key: cord-0707554-sy9k6t6y
authors: Bun, Sok‐Sithikun; Taghji, Philippe; Courjon, Johan; Squara, Fabien; Scarlatti, Didier; Theodore, Guillaume; Baudouy, Delphine; Sartre, Benjamin; Labbaoui, Mohamed; Dellamonica, Jean; Doyen, Denis; Marquette, Charles‐Hugo; Levraut, Jacques; Esnault, Vincent; Bun, Sok‐Siya; Ferrari, Emile
title: QT interval prolongation under hydroxychloroquine/ azithromycin association for inpatients with SARS‐CoV‐2 lower respiratory tract infection
date: 2020-06-26
journal: Clin Pharmacol Ther
DOI: 10.1002/cpt.1968
sha: 2f089827c74590d1dd30b23c35b88b99e1d2d2be
doc_id: 707554
cord_uid: sy9k6t6y

Association between Hydroxychloroquine (HCQ) and Azithromycin (AZT) is under evaluation for patients with lower respiratory tract infection (LRTI) caused by the Severe Acute Respiratory Syndrome (SARS‐CoV‐2). Both drugs have a known torsadogenic potential, but sparse data are available concerning QT prolongation induced by this association. Our objective was to assess for COVID‐19 LRTI variations of QT interval under HCQ/AZT in patients hospitalized, and to compare manual versus automated QT measurements. Before therapy initiation, a baseline 12 lead‐ECG was electronically sent to our cardiology department for automated and manual QT analysis (Bazett and Fridericia’s correction), repeated 2 days after initiation. According to our institutional protocol (Pasteur University Hospital), HCQ/AZT was initiated only if baseline QTc ≤ 480ms and potassium level > 4.0 mmol/L. From March 24(th) to April 20(th) 2020, 73 patients were included (mean age 62 ± 14 y, male 67 %). Two patients out of 73 (2.7 %) were not eligible for drug initiation (QTc ≥ 500ms). Baseline average automated QTc was 415 ± 29 ms and lengthened to 438 ± 40 ms after 48 hours of combined therapy. The treatment had to be stopped because of significant QTc prolongation in 2 out of 71 patients (2.8 %). No drug‐induced life‐threatening arrhythmia, nor death was observed. Automated QTc measurements revealed accurate in comparison with manual QTc measurements. In this specific population of inpatients with COVID‐19 LRTI, HCQ/AZT could not be initiated or had to be interrupted in less than 6% of the cases.

Introduction Several therapeutic strategies are currently investigated for the management of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. Among them, the association between Hydroxychloroquine (HCQ) and Azithromycin (AZT) is under evaluation, with contrasting results. 1 , 2 When used in established indications for well-known diseases, both drugs have a reported torsadogenic potential. 3 , 4 In the context of COVID-19 disease, very new data are being rapidly reported by different research teams worldwide, and raising some serious safety concerns about QT prolongation and potential arrhythmogenic effects with HCQ/AZT association. 5 , 6 Because of the severity of this disease, a significant proportion of critically-ill patients (eventually mechanically-ventilated, MV) has been evaluated in these recent studies, this population being particularly prone to experience drug-induced QT prolongation. 7 Furthermore, it is well established that more severe forms of pneumonia could represent a risk factor for QT prolongation per se. 8 To avoid any life-threatening drug-induced event in the context of COVID-19 disease, several national documents have been recently published to guide physicians for QT monitoring during this pandemic. 9 , 10 Previous studies reported the validation of automated QT measurement, i.e. generated by electrocardiographic (ECG) machines, in comparison with manual measurement of the QT interval; but most of them included healthy volunteers. 11

In the present study, we aimed to: (1) assess the proportion of inpatients (outside the critical care unit) suffering from Lower Respiratory Tract Infection (LRTI), and potentially eligible for a combined therapy HCQ/AZT; according to strict predetermined baseline clinical and ECG criteria;

(2) evaluate QT variation/prolongation 48 hours after initiation of HCQ/AZT association in this specific population of SARS-CoV-2 LRTI (safety profile with the use of a dedicated institutional protocol); (3) assess the accuracy of automated corrected QT (QTc) measurement in patients hospitalized in this specific setting, in comparison with a manual method of QT measurement.

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Before therapy initiation, a baseline digital 12 lead-ECG was electronically sent to our cardiology department for QT analysis. The ECGs were performed after 5 minutes supine rest, at a paper speed of 25 mm/s and amplification of 10 mm/mV, filter 40 Hz, with at least 10 second ECG at stable heart rate. Analysis of the digital ECG was performed on a computer screen with optimal resolution and manual calipers (magnifying or "zooming" by 3 to 4 folds). Heart rate (RR interval values) and uncorrected QT measurements were performed by one electrophysiologist in order to reduce any inter-operator variability (S.-S. B); 14 they were entered into a database and QT intervals were rate corrected using Bazett's correction (heart rate < 90 beats per minute), and

Fridericia's correction (heart rate ≥ 90 beats per minute). For manual measurements, all 12 leads were visually analyzed; the lead where the QT interval was the most readily measured was selected for measurement (usually the precordial leads V2 or V3 

This article is protected by copyright. All rights reserved Two days after initiation of combined therapy HCQ/AZT, 12-lead ECG was repeated and sent for new analysis for each hospitalized patient.

