Cardiology , DOI: 10.

1159/000529670
Received: October 25, 2022
Accepted: February 8, 2023
Published online: March 6, 2023

Pharmacotherapy in Ventricular Arrhythmias

Apte N, Kalra D

ISSN: 0008-6312 (Print), eISSN: 1421-9751 (Online)

https://www.karger.com/CRD
Cardiology

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© 2023 S. Karger AG, Basel
Pharmacotherapy in Ventricular Arrhythmias

Nachiket Apte, MDa, Dinesh K. Kalra, MDa

a
Division of Cardiology, University of Louisville School of Medicine, Louisville, KY

Running head: Pharmacotherapy in Ventricular Arrhythmias

Keywords: Ventricular arrhythmias, antiarrhythmic drugs, Sudden cardiac death, Ventricular tachycardia

Abstract Word count: 312

Body Word count: 4586 words
Number of Tables: 2
Number of Figures: 3

Corresponding Author:

Dinesh Kalra, MD, MBA, FACC, FNLA, FSCCT, FSCMR

Chief, Division of Cardiovascular Medicine
Vice Chair of Quality, Department of Medicine
Professor of Medicine & Endowed Chair in Cardiovascular Innovations
Director of Advanced Cardiac Imaging, Lipid Clinic
& Infiltrative Heart Disease Program
University of Louisville School of Medicine
Rudd Heart & Lung Center
201 Abraham Flexner Way, Suite 600
Louisville, KY 40202
dinesh.kalra@louisville.edu
@DineshKalra
O: 502-852-9505
F: 502-852-6233
Acronyms

AAD = Anti arrhythmic drug, ACS = Acute coronary syndrome, APD = Action potential duration, BrS = Brugada
Syndrome, CASCADE = Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation, CAST =
Cardiac Arrhythmia Suppression Trial, CHD = Coronary Heart Disease, CIDS = Cardiac Implantable Defibrillator
Study, CPVT = Catecholaminergic Paroxysmal Ventricular Tachycardia, CPR = Cardiopulmonary Resuscitation, EF=
Ejection Fraction, EWS = Early Wave Syndrome, ES = Electrical Storm, ICD = Intra-Cardiac Defibrillator, HOCM =
Hypertrophic Obstructive Cardiomyopathy, JWS = J Wave Syndrome, LQTS = Long QT Syndrome, MMVT=
monomorphic ventricular tachycardia, NSVT = non-sustained ventricular tachycardia, PCI = Percutaneous
Coronary Intervention, PMVT = Polymorphic Ventricular Tachycardia, PVC = premature ventricular contraction,
SCD= Sudden Cardiac Death, SQTs = Short QT Syndrome, STEMI = ST Elevation in Myocardial Infarction, TdP =
torsades de pointes, TDR = Transmural Dispersion of Repolarization, VA = ventricular arrhythmia, VANISH =
Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock, VT = ventricular tachycardia, VF = ventricular
fibrillation

Abstract
Background
Ventricular ectopy is observed in most of the population ranging from isolated premature ventricular contractions
to rapid hemodynamically unstable ventricular tachyarrhythmias like ventricular tachycardia and ventricular
fibrillation. Multiple mechanisms exist for ventricular arrhythmias such as triggered activity, reentry, and
automaticity. Scar-based reentry forms the basis of most malignant VA that can lead to sudden cardiac death.
Many antiarrhythmic drugs have been utilized for the suppression of ventricular arrhythmia. They are commonly
classified using the Vaughan-Williams-Singh classification which distinguishes them based on the predominant
action on different phases of the cardiac action potential. Class Ic agents are widely used in premature ventricular
contraction suppression but are contraindicated in patients with prior myocardial infarction or ischemic scar, and
heart failure. Beta-blockers continue to be a mainstay in the treatment of most symptomatic VA and are well
tolerated, relatively safe, and have additional benefits in symptomatic coronary heart disease and left ventricular
systolic dysfunction. Amiodarone continues to be used for the management of most cases of serious VA especially
in the acute setting when accompanied by hemodynamic perturbations but has the disadvantage of having a poor
toxicity profile for long-term use
Summary
Historically used for long-term ventricular arrhythmia suppression and prevention of sudden cardiac death,
antiarrhythmics are now used to reduce implantable defibrillator shocks and symptoms. They still have a role in
premature ventricular complex suppression in patients with failed catheter ablation or those who are not
candidates for invasive therapy. Newer concepts in cardiac imaging and the use of artificial intelligence may help
further delineate sudden cardiac risk and identify patients that may benefit from pharmacological management.
Key Message
Anti-arrhythmic agents continue to perform an important role in the suppression of ventricular arrhythmias
especially channelopathies, polymorphic VT, and idiopathic ventricular fibrillation. Judicious use of these agents
while recognizing side effects can help reduce the long-term effects of ventricular arrhythmias on cardiac
function.

