key: cord-0988181-34l5ywz1
authors: Diaz‐Arocutipa, Carlos; Brañez‐Condorena, Ana; Hernandez, Adrian V.
title: QTc prolongation in COVID‐19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir: A systematic review and meta‐analysis
date: 2021-04-03
journal: Pharmacoepidemiol Drug Saf
DOI: 10.1002/pds.5234
sha: a34f4522d1897c6503e4f2dcfa31dd564b485e46
doc_id: 988181
cord_uid: 34l5ywz1

PURPOSE: Hydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir are drugs that were used for the treatment of coronavirus disease 2019 (COVID‐19) during the early pandemic period. It is well‐known that these agents can prolong the QTc interval and potentially induce Torsades de Pointes (TdP). We aim to assess the prevalence and risk of QTc prolongation and arrhythmic events in COVID‐19 patients treated with these drugs. METHODS: We searched electronic databases from inception to September 30, 2020 for studies reporting peak QTc ≥500 ms, peak QTc change ≥60 ms, peak QTc interval, peak change of QTc interval, ventricular arrhythmias, TdP, sudden cardiac death, or atrioventricular block (AVB). All meta‐analyses were conducted using a random‐effects model. RESULTS: Forty‐seven studies (three case series, 35 cohorts, and nine randomized controlled trials [RCTs]) involving 13 087 patients were included. The pooled prevalence of peak QTc ≥500 ms was 9% (95% confidence interval [95%CI], 3%–18%) and 8% (95%CI, 3%–14%) in patients who received hydroxychloroquine/chloroquine alone or in combination with azithromycin, respectively. Likewise, the use of hydroxychloroquine (risk ratio [RR], 2.68; 95%CI, 1.56–4.60) and hydroxychloroquine + azithromycin (RR, 3.28; 95%CI, 1.16–9.30) was associated with an increased risk of QTc prolongation compared to no treatment. Ventricular arrhythmias, TdP, sudden cardiac death, and AVB were reported in <1% of patients across treatment groups. The only two studies that reported individual data of lopinavir/ritonavir found no cases of QTc prolongation. CONCLUSIONS: COVID‐19 patients treated with hydroxychloroquine/chloroquine with or without azithromycin had a relatively high prevalence and risk of QTc prolongation. However, the prevalence of arrhythmic events was very low, probably due to underreporting. The limited information about lopinavir/ritonavir showed that it does not prolong the QTc interval.

Currently, there is evidence that only a few drugs such as dexamethasone 3 and remdesivir 4 have shown a beneficial effect in patients with COVID-19, although several clinical trials for other therapies are still ongoing. 5, 6 It was reported that hydroxychloroquine and chloroquine possess antiviral properties in vitro against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 7, 8 Thus, has been initially hypothesized that these drugs could be useful for the management of COVID- 19. An early open-label non-randomized clinical trial suggested a potential benefit with the use of hydroxychloroquine with or without azithromycin in COVID-19 patients. 9 On March 28, 2020, the Food and Drug Administration authorized the emergency use of hydroxychloroquine and chloroquine in hospitalized COVID-19 patients. 10 Although this authorization was posteriorly withdrawn (June 15, 2020) for use in the United States of America, 11 it was a treatment option in many countries where they were administered alone or in combination with azithromycin. 12, 13 Lopinavir/ritonavir is another class of drug which, based on his in vitro activity against other coronavirues, has also been used in COVID-19 patients. 14, 15 As a result, these agents were widely used off-label for COVID-19 treatment worldwide during the early pandemic period. However, it is previously recognized that these drugs can prolong the corrected QT (QTc) interval which, in turn, can trigger life-threatening arrhythmias, particularly Torsades de Pointes (TdP). 16 Thus, there is an increasing concern about these serious adverse events in the current COVID-19 pandemic.

Recently, several studies that assessed the cardiac safety profile of these drugs have been published. Therefore, we conducted a systematic review and meta-analysis to evaluate the prevalence and risk of QTc prolongation and arrhythmic events in COVID-19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir.

