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\begin{document}

\title{Reply to ``Pro-arrhythmia with Anti-arrhythmic Drugs in Patients with
Idiopathic Ventricular Arrhythmia: A Common Problem with Vague
Definitions and Complex Interactions''}



\author[1]{Jacky Tang}%
\author[1]{Marc Deyell}%
\affil[1]{University of British Columbia}%


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  \date{May 24, 2024}


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Title: Reply to ``Pro-arrhythmia with Anti-arrhythmic Drugs in Patients
with Idiopathic Ventricular Arrhythmia: A Common Problem with Vague
Definitions and Complex Interactions''

Jacky K. K. Tang MD\textsuperscript{1} and Marc W. Deyell MD
MSC\textsuperscript{1,2}

Heart Rhythm Services, Division of Cardiology, University of British
Columbia

Centre for Cardiovascular Innovation, University of British Columbia

Word Count: 538 (including references)

Address for correspondence:

Dr. Marc William Deyell

Heart Rhythm Services, St. Paul's Hospital

200 -- 1033 Davie St.

Vancouver, B.C., Canada, V6E 1M7

Phone: 604-806-8256; Fax: 604-806-8723

Email: mdeyell@mail.ubc.ca

@MarcDeyell

Competing Interests: Dr. Deyell reports research grants from Biosense
Webster and honoraria from Biosense Webster, Medtronic and Abbott.

Funding: This work was supported by the UBC Division of Cardiology
Academic Practice Plan.

Drs. Hasdemir and Payzin have cogently brought up one of the primary
challenges in studying patients with frequent premature ventricular
complexes (PVCs) and evaluating the impact of therapy. They highlight,
based on their prior study,(1) that a group of patients may actually
experience a significant increase in PVC burden (\textgreater{}50\%)
with medical therapy, which obviously raises concerns that this may
enhance deleterious effects of PVCs, particularly in the long term.

With the advent of ambulatory monitoring, it was recognized early that
PVC burden could be highly variable, leading to measurement error when
using a 24-hour monitor. This error is highest when performing
before-and-after studies of the effect of intervention on PVC burden,
using single monitoring periods of 24 hours prior to and after
intervention. In particular, spontaneous reductions in PVC burden can
overestimate treatment effects. This error can be minimized in two ways,
through serial monitoring (repeated measures) or longer-term monitoring
(\textgreater{}48h). Indeed, an elegant study by Dr. Mullis and
colleagues, using 14 day patch monitors, showed a median absolute
day-to-day fluctuation in PVC burden of almost 10\% among patients with
a high burden of PVC.(2) Thus, an apparent ``pro-arrhythmic'' effect of
a medication may simply reflect inefficacy and expected variation in PVC
burden.

In our prior work,(3) published in this journal and referenced by Drs.
Hasdemir and Payzin, we were also limited by using only 24-hour
ambulatory monitors to assess PVC burden. However, we did include a
control group on no medical therapy, to mitigate the effect of
measurement error, by obtaining an estimate of variation in PVC burden
in the absence of therapy. In our study, we observed a ``pro-arrhythmic
effect'' (\textgreater{}50\% increase in PVC burden), in 2.5\% (1/40) of
patients on no medical therapy, 7.5\% (4/53) on beta blockers/calcium
channel blockers and 11.1\%\% (3/27) on class I/III antiarrhythmic
therapy. Despite the trend, these were not significantly different
(p=0.28 and p=0.14 for beta blocker/calcium channel blocker and class
I/III antiarrhythmics versus no therapy).

This does not negate a potential pro-arrhythmic effect of medical
therapy in a minority of patients. However, more definitive proof of a
pro-arrhythmic effect, distinguishing this from spontaneous variation in
PVC burden, would require demonstration of a decrease in PVC burden with
cessation of therapy. This would best be accomplished with a blinded,
cross-over trial design.

Drs. Hasdemir and Payzin remind us to always critically assess, and
reassess, our therapies for patients with frequent PVCs. We must always
evaluate whether treatment is warranted (in the majority of cases it is
not), and whether patients are at risk for adverse events, particularly
from class I and III antiarrhythmics. Frequent PVCs make physicians
uncomfortable but we should not rush to treatment and expose patients to
unnecessary harm.

References:

1. Turan OE, Aydin M, Odabasi AY, Inc M, Payzin S, Hasdemir C.
Therapeutic Inefficacy and Proarrhythmic Nature of Metoprolol Succinate
and Carvedilol Therapy in Patients With Idiopathic, Frequent,
Monomorphic Premature Ventricular Contractions. Am J Ther
2021;29:e34-e42.

2. Mullis AH, Ayoub K, Shah J et al. Fluctuations in premature
ventricular contraction burden can affect medical assessment and
management. Heart Rhythm 2019;16:1570-1574.

3. Tang JKK, Andrade JG, Hawkins NM et al. Effectiveness of medical
therapy for treatment of idiopathic frequent premature ventricular
complexes. Journal of Cardiovascular Electrophysiology
2021;32:2246-2253.

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