Drug-Induced Prolongation of the QT Interval
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Roden (March 4 issue)1 provides a concise review of drug-induced prolongation of the QT interval. However, in Table 2 of the article, which lists risk factors for torsade de pointes, diet and fasting are not mentioned. There have been several reports of prolongation of the QT interval and associated torsade de pointes resulting from protein-sparing diets, starvation, anorexia nervosa, and fasting during a hunger strike.2,3,4,5 Consequently, physicians should pay particular attention whenever prescribing QT-interval–prolonging drugs in patients in such circumstances.
Panagiotis Korantzopoulos, M.D.
Konstantinos Siogas, M.D.
G. Hatzikosta General Hospital of Ioannina
45001 Ioannina, Greece
pkor@oneway.gr
References
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-1022.
Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58-66.
Ahmed W, Flynn MA, Alpert MA. Cardiovascular complications of weight reduction diets. Am J Med Sci 2001;321:280-284.
Swenne I, Larsson PT. Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QTc interval prolongation and dispersion. Acta Paediatr 1999;88:304-309.
Altun G, Ugur-Altun B, Altun A, Azmak D. Sudden cardiac death in a hunger strike. Cardiology 2003;100:107-108.
To the Editor: New data could be added to Roden's review. First, only 19 percent of QT-related arrhythmias due to the use of noncardiac drugs strike within 72 hours after the initiation of therapy.1 Thus, starting noncardiac drugs that have the potential for causing prolongation of the QT interval while the patient is under observation (as recommended for antiarrhythmic drugs)2 would be futile in most cases. Second, 96 percent of patients in whom torsade de pointes develops in association with the use of noncardiac drugs have at least one risk factor, and 72 percent have two risk factors, that can be easily identified before administration of the culprit drug is initiated. These risk factors include female sex; cardiac, renal, or liver disease; hypokalemia; a history of the long-QT syndrome; and prescription of a QT-prolonging medication in excessive doses or in combination with a second drug that impairs its metabolism or further prolongs the QT interval.1 Finally, only "arrhythmia specialists" can reliably recognize a long QT interval. Other physicians, including many cardiologists, are likely to miss a prolonged QT.3 Accordingly, strategies could be developed for the physician prescribing medication with the potential for causing prolongation of the QT interval.3
Sami Viskin, M.D.
Dan Justo, M.D.
David Zeltser, M.D.
Tel Aviv Sourasky Medical Center
Tel Aviv 64239, Israel
saviskin@tasmc.health.gov.il
References
Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore) 2003;82:282-290.
Prystowsky EN, Benson DW Jr, Fuster V, et al. Management of patients with atrial fibrillation: a statement for healthcare professionals: from the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation 1996;93:1262-1277.
Viskin S, Justo D, Halkin A, Zeltser D. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis 2003;45:415-427.
To the Editor: Clinical measurement of the QT interval is subject to substantial variability, which can cloud interpretation, owing to factors such as circadian effects, differences in autonomic tone, electrolytes, and intraobserver and interobserver variability.1,2 Obviously, there are unavoidable limitations, but methodologic improvements should be feasible. In February 2002, the Food and Drug Administration International Conference on Harmonization S7B guidelines were proposed; they provide more specific direction for the testing of new drugs for cardiac safety.3
Nevertheless, no data exist about how and when to monitor the QT interval during pharmacotherapy. As medical oncologists involved in phase 1 studies, we find assessment of the corrected QT interval (QTc) before and during drug administration a key way to enhance risk management of QT-interval–prolonging medications. Specific guidance is needed in order to standardize cardiovascular testing of anticancer and other drugs with potential health benefits. Guidelines should consider each patient's pharmacogenomic profile, the pharmacokinetics of drugs, and the time of administration in order to determine the timing of QTc assessment.
Giuseppe Curigliano, M.D.
Carlo Cipolla, M.D.
Filippo de Braud, M.D.
European Institute of Oncology
20141 Milan, Italy
giuseppe.curigliano@ieo.it
References
Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-776.
