key: cord-0009589-47z9jqzx authors: Roden, Dan M.; Harrington, Robert A.; Poppas, Athena; Russo, Andrea M. title: Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment date: 2020-04-10 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2020.04.016 sha: e7522f4e4b1359da1656fa2c5e1ee9cba9d16909 doc_id: 9589 cord_uid: 47z9jqzx nan Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19 (coronavirus disease 2019) infection. Both drugs are listed as definite causes of torsade de pointes at crediblemeds.org. There are occasional case reports of hydroxychloroquine prolonging the QT interval and provoking torsade de pointes 1-4 when used to treat systemic lupus erythematosus. Antimalarial prophylactic drugs, such as hydroxychloroquine, are believed to act on the entry and post-entry stages of SARS-CoV (severe acute respiratory syndrome-associated coronavirus) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, likely via effects on endosomal pH and the resulting under-glycosylation of angiotensinconverting enzyme 2 receptors that are required for viral entry. 5 The 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 death 10 ; advanced age and female sex have been implicated as risk factors. Interestingly, azithromycin can also provoke non-pause-dependent polymorphic ventricular tachycardia. 11, 12 The FDA Perspective supported the observations that azithromycin administration leaves the patient vulnerable to QTc interval prolongation and torsade de pointes. 13 Basic electrophysiologic studies suggest that both drugs can provoke proarrhythmia via mechanisms beyond block of I Kr 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 very limited data evaluating the safety of combination therapy. Multiple randomized trials are currently being initiated. Seriously ill patients often have comorbidities that can increase risk of serious arrhythmias. These include hypokalemia, hypomagnesemia, fever, 16 and an inflammatory state. 17 Mechanisms to minimize arrhythmia risk include: o In patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible. • Correction of hypokalemia to levels of >4 mEq/L and hypomagnesemia to levels of >2 mg/dL. • Avoid other QTc prolonging agents 5 whenever feasible. Safety considerations for use of hydroxychloroquine and azithromycin in clinical practice have been described. 18 Some of the current COVID-19 repurposed drugs are listed in the Table. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus Life threatening severe QTc prolongation in patient with systemic lupus erythematosus due to hydroxychloroquine Toxicokinetics of hydroxychloroquine following a massive overdose Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19 Risk evaluation of azithromycin-induced QT prolongation in real-world practice Incidence of sustained ventricular tachycardia in patients with prolonged QTc after the administration of azithromycin: a retrospective study Azithromycin-induced torsade de pointes Azithromycin as a cause of QTinterval prolongation and torsade de pointes in the absence of other known precipitating factors Azithromycin and the risk of cardiovascular death Polymorphic ventricular tachycardia with a normal QT interval following azithromycin Azithromycin causes a novel proarrhythmic syndrome Cardiovascular risks with azithromycin and other antibacterial drugs Electrophysiologic studies on the risks and potential mechanism underlying the proarrhythmic nature of azithromycin Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: novel electrophysiological insights and therapeutic potential Assessment of temperature-induced hERG channel blockade variation by drugs Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19