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Cardiac Toxicity of Chloroquine or Hydroxychloroquine in Patients With COVID-19: A Systematic Review and Meta-regression Analysis

Open AccessPublished:October 31, 2020DOI:https://doi.org/10.1016/j.mayocpiqo.2020.10.005

      Abstract

      Objective

      To systematically review the literature and to estimate the risk of chloroquine (CQ) and hydroxychloroquine (HCQ) cardiac toxicity in patients with coronavirus disease 2019 (COVID-19).

      Methods

      We searched multiple data sources including PubMed/MEDLINE, Ovid Embase, Ovid EBM Reviews, Scopus, and Web of Science and medrxiv.org from November 2019 through May 27, 2020. We included studies that enrolled patients with COVID-19 treated with CQ or HCQ, with or without azithromycin, and reported on cardiac toxic effects. We performed a meta-analysis using the arcsine transformation of the different incidences.

      Results

      A total of 19 studies with a total of 5652 patients were included. The pooled incidence of torsades de pointes arrhythmia, ventricular tachycardia, or cardiac arrest was 3 per 1000 (95% CI, 0-21; I2=96%) in 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5% (95% CI, 1-11; I2=98%). The pooled incidence of change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more was 9% (95% CI, 3-17; I2=97%). Mean or median age, coronary artery disease, hypertension, diabetes, concomitant QT-prolonging medications, intensive care unit admission, and severity of illness in the study populations explained between-studies heterogeneity.

      Conclusion

      Treatment of patients with COVID-19 with CQ or HCQ is associated with an important risk of drug-induced QT prolongation and relatively higher incidence of torsades de pointes, ventricular tachycardia, or cardiac arrest. Therefore, these agents should not be used routinely in the management of COVID-19 disease. Patients with COVID-19 who are treated with antimalarials for other indications should be adequately monitored.

      Abbreviations and Acronyms:

      CAD (coronary artery disease), COVID-19 (coronavirus disease 2019), CQ (chloroquine), DM (diabetes mellitus), HCQ (hydroxychloroquine), ICU (intensive care unit), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), TdP (torsades de pointes)
      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has spread across the globe, claiming hundreds of thousands of lives and causing enormous economic losses. Repurposing of approved drugs for the treatment of COVID-19 was a logical approach before the availability of an effective vaccine.
      Among the drugs that received early attention were the antimalarial medications chloroquine (CQ) and hydroxychloroquine (HCQ). CQ and HCQ are weak bases that increase the pH of the intracellular vesicles like endosomes.
      • Tripathy S.
      • Dassarma B.
      • Roy S.
      • Chabalala H.
      • Matsabisa M.G.
      A review on possible modes of actions of chloroquine/hydroxychloroquine: repurposing against SAR-COV-2 (COVID 19) pandemic.
      These changes could affect several stages of viral life cycles from cell entry, viral replication, and viral particle assembly to viral particle release from the host cells.
      • Tripathy S.
      • Dassarma B.
      • Roy S.
      • Chabalala H.
      • Matsabisa M.G.
      A review on possible modes of actions of chloroquine/hydroxychloroquine: repurposing against SAR-COV-2 (COVID 19) pandemic.
      In addition, these vesicle pH changes interfere with antigen processing and presentation and consequently immune cell activation and production of proinflammatory cytokines.
      • Tripathy S.
      • Dassarma B.
      • Roy S.
      • Chabalala H.
      • Matsabisa M.G.
      A review on possible modes of actions of chloroquine/hydroxychloroquine: repurposing against SAR-COV-2 (COVID 19) pandemic.
      This effect is favorable in the management of autoimmune diseases like systemic lupus erythematosus and may have a favorable impact in patients with COVID-19 with cytokine storm. HCQ was also reported to improve endothelial function and to reverse prothrombotic state,
      • Miranda S.
      • Billoir P.
      • Damian L.
      • et al.
      Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: role of reduced inflammation and endothelial dysfunction.
      which is relevant to patients with COVID-19 because they manifest pulmonary vascular endothelialitis and microvascular thrombosis.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      The successful demonstration of in vitro antiviral properties of CQ and HCQ against SARS-CoV-2 led to initiation of several clinical studies testing the therapeutic potential of CQ and HCQ in COVID-19.
      • Yao X.
      • Ye F.
      • Zhang M.
      • et al.
      In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
      ,
      • Weston S.
      • Haupt R.
      • Logue J.
      • Matthews K.
      • Frieman M.B.
      FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro. bioRxiv.
      The early encouraging experience of CQ therapy in 100 patients from China led to its recommendation by the National Health Commission of China.
      • Gao J.
      • Tian Z.
      • Yang X.
      Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
      ,
      Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia
      [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia.].
      Another nonrandomized study of 20 patients with COVID-19 treated with HCQ alone or in combination with azithromycin in France showed reduced nasopharyngeal viral carrier sate at 6 days after the initiation of treatment.
      • Gautret P.
      • Lagier J.C.
      • Parola P.
      • et al.
      Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
      Despite its serious methodologic limitations, this report received exceptional attention by media and politicians and triggered a widespread off-label use of CQ and HCQ for COVID-19, with subsequent reports of CQ-related deaths.
      Arizona man dies after attempting to take Trump coronavirus 'cure.'.
      Whereas CQ and HCQ are generally considered safe, QT prolongation and torsades de pointes (TdP), ventricular tachycardia as well as other arrhythmias, myocarditis, and cardiomyopathy have been reported with chronic HCQ use.
      • Chen C.Y.
      • Wang F.L.
      • Lin C.C.
      Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia.
      • Keating R.J.
      • Bhatia S.
      • Amin S.
      • Williams A.
      • Sinak L.J.
      • Edwards W.D.
      Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction.
      • Yogasundaram H.
      • Hung W.
      • Paterson I.D.
      • Sergi C.
      • Oudit G.Y.
      Chloroquine-induced cardiomyopathy: a reversible cause of heart failure.
      • Yogasundaram H.
      • Putko B.N.
      • Tien J.
      • et al.
      Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment.
      Recent reports confirmed the increased risk of QT prolongation among patients with COVID-19.
      • Chorin E.
      • Wadhwani L.
      • Magnani S.
      • et al.
      QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.
      ,
      • Mercuro N.J.
      • Yen C.F.
      • Shim D.J.
      • et al.
      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).
      The indiscriminate use of the antimalarial medications for the treatment of COVID-19 in the absence of robust clinical evidence for their efficacy coupled with associated potential harm calls for rigorously conducted systematic reviews and meta-analyses of the available clinical data to present a clearer picture about their safety and efficacy and to provide a data-informed view regarding their utility in the treatment of COVID-19. In this study, we set to systematically review the literature regarding the cardiac toxicity of CQ or HCQ in patients with COVID-19.

