US Pharm. 2014;39(5):47-51.
ABSTRACT: Long QT syndrome (LQTS), in which cardiac repolarization
is delayed following a heartbeat, can be measured by ECG. Universal ECG
screening is not standard practice in the United States, and many
children with congenital LQTS go undiagnosed. LQTS creates an
electrophysiological environment that favors the development of serious
ventricular dysrhythmias. Pharmacist awareness is important because
drugs can play a major role in exacerbating underlying LQTS or causing
acquired LQTS. Common symptoms of LQTS include fainting spells, heart
palpitations, and seizures. Most importantly, LQTS is a major risk
factor for ventricular arrhythmias, which can quickly deteriorate,
leading to cardiac arrest and sudden cardiac death.
Long QT syndrome (LQTS), a heart condition in which cardiac
repolarization is delayed following a heartbeat, can be detected by
measuring the QT interval on an ECG. A long QT interval creates an
electrophysiological environment that favors the development of
life-threatening, prolonged ventricular dysrhythmias. Because drugs can
figure significantly in the development of symptoms in patients with
LQTS, pharmacist awareness is important. Common manifestations are heart
palpitations, fainting spells, and seizures. Sudden cardiac death
(SCD), to which LQTS is a major contributor, is estimated to occur in as
many as 6.2 of 100,000 children per year.1 SCD also accounts
for 50% of all adult deaths from cardiovascular (CV) disease, with 80%
to 85% of cases caused by acute ventricular arrhythmias.2
Given many recent FDA warnings about drugs that can prolong the QT
interval and potentially increase the risk of ventricular dysrhythmias,
it is becoming increasingly more important for pharmacists to heighten
their awareness of this condition in order to help patients use their
medications safely and effectively.3,4
The QT Interval and LQTS
The QT segment of the larger PQRST(U) complex of the ECG represents
the duration of ventricular depolarization and subsequent repolarization
(i.e., the heartbeat). A heart with a rate of 60 bpm beats an average
of once per second; or, as depicted on an ECG, the rhythm repeats every
1,000 msec. LQTS is typically diagnosed by the measurement (and
mathematical correction) of an extended QT interval on an ECG. FIGURE 1
demonstrates, in simplified fashion, how a prolonged QT interval may
appear on a single lead of an ECG. Measurement can be affected by many
factors, including which lead is used and what is determined to be the
exact end of the T wave. On a 12-lead ECG, the lead showing the longest
QT interval is the most sensitive for making the calculation. A newer,
more sophisticated, and perhaps more sensitive and specific approach for
the detection of acquired and congenital long QT syndrome is to apply
the root mean square ECG.5 This newer method has yet to become the standard of practice.
Most clinicians consider a corrected QT interval (QTc) of >440
msec for males and >450 msec for females to be prolonged. As the
heart rate increases, the QT interval shortens. Therefore, it is
important to calculate QTc in patients with elevated heart rates so that
the QT interval is not underestimated. In the absence of provoking
factors (e.g., QT-prolonging drugs), a QTc >470 msec in males and
>480 msec in females is suggestive of LQTS. Patients with a QT
interval longer than normal, whether it is borderline (440-470 msec in
males and 450-480 msec in females) or suggestive of LQTS, should undergo
repeat or additional diagnostic testing.6
The Impact of LQTS
LQTS, hypertrophic cardiomyopathy, and Wolff-Parkinson-White syndrome
are the most common causes of SCD in children that can be detected by
ECG. Universal ECG screening is not standard practice in the United
States, so many children with congenital LQTS are not diagnosed.7 LQTS may be inherited or acquired. Acquired LQTS, which is usually drug-induced, is more common than inherited LQTS.2
The prevalence of inherited LQTS in the U.S. is estimated to be one in 2,000 to 2,500 live births.2
It is unknown precisely how many deaths are caused by the acquired form
or what is the exact risk of developing LQTS after taking a drug, since
these factors are unpredictable and have not been thoroughly
researched; however, a decade ago, the single most common reason for FDA
withdrawal of a prescription drug from the market was the associated
risk of QT-interval prolongation.8 Many individuals with
