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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)

Educational Objective
To understand the risks of QT (QTc) prolongation when taking hydroxychloroquine with or without azithromycin?
1 Credit CME
Key Points

Question  In hospitalized patients with coronavirus disease 2019 (COVID-19), what is the risk of corrected QT (QTc) prolongation when taking hydroxychloroquine with or without azithromycin?

Findings  In a cohort study of 90 hospitalized patients with coronavirus disease 2019, use of hydroxychloroquine with or without azithromycin for treatment of COVID-19 was associated with frequent QTc prolongation, and those taking hydroxychloroquine and azithromycin had greater QT prolongation than those taking hydroxychloroquine alone. One patient developed torsades de pointes.

Meaning  Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.

Abstract

Importance  Administration of hydroxychloroquine with or without azithromycin for the treatment of coronavirus disease 2019 (COVID-19)–associated pneumonia carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias.

Objective  To characterize the risk and degree of QT prolongation in patients with COVID-19 in association with their use of hydroxychloroquine with or without concomitant azithromycin.

Design, Setting, and Participants  This was a cohort study performed at an academic tertiary care center in Boston, Massachusetts, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal polymerase chain reaction test result and clinical findings consistent with pneumonia who received at least 1 day of hydroxychloroquine from March 1, 2020, through April 7, 2020.

Main Outcomes and Measures  Change in QT interval after receiving hydroxychloroquine with or without azithromycin; occurrence of other potential adverse drug events.

Results  Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin; 44 (48.9%) were female, and the mean (SD) body mass index was 31.5 (6.6). Hypertension (in 48 patients [53.3%]) and diabetes mellitus (in 26 patients [28.9%]) were the most common comorbid conditions. The overall median (interquartile range) baseline QTc was 455 (430-474) milliseconds (hydroxychloroquine, 473 [454-487] milliseconds vs hydroxychloroquine and azithromycin, 442 [427-461] milliseconds; P < .001). Those receiving concomitant azithromycin had a greater median (interquartile range) change in QT interval (23 [10-40] milliseconds) compared with those receiving hydroxychloroquine alone (5.5 [−15.5 to 34.25] milliseconds; P = .03). Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (8%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. The likelihood of prolonged QTc was greater in those who received concomitant loop diuretics (adjusted odds ratio, 3.38 [95% CI, 1.03-11.08]) or had a baseline QTc of 450 milliseconds or more (adjusted odds ratio, 7.11 [95% CI, 1.75-28.87]). Ten patients had hydroxychloroquine discontinued early because of potential adverse drug events, including intractable nausea, hypoglycemia, and 1 case of torsades de pointes.

Conclusions and Relevance  In this cohort study, patients who received hydroxychloroquine for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc. Clinicians should carefully weigh risks and benefits if considering hydroxychloroquine and azithromycin, with close monitoring of QTc and concomitant medication usage.

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Article Information

Accepted for Publication: April 17, 2020.

Corresponding Authors: Howard S Gold, MD, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, MASCO 426, Boston, MA 02215 (hogold@bidmc.harvard.edu) and Peter J. Zimetbaum, MD, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Rd, Boston, MA 02215 (pzimetba@bidmc.harvard.edu).

Published Online: May 1, 2020. doi:10.1001/jamacardio.2020.1834

Correction: This article was corrected on June 17, 2020, to fix 3 errors. The first was a misstated percentage in the Abstract and Results; “3 patients (3%)” should have said “3 patients (8%).” In addition, “(26 patients [289%]…)” should have said “(26 patients [28.9%]…)” in the Results section. Finally, the Corresponding Author information was inadvertently omitted and has been added.

Author Contributions: Drs Mercuro and Yen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mercuro and Yen share first author status.

Concept and design: Mercuro, Yen, Maher, McCoy, Zimetbaum, Gold.

Acquisition, analysis, or interpretation of data: Mercuro, Yen, Shim, McCoy, Zimetbaum, Gold.

Drafting of the manuscript: Mercuro, Yen, Shim.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mercuro, Yen, Shim, Maher.

Administrative, technical, or material support: Yen, Shim, Maher.

Supervision: Yen, McCoy, Zimetbaum, Gold.

Conflict of Interest Disclosures: None reported.

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