      Methods

      Inclusion and Exclusion Criteria

      We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      and Meta-analysis Of Observational Studies in Epidemiology
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      guidelines for reporting systematic review and meta-analysis of observational studies. Studies that reported electrocardiographic changes or cardiac arrhythmias in patients with COVID-19 treated with CQ or HCQ with and without azithromycin were included using prespecified inclusion criteria, as follows: population of patients with COVID-19; the study included more than 10 patients receiving either one of the agents; and electrocardiographic changes or cardiac arrhythmias were reported. To avoid introducing nonindependence by including patients in the analysis more than once, we included results from the same study with the larger sample size if more than one study reported data of overlapping populations of patients.
      • Chorin E.
      • Wadhwani L.
      • Magnani S.
      • et al.
      QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.

      Literature Search

      The literature was searched by a medical librarian for the concepts of CQ or HCQ combined with COVID-19 on several databases including PubMed/MEDLINE, Ovid Embase, Ovid EBM Reviews, Scopus, and Web of Science. The search strategies were created using a combination of keywords and standardized index terms and were run up to May 27, 2020 (Supplement, available online at http://mcpiqojournal.org). We also searched for unpublished manuscripts using the medRxiv in addition to Google Scholar and the references of eligible studies and review articles.

      Data Collection and Quality Assessment

      Two authors (Z.K., O.A.) independently identified eligible studies, and 4 authors (Z.K., M.G., O.A., H.T.) extracted the data into a prespecified data collection form. We collected data about the study’s population and characteristics and different cardiac toxicity end points. A senior author verified all data included in the analyses thrice (T.K.).
      The eligible studies were assessed by the Newcastle-Ottawa quality assessment scale according to only 4 parameters relevant to our single-arm meta-analysis (by H.T., O.A., Z.K.): exposure assessment, outcome assessment, length of follow-up, and loss to follow-up rate.
      • Wells G.
      • Shea B.
      • O'Connell D.
      • et al.
      The Newcastle-Ottawa scale (NOS) for assessing the quality of non-randomized studies in meta-analysis.

      Study End Points

      End points included the incidence of the following: change in QTc interval from baseline of 60 milliseconds or more; QTc of 500 milliseconds or more; composite of change in QTc interval from baseline of 60 milliseconds or more and QTc of 500 milliseconds or more; TdP arrhythmia, ventricular tachycardia, or cardiac arrest; and discontinuation of treatment due to prolonged QT or arrhythmias.