Molnar J, Zhang F, Weiss J, Ehlert FA, Rosenthal JE. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996;27:76-83.
S7B safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. Washington, D.C.: Food and Drug Administration, 2002.
To the Editor: In his review of QTc prolongation, Roden cites www.torsades.org,1 the Web site of the Arizona Center for Education and Research on Therapeutics (CERT), as the primary reference for drugs associated with this effect. To assess the validity of this source, we compared the risk levels assigned to drugs on this Web site with those published by Al-Khatib et al.2 Generic names from both lists were compared between the two data sets. Table 1 shows a cross-tabulation of risk levels from the two sources. Forty-nine drugs are listed only by the Arizona CERT, and six are listed only in the article by Al-Khatib et al. Comparing levels of risk for the 34 drugs that are listed in both sources and that are not listed as having "unknown" risk by Al-Khatib et al. results in a Kendall's tau nonparametric correlation3 of 0.51, which is significant (P=0.001) but indicates a poor level of agreement. Despite extensive research on risk factors for QTc prolongation,4 there is still substantial discrepancy among experts about the drugs that may cause this complication.
Table 1. Comparison of Risks of Prolongation of the Corrected QT Interval Associated with Drugs Listed in Two Sources.
Ricardo A. Cruciani, M.D., Ph.D.
Russell K. Portenoy, M.D.
Peter Homel, Ph.D.
Beth Israel Medical Center
New York, NY 10003
rcrucian@bethisraelny.org
References
Arizona Center for Education and Research on Therapeutics home page. (Accessed May 27, 2004, at http://www.torsades.org.)
Al-Khatib SM, Allen LaPointe NMA, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003;289:2120-2127.
Daniel WW. Applied nonparametric statistics. 2nd ed. Boston: PWS-Kent Publishing, 1990.
Moss AJ, Zareba W, Benhorin J, et al. ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation and other alterations in ventricular repolarization: task force summary: a report of the Task Force of the International Society for Holter and Noninvasive Electrocardiology (ISHNE), Committee on Ventricular Repolarization. Ann Noninvasive Electrocardiol 2001;6:333-341.
Dr. Roden replies: I concur with Viskin and colleagues' contention that detailed screening — beyond the assessment of demographic factors — is unlikely to be useful in the prevention of marked QT-interval prolongation and associated arrhythmias due to "noncardiac" drugs.
Curigliano et al. reiterate the difficulty of accurately measuring small changes in the QT interval and emphasize the need to incorporate pharmacokinetic considerations into standardized cardiovascular testing of noncardiac drugs. They also argue for consideration of each patient's pharmacogenomic profile. Although I look forward to the day when genomic information is routinely incorporated into clinical decision making and drug development, the technology required for implementation of this vision is still immature. Meanwhile, I urge investigators and companies involved in drug development to obtain, with appropriate consent, DNA samples from patients participating in clinical trials — a valuable resource for pharmacogenetic research.
Korantzopoulos and Siogas point out that extreme fasting and associated conditions are risk factors for prolongation of the QT interval and sudden death. I agree that in these extreme conditions any drug therapy should be used judiciously and very close attention be paid to maintenance of normal electrolyte levels.
Cruciani and colleagues point out discrepancies between the lists presented on www.torsades.org and those presented by Al-Khatib et al. Both lists were generated by polling experts, an imperfect approach that reinforces the small numerators and very large denominators at hand when one is studying rare drug-related adverse effects. In fact, I am struck by the concordance between the two lists, and I note that the disagreements do not occur in the extreme categories ("very probable" or "improbable"). I believe the two lists reflect a reasonable summary of culprit drugs as we now understand them. As I discuss in my review, it is not so clear how to classify newer drugs associated with small or moderate QT-interval prolongations but no torsade de pointes or drugs in very widespread use with a few verifiable cases of torsade de pointes. Nevertheless, the recent history of drug-induced QT-interval prolongation reinforces the concept that physicians must remain alert to the possibility that arrhythmias or other unexpected clinical outcomes may be related to drugs.