Introduction
Ventricular ectopy encompasses a spectrum of ventricular arrhythmia (VA) ranging from isolated asymptomatic
premature ventricular contractions (PVCs) to rapid ventricular tachycardia (VT) and ventricular fibrillation (VF)
which may lead to sudden cardiac death (SCD). The incidence of PVCs in the population is highly dependent on
patient characteristics including comorbidities as well as the duration of monitoring. In a healthy military
population, PVCs were found in only 0.6% of people <20 years of age on a routine screening electrocardiogram
(EKG). However, the prevalence increased to >2.7% in those 50 years of age or older (1). Traditionally, the
incidence of PVCs has been determined based on the EKG and/or limited Holter monitoring. However,
increasingly with long-term monitoring that includes implantable monitors, portable devices, and wearables, the
incidence of PVCs is likely to be far greater. For example, in the Atherosclerosis Risk in Communities(ARIC) study
which used 2 minutes of EKG monitoring, or the Framingham study which used 1 hour, the incidence of PVCs was
5.5% and 12 % respectively, and was more than twice as likely in the population with coronary heart disease
(CHD) (2, 3). When healthy adults were monitored on 24-hour Holter monitoring, the incidence of PVCs was found
to be as high as 69 % with the median number of PVCs being two. More recently, in the Multiethnic Study of
Atherosclerosis (MESA) study, the incidence was as high as 99.5% in 1122 individuals who wore a Zio Patch XT®
(iRhythm Technologies, Inc, San Francisco, CA) for 14 days (4). It is likely that with increasing implantable and/or
wearable technologies, every individual would likely have some ventricular ectopic activity at a point in time with
long enough monitoring. Thus, such kind of data is needed to inform guidelines as to what constitutes normal or
benign findings and what burden of VA in patients with structural heart disease confers a higher risk of SCD.
Typically, PVCs - especially if they are multifocal and frequent, defined as more than 1000 in 24 hours - have been
considered a risk factor for major adverse cardiovascular outcomes (MACE) including heart failure, stroke, and
SCD. A recent study by Refaat et al. showed that in asymptomatic individuals, PVCs during recovery that were
frequent (>10 per minute), multifocal, or complex (R-on-T type, or ≥2 PVCs in a row) were associated with
increased long-term cardiovascular mortality while exercise-induced PVCs did not have the same risk profile (5).
On the other hand, VA such as VT and VF have a distinct risk profile when compared to isolated PVCs. Non-
sustained VT (NSVT), defined as VT lasting less than 30 seconds, is challenging in terms of prognosis and
predictability for SCD. It remains to be seen if it is a precursor for sustained VT and SCD or simply a marker for the
underlying myocardial disease (6). In the MERLIN-TIMI 36 trial, there was no increased risk with NSVT lasting 3
beats, however, in the subgroups with 4-7 beats and more than 8 beats, the risk of SCD was statistically higher (7).
Interestingly it was observed in populations with and without high risk. Other studies have not found any
increased risk with NSVTs, especially in the acute myocardial infarction(AMI) population (8).
Sustained VT and ventricular fibrillation are associated with a high risk of SCD. Ventricular arrhythmias in the
acute MI setting may frequently be polymorphic or present as VF while monomorphic VT in the CHD population is
suggestive of scar-based reentry. VT or VF in the non-ACS population is suggestive of scar-based re-entry,
metabolic disorders as well as inherited cardiomyopathies either secondary to myocardial degeneration or
channelopathies. Lastly, triggered activity in the form of Early After depolarizations (EADs) as well as Delayed
After Depolarizations (DADs) has been implicated in initiation of VAs. EADs occur in phase 2 and 3 of the action
potential and may give rise to VAs in conditions like prolonged QT and heart failure while DADs arise during phase
4 of the action potential resulting in high intracellular Ca+2 release and are usually seen in conditions like digitalis
toxicity, high catecholamine release like CPVT as well as dyselectrolytemias.
Management of ventricular arrhythmias is a multi-pronged approach that includes general care, pharmacological
therapy as well as procedures like catheter ablation. Moderation of alcohol and caffeine and management of
stress may help in decreasing PVCs In this review article, we will take a look at commonly used pharmacological
agents to treat or prevent ventricular arrhythmias.
Classification of Anti-arrhythmic agents
Pharmacological agents for the prevention or treatment of VAs can be broadly classified using the Vaughn
Williams Singh classification which divides medications into classes depending on the predominant mechanism of
channel or receptor-blocking action as shown in Figure 1 (9). Though the most widely used, it has several
limitations and may not accommodate all anti-arrhythmias. Most prominently, drugs like amiodarone may have
actions across classes. Classification systems like the Sicilian Gambit classification and a modernized Oxford
classification by Lei and colleagues have been proposed (10, 11). As shown in Table 1, these systems can be
overlapped to describe the anti-arrhythmic effects of each drug and to accommodate drugs that have actions
across multiple channels.
Class I
Medications in this class have been used for a long time for the prevention of sudden death. They primarily act by
reducing peak INa and increasing the excitation threshold. Given their arrhythmic effects as well as increased
mortality in patients with myocardial infarction and structural heart disease their use is limited. They are divided
into three classes as given in Table 1, however, newer classifications have additional subclasses depending on
other actions. We will discuss the more commonly used anti-arrhythmic drugs as given below.
Flecainide
Flecainide was originally developed as a new fluorinated anesthetic but was found to have anti-arrhythmic
properties. It was approved in 1984 for suppression of sustained VT (12). It is a potent and selective blocker of the
cardiac fast inward sodium (Na+) current with high affinity in the open state. It has also been shown to inhibit the
delayed rectifier IKr current. Due to this action, it shortens Na-regulated action potential duration (APD) in Purkinje
fibers but prolongs it in the atrial and ventricular muscle fibers which are regulated by the fast K channel IKr (13).
It blocks the opening of the ryanodine receptor thus inhibiting the release of Ca++ from the sarcoplasmic reticulum
(SR) thereby decreasing triggered activity. This makes it a potent inhibitor of Catecholaminergic Polymorphic
Ventricular Tachycardia (CPVT), associated with ryanodine and calsequestrin mutations (14).
Flecainide increases the sinus node recovery time (SNRT) and delays intra-atrial and atrioventricular conduction,
thus increasing the PR, QRS, and QT intervals without an increase in QTc duration (15). It may cause an increase in
the pacing threshold, however, no adverse impact has been noted in patients with pacemakers including those
utilizing conduction system pacing (16, 17).
The proarrhythmic effects of flecainide were well highlighted after the findings of the CAST trial which tested the
effect of class Ic antiarrhythmic agents in patients with asymptomatic or mildly symptomatic VA in patients with
myocardial infarction (18). Patients received one of three drugs - encainide, flecainide, or moricizine or placebo.
At a median follow-up of 10 months, the trial was stopped early after it was noted that patients in the drug arm
had higher deaths from arrhythmias as well as higher all-cause mortality than in the placebo arm. This trial’s
findings changed concepts and guidelines regarding the use of this class of antiarrhythmic drugs for the
suppression of VA. Notably, deaths were observed even in patients with EF >40% (18).
Multiple factors may explain these findings. Flecainide exerts a negative inotropic effect by decreasing stroke
volume and increasing pulmonary capillary wedge pressures, even when administered to patients with normal
ejection fraction. Even in patients with CPVT, flecainide can bind to separate activation and inhibition sites on
RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels,
thus having a potential pro-arrhythmic effect (19).
Flecainide is currently administered for suppression of PVCs in structurally normal hearts without a history of
myocardial infarction or heart failure where it has a Class IIa indication (14). It has been shown to significantly
suppress RV outflow tract PVCs. It has been shown to suppress exercise-induced ventricular arrhythmias in both
genotype-positive patients,(20) as well as genotype-negative patients (21) as well as prevent ICD shocks in CPVT
patients in combination with beta-blockers (14).
It is usually administrated twice daily and is absorbed with a bioavailability of 90%. PR and QRS duration may be
prolonged in a dose-dependent manner with toxic doses causing bradycardia and conduction abnormalities.
Propafenone
Propafenone also blocks the fast inward sodium channel like flecainide, however, it has additional β blocking and
calcium-blocking activity. Like Flecainide it reduces the prolongation of conduction and refractoriness in all areas
of the myocardium, particularly in the intraventricular conduction. Its bioavailability is dose-dependent and it also
shows use dependence. It is effective in suppressing PVCs as well as nonsustained VT. Though contra-indicated in
patients with low ejection fraction, it has been given in small studies with improvement in ejection fraction (22). It
has also been described for CPVT with its benefit likely from its β blocking action (14).
It is metabolized in the liver via the cytochrome P450 2D6 (CYP2D6) pathway. Alcohol may increase propafenone
levels even at regular doses (23). Propafenone is also proarrhythmic though the action is more likely due to its
actions on delaying His Purkinje conduction which may allow for ventricular re-entry.