      Statistical Analyses

      The number and percentage of patients experiencing different end points were extracted from each study. Because of the very low incidence of TdP and other end points (rare events), the arcsine transformation was used to obtain a pooled estimate of the different incidences. For meta-analyses of rare events, this transformation is more appropriate than the commonly used logit transformation as it can accommodate studies with no observed events, without requiring a continuity correction.
      • Andrikopoulou E.
      • Morgan C.J.
      • Brice L.
      • et al.
      Incidence of atrioventricular block with vasodilator stress SPECT: a meta-analysis.
      • Andreano A.
      • Rebora P.
      • Valsecchi M.G.
      Measures of single arm outcome in meta-analyses of rare events in the presence of competing risks.
      • Rücker G.
      • Schwarzer G.
      • Carpenter J.
      • Olkin I.
      Why add anything to nothing? The arcsine difference as a measure of treatment effect in meta-analysis with zero cells.
      The random effect DerSimonian and Laird model with inverse variance method was used to pool the effect estimates.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      We evaluated between-studies heterogeneity using the I2 statistic, which estimates the variability percentage in effect estimates that is due to heterogeneity rather than to chance.
      Multiple meta-regression analyses were used to assess whether the incidence of different end points significantly varied by multiple variables specified a priori. These variables were chosen on the basis of risk factors that are known to potentially increase the risk of cardiac arrhythmias (age, sex, coronary artery disease [CAD], congestive heart failure, diabetes mellitus [DM], disease severity, chronic kidney disease, intensive care unit [ICU] admission, and mortality as another surrogate of disease severity).
      We then performed sensitivity analyses by repeating these analyses after excluding 2 studies that used high-dose CQ or HCQ. Two-tailed P values less than .05 were considered to be statistically significant. All statistical analyses were performed using meta and metafor packages in R statistical software, version 3.6.3 (R Foundation for Statistical Computing).
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.

      Results

      Included Studies

      A total of 19 studies with a total of 5652 patients, including single-center and multicenter studies, were included in our systematic review.
      • Chorin E.
      • Wadhwani L.
      • Magnani S.
      • et al.
      QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.
      ,
      • Mercuro N.J.
      • Yen C.F.
      • Shim D.J.
      • et al.
      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).
      ,
      • Tang W.
      • Cao Z.
      • Han M.
      • et al.
      Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial.
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      • Perinel S.
      • Launay M.
      • Botelho-Nevers É.
      • et al.
      Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients.
      • Mahévas M.
      • Tran V.T.
      • Roumier M.
      • et al.
      Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.
      • van den Broek M.P.H.
      • Möhlmann J.E.
      • Abeln B.G.S.
      • Liebregts M.
      • van Dijk V.F.
      • van de Garde E.M.W.
      Chloroquine-induced QTc prolongation in COVID-19 patients.
      • Saleh M.
      • Gabriels J.
      • Chang D.
      • et al.
      The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection.
      • Bessière F.
      • Roccia H.
      • Delinière A.
      • et al.
      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.
      • Ip A.
      • Berry D.A.
      • Hansen E.
      • et al.
      Hydroxychloroquine and tocilizumab therapy in COVID-19 patients—an observational study.
      • Jain S.
      • Workman V.
      • Ganeshan R.
      • et al.
      Enhanced ECG monitoring of COVID-19 patients.
      • Million M.
      • Lagier J.C.
      • Gautret P.
      • et al.
      Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France.
      • Molina J.M.
      • Delaugerre C.
      • Le Goff J.
      • et al.
      No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection.
      • Rosenberg E.S.
      • Dufort E.M.
      • Udo T.
      • et al.
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state.
      • Fernández-Ruiz M.
      • Andrés A.
      • Loinaz C.
      • et al.
      COVID-19 in solid organ transplant recipients: a single-center case series from Spain.
      • Pereira M.R.
      • Mohan S.
      • Cohen D.J.
      • et al.
      COVID-19 in solid organ transplant recipients: initial report from the US epicenter.
      • Ramireddy A.
      • Chugh H.S.
      • Reinier K.
      • et al.
      Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring.
      • Cipriani A.
      • Zorzi A.
      • Ceccato D.
      • et al.
      Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin.
      • Chang D.
      • Saleh M.
      • Gabriels J.
      • et al.
      Inpatient use of ambulatory telemetry monitors for COVID-19 patients treated with hydroxychloroquine and/or azithromycin.
      Figure 1 shows the result of our search strategy. A total of 1077 records were identified; 475 were excluded because they were duplicates, and 565 records were further excluded because they were irrelevant (reviews, letters, basic science). The remaining 37 studies were fully reviewed, of which 18 studies were excluded (1 duplicate and 17 did not meet inclusion criteria). Table 1 illustrates the general characteristics of the included studies. All included studies were of high methodologic quality in terms of exposure ascertainment or outcome assessment (Table 2). Several important cardiovascular adverse events have been observed in our meta-analysis. However, reported cardiovascular adverse events varied among the included studies; therefore, we were able to include some events in the quantitative meta-analysis, whereas other events were included only in the synthesized systematic review because of insufficient data.
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of eligible studies. RCTs = randomized controlled trials.
      Table 1Characteristics of Included Studies
      StudyCountryStudy populationDrugs usedCardiac toxicityMonitoring method
      Tang et al
      • Tang W.
      • Cao Z.
      • Han M.
      • et al.
      Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial.
      ChinaHospitalized adult patients with mild to moderate or severe COVID-19 infection based on the fifth version of Chinese guidelinesHCQ 1200 mg daily for 3 days, then 800 mg daily for 2 weeks or 3 weeksQTc prolongation

