Login Register Cart 0
Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Drug-Induced QTc Prolongation: What We Know and Where We Are Going

Author(s): Erinn Mangona*, Elisa Sandonato, Todd N. Brothers and Jayne Pawasauskas

Volume 17, Issue 2, 2022

Published on: 17 January, 2022

Page: [100 - 113] Pages: 14

DOI: 10.2174/1574886316666210922153059

Price: $65

Abstract

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: “known,” “possible,” and “conditional risk” of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Keywords: Torsade de Pointes, QT interval, QT prolongation, risk assessment, drug-induced arrhythmia, technology, monitoring, COVID-19.

Next »
Graphical Abstract

[1]
Cohagan B, Brandis D. Torsade de Pointes Torsade de Pointes Treasure Island, FL StatPearls Publishing 2020. Available from:https://www.ncbi.nlm.nih.gov/books/NBK459388/
[2]
Poncet A, Gencer B, Blondon M, et al. Electrocardiograph screening for prolonged QT interval to reduce sudden cardiac death in psychiatric patients: A cost-effectiveness analysis. PLoS One 2015; 10(6): e0127213. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466505/pdf/pone.0127213.pdf
[http://dx.doi.org/10.1371/journal.pone.0127213] [PMID: 26070071]
[3]
Tisdale JE, Chung MK, Campbell KB, et al. Drug-induced arrhythmias: A scientific statement from the American Heart Association. Circulation 2020; 142(15): e214-33. Available from:https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000905
[http://dx.doi.org/10.1161/CIR.0000000000000905] [PMID: 32929996]
[4]
Zolezzi M, Cheung L. A literature-based algorithm for the assessment, management, and monitoring of drug-induced QTc prolongation in the psychiatric population. Neuropsychiatr Dis Treat 2018; 15: 105-14.
[http://dx.doi.org/10.2147/NDT.S186474] [PMID: 30636876]
[5]
Daniel NM, Walsh K, Leach H, Stummer L. Implementation of a QTc-interval monitoring protocol by pharmacists to decrease cardiac risk in at-risk patients in an acute care inpatient psychiatric facility. Ment Health Clin 2019; 9(2): 82-7.
[http://dx.doi.org/10.9740/mhc.2019.03.082] [PMID: 30842915]
[6]
Fernandes FM, Silva EP, Martins RR, Oliveira AG. QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications. PLoS One 2018; 13(6): e0199028. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999273/pdf/pone.0199028.pdf/
[http://dx.doi.org/10.1371/journal.pone.0199028] [PMID: 29898002]
[7]
van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010; 70(1): 16-23.
[http://dx.doi.org/10.1111/j.1365-2125.2010.03660.x] [PMID: 20642543]
[8]
Oberman R, Bhardwaj A. Physiology, Cardiac StatPearls [Internet] Treasure Island, FL StatPearls Publishing 2020. Available from:https://www.ncbi.nlm.nih.gov/books/NBK526089/?report=classic
[9]
Perry RS, Illsley SS. Basic cardiac electrophysiology and mechanisms of antiarrhythmic agents. Am J Hosp Pharm 1986; 43(4): 957-74.
[http://dx.doi.org/10.1093/ajhp/43.4.957] [PMID: 2871752]
[10]
Vandael E, Vandenberk B, Vandenberghe J, Van den Bosch B, Willems R, Foulon V. A smart algorithm for the prevention and risk management of QTc prolongation based on the optimized RISQ-PATH model. Br J Clin Pharmacol 2018; 84(12): 2824-35.
[http://dx.doi.org/10.1111/bcp.13740] [PMID: 30112769]
[11]
De Vecchis R, Ariano C, Di Biase G, Noutsias M. Acquired drug-induced long QTc: new insights coming from a retrospective study. Eur J Clin Pharmacol 2018; 74(12): 1645-51.
[http://dx.doi.org/10.1007/s00228-018-2537-y] [PMID: 30112668]
