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J Arrhythmia Vol 25 No 2 2009

Review Article

Clinical Background and Evaluation of Drug-Induced Prolongation of QT Interval

Takao Katoh MD, PhD Department of Medicine, Division of Cardiology, Hepatology, Geriatrics and Integrated Medicine, Nippon Medical School

Prolongation of QT/QTc interval during medical treatment can occur not only with cardiovascular drugs but also with non-cardiovascular drugs. It may result in ventricular tachyarrhythmia, a high-risk condition which may trigger sudden cardiac death. Thus, to avoid drug-induced long QT syndrome and serious complications careful attention should be paid in the clinical setting. Moreover, in the last several years objective evaluation by strictly applying electrocardio- gram (ECG) data has been strongly recommended for the development of all new drugs in discussions held at the International Conference on Harmonization (ICH). This recommen- dation has already been adopted in the USA and the EU and is expected to be announced shortly in our country. Not only the drugs but a variety of patient background factors may influence ECG parameters, especially the QT/QTc interval. It is necessary to introduce an appropriate study protocol that can evaluate the risk for QT/QTc prolongation related to the drug. Additionally, an adequate system to record, measure, and evaluate ECG with high objectivity must be applied to all clinical trials. (J Arrhythmia 2009; 25: 56–62)

Drug-induced long QT syndrome, QT/QTc interval, K-, Non-cardiovascular Key words: drug, Clinical study, ICH

through the K channel (h-ERG channel) of myocar- Introduction dial cell, resulting in the prolongation of the action potential duration of ventricular myocytes. An Drug-induced prolongation of QT interval has excess prolongation of action potential may some- recently received intensive attention in the clinical times cause triggered activity due to early after- setting, because it may be followed by the appear- depolarization at phase 3 of the action potential that ance of torsade de pointes-type ventricular arrhyth- is thought to be a trigger of Tdp. mias (Tdp), sometimes resulting in sudden cardiac Class III antiarrhythmic drugs including , death.1–3) It is thought that the most likely candidate nifekalant, and exhibit a for the mechanism responsible for the prolongation potent blocking action on IKr as their principal of the QT interval is a suppression of the IKr current pharmacological effects, and may exert significant

Address for Correspondence: Takao Katoh, MD, PhD, Department of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 Japan. Tel: 813-3822-2131 Fax: 813-5685-0987 E-mail: [email protected]

56 Katoh T Drug-Induced Long QT Syndrome

QT/QTc prolongation in the course of routine conditions and that all patients who are taking any treatment with the drugs. Because these effects are kind of drugs have a risk for QT/QTc prolongation. well known and are expected beforehand, QT/QTc However, in the real world, it is not appropriate to prolongation should be checked and managed check ECG at every hospital visit in all patients. throughout the therapy. However, not only these Practically, it is important to know which types of class III drugs but many other drugs that are used for drugs have the potential to prolong QT/QTc interval non-cardiac purposes are also known to the latent due to their K channel blocking action under usual effect of prolonging the QT interval. Besides, we clinical dosage. know that many non-pharmacological factors sur- Table 2 is a list of drugs other than class III rounding the patients may have an influence on antiarrhythmic agents with the potential for prolon- electrocardiographic parameters including the QT gation of QT/QTc interval as reported in the interval. Are drugs always entirely responsible for literature.5,6) Not only drugs for cardiovascular dis- QT prolongation during medical therapy? Do we eases including Na channel blocking agents and anti- have a definite answer to this question? anginal drugs, but also many other drugs for non- cardiovascular use such as neuroleptics, antidepres- Definition of Drug-Induced Long QT Syn- sants, antihistamines, antibiotics, and antineoplastics drome are listed. We have to be very careful to see that the list is never complete. It is thought that many drugs When we observe excess QT/QTc prolongation not on this list might prolong QT/QTc interval. This during a certain medical therapy, drug-induced long list should be considered the ‘‘tip of an iceberg.’’ QT syndrome should be highly suspected, even with non-cardiac drugs.4) In strict terms, drug-induced Problems of QT/QTc Prolongation due to Non- long QT syndrome is defined as QT/QTc interval Cardiovascular Drugs prolongation greater than the normal range due to direct pharmacological action to the myocardial cell. It is sometimes very difficult to check QT/QTc However, it may be difficult to definitely differ- interval in the daily clinical practices especially entiate QT/QTc prolongation associated with a during non-cardiovascular drug therapy. There are direct effect of the drug on the myocardium from many problems in the management of QT/QTc the effect of the drug on other tissues or organs with interval because the targets of the treatment are not no effect on myocardial cells. For example, we cardiovascular diseases. Related problems are listed sometimes find that the QT/QTc interval has been in Table 3. Usually non-cardiovascular drugs are prolonged by loop diuretic agents associated with prescribed by physicians who are not cardiology lowering the serum [K+] level. Also, we may not be specialists. These physicians will not attempt to able to differentiate the effect on QT/QTc prolon- record ECGs before and after the prescription except gation of various acquired factors including brady- in the specific patients who have underlying cardi- cardia, myocardial ischemia, cerebrovascular dis- ovascular diseases, because they may not be familiar eases, and electrolyte imbalance, as listed in Table 1, with the clinical importance of QT/QTc prolonga- from that of drugs only. tion induced by non-cardiovascular drugs. We must assume that there are no drugs which Since automatic measurement of QT/QTc by the never prolong the QT/QTc interval under any built-in computers of ECG systems is sometimes