      Cardiac arrhythmia during therapy course
      NR
      Borba et al
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      BrazilHospitalized adult patients with suspected COVID-19 and respiratory rate >24, heart rate >125, Spo2 <90% on room air, or shock stateHigh-dose (total dose, 12 g) or low-dose (total dose, 2.7 g) HCQ for 10 days

      Azithromycin 500 mg for 5 days
      QTc >500 milliseconds or ventricular arrhythmia for 28 daysECG on days 13 and 28

      ECG obtained at clinician’s discretion
      Perinel et al
      • Perinel S.
      • Launay M.
      • Botelho-Nevers É.
      • et al.
      Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients.
      FranceHospitalized critically ill patientsHCQ 200 mg 3 times daily for 5 daysNRNR
      Ramireddy et al
      • Ramireddy A.
      • Chugh H.S.
      • Reinier K.
      • et al.
      Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring.
      United StatesHospitalized patients with COVID-19 who were treated with azithromycin or HCQAzithromycin or HCQQT prolongation

      Cardiac arrhythmia during therapy course
      Daily ECG
      Mahévas et al
      • Mahévas M.
      • Tran V.T.
      • Roumier M.
      • et al.
      Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.
      FranceHospitalized patients with COVID-19 who received oxygen therapyHCQ 600 mg daily

      Duration NR
      QTc prolongation

      Arrhythmia
      Daily ECG until 5 days after drug discontinuation
      Cipriani et al
      • Cipriani A.
      • Zorzi A.
      • Ceccato D.
      • et al.
      Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin.
      FranceHospitalized patients with COVID-19 who were treated with azithromycin and HCQHCQ 200 mg twice daily for at least 3 days

      Azithromycin 500 mg daily
      QTc prolongation

      Arrhythmia
      Basal ECG and ECG on day 3

      Or 24-hour cardiac monitor for duration of therapy
      Chorin et al
      • Chorin E.
      • Wadhwani L.
      • Magnani S.
      • et al.
      QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.
      United States/ItalyHospitalized patients with COVID-19 who were treated with azithromycin and HCQHCQ 400 mg twice daily on day 1, then 200 mg twice daily for 4 days

      Azithromycin 500 mg daily
      QTc prolongationBaseline ECG and at least one ECG after drug administration
      van den Broek et al
      • van den Broek M.P.H.
      • Möhlmann J.E.
      • Abeln B.G.S.
      • Liebregts M.
      • van Dijk V.F.
      • van de Garde E.M.W.
      Chloroquine-induced QTc prolongation in COVID-19 patients.
      The NetherlandHospitalized patients with COVID-19 who received respiratory supportChloroquine 600 mg daily for 5 daysQTc prolongationBaseline ECG and at least one ECG after drug administration
      Saleh et al
      • Saleh M.
      • Gabriels J.
      • Chang D.
      • et al.
      The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection.
      United StatesHospitalized patients with COVID-19 who were treated with HCQ ± azithromycinHCQ ± azithromycin

      Dose and duration NR
      QTc prolongation

      Arrhythmia
      Baseline ECG, then twice-daily ECG or mobile cardiac monitoring
      Bessière et al
      • Bessière F.
      • Roccia H.
      • Delinière A.
      • et al.
      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.
      FranceHospitalized patients with COVID-19 who were admitted to intensive care unitHCQ 200 mg twice daily for 10 days ± azithromycin 250 mg for 3 daysQTc prolongationDaily ECG