[12]
Giudicessi JR, Noseworthy PA, Ackerman MJ. The QT Interval. Circulation 2019; 139(24): 2711-3.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.039598] [PMID: 31180747]
[13]
Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf 2012; 3(5): 241-53.
[http://dx.doi.org/10.1177/2042098612454283] [PMID: 25083239]
[14]
Lorberbaum T, Sampson KJ, Chang JB, et al. Coupling data mining and laboratory experiments to discover drug interactions causing QT prolongation. J Am Coll Cardiol 2016; 68(16): 1756-64.
[http://dx.doi.org/10.1016/j.jacc.2016.07.761] [PMID: 27737742]
[15]
Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J 2016; 149(3): 139-52.
[http://dx.doi.org/10.1177/1715163516641136] [PMID: 27212965]
[16]
Isbister GK. Risk assessment of drug-induced QT prolongation. Aust Prescr 2015; 38(1): 20-4.
[http://dx.doi.org/10.18773/austprescr.2015.003] [PMID: 26648606]
[17]
Titelbaum N, Simpson M, Randall S, Baska K, Peterson A. QTc: So many formulae, but which one to use?. ACEP Toxicology Section 2021. Available from:www.acep.org/how-we-serve/sections/toxicology/news/toxicology-section-newsletter- february-2021/
[18]
Camm AJ, Janse MJ, Roden DM, Rosen MR, Cinca J, Cobbe SM. Congenital and acquired long QT syndrome. Eur Heart J 2000; 21(15): 1232-7.
[http://dx.doi.org/10.1053/euhj.2000.2222] [PMID: 10924312]
[19]
Castelletti S, Dagradi F, Goulene K, et al. A wearable remote monitoring system for the identification of subjects with a prolonged QT interval or at risk for drug-induced long QT syndrome. Int J Cardiol 2018; 266: 89-94.
[http://dx.doi.org/10.1016/j.ijcard.2018.03.097] [PMID: 29887480]
[20]
Page A, Aktas MK, Soyata T, Zareba W, Couderc JP. “QT clock” to improve detection of QT prolongation in long QT syndrome patients. Heart Rhythm 2016; 13(1): 190-8.
[http://dx.doi.org/10.1016/j.hrthm.2015.08.037] [PMID: 26334569]
[21]
Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89(11): 1363-72.
[http://dx.doi.org/10.1136/heart.89.11.1363] [PMID: 14594906]
[22]
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350(10): 1013-22.
[http://dx.doi.org/10.1056/NEJMra032426] [PMID: 14999113]
[23]
Al-Khatib SM, LaPointe NMA, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA 2003; 289(16): 2120-7.
[http://dx.doi.org/10.1001/jama.289.16.2120] [PMID: 12709470]
[24]
Gachoka DN, Sheikh M, Al Ahwel Y, et al. QT prolongation during therapeutic hypothermia of sudden cardiac arrest patients does not cause predisposition to ventricular arrhythmias. J Innov Card Rhythm Manag 2012; 3: 996-1001.
[25]
Woosley RL, Black K, Heise CW, Romero K. CredibleMeds.org: What does it offer? Trends Cardiovasc Med 2018; 28(2): 94-9.
[http://dx.doi.org/10.1016/j.tcm.2017.07.010] [PMID: 28801207]
[26]
Meid AD, Bighelli I, Mächler S, et al. Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature. Ther Adv Psychopharmacol 2017; 7(12): 251-64.
[http://dx.doi.org/10.1177/2045125317721662] [PMID: 29201344]
[27]
Wiśniowska B, Tylutki Z, Wyszogrodzka G, Polak S. Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials. BMC Pharmacol Toxicol 2016; 17: 12. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785617/pdf/40360_2016_Article_53.pdf
[http://dx.doi.org/10.1186/s40360-016-0053-1] [PMID: 26960809]
[28]
Jin Y, Xu Z, Yan H, He Q, Yang X, Luo P. A comprehensive review of clinical cardiotoxicity incidence of FDA-approved small- molecule kinase inhibitors. Front Pharmacol 2020; 11: 891. Available from:https://www.frontiersin.org/articles/10.3389/fphar.2020.00891/full