This review was reported according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement 17 Table S1 in Data S1.

We conducted a hand-searching of reference lists of all included articles and relevant reviews to identify further studies. We also searched the articles citing the selected studies (retrieve through Google Scholar), the clinicaltrials.gov registry, and the preprint servers medRxiv (https://www.medrxiv.org/) and SSRN (https:// www.ssrn.com/).

The inclusion criteria were the following: (i) studies that included adult patients (≥18 years of age) with COVID-19 confirmed by reverse transcription-polymerase chain reaction; (ii) studies that evaluated any dose, timing, and duration of hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir treatment;

(iii) studies that reported at least one of the primary or secondary outcomes; (iv) case series, cross-sectional, case-control, cohort studies, and randomized controlled trials (RCTs). Case reports, abstracts, editorials, commentaries, systematic reviews, and narrative reviews were excluded.

• Our systematic review and meta-analysis showed that the prevalence of QTc prolongation was relatively high in COVID-19 patients treated with hydroxychloroquine/ chloroquine alone or in combination with azithromycin.

• The use of hydroxychloroquine or hydroxychloroquine + azithromycin was associated with three times higher risk of QTc prolongation in comparison to no treatment.

• The prevalence of ventricular arrhythmic events was very low across treatment groups, probably due to underreporting.

• The scarce published data about lopinavir/ritonavir showed that it does not prolong the QTc interval.

• Hydroxychloroquine, chloroquine, azithromycin and lopinavir/ritonavir should be used under adequate clinical and electrocardiographic monitoring.

Two review authors (CDA and ABC) downloaded all articles from electronic search to EndNote X8 and duplicate records were removed. All unique articles were uploaded to Rayyan QCRI (https://rayyan.qcri. org/). Titles and abstracts were independently screened by two review authors (CDA and ABC) to identify relevant studies. Likewise, two review authors (CDA and ABC) independently examined the fulltext of all selected studies and registered the reasons for exclusion.

Any disagreement on title/abstract and full-text selection was resolved by consensus through face-to-face discussion.

The primary outcome was peak QTc interval ≥ 500 ms (maximum QTc during or after treatmentbaseline QTc ≥500 ms). Secondary outcomes were peak QTc interval (maximum QTc during or after treatment), peak change of QTc interval (maximum QTc during or after treatmentbaseline QTc), peak QTc change ≥60 ms (maximum QTc during or after treatmentbaseline QTc ≥60 ms), ventricular arrhythmias, TdP, sudden cardiac death, and atrioventricular block (atrioventricular block). Author-reported definitions were used for all outcomes. We decided to change the primary outcome to peak QTc interval ≥500 ms due to its higher reporting across included studies in comparison to the outcome described in the protocol.

The information from each selected study was independently extracted by two review authors (CDA and ABC) using a standardized data extraction form in an Excel spreadsheet that was previously piloted. Any disagreement was resolved by consensus. If additional data was needed, we contacted the corresponding author through email to request further information. The following data were extracted: first author name, publication year, country, study design, sample size, eligibility criteria, age, sex, comorbidities, use of hydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir (dose, timing, and duration), use of other QT-prolonging drugs, timing of electrocardiogram (ECG) assessment, QT interval correction formula, peak QTc interval ≥500 ms, peak QTc change ≥60 ms, peak QTc interval, peak change of QTc interval, ventricular arrhythmias, TdP, sudden cardiac death, and atrioventricular block. 

The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias for cohort studies. 18 Each study was classified in the following groups: high risk of bias (0-4 points), moderate risk of bias (5-7 points), and low risk of bias (8-9 points). RCTs were evaluated using the Cochrane Risk of Bias 2.0 tool. 19 Overall, each RCT was judged as having a low, some concerns, or a high risk of bias. The risk of bias of case series studies was not possible to assess given these studies do not have control groups by definition. Two review authors (CDA and ABC)

independently assessed the risk of bias for each study and any disagreement was resolved by consensus.