Lidocaine and mexiletine

Lidocaine and its oral form mexiletine bind to Na channels in the inactivated state and rapidly unbind during the
resting state. They demonstrate use-dependent inhibition of fast Na+ current at higher heart rates while at low
heart rates, they mostly block late Na+ current (24). In animal studies, mexiletine dose-dependently shortened
action potential duration (APD) in mid-myocardial cells and decreased transmural dispersion of repolarization
(TDR). It also prevents torsades de pointes (TdP) by inhibiting late sodium channels (INa-L), a property that makes
it a useful agent and a Class I agent in the 2022 ESC guidelines for preventing TdP in LQT3 a disorder involving the
sodium channel (14). It increases QRS duration at higher heart rates but does not prolong QTc. In the VANISH
trial, mexiletine and amiodarone were found to be inferior when compared to catheter ablation when compared
for the composite outcome of death, electrical storm, or appropriate ICD shock (25).
Lidocaine is used in the IV form for the suppression of sustained VT and VF including electrical storm and is now
used as an adjunct or alternative to amiodarone (14). In early trials, Out of hospital cardiac (OHCA) patients
randomized to amiodarone or lidocaine had lesser episodes of subsequent shocks or required CPR and were more
likely to survive hospitalization than those receiving a placebo, however rate of survival or favorable neurologic
outcome was not significantly higher in the anti-arrhythmic group. Initially used for the treatment of ventricular
arrhythmias in ischemic VT, it has now been superseded by amiodarone in the acute setting due to lack of any
substantial benefit (14). A large meta-analysis showed equivocal results for both amiodarone and lidocaine with
regard to survival at hospital admission though there was no difference in the long-term outcome (26).

