagnesemia as well a fluoxetine and
amiodarone, which have been associated with TdP. Based on this
report, CredibleMeds® moved ranolazine from ‘Possible Risk’
list to the ‘Conditional Risk (CR) of TdP’ list, but not to
the ‘Known Risk’ list [25].
Ranolazine in ventricular arrhythmias
MERLIN-TIMI 36 showed a reduced risk of ventricular
tachycardia lasting at least eight beats on one-week ECG
monitoring in the first week after admission for acute
coronary syndrome (5.3% versus 8.3%; P<0.001) [4]. The
study randomized 6560 patients admitted with non-ST-elevation
acute coronary syndrome to either ranolazine or placebo.
Ninety seven percent of patients in this study had ECG
tracings which could analysed in a core laboratory for a
pre-specified set of arrhythmias. Supraventricular tachycardia
was also lower in the study group (44.7% versus 55.0%;
P<0.001).
Ranolazine in High-Risk Patients With Implanted
Cardioverter-Defibrillators: The RAID Trial was a double-blind
placebo controlled clinical trial in patients high-risk
patients with an implantable cardioverter defibrillator (ICD)
[26]. The patients with either ischemic or non-ischemic
cardiomyopathy were randomized to receive either 1000 mg
ranolazine twice daily or placebo. Ventricular tachycardia
(VT) or fibrillation (VF) requiring appropriate ICD therapy of
death, whichever occurred first, was the primary endpoint.
Pre-specified secondary end points were ICD shock requiring
VT/VF or death and recurrent VT or VF. Ranolazine did not
significantly reduce the primary endpoint. But the study was
underpowered to detect a difference in the primary endpoint.
Pre-specified secondary analysis showed that ranolazine
marginally reduced recurrent VT or VF (hazard ratio: 0.70; 95%
confidence interval: 0.51 to 0.96; p = 0.028), without
increasing mortality.
Conclusion
Several studies have demonstrated the anti-arrhythmic role of
ranolazine. Recognizing this, the new modernized
classification of anti-arrhythmic agents has designated
ranolazine as Class Id agent. Additional randomized trial data
are needed to elevate ranolazine to the status of a dedicated
anti-arrhythmic agent like amiodarone. Though a single case
report has raised caution about potential role in
proarrhythmia (TdP), multiple confounding factors noted in the
case makes the direct causation less likely.
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