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, MDCM, Robert A. Harrington, MD, Athena Poppas, MD and Andrea M. Russo, MD 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.). Search for more papers by this author , Robert A. HarringtonRobert A. Harrington Department of Medicine, Stanford University, CA (R.A.H.). Search for more papers by this author , Athena PoppasAthena Poppas Cardiology Division, Brown University School of Medicine, Providence, RI (A.P.). Search for more papers by this author 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.). Search for more papers by this author 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.[email protected]org