Procainamide
Procainamide is a benzamide, similar to procaine but with an amide moiety which gives it a longer half life. It and
its active metabolite N-acetyl – procainamide block sodium channels delaying phase 0 of the cardiac cycle. They
also block the rectifier K+ channel, IKr. Procainamide is used to rapidly terminate monomorphic VT. In the
PROCAMIO study, it was shown to have lesser cardiac adverse effects than amiodarone (9 % vs 41%. P = 0.006%)
with an almost double the incidence of VT termination (67% vs 38%, P=0.026) (27). It was also shown to be
superior to lidocaine in terminating acute VT episodes in a small randomized trial of 29 patients (28). However, in
another study, procainamide recipients who received more shocks and pharmacologic interventions and had
lengthier resuscitations were less likely to survive hospital discharge, though these results were probably
confounded by the administration of other cardiac medications (29). Oral procainamide was also shown to reduce
sustained VT and VF as well as ICD therapies in a small study of 34 patients (25). Though 55 % of these had a
previous catheter ablation for VT, it was initiated after VT was inducible in these patients (25). Though this could
be a confounding factor, it is not necessarily a negative study as a combination of anti-arrhythmias and catheter
ablation are routinely used to decrease the burden of VT and ICD therapies in everyday practice. Currently,
procainamide is mainly used in the acute setting to terminate monomorphic VT not amenable to IV amiodarone
or lidocaine (27, 28). In the 2022 ESC Guidelines for the management of ventricular arrhythmias, it has a Class IIa
recommendation for acute management of idiopathic VT over other AADs like amiodarone and sotalol which are
Class IIb (14). Being a sodium channel blocker like flecainide, it can unmask Brugada syndrome (BrS) and is used
for provocative testing in patients with BrS (25).

Quinidine
Quinidine is a stereoisomer of the anti-malarial drug quinine. Given a Class Ia agent, its effect on conduction
velocity is lesser than lidocaine but greater than Class Ic agents. Like procainamide, it also acts on IKr and IKs with
an additional blocking action on the L-type ICa and the late INa inward currents Ito with prolongation of the APD. It
is primarily used as a second line or an adjunctive drug for drug-resistant VT. It has been shown to reduce drug
refractory idiopathic and post-infarct polymorphic VT in patients with ischemic heart disease (IHD) (14). Recently
in a small retrospective analysis, quinidine initiation reduced recurrent VA in patients hospitalized with electrical
storm though about 54 % of patients had recurrent VA post-discharge (30). More, as a strong Ito blocker, it has
been studied in J wave syndromes (JWS) namely Brugada syndrome(BrS) and early repolarization syndrome (ERS).
It has been shown in multiple small studies to reduce ectopy-induced recurrent ventricular arrhythmias in BrS
both at initiation and follow-up (31) as well as reduce ICD shocks in observational cohorts (32). In ERS, quinidine
may reduce the early repolarization pattern or even restore a normal ECG in patients. (33). Even in acquired ERS
secondary to hypothermia, quinidine has been administered to reduce VF due to its ability to reverse
hypothermia-induced repolarization abnormalities (34). Quinidine, because of its potassium-blocking action has
been shown, particularly in patients with a KCNH2 mutation (sQTS type I), to increase QTc duration, prolong
ventricular refractory period and prevent induction of ventricular fibrillation during EPS though its action on other
mutations for SQT is not completely understood (35). It currently has a Class IIa indication for management of
polymorphic VA secondary to Brugada syndrome, ERS as well as idiopathic VF and a Class IIb indication for PVC-
induced polymorphic VAs (14).

