Expert Opinion on Pharmacotherapy

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Current pharmacotherapeutic strategies for

cardiac arrhythmias in heart failure

Ashish Correa, Yogita Rochlani & Wilbert S. Aronow

To cite this article: Ashish Correa, Yogita Rochlani & Wilbert S. Aronow (2020): Current
pharmacotherapeutic strategies for cardiac arrhythmias in heart failure, Expert Opinion on
Pharmacotherapy, DOI: 10.1080/14656566.2019.1703950

To link to this article: https://doi.org/10.1080/14656566.2019.1703950

Published online: 11 Jan 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2019.1703950

REVIEW

Current pharmacotherapeutic strategies for cardiac arrhythmias in heart failure

Ashish Correaa, Yogita Rochlanib and Wilbert S. Aronowb
a
Division of Cardiology, Mount Sinai St. Luke’s and Mount Sinai West, New York, NY, USA; bDivision of Cardiology, Westchester Medical Center and
New York Medical College, Valhalla, NY, USA

ABSTRACT ARTICLE HISTORY

Introduction: Heart failure (HF) affects over 6 million Americans and is the most common cause of Received 28 June 2019
hospital readmissions in the United States. Cardiac arrhythmias are common comorbidities seen in Accepted 9 December 2019
patients with HF and are associated with an increase in morbidity and mortality. Pharmacotherapeutic KEYWORDS
agents along with device and ablation therapies are the mainstays of treatment for cardiac arrhythmias Congestive heart failure;
in HF. cardiac arrhythmias;
Areas covered: An extensive literature review of articles and clinical trials on PUBMED on the topic of antiarrhythmic drugs; atrial
pharmacotherapy for cardiac arrhythmias in heart failure was conducted. This review article summarizes fibrillation; ventricular
the above literature to describe the prevalence of the various types of arrhythmias in HF, the tachycardia
recommended pharmacotherapies for the treatment of these arrhythmias in HF and the evidence
that supports these recommendations.
Expert opinion: Cardiac arrhythmias are common in HF and are the leading cause of death in this
patient population. The management of cardiac arrhythmias in HF is challenging. Pharmacotherapy is
the primary though increasingly adjunctive therapy for most cardiac arrhythmias. Further, antiarrhyth-
mic drugs must be used with caution in this patient population due to their potential adverse effects.

1. Introduction Evidence suggests that bradyarrhythmias may account for

a substantial portion of SCD in HF [10,11].
Heart failure (HF) is a challenging disease, both for patients
The management of arrhythmias in HF depends on the
and health-care providers. It is widely prevalent in the United
type of arrhythmia and etiology of the arrhythmia and is
States, affecting 6.2 million Americans [1], and the number is
multifaceted and wide-ranging. Further, HF with reduced ejec-
projected to increase to over 8 million by 2030 [2]. Though HF
tion fraction (HFrEF) and HF with preserved ejection fraction
hospitalizations are gradually declining, there are still over
(HFpEF) are very different conditions, and arrhythmias tend to
900,000 hospitalizations for HF annually [1,3]. Many of these
affect them differently. Treatment strategies span a variety of
hospitalizations are due to arrhythmias and arrhythmias are
therapeutic options including pharmacotherapy, catheter-
highly prevalent in HF [4–6]. The management of HF and
ablation, device therapy (including pacemakers, defibrillators,
concomitant cardiac arrhythmias is a complex issue, whether
and ventricular assist devices) and – in the most advanced
it be in the inpatient or outpatient office setting.
cases of HF or in the setting of unremitting lethal arrhythmias –
A variety of tachy and bradyarrhythmias are seen in HF.
explantation of the native heart and implantation of a total
Atrial fibrillation (AF) is the most common arrhythmia asso-
artificial heart or cardiac transplantation. This review focuses
ciated with HF, and over half of patients with advanced HF
exclusively on the pharmacotherapeutic strategies for the
have AF [6]. Patients with HF tend to have worse outcomes
wide variety of cardiac arrhythmias in heart failure. While
when they have concomitant AF [7]. Ventricular arrhythmias –
many of the interventions described can apply to both HFrEF
including ventricular tachycardia (VT) and ventricular fibrilla-
and HFpEF, this is not always the case. In general, the strate-
tion (VF) – are also frequently seen with HF, particularly those
gies described below pertain to patients with HFrEF, unless
with advanced HF [8]. Patients with HF have 6 to 9 times
otherwise specified.
higher rates of sudden cardiac death (SCD) than the general
population, and in a majority of cases, the mechanism of
death is a lethal arrhythmia like pulseless VT or VF [9]. 2. Arrhythmias in heart failure
However, arrhythmias in HF are not just tachyarrhythmias.
HF is associated with both tachyarrhythmias and bradyar-
Bradyarrhythmias are also fairly common in the setting of
rhythmias, and SCD remains the most common mode of
HF, as the pathology causing cardiac dysfunction frequently
death in this population. A majority of these cases of SCD
affects the conduction system. These bradyarrhythmias
are due to malignant ventricular arrhythmias [9]. The occur-
include a variety of conditions like sinus nodal dysfunction,
rence of arrhythmias in HF is thought to reflect the diseased
atrioventricular block and ventricular conduction delay [10].
state of the myocardium and is a marker of progressive

