Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: a Meta-analysis

https://www.sciencedirect.com/science/article/pii/S0924857920304234

Author links open overlay panelTeodoro J.OscanoaaXavierVidalbJørgen K.KanterscRomanRomero-Ortunode

Show more

https://doi.org/10.1016/j.ijantimicag.2020.106212Get rights and content

Highlights

•

In the midst of the SARS-CoV-2 pandemic, controversy has arisen regarding the cardiotoxicity of Hydroxychloroquine (HCQ)

•

The main findings of the present study are that the frequency of LQT during HCQ treatment in SARS-CoV-2 infection patients and, HCQ discontinuation due to this cause were 6.7% and 3.7%respectively. The frequency of Torsades de Pointes, ventricular arrhythmias and arrhythmogenic death were 0.06%, 1.7% and 0.69%, respectively.

•

HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring especially in those older than 60 years and/or taking other QT-prolonging drugs.

Abstract

Introduction

Hydroxychloroquine (HCQ) has been proposed as SARS-CoV-2 treatment but the frequency of Long QT (LQT) during use is unknown.

Objective

Conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ.

Data Sources

We searched PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) for studies published between December 2019 and June 30, 2020.

Methods

Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively.

Outcomes

Critical LQT was defined as: (1) maximum QT corrected (QTc)≥500 ms (if QRS<120 ms) or QTc≥550 ms (if QRS≥120 ms), and (2) QTc increase of ≥60 ms.

Results

In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% CI: 3.7-10.2%). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs; the frequency of LQT in the other 8 studies (n=1299) was 1.7% (95% CI:0.3-3.9%). 20 studies (n=6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-.6%). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). The group with highest risk of HCQ-associated LQT were those older than 60 years (p<0.001).

Conclusions

HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring especially in those older than 60 years and/or taking other QT-prolonging drugs.

Keywords

SARS Virus

COVID-19

Hydroxychloroquine

Long QT Syndrome, Torsades de Pointes

1. Introduction

During the SARS-CoV-2 pandemic, Hydroxychloroquine (HCQ) has been used as one of the drugs in the still limited therapeutic armamentarium. HCQ may block virus infection by increasing the endosomal pH required for virus/cell fusion, and by interfering with the glycosylation of cellular receptors of SARS‐CoV [1]. HCQ is a safe drug in rheumatoid arthritis and systemic lupus erythematosus; however, adverse reactions in patients with SARS-CoV-2 are currently under scrutiny. In the midst of the pandemic, controversy has arisen regarding the cardiotoxicity of HCQ, especially HCQ-induced long QT (LQT) [2]. In the electrocardiogram (ECG), the QT interval is the time between the start of the QRS complex and the end of the T wave. Physiologically, it represents the sum of the action potential (AP) of ventricular myocytes, and the total duration of the depolarization phase and cardiac repolarization [3]. Normally, the clinical reading of the QT interval takes into account a correction for the heart rate (QTc).

The mechanism of HCQ-induced LQT is by blocking the rapidly activating delayed rectifier K+ current encoded by the human ether-a-go-go-related gene (hERG) and also by blocking sodium, calcium and other potassium channels. Inhibition of the hERG channel can cause prolongation of the action potential duration and consequently, of the QT interval [2]. When a QT prolongation occurs, there is a potential risk of causing one-way block, recurrent extrasystoles, re-entry, and Torsades de pointes (“twisting of the points”, TdP). TdP is a form of ventricular tachycardia, which clinically presents as reversible syncope or may degenerate into ventricular fibrillation, cardiac arrest, and sudden death [4]. Drugs used in the treatment of SARS-CoV-2 infection that are associated with drug-induced LQT include Chloroquine (CQ), HCQ, Azithromycin (AZI), and Lopinavir/Ritonavir. A criterion for the diagnosis of drug-induced LQT is a QT prolongation to values ≥ 500 milliseconds (ms) [5].

