key: cord-0988834-7hdfzbkw
authors: Voisin, Olivier; Lorc’h, Erwan le; Mahé, Annabelle; Azria, Philippe; Borie, Marie-Françoise; Hubert, Sidonie; Ménage, Elodie; Guillerm, Jean-Christophe; Mourad, Jean-Jacques
title: ACUTE QT INTERVAL MODIFICATIONS DURING HYDROXYCHLOROQUINE-AZITHROMYCIN TREATMENT IN THE CONTEXT OF COVID-19 INFECTION.
date: 2020-05-20
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.005
sha: 1103bdb4a28f5440dfcafbaee7794f974cd5ca95
doc_id: 988834
cord_uid: 7hdfzbkw

Abstract Among candidate drugs to treat COVID-19, the combination of hydroxychloroquine (HCQ) and azithromycin (AZ) has received intense attention. Even if the efficacy of this combination is under evaluation, clinicians have begun to use it largely. As these medications are known to prolong QT interval, we analyzed serial electrocardiograms (ECG) performed in patients hospitalized for COVID-19 pneumonia and treated with HCQ + AZ. 50 consecutive patients received the combination of HCQ (600mg/d for 10 days) and AZ (500mg Day 1 and 250mg daily days 2 to 5). Twelve-lead ECG were performed before treatment, at Day 3, 5 and at discharge. Median age of patients was 68 years, 55.2% were males. Main comorbidities were hypertension (37%) and diabetes (17%). Mean QTc was 408 ms at baseline and rose up to 437 ms at Day 3 and to 456 ms at Day 5. 38 patients (76 %) presented short term modifications of QTc (> 30 ms). Treatment discontinuation was decided in 6 patients (12%) leading to QTc normalization in 5 of them. No death, no cardiac arrhythmic event were observed in this cohort. Our report confirms that a short duration treatment with HCQ + AZ modifies QTc interval. Treatment has to be stopped for QTc modifications in 12% of patients. Nevertheless, in inpatients hospitalized for COVID-19, we did not observe any clinically relevant consequence of these transitory modifications. In conclusion, when patients are treated with HCQ+AZ, cardiac monitoring should be regularly performed and hospital settings allow to do it in safe conditions.

to QTc normalization in 5 of them. No death, no cardiac arrhythmic event were observed in this cohort.

Our report confirms that a short duration treatment with HCQ + AZ modifies QTc interval. Treatment has to be stopped for QTc modifications in 12% of patients. Nevertheless, in inpatients hospitalized for COVID-19, we did not observe any clinically relevant consequence of these transitory modifications. In conclusion, when patients are treated with HCQ+AZ, cardiac monitoring should be regularly performed and hospital settings allow to do it in safe conditions. ABBREVATIONS: AZ = Azithromycin; ECG = electrocardiogram; HCQ = Hydroxychloroquine; IQR = interquartile range; TdP = Torsades de pointe CONTEXT Since December 2019, world has faced an emerging and pandemic COVID-19 disease, leading to severe acute respiratory syndrome caused by a newly discovered coronavirus (SARS-CoV-2). As this report is submitted (mid-April 2020), 2 million people are already infected across the world, resulting in 150000 deaths. 1 Thus, there is an urgent need for both effective and safe treatments to prevent hypoxemic respiratory failure and death. 2 Among candidate drugs to treat COVID-19, hydroxychloroquine (HCQ) and azithromycin (AZ) have received intense worldwide attention. HCQ was recently associated with viral load reduction both in vitro and in infected patients, alone or combined with AZ. 3, 4 Even if clinical efficacy of HCQ +/-AZ is still under evaluation with controversial results, these agents, alone or combined, are up to now among the most largely tested and clinicians have begun to use them for compassionate reason in COVID-19 patients. 5, 6 In early April 2020, FDA has even issued an emergency use authorization for HCQ in the treatment of COVID-19 patients. 7 However, as HCQ and AZ are medications known to prolong QT interval, their large use raises concerns about the potential risk of "torsades de pointes" (TdP) and arrhythmic death. 8 This warning was recently pointed out by several scientific societies and national health authorities, which reinforce that such treatments given in the COVID context should be exclusively monitored at hospital level, notably in elderly population with frequent concomitant cardiac disease or electrolyte disorders (i.e., hypokalemia, hypomagnesemia, hypocalcemia). [9] [10] [11] [12] The interference of HCQ on ventricular repolarization is known to be dose-dependent but significantly varies among individuals. 13-15 AZ does not usually cause significant prolongation of the QTc interval but its use in combination with HCQ could theoretically increase the risk of TdP. 16 To date, there is limited data evaluating the ECG modifications induced by the combination therapy 17 and very few in the context of COVID-19 infection. 18, 19 AIM Given the vast adoption of this regimen, we decided to analyze serial ECG's performed in patients hospitalized in our department for COVID-19 pneumonia and treated with both HCQ and AZ.