CONTACT Wilbert S. Aronow wsaronow@aol.com Division of Cardiology, Westchester Medical Center and New York Medical College, 100 Woods Road,
Macy Pavilion, Room 141, Valhalla, NY 10595, USA
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 A. CORREA ET AL.
Article highlights
● A variety of arrhythmias are seen in heart failure, including atrial
fibrillation, atrial flutter, premature ventricular contractions, non-
sustained and sustained ventricular tachycardias, and ventricular
fibrillation.
● Sudden cardiac death is the most common mechanism of death in
heart failure. While a majority of these are due to malignant ventri-
cular arrhythmias, it is now being recognized that many instances of
sudden death are due to bradyarrhythmias and electromechanical
dissociation.
● While trials have not shown any difference in mortality benefit
between rate-control and rhythm-control strategies in atrial fibrilla-
tion, rhythm control – primarily the maintenance of sinus rhythm –
may be beneficial in patients with heart failure due to improved
hemodynamics. Recent trial evidence has shown that catheter abla-
tion is superior to medical therapy (either rate or rhythm control).
● Implantable cardioverter-defibrillators are the mainstay for the pri-
mary and secondary prevention of sudden cardiac death (by malig-
nant ventricular arrhythmias). However, anti-arrhythmics may be
needed to supplement therapy (especially to reduce the frequency
of shocks).
● While there have been improvements in catheter ablation techniques
in recent years, anti-arrhythmics are falling out of favor due to their
pro-arrhythmic and toxic side-effects. There have been few recent
advances in anti-arrhythmic pharmacology, and this remains
a potential area of discovery in the coming years.
This box summarizes key points contained in the article.
worsening of cardiac function. A variety of mechanisms are
implicated in the pathogenesis of these arrhythmias – struc-
tural and hemodynamic abnormalities, metabolic abnormal-
ities (like neurohormonal activation and electrolyte
abnormalities) and various electrophysiologic changes [12].
Conversely, arrhythmias can precipitate HF. For instance,
tachyarrhythmias resulting in rapid ventricular rates, ventricu-
lar dyssynchrony, and loss of the atrial kick can also be the
underlying cause of HF, as in the case of tachycardia-mediated
cardiomyopathy.
Atrial arrhythmias such as AF and atrial flutter are fre-
quently associated with HF. AF is the most commonly encoun-
tered sustained arrhythmia among adults [13], and this is
certainly the case among HF patients as well. Over 50% of
the patients with advanced HF have AF and the presence of
AF portends a worse prognosis [6]. Conversely, both AF and
atrial flutter can precipitate exacerbations of HF and worsen
cardiac function.
A variety of ventricular arrhythmias are frequently seen in
HF patients – these include premature ventricular contractions
(PVC), non-sustained ventricular tachycardia (NSVT), sustained
VT and VF [5,8]. Ventricular arrhythmias, especially malignant
arrhythmias like sustained VT and VF associated with SCD, are
even more common in advanced HF [14,15]. Interestingly, no
direct relationship has been demonstrated between the occur-
rence of ambulatory asymptomatic ventricular arrhythmias –
like PVCs and NSVT – and an increased risk of SCD, even if
these arrhythmias are frequent and complex [16,17]. In fact,
such arrhythmias may simply be the manifestations of
a diseased ventricle and their occurrence may herald the
clinical progression of HF, rather than an increased risk of SCD.
Bradyarrhythmias, due to conduction system disease,
resulting in sinus nodal dysfunction, atrioventricular nodal
dysfunction, and interventricular conduction delays are also
seen with HF. The prevalence and frequency of malignant
bradycardias may be difficult to quantify, as many patients
with severe heart failure may be implanted with implantable
cardioverter-defibrillators and resynchronization therapy
devices, which have pacing functions [10]. It is now being
recognized that in a substantial number of cases of sudden
death, the mechanism may be a severe bradyarrhythmia or
electromechanical dissociation from pump failure, i.e. pulse-
less electrical activity (PEA) arrest [16].
Management of bradyarrhythmias in HF, beyond stopping
or reducing agents with negative chronotropic effects,
involves device therapy with pacemakers. This is beyond the
scope of this article, which will focus on the pharmacothera-
peutic strategies for tachyarrhythmias in HF.
3. Pharmacologic management of atrial fibrillation
and atrial flutter in heart failure
AF accounts for over one-third of all hospitalizations for car-
diac dysrhythmias and is the most commonly encountered
sustained arrhythmia in medical practice [13,18]. AF is more
prevalent among patients with HF compared to the general
population, and this prevalence steadily rises with worsening
degrees of HF [19–21], to the point that over 50% of the
patients with advanced HF also have AF [6,22]. The increased
prevalence of AF in HF patients can be explained in part by
the fact that they share many risk factors. However, it has also
been shown that AF can predispose to both the development
and the progression of HF and vice-versa. AF can exacerbate
HF due to rapid ventricular response, reduced diastolic left
ventricular filling time, loss of atrial systolic kick and increased
mitral regurgitation. Further, AF is the most common cause of
tachycardia-induced cardiomyopathy, which can cause HF and
hasten its progression. HF, in turn, can cause or trigger AF due
elevated filling pressures, dysregulation of intracellular cal-
cium, neurohormonal activation and atrial dilation [18].
A similar relationship exists between HF and atrial flutter,
though rate control is generally much harder to achieve with
flutter, and cardioversion and catheter ablation tend to be of
greater importance.
3.1. Rhythm control versus rate control for AF in HF
There has long been a debate about the appropriate strategy
for the management of AF: restoration of sinus rhythm, i.e.
rhythm control, or the management of ventricular rate, i.e. rate
control. Major trials comparing the two strategies in the gen-
eral population – the Atrial Fibrillation Follow-Up Investigation
of Rhythm Management (AFFIRM) and the Rate Control Versus
Electrical Cardioversion for Persistent AF (RACE) – found no
significant differences between the two strategies but there
was a trend toward harm in the rhythm-control arms [23,24].
In the AFFIRM Trial, the largest trial comparing the two stra-
tegies, patients were randomly assigned to rate control and
anticoagulation (with warfarin) or rhythm control with antic-
oagulation (with warfarin) being at the discretion of the trial-
ists. It found no significant difference in the primary endpoint
of all-cause mortality or any of the secondary endpoints

between the two strategies (though with a trend toward
reduced mortality in the rate-control arm). There was
a significant reduction in hospitalizations with the rate-
control strategy. However, a subsequent analysis of the trial
found a significant reduction in mortality among patients who
successfully maintained sinus rhythm [25]. Again, with the
RACE trial, no significant difference was seen between the
two strategies, with a trend toward improved mortality with
the rate-control strategy. The Atrial Fibrillation and Congestive
Heart Failure (AF-CHF) trial found similar results in patients
with HF and AF, with the rhythm-control arm providing no
significant benefits [26]. It has been postulated that while the
maintenance of sinus rhythm is probably beneficial in and of
itself, this is offset more broadly by the adverse and pro-
arrhythmic effects of anti-arrhythmic medications that are
used to maintain sinus rhythm [18]. For instance, in the above-
mentioned analysis of the AFFIRM trial, while the attainment
of sinus rhythm conferred a mortality benefit, anti-arrhythmic
drugs themselves were associated with increased mortality
after adjusting for the presence of sinus rhythm [25].
Theoretically, the attainment of sinus rhythm with rhythm-
control strategies affords benefit in HF, since the atrial kick,
slower heart rates, and better diastolic filling can result in
improved hemodynamics. However, HF with reduced ejection
fraction and HF with preserved ejection fraction are two very
different conditions, and a rhythm-control strategy may pos-
sibly be more effective in the latter group of patients. It is
important to note that AF-CHF focused only on patients with
systolic dysfunction [18,26].
Recent data have shown that rhythm control by catheter
ablation in particular (rather than by anti-arrhythmic drugs) is
a beneficial strategy in patients with HF [27]. In fact, the 2018
Catheter Ablation versus Standard Conventional Therapy in
Patients with Left Ventricular Dysfunction and Atrial
Fibrillation (CASTLE-AF) study showed that catheter ablation
in patients with concomitant HFrEF and AF was superior to
medical therapy (either rate control or medical rhythm con-
trol) [28].
3.2. Rate control
For rate control, three types of agents may be used (see Table
1), and they will be discussed below – beta-blockers, digoxin,
and non-dihydropyridine calcium channel blockers. While
amiodarone is primarily used in rhythm-control strategies, it
can slow ventricular rates and can be acutely used for the
purpose of rate control (Table 1). Long-term therapy with oral
amiodarone is rarely used for chronic rate control, and usually
only when first-line agents are insufficient or have failed. The
target heart rate has also been a matter of some debate, and
this issue will be discussed below as well.
3.2.1. Beta-blockers
Data regarding the use of beta-blockers for ventricular rate
control in concomitant AF and HF are mixed. One large indi-
vidual-patient data-level meta-analysis of randomized control
trials comparing beta-blockers versus placebo in HF concluded
EXPERT OPINION ON PHARMACOTHERAPY 3
that beta-blockers used for rate-control in concomitant AF and
HF do not offer any mortality benefit or benefit in terms of
reduction in hospitalizations [29]. However, retrospective ana-
lyses of some randomized controlled trials of carvedilol in HF
management showed improved outcomes and even survival
benefit for beta-blockers in patients with both AF and HF
[30,31].
Regardless, beta-blockers are effective for both ventricular
rate control in AF and improve survival in patients with HFrEF.
Thus, they should be the first choice for rate control in
patients with concomitant AF and HF [18,32].
For AF with a rapid ventricular response, initial intravenous
therapy may be used, but ultimately patients should be
bridged to oral beta-blocker therapy (see Table 1 for details
regarding the route of administration and dosing).
Metoprolol and esmolol are usually used as intravenous
agents for ventricular rate control. Intravenous metoprolol
may be given as 2.5 to 5 mg bolus over 2 min, with the
dose repeated every 5 min until adequate rate control is
achieved, but to a maximum of 15 mg. After this point, the
therapy should be switched to an oral regimen. Esmolol is
often used as a trial of beta-blocker therapy, especially in
patients in whom there is concern regarding starting beta-
blockers. This is because esmolol as a very rapid onset of
action, and due to its rapid metabolism in the blood, it has
a short duration of action [33]; thus, when an esmolol infusion
is discontinued, its effects are short-lasting. For acute rate
control, esmolol may be given as an intravenous bolus, fol-
lowed by an infusion until oral medications can be started
(see Table 1 for details).
Regardless of whether an intravenous beta-blocker is used
for ventricular rate control in acute AF, patients should ulti-
mately be transitioned to oral beta-blockers. Oral beta-
blockers can be used as first-line for rate control, or they can
be started after initial intravenous therapy. There are a wide
variety of oral beta-blockers that could potentially achieve rate
control in AF, and most agents in this class are effective.
However, only certain agents are known to be beneficial in
HF as well. Bisoprolol, carvedilol, and metoprolol succinate
extended-release are the only beta-blockers that have proven
mortality benefit in HFrEF in large randomized control trials –
CIBIS-II [34], COPERNICUS [35] and MERIT-HF [36] – and are
now considered part of guideline-directed medical therapy
(GDMT) for HFrEF [37].
It thus follows that any of these agents should ultimately
be used to achieve both long-term rate control for AF and
GDMT for HF, regardless of what intravenous and/or oral
agent is used for initial rate control (refer to Table 1).
However, it should be noted that it is unclear whether any
benefit derived from beta-blockers comes from their effect in
reducing the ventricular rate or from their long-term effects in
HFrEF management. For instance, in the United States
Carvedilol Heart Failure Trials, 136 of 1094 patients with
HFrEF also had AF. Patients treated with carvedilol achieved
significant improvements in left ventricular ejection fraction
and a trend toward reduction in mortality and hospitalization
[30]. However, it is unclear whether this was due to the
4 A. CORREA ET AL.