inherited LQTS are asymptomatic, and the condition is often discovered
incidentally upon ECG or after an episode has occurred. Subtypes of
inherited LQTS are caused by mutations in the genes that encode for
cardiac ion channels (TABLE 1).9 Individuals with
inherited LQTS may remain asymptomatic for a lifetime, or they may
experience symptoms from as early as the first months of life to as late
as middle age.2
LQTS can be detected in children through ECG, although widespread
routine screening in asymptomatic patients is not currently recommended
in the U.S.7 The prognosis for untreated patients presenting
with syncope is a 20% chance of death after 1 year, and a 50% chance
within 10 years. In symptomatic patients, episodes may be brought on by
QT-prolonging drugs, ill-advised drug doses or combinations, physical
activity such as swimming, or being startled; an episode may even occur
Screening for LQTS
As of early 2014, only one country worldwide was found to require
universal ECG screenings. For more than 25 years, Italy has mandated
medical screening for any individual wishing to participate in
competitive sports. This screening includes personal and family history,
physical examination, and resting and exercise 12-lead ECG for
detecting cardiovascular (CV) abnormalities that would put a person at
risk for ventricular arrhythmias.10
Universal screening for phenylketonuria, which has an estimated
prevalence of one per 10,000 to one per 12,000 live births, is
recommended for newborns in the U.S.11 When phenylketonuria
prevalence is compared with that of congenital LQTS (one in 2,000-2,500
live births), it would appear reasonable to adopt universal screening
for LQTS. However, factors other than prevalence—like the sensitivity
and specificity of ECG or other screening tests—also must be considered.
A recent meta-analysis estimated that, at the maximum accuracy point,
the number needed to screen to detect one case of LQTS by ECG exceeded
16,000.7 However, at this accuracy point, 14% of patients who
actually had LQTS were missed (false-negatives), and more than 2,000
false-positives (for each true positive) were detected. Since the
specificity was low (high rate of false-positives), if the maximum
specificity point were to be used instead of maximum accuracy,
false-positives could be reduced to 135 for each true LQTS case
detected, but the number needed to screen to detect one case would
increase to 135,000, and 91% of cases would be missed.6 Therefore, it is understandable why universal screening has not been implemented in the U.S.
Screening Prior to Initiating Certain Drugs
In 2008, the American Heart Association (AHA) released a statement
recommending that screening be performed prior to initiation of
stimulant therapy in children with attention-deficit/hyperactivity
disorder (ADHD). Shortly thereafter, the American Academy of Pediatrics
(AAP) released a joint statement with the AHA recommending that children
with ADHD be assessed with a targeted history and cardiac examination,
but that an ECG should be performed only if indicated. A recent study,
however, found that only 48% of more than 800 pediatricians completed an
in-depth cardiac history and physical, and that only 14.7% ordered an
ECG prior to initiating stimulant therapy.12 Most recently,
the AAP has withdrawn recommendations for pretreatment ECG screening,
except for medications that clearly heighten the risk of ventricular
arrhythmias.13 Presumably, this exception refers to drugs that are contraindicated in LQTS patients.
Warnings Issued and Actions Taken
Recent warnings have been issued by the FDA to inform practitioners about CV risks associated with certain medications.3,4
Unfortunately, these warnings come with no recommendations on how to
assess risk, instead simply advising that patients discuss any questions
or concerns with their healthcare provider. This leaves healthcare
practitioners, and particularly pharmacists, in a quandary about how to
incorporate information on CV risks into clinical practice. There are a
number of questions that could logically be asked: Is there a way to
screen or risk-stratify to determine who is at higher risk for
developing a life-threatening ventricular arrhythmia? Have the risks of
significant QT prolongation and the corresponding development of
ventricular dysrhythmia been quantified? Has a clinically significant
degree of QT prolongation been defined? Should healthcare practitioners
routinely require ECG before initiating certain medications?