All meta-analyses were conducted using a random-effects model. The between-study variance (tau 2 ) was estimated using the DerSimonian-Laird estimator. We pooled the prevalence of patients with peak QTc interval ≥500 ms and peak QTc change ≥60 ms with their 95% confidence interval (95%CI) using the inverse variance method and the Freeman-Tukey double arcsine transformation. For combining studies with a control group and data on QTc prolongation, we use risk ratio (RR) with their 95%CI. The means of peak QTc interval and peak change of QTc interval with their 95%CI were also pooled. Also, we estimate point-prevalence with their 95%CI for ventricular arrhythmias, TdP, sudden cardiac death, and atrioventricular block.

All meta-analyses were performed according to the treatment groups (hydroxychloroquine/chloroquine and hydroxychloroquine/ chloroquine + azithromycin) and only studies with 10 or more patients were combined. In the case of studies have only reported median and interquartile range, the mean and standard deviation were calculated using the method proposed by Wan et al. 20 We evaluated statistical heterogeneity using the chi-squared test (threshold p < 0.10) and the I 2 statistic. Statistical heterogeneity was defined as low if I 2 < 30%, moderate if I 2 is 30%-60%, and high if I 2 > 60%. Funnel plots were used to F I G U R E 2 Prevalence of peak QTc interval ≥500 ms in COVID-19 patients evaluate publication bias and the Egger's test was performed to measure asymmetry of funnel plots only if 10 or more studies were included. 21 We performed all meta-analyses using the "meta" package from R 3.6.3 (http://www.r-project.org/). A two-tailed p < 0.05 was considered as statistically significant. 

The main characteristics of the 47 included studies (three case series, 35 cohorts, and nine RCTs, n = 13 087) are summarized in Table S2 in Data S1. Fifty-eight percent of the study population was (Table S2 in Data S1).

The timing of ECG evaluation was most frequently performed before and after initiation of treatment in 25 out of 35 studies, while the daily evaluation was only conducted in four studies. The most common method (27 studies) for heart rate correction of the QT interval was the Bazett's formula. In 19 of 23 studies, the QT interval was measured by a cardiologist (Table S2 in Data S1).

Thirty-four out of 35 cohort studies were at moderate risk of bias while the remaining one cohort study was at low risk of bias (Table S3 in Data S1). Four RCTs were scored as high risk of bias, two RCTs as some concerns, and three studies as low risk of bias ( Figure S1 in Data S1).

3.4 | Hydroxychloroquine/chloroquine with or without azithromycin

In eight studies (seven cohorts and one RCT, n = 831), the pooled prevalence of patients with peak QTc interval ≥500 ms was 9% (95% CI, 3%-18%; I 2 = 90%) in the hydroxychloroquine/chloroquine group ( Figure 2 ).

In 15 studies (one case series, 13 cohorts, and one RCT, n = 1562), the pooled prevalence of patients with peak QTc interval F I G U R E 4 Mean peak QTc interval in COVID-19 patients ≥500 ms was 8% (95%CI, 3%-14%; I 2 = 92%) in the hydroxychloroquine/chloroquine + azithromycin group (Figure 2) . The funnel plot did not show asymmetry and Egger's test was not significant (p = 0.12) ( Figure S2 in Data S1).

In six cohort studies (n = 366), the pooled prevalence of patients with peak QTc change ≥60 ms was 6% (95%CI, 0%-16%; I 2 = 73) in the hydroxychloroquine/chloroquine group (Figure 3 ).

In 12 studies (two case series and 10 cohorts, n = 4274), the pooled prevalence of patients with peak QTc change ≥60 ms was 10% (95%CI, 5%-16%; I 2 = 96%) in the hydroxychloroquine/chloroquine + azithromycin group (Figure 3) . The funnel plot showed asymmetry which was significant on Egger's test (p < 0.01) ( Figure S3 in Data S1).