Table 1. Pharmacologic agents for the management of atrial fibrillation and atrial flutter.
DRUG DOSE COMMENT
RATE CONTROL
Beta Blockers
Acute Rate Control
● Metoprolol IV: 2.5 - 5 mg over 2 min Can repeat every 5 min; max dose 15 mg
tartrate
● Esmolol IV: Option 1: with loading dose, rapid increments Can rebolus with a 500 mcg/kg loading dose over 1 min with every dose increment, to a
● First, 500 mcg/kg over 1 min –loading dose total of 3 loading doses
● Then, 50 mcg/kg/min infusion
● Then, 50 mcg/kg/min increments every 4 min if Max dose 200 mcg/kg/min
response is inadequate
IV: Option 2: without loading dose or rapid Max dose 200 mcg/kg/min
increments
● First, 50 mcg/kg/min infusion

● Then, 50 mcg/kg/min increments every 30 min

● Propanolol IV: 1 mg over 1 min Can repeat every 2 min; max 3 doses
Chronic Rate Control
● Metoprolol PO: 25 - 100 mg twice daily Can use more frequent divided doses when achieving maintenance dose
tartrate
● Metoprolol PO: 50 - 400 mg once daily
succinate
● Carvedilol PO: 3.125 - 25 mg twice daily May need to use 50 mg twice daily for patients weighing >85 kg
● Bisoprolol PO: 2.5 - 10 mg once daily
Digoxin
Loading Dose: IV: 0.125 - 0.25 mg over 5 min, with repeat doses Max dose 8-12 mcg/kg over 24 h
of 0.125 – 0.25 mg every 6 h Referred to as total digitalizing dose (TDD)
Maintenance PO: 0.125 - 0.25 mg once daily Dose adjustments needed to maintain serum levels <0.9 ng/dL
Dose:
Calcium
Channel
Blockers
Acute Rate Control
● Diltiazem IV: Bolus – 0.25 mg over 2 min Can be increased in 5 mg/h increments; max dose 15 mg/h
IV: Continuous infusion – 5 - 10 mg/h
● Verapamil IV: Bolus – 0.075 - 0.15 mg/kg over 2 min Can rebolus 10 mg after 30 min
IV: Continuous infusion – 0.005 mg/kg/min
Chronic Rate Control
● Diltiazem PO: Immediate release:
● Initial dose – 30 mg every 6 h

● Usual dose – 120 - 480 mg/d in 3 - 4 divided

doses
PO: Extended release:
● Initial dose – 120 mg every 12 - 24 h
● Usual dose – 120 - 480 mg/d
● Verapamil PO: Immediate release: 240 - 480 mg/d in 3 - 4
divided doses
PO: Extended release: 180 - 480 mg/d
Amiodarone
While amiodarone is primarily used in rhythm control strategies, it can slow ventricular rates, and can be acutely used for this purpose. Long-term therapy with oral
amiodarone is rarely used for chronic rate control, usually when first-line agents are insufficient or have failed.
For dosing recommendations for amiodarone, please refer to the rhythm control section below.
RHYTHM
CONTROL
Drug used for Chemical Cardioversion
● Amiodarone IV: Option 1: It is not very effective for chemical cardioversion, and it is not approved by the US FDA for
● First, 150 mg over 10 min the same.
● Then, 1 mg/min for 6 h
● Then, 0.5 mg/min for 18 h It can be used as an adjunctive agent for electrical cardioversion or for chemical
cardioversion if long term maintenance therapy is being planned.
● Then, PO maintenance dosing – 100 - 200 mg
daily
PO: Option 2:
● First, 600 - 800 mg daily in divided doses to a
total load of 10 g
● Then, maintenance dosing – 100 - 200 mg daily

(Continued )
 EXPERT OPINION ON PHARMACOTHERAPY 5

Table 1. (Continued).
● Dofetilide PO: 500 mcg twice a day Dose adjustments need to be made based on renal function and change in QTc interval.
Inpatient admission for 72 h needed for initiation of drug therapy, to monitor QTc.
● Ibutilide IV: <60 kg – 0.01 mg/kg over 10 min Should not be used in decompensated HF
IV: ≥60 kg – 1 mg over 10 min
● Sotalol PO:
● Initial dose – 80 mg twice daily

