With Left Ventricular Hypertrophy?
Gerald V. Naccarelli MD 1
Peter R. Kowey MD 2
From: Penn State University College of Medicine
Penn State Heart and Vascular Institute.
The Milton S. Hershey Medical Center
Hershey, Pa, USA (1)
And
Lankenau Heart Institute
Wynnewood, Pa, USA
And
Thomas Jefferson University
Philadelphia, Pa, USA (2)
Running Title: Antiarrhythmic Drugs in Left Ventricular Hypertrophy
Key Words: Antiarrhythmic Drugs; Atrial Fibrillation; Left Ventricular
Hypertrophy
Total Word Count: Editorial (1013) and with references (1787)
Corresponding Author:
Gerald V. Naccarelli MD
Penn State University College of Medicine
Penn State Hershey Heart & Vascular Institute
500 University Drive, Room H1511
Hershey PA 17033
Phone: 1-717-531-3907
Fax: 1-717-531-4077
ORCID#: 0000-0001-8196-4554
gnaccarelli@penntatehealth.psu.edu
Potential Conflicts; Gerald V. Naccarelli MD (Consultant: Milestone,
Sanofi, InCarda Therapeutics, Acesion, Glaxo Smith Kline); Peter R.
Kowey MD (Consultant: Sanofi, Acesion, InCarda Therapuetics)
Left ventricular hypertrophy (LVH) occurs commonly in cardiac and
hypertensive patients and those with structural heart disease and is
associated with an increased risk of atrial fibrillation (AF),
ventricular arrhythmias and sudden death (1,2). Over the years,
guidelines have cautioned against using class III antiarrhythmic drugs
in patients with LVH due to a presumed increased risk of torsade de
pointes and death (3). This concern was based on electrophysiological
studies demonstrating that hypertrophied cells have longer action
potentials and are more likely to develop phase 2 after-depolarizations
that could trigger a ventricular tachyarrhythmia (4-6). In contrast,
Gillis et al (7) reported that an increased dispersion of ventricular
action potential duration occurs in the rabbit model of LVH and that
dofetilide did not significantly increase action potential duration in
hypertrophied versus control hearts. In a cat model study of LVH, Kowey
et al (8) reported that blockade of the voltage dependent potassium
current, but not the slow inward calcium current, narrows the dispersion
of recovery of excitability and could protect against the development of
ventricular fibrillation.
Clinical trials and real-world data have reported findings that are less
concerning. In this issue, Wann et al (9) report on a retrospective
analysis of 359 patients with AF and LVH > 1.4 cm.
treated with dofetilide compared to a propensity matched control group
without a history of antiarrhythmic drug therapy. In this study, 32% of
patients treated with dofetilide had LV wall thickness >
1.5 cm. The primary outcome of all-cause mortality occurred in 7% of
dofetilide patients versus 12% in the control group (pNS) over a 3
-year follow-up period. Total all-cause hospitalizations were higher in
the control group (p =0.005), but AF hospitalizations were similar.
These data are consistent with Abraham et al (10) in which dofetilide
caused torsade de pointes in 5/429 (1.1%) with LVH and 12/958 (1.2%)
without LVH.
Given theoretic concerns that LVH increases the dispersion of
refractoriness and the fact that class III antiarrhythmic drugs, such as
dofetilide and sotalol, prolong the QT interval, guidelines have not
recommended the use of these drugs and have favored drugs such as
amiodarone and dronedarone (11). However, Chung et al (12) reported that
amiodarone was associated with a lower survival compared to
non-amiodarone drugs such as the class IC agent’s flecainide and
propafenone.
Complicating these recommendations is that the guideline definition of
LVH started arbitrarily at > 1.4 cm. then moved to> 1.5 cm. without any data to support the initial
recommendation or change. Newer guidelines have left the definition of
meaningful LVH as undefined. Fortunately, most patients treated with
antiarrhythmic drugs with LVH by echocardiographic criteria have LV wall
thicknesses less than 1.4 cm. The complexity of the defining LVH by
echocardiographic criteria has been well-documented and can include LV
mass measurements in addition to LV wall thickness (13). To complicate
things further, LV remodeling can occur. LVH can be present with or
without coronary artery disease, electrolyte disturbances and clinical
heart failure all of which increases the risk of ventricular
arrhythmias. In all patients with hypertension and LVH, strict control
of blood pressure may lead to regression of LVH and atrial and
ventricular arrhythmias and is an important part of the treatment of
such patients (14).
A small case series of patients with hypertrophic cardiomyopathy,
treated with dofetilide, that demonstrated no significant proarrhythmia
(15) support Wann’s findings. More relevant risk factors for torsade de
pointes during dofetilide dosing include overdosing, renal function,
systolic heart failure, female gender, QTc prolongation from baseline,
hypokalemia, or hypomagnesemia (10).
We conclude that antiarrhythmic agent choice does not have to be altered
in patients with LVH except in patients with the distinct syndrome of
hypertrophic cardiomyopathy, for whom more data are needed. Large
clinical trials, such as ATHENA, have been helpful in collecting data in
patients with hypertension and LVH (16). Antiarrhythmic choice should
follow guideline recommendations based on the absence or presence of
structural heart diseases, ischemic heart disease and systolic heart
failure although the overuse of amiodarone ignoring guideline
recommendations continues to be an issue (17). Antiarrhythmic drugs with
a minimal risk of causing torsade de pointes, such as dronedarone and
amiodarone, continue to have a role is such patients.
There is little evidence that class IC and III antiarrhythmic drugs
should be excluded in such patients. Furthermore, in patients without
other evidence of structural heart disease, class IC drugs are safe and
effective (18). The DIAMOND-HF trial demonstrated that dofetilide has
neutral effects on mortality in systolic heart failure patients (19).
Recent data reported that dofetilide was as effective as amiodarone in
suppressing AF recurrences (20). Dofetilide and sotalol can be used with
caution in patients with LVH with inpatient telemetry to monitor for any
proarrhythmic activity. Other pharmacologic principles such as avoiding
important drug interactions, dosing based on food effects and renal
function, and maintaining electrolytes in the normal range all have
importance.
We believe that antiarrhythmic drug choices should not be limited by
inference or extrapolation. Careful patient and antiarrhythmic drug
selection, based on validated clinical trial data, will permit the use
of a wider variety of drugs to treat arrhythmias that plague our
patients with LVH.