[http://dx.doi.org/10.3389/fphar.2020.00891] [PMID: 32595510]
[29]
Woosley RL, Heise CW, Romero KA. QT Drugs List. Available from:www.crediblemeds.org (Accessed February 1, 2021).
[30]
Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: A scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9): 934-47.
[http://dx.doi.org/10.1016/j.jacc.2010.01.001] [PMID: 20185054]
[31]
U.S. Food and Drug Administration. Novel drug approvals for 2018. Available from:https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2018 (Accessed February 1, 2021).
[32]
Xospata® (gilteritinib). Package insert Northbrook, IL : Astellas Pharma, Inc 2019.
[33]
Rozlytrek®. (entrectinib) Package insert San Francisco, CA Greentech, Inc 2019.
[34]
CredibleMeds. Eight New Drugs added to QTdrugs.org Lists. Available from:crediblemeds.org/blog/eight-new-drugs-added-qtdrugsorg-lists/ (Accessed February 1, 2021).
[35]
Tisdale JE, Jaynes HA, Kingery JR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2013; 6(4): 479-87.
[http://dx.doi.org/10.1161/CIRCOUTCOMES.113.000152] [PMID: 23716032]
[36]
Reference Values for Common Laboratory Tests Lenexa, KS American College of Clinical Pharmacy 2019.
[37]
Jardin CGM, Putney D, Michaud S. Assessment of drug-induced torsade de pointes risk for hospitalized high-risk patients receiving QT-prolonging agents. Ann Pharmacother 2014; 48(2): 196-202.
[http://dx.doi.org/10.1177/1060028013512614] [PMID: 24301687]
[38]
Niemeijer MN, van den Berg ME, Franco OH, et al. Drugs and ventricular repolarization in a general population: the Rotterdam Study. Pharmacoepidemiol Drug Saf 2015; 24(10): 1036-41.
[http://dx.doi.org/10.1002/pds.3853] [PMID: 26248883]
[39]
Sala M, Vicentini A, Brambilla P, et al. QT interval prolongation related to psychoactive drug treatment: A comparison of monotherapy versus polytherapy. Ann Gen Psychiatry 2005; 4(1): 1. Available from:https://pubmed.ncbi.nlm.nih.gov/15845138/
[http://dx.doi.org/10.1186/1744-859X-4-1] [PMID: 15845138]
[40]
Zeuli JD, Wilson JW, Estes LL. Effect of combined fluoroquinolone and azole use on QT prolongation in hematology patients. Antimicrob Agents Chemother 2013; 57(3): 1121-7.
[http://dx.doi.org/10.1128/AAC.00958-12] [PMID: 23229485]
[41]
Thomas SHL, Behr ER. Pharmacological treatment of acquired QT prolongation and torsades de pointes. Br J Clin Pharmacol 2016; 81(3): 420-7.
[http://dx.doi.org/10.1111/bcp.12726] [PMID: 26183037]
[42]
Li M, Ramos LG. Drug-induced QT prolongation and torsades de pointes. P&T 2017; 42(7): 473-7.
[PMID: 28674475]
[43]
Toh S, Li Q, Cheetham TC, et al. Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001-2007: A population-based study of 585,615 deliveries. Arch Women Ment Health 2013; 16(2): 149-57.
[http://dx.doi.org/10.1007/s00737-013-0330-6] [PMID: 23389622]
[44]
Domino ME, Swartz MS. Who are the new users of antipsychotic medications? Psychiatr Serv 2008; 59(5): 507-14.
[http://dx.doi.org/10.1176/ps.2008.59.5.507] [PMID: 18451006]
[45]
Tikosyn® (dofetilide). Package insert New York, NY Pfizer, Inc 2014.
[46]
Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: A clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain 2014; 15(4): 321-37.
[http://dx.doi.org/10.1016/j.jpain.2014.01.494] [PMID: 24685458]
[47]
Mayet S, Gossop M, Lintzeris N, Markides V, Strang J. Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation? Drug Alcohol Rev 2011; 30(4): 388-96.