Table 1 Patient background that may affect the electrocardiogram. 1. Cardiac dysfunction, heart failure, electrocardiographic abnormalities 2. Past and/or family history of arrhythmias, gender 3. Electrolyte imbalance (hypopotassemia, hypomagnesemia, etc.) 4. Bradycardias, tachycardias 5. Hypoproteinemia, anemia, diarrhea, dehydration 6. Liver dysfunction, renal dysfunction 7. Age (elderly or pediatric patients) 8. Autonomic nervous dysfunction, sleep disorder, mental stress 9. Excess , smoking 10. Drugs

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Table 2 Drugs that may prolong QT/QTc interval other than class III antiarrhythmic drugs.5Þ Non-class III cardiovascular drugs Non-cardiovascular drugs blockers Neuroleptics Antidepressants Antimicrobials Anticancer drugs Anthracycline Triflupromazine Protriptyline Co-trimoxazole Aclarubicin N-acetyl- Promazine Sulfamethoxazole 5-fluorouracil Lorcainide Perphenazine Butriptyline Pentamidine Acodazole 3-Methoxy-O-demethyl- Fluphenazine Amantidine Adriamycin (MODE) Prochlorperazine Grepafloxacin Tamoxifen Trifluoperazine Lofepramine Levofloxacin S9788 Triethylperazine Moxifloxacin 502U83 Antianginals Sparfloxacin Arsenic trioxide Trifluoperidol Maprotiline Gatifloxacin Efavirenz Droperidol Dothiepin Lidoflazine Penfluridol Citalopram Spiramycin Miscellaneous Fluspirilene Zimeldine Fluconazole Vincamine Risperidone D0870 Probucol Ziprasidone Antimoniates Amisulpride H1-Antihistamines Epoprostenol Amiodarone Chlorprothixene Serotonin (5-HT2)-antagonists Chloral hydrate Thiothixene Ketanserin Amperozide Bromocriptine Retanserin Sevoflurane 1=-blockers Hydroxyzine Pipamperone Sotalol Zotepine Tacrolimus Oxprenolol Quetiapine Antimalarials Serotonin (5-HT3)-antagonists Levacetylmethadol Nifenalol Olanzapine Halofantrine Dolasetron Lubelozole Indoramin Chloroquine Zatosetron Tiapride Melperone Arteether Tizanidine Amosulalol Rivastigmine Inotropic agents Dobutamine

Table 3 Problems in evaluation of QT interval under non-cardiovascular drug therapy. 1. Treatment target is not cardiovascular disease. 2. Attending doctor is not a cardiology specialist. 3. ECG will not be record before prescription of the drug. 4. ECG will not be record even after prescription of the drug. 5. Attending doctor may not be familiar with QT/QTc prolongation. 6. Accuracy of automatic measurement of QT interval is not always enough. 7. QT/QTc prolongation is sometimes concealed and may appear suddenly. 8. Unexpected prolongation may occur due to pharmacological interaction. inaccurate, especially under noisy conditions, a drug that has little effect on QT/QTc interval physician with sufficient experience and knowledge prolongation during the administration of a single in accurately reading ECGs may be requested for the drug may exert significant prolongation suddenly appropriate evaluation of QT/QTc prolongation.7,8) with an unexpected elevation of the serum concen- It is not easy to monitor QT/QTc intervals tration due to drug interaction when another drug is thoroughly throughout a drug therapy. A certain prescribed concomitantly.