      Continuous cardiac monitor
      Chang et al
      • Chang D.
      • Saleh M.
      • Gabriels J.
      • et al.
      Inpatient use of ambulatory telemetry monitors for COVID-19 patients treated with hydroxychloroquine and/or azithromycin.
      United StatesHospitalized patients with COVID-19 who were treated with HCQ ± azithromycinHCQ 400 mg twice daily on day 1, then 200 mg twice daily for 4 days

      ± Azithromycin 500 mg daily
      QTc prolongationMobile cardiac monitor
      Mercuro et al
      • Mercuro N.J.
      • Yen C.F.
      • Shim D.J.
      • et al.
      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).
      United StatesHospitalized patients with COVID-19 who were treated with HCQ ± azithromycinHCQ 400 mg twice daily on day 1, then 200 mg twice daily for 4 daysQTc prolongationECG in electronic health records
      Ip et al
      • Ip A.
      • Berry D.A.
      • Hansen E.
      • et al.
      Hydroxychloroquine and tocilizumab therapy in COVID-19 patients—an observational study.
      United StatesHospitalized patients with COVID-19 who were treated with HCQ ± azithromycinHCQ, azithromycin, or combination

      Dose and duration NR
      QTc prolongation

      Arrhythmia
      ECG in electronic health records
      Jain et al
      • Jain S.
      • Workman V.
      • Ganeshan R.
      • et al.
      Enhanced ECG monitoring of COVID-19 patients.
      United StatesHospitalized patients with COVID-19HCQ, dose and duration NRQTc prolongationECG or telemetry monitoring
      Million et al
      • Million M.
      • Lagier J.C.
      • Gautret P.
      • et al.
      Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France.
      FranceInpatients and outpatients with COVID-19HCQ 600 mg daily for 10 days

      Azithromycin 500 mg on day 1, then 250 mg for 4 days
      QTc prolongationBaseline ECG, then ECG on day 2 of treatment
      Molina et al
      • Molina J.M.
      • Delaugerre C.
      • Le Goff J.
      • et al.
      No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection.
      FranceHospitalized patients with COVID-19HCQ 600 mg daily for 10 days

      Azithromycin 500 mg on day 1, then 250 mg for 4 days
      QTc prolongationNR
      Pereira et al
      • Pereira M.R.
      • Mohan S.
      • Cohen D.J.
      • et al.
      COVID-19 in solid organ transplant recipients: initial report from the US epicenter.
      United StatesHospitalized solid organ transplant patients with COVID-19HCQ 600 mg twice daily on day 1, then 200 mg twice daily for 4 days

      Azithromycin 500 mg on day 1, then 250 mg for 4 days
      QTc prolongationBaseline ECG

      ECG on day 2 or 3 of therapy
      Rosenberg et al
      • Rosenberg E.S.
      • Dufort E.M.
      • Udo T.
      • et al.
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state.
      United StatesHospitalized patients with COVID-19HCQ and azithromycin alone or as combination