● Usual dose – 160 mg twice daily

Flecainide is contraindicated in structural heart disease. Propafenone is contraindicated heart failure. Vernakalant is contraindicated in NYHA Class III and IV heart
failure and within 30 days of an episode of acute decompensated heart failure. It can be used with extreme caution in NYHA Class I and II heart failure. It is
available in Canada and Europe, but is not approved for use in the United States.
Drugs used for the maintenance of sinus rhythm
● Amiodarone PO:
● First, 400 - 600 mg daily in divided doses for 2 -
4 weeks,
● Then, maintenance dosing – 100 - 200 mg daily
● Dofetilide PO: 500 mcg twice a day Dose adjustments need to be made based on renal function and change in QTc interval.
Inpatient admission for 72 h needed for initiation of drug therapy, to monitor QTc.
● Sotalol PO: Can increase dose in 3 days, if the initial dose does not reduce frequency of relapse and
● Initial dose – 80 mg twice daily excessive QTc prolongation does not occur
● Usual dose – 160 mg twice daily
Flecainide is contraindicated in structural heart disease. Propafenone is contraindicated heart failure. Vernakalant is contraindicated in NYHA Class III and IV heart
failure and within 30 days of an episode of acute decompensated heart failure. It can be used with extreme caution in NYHA Class I and II heart failure. It is
available in Canada and Europe, but is not approved for use in the United States.
Abbreviations: IV – intravenous; PO – per oral; US FDA – United States Food and Drug Administration; HF – heart failure; NYHA – New York Heart Association.

beneficial effects afforded by beta-blockers in HFrEF or due to
rate reduction produced by the beta-blockers in the context
of AF.
3.2.2. Digoxin
The role of digoxin in the management of AF in patients with
concomitant HF differs from that in the general population.
Further, there are several considerations to be taken into
account when using digoxin, both in HF patients and in the
general population, most especially concerns regarding toxi-
city from high serum levels of the drug.
Firstly, there seems to be no clear consensus regarding
the safety of digoxin. A number of recent observational
studies and post-hoc analyses of randomized control trials
have shown adverse outcomes with the use of digoxin for
rate-control management in AF, including significant
increases in all-cause mortality and cardiovascular mortality
[38–41]. However, in contrast to these studies, there are
several other studies showing that digoxin does not, in fact,
increase mortality. For instance, a large systematic review
and meta-analysis of comparative studies on digoxin versus
controls showed that data derived from randomized trials
demonstrated digoxin having a neutral effect on mortality
and reducing hospital admissions [42]. It further concluded
that the perceived negative outcomes of digoxin demon-
strated by observational studies were due to residual con-
founders that could not be mitigated by statistical models.
The study postulated that in observational studies, practi-
tioners administered digoxin to their sickest patients who
were more likely to die, resulting in a bias that digoxin was
associated with higher mortality. Beyond this, there are sev-
eral other studies that have shown that digoxin use is not
associated with increased mortality [43–45].
In the only randomized control trial of the use of digoxin
versus placebo in HF – the DIG Trial – digoxin had a neutral
effect on mortality, but did reduce hospitalizations [46]. To
date, there is no randomized control trial evaluating the use of
digoxin in AF, either in HF patients or patients without HF.
A post-hoc subgroup analysis of the 2011 Apixaban for
Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation (ARISTOTLE) Trial came to some useful con-
clusions about the relationship of digoxin and mortality in AF
patients [47]. This analysis concluded that digoxin use in and
of itself was not associated with higher mortality. However,
patients with a serum digoxin concentration ≥1.2 ng/mL there
was 56% increased risk of death compared with those not
taking the drug. When digoxin level was >0.9 but less than
1.2 ng/mL, there was a trend toward higher mortality. There
was no increase in the risk of mortality for those with levels
<0.9 ng/mL. Further, these associations were not different
between those with and without heart failure, suggesting
digoxin could indeed be used in patients with concomitant
HF and AF, as long as appropriate therapeutic serum levels
were maintained.
Beyond issues related to potential increased mortality from
supratherapeutic levels of digoxin, there are other issues with
the use of digoxin (both in patients with and without HF).
Most prominent among these is the fact that the principal
ventricular rate-controlling effect of digoxin stems from its
ability to augment vagal tone at the atrioventricular node. As
such, while a patient is at rest, it may afford effective rate
control. But, in states of increased sympathetic stimulation (or,
for that matter, in acute HF, when there are increased adre-
nergic surges), the rate-controlling effects of digoxin would be
mitigated.
Still, digoxin affords very important theoretical benefits in
concomitant HF and AF. With respect to HF, it augments
6 A. CORREA ET AL.
ventricular contractility, while for AF it slows down ventricular
rates. As such, for patients with HF and AF who are on max-
imum-tolerated beta-blockers, but need further rate control,
digoxin could be used. This is especially important in patients
in acute decompensated HF in whom beta-blocker therapy
cannot be tolerated, or in patients in with rapid AF in whom
uptitration of beta-blockade leads to hypotension. Digoxin is
usually started with an initial loading dose followed by a daily
maintenance dosing based on renal function (see Table 1) [48].
Care should be taken to maintain a serum level of 0.5–0.9 ng/
mL, in order to avoid the deleterious effects associated with
digoxin use [49,50].
While digoxin toxicity can take on numerous nonspecific
manifestations – weakness, fatigue, confusion, nausea, vomit-
ing – its cardiac effects (specifically electrocardiographic man-
ifestations) are the most important. Just as the therapeutic
benefits of digoxin are derived from slowing of ventricular rate
through AV nodal suppression, so also digoxin toxicity stems
from excessive AV nodal blockade and conduction system
slowing. Digoxin toxicity can present as sinus bradycardia,
sinoatrial exit blocks, various degrees of AV nodal block, accel-
erated junctional rhythms, junctional exit blocks, PVCs, bigem-
inal and trigeminal rhythms, ventricular bigeminy, VT
(including bidirectional VT) and VF [51,52].
3.2.3. Calcium channel blockers
Like beta-blockers, non-dihydropyridine calcium channel
blockers can suppress AV nodal conduction and thus can be
used for ventricular rate control in AF. However, these agents
have negative inotropic effects and thus they should be used
with great caution in patients with HFrEF as they can cause
significant hypotension [53], especially when used being used
in the presence of other agents that cause negative inotropy
(such as beta-blockers, which are commonly used in patients
with HF) [18]. Non-dihydropyridine calcium channel blockers
are generally not recommended for ventricular rate control of
AF in patients with HFrEF [32].
When they are used, care should be taken to avoid hypo-
tension, and diltiazem is preferred over verapamil due to less
significant negative inotropic effects [53]. Regardless, initial
rate control for acute AF may require the use of intravenous
boluses followed by continuous infusions. But, like beta-
blockers, the aim is to transition patients to a chronic oral
regimen (refer to Table 1).
3.2.4. Rate-control goal
In the Atrial Fibrillation Follow-Up Investigation of Rhythm
Management (AFFIRM) trial that compared rate control versus
rhythm control, the target heart rate for the rate-control group
was <80 bpm at rest and <110 bpm with moderate exercise.
However, goal heart rate continued to be a matter of some
debate [23]. The Rate Control Versus Electrical Cardioversion
for Persistent AF II (RACE II) randomized physically active
patients with permanent AF to either a lenient strategy (target
heart rate <110 bpm) or a strict strategy (target heart rate at
rest <80 bpm and <110 bpm with moderate exercise) [54]. The
trial found that lenient control was non-inferior to the strict
rate-control group. It should be pointed out that at the end of
the follow-up period, the average heart rate in the lenient
group was 85 bpm, and in the strict control group was 75
bpm. Targeting the more lenient rate is a reasonable option,
as it is likely to involve fewer medications, lower cost, and
probably fewer side-effects. In RACE II, in the lenient group,
98% achieved target rate, while in the strict group, only 75%
achieved the target. However, it must be clarified that both
the AFFIRM trial and the RACE II Trial included patients con-
sisting of the general population, and not specifically HF
patients. Thus, conclusions extrapolated from these trials
should be interpreted keeping this fact in mind.
3.3. Rhythm control
Rhythm control in AF includes strategies for the restoration of
sinus rhythm and the maintenance of sinus rhythm. In general,
restoration of sinus rhythm may be achieved by electrical or
chemical cardioversion. Normal sinus rhythm is often main-
tained with pharmacologic therapy. A more definitive strategy,
however, may be ablation – either catheter ablation, and
much less frequently surgical ablation (usually in the setting
of concomitant surgery for another indication).
Electrical cardioversion may be used for the emergent
restoration of sinus rhythm. This strategy is employed if
a patient in AF and HF is hemodynamically unstable due to
decompensation of HF or attempts at ventricular rate control
have resulted in hypotension due to negative inotropy.
Electrical cardioversion may also be an elective strategy for
the restoration of sinus rhythm. While electrical cardioversion
has high initial success rates, this strategy often requires the
support of concomitant antiarrhythmics to maintain sinus
rhythm in patients with HF. Reversion to sinus rhythm can
also be achieved by chemical cardioversion with anti-
arrhythmic drugs. Anti-arrhythmic drugs can be used to main-
tain sinus rhythm after achieving rhythm restoration by either
electrical or chemical cardioversion. The agents that may be
safely used in HF are dofetilide and amiodarone. Ibutilide and
sotalol may be used with caution.
3.3.1. Dofetilide
Dofetilide is a class III anti-arrhythmic drug and is one of the
few agents that is safe for use in patient with AF and HF. The
Danish Investigations of Arrhythmia and Mortality on
Dofetilide (DIAMOND) studies showed that dofetilide used in
patients with HF is effective in chemically cardioverting
patients from AF to normal sinus rhythm and then maintain-
ing sinus rhythm [55,56]. Additionally, these studies showed
that dofetilide reduces HF hospitalizations and does not
increase mortality. Dofetilide can be safely used to restore
and maintain sinus rhythm in patients with HF related to
structural or ischemic heart disease [57].
Safety concerns around dofetilide relate to its QT-
prolonging effects and dose adjustments are necessary for
the setting of renal dysfunction. The United States Food and
Drug Administration (US FDA) requires that dofetilide be
started in a monitored hospital setting for 3 days (6 doses)
with a regular electrocardiographic evaluation to check for QT
prolongation. Dosing is based on renal function and QT inter-
val (see Table 1). Prolongation of the QT interval beyond 500