Class II
Beta-blockers
Beta-blockers manifest their anti-arrhythmic activity in multiple ways. In the ischemic population, beta blockers
predominantly have an anti-ischemic action and serve to decrease myocardial oxygen demand, slow heart rate to
allow ventricular filling, as well as possibly prevent plaque rupture. Sympathetic activity increases post-acute
myocardial infarction and that can predispose to VA by lowering the VF threshold (36). Beta-blockers inhibit
catecholamine-initiated cAMP activation and may exert their anti-arrhythmic effect by sympathetic blockade and
membrane stabilizing activity (25). Due to their safety profile, availability as well adrenergic blockade, beta
blockers are among the first-line agents for the prevention of VA in the CHD population. In the non-ischemic
population, possible mechanisms include slowing of the sinus rate as well as inhibition of the ryanodine receptor,
the mutation of which is an important mechanism in CPVT.
Beta-blockers like nadolol and propranolol have been used in LQTS and CPVT. Nadolol has long been used in
LQTS1 and LQTS2. They are thought to have a heart rate-dependent decrease in the QT interval and are the first
line in decreasing syncope and mortality in the LQTS1 and LQTS2 populations (37). Though all beta blockers are
effective, nadolol has shown significant risk reduction in LQTS2 patients. Similarly, in CPVT, beta-blockers,
especially nonselective β blockers like nadolol were found to be associated with lesser SCA, ICD shocks, or
syncope (14).
Class III
Sotalol
Sotalol, a racemic mixture of d- and l isoforms, is a nonselective ß-blocker but differs from other drugs in its class
by also having class III inhibition of delayed potassium rectifier channel. It is thus able to increase APD and ERP.
Sotalol has been shown to reduce ventricular arrhythmias and suppress PVCs. It exhibits reverse use dependence,
binding more avidly in slower heart rates. It has been shown to reduce ICD shocks with no difference in mortality.
The use of pure d-sotalol, with predominantly potassium-blocking action with no clinically significant beta-blocker
activity, was shown to have higher mortality in the SWORD trial which was subsequently stopped (25). In a large
meta-analysis of 22 randomized trials, when compared to amiodarone, sotalol significantly increased VT
recurrences and ICD shocks (38). It remains a second-line drug for managing PVCs and VT in those patients who
are intolerant or refractory to amiodarone. Sotalol requires dosing depending on QTc and renal clearance. More
recently, IV sotalol has been used for rapid loading in 1 day versus the conventional 3-day dosing. It has been
shown to rapidly increase the ventricular refractory period and terminate sustained VT (39).

Dofetilide
Dofetilide is a selective delayed IKr blocker that is approved for use in atrial tachyarrhythmias. However, its use in
VAs is less established with mixed results in trials. It has been used in select settings for reducing ICD therapies as
well as the recurrence of VT where other AADs have not been successful (25).

Amiodarone
Amiodarone functions as an inhibitor of the IKr channel but also has actions on the sodium channel as well as an
anti-adrenergic action. It remains the most commonly prescribed drug for supraventricular and ventricular
arrhythmias. It increases refractoriness in all tissues as well as the SA and AV nodes. It uniformly delays
ventricular depolarization in all myocardial layers leading to QT prolongation without any increased transmural
heterogeneity of repolarization. Thus, TdP is however rare and in general, amiodarone has a better safety profile
in terms of inducing arrhythmias (40). However, a 2017 study by Shenthar et al has shown that IV amiodarone has
a higher risk of inducing TdP than oral amiodarone, a finding shared by other studies with female sex,
concomitant drug therapy, left ventricular dysfunction and electrolyte abnormalities being at higher risk (41). It
has been given for a long term for the suppression of VT and VF before the popularization of ICDs. Multiple large
trials have shown the benefit of amiodarone for the secondary prevention of VT and VF. The EMIAT and CAMIAT
trials showed that amiodarone reduced the incidence of VF or arrhythmic death among MI patients (25). The
CASCADE study was a randomized trial that showed that cardiac arrest survivors with ICDs on amiodarone had a
lesser incidence of the composite of cardiac death and sustained VA. Amiodarone reduces the incidence of
ventricular fibrillation or arrhythmic death among survivors of acute myocardial infarction, sustained VT/VF, or
syncope and ICD shocks when compared to Class Ic antiarrhythmics. Other trials have shown similar results with
other anti-arrhythmias (26). When compared to ICDs however, ICDs showed a greater mortality reduction in
multiple trials which compared ICDs to medical therapy namely amiodarone. In the CIDs study, the risk reduction
was nonsignificant, however, long-term follow-up showed significance towards the ICD group, namely from side
effects and discontinuation of long-term amiodarone. The AVID study followed patients randomized to ICDs vs
medical therapy, namely amiodarone, over 4 years and found ICDs to be superior. A meta-analysis of all these
trials showed significant risk reduction in death from arrhythmia from ICDs with patients with an EF of less than
35 % deriving the most benefit (42). Thus amiodarone has fallen out of favor as a standalone drug for secondary
prevention, though it is often given concomitantly to reduce the incidence of VT in these patients. A combination
of beta blockers and amiodarone in patients has been shown to reduce cardiac death and arrhythmic death or
resuscitated cardiac arrest.
Though there is plenty of clinical data for the short-term use of amiodarone for VT suppression, there is a
concern for short-term and long-term amiodarone use, especially its toxic effects on the liver, thyroid, skin, eyes,
and lungs. A meta-analysis of randomized trials comparing amiodarone to placebo estimated the 1-year risk of
these complications to be 0.6% for hepatic toxicity, 0.3% for peripheral neuropathy, 6 % for hypothyroidism, and
0.9% for hyperthyroidism while the risk of lung toxicity is estimated to be 5-10 % at doses of 400 mg/daily over 5
years or above. Table 2 describes monitoring at initiation and maintenance for AADs including amiodarone.