Dan M. Roden, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232
dan.roden@vanderbilt.edu
Panagiotis Korantzopoulos, M.D.
Konstantinos Siogas, M.D.
G. Hatzikosta General Hospital of Ioannina
45001 Ioannina, Greece
pkor@oneway.gr
References
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-1022.
Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112:58-66.
Ahmed W, Flynn MA, Alpert MA. Cardiovascular complications of weight reduction diets. Am J Med Sci 2001;321:280-284.
Swenne I, Larsson PT. Heart risk associated with weight loss in anorexia nervosa and eating disorders: risk factors for QTc interval prolongation and dispersion. Acta Paediatr 1999;88:304-309.
Altun G, Ugur-Altun B, Altun A, Azmak D. Sudden cardiac death in a hunger strike. Cardiology 2003;100:107-108.
To the Editor: New data could be added to Roden's review. First, only 19 percent of QT-related arrhythmias due to the use of noncardiac drugs strike within 72 hours after the initiation of therapy.1 Thus, starting noncardiac drugs that have the potential for causing prolongation of the QT interval while the patient is under observation (as recommended for antiarrhythmic drugs)2 would be futile in most cases. Second, 96 percent of patients in whom torsade de pointes develops in association with the use of noncardiac drugs have at least one risk factor, and 72 percent have two risk factors, that can be easily identified before administration of the culprit drug is initiated. These risk factors include female sex; cardiac, renal, or liver disease; hypokalemia; a history of the long-QT syndrome; and prescription of a QT-prolonging medication in excessive doses or in combination with a second drug that impairs its metabolism or further prolongs the QT interval.1 Finally, only "arrhythmia specialists" can reliably recognize a long QT interval. Other physicians, including many cardiologists, are likely to miss a prolonged QT.3 Accordingly, strategies could be developed for the physician prescribing medication with the potential for causing prolongation of the QT interval.3
Sami Viskin, M.D.
Dan Justo, M.D.
David Zeltser, M.D.
Tel Aviv Sourasky Medical Center
Tel Aviv 64239, Israel
saviskin@tasmc.health.gov.il
References
Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore) 2003;82:282-290.
Prystowsky EN, Benson DW Jr, Fuster V, et al. Management of patients with atrial fibrillation: a statement for healthcare professionals: from the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation 1996;93:1262-1277.
Viskin S, Justo D, Halkin A, Zeltser D. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis 2003;45:415-427.
To the Editor: Clinical measurement of the QT interval is subject to substantial variability, which can cloud interpretation, owing to factors such as circadian effects, differences in autonomic tone, electrolytes, and intraobserver and interobserver variability.1,2 Obviously, there are unavoidable limitations, but methodologic improvements should be feasible. In February 2002, the Food and Drug Administration International Conference on Harmonization S7B guidelines were proposed; they provide more specific direction for the testing of new drugs for cardiac safety.3
Nevertheless, no data exist about how and when to monitor the QT interval during pharmacotherapy. As medical oncologists involved in phase 1 studies, we find assessment of the corrected QT interval (QTc) before and during drug administration a key way to enhance risk management of QT-interval–prolonging medications. Specific guidance is needed in order to standardize cardiovascular testing of anticancer and other drugs with potential health benefits. Guidelines should consider each patient's pharmacogenomic profile, the pharmacokinetics of drugs, and the time of administration in order to determine the timing of QTc assessment.
Giuseppe Curigliano, M.D.
Carlo Cipolla, M.D.
Filippo de Braud, M.D.
European Institute of Oncology
20141 Milan, Italy
giuseppe.curigliano@ieo.it
References
Morganroth J, Brozovich FV, McDonald JT, Jacobs RA. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991;67:774-776.
Molnar J, Zhang F, Weiss J, Ehlert FA, Rosenthal JE. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996;27:76-83.