ms requires discontinuation of the drug, due to the risk of
torsades des pointes.
3.3.2. Amiodarone
Amiodarone is a class III anti-arrhythmic agent that is very
frequently used for the management of AF, both in patients
with HF and without it. As mentioned previously, it is used to
great effect for rate control in patients intolerant to first-line
rate-controlling agents (like beta-blockers) in the setting of
hypotension. But, to a large extent, it is used for its rhythm-
controlling effects. Amiodarone is effective in HF for maintain-
ing sinus rhythm and to some extent for cardioverting
patients, though it is much weaker when compared to other
agents for chemical cardioversion and often requires days to
weeks to cardiovert patients. The benefits of amiodarone for
rhythm-control purposes in HF are many: it can safely be
started in the outpatient setting, it is not very proarrhythmic
and due to negative chronotropic effects, it provides rate
control while a patient is in AF.
However, these benefits are offset to some extent by the
adverse effects of amiodarone, which reduces the favorability
of its long-term use. It can cause marked bradycardia limiting
its use, requiring discontinuation of other agents or even the
implantation of pacemakers. It has some QT-prolonging
effects and can raise the defibrillation threshold of ICDs. It
also causes hepatotoxicity, thyroid dysfunction, and pulmon-
ary toxicity, all of which can lead to irreversible organ damage.
For effective rhythm-controlling effects, amiodarone requires
to be loaded. This can be achieved intravenously, orally or by
a combination of routes. However, well before effective load-
ing has been achieved, amiodarone can result in slowing of
the ventricular rate. Amiodarone can be used intravenously or
orally in the acute setting followed by extended maintenance
oral dosing (refer to Table 1).
3.3.3. Sotalol
Sotalol should be used with caution in patients with HF. It is
particularly problematic in patients with HFrEF with marked
systolic dysfunction (ejection fraction ≤ 30%) or acute decom-
pensated heart failure, and in the setting of renal dysfunction.
This is mainly due to the reported risk of precipitating torsade
des pointes [58].
3.3.4. Other agents
Dronedarone is an antiarrhythmic drug, similar to amiodarone,
that is frequently used for the rhythm control in AF. However,
its use in patients with concomitant HF and AF has proven to
be less favorable as shown by the Antiarrhythmic Trial with
Dronedarone in Moderate to Severe CHF Evaluating Morbidity
Decrease Study (ANDROMEDA) [59]. This trial randomized
patients with severe HFrEF and New York Heart Association
(NYHA) functional class III or IV to either dronedarone or
placebo. The trial had to be stopped early by its data and
safety monitoring board due to significantly increased deaths
and worsening HF in the dronedarone arm. As such, drone-
darone must be used with extreme caution, if at all, in patients
with HF, and definitely not in patients with severe HFrEF in
whom it is contraindicated.
EXPERT OPINION ON PHARMACOTHERAPY 7
Ibutilide is also a class III anti-arrhythmic which is very effec-
tive for rapid chemical cardioversion. However, it is not generally
recommended for use in acute decompensated HF and should
be used with caution when employed in HF patients.
Vernakalant is a rapidly-acting antiarrhythmic that acts pri-
marily on the atria and is effective for a chemical cardioversion
in the absence of structural heart disease [60]. It cannot be
used in the setting of decompensated HF or NYHA Class III or
IV symptoms. It may be used with caution in the setting of
NYHA Class I and II symptoms. It is available in Europe and
Canada, but not in the United States.
The Cardiac Arrhythmia Suppression Trial (CAST I) showed
the marked pro-arrhythmic effects of class I antiarrhythmics
(flecainide, encainide, propafenone) in the post-myocardial
infarction population [61]. Extrapolating this information to
the HF population, these agents are generally avoided in
patients with HF.
Another class of pharmacotherapeutics agents recom-
mended for use in patients with HF and AF or atrial flutter
are anticoagulants to help reduce stroke risk from these atrial
arrhythmias. Recommendations for use of anticoagulation in
HF and AF/atrial flutter are similar to that in the general
population, based on the CHA2DS2-VASc score. Since this
review focusses on the pharmacotherapeutic agents used in
cardiac arrhythmias in HF, a detailed discussion on anticoagu-
lation in this population is beyond the scope of this review.
4. Pharmacologic management of ventricular
arrhythmias in heart failure
As previously mentioned, patients with HF have a high pre-
valence of VAs – PVCs, NSVT, sustained VT and VF – and this
prevalence increases with the severity of HF [5,8,14,15].
A variety of pathophysiologic mechanisms have been postu-
lated to be responsible for these arrhythmias. These include
myocardial fibrosis due to ventricular remodeling, regional
hypertrophic changes and changes in the mechanical-
electrical function of the myocytes [62].
Management strategies for VAs are diverse, and pharma-
cotherapy is one among many therapeutic options. To a large
extent, VAs are a marker of progressive pump failure and/or
disease progression in HF. As such, the pharmacologic man-
agement of HF consisting of GDMT to prevent the progression
of HF and improve remodeling, including the use of beta-
blockers and blockers of the renin-angiotensin-aldosterone
system (RAAS), should reduce VAs [62]. However, often antiar-
rhythmic drugs are required to supplement such therapies.
Beyond this, other non-pharmacologic strategies that are
employed include catheter ablation and implantable cardio-
verter-defibrillators.
Ultimately, in the setting of refractory unremitting VAs,
mechanical circulatory support (MCS) devices like LVADs and
even heart transplantation may be needed. It should be noted,
however, that VAs in this context serve as markers of end-
stage HF and acute cardiac decompensation, and such
advanced therapies are directed toward severe HF rather
than the arrhythmias themselves. In fact, patients with
LVADs may continue to have a high prevalence of VAs [63].
8 A. CORREA ET AL.