Dronedarone
Dronedarone is structurally related to amiodarone without the iodine moiety. It has mainly been studied
retrospectively when used for AF patients where patients on dronedarone have lower rates of sustained VA.
Notably, its use is limited due to the lack of randomized controlled trials as well as its contraindication in heart
failure (25).

Class IV
Calcium channel blockers
Nondihydropyridine calcium channel blockers like verapamil and diltiazem are generally contraindicated in most
ventricular tachyarrythmias due to their propensity to cause severe hemodynamic collapse secondary to
hypotension and death (43). In patients with structurally normal hearts, calcium channel blockers have been
shown to reduce outflow tract PVCs. Verapamil can suppress calcium-dependent slow conduction. Fascicular VT
is a unique subtype of VT. It is thought to be a reentrant tachycardia where one of the fascicles is the anterior
limb, thus making it a relatively narrow complex tachycardia. Verapamil is most effective in terminating fascicular
VT as this VT is initiated in a verapamil sensitive slow conducting zone near the His bundle/left bundle region
(44). Partially depressing sodium channel conduction seems to also play a part as lidocaine can slow down and
terminate fascicular VT with variable success. In the 2022 ESC guidelines, it has a class I indication for fascicular VT
and a Class IIa indication for idiopathic VF (14).

Other medications
Ranolazine
Ranolazine is a late Na+ channel blocker but also blocks the delayed rectifier current IKr. With its Na blocking
action, it inhibits DADs, and decreases TDR by decreasing APD in the mid-myocardial cells, while increasing it in
epicardial cells, thus decreasing EADs and reducing the risk of PMVT, especially in LQTS3. The multicenter RAID
trial compared ranolazine to placebo in ICD patients with ischemic and nonischemic cardiomyopathy did not
reduce the composite primary endpoint of ICD-treated VT/VF or Death. However, it did reduce the number of VT
or VF episodes significantly. The study was associated with almost 49 % of patients discontinuing ranolazine
during follow-up while 39 % discontinued placebo (25). In the MERLIN-TIMI study, ranolazine reduced ventricular
arrhythmias when compared to placebo on 7-day Holter monitoring. Its anti-anginal effects may contribute to its
anti-arrhythmic effects as seen in a small study where patients with angina had a better reduction in VA when
compared to patients for whom it was prescribed for its anti-arrhythmic use (45). There is great interest in its role
in two conditions – namely LQTS3 and HOCM. In experimental models, ranolazine reduced QTc interval at all
heart rates in LQTS3 patients with the D1790G mutation (46).

Magnesium and calcium

Magnesium and calcium play a significant role in maintaining proper cardiac rhythm. Magnesium is required for
the functioning of the Na+/K+ ATPase pump. It also interacts with calcium in maintaining low intracellular calcium
levels. Hypomagnesemia leads to higher irritability of cardiac tissue making it more susceptible to arrhythmias.
The classic arrhythmia is TdP and IV magnesium has been used successfully to treat TdP possibly by reducing early
depolarizations. Hypomagnesemia may increase the toxicities of other drugs like digoxin and isoproterenol.
Similarly, calcium acts as a membrane stabilizer and is given in the intravenous form for VT secondary to
hyperkalemia.

Isoproterenol
Isoproterenol or isoprenaline is a beta 1 and beta 2 agonist. It increases heart rate and thus shortens QT interval.
It is used to suppress polymorphic VT and VF in patients with bradycardia and acquired long QT syndrome (14). It
is also used in electrical storm in patients with BrS and SQTs as well as for suppression of polymorphic VT and VF
in patients with acquired long QT syndrome (14).