      Dose and duration NR
      Abnormal ECG (arrhythmia or QT prolongation)Random ECG screening
      Fernández-Ruiz et al
      • Fernández-Ruiz M.
      • Andrés A.
      • Loinaz C.
      • et al.
      COVID-19 in solid organ transplant recipients: a single-center case series from Spain.
      SpainHospitalized solid organ transplant patients with COVID-19HCQ 400 mg twice daily on day 1, then 200 mg twice daily for 4 daysNRNR
      COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; HCQ = hydroxychloroquine; NR = not reported.
      Table 2Modified Newcastle-Ottawa Quality Assessment Score
      A score of 1 means a low risk of bias per the original score of 1 star.
      StudyAscertainment of exposureAssessment of outcomeFollow-up lengthLoss to follow-up rate
      Tang et al
      • Tang W.
      • Cao Z.
      • Han M.
      • et al.
      Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial.
      1111
      Borba et al
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      1111
      Perinel et al
      • Perinel S.
      • Launay M.
      • Botelho-Nevers É.
      • et al.
      Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients.
      1000
      Ramireddy et al
      • Ramireddy A.
      • Chugh H.S.
      • Reinier K.
      • et al.
      Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring.
      1111
      Mahévas et al
      • Mahévas M.
      • Tran V.T.
      • Roumier M.
      • et al.
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      reported the incidence of any arrhythmia (unspecified) in 19.3% and cardiac arrest in 15% of their cohort of 1006 patients who received HCQ alone or in combination with azithromycin. Nonsustained ventricular tachycardia was reported by 6 studies and was encountered in 0% to 5% of patients treated with CQ or HCQ. On the other hand, sustained ventricular tachycardia was described by 9 studies in 0% to 2.7% of patients. Only two investigators reported about new-onset atrial fibrillation; it was detected in 12.8% of patients by Chang et al
      • Chang D.
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      and in 8.5% by Saleh et al.
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      Four studies reported on conduction abnormalities, which developed in 1% to 3.4% of their patients. Moreover, 2 studies observed acute cardiac injury, defined as elevated troponin levels in 27.8%
      • Mercuro N.J.
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      • Shim D.J.
      • et al.
      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).
      and as elevated cardiac-specific creatine kinase (CK-MB isoenzyme) in 31.8%.
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      In the last study, it was noted that the CK-MB elevation was higher in the high CQ dose in comparison with the lower dose (50% vs 31.6%).
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      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.
      Acute myocardial infarction (MI) was reported by 2 studies. Ramireddy et al
      • Ramireddy A.
      • Chugh H.S.
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      Experience with hydroxychloroquine and azithromycin in the COVID-19 pandemic: implications for QT interval monitoring.
      observed acute MI in 17% of their patients, and Mercuro et al
      • Mercuro N.J.
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      • et al.
      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).
      identified acute MI in 1 patient of their cohort of 90 patients. Acute myocarditis was observed by Saleh et al
      • Saleh M.
      • Gabriels J.
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      • et al.
      The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection.
      in 1 patient (0.5%) and by Borba et al
      • Borba M.G.S.
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      • et al.
      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.
      in 2 patients (8.6%).

      Meta-analysis Results

      TdP tachycardia, ventricular tachycardia, and cardiac arrest events were observed in 156 patients in 17 studies with a total of 3725 patients. The pooled incidence of these events was 3 per 1000 (95% CI, 0-21; I2=96%; Figure 2). However, only 2 episodes of TdP tachycardia were reported among 2719 patients. The pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5% (95% CI, 1-11; I2=98%) among 4334 patients from 13 studies (Figure 3). Among 11 studies with 3127 patients, the pooled incidence of change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more was 9% (95% CI, 3-17; I2=97%; Figure 4). In 12 studies of 2008 patients, the pooled incidence of change in QTc from baseline of 60 milliseconds or more was 7% (95% CI, 3-14; I2=94%; Figure 5). Furthermore, the pooled incidence of QTc of 500 milliseconds or more was 6% (95% CI, 2-12; I2=95%) from 16 studies with 2317 patients (Figure 6). Visual inspection of all funnel plots did not show asymmetry consistent with absence of publication bias (Supplemental Figures 1 to 3, available online at http://mcpiqojournal.org).
      Figure thumbnail gr2
      Figure 2Forest plot of the pooled incidence of torsades de pointes, ventricular tachycardia, or cardiac arrest.
      Figure thumbnail gr3
      Figure 3Forest plot of the pooled incidence of discontinuation of chloroquine or hydroxychloroquine due to prolonged QTc or arrhythmias.
      Figure thumbnail gr4
      Figure 4Forest plot of the pooled incidence of change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more.
      Figure thumbnail gr5
      Figure 5Forest plot of the pooled incidence of change in QTc from baseline of 60 milliseconds or more.
      Figure thumbnail gr6
      Figure 6Forest plot of the pooled incidence of QTc of 500 milliseconds or more.

      Exploring Heterogeneity

      We performed multiple meta-regression analyses to identify factors associated with the observed heterogeneity. For TdP arrhythmia, ventricular tachycardia, or cardiac arrest, the prevalence of concomitant QT-prolonging medication use in the included studies was associated with the observed heterogeneity. Regarding discontinuation due to prolonged QTc or arrhythmias, age, CAD, and DM were associated with heterogeneity. For the change in QTc from baseline of 60 milliseconds or more and QTc of 500 milliseconds or more, age, CAD, and hypertension and ICU admission or illness severity were associated with heterogeneity. Finally, age, CAD, hypertension, concomitant QT-prolonging medications, ICU care, and severity of illness were associated with the observed heterogeneity for the change in QTc from baseline of 60 milliseconds or more or QTc of 500 milliseconds or more.

      Sensitivity Analysis

      After excluding the 2 studies that used high-dose CQ or HCQ,
      • Tang W.
      • Cao Z.
      • Han M.
      • et al.
      Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial.
      ,
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      we did not observe an important change in pooled estimates or associated heterogeneity.

