Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit

The novel coronavirus disease 2019 (COVID-19) outbreak is an ongoing situation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹ Studies in patients with mild to moderate COVID-19 symptoms have suggested benefits of hydroxychloroquine alone or in combination with azithromycin against SARS-CoV-2 and raised hope for treating the disease.² As a result, these treatments are increasingly used off-label for patients with COVID-19, including for those in intensive care units (ICUs).^2,3 However, both medications are known to induce QT prolongation via a human Ether-à-go-go–related gene potassium channel blockade, which can promote life-threatening ventricular arrhythmias.^4,5 Safety data for these treatments are largely lacking for patients with COVID-19. This is even more relevant for critically ill patients who are particularly exposed to electrolyte imbalance and/or drugs leading to an increased risk of QT prolongation.⁶ Therefore, we aimed to examine the safety of hydroxychloroquine with or without azithromycin regarding QT interval in ICU patients with COVID-19.

This study was approved by our institutional ethics committee (Comité d’Ethique du CHU de Lyon) with a waiver for informed consent because of the retrospective nature of the study. All consecutive patients with COVID-19 confirmed by positive reverse transcription–polymerase chain reaction results on respiratory samples admitted to the ICU who received hydroxychloroquine (200 mg, twice a day, for 10 days) with or without azithromycin (250 mg, daily, for 5 days) were included. Treatment began in the absence of contraindication, including corrected QT (QTc) intervals greater than 460 milliseconds (Bazett formula). All other drugs (given before or after ICU admission) listed in CredibleMeds (https://crediblemeds.org) with known or possible risk of QT prolongation/torsades de pointes were classified as drugs favoring prolonged QT. The QTc interval was continuously monitored; an electrocardiogram (ECG) was recorded daily. All ECGs were retrospectively reviewed by 2 masked cardiac electrophysiologists. As previously described, prolonged QTc was defined as an increase in QTc intervals of more than 60 milliseconds (ΔQTc >60 milliseconds) compared with baseline or as a QTc of 500 milliseconds or greater.⁴ Data, expressed as median (interquartile range [IQR]) and number (percentage), were compared using Mann-Whitney U, Wilcoxon matched-pairs signed rank, or Fisher exact tests as appropriate.

Forty patients with COVID-19 (median age, 68 years [IQR, 58-74 years]; 32 men [80%]) were included between March 15 and March 29, 2020 (Table). Thirty patients (75%) required invasive mechanical ventilation and 25 (63%) received vasoactive drugs (Table). Hydroxychloroquine with or without azithromycin was given to 18 (45%) and 22 patients (55%), respectively. Twenty patients (50%) also received other treatments favoring QT prolongation in the ICU (Table). Most patients (37 [93%]) showed an increase in QTc after the administration of antiviral therapy (Figure). Prolonged QTc was observed in 14 patients (36%) (10 with ΔQTc >60 milliseconds and 7 with QTc ≥500 milliseconds) after a duration of antiviral treatment of 2 to 5 days. No ventricular arrhythmia, including torsades de pointes, was recorded. As shown in the Figure, among patients treated with hydroxychloroquine and azithromycin, 6 of 18 (33%) developed an increase in QTc of 500 milliseconds or greater vs 1 of 22 (5%) of those treated with hydroxychloroquine alone (P = .03). The antiviral treatment ceased before completion for 7 patients (17.5%) following ECG abnormalities and in 10 (25%) for acute renal failure.

This study raises safety concerns about the use of hydroxychloroquine with or without azithromycin for patients with COVID-19, particularly when both drugs are administered together. There were no baseline clinical factors associated with subsequent QT prolongation. In our cohort, close monitoring of patients (including continuous QTc interval monitoring, daily ECGs, and laboratory tests), which led to an interruption of these drugs for 17 patients (42.5%), may have averted further complications, including drug-induced torsades de pointes. Key limitations of the present case series include a potential lack of generalizability beyond the ICU. However, the finding that QTc intervals increased in more than 90% of patients raises concerns about the widespread use of hydroxychloroquine, with or without azithromycin, to treat COVID-19 in settings where patients cannot be adequately monitored.

Accepted for Publication: April 14, 2020

Corresponding Author: Martin Cour, MD, PhD, Médecine Intensive-Réanimation, Hôpital Edouard Herriot, 5, Place d’Arsonval, 69437 Lyon Cedex 03, France (martin.cour@chu-lyon.fr).

Author Contributions: Drs Bessière and Cour had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Bessiere, Roccia, Chevalier, Argaud, Cour.

Acquisition, analysis, or interpretation of data: Bessiere, Roccia, Deliniere, Charriere, Chevalier, Cour.

Drafting of the manuscript: Bessiere, Roccia, Chevalier, Cour.

Critical revision of the manuscript for important intellectual content: Bessiere, Roccia, Deliniere, Charriere, Argaud, Cour.

Statistical analysis: Bessiere, Cour.

Supervision: Bessiere, Deliniere, Chevalier, Argaud, Cour.

Conflict of Interest Disclosures: Dr Bessière reports grants and personal fees from Abbott, Boston Scientific, Medtronic, Biosense, and Volta Medical outside the submitted work. Dr Chevalier reports grants from Abbott, Boston Scientific, and Medtronic outside the submitted work. No other disclosures were reported.

Published Online: May 1, 2020. doi:10.1001/jamacardio.2020.1787

Correction: This article was corrected on June 24, 2020, to fix errors in the Conflict of Interest Disclosures.

Additional Contributions: We thank Verena Landel, DRCI, Hospices Civils de Lyon, for her help in manuscript preparation. She was not compensated for her contributions.