Now that all new drugs must undergo QT-prolongation studies prior to
FDA approval, the FDA has formalized 10-msec QT prolongation as the
threshold for regulatory concern.14 It is common for drugs to
evoke a dose-response relationship according to the degree of
QT-interval prolongation. For example, it is well established that class
III antiarrhythmics cause QT prolongation by extending the duration of
cardiac-action potential. The best example is sotalol, which is
classified as both a class II and a class III antiarrhythmic. Sotalol,
which has been studied in children for treatment of supraventricular and
ventricular arrhythmias at three different body-surface area–based
doses (10, 30, and 70 mg/m2), demonstrated both dose-related and body type–related differences in QT prolongation.15
This knowledge, as well as new information on several drugs, has led
the FDA to restrict certain drugs to new maximum doses, apparently
targeting their established 10-msec threshold (TABLE 2).
FDA actions against drugs that prolong the QT interval have included reducing the maximum dose (TABLE 2), withdrawing the drug from the market (TABLE 3), and labeling the drug as contraindicated in patients with LQTS (TABLE 4).14,16,17
The maximum dose of citalopram has been restricted to 20 mg in patients
who slowly metabolize citalopram by the isoenzyme CYP2C19, whether due
to genetics (i.e., poor CYP2C19 metabolization) or to a drug interaction
(i.e., concurrent use with a CYP2C19 inhibitor, such as omeprazole).18
The FDA issued a warning in response to a 2012 study that reported
increased CV mortality with azithromycin versus amoxicillin use.19,20
The azithromycin label has been updated with a brief statement on
azithromycin’s propensity to prolong the QT interval at doses of 500,
1,000, and 1,500 mg. The FDA noted that azithromycin can cause abnormal
changes in the heart’s electrical activity that may result in a
potentially fatal irregular heart rhythm, and that patients with known
risk factors (e.g., existing QT-interval prolongation, low potassium or
magnesium blood levels, slower-than-normal heart rate, or the use of
certain drugs that treat abnormal heart rhythms) are at greater risk for
developing this condition.20
Assessing Drug-Induced Ventricular Dysrhythmia Risk
On a per capita basis, U.S. residents appear to be the world’s
foremost consumers of healthcare services. Per capita healthcare costs
in the U.S. exceed the median per capita costs of 11 comparator nations
by 250%, and those of the nearest comparator by 150%.21 Given
recent warnings about citalopram doses and drug interactions, as well
as long-standing precautions about arrhythmias from trazodone and
tricyclic antidepressants, it is noteworthy than between 2005 and 2008,
11% of Americans aged 12 years and older were taking an antidepressant.4,21
It is widely acknowledged that all medications are associated with
risks—many that are known, but also a great number that are unknown or
debated. Since only drugs approved by the FDA in the last decade or so
have been required to undergo QT-prolongation testing as a part of the
New Drug Application, it is not necessarily known whether some older
drugs may prolong the QT interval.
Over the last few years, the FDA has issued CV warnings for a variety
of drugs in the form of black box warnings, letters to healthcare
professionals, alterations in prescribing information, and even
restricted access to certain drugs. This has required changes in
practice, sometimes before the availability of sufficient or convincing
data. The FDA’s premature action against rosiglitazone (proposed
association with myocardial infarction), followed by the recent removal
of this restriction once better evidence became available, serves as a
potent recent reminder of this agency’s reactive tendency.
Treatment and Management
LQTS treatment may include medications, medical devices or surgery,
or simple lifestyle changes. In most cases, patients are advised to
avoid the specific triggers that usually precede an event, but if this
is inadequate for symptom control, medication may be necessary. Since
sleep and startle are precipitating factors for ventricular arrhythmias
in patients with LQTS (depending on LQTS type), some triggers cannot be
easily avoided. Beta-adrenergic receptor antagonists (i.e.,
beta-blockers) are the most common class of medications used to manage
LQTS symptoms. If needed, a defibrillator, which can deliver an
electrical shock in order to restore heart rhythm, may be surgically
implanted in the chest. For patients who continue to have symptoms while
on beta-blockers or who otherwise appear to be at risk for
life-threatening arrhythmias, left cardiac sympathetic denervation is
Pharmacists are placed in a challenging situation when assessing or
explaining the risks and associated warnings for drugs that modestly
prolong the QT interval. Without a standardized screening program for
LQTS in the U.S., pharmacists might be expected to presuppose that any
given patient could be the estimated one in 2,500 who is predisposed to a
prolonged QT interval. Despite the FDA’s warning, azithromycin
obviously continues to have an important role in treating certain
infections (especially pertussis) in the pediatric population. For a
drug (or drug dose) known to significantly prolong the QT interval, and
especially for a drug known to be associated with the risk of
ventricular arrhythmias, the pharmacist should recommend both baseline
and follow-up ECGs, or at least investigate whether an ECG has ever been
performed in the patient. If this information is not available, it may
be useful to ask the patient about signs of LQTS (e.g., syncope) or
family history of sudden cardiac death, although these screening
questions probably lack sufficient sensitivity and specificity.