      Discussion

      In this meta-analysis, we systematically examined the risk of QTc prolongation and its associated complications in patients with COVID-19 treated with the antimalarial medications CQ and HCQ. The majority of studies included in this analysis used HCQ alone or in combination with azithromycin. Our analysis revealed treatment with CQ or HCQ to be associated with a clinically important increased risk of QTc prolongation and discontinuation of drug due to this risk. In addition, CQ or HCQ was associated with a clinically important risk of TdP, ventricular tachycardia, or cardiac arrest of 3 per 1000 (95% CI, 0.0-21).
      The incidence of critical QTc prolongation, defined as QTc of 500 milliseconds or more or change in QTc of 60 milliseconds or more, ranged from 0% to 36%. One of the most remarkable findings is that in the study by Bessière et al,
      • Bessière F.
      • Roccia H.
      • Delinière A.
      • et al.
      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.
      93% of the studied 40 patients exhibited an increase in QTc prolongation and 36% had critical QTc prolongation. In our pooled analysis, critical QTc prolongation ranged between 6% and 9% with marked heterogeneity among the studies (I2 of up to 98%). Several factors that contributed to the observed heterogeneity were identified by the meta-regression analysis. These include age, hypertension, CAD, ICU admission, DM, use of other QTc-prolonging agents, and COVID-19 disease severity. These factors are concordant with the biologic explanation for the observed differences as it is well known that underlying cardiac conditions, comorbidities, and inflammatory states increase the risk of drug-induced QTc prolongation.
      • Haugaa K.H.
      • Bos J.M.
      • Tarrell R.F.
      • Morlan B.W.
      • Caraballo P.J.
      • Ackerman M.J.
      Institution-wide QT alert system identifies patients with a high risk of mortality.
      ,
      • Pickham D.
      • Helfenbein E.
      • Shinn J.A.
      • et al.
      High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality: results of the QT in Practice (QTIP) Study.
      This meta-analysis revealed low but clinically important risk of the combined end point of TdP, ventricular tachycardia, and cardiac arrest. However, we could not perform a meta-analysis on TdP separately because there were only 2 reported cases of TdP among 2719 patients from 16 studies (0.073%). The low incidence of TdP is probably an underestimate. A number of factors can explain this low incidence of TdP; most important are the precautionary discontinuation of the drugs when QTc reaches a certain threshold (QTc ≥500 milliseconds or ΔQTc ≥60 milliseconds), short duration of therapy, and, in certain instances, the therapeutic intervention for long QT using QT-shortening agents as reported by Saleh et al,
      • Saleh M.
      • Gabriels J.
      • Chang D.
      • et al.
      The effect of chloroquine, hydroxychloroquine and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection.
      for example. Indeed, in our pooled analysis, 5% of patients had their medication discontinued because of QTc prolongation, and in the study by Jain et al,
      • Jain S.
      • Workman V.
      • Ganeshan R.
      • et al.
      Enhanced ECG monitoring of COVID-19 patients.
      30% of patients had CQ or HCQ discontinued because of QTc prolongation. Moreover, some TdP cases could have been missed because of underreporting or misclassification. In fact, the 2 largest studies in this meta-analysis did not specifically include TdP as a separate end point but grouped all arrhythmias under 1 category. The study by Rosenberg et al
      • Rosenberg E.S.
      • Dufort E.M.
      • Udo T.
      • et al.
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state.
      observed arrhythmias in 19.3% and cardiac arrest in 15% of patients, and it is possible that some of these arrhythmias were TdP or some of the cardiac arrests were preceded by TdP.
      Nonetheless, the incidence of TdP reported here is consistent with the published data on the drug-induced TdP. The risk for development of TdP in association with non-antiarrhythmic drugs is relatively low; for instance, the risk for cisapride, which has been removed from the market, was 0.001%.
      • Barbey J.T.
      • Lazzara R.
      • Zipes D.P.
      Spontaneous adverse event reports of serious ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride.
      The risk of TdP with other non-antiarrhythmic drugs is in the range of that reported with cisapride. The incidence of TdP observed in this meta-analysis (0.073%) is 73-fold higher than that of cisapride. Cisapride and terfenadine (a nonsedating antihistamine) were taken off the market because of the risk of TdP, even though the risk of TdP associated with their use in absolute terms was very low. This underscores the importance of taking into account the total number of potential lethal events rather than the expressed ratios in assessing the risk of drug-induced arrhythmias. It is also well known that the highest risk for drug-induced QT prolongation and TdP is associated with class III antiarrhythmic drugs, which ranges between 1% and 3% during 1 to 2 years.
      • Kannankeril P.
      • Roden D.M.
      • Darbar D.
      Drug-induced long QT syndrome.
      The risk of TdP with sotalol therapy at a low daily dose of 80 mg is only 0.3%.
      • Vlachos K.
      • Georgopoulos S.
      • Efremidis M.
      • Sideris A.
      • Letsas K.P.
      An update on risk factors for drug-induced arrhythmias.
      This risk is much higher than the observed risk with CQ and HCQ in this study; however, the estimated risk reported for the antiarrhythmic drugs was during long-term use of 1 to 2 years as opposed to the risk reported here for CQ and HCQ during a short-term use. In fact, this further increases the concern about the cardiac risk associated with CQ and HCQ treatment in COVID-19 disease.
      A number of other cardiac adverse events documented in the included studies were not negligible and include myocardial injury, acute MI, myocarditis, and others. Notwithstanding, a cause and effect relationship between CQ or HCQ exposure and these complications cannot be inferred from these studies. However, in the study by Borba et al,
      • Borba M.G.S.
      • Val F.F.A.
      • Sampaio V.S.
      • et al.
      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.
      the incidence of acute cardiac injury was higher in the high-dose CQ group in comparison with low-dose CQ (50% vs 31.6%), and the 2 patients with sustained ventricular tachycardia also were in the high-dose CQ group, which could imply a dose-response relationship and probable cause and effect link. In a meta-analysis of HCQ effects on the cardiovascular system, ventricular hypertrophy was noted in 22% of patients, whereas heart failure was noted in 26.8% of patients.
      • Chatre C.
      • Roubille F.
      • Vernhet H.
      • Jorgensen C.
      • Pers Y.M.
      Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature.
      It has been a common practice to use HCQ in combination with azithromycin for COVID-19 during the current pandemic. Azithromycin has been identified as a potential cause of serious cardiac arrhythmias through mechanisms dependent on and independent of QT prolongation and has been linked to increased risk of sudden cardiac death.
      • Ray W.A.
      • Murray K.T.
      • Hall K.
      • Arbogast P.G.
      • Stein C.M.
      Azithromycin and the risk of cardiovascular death.
      ,
      • Yang Z.
      • Prinsen J.K.
      • Bersell K.R.
      • et al.
      Azithromycin causes a novel proarrhythmic syndrome.
      Hence, the concomitant use of CQ or HCQ and azithromycin or other QT-prolonging agents could potentially increase the risk of serious cardiac arrhythmias and death, particularly in critically ill patients or those with risk factors for QT prolongation.
      Our findings indicate that the cardiac risk imposed by CQ or HCQ use in COVID-19 disease is not trivial and support the need for close monitoring of patients with COVID-19 who are treated with CQ or HCQ alone or in combination with azithromycin. Because their efficacy in improving the outcomes of patients with COVID-19 is lacking, these agents should be used only in the context of randomized clinical trials, given the potential harm that could be associated with their widespread use. This position is supported by the recent Food and Drug Administration statement.
      FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. U.S. Food and Drug Administration.