Challenging existing dogmas

Cardiac imaging including cardiac MRIs and PET scanning have helped better define myocardial scar. It remains to
be seen if Class Ic agents can be used to suppress PVCs in patients who have no scar on cardiac MRI despite
having a history of coronary disease. As shown in Figure 2, coronary artery disease may not always correlate with
a scar. The CAST trial was conducted before the advent of effective thrombolysis, primary PCI, and the remarkable
efficiency of cath lab teams in managing patients with STEMI. There is increasing recognition that though ICDs
have a proven superiority over AADs when compared for the prevention of SCD, they do not improve quality of
life, change ejection fraction or prevent VA. More studies have pointed out a reduction in ICD shocks and VA
burden as a QoL measure versus SCD prevention alone. PVC burden ≥ 24 % has been regarded as a risk factor for
cardiomyopathy based on early studies. However, even PVCs with a lower burden can cause a decrease in
ejection fraction based on their location, coupling interval, and QRS duration which merits early recognition and
treatment. Recognition of long-term side effects of amiodarone has led to a major shift in prevailing concepts
amongst clinicians concerning choosing the right AAD. In the latest ESC Guidelines, it is a Class III drug for the
management of PVCs with normal LV function where catheter ablation and other AADs are the mainstay (14).
Artificial Intelligence (AI) has been recently used to localize PVCs from a 12-lead EKG and newer research may
expand its use in identifying sites as well as grading the lethality of VAs (47). Newer devices have been used to
monitor QTc duration during drug loading and avoid the need for inpatient monitoring as shown in Figure 3 (48).
Despite these developments, there hasn’t been any drug or compound that has been mainstream in the last two
decades. Further work is needed in the development of drugs that can specifically target sites in the cardiac
muscle cell thus avoiding systemic side effects. Recently adeno-associated viruses (AAV) were used to deliver the
gene expressing cardiac calsequestrin (CASQ2) in a murine model with CPVT2 secondary to CASQ2 gene knockout
and mutation and were shown to increase CASQ2 expression resulting in lower VT events (49). Arresting
degradation of CASQ2 by administering bortezomib, a proteasome inhibitor has been shown to lower PVCs in
CPVT2 in a murine model (50).

Conclusions
With the superiority of ICD in the prevention of SCD as well as advances in catheter ablation, the role of AADs in
the management of ventricular arrhythmias has changed over time. They continue to play a key role in the
suppression of VA and in preventing ICD shocks. Though amiodarone continues to be the most used medication
for VA suppression, other drugs like non-selective beta-blockers and class I agents are now increasingly used in
special populations with inherited arrhythmias. Cardiac imaging modalities and AI may help to open new avenues
for the safe and more specialized use of these agents.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any funding for researching this article.
Author Contributions
NA and DKK contributed equally to the manuscript. NA was responsible for drafting the manuscript including
collecting references and making tables and figures. DKK was responsible for review and overall supervision.
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Legends and Captions

Figure 1: Ventricular myocardial action potential and primary actions of common anti-arrhythmic drugs
Figure 2: Cardiac MRI with both four-chambered and short-axis views of a patient with high PVC burden and CAD
with a stent. No LGE was observed on delayed contrast imaging
Legend: MRI: Magnetic Resonance Imaging; PVC: Premature Ventricular Contractions; CAD: Coronary artery
disease; LGE: Late gadolinium enhancement
Figure 3: QTc interval measured by 6 lead EKG using the KardiaMobile® portable monitor
Legend: Reproduced with permission from AliveCor®
Table 1: Classification of anti-arrhythmic drugs using current and proposed classification systems
Vaughan Characteristics Metabolism Dosing Current Use in VA Caution
Drug Williams
Singh Class
(Modernized
Class)
Ivabradine (0) If blocker Hepatic 2.5 mg to 7.5 mg Has been used for Bradycardia,
CYP3A4 twice daily suppression of VT QT
in CPVT prolongation
with other
AADs
Predominantly Sodium Channel Blockers
Quinidine Ia Medium Na blocker with CYP2D6 Sulfate - 200-300 sQTS1, Brugada, Cinchonism,
K+channel blocking mg three to four ERS, ES poor
action times daily availability, QT
Hydroquidine-600- prolongation
900 mg daily
Procainamide Ia Medium Na+ blocker with Acetylation 450-900 mg daily in MMVT Unmask QT
K+channel blocking 2-3 divided doses BrS prolongation,
action Decrease ICD Lupus like
shocks symptoms,
Agranulocytosis
Disopyramide Ia Medium Na+ blocker with CYP3A4 - 250-750 mg daily None for VA Negatively
K+channel hepatic prevention or inotropic, QT
Renal treatment prolongation
excretion
Lidocaine Ib Fast Na+ channel 95 % hepatic Lidocaine- no oral TdP, MMVT and Tremors
Mexiletine blocker CYP3A4 dose. PMVT, VF,
I.V. – 50-200 mg Mexiletine – LQTS3
bolus
Maintenance 1-4
mg/min
Mexiletine – Oral
400 mg followed by
200-400 mg three
times daily
Flecainide Ic Slow Na+ channel CYP2D6 50-150 mg twice PVC suppression Prolong PR,
blocker Renal daily LQT3 QRS
(Class IVb RyR2 Ca2+ Proarrhythmic,
receptor blocker) drowsiness,
headache
Propafenone Ic Slow Na+ channel CYP2D6 200-300 mg three PVC suppression Bronchospasm,
blocker CYP3A4 times daily prolonged PR
(Class IVb RyR2 Ca2+ QRS,
receptor blocker) proarrhythmic
Ranolazine (Id) Late Na+ channel CYP3A4, 500-1000 mg twice Rarely used as 2nd Dizziness,
blocker CYP2D6 daily line for PVCs constipation
Renal Combination
excretion therapy for VT
Drugs affecting receptors of the autonomic system