The association between HCQ use and drug-induced LQT in patients with SARS-CoV-2 infection is unknown. The objective of the present meta-analysis was to evaluate the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ. Data were also collected on discontinuation of HCQ, simultaneous use of other QT-prolonging medications, frequency of arrhythmias during HCQ treatment, and arrhythmogenic death.

2. Methods

This study was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [6].

2.1. Search strategy

Two independent investigators performed a systematic search in PubMed, EMBASE, Google Scholar, preprint servers (medRxiv, Research Square) and the Cochrane Database of Systematic Reviews for studies published between December 2019 and June 30, 2020. In addition, we conducted a secondary search based on the references lists of retrieved articles. The PubMed search strategy is detailed in Supplementary Table A.

2.2. Eligibility criteria

We searched for randomized controlled trials (RCTs) or observational studies reporting data on LQT in patients with SARS-CoV-2 infection taking HCQ. We included studies in English or other languages (all ages) meeting the following criteria: a) COVID-19 patients were diagnosed according to the interim guidance of the World Health Organization [7]; b) studies assessing the risk of HCQ-associated LQT in SARS-CoV-2 infection in which ECGs were recorded at documented timepoints before and after drug administration; c) critical QTc prolongation was defined as: (1) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 ms (if QRS ≥120 ms) and (2) QTc increase of ≥60 ms [8]; d) sufficient data was reported to calculate frequency of HCQ-induced LQT, arrhythmias during treatment, arrhythmogenic death, discontinuation of HCQ, and simultaneous use of other QT-prolonging agents.

2.3. Quality assessment

The quality of observational studies (cohort, case-control, cross-sectional studies) and randomized controlled trials (RCTs) were appraised according to The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [9] and the Cochrane Risk of Bias Assessment Tool [10], respectively. Two investigators evaluated the quality of the studies independently. Conflicting results were resolved by discussion and involvement of a third reviewer if necessary.

2.4. Data extraction

The following data were extracted from each study: authors, study location, year of publication, study design, number of participants, sex, age at baseline, outcome definition, exposure definition, follow-up, effect estimates and 95% CIs. We also collected: a) anti-COVID-19 treatment indication, participants’ inclusion and exclusion criteria, and number of study participants who had ECG monitoring; b) ECG measurement methodology (e.g. centralized or study site-based, manual or automated, cardiologist or other physician reader, intermittent or continuous, any other relevant details); and c) cardiovascular adverse events: sudden cardiac death, life-threatening ventricular tachyarrhythmias (ventricular fibrillation, ventricular tachycardia, TdP), any other clinically significant arrhythmias or cardiovascular adverse events.

2.5. Statistical analyses

The frequency of LQT during HCQ treatment, arrhythmogenic death, discontinuation of HCQ, frequency of simultaneous use of other QT-prolonging agents and frequency of arrhythmias during treatment were calculated. We used random effects with an inverse variance method to calculate the pooled risk ratios (RRs) and 95% confidence intervals (CI) according to the heterogeneity between studies [11]. The overall estimates in the pooled analysis were obtained using Stata 13 software (Stata Corp LP, College Station, TX).

3. Results

After screening 833 citations, 28 studies (27 observational and 1 RCT) [8,[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38]] were included (Figure 1), with a total sample of 9124 participants. The characteristics of included studies are summarized in Table 1. Eleven studies were from USA, with the other 17 being from France (6), China (1), India (1), Tunisia (1) Brunei (1), Italy (2), Malaysia (1), Cameroon (1) and Spain (2); one study included patients from USA and Italy. Overall, mean (SD) age was 59.0 (9.1) years and 63.1% were men. In 25 studies, the proportion of men was more than 50%. In the 24 studies (7646 patients) where the dose of HCQ administered and the duration of treatment were reported the mean (SD) total cumulative dose of HCQ was 3458 (2521) mg with a mean exposure duration of 7 (3) days. The three most frequent comorbidities were hypertension (73%), diabetes mellitus (49%) and chronic obstructive pulmonary disease (20%) (Table 1). The mean STROBE score of included studies was 85.6 (SD 8.3).

