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The dangers of QTc interval prolongation and medications used for cancer treatment
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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 interval.
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.
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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.
Drugs of concern
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 drug’s activation of a K-ATPase, which promotes repolarization.
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.
Use of drugs in practice
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 abnormalities.
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 factors.
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 US Pharmacist (www.uspharmacist.com/content/d/health_systems/c/26648/).
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 financial disclosures.
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.