[http://dx.doi.org/10.1111/j.1465-3362.2010.00237.x] [PMID: 21355918]
[48]
Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high- dose methadone. Ann Intern Med 2002; 137(6): 501-4.
[http://dx.doi.org/10.7326/0003-4819-137-6-200209170-00010] [PMID: 12230351]
[49]
Khan Q, Ismail M, Haider I, Khan F. Prevalence of QT interval prolonging drug-drug interactions (QT-DDIs) in psychiatry wards of tertiary care hospitals in Pakistan: A multicenter cross-sectional study. Int J Clin Pharm 2017; 39(6): 1256-64.
[http://dx.doi.org/10.1007/s11096-017-0532-5] [PMID: 28895028]
[50]
Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf 2010; 5(1): 97-104.
[http://dx.doi.org/10.2174/157488610789869265] [PMID: 20210726]
[51]
Tisdale JE, Jaynes HA, Kingery JR, et al. Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes 2014; 7(3): 381-90.
[http://dx.doi.org/10.1161/CIRCOUTCOMES.113.000651] [PMID: 24803473]
[52]
Khan Q, Ismail M, Khan S. Frequency, characteristics and risk factors of QT interval prolonging drugs and drug-drug interactions in cancer patients: A multicenter study. BMC Pharmacol Toxicol 2017; 18(1): 75. Available from:https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-017-0181-2
[http://dx.doi.org/10.1186/s40360-017-0181-2] [PMID: 29191244]
[53]
Coppola C, Rienzo A, Piscopo G, Barbieri A, Arra C, Maurea N. Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs. Cancer Treat Rev 2018; 63: 135-43.
[http://dx.doi.org/10.1016/j.ctrv.2017.11.009] [PMID: 29304463]
[54]
MedSafety Scan. Covid-19 Clinical Decision Support. Available from:medsafetyscan.org (Accessed February 1, 2021).
[55]
CredibleMeds. Recommendations re: COVID-19 Treatments. Available from:https://crediblemeds.org/blog/recommendations-re-covid-19-treatments/ (Accessed February 1, 2021).
[56]
Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). Mayo Clin Proc 2020; 95(6): 1213-21.
[http://dx.doi.org/10.1016/j.mayocp.2020.03.024] [PMID: 32359771]
[57]
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the new york city area. JAMA 2020; 323(20): 2052-9.
[http://dx.doi.org/10.1001/jama.2020.6775] [PMID: 32320003]
[58]
Wang Y, Wang Z, Tse G, et al. Cardiac arrhythmias in patients with COVID-19. J Arrhythm 2020; 36(5): 827-36.
[http://dx.doi.org/10.1002/joa3.12405] [PMID: 33024460]
[59]
Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for drug interactions on QTc in exploratory COVID-19 treatment. Circulation 2020; 141(24): e906-7. Available from:https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.047521
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047521] [PMID: 32267732]
[60]
Chorin E, Wadhwani L, Magnani S, et al. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm 2020; 17(9): 1425-33.
[http://dx.doi.org/10.1016/j.hrthm.2020.05.014] [PMID: 32407884]
[61]
Saleh M, Gabriels J, Chang D, et al. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol 2020; 13(6): e008662. Available from:https://pubmed.ncbi.nlm.nih.gov/32347743/
[http://dx.doi.org/10.1161/CIRCEP.120.008662] [PMID: 32347743]
[62]
Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020; 5(9): 1036-41.
[http://dx.doi.org/10.1001/jamacardio.2020.1834] [PMID: 32936252]
[63]
Asensio E, Acunzo R, Uribe W, Saad EB, Sáenz LC. Recommendations for the measurement of the QT interval during the use of drugs for COVID-19 infection treatment. Updatable in accordance with the availability of new evidence. J Interv Card Electrophysiol 2020; 59(2): 315-20.