58 Katoh T Drug-Induced Long QT Syndrome

Table 4 Methods to measure QT interval from the electrocardiogram. 1. Manual measurement Using a manual caliper, paper speed with 50 mm/sec desirable, need skill and time-consuming. 2. Automatic measurement Using digital electrocardiography, automatically measured by built-in computer, precisely measured but unstable with noise or drift. 3. Semi-automatic measurement Using a digital caliper, displayed on the monitor, scanned data from paper-base electrocardiogram, need some skill, time-consuming. 4. Measurement with mathematical adjustment The first-differentiated or the second-differentiated electrocardiogram, time-frequency analysis using FFT or wavelet transform.

405 msec 397 msec

Figure 1 An example of wavelet analysis Z-lead Surface ECG Wavelet-transformed ECG of QT interval.

cardiology specialist, especially in the early phase Measurement of QT Interval of study for new drug development.20) Several secondary analyses applying certain mathematical Recently, ICH-E14 reached step 5 agreement and approaches are expected as shown in Table 4. We are has requested that millisecond-level variation of QT studying the possibility of using the wavelet trans- interval should be precisely detected using an form analysis for the measurement of QT interval.21) authorized method during clinical trials for all new Since the wavelet analysis has a time- and frequen- drugs even if they have little or no cardiovascular cy-domain nature, time-relevant information might effect (thorough QT/QTc study).9–11) Thus, the be preserved even during frequency analysis.22,23) construction of an objective QT measurement system We believe that the method will be applicable for the with high quality and performance is urgently accurate measurement of QT interval in cases of flat needed to meet the request of ICH (cf. http:// or inverted T wave as illustrated in Figure 1, but www.ich.org). whether or not the method will be used is still under Table 4 shows various methods that measure QT consideration. interval in the clinical setting.12–19) An automatic measurement using the built-in computer of ECG Determination of the Terminal Point of T machines will be the easiest way to measure a large Wave quantity of ECGs. However, the ICH does not recommend it because of the questionable reliability In the clinical setting, it is sometimes difficult to of the data. ICH requests a manual over-read system determine the real point of termination of the T wave to check the measured data by an authorized on the ECG not only due to noise, drift, and artifacts

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Over the signal or under the signal? Baseline was PP or QQ?

Terminal point of T wave? Baseline in case of severe drift?

Figure 2 How to draw the baseline and the tangent line on the electrocardiogram.

Table 5 Various methods for correction of QT interval. 1. Bazett’s formula QTcB = QT/RR1=2 2. Fridericia’s formula QTcF = QT/RR1=3 3. Framingham’s formula QTcFR = QT + 0.154(1-RR) 4. Individual linear regression method QTcI = QT + b(1-RR) 5. RR bin method Compare QT at HR 60–70/min before and after drug administration

but also due to flattened or biphasic T waves or a should be used only to make corrections in case of prominent U wave, depending upon the underlying significant discrepancies in the value of QT interval disease.24) It is very difficult to measure QT intervals measurement. in every beat with a high grade of accuracy.25) Before starting QT interval measurement, it is There are many options as to the methods for essential to reach an agreement on the basic of determining the terminal point of the T wave from method where to draw the baseline and the tangent the ECG recordings. Among them the tangent line as illustrated in Figure 2. method and the threshold method are widely used. It is known that the tangent method is slightly Correction of Measured QT Interval (QTc) superior in reproducibility of measurement and has less inter-observer variation than the threshold QT intervals may fluctuate frequently and instan- method. However, in case of biphasic or bizarre T taneously due to the change of various physiological wave or severe baseline drift, a tangent line at the or pathological factors of the patients. Change of down slope of the T wave sometimes cannot be heart rate is the main factor that may influence QT drawn appropriately. The threshold method can be interval. Many methods have been developed to applied even in those cases. It is thought that in the correct the QT interval for heart rate.26–32) The real world QT intervals are measured using both measured QT intervals should be corrected by the methods on a case-by-case basis. It is better, heart rate using several correction formulae as shown = however, that these methods are not mixed during in Table 5. Bazett’s formula (QTc = QT/RR1 2)is the drug study if at all possible. A second method most widely used. It is simple and easily applicable,

