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Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

2020; Lippincott Williams & Wilkins; Volume: 141; Issue: 24 Linguagem: Inglês

10.1161/circulationaha.120.047521

1524-4539

Dan M. Roden, Robert A. Harrington, Athena Poppas, Andrea M. Russo,

ECG Monitoring and Analysis

HomeCirculationVol. 141, No. 24Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBConsiderations for Drug Interactions on QTc in Exploratory COVID-19 Treatment Dan M. Roden, Robert A. Harrington, Athena Poppas and Andrea M. Russo Dan M. RodenDan M. Roden Dan M. Roden, MDCM, Vanderbilt University School of Medicine, 1285B Medical Research Building-IV, 2215B Garland Avenue, Nashville, TN 37232. Email E-mail Address: [email protected] Division of Cardiovascular Medicine and Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (D.M.R.). , Robert A. HarringtonRobert A. Harrington Department of Medicine, Stanford University, CA (R.A.H.). , Athena PoppasAthena Poppas Cardiology Division, Brown University School of Medicine, Providence, RI (A.P.). and Andrea M. RussoAndrea M. Russo Electrophysiology and Arrhythmia Services, Cooper University Hospital, Camden, NJ (A.M.R.). Clinical Cardiac Electrophysiology Fellowship Program, Cooper Medical School of Rowan University, Camden, NJ (A.M.R.). Originally published8 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.047521Circulation. 2020;141:e906–e907Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 8, 2020: Ahead of Print Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for coronavirus disease 2019 (COVID-19). Both drugs are listed as definite causes of torsade de pointes on crediblemeds.org. There are occasional case reports of hydroxychloroquine prolonging the QT interval and provoking torsade de pointes1–4 when used to treat systemic lupus erythematosus. Antimalarial prophylactic drugs, such as hydroxychloroquine, are believed to act on the entry and postentry stages of SARS-CoV (severe acute respiratory syndrome coronavirus) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, likely through effects on endosomal pH and the resulting underglycosylation of angiotensin-converting enzyme 2 receptors that are required for viral entry.5The widely used antibiotic azithromycin is increasingly recognized as a rare cause of QT prolongation,6,7 serious arrhythmias,8,9 and increased risk for sudden death10; advanced age and female sex have been implicated as risk factors. It is interesting that azithromycin also can provoke nonpause-dependent polymorphic ventricular tachycardia.11,12 The US Food and Drug Administration Perspective supported the observation that azithromycin administration leaves the patient vulnerable to QTc interval prolongation and torsade de pointes.13Basic electrophysiologic studies suggest that both hydroxychloroquine and azithromycin can provoke proarrhythmia by mechanisms beyond blockage of IKr implicated in usual cases of torsade de pointes.14,15 The effect of the combination of these agents on QT or arrhythmia risk has not been studied. There are limited data evaluating the safety of combination therapy. Multiple randomized trials are currently being initiated.Seriously ill patients often have comorbidities that can increase the risk of serious arrhythmias. These include hypokalemia, hypomagnesemia, fever,16 and an inflammatory state.17 Mechanisms to minimize arrhythmia risk include the following:Electrocardiographic/QT interval monitoringWithhold the drugs in patients with baseline QT prolongation (eg, QTc ≥500 ms) or with known congenital long QT syndrome.Monitor cardiac rhythm and QT interval; withdraw the drugs if QTc exceeds a preset threshold of 500 ms.In critically ill patients with COVID-19, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.Correction of hypokalemia to >4 mEq/L and hypomagnesemia to >2 mg/dLAvoidance of other QTc-prolonging agents5 whenever feasibleSafety considerations for use of hydroxychloroquine and azithromycin in clinical practice have been described.18Some of the current drugs repurposed for COVID-19 treatment are listed in the Table.Table. TdP Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed