The QT interval is an electrocardiogram representation
of ventricular depolarization and repolarization. It is measured from the start
of the QRS complex until the T wave termination on ECG. Because heart rate can
affect the QT interval the QT interval lengthens with bradycardia and
shortens with tachycardia it is recommended to calculate a corrected QT
The length of the corrected QT (QTc) interval has many
factors, including electrolyte abnormalities, a diurnal effect, race, autonomic
fluctuations, ECG variability and human error. Medications can also cause a
prolongation of the QTc interval. Most commonly, medications, through various
mechanisms, block the potassium rectifying current (the efflux of K causing the
repolarization of the cardiac tissue). This causes a delay in rapid
repolarization of the cell and, thus, increases the action potential duration.
This increase in the duration of the action potential is reflected as the
prolonged QTc interval in the ECG reading. QTc prolongation is one of the most
common reasons drugs are removed from the market or restricted.
Patients who experience a prolonged QTc interval are at
risk for developing torsade de pointes (torsades). Torsade de pointes is a
ventricular tachycardia that is characterized by fluctuation of the QRS
complexes around the electrocardiographic baseline. Torsades is a
life-threatening arrhythmia, but not every patient who has a prolonged QTc
develops torsades. Patients are more likely to experience a torsades event if,
before their QTc prolongation, they have risk factors for drug-induced QTc
prolongation. These risk factors include female sex, structural heart damage
(myocardial infarction, heart failure, valvular disease or cardiomyopathy),
hypokalemia, multiple QT prolonging drugs or agents, prolonged baseline QTc
(>450 ms), family history of congenital QTc prolongation and prior
drug-induced torsades. Risk factors for drug-induced prolonged QTc put patients
at higher risk for developing torsades if they have a prolonged QTc interval.
QTc intervals of less than 440 ms are considered to be
normal in healthy patients. QTc intervals of 440 ms to 460 ms in men and 440 ms
to 470 ms in women are considered borderline.
Anthracycline chemotherapy has been associated with ECG
alterations, including decreased QRS voltage; ST-T wave changes; prolongation
of the QTc interval; development of ventricular late potentials; and various
arrhythmias. Risk factors that have been identified for developing cardiac
toxicity while on anthracycline therapy include cumulative dose; age, heart
irradiation; concomitant use of other cardio-toxic drugs; and underlying
cardiac disease. Cardiac cells have a decreased amount of antioxidant enzymes,
and it is hypothesized that this leaves cardiac tissue more vulnerable to free
radicals formed by anthracyclines causing cardiac cell death.
5-FU has had cardiac toxicity associated with its
administration as a continuous infusion. This agent has very few risk factors
for cardiac toxicity, including a history of coronary disease and irradiation.
The mechanism of cardiac toxicity has not yet been established.
Arsenic trioxide, used in the treatment of acute
promyelocytic leukemia, has a very high incidence of QTc prolongation but low
rate of torsades occurrence. Arsenic blocks the K repolarization and also
causes reduced expression of cell surface K channels. Despite the high
incidence of increased QTc interval, the low incidence of torsades may be
explained by the drugs activation of a K-ATPase, which promotes
Sunitinib (Sutent, CPPI CV), dasatinib (Sprycel,
Bristol-Myers Squibb), vandetanib (IPR Pharms), sorafenib (Nexavar, Bayer),
lapatinib (Tykerb, SmithKline Beecham) and nilotinib (Tasigna, Novartis) have
all been shown to prolong the QTc interval. Although it has not been
established how these drugs prolong the QTc, sunitinib has been shown to
interact with the hERG gene. The hERG gene codes for K ion
channels responsible for repolarization in cardiac tissue.
Eribulin mesylate (Halaven, Eisai) is a non-taxane
microtubule inhibitor used in patients with metastatic breast cancer who have
received at least two prior chemotherapy regimens. In open-label studies,
patients developed QTc prolongation while on eribulin, independent of the
dosage received. The mechanism of action of this interaction is not understood
at this time.
Platinum compounds (cisplatin and carboplatin), as well
as taxanes may be associated with QTc prolongation. It is difficult to
establish whether these agents cause QTc prolongation or if they contribute to
QTc prolongation caused by co-administered chemotherapies.
Several medications used as supportive care therapy in
patients being treated with chemotherapy may also cause QTc prolongation. For
example, methadone, used to treat chronic pain in cancer patients, blocks K
repolarization. The blockade of repolarization by methadone is a dose-dependent
blockade. 5-HT3 antagonists ondansetron, granisetron and dolasetron
(Anzemet, Sanofi-Aventis) have also been shown to prolong the QTc
interval. Fluoroquinolones, used to treat patients with neutropenic fever, can
also cause QT prolongation.
Clinicians should assess risks vs. benefits and decrease
modifiable risk factors for patients starting chemotherapy agents known to
carry the risk for QTc prolongation. This includes performing a thorough
profile review for drugs that prolong the QTc and correcting electrolyte
No concrete guidelines can be found directing how to
guide therapy in patients at risk for QTc prolongation with anthracyclines/5-FU
or patients who develop QTc prolongation while taking active therapy. Follow
general guidelines and assess risk vs. benefit.
The package insert of arsenic provides the following
recommendations: Before therapy, perform a 12-lead ECG, correct pre-existing
electrolyte abnormalities and, if possible, drugs that are known to prolong the
QT interval should be discontinued. For a baseline QTc of more than 500 ms,
corrective measures should be completed, then reassess with ECGs before
considering initiating therapy. During therapy, maintain potassium levels of
more than 4 mEq/L and magnesium levels of more than 1.8 mg/dL. Patients who
reach an absolute QT interval value of more than 500 ms should be reassessed,
and immediate action should be taken to correct any possible concomitant risk
The risk/benefit of continuing vs. suspending arsenic
trioxide therapy should be considered. If syncope, rapid or irregular heartbeat
develops, the patient should be hospitalized for monitoring; electrolyte labs
should be assessed; arsenic trioxide therapy should be temporarily discontinued
until the QTc interval decreases to less than 460 ms and electrolyte
abnormalities are corrected; and the syncope and irregular heartbeat cease.
Data are not available to drive therapeutic decisions if
a patient develops QTc prolongation while taking a TKI. Dasatinib may be used
if clinically appropriate. Dasatinib was shown to increase the QTc interval to
a lesser degree compared with other TKIs (7-13.4 ms in one phase 2 clinical
trial). This has led to the hypothesis that dasatinib is safer for patients at
risk for QTc prolongation.
The package insert of eribulin provides the following
recommendations: ECG monitoring is recommended if therapy is initiated in
patients with congestive heart failure; bradyarrhythmias; drugs known to
prolong the QT interval, including Class Ia and III antiarrhythmics; and
electrolyte abnormalities. Correct electrolyte abnormalities before initiating
eribulin and monitor these electrolyte labs periodically during treatment.
Avoid eribulin in patients with congenital long QT syndrome.
Several online resources are available to help determine
whether a patient is taking medications that may increase their risk for QT
prolongation. These resources include Arizona Cert Center for Education and
Research on Therapeutics (www.azcert.org/medical-pros/drug-lists/drug-lists.cfm) and
Paul Morales, PharmD, is a pharmacy specialty
oncology resident at the University of Minnesota Medical Center, Fairview, and
Maple Grove Medical Center, Fairview, Minnesota. He reports no relevant
For more information:
- Bagnes C. Curr Drug Saf. 2010;5:93-96.
- Gupta A. Am Heart J. 2007;153:891-899.
- Strevel EL. J Clin Oncol. 2007;25:3362-3371.