1. Download : Download high-res image (399KB)
2. Download : Download full-size image

Figure 1. Flowchart of included studies.

Table 1. Characteristics of the 28 studies included in the meta-analysis.

HCQ: Hydroxychloroquine; CC: case control study; RCT: randomized controlled trial; O: observational study; NR: Not reported. AZI: Azithromycin.

In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% CI: 3.7-10.2%) (Figure 2). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs as well as HCQ. In 18 studies (n=7399), patients were reported to be taking Azithromycin (AZI) and in 8 of those 18 studies, patients were also on other QT-prolonging drugs, with the three most frequent being Lopinavir/Ritonavir, Propofol and Amiodarone [12,15,[19], [20], [21],23,32,33]. The frequency of LQT in the 8 studies where HCQ was not taken with other QT-prolonging drugs (n=1299) was 1.7% (95% CI:0.3-3.9%). (Figure A, Supplementary file). 20 studies (n=6869) reported HCQ discontinuation due to LQT, with an overall frequency of 3.7% (95% CI: 1.5-.6%) (Figure B, Supplementary file).

1. Download : Download high-res image (1MB)
2. Download : Download full-size image

Figure 2. Forest plot of the meta-analysis of the frequency of Hydroxychloroquine-associated QT prolongation in patients with SARS-CoV-2 infection (28 studies, n=9124). Analysis model: random effect. CI: confidence interval.

Overall, the frequency of ventricular arrhythmias during HCQ treatment was 1.69% (127/7539, reported in 22/28 studies) and that of arrhythmogenic death 0.69% (39/5648 reported in 22/28 studies). Torsades de Pointes occurred in 0.06% (3/5066 reported in 21/28 studies).

In the subgroup analyses (Table 2), those older than 60 years had a higher risk of HCQ-associated LQT (p <0.001). The frequency of LQT also seemed higher in the studies that reported HCQ combination with AZI and/or other QT-prolonging agents (p=0.002). No significant difference was evidenced when the total HCQ dose was greater than 3000 mg.

Table 2. Hydroxychloroquine-associated QT prolongation in Patients with SARS-CoV-2 Infection: Summary of subgroup analyses.

HCQ: Hydroxychloroquine.

In 5/28 studies, a subgroup analysis was performed that suggested several risk factors related to the frequency of HCQ-associated LQT. The main risk factor was simultaneously taking other QT-prolonging agents, among which were propofol and amiodarone [8,19,32,33]. Other statistically significant risk factors were renal failure or increased creatinine [33,37], structural heart disease [8] and ≥2 points in Systemic Inflammatory Response Syndrome score [32].

4. Discussion

The frequency of LQT in SARS-CoV-2 patients treated with HCQ was 6.7%. However, most patients were also taking other QT-prolonging drugs. In the minority of studies where HCQ was the only QT-prolonging drug, the frequency of LQT seemed smaller (1.7%). Overall, the frequency of HCQ discontinuation due to LQT was 3.7%. During HCQ treatment, the frequency of Torsades de Pointes, ventricular arrhythmias and arrhythmogenic death were very low. The risk of LQT in COVID-19 patients treated with HCQ seemed higher in patients older than 60 years.

Our findings can be compared with those of four related types of studies, namely: similar systematic reviews in SARS-CoV-2 infection, studies with HCQ used for short periods against malaria, studies of HCQ used chronically for rheumatologic diseases, and studies with other drugs that cause LQT. Currently, three meta-analytic studies on cardiotoxicity of antimalarials used in SARS-CoV-2 infection have been published [39], [40], [41] and the differences with the present study (which reports lower risk frequencies) may be due to the fact that our study had the largest numbers of subjects and we only included studies with HCQ. Indeed, studies with CQ [42,43] were purposefully excluded after Borba et al.’s study [43] was prematurely discontinued due to high mortality associated with high doses of CQ. Since then, clinical guidelines for treatment for SARS-CoV-2 include HCQ and not CQ, and there is evidence that the cardiotoxicity of CQ is greater than HCQ in patients with SARS-CoV-2 infection [44].