The statistical analysis was completed using Excel (Microsoft, CA, USA). Numerical variables are expressed as mean ± standard deviation (SD). Continuous variables were analyzed using the t-test.

The 5% level of significance (p < 0.05) was selected as representing a statistically significant difference.

To compare the QT intervals generated by manual and machine methods in a pairwise fashion, the method proposed by Bland and Altman was employed. 17 In these plots, the difference between uncorrected QT intervals obtained on the same ECG by machine and manual measurements (machine minus manual) was plotted versus the mean of the 2 values. Limits of agreements (LOA)

were defined as the mean ± 1.96 × SD of these differences.

The clinical characteristics of the patients are reported in Table 1 

This article is protected by copyright. All rights reserved QTc (Bazett's correction) calculated at 502 ms. He experienced a symptomatic sustained ventricular flutter, spontaneously resolutive, despite amiodarone. He did not receive the combined HCQ/AZT therapy.

In 2 out of 71 patients (2.8 %), the treatment had to be stopped because of significant QTc prolongation (≥ 500 ms): concurrent QT-prolonging medication polypharmacy in both patients.

The first patient was a 55 years-old female patient who was receiving an association of alimemazine/levomepromazine/zuclopenthixol (Figure 1 and 2) Figure 3 ). Of note, 9 out of 71 (12.6 %) patients showed a delta QTc prolongation above 60 ms after two days of combined therapy. No further QTc prolongation above 500 ms was observed at the end of the therapy in these 9 patients. The delta QTc variations are provided in Figure 4 .

This article is protected by copyright. All rights reserved major differences concern the methods of QT measurement (automated and manual, with Bazett and Fridericia's correction in our study); in comparison with a "manual-only" QT determination (Bazett's correction in the Lyon experience). 5 Nevertheless, the exact similar proportion of patients with a delta QTc prolongation above 60 ms was found in all centers (12.6 % in our study, 12 % in the experience from New York, 13 % in Boston).

This safety profile could be achieved thanks to the validation of an institutional protocol combining strict clinical, biological (potassium level above 4.0 mmol/L), and ECG criteria. Of

This article is protected by copyright. All rights reserved note, our protocol was in line with the guidance document edited from the Heart Rhythm Society, Conflicting results may be observed concerning the potential for QT prolongation with AZT.

While several cases reported the occurrence TdP with AZT, either in the presence of congenital long QT syndrome or without. 28 , 29 In contrast, another study showed the absence of QTc prolongation in hospitalized patients treated with AZT. 8 The authors showed that communityacquired pneumonia by itself creates an arrhythmogenic situation (with a higher pneumonia score representing a risk factor for QT prolongation ECG monitoring for hospitalized patients is challenging. 12-lead ECG acquisition for each COVID-19 infected patient faces significant limitation because it implies an additional exposure for the nurses, and the necessity to repeat the ECG increases exposure of complex equipment

What is the current knowledge on the topic?

. Few data are available concerning QT prolongation induced by HCQ/AZT association, and their torsadogenic potential, in the context of COVID-19 disease. But safety concerns have been recently raised in recently published data (33% of extreme QT prolongation above 500 ms).

What question did this study address?

. Our objective was to assess in patients hospitalized for COVID-19 LRTI variations of QT interval under HCQ/AZT, applying a strict protocol for QT monitoring. Secondly, we wanted to compare manual versus automated QT measurements.

What does this study add to our knowledge?

. Our study showed that the combined therapy HCQ/AZT (currently under evaluation for the treatment of COVID-19 disease), could be administered in more than 94% of inpatients who presented LRTI, after careful clinical, ECG and biological assessment followed by ECG monitoring. The safety profile of this therapeutic association (delivered over a short period of time) was achieved provided a strict institutional protocol was followed.

How might this change clinical pharmacology or translational science?

. While relatively accurate, the automated QTc measurement moderately underestimates the QTc interval compared to manual measurement. Thus, confirmation of definitive QTc value by a cardiologist is still warranted.

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Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine. Case Rep Cardiol

Azithromycin-induced proarrhythmia and cardiovascular death

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

Risk of QT Interval Prolongation Associated With Use of

We thank all the teams (medical and paramedical staffs) involved in the care of inpatients and facing the SARS-CoV-2 pandemic every day. 

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