Table 2. Pharmacologic agents for the management of ventricular arrhythmias.

DRUG DOSE COMMENT
PREMATURE VENTRICULAR CONTRACTIONS AND NON-SUSTAINED VENTRICULAR TACHYCARDIAS
Beta Blockers First-line agents
● Metoprolol tartrate PO: 25–100 mg twice daily Can use more frequent divided doses
● Metoprolol succinate PO: 50–200 mg once daily
● Carvedilol PO: 3.125–25 mg twice daily
● Bisoprolol PO: 2.5–10 mg once daily
Calcium Channel Second-line agents
Blockers
● Diltiazem PO: Immediate or extended release
● Initial dose – 120 mg/d in single or divided doses
● Usual dose – 240 – 360 mg/d in single or divided
doses
● Verapamil PO: Immediate release: 360 mg/d in 3–4 divided
doses
PO: Extended release: 240–480 mg/d
Amiodarone PO:
● Initial dose – 400 mg every 8–12 h for 1 to 2
weeks
● Maintenance dose – 200– 400 mg daily

Sotalol PO: Dose increments every 3 days

● Initial dose – 80 mg twice daily Max dose 320 mg daily
● Usual dose – 160 to 320 mg/day in 2 divided
doses
PULSELESS VENTRICULAR TACHYCARDIA AND VENTRICULAR FIBRILLATION
Amiodarone IV/IO: During cardiac arrest Cannot convert pulseless VT/VF to stable rhythm itself.
● First, 300 mg bolus
Rather, it facilitates return to stable rhythm by shock therapy and maintains
● Then, can rebolus 150 mg
stable rhythm.
IV/IO: After return of spontaneous circulation
● First, 1 mg/min for 6 h
● Then, 0.5 mg/min for 18 h
● Then, PO maintenance dosing – 100 – 200 mg
daily
Lidocaine IV/IO: During cardiac arrest Max cumulative dose 3 mg/kg
● First, 1–1.5 mg/kg bolus
● Then, can rebolus 0.5–0.75 mg/kg every 5 min

IV/IO: After return of spontaneous circulation

● 1–4 mg/min continuous infusion
Magnesium IV: 1–2 g bolus over 15 min To be given when pulse VT/VF associated with TdP
SUSTAINED VENTRICULAR TACHYCARDIA, HEMODYNAMICALLY-STABLE
Amiodarone IV: Initial IV resuscitation Can give additional boluses of 150 mg over 10 min
● First, 150 mg over 10 min
● Then, 1 mg/min for 6 h
● Then, 0.5 mg/min for 18 h

PO: Initial PO loading

● 400 mg every 8–12 h for 1 to 2 weeks

PO: Maintenance dose

● 200–400 mg daily
Sotalol IV: 100 mg or 1.5 mg/kg over 5 min Should be avoided when QT is prolonged
Lidocaine IV: Second-line agent after amiodarone and sotalol
● First, 1–1.5 mg/kg bolus
● Then, 1–4 mg/min continuous infusion

SECONDARY PREVENTION OF SUDDEN CARDIAC DEATH AND HEMODYNAMICALLY-STABLE VENTRICULAR TACHYCARDIA

Amiodarone PO: Should be given in combination with beta-blockers
● Initial dose – 400 mg every 8–12 h for 1 to 2
weeks
● Maintenance dose – 200– 400 mg daily

Sotalol PO: Dose increments every 3 days

● Initial dose – 80 mg twice daily Max dose 480 to 640 mg daily
● Usual dose – 160 to 320 mg/day in 2 divided
doses
Mexiletine PO: Max dose 1,200 mg/day
● Initial – 150 – 200 mg every 8–12 h
● Usual dose – 150 – 300 mg every 8–12 h

Abbreviations: IV – intravenous; PO – per oral; US FDA – United States Food and Drug Administration; HF – heart failure; NYHA – New York Heart Association.