In 10 cohort studies (n = 1052), the pooled mean peak QTc interval was 458.5 ms (95%CI, 436.6-480.4 ms; I 2 = 99%) in the hydroxychloroquine/chloroquine group (Figure 4) . The funnel plot did not show asymmetry and Egger's test was not significant (p = 0.08) ( Figure S4 in Data S1).

In 18 studies (two case series and 16 cohorts, n = 1449), the pooled mean peak QTc interval was 457.4 ms (95%CI, 451.5-463.4 ms; I 2 = 88%) in the hydroxychloroquine/chloroquine + azithromycin group (Figure 4) . The funnel plot showed asymmetry which was significant on Egger's test (p = 0.04) ( Figure S5 in Data S1).

In seven studies (one case series and six cohorts, n = 505), the pooled mean peak QTc change was 24.8 ms (95%CI, 9.6-40.1 ms; I 2 = 95%) in the hydroxychloroquine/chloroquine group ( Figure 5 ).

In 11 studies (one case series and 10 cohorts, n = 1168), the pooled mean peak QTc change was 29.6 ms (95%CI, 22.5-36.7 ms; I 2 = 89%) in the hydroxychloroquine/chloroquine + azithromycin group ( Figure 5 ).

The funnel plot did not show asymmetry and Egger's test was not significant (p = 0.14) ( Figure S6 in Data S1).

F I G U R E 5 Mean peak QTc change in COVID-19 patients

In 15 studies (one case series, 11 cohorts, and three RCTs, n = 2340), 16 episodes (0.68%; 95%CI, 0.39%-0.11%) of ventricular arrhythmias were reported in patients treated with hydroxychloroquine/chloroquine (Table S2 in Data S1).

In 24 studies (two case series, 19 cohorts, and three RCTs, n = 6368), 25 episodes (0.39%; 95%CI, 0.25%-0.58%) of ventricular arrhythmias were reported in patients treated with hydroxychloroquine/ chloroquine + azithromycin (Table S2 in Data S1).

In nine studies (one case series, seven cohorts, and one RCT, n = 1500), one episode (0.07%; 95%CI, 0%-0.37%) of TdP were reported in patients who received hydroxychloroquine/chloroquine (Table S2 in Data S1).

In 14 studies (one case series and 13 cohorts, n = 5338), three episodes (0.06%; 95%CI, 0.01%-0.16%) of TdP were reported in patients who received hydroxychloroquine/chloroquine + azithromycin (Table S2 in Data S1).

In seven studies (six cohorts and one RCT, n = 660), no episodes of sudden cardiac death were reported in patients treated with hydroxychloroquine/chloroquine (Table S2 in Data S1).

In 15 studies (13 cohorts and two RCTs, n = 5199), two episodes (0.04%; 95%CI, 0%-0.14%) of sudden cardiac death were reported in patients treated with hydroxychloroquine/chloroquine + azithromycin (Table S2 in Data S1).

In six studies (five cohorts and one RCT, n = 1207), a total of 12 episodes (0.99%; 95%CI, 0.52%-1.73%) of atrioventricular block were reported. Eleven episodes of first-degree atrioventricular block and one episode of atrioventricular block requiring intervention were founded (Table S2 in Data S1). These patients received hydroxychloroquine with or without azithromycin.

Eight studies with data on QTc prolongation reported a control group (five cohorts and three RCTs). All studies defined the control group without treatment. The dosage of hydroxychloroquine and azithromycin was heterogeneous across studies. Also, only four studies reported the cut-off for the definition of QTc prolongation (range 450-500 ms) and five studies did not describe the timing of ECG assessment.

In seven studies (four cohorts and three RCTs, n = 1139), the use of hydroxychloroquine was associated with a higher risk of QTc prolongation (RR, 2.68; 95%CI, 1.56-4.60; p < 0.01; I 2 = 0%) ( Figure 6 ).

F I G U R E 6 Forest plot showing risk ratio and 95% confidence intervals for the effect of hydroxychloroquine on QTc prolongation in COVID- 19 patients In three studies (two cohorts and one RCT, n = 1264), the use of hydroxychloroquine + azithromycin was also associated with a higher risk of QTc prolongation (RR, 3.28; 95%CI, 1. 16-9.30 ; p = 0.03; I 2 = 40%) (Figure 7 ).