60 Katoh T Drug-Induced Long QT Syndrome

but the formula is aimed to adjust the QT interval ICH has recommended a rule in the clinical during a heart rate around 60 beats per minute. evaluation of risk for QT/QTc prolongation in its However, Bazett’s formula becomes less accurate, E14 documents. The recommendations contained in underestimating repolarization duration at slow heart this document are generally applicable to new drugs rates and overestimating at fast heart rates. It may having systemic bioavailability, but may not apply to not be suitable for studies involving drugs that may products with highly localized distribution and those bring a great change of the heart rate. Fridericia’s administered topically and not absorbed. Antiar- formula (QTc = QT/RR1=3) is also available. Com- rhythmic drugs known to prolong the QT/QTc pared to Bazett’ formula, the overestimation at faster interval are excluded from this concept. Although heart rates is thought to be less and it is used most E14 is primarily concerned with the development of frequently in the drug approval process. However, new drugs, the recommendations might also be the calculation process is more complicated. Several applicable to approved drugs when a higher dose or a new methods for correction of QT interval using new route of administration results in significantly linear regression analysis have been recently applied. higher exposure. Besides, the evaluation of QT If sufficient data of successive QT and RR intervals interval would also be considered important if the are available to get the QT/RR relationship before drugs with similar pharmacological action have been and after the study, QTcI might be the most reliable associated with QT/QTc interval prolongation, TdP, correction method in individual patients. Another or sudden cardiac death during post-marketing approach to deal with QT interval is the so-called RR surveillance. bin method. When the stable Holter ECG before and after the drug administration have been recorded, Conclusion absolute QT intervals at similar heart rates can simply be compared without mathematical heart rate I have raised the question at the beginning of this corrections. review whether drugs are always fully responsible for QT prolongation during medical therapy. Un- Thorough QT/QTc Study fortunately, we have no definite answer to that question. Because various non-pharmacological fac- According to the recently-issued ICH E-14 state- tors other than drugs used may have an influence on ment, a ‘‘thorough QT/QTc study’’ is intended to the QT/QTc interval, we must be very careful in determine whether the drug has a threshold pharma- evaluating ECG data during the clinical study of new cologic effect on cardiac repolarization, as detected drugs. It is essential to plan studies elaborately in a by QT/QTc prolongation.10,11) The threshold level of highly individualized manner taking into consider- regulatory concern is around 5 msec as evidenced by ation the characteristics of each drug. an upper boundary of the 95% confidence interval around the mean effect on QTc of 10 msec. The study is typically carried out in healthy volunteers References and is used to determine whether or not the effect of 1) Monahan BP, Ferguson CL, Killeavy ES, et al: Torsades a drug on the QT/QTc interval in target patient de pointes occurring in association with terfenadine use. populations should be studied intensively during JAMA 1991; 266: 2375–2376 later stages of drug development including phase II 2) June RA, Nasr I: Torsades de pointes with terfenadine and phase III clinical studies. It is not intended to ingestion. Am J Emerg Med 1997; 15: 542–543 identify drugs as being pro-arrhythmic. The results 3) Haddad PM, Anderson IM: Antipsychotic-related QTc of the ‘‘thorough QT/QTc study’’ is not expected to prolongation, torsade de pointes and sudden death. Drugs 2002; 62: 1649–1671 be affected by ethnic factors. 4) Shah RR: The significance of QT interval in drug development. Br J Clin Pharmacol 2002; 54: 188–202 Planning of the Clinical Trials in the Develop- 5) Shah RR: Drugs, QTc interval prolongation and final ment of New Drugs ICH E14 guideline: An important milestone with challenges ahead. Drug Saf 2005; 28: 1009–1028 Regardless of whether the drug is a cardiac or 6) Shah RR, Hondeghem LM: Refining detection of drug- non-cardiac agent, drug companies are requested to induced proarrhythmia: QT interval and TRIaD. Heart Rhythm 2005; 2: 758–772 perform an adequate pre-marketing investigation to 7) Katoh T, Saitoh H, Ohno N, et al: Drug interaction demonstrate safety, including detailed characteriza- between mosapride and erythromycin without electro- tion of the drug’s effects on the QT/QTc interval in cardiographic changes. Jpn Heart J 2003; 44: 225–234 humans. 8) Katoh T, Ueno A, Murata H: The effects of donepezil