Other than drugs, risk factors that cause repolarization reserve reduction and increase the risk of TdP include drug interactions affecting drug serum levels, sex, structural heart disease, genetic polymorphisms, electrolyte disturbances, bradycardia, and hepatic disease [12]. In the present study, the majority of patients were simultaneously taking other QT-prolonging agents including AZI, lopinavir/ritonavir, Propofol or Amiodarone. AZI is known to be associated with QT interval prolongation [45], [46], [47], TdP [48] and polymorphic ventricular tachycardia in the absence of QT interval prolongation [49]. The proarrhythmic mechanism of AZI is that it potentiates cardiac Na+ current to promote intracellular Na+ loading [50]; however, the frequency of this is low, as AZI has been calculated to cause 47 additional cardiovascular deaths per million treatments [51].

Antimalarials are also associated with LQT, especially Quinidine and Halofantrine [52], [53], [54]. In the pre-COVID-19 era, sudden cardiac death with CQ has been reported only by rapid intravenous administration or by self-inflicted overdose, causing hypotension due to vasodilation and negative inotropy [55]. Mortality associated with the administration of CQ (not HCQ) in the treatment of plasmodium falciparum and vivax malaria has been reported to be 0.07% (10/23773) and 0% (0/11 848), respectively [52]. HCQ is used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. A study [56] found a 15.8% frequency of HCQ-induced LQT in rheumatoid arthritis and systemic lupus erythematosus patients who received 200-400 mg/day of HCQ for a mean of 3.6 years; it should be noted that these patients were simultaneously taking more than one medication that could prolong the QT interval. Chatre et al. investigated 127 cases published until 2017 of CQ and HCQ-induced cardiac adverse reactions and found 3 cases of HCQ-induced LQT (2.4%) [57]. In a study of a cohort of 453 systemic lupus erythematosus patients on antimalarial-induced ECG abnormalities, 0.7% frequency of HCQ-induced LQT and 0.4% of ventricular bigeminy were found [58]. Recently, Hooks et al studied patients with rheumatologic diseases and found a frequency of 1.5% of HCQ-induced LQT; additionally, they found that chronic kidney disease (CKD), history of atrial fibrillation (AF), and heart failure were independent risk factors for LQT; the median dosage of HCQ was 400 mg daily and duration of HCQ therapy was 1006 (471–2075) days [59].

The detection of drug-induced LQT is important because it increases the risk of TdP, which in turn can degenerate into ventricular fibrillation in 10% of cases [60,61]. Medications that increase QTc > 500 ms are generally discontinued because they increase the risk of TdP by 3 to 4-fold [62,63]. Of all the drugs that are associated with LQT, antiarrhythmic drugs are those that have the highest risk of TdP with an incidence of 1 to 5%, while in non-cardiovascular drugs the incidence is much less (0.001%) [61]. According to CredibleMeds (www.Crediblemeds.org) there are currently 63 drugs marketed with known risk of TdP. Many healthcare organizations have attempted to increase awareness of QT-prolonging drugs and recognition of LQT through educational strategies [64].

The present study has limitations, among which is the design of the included studies (mostly observational) and the strategies used to detect HCQ-induced LQT by these studies. Many studies where HCQ has been used for COVID-19 infection have not been able to measure QTc because this requires special devices (e.g. mobile cardiac outpatient telemetry) to avoid exposure to the virus, or the use of special personal protective equipment (PPE) for its measurement [15]. On the other hand, Cipriani et al. reported 24-h QTc dynamics in COVID-19 patients versus controls and reported that the former had higher QTc values with no significant hourly variability, recommending that there is no need to preform multiple daily ECGs for the monitoring of possible treatment toxicity [26]. Given the very low number of studies including a majority of women, the sex differences between the risk of HCQ-associated LQT warrant further investigation.