Beta-blockers II(a) Non-selective (nadolol, Nadolol – Nadolol -40 -120 LQTS1, LQT2, Bradycardia
– nadolol, propranolol) and renal mg daily CPVT may worsen
propranolol, selective(metoprolol)beta excretion Propranolol 80-320 (nadolol, cardiogenic
metoprolol, blockers without mg daily propranolol), PVC shock,
carvedilol unchanged Metoprolol and VT
Propranolol – suppression with
hepatic – other AADs
CYP2D6
 Isoproterenol (IIb) Nonselective Beta Hepatic and 0.5-10 µg/min ES, TdP Tachycardia,
activator lung sudden
MAOI and hypotension,
COMT
Atropine, (IIc) M2 muscarinic blockers Hepatic - I.V. 0.5 to 1.0 mg Not routinely given Dry mouth,
hyoscyamine hydrolysis single dose but reportedly constipation,
reduced VA in AMI confusion
(70)
Digoxin (IId) M2 muscarinic activators P- No data for routine Digoxin toxicity,
Na/K ATPase antagonist glycoprotein use Bidirectional VT
Renal
excretion
Adenosine (IIe) Adenosine A1 blocker In blood Used to Dyspnea, facial
differentiate WCTs. flushing
Not given for (transient)
treatment
Predominantly Potassium channel blockers

Amiodarone III(a) Nonselective K+ blocker Hepatic – Loading dose – PVCs Liver, Thyroid,
Blocks β receptors, CYP3A4 Oral – 600-1200 VT Skin, Corneal
No dose mg/24 hours for 8- VF toxicity, Lung
change in 10 days fibrosis with
renal I.V. – 150 mg IV long-term use.
dysfunction bolus followed by 1 Requires
mg/min infusion for routine
6 hours followed by surveillance
0.5mg/min over 18 with prolonged
hours. use
Maintenance
Oral-200-400
mg/day
I.V. -0.5mg/min
Dronedarone III(a) Nonselective K+ blocker Hepatic 400 mg BID Limited data for use
CYP3A4
Dofetilide III(b) IKr blocker Renal 125-500 mg BID Limited data for use QTc
excretion Renally dosed in VA prolongation
Sotalol III(b) IKr blocker Not Oral - 80-160 mg PVC and VT QTc
metabolized BID suppression prolongation,
Renal Renally dosed bradycardia
excretion I.V. form
Calcium channel blockers
Verapamil IV(a) Calcium channel blocker Hepatic – PVC suppression, Bradycardia,
Diltiazem CYP3A4 CPVT caution in heart
failure
AAD = Anti-arrhythmic drug, AMI = Acute Myocardial Infarction, BrS = Brugada Syndrome, CPVT = Catecholaminergic Polymorphic Ventricular Tachycardia, CYP =
Cytochrome P, COMT = Catechol-O-methyl transferase inhibitors, ERS = Early Repolarization Syndrome, ES = Electrical Storm, LQTS = Long QT Syndrome, MAO =
Monoamine Oxidase Inhibitors, MMVT = Monomorphic Ventricular Tachycardia, PVC = Premature Ventricular Contraction, RyR2 = Ryanodine Receptor 2, sQTS = short QT
syndrome, WCT = Wide Complex Tachycardia, VT = Ventricular Tachycardia, VF = Ventricular Fibrillation,
Table 2: Drug initiation and monitoring
Drug Initiation
Flecainide Baseline EKG and ejection fraction.
Propafenone Baseline BMP
Mexiletine BMP, Liver function test
Baseline EKG to monitor high-degree AV
Block
Sotalol BMP for creatinine clearance, baseline
Dofetilide EKG for QTc monitoring, cessation of QT-
prolonging medications and monitoring for
drug-drug interactions, hospital-based
administration recommended for oral
loading
Amiodarone Baseline EKG, Liver function tests, Thyroid
function tests, lung function testing,
ophthalmological testing
Beta-blockers Baseline EKG, BMP, liver function tests.
Calcium channel blockers Baseline EKG,
Monitoring
EKG with dose escalation to monitor PR
and QRS duration. Consider plasma
levels to monitor toxicity.
Stress testing to rule out underlying CAD
Liver function tests every 6 months. 0.8-
2.0 mcg/mL range for prevention of VA
post MI however side effects are seen at
lower doses. Drug monitoring in liver
disease, dose reduction for other side
effects like paresthesias and tremors
Initiation - EKG 2-3 hours after dose till
4-5 doses. BMP and liver function tests
at 6-12 months. EKG at follow-up.
Consider reinitiating if the drug is
interrupted for more than 5 doses.
BMP, liver function tests and thyroid
function tests every 6 months,
Ophthalmological evaluation every 12
months
Lung function testing for new dyspnea,
HRCT for suspected lung toxicity
EKG at follow-up, routine labs every 6-
12 months
EKG at follow-up