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 | Cardiology | JAMA Cardiology | JAMA Network
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Figure.  Individual Baseline and Maximal Corrected QT Interval Values in Patients With Coronavirus Disease 2019 (COVID-19) Treated With Hydroxychloroquine and Azithromycin
Individual Baseline and Maximal Corrected QT Interval Values in Patients With Coronavirus Disease 2019 (COVID-19) Treated With Hydroxychloroquine and Azithromycin

Individual baseline (pretreatment) and maximal corrected (QTc) interval values are shown for 40 critically ill patients with COVID-19 treated with hydroxychloroquine alone (22 [55.0%]) or in association (18 [45.0%]) with azithromycin. Median and interquartile range values of QTc before and after the start of hydroxychloroquine/azithromycin. Horizontal blue and orange dashed lines represent the upper normal value of the QTc interval (460 milliseconds) and the QTc cutoff value of 500 milliseconds (high risk of ventricular arrhythmia).

aP < .01.

Table.  Patient Characteristics According to QT Interval Prolongation After Beginning Antiviral Therapy
Patient Characteristics According to QT Interval Prolongation After Beginning Antiviral Therapy
1.
Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. Published online February 24, 2020. doi:10.1001/jama.2020.2648PubMedGoogle Scholar
2.
Kupferschmidt  K, Cohen  J.  Race to find COVID-19 treatments accelerates.   Science. 2020;367(6485):1412-1413. doi:10.1126/science.367.6485.1412PubMedGoogle ScholarCrossref
3.
Mahase  E.  Covid-19: six million doses of hydroxychloroquine donated to US despite lack of evidence.   BMJ. 2020;368:m1166. doi:10.1136/bmj.m1166PubMedGoogle ScholarCrossref
4.
Drew  BJ, Ackerman  MJ, Funk  M,  et al; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, the Council on Cardiovascular Nursing, and the American College of Cardiology Foundation.  Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.   Circulation. 2010;121(8):1047-1060. doi:10.1161/CIRCULATIONAHA.109.192704PubMedGoogle ScholarCrossref
5.
Yazdany  J, Kim  AHJ.  Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: what every clinician should know.   Ann Intern Med. Published online March 31, 2020. doi:10.7326/M20-1334PubMedGoogle Scholar
6.
Etchegoyen  CV, Keller  GA, Mrad  S, Cheng  S, Di Girolamo  G.  Drug-induced QT interval prolongation in the intensive care unit.   Curr Clin Pharmacol. 2017;12(4):210-222. doi:10.2174/1574884713666180223123947PubMedGoogle ScholarCrossref
Research Letter
May 1, 2020

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

Author Affiliations
  • 1Hospices Civils de Lyon, Hôpital Cardiologique Louis Pradel, Service d’électrophysiologie et de Stimulation Cardiaque, Université de Lyon, Lyon, France
  • 2Hospices Civils de Lyon, Hôpital Cardiologique Louis Pradel, Centre de Référence National des Troubles du Rythme Cardiaque d’origine Héréditaire, Lyon, France
  • 3Hospices Civils de Lyon, Hôpital Edouard Herriot, Médecine Intensive - Réanimation, Lyon, France
  • 4Centre Hospitalier de Valence, Service de Maladies Infectieuses, Valence, France
JAMA Cardiol. 2020;5(9):1067-1069. doi:10.1001/jamacardio.2020.1787

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.

Methods

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.

Results

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.

Discussion

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.

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Article Information

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.

References
1.
Wu  Z, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. Published online February 24, 2020. doi:10.1001/jama.2020.2648PubMedGoogle Scholar
2.
Kupferschmidt  K, Cohen  J.  Race to find COVID-19 treatments accelerates.   Science. 2020;367(6485):1412-1413. doi:10.1126/science.367.6485.1412PubMedGoogle ScholarCrossref
3.
Mahase  E.  Covid-19: six million doses of hydroxychloroquine donated to US despite lack of evidence.   BMJ. 2020;368:m1166. doi:10.1136/bmj.m1166PubMedGoogle ScholarCrossref
4.
Drew  BJ, Ackerman  MJ, Funk  M,  et al; American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, the Council on Cardiovascular Nursing, and the American College of Cardiology Foundation.  Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.   Circulation. 2010;121(8):1047-1060. doi:10.1161/CIRCULATIONAHA.109.192704PubMedGoogle ScholarCrossref
5.
Yazdany  J, Kim  AHJ.  Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: what every clinician should know.   Ann Intern Med. Published online March 31, 2020. doi:10.7326/M20-1334PubMedGoogle Scholar
6.
Etchegoyen  CV, Keller  GA, Mrad  S, Cheng  S, Di Girolamo  G.  Drug-induced QT interval prolongation in the intensive care unit.   Curr Clin Pharmacol. 2017;12(4):210-222. doi:10.2174/1574884713666180223123947PubMedGoogle ScholarCrossref
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