PharmacotherapiesPossible COVID-19 TreatmentCredibleMeds.org ClassificationVT/VF/TdP/LQTS in FAERSCardiac Arrest in FAERSRepurposed antimalarial agents ChloroquineKnown risk7254 HydroxychloroquineKnown risk222105Repurposed antiviral agent Lopinavir/ritonavirPossible risk2748Adjunct agent AzithromycinKnown risk396251COVID-19 indicates coronavirus disease 2019; FAERS, US Food and Drug Administration Adverse Event Reporting System; LQTS, long QT syndrome; TdP, torsade de pointes; VF; ventricular fibrillation; and VT, ventricular tachyarrhythmia. Modified from Giudicessi et al5 with permission from the publisher. Copyright © 2020 Mayo Foundation for Medical Education and Research.DisclosuresDr Roden has nothing to disclose. Dr Harrington is the president of the American Heart Association (unpaid) and served on the Stanford Healthcare Board of Directors from 2016 to 2018 (unpaid). Dr Poppas is the president of the American College of Cardiology. Dr Russo is the president of the Heart Rhythm Society; receives research study support from Boehringer Ingelheim, Boston Scientific, and Medilynx (all funding to the hospital); and serves on the Research Steering Committee for Boston Scientific and the Apple Heart Study (no honoraria).FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circDan M. Roden, MDCM, Vanderbilt University School of Medicine, 1285B Medical Research Building-IV, 2215B Garland Avenue, Nashville, TN 37232. Email dan.roden@vumc.orgReferences1. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia.Clin Toxicol (Phila). 2006; 44:173–175. doi: 10.1080/15563650500514558CrossrefMedlineGoogle Scholar2. Morgan ND, Patel SV, Dvorkina O. 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Azithromycin-induced torsade de pointes.Pacing Clin Electrophysiol. 2007; 30:1579–1582. doi: 10.1111/j.1540-8159.2007.00912.xCrossrefMedlineGoogle Scholar9. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors.J Interv Card Electrophysiol. 2007; 18:243–246. doi: 10.1007/s10840-007-9124-yCrossrefMedlineGoogle Scholar10. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death.N Engl J Med. 2012; 366:1881–1890. doi: 10.1056/NEJMoa1003833CrossrefMedlineGoogle Scholar11. Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin.Pacing Clin Electrophysiol. 2005; 28:1221–1222. doi: 10.1111/j.1540-8159.2005.50146.xCrossrefMedlineGoogle Scholar12. Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, et al. Azithromycin causes a novel proarrhythmic syndrome.Circ Arrhythm Electrophysiol. 2017; 10:e003560. doi: 10.1161/CIRCEP.115.003560LinkGoogle Scholar13. Mosholder AD, Mathew J, Alexander JJ, Smith H, Nambiar S. Cardiovascular risks with azithromycin and other antibacterial drugs.N Engl J Med. 2013; 368:1665–1668. doi: 10.1056/NEJMp1302726CrossrefMedlineGoogle Scholar14. Zhang M, Xie M, Li S, Gao Y, Xue S, Huang H, Chen K, Liu F, Chen L. Electrophysiologic studies on the risks and potential mechanism underlying the proarrhythmic nature of azithromycin.Cardiovasc Toxicol. 2017; 17:434–440. doi: 10.1007/s12012-017-9401-7CrossrefMedlineGoogle Scholar15. Capel RA, Herring N, Kalla M, Yavari A, Mirams GR, Douglas G, Bub G, Channon K, Paterson DJ, Terrar DA, et al. Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: novel electrophysiological insights and therapeutic potential.Heart Rhythm. 2015; 12:2186–2194. doi: 10.1016/j.hrthm.2015.05.027CrossrefMedlineGoogle Scholar16. Kauthale RR, Dadarkar SS, Husain R, Karande VV, Gatne MM. Assessment of temperature-induced hERG channel blockade variation by drugs.J Appl Toxicol. 2015; 35:799–805. doi: 10.1002/jat.3074CrossrefMedlineGoogle Scholar17. Aromolaran AS, Srivastava U, Alí A, Chahine M, Lazaro D, El-Sherif N, Capecchi PL, Laghi-Pasini F, Lazzerini PE, Boutjdir M. Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation.PLoS One. 2018; 13:e0208321. doi: 10.1371/journal.pone.0208321CrossrefMedlineGoogle Scholar18. Simpson TF, Kovacs RJ, Stecker EC. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19 [published online March 29, 2020].Cardiology Magazine. https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19Google Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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