4.1. Management of PVCs and NSVT
PVCs and NSVT are common in patients with HF [17]. Most
patients are asymptomatic with respect to these arrhythmias.
Further, while these arrhythmias are indicative of the progres-
sion of HF, they do not necessarily correlate with an increased
risk of sudden death [17].
Treatment is generally reserved for patients who are symp-
tomatic or who develop worsening LV systolic dysfunction as
a result of these arrhythmias. Initial treatment consists of beta-
blockers [64]. (Refer to Table 2.) Optimization with beta-
blockers is a beneficial strategy in patients with HFrEF, as beta-
blockers form a major component of GDMT for HF [34–37]. If
patients remain symptomatic despite beta-blocker therapy or
are intolerant to them, other antiarrhythmic agents or catheter
ablation are considered.
Catheter ablation is an option in some patients, but there
are specific indications for this. Most commonly, ablation can
be considered when medical therapy is not effective or is not
tolerated or is not preferred by the patient. Most importantly,
if these arrhythmias are causing cardiomyopathy because of
their frequency, ablation is certainly considered. Finally,
in situations like fascicular PVCs, which can trigger VF, ablation
is indicated [64,65].
When catheter ablation is not an option, antiarrhythmics
may be used. Very few antiarrhythmics are permissible in HF
for such an indication, due to their adverse effects – particu-
larly their proarrhythmic effects. Class I antiarrhythmics are
generally avoided due to their potent negative inotropic and
pro-arrhythmic effects [66,67]. In general, Class III agents like
amiodarone or sotalol may be used [12,68]. (Refer to Table 2.)
4.2. Management of sustained VT and VF
Management of malignant VAs – sustained VTs and VF – is
a complex issue, and includes prevention of such arrhythmias
(both primary and secondary prevention) and treatment of
these arrhythmias (hemodynamically stable and unstable
patients). In advanced HF, SCD is very common, and while
bradyarrhythmias and electrical-mechanical dissociation are
now being recognized as possible mechanisms of SCD in
a substantial portion of patients, malignant VAs still account
for a large proportion of SCD [9].
4.2.1. Primary prevention
In the past, there was a great interest in the use of pharma-
cotherapy for the prevention of SCD from malignant arrhyth-
mias, and antiarrhythmics were frequently used for this
purpose. However, over the years, antiarrhythmics fell out of
favor due to their proarrhythmic adverse effects. To a large
extent, this began with CAST I which assessed the post-
myocardial infarction (MI) population and randomized post-
MI patients to either antiarrhythmic therapy (flecainide, encai-
nide, and/or moricizine) or placebo for the suppressions of
PVCs and NSVT to prevent SCD by malignant arrhythmias [61].
Most unexpectedly, while these agents indeed suppressed
these arrhythmias, they significantly increased mortality, pri-
marily by their proarrhythmic effects. In fact, the trial was
stopped early for this reason. The conclusions of this trial
EXPERT OPINION ON PHARMACOTHERAPY 9
can be extrapolated to the HF population. Additionally, Class
I antiarrhythmics are avoided in HF due to their effects of
blood pressure [66,67]. In subsequent years, many other trials
were conducted to evaluate Class III antiarrhythmics for
arrhythmia suppression in post-MI or in HF, and the trials
either showed no benefit or actual harm [59,69,70].
Amiodarone is not as proarrhythmic when compared with
other agents, and a number of trials have been conducted
over the years to evaluate its efficacy in heart failure and post-
MI in reducing mortality and preventing arrhythmias. The
Gruppo de Estudo de la Sobrevida en la Insuficiencia
Cardiaca en Argentina (GESICA) trial was performed in
Argentina and it evaluated the efficacy of amiodarone when
added to the regimen of optimally treated HF patients [71].
The trial strongly came in favor of amiodarone showing sig-
nificant reductions in mortality, progression of HF, and hospi-
tal admissions. The results of the trial were in contradiction to
the results of the Survival Trial Of Antiarrhythmic Therapy In
Congestive Heart Failure (CHF-STAT) [72]. This trial was con-
ducted in Veterans’ Administration hospitals, and it showed no
mortality benefit or reduction in SCD when amiodarone was
added to the standard regimen of optimally treated HF
patients, though it did reduce ventricular arrhythmias and
improve ejection fraction. There are many postulated explana-
tions for the differences in the results of these two trials.
Primarily, it is suggested that differences in the populations
studied may account for the differences. For instance, only
40% of the patients in GESICA had ischemic cardiomyopathy,
while the number in CHF-STAT was 72%. A trend toward
mortality benefit was seen in patients with non-ischemic car-
diomyopathy (NICM) in CHF-STAT which aligns with the find-
ings of GESICA where the majority of patients had NICM.
Finally, it may be possible that the benefits seen with amio-
darone in GESICA may be related to a worse degree of HF,
suggesting that amiodarone may be beneficial in sicker
patients [73]. As such, there was no clear consensus on
whether amiodarone was beneficial in preventing SCD in HF.
However, this debate was put to rest by the Sudden
Cardiac Death in Heart Failure Trial (SCD-HeFT), which pitted
implantable cardioverter-defibrillators (ICDs) against amiodar-
one for the primary prevention of SCD [74]. The Multicenter
Automatic Defibrillator Implantation Trial II (MADIT-II) had
already shown that ICDs reduced SCD in severe HF secondary
to ICM post-MI [75]. In SCD-HeFT, a large multicenter, double-
blinded, parallel-group, randomized, placebo-controlled trial,
ICDs were compared against amiodarone or a placebo in
patients with HFrEF regardless of whether it was due to an
ICM or NICM. The trial concluded that ICDs reduced mortality
in such patients, effectively reducing SCD, while amiodarone
conferred no mortality benefit [74].
4.2.2. Treatment of pulseless VT or VF (VT/VF arrest)
In cardiac arrest due to pulseless VT or VF, the most important
step is the restoration of a stable ventricular rhythm that
permits spontaneous circulation and perfusion of the vital
organs. The definitive way to achieve this is shock termination
of the unstable rhythm with defibrillation with continued
cardiopulmonary resuscitation (CPR) and vasopressors (primar-
ily epinephrine) to maintain circulation. The present American
10 A. CORREA ET AL.
Heart Association (AHA) Advanced Cardiac Life Support (ACLS)
guidelines support the consideration of amiodarone for pulse-
less VT or VF that is refractory to CPR, defibrillation, and
vasopressors [76,77]. Lidocaine may be considered as an alter-
native. Routine use of magnesium is no longer recommended,
though it is still regularly used for torsades des pointes [76,77].
(Refer to Table 2)
There is insufficient evidence to support or refute the rou-
tine use of lidocaine or beta-blockers immediately after car-
diac arrest from VT or VF. While antiarrhythmics play a role in
the short term as a part of ACLS for resuscitation from cardiac
arrest, no studies have shown their long-term benefit in terms
of mortality [76,77].
4.2.3. Treatment of sustained VT without cardiac arrest
The management of sustained VT that does not present with
cardiac arrest varies depending on the presence or absence of
hemodynamic stability. Consideration should also be given to
alternate diagnoses of the presenting wide-complex tachyar-
rhythmia (i.e. an SVT with aberrancy).
If a patient with a wide-complex tachyarrhythmia manifests
evidence of hemodynamic instability, regardless of the suspi-
cion for VT or SVT with aberrancy, the first step is the restora-
tion of a stable rhythm [78]. Hemodynamic instability may be
manifested by hypotension, cardiogenic shock, dyspnea,
altered mental status or ischemic chest pain. In these situa-
tions, the patient should immediately be delivered therapy
with synchronized cardioversion [78].
In the absence of hemodynamic instability, appropriate
intravenous drug therapy can be given. Appropriate therapy
for proven or presumed sustained VT is intravenous infusion of
an anti-arrhythmic agent. While procainamide is the preferred
option in most patients without HF (in the absence of QT
prolongation), it should be avoided in HF patients due to its
potent negative inotropic effects [78]. Intravenous amiodarone
or sotalol are preferred agents in HF. (Refer to Table 2) Sotalol
should be used cautiously in patients with a prolonged QT
interval. Both these agents have been found to be superior to
lidocaine [79,80], which is a second-line agent. When used,
lidocaine is given as an intravenous bolus followed by
a maintenance infusion of 1 to 4 mg/min (Refer to Table 2).
4.2.4. Secondary prevention
In HF patients who are survivors of cardiac arrest due to VT or
VF or have experienced sustained VT, once reversible causes
have been ruled out, a variety of options are available for the
secondary prevention of SCD. These range from device ther-
apy to catheter ablation to anti-arrhythmic agents to certain
surgical interventions.
Multiple trials over the years have shown that for patients
undergoing cardiac arrest from either sustained VT or VF or
undergoing hemodynamically significant sustained VT,
implantation of an ICD is a beneficial strategy [81–83]. There
is a broad consensus about this, and there are guideline
recommendations supporting the use of ICDs for the second-
ary prevention of SCD when there is expected meaningful
survival of greater than 1 year [68].
Anti-arrhythmic drugs and/or catheter ablation may be used
to supplement ICD implantation, and only in very rare
circumstances (for example, when a patient declines implanta-
tion of an ICD) are they used as the first-line therapies for the
secondary prevention of SCD. The main indication for the use of
drug therapy is the prevention of ICD shocks, which can
adversely affect the quality of life of patients. In HF patients,
drug therapy is usually limited to amiodarone, sotalol, and mex-
iletine. Sotalol has been shown to be a safe and effective option
for reducing ICD shocks, regardless of the presence or absence of
HFrEF [84]. The Optimal Pharmacological Therapy in Implantable
Cardioverter Defibrillator Patients (OPTIC) trial showed that
amiodarone (with a beta-blocker) was effective in reducing ICD
shocks and was better than sotalol [85]. However, the trial also
showed that amiodarone was less well tolerated and was asso-
ciated with a number of adverse reactions, which is why sotalol is
often tried before amiodarone. Sotalol has both class III anti-
arrhythmic effects and beta-blocker effects. Amiodarone is
usually combined with beta-blockers, as it primarily has class III
anti-arrhythmic effects and weaker negative chronotropy. It
should also be remembered that amiodarone can raise the defi-
brillation threshold of ICDs, and this can affect its efficacy.
Mexiletine has also been used alone or usually in combination
with a class III agent [86]. (Refer to Table 2.)
Supraventricular tachycardias, most commonly atrial fibril-
lation, are often misinterpreted by ICDs as ventricular arrhyth-
mias resulting in inappropriate device therapy. Agents like
beta-blockers or anti-arrhythmics like dofetilide which reduce
these arrhythmias will thus also play a role in the reduction of
ICD shocks.
Various non-pharmacologic therapies like catheter ablation
or surgical autonomic modulation (like cardiac sympathetic
denervation) may be useful strategies to reduce ventricular
arrhythmias and ICD shocks in certain circumstances [62,68].
4.3. Considerations for advanced HF
While management of advanced HF (ACC/AHA Stage D HF),
including management of ventricular arrhythmias, in a large
part involves the use of MCS devices and ultimately cardiac
transplantation, anti-arrhythmic drugs still play a major role.
Since refractory arrhythmias are symptomatic of a failing
heart, LVADs are certainly an option for arrhythmias refractory
to medical therapy and/or catheter ablation [62].
However, regardless of what the indication for LVAD
implantation is, patients with durable LVADs often have ven-
tricular arrhythmias and sometimes more arrhythmias than
before LVAD placement. Interestingly, despite attendant fibro-
sis around the inflow cannula site at the left ventricular apex
which could generate monomorphic VTs, a majority of
arrhythmias in these patients are due to the diseased sub-
strate of the failing ventricle or due to aberrant hemody-
namics associated with the LVAD [87]. Due to the frequency
of ventricular arrhythmias in patients with LVADs, periopera-
tive ablation is often pursued around the time of LVAD
implantation [62]. This may be surgical cryoablation during
the implantation or perioperative catheter ablation.
The role of anti-arrhythmic drugs is unclear, with little trial
evidence to support or refute their use. It has been suggested
that LVAD patients receive anti-arrhythmic drugs in the same
fashion as patients without LVADs [62]. Amiodarone, sotalol,