S7B safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. Washington, D.C.: Food and Drug Administration, 2002.
To the Editor: In his review of QTc prolongation, Roden cites www.torsades.org,1 the Web site of the Arizona Center for Education and Research on Therapeutics (CERT), as the primary reference for drugs associated with this effect. To assess the validity of this source, we compared the risk levels assigned to drugs on this Web site with those published by Al-Khatib et al.2 Generic names from both lists were compared between the two data sets. Table 1 shows a cross-tabulation of risk levels from the two sources. Forty-nine drugs are listed only by the Arizona CERT, and six are listed only in the article by Al-Khatib et al. Comparing levels of risk for the 34 drugs that are listed in both sources and that are not listed as having "unknown" risk by Al-Khatib et al. results in a Kendall's tau nonparametric correlation3 of 0.51, which is significant (P=0.001) but indicates a poor level of agreement. Despite extensive research on risk factors for QTc prolongation,4 there is still substantial discrepancy among experts about the drugs that may cause this complication.
Table 1. Comparison of Risks of Prolongation of the Corrected QT Interval Associated with Drugs Listed in Two Sources.
Ricardo A. Cruciani, M.D., Ph.D.
Russell K. Portenoy, M.D.
Peter Homel, Ph.D.
Beth Israel Medical Center
New York, NY 10003
rcrucian@bethisraelny.org
References
Arizona Center for Education and Research on Therapeutics home page. (Accessed May 27, 2004, at http://www.torsades.org.)
Al-Khatib SM, Allen LaPointe NMA, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003;289:2120-2127.
Daniel WW. Applied nonparametric statistics. 2nd ed. Boston: PWS-Kent Publishing, 1990.
Moss AJ, Zareba W, Benhorin J, et al. ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation and other alterations in ventricular repolarization: task force summary: a report of the Task Force of the International Society for Holter and Noninvasive Electrocardiology (ISHNE), Committee on Ventricular Repolarization. Ann Noninvasive Electrocardiol 2001;6:333-341.
Dr. Roden replies: I concur with Viskin and colleagues' contention that detailed screening — beyond the assessment of demographic factors — is unlikely to be useful in the prevention of marked QT-interval prolongation and associated arrhythmias due to "noncardiac" drugs.
Curigliano et al. reiterate the difficulty of accurately measuring small changes in the QT interval and emphasize the need to incorporate pharmacokinetic considerations into standardized cardiovascular testing of noncardiac drugs. They also argue for consideration of each patient's pharmacogenomic profile. Although I look forward to the day when genomic information is routinely incorporated into clinical decision making and drug development, the technology required for implementation of this vision is still immature. Meanwhile, I urge investigators and companies involved in drug development to obtain, with appropriate consent, DNA samples from patients participating in clinical trials — a valuable resource for pharmacogenetic research.
Korantzopoulos and Siogas point out that extreme fasting and associated conditions are risk factors for prolongation of the QT interval and sudden death. I agree that in these extreme conditions any drug therapy should be used judiciously and very close attention be paid to maintenance of normal electrolyte levels.
Cruciani and colleagues point out discrepancies between the lists presented on www.torsades.org and those presented by Al-Khatib et al. Both lists were generated by polling experts, an imperfect approach that reinforces the small numerators and very large denominators at hand when one is studying rare drug-related adverse effects. In fact, I am struck by the concordance between the two lists, and I note that the disagreements do not occur in the extreme categories ("very probable" or "improbable"). I believe the two lists reflect a reasonable summary of culprit drugs as we now understand them. As I discuss in my review, it is not so clear how to classify newer drugs associated with small or moderate QT-interval prolongations but no torsade de pointes or drugs in very widespread use with a few verifiable cases of torsade de pointes. Nevertheless, the recent history of drug-induced QT-interval prolongation reinforces the concept that physicians must remain alert to the possibility that arrhythmias or other unexpected clinical outcomes may be related to drugs.
Dan M. Roden, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232
dan.roden@vanderbilt.edu