[http://dx.doi.org/10.1007/s10840-020-00765-3] [PMID: 32418181]
[64]
Saleh M, Gabriels J, Chang D, et al. Safely administering potential QTc prolonging therapy across a large health care system in the COVID-19 era. Circ Arrhythm Electrophysiol 2020; 13(11): e008937. Available from:https://pubmed.ncbi.nlm.nih.gov/33003964/
[http://dx.doi.org/10.1161/CIRCEP.120.008937] [PMID: 33003964]
[65]
Bauman JL, Tisdale JE. Chloroquine and hydroxychloroquine in the era of SARS-CoV2: caution on their cardiac toxicity. Pharmacotherapy 2020; 40(5): 387-8. Available from:https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2387
[http://dx.doi.org/10.1002/phar.2387] [PMID: 32285489]
[66]
U.S. Food and Drug Administration. FDA approves first treatment for COVID-19. Available from:https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19 (Accessed February 1, 2021).
[67]
Mayo Clinic. COVID-19 (coronavirus) Drugs: Are there any that work?. Available from:https://mayoclinic.org/diseases-conditions/coronavirus/expert-answers/coronavirus-drugs/faq-20485627 (Accessed February 1, 2021).
[68]
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. 2019. Available from:https://www.covid19treatmentguidelines.nih.gov/ (Accessed February 1, 2021).
[69]
U.S. food and drug administration. frequently asked questions of the revocation of the emergency use authorization for hydroxychloroquine sulfate and chloroquine phosphate Available from:https://www.fda.gov/media/138946/download (Accessed February 1, 2021).
[70]
BodyGuardian (BG) Heart Eagan, MN Preventice Solutions 2012. Available from: https://www.preventicesolutions.com/patients/body-guardian-heart.
[71]
Apple Watch Series 4®. Cupertino, Ca: Apple 2018. Available from: https://www.apple.com/newsroom/2018/09/redesigned-apple-watch-series-4-revolutionizes-communication-fitness-and-health/.
[72]
AliveCor Kardia System. San Francisco, CA AliveCor Inc 2019. Available from: https://www.kardia.com/.
[73]
Chinitz JS, Goyal R, Morales DC, Harding M, Selim S, Epstein LM. Use of a smartwatch for assessment of the QT interval in outpatients with coronavirus disease 2019. J Innovat Cardiac rhythm Manag 2020; 11(9): 4219. Available from:https://www.innovationsincrm.com/cardiac-rhythm-management/articles-2020/september/1634-covid-19-smartwatch-for-assessment-of-the-qt-interval
[74]
G Medical VSMS ECG Patch (VSMS Patch)® Rehovot, Israel:. GMedical Innovations Ltd 2020. Available from: https://www.fda.gov/media/138108/download.
[75]
G Medical VSMS ECG Patch®. Fact Sheet for Healthcare Providers Spring, MD U.S. Food and Drug Administration 2020. Available from: https://www.fda.gov/media/138108/download.
[76]
VitalPatch Biosensor. San Jose, CA: VitalConnect 2020. Available from: https://vitalconnect.com/.
[77]
VitalPatch Biosensor®. Fact Sheet for Healthcare Providers Spring, MD U.S. Food and Drug Administration 2020. Available from: https://www.accessdata.fda.gov/cdrh_docs/pdf19/K192757.pdf.
[78]
PhysiolGuard ECG-QT Analysis System®. New Taipei City, Taiwan PhysiolGuard Corporation Ltd 2020. Available from: https://www.fda.gov/media/137691/download.
[79]
PhysiolGuard ECG-QT Analysis System®. Fact Sheet for Healthcare ProvidersSpring, MD: U.S Food and Drug Administration 2020. Available from: https://www.fda.gov/media/137691/download.

Rights & Permissions Print Cite
Article Metrics
48
1
© 2024 Bentham Science Publishers | Privacy Policy