From March 18 th 2020 to March 25 th 2020, 50 consecutive patients were proposed to be treated with the combination of hydroxychloroquine (600mg/d for 10 days) and azithromycin (500mg Day 1 and 250mg daily days 2 to 5). Twelve-lead electrocardiograms (ECG) were performed on each patient before treatment, three and five days after treatment intake and the day of discharge. The treatment was not started in patients with contraindications, including hypokalemia or when the corrected QT (QTc) was > 500 ms, taking as a reference the Bazett's formula. The treatment was discontinued if there was a QTc increase of + 60 ms compared to baseline or when the QTc was > 500 ms. 20 We also paid close attention to potential drug interactions, especially those that could prolong the QTc (i.e., to prespecified QTc criteria was decided in 6 patients (12%). Of these patients, 5 normalized their QTc when treatment was stopped. One patient remained stable (500 ms) at Day 2 after withdrawal, and then was discharged. In the population where HCQ+AZ had to be interrupted, mean baseline QTc were higher than in the global population of this study (433 ms and 408 ms, respectively). No death, no clinical cardiac event or torsades de pointes were observed in this cohort.

These results demonstrate that treatment with the combination of HCQ + AZ significantly and progressively increases QTc intervals (+ 29 ms at Day 3, + 48 ms at Day 5). These increases appear to be dose and time dependent, as previously described in literature. 16 Importantly, QTc intervals decrease when AZ was stopped and HCQ maintained, between Day 5 and discharge. They confirm the need for regular cardiac monitoring even if the treatment had to be stopped in a relatively small proportion of patients (12%). Hospital settings seems an appropriate location to perform the monitoring, according to the number of ECG needed. Interestingly, higher baseline QTc were observed in the population where HCQ+AZ has to be interrupted, highlighting the need for careful monitoring when initial QTc values are above 430 ms.

To date, there is very few data evaluating the ECG modifications induced by the HCQ + AZ combination in the context of COVID-19 infection. In a retrospective study of 84 patients, Chorin et al. showed that in 30% of patients QTc increased by greater than 40ms. In 11% of patients QTc increased to > 500 ms. These findings are in line with our results. Interestingly, they noted that the development of acute renal failure but not baseline QTc was a strong predictor of extreme QTc prolongation. 19 More recently, Mahevas et al. performed a cohort study with 84 SARS-CoV-2 pneumonia patients treated with HCQ. 6 Even if the proportion of patients concomitantly receiving HCQ + AZ was not described in the study, 9.5% of patients experienced ECG modifications requiring HCQ discontinuation at a median of 4 days after its introduction. Here again, these results are in line with our findings, highlighting the additive effect, even if probably moderate, of AZ on QT modification when combined to HCQ.

Our study has several limitations. Among them, its monocentric character with limited number of patients is the most important. Secondly, ECG monitoring data were not available after discharge.

Finally, it is still premature to consider HCQ + AZ as a validated option to treat COVID patients.

However, our study allows a preliminary assessment of the electrophysiologic safety of a treatment that is currently largely used in the context of COVID-19 infection.

These results confirmed that a short duration of treatment with the combination of hydroxychloroquine and azithromycin do modify QTc interval. Nevertheless, in inpatients hospitalized for COVID-19, we did not observe any clinically relevant consequence of these transitory modifications. The treatment has to be stopped for QTc modifications in 12% of patients. In conclusion, when patients are treated with the combination of hydroxychloroquine and azithromycin, cardiac monitoring should be regularly performed and hospital settings allow to do it in safe conditions. 

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