and mexiletine are usually the drugs of choice. In LVAD
patients without an ICD, and experiencing frequent arrhyth-
mias, ICD placement is a reasonable option [68].
Cardiac transplantation is often the last option in refractory
arrhythmias. In the United States, while ventricular arrhyth-
mias are not a listing criterium of the International Society of
Heart and Lung Transplantation (ISHLT) for heart transplanta-
tion [88], the Organ Procurement and Transplantation
Network (OPTN) of the United Network of Organ Sharing
(UNOS) gives waitlist status 1 to patients with MCS and refrac-
tory ventricular arrhythmias and status 2 to patients with such
arrhythmias without MCS. Following a transplant, arrhythmias
are uncommon but may occur in the setting of acute rejection
or severe allograft vasculopathy. Anti-arrhythmics may be
used, but there is no trial evidence to guide the use of these
agents. It is reasonable to use standard anti-arrhythmics like
amiodarone, sotalol, and lidocaine to manage these arrhyth-
mias. Ultimately, consideration for ICD should be made in
a standard fashion as would be the case with any patient
with HF, and anti-arrhythmic drugs would supplement this
therapy [89].
5. Expert opinion
Cardiac arrhythmias are frequently seen in patients with HF.
These rhythm disturbances can be related to the underlying
pathology that causes the HF (such as atrial myopathy,
ischemic cardiomyopathy, and scar related arrhythmia).
Conversely, the arrhythmia itself can precipitate HF, such as
with tachycardia-mediated cardiomyopathy. Regardless of the
etiology, arrhythmias often lead to worsening of HF and are
the leading cause of death in this patient population. It is
important to treat these arrhythmias to control symptoms,
slow disease progression and prevent sudden death.
Management depends on the type of arrhythmia (atrial or
ventricular), the stage of HF and other comorbidities.
Antiarrhythmic agents are often used along with device ther-
apy and catheter ablation. However, antiarrhythmic agents
come with their own problems, such as proarrhythmic and
negative inotropic effects. The knowledge of cardiac arrhyth-
mias seen in HF patients and their evidence-based pharmaco-
logic management strategies are important for physicians
caring for these patients.
Atrial arrhythmias are commonly seen in HF, with atrial
fibrillation being the most common arrhythmia in this popula-
tion [19–21]. Studies that have assessed the use of rate-control
versus rhythm-control strategies for AF in HF have determined
that either could be preferred based on the patient profile and
symptoms. However, the analysis of trials on rate versus
rhythm-control strategies has in fact shown that the attain-
ment of sinus rhythm is beneficial in HF patients [25].
Theoretically, the attainment of sinus rhythm with rhythm-
control strategies affords benefit in HF, since the atrial kick,
slower heart rates, and better diastolic filling can result in
improved hemodynamics. Beta-blockers remain the primary
drug of choice for rate control, while amiodarone and dofeti-
lide can be used for rhythm control. While pharmacotherapy
remains the first-line treatment for AF, catheter ablation of AF
in HF has also been shown to be beneficial in HF patients
EXPERT OPINION ON PHARMACOTHERAPY 11
[27,28]. For atrial flutter, catheter ablation is the recommended
first-line treatment strategy. Based on the available evidence,
for patients with HF presenting with new-onset of AF or flutter
or an exacerbation of the same, we propose initial rate-control
therapy in the acute setting. A trial of electrical cardioversion
is reasonable after left atrial appendage thrombi have been
excluded, as long as there are no contraindications. If this
strategy fails or the arrhythmia recurs, anti-arrhythmics are
reasonable in the short term. Ultimately, a strategy of rhythm
control by catheter ablation is recommended in HF patients. In
persistent AF, long-term rate-control therapy is the mainstay.
Ventricular arrhythmias can range from PVCs and NSVT to
sustained VT and VF. While PVCs and NSVT have not been
shown to have a direct effect on increasing mortality, these
arrhythmias often reflect the progression of the heart disease.
Due to the high risk of SCD, patients with severe systolic heart
failure usually have an ICD implanted for SCD prevention
[74,75]. Antiarrhythmics are used for suppression of ventricular
arrhythmias when the arrhythmias become frequent and
symptomatic or cause recurrent ICD shocks. Amiodarone and
mexiletine are the most frequently used medications in this
population. Recent studies looking at the use of catheter
ablation in patients with severe HF and ventricular tachycar-
dias have shown that ablation when successful reduces mor-
tality and improves HF symptoms.
With improvements in catheter-based ablation techniques for
both atrial and ventricular arrhythmias, antiarrhythmic drugs are
gradually falling out favor given the proarrhythmic and toxic
adverse effects associated with these medications. There have
been very few recent advances in antiarrhythmic pharmacology
and that remains a potential area of discovery over the next few
years.
Funding
This manuscript was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
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