In conclusion, HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring especially in those older than 60 years and/or taking other QT-prolonging drugs.

Declaration of Competing Interest

No

Funding

No

Ethical Approval

Not required

Appendix. Supplementary materials

Download : Download Word document (174KB)

References

[1]

B. Yousefi, S. Valizadeh, H. Ghaffari, A. Vahedi, M. Karbalaei, M. EslamiA global treatments for coronaviruses including COVID‐19

J Cell Physiol (2020)

jcp.29785

https://doi.org/10.1002/jcp.29785

Google Scholar

[2]

J.R. Giudicessi, P.A. Noseworthy, P.A. Friedman, M.J. AckermanUrgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19)

Mayo Clin Proc, 95 (2020), pp. 1213-1221

https://doi.org/10.1016/j.mayocp.2020.03.024

ArticleDownload PDFView Record in ScopusGoogle Scholar

[3]

S. Nachimuthu, M.D. Assar, J.M. SchusslerDrug-induced QT interval prolongation: mechanisms and clinical management

Ther Adv Drug Saf, 3 (2012), pp. 241-253

https://doi.org/10.1177/2042098612454283

CrossRefView Record in ScopusGoogle Scholar

[4]

P.J. Schwartz, R.L. WoosleyPredicting the Unpredictable

J Am Coll Cardiol, 67 (2016), pp. 1639-1650

https://doi.org/10.1016/j.jacc.2015.12.063

ArticleDownload PDFView Record in ScopusGoogle Scholar

[5]

R.L. Woosley, P.J. Schwartz, Q.T Drug-Induced LongSyndrome and Torsades de Pointes. Card. Repolarization

Springer International Publishing, Cham (2020), pp. 185-200

https://doi.org/10.1007/978-3-030-22672-5_10

CrossRefGoogle Scholar

[6]

D. Moher, A. Liberati, J. Tetzlaff, D.G. AltmanPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

BMJ, 339 (2009), p. b2535

https://doi.org/10.1136/bmj.b2535

CrossRefView Record in ScopusGoogle Scholar

[7]

W.H. OrganizationClinical management of COVID-19: interim guidance

(2020)

27 may

https://www.who.int/publications/i/item/clinical-management-of-covid-19

n.d.

Google Scholar

[8]

A. Ramireddy, H. Chugh, K. Reinier, J. Ebinger, E. Park, M. Thompson, et al.Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring

J Am Heart Assoc, 9 (2020)

https://doi.org/10.1161/JAHA.120.017144

Google Scholar

[9]

E. von Elm, D.G. Altman, M. Egger, S.J. Pocock, P.C. Gøtzsche, J.P. VandenbrouckeThe Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies

Int J Surg, 12 (2014), pp. 1495-1499

https://doi.org/10.1016/j.ijsu.2014.07.013

ArticleDownload PDFView Record in ScopusGoogle Scholar

[10]

J.P.T. Higgins, D.G. Altman, P.C. Gotzsche, P. Juni, D. Moher, A.D. Oxman, et al.The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

BMJ, 343 (2011), p. d5928

https://doi.org/10.1136/bmj.d5928

CrossRefView Record in ScopusGoogle Scholar

[11]

R. DerSimonian, N. LairdMeta-analysis in clinical trials

Control Clin Trials, 7 (1986), pp. 177-188

https://doi.org/10.1016/0197-2456(86)90046-2

ArticleDownload PDFView Record in ScopusGoogle Scholar

[12]

M. Saleh, J. Gabriels, D. Chang, B. Soo Kim, A. Mansoor, E. Mahmood, et al.Effect of Chloroquine, Hydroxychloroquine, and Azithromycin on the Corrected QT Interval in Patients With SARS-CoV-2 Infection

Circ Arrhythmia Electrophysiol, 13 (2020)

https://doi.org/10.1161/CIRCEP.120.008662

Google Scholar

[13]

A. Ip, D.A. Berry, E. Hansen, A.H. Goy, A.L. Pecora, B.A. Sinclