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JACC Vol . 14, No . I

July 1 8 1 2-3

Editorial Comment

Flecainide for Pediatric

Arrhythmias Do Children
Behave Like Little Adults?*
ANDREW E . EPSTEIN, MD, FACC
Birmingham, Alabama

Flecainide acetate is approved for the treatment of lifethreatening ventricular arrhythmias in adults . Although recognized as effective treatment for supraventricular arrhythmias, it has not received approval for this indication .
Furthermore, the package insert warns that the safety and
efficacy of flecainide in children < 18 years old has not been
established . Thus, Perry et al . (1) have advanced our understanding of the drug's usefulness and pharmacology . Of the
63 patients studied, 5 were !518 years old . Particularly
gratifying responses were seen in the treatment of the
permanent form of junctional reciprocating tachycardia,
atrial ectopic tachycardia and chaotic atrial tachycardia .
Eighteen of 25 patients with accessory connections achieved
either full or partial control of their arrhythmia . A remarkable 100% responsiveness was seen in the 10 patients with
ventricular tachycardia . Not only did the drug prove efficacious, but also it was remarkably devoid of adverse drug
effects including the precipitation of life-threatening proarrhythmic events and congestive heart failure .
How are children different from adults? Garson (2) has
called attention to important changes of the autonomic
nervous system, gastric secretion, gastric motility, protein
binding and drug metabolism that occur during maturation .
Furthermore, the mechanisms and substrates of arrhythmias, and therefore drug responsiveness, differ in children
and adults . For example, atrial tachycardia caused by abnormal automaticity occurs commonly in children (3) but
only rarely in adults (4) . Whereas ventricular tachycardia in
children is often idiopathic (5,6) or caused by cardiac tumors
(7) and congenital heart disease (8), coronary artery disease
is by far the most common underlying substrate in older
patients .
Perry et al . (1) have reiterated Garson's prior suggestion

*Editorials published in Journal of the American College of Cardiology

reflect the views of the authors and do not necessarily represent the views of
JACC or the American College of Cardiology .
From the Division of Cardiovascular Disease, Department of Medicine,
University of Alabama at Birmingham, Birmingham, Alabama .
Address for reprints Andrew E . Epstein, MD, Division of Cardiovascular
Disease, Department of Medicine, Tinsley Harrison Tower . Room 321L,
University of Alabama at Birmingham, Birmingham . Alabama 352 4 .
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by the American College of Cardiology

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(2) that drug dosages be based on the adult dose normalized

for body surface area . This recommendation is founded on
observations that the intestinal surface area, total body
water, cardiac output, hepatic blood flow and renal function
all influence serum drug levels and each also varies directly
with the body surface area . Nevertheless, Perry et al . show
that a wide range of flecainide dosage regimens (5 to 225
mg/m 2 per day) were required to achieve therapeutically
effective serum trough levels even though dosing was based
on scaled down adult doses . Measurement of serum levels of
flecainide is therefore important to evaluate drug doses in
children .
A notable difference between children and adults in this
series is the low incidence of proarrhythmia . Indeed, it was

seen only in individuals with accessory atrioventricular

connections, and no life-threatening proarrhythmia occurred
in any patient . Furthermore, because these patients presumably had normal left ventricular function, the absence of
proarrhythmia in the study patients with left ventricular
dysfunction is of even more interest . Adult cardiologists
have learned that adverse cardiac events from flecainide are
related to both the type of ventricular arrhythmia being
treated ( ) and the degree of underlying left ventricular
dysfunction (10) . One explanation for the absence of lifethreatening proarrhythmia or of heart failure observed by
Perry et al . (I) is that few of their patients had left ventricular
dysfunction . Most had supraventricular tachycardia and 8 of
the 10 patients with ventricular tachycardia had well preserved left ventricular function . Thus, the relative safety of
flecainide observed by Perry et al . should not lull clinicians
into complacency when treating children who have lethal or
potentially lethal arrhythmias with this drug, especially if left
ventricular dysfunction is present . In addition, the responsiveness of the one child with a suspected myocardial
hamartoma should not be construed to suggest responsiveness in all such patients, as the authors warn in their
discussion .
How should efficacy be assessed? Perry et al . (1) report
that the mean flecainide trough levels in patients with full
and partial arrhythmia control were 0 .36 and 0 .41 Ag/ml,
respectively, which are somewhat lower than the target
levels often used in the treatment of adult patients . It must
be recognized, however, that previously reported therapeutic ranges were usually determined during treatment of
adults with ventricular rather than supraventricular arrhythmias . Because the majority of the young patients treated by
Perry et al . had the latter type of arrhythmia, direct comparison is difficult . Furthermore, Woosley (11) has wisely
warned that use of the term "therapeutic range" may be
misleading because there is great variability in the blood
concentration required for drug efficacy and that the deter0735-10 7/8 /$3 .50

JACC Vol . 14 . No . I
July 1 8 1 2-3

mination of efficacy should be measured in conjunction with

the patient's clinical response, electrocardiographic (ECG)
monitoring, exercise testing and programmed stimulation .
For patients with arrhythmias that are not life-threatening .
ECG and ambulatory monitoring techniques are particularly
appropriate . Because flecainide causes important widening
of the PR and QRS intervals (1), the ECG is useful to assess
when electrophysiologic effects are occurring (12) . By virtue
of its noninvasive nature . noninvasive monitoring is particularly attractive for the follow-up of young patients .
How desirable is long-term drug therapy for young patients? Especially for the young . commitment to long-term
drug therapy may be less desirable than a curative procedure . For many arrhythmias, ablation by either catheter or
surgical techniques is especially effective . Catheter ablation
has been used to treat ventricular tachycardia (13), reentrant
atrioventricular tachycardia utilizing both right- and leftsided accessory connections (14), atrial tachycardia (15) and
most recently bundle branch reentrant (16) and atrioventricular nodal reentrant (17) tachycardias . However, surgery is
especially effective in the treatment of supraventricular
arrhythmias mediated by accessory connections and should
be considered in young patients as an alternative to longterm drug therapy . Commitment to long-term amiodarone
usage certainly must be considered a less optimal treatment
modality in view of the complications that occur during
long-term use of this agent .
New areas for research . The long-term efficacy of the
treatment of young patients with flecainide is unknown . As
Perry et al . (1) state, further investigation of the pharmacokinetics of flecainide is needed, especially in children < I
year of age . Furthermore, because age alters pharmacokinetics, a "therapeutic" dosage at one age may not provide
long-term efficacy if absorption, metabolism and distribution
also change with maturation . One special area of interest will
be the use of flecainide in young patients with left ventricular
dysfunction due to rate-related cardiomyopathies . In these
individuals, drug therapy could potentially be used as a
bridge to achieve either full or parital arrhythmia control and
thereby allow improvement of left ventricular dysfunction
and later surgical cure with lower risk due to improved
hemodynamics . However, the risk of flecainide use in patients with overt heart failure cannot be advised . Finally, the
development of new drugs with a longer half-life, wider
dosing interval and less toxicity will be welcomed .
Conclusions . Given the difficulty of performing clinical
investigations in young patients because of the problems of
consent, compliance and changing pharmacokinetics with
age, Perry et al . (1) are to be commended for their careful

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EPSTEIN
EDITORIAL COMMENT

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study . Their work not only extends prior studies by demonstrating the usefulness of flecainide in the treatment of both
supraventricular and ventricular arrhythmias in young patients, but also provokes interesting questions for further
study in arrhythmia treatment of these individuals .

References
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