The individual effect of lopinavir/ritonavir on cardiac safety outcomes was only evaluated in three studies (n = 156). Two studies reported no cases of QTc prolongation and one study reported one episode of third-degree atrioventricular block (Table S2 in Data S1).

A sensitivity analyses were performed excluding studies that used the Fridericia formula as the only method for the correction of the QT interval and excluding the case series. No significant differences were found compared to the main analysis (Tables S4 and S5 in Data S1).

In our review, we found that the pooled prevalence of peak QTc interval ≥500 ms and peak QTc change ≥60 ms ranged from 6% to 10% in patients treated with hydroxychloroquine/chloroquine with or without azithromycin. The use of hydroxychloroquine and hydroxychloroquine + azithromycin was associated with three times higher risk of QTc prolongation compared with no treatment. The pooled mean peak QTc change varied between 24.8 and 29.6 ms across treatment groups. In contrast, the prevalence of ventricular arrhythmias, TdP, sudden cardiac death, and atrioventricular block was <1%.

Two studies that reported individual data about cardiac safety of lopinavir/ritonavir found no patients with QTc prolongation. The only two studies that reported individual data of lopinavir/ritonavir on QTc prolongation found no cases.

Given the urgent need for useful drugs for COVID-19 management, many repurposed drugs were prescribed in a compassionate manner until more robust data was available. 14 However, two recent systematic reviews have shown that there is insufficient and conflicting evidence of the benefit of treatment with hydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir in COVID-19. 5, 69 It is important to remark that repurposing medications for new diseases does not come without the medications known adverse effects and these need to be considered when using them outside of their primary indication. Hydroxychloroquine and chloroquine are drugs commonly used for the treatment of malaria and rheumatological conditions. Although both drugs are generally well-tolerated, they have been associated with an increased risk of QTc prolongation and TdP through blockage of HERG/Kv11.1 potassium channel. 16 The torsadogenic potential of these drugs could be amplified if other QTc-prolonging drugs such as azithromycin and lopinavir/ritonavir are additionally used.

Moreover, it is possible that the arrhythmic risk can be even worse in patients with COVID-19 due to the high prevalence of pre-existing heart diseases, electrolyte imbalance, systemic inflammatory process, and myocardial injury observed in COVID-19 patients. 16 In a large pre-pandemic study of 41 649 hospitalized patients, QTc prolongation was present in the 0.7%, but only 3.8% of those with prolonged QTc interval experienced life-threatening arrhythmias. 70 Other agents (such as procainamide, sotalol, and dofetilide) with known QTc-prolonging effect appears to have a TdP incidence of 1% to 10%. 71 In comparison, our study found a prevalence of about 10% of QTc prolongation in COVID-19 patients who were treated with hydroxychloroquine with or without azithromycin. Furthermore, F I G U R E 7 Forest plot showing risk ratio and 95% confidence intervals for the effect of hydroxychloroquine + azithromycin on QTc prolongation in COVID-19 patients it has been reported that up to 38% of critically ill COVID-19 patients presented mild QTc prolongation (>460 ms) at hospital admission, before starting any potentially QT-prolonging drug. 72 This suggests that additional mechanisms responsible for QTc prolongation exist in patients with COVID-19. However, when studies with a control group were pooled, we found that the risk of QTc prolongation was higher in patients who received hydroxychloroquine or hydroxychloroquine + azithromycin compared to those who did not. In addition, many other factors (such as the use of other QT-prolonging drugs and frequency of ECG evaluation) could have influenced the prolongation of QT interval. Therefore, it seems clear that the use of these drugs in COVID-19 patients increases the risk of QTc prolongation, but the relatively high estimated proportion could be overestimated. Our review also shows that ventricular arrhythmias, TdP, and sudden cardiac death were rare events. The very low proportion of these arrhythmic complications can be explained by the short-course duration of COVID-19 therapy, underreporting of arrhythmias, and close ECG monitoring in high-risk cases which allows early discontinuation of QTc-prolonging drugs.