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hydrochloride on QT interval evaluated by objective 21) Yodogawa K, Ogano M, Katoh T: A novel approach to measurements of electrocardiogram. Jpn J Electrocardiol measure QT interval using wavelet transform analysis. 2007; 27: 588–595 (in Japanese) Annual Report on the Study of Regulatory Science on 9) ICH S7B: The non-clinical evaluation of the Potential for Drugs and Medical Devices. 2005 (in Japanese) Delayed Ventricular Repolarization (QT Interval Pro- 22) Yodogawa K, Morita N, Kobayashi Y, Takayama H, longation) by Human Pharmaceuticals. Step 4. May 12, Ohara T, Katoh T, Takano T: High frequency potentials 2005 developed in wavelet-transformed electrocardiogram as a 10) ICH E14: The clinical evaluation of QT/QTc interval novel indicator for detecting Brugada syndrome. Heart prolongation and proarrhythmic potential for non-anti- Rhythm 2006; 3: 1436–1444 arrhythmic drugs Step 4. May 12, 2005 23) Takayama H, Yodogawa K, Katoh T, Takano T: 11) E14 Implementation Working Group: Questions & Evaluation of arrhythmogenic substrate in patients with Answers. June 4, 2008 hypertrophic cardiomyopathy using wavelet transform 12) Katoh T: How to evaluate a drug-induced prolongation analysis. Circ J 2006; 70: 69–74 of QT interval. Shinzo 2006; 38: 4–8 (in Japanese) 24) Lepeshkin E, Surawicz B: The measurement of the QT 13) Laguna P, Caminal P, Jane R, et al: Automatic QT interval of the electrocardiogram. Circulation 1952; 6: interval analysis in postmyocardial infarction patients. 378–388 J Amb Monitoring 1991; 4: 93–111 25) Murray A, McLaughlin NB, Bourke JP, Doig JC, Furniss 14) Badilini F, Sarapa N: Implications of methodological SS, Campbell RWP: Errors in manual measurement of differences in digital electrocardiogram interval meas- QT intervals. Br Heart J 1994; 71: 386 urement. J Electrocardiol 2006; 39: S152–156 26) Bazett HC: An analysis of time relations of electro- 15) McLaughlin NB, Campbell RWF, Murray A: Accuracy cardiograms. Heart 1920; 7: 353–367 of four automatic QT measurement techniques in cardiac 27) Fridericia LS: Duration of systole in electrocardiogram. patients and healthy subjects. Heart 1996; 76: 422–426 Acta Med Scandinav 1920; 53: 469 16) Glancy JM, Weston PJ, Bhullar HK, et al: Reproduci- 28) Sagie A, Larson MG, Goldberg RJ, et al: An improved bility and automatic measurement of QT dispersion. Eur method for adjusting the QT interval for heart rate (the Heart J 1996; 17: 1035–1039 Framingham Heart Study). Am J Cardiol 1992; 70: 797– 17) Savelieva I, Yi G, Guo X, et al: Agreement and 801 reproducibility of automatic versus manual measurement 29) Hodges M, Salerno D, Erlien D: Bazett’s QT correction of QT interval and QT dispersion. Am J Cardiol 1998; reviewed: Evidence that a linear QT correction for heart 81: 471–477 rate is better. J Am Coll Cardiol 1983; 1: 694 18) Darpo B, Agin M, Kazierad DJ, et al: Man versus 30) Rautaharju PM, Zhou SH, Wong S, et al: Sex differences machine: Is there an optimal method for QT measure- in the evolution of electrocardiographic QT interval with ment in thorough QT studies? J Clin Pharmacol 2006; age. Can J Cardiol 1992; 8: 690–695 46: 598 31) Karjalainen J, Viitasalo M, Manttari M: Relation 19) Kors JA, van Herpen G: Methodology of QT-interval between QT intervals and heart rates from 40 to 120 measurement in the modular ECG analysis system beats/min in rest electrocardiogram of men and a simple (MEANS). Ann Noninvasive Electrocardiol 2009; method to adjust QT interval values. J Am Coll Cardiol 14(Suppl 1): S48–53 1994; 23: 1547–1553 20) Yashima M, Katoh T: Development of a novel computer- 32) Extramiana F, Maison-Blanche P, Haggui A, et al: assisted system for the measurement of QT interval. The Control of rapid heart rate changes for electrocardio- 24th annual meeting of the Japanese Society of Clinical graphic analysis: implications for thorough QT studies. Pharmacology. 2003 (in Japanese) Clin Cardiol 2006; 29: 534–539

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