      Strength and Limitations

      Our meta-analysis is the first comprehensive systematic review examining the risk of QT prolongation and its associated adverse events in patients with COVID-19 treated with CQ or HCQ. However, like any meta-analysis, it has several limitations. First, because of the retrospective nature of most of the included studies, they are likely to have incomplete or missing data. Second, there were variations in the variables collected by individual studies particularly related to reporting of QTc parameters and adverse events and differences in the populations of patients enrolled by these studies. Third, there was marked heterogeneity in our pooled estimates; however, we performed a meta-regression that allowed us to identify contributors to the observed heterogeneity and to determine populations at risk for CQ- or HCQ-induced QT prolongation, which further strengthens our study and its conclusions.

      Conclusion

      Our meta-analysis indicates that the treatment of patients with COVID-19 with CQ or HCQ alone or in combination with azithromycin is associated with an important risk of drug-induced QT prolongation. CQ or HCQ use resulted in a relatively higher incidence of TdP compared with drugs withdrawn from the market for this particular adverse effect. Therefore, these agents should not be used routinely in the treatment of COVID-19 disease. Patients with COVID-19 who are treated with antimalarials for other indications should be adequately monitored.

      Acknowledgment

      We thank Ms Leslie Hassett, MLS, Librarian, at Mayo Clinic Libraries for her help with the literature search.

      Supplemental Online Material

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      2. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. U.S. Food and Drug Administration.