In a recent pharmacovigilance study involving more than 10 million patients, the hydroxychloroquine use was associated with higher reporting of complete atrioventricular block (odds ratio: 2.30, 95%CI 1. 55-3.41) . 73 Has been found that in nearly half of COVID-19 patients, the PR interval showed paradoxical prolongation or lack of shortening with increasing heart rate. 74 This abnormal PR interval behavior could be explained by the action of anticardiolipin antibodies (reported in COVID-19 patients) on the cardiac conduction system. 74 Although we found a low prevalence (1%) of atrioventricular block in COVID-19 patients, only one case of atrioventricular block requiring intervention was documented.

Lopinavir/ritonavir is a combination of protease inhibitor with nucleoside analog that is commonly used for the treatment of human immunodeficiency virus. This drug has shown a favorable clinical response in patients with severe acute respiratory syndrome caused by a previous coronavirus, thus it has been used in the current COVID-19 pandemic. 14 However, recent studies have reported no clinical benefits in COVID-19. 26, 75 Although lopinavir/ritonavir is included in the group of agents that can prolong the QTc interval, the limited information about their pro-arrhythmic effect in COVID-19 patients showed no cases with QTc prolongation. 76 However, there is still insufficient evidence about the cardiac safety profile of this drug.

In the absence of strong efficacy data, all treatments should be individualized in each patient. Our study raises important cardiac safety concerns about the "off-label" use of these repurposed drugs in COVID-19. Although the proportion of individuals at risk for lethal arrhythmias is very small, given the rapid global spreading of COVID-19, the absolute number of potentially affected people is large. Several scientific societies such as the European Society of Cardiology, 77 Heart Rhythm Society, 78 and Canadian Heart Rhythm Society 79 have issued recommendations to minimize the risk of QTc prolongation and arrhythmic events during COVID-19 treatment.

These recommendations are focused on the identification of patients at high risk for drug-induced ventricular arrhythmias through baseline and follow-up ECG monitoring, discontinuation of unnecessary drugs that can prolong the QTc interval, and correction of electrolyte disturbances (e.g., hypocalcemia, hypokalemia, and hypomagnesemia).

There is only one published systematic review examining the effect of hydroxychloroquine or chloroquine on QTc interval and its related arrhythmic events in COVID-19. 80 However, this review only conducted a narrative synthesis of 11 studies without risk of bias assessment. In comparison, our review included more studies (n = 47), performed the meta-analyses for relevant cardiac safety outcomes, and evaluated the risk of bias for all studies.

Our study has some limitations. First, given that most of the included studies were observational, causality cannot be concluded. 

Our meta-analysis shows evidence that COVID-19 patients treated with hydroxychloroquine/chloroquine with or without azithromycin had a relatively high prevalence of peak QTc interval ≥500 ms and peak QTc change ≥60 ms. Likewise, the risk of QTc prolongation was higher in patients who received hydroxychloroquine and hydroxychloroquine + azithromycin compared to no treatment. In contrast, the prevalence of reported arrhythmic events was very low, probably due to underreporting. The limited data about lopinavir/ritonavir showed that it does not prolong the QTc interval. Therefore, these drugs should be used under adequate clinical and electrocardiographic monitoring.

The authors declare no conflict of interest.

All authors contributed to the study conception and design. Articles selection, data extraction, and data analysis were performed by Carlos Diaz-Arocutipa and Ana Brañez-Condorena. The first draft of the manuscript was written by Carlos Diaz-Arocutipa and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

The authors state no ethical approval was needed.