Despite the poorly quantified (or even qualified) risk, pharmacists
should be cautious and abide by maximum dose recommendations, avoid bad
drug combinations, and help guide therapy toward alternatives to
QT-prolonging agents when equally cost-effective therapeutic agents are
available. Pharmacists can also monitor for some of the milder symptoms
of LQTS, especially in patients taking QT-prolonging drugs, and refer
the patient to an appropriate healthcare practitioner if there is any
suspicion of ventricular arrhythmias.
1. Gajewski KK, Saul JP. Sudden cardiac death in children and adolescents (excluding Sudden Infant Death Syndrome). Ann Pediatr Cardiol. 2010;3:107-112.
2. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70:16-23.
3. FDA. FDA Drug Safety Communication: new information regarding QT
prolongation with ondansetron (Zofran).
www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Accessed January 30, 2014.
4. FDA. FDA Drug Safety Communication: revised recommendations for
Celexa (citalopram hydrobromide) related to a potential risk of abnormal
heart rhythms with high doses.
www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed January 30, 2014.
5. Lux RL, Sower CT, Allen N, et al. The application of root mean
square electrocardiography (RMS ECG) for the detection of acquired and
congenital long QT syndrome. PLoS One. 2014;9:e85689.
6. SADS Foundation. Long QT syndrome. www.sads.org/library/long-qt-syndrome. Accessed January 30, 2014.
7. Rodday AM, Triedman JK, Alexander ME, et al. Electrocardiogram
screening for disorders that cause sudden cardiac death in asymptomatic
children: a meta-analysis. Pediatrics. 2012;129:3999-1010.
8. Roden DM. Drug-induced prolongation of the QT interval. New Engl J Med. 2004;350:1013-1022.
9. ClinicalTrials.gov. Efficacy study of sodium channel blocker in
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January 30, 2014.
10. Sofi F, Capalbo A, Pucci N, et al. Cardiovascular evaluation,
including resting and exercise electrocardiography, before participation
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11. Koch RK. Issues in newborn screening for phenylketonuria. Am Fam Physician. 1999;60:1462-1466.
12. Leslie LK, Rodday AM, Saunders TS, et al. Cardiac screening prior
to stimulant treatment of ADHD: a survey of US-based pediatricians. Pediatrics. 2012;129:222-230.
13. Perrin J, Friedman R, Knilans TK. Cardiovascular monitoring and
stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics. 2008;122:451-453.
14. FDA. ICH E14 Step 2: The Clinical Evaluation of QT/QTc Interval
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.
Accessed January 30, 2014.
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16. CDER 2005 Report to the Nation: Improving Public Health Through Human Drugs. Rockville, MD: Food and Drug Administration; 2005.
17. Clinical Pharmacology [subscription database]. Drugs absolutely
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Accessed January 30, 2014.
18. Celexa (citalopram hydrobromide) product information. St. Louis, MO: Forest Pharmaceuticals, Inc; November 2013.
19. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890.
20. FDA. FDA Drug Safety Communication: azithromycin (Zithromax or
Zmax) and the risk of potentially fatal heart rhythms.
www.fda.gov/drugs/drugsafety/ucm341822.htm. Accessed April 2, 2014.
21. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS Data Brief. 2011;76:1-8.
22. National Heart Lung and Blood Institute. Long QT syndrome.
January 30, 2014.
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