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Dexamethasone in hospitalized patients with Covid-19 -preliminary report

Remdesivir for the treatment of Covid-19 -Final Report

Drug treatments for covid-19: living systematic review and network meta-analysis

Characteristics of COVID-19 clinical trials registered with ClinicalTrials.gov: cross-sectional analysis

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

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

Request for Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease

Letter revoking EUA for chloroquine phosphate and hydroxychloroquine sulfate

Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment

Orientações do ministério da saúde para manuseio medicamentoso precoce de pacientes com diagnóstico da COVID-19

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19)

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis

RoB 2: a revised tool for assessing risk of bias in randomised trials

Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range

Bias in metaanalysis detected by a simple, graphical test

Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19: a quasirandomized comparative study

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

Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial

QT interval prolongation under hydroxychloroquine/ azithromycin association for inpatients with SARS-CoV-2 lower respiratory tract infection

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Inpatient use of ambulatory telemetry monitors for COVID-19 patients treated with hydroxychloroquine and/or azithromycin

Randomized, Open-label, Controlled Trial to Evaluate the Efficacy and Tolerability of Hydroxychloroquine and a Retrospective Study in Adult Patients with Mild to Moderate Coronavirus Disease 2019 (COVID-19). medRxiv

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin

QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin

Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary Results from a

Controlled Trial. medRxiv

QT prolongation in a diverse, urban population of COVID-19 patients treated with hydroxychloroquine, chloroquine, or azithromycin

Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients -An Observational Study. medRxiv

Enhanced electrocardiographic monitoring of patients with Coronavirus Disease

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis

Comparison of hydroxychloroquine, lopinavir/ritonavir, and standard of care in critically ill patients with SARS-CoV-2 pneumonia: an opportunistic retrospective analysis

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

Incidence and determinants of QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin

Association of hydroxychloroquine with QTc interval in patients with COVID-19. Circulation

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)

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe Covid-19 in a French university hospital

Experience of short-term hydroxychloroquine and azithromycin in COVID-19 patients and effect on QTc trend

COVID-19 in solid organ transplant recipients: initial report from the US epicenter

Safety use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: clinical experience in a Belgian tertiary center

Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring

Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State

Effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection

The risk of QTcinterval prolongation in COVID-19 patients treated with chloroquine

Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

Chloroquine-induced QTc prolongation in COVID-19 patients

The effect of 5-day course of hydroxychloroquine and azithromycin combination on QT interval in non-ICU COVID19(+) patients

Assessing QT interval in COVID-19 patients: safety of hydroxychloroquine-azithromycin combination regimen

Lopinavirritonavir treatment for COVID-19 infection in intensive care unit: risk of bradycardia

A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19

Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19

Prolonged QT interval in SARS-CoV-2 infection: prevalence and prognosis

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial

Hydroxychloroquine and azithromycin tolerance in haemodialysis patients during COVID-19 infection

Clinical outcomes and adverse events in patients hospitalised with COVID-19, treated with off-label hydroxychloroquine and azithromycin

Hydroxychloroquine and azithromycin as a treatment of Covid-19: electrocardiogram variability

Predictive factors for cardiac conduction abnormalities with hydroxychloroquine-containing combinations for COVID-19

Safety and effectiveness of azithromycin in patients with COVID-19: an open-label randomised trial

QT interval and arrhythmic safety of hydroxychloroquine monotherapy in coronavirus disease 2019

QT interval measurement with portable device during COVID-19 outbreak

Update alert 2: hydroxychloroquine or chloroquine for the treatment or prophylaxis of COVID-19

Acquired long QT syndrome in hospitalized patients

Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation

Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement

A pharmacovigilance study of hydroxychloroquine cardiac safety profile: potential implication in COVID-19 mitigation

No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY

Efficacy and safety of antiviral treatment for COVID-19 from evidence in studies of SARSCoV-2 and other acute viral infections: a systematic review and meta-analysis

ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic

Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology

Guidance on minimizing risk of drug-induced ventricular arrhythmia during treatment of COVID-19: a statement from the Canadian Heart Rhythm Society

QT prolongation, Torsades de Pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review

QTc prolongation in COVID-19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir: A systematic review and meta-analysis

PATIENT CONSENT Not applicable.

Carlos Diaz-Arocutipa https://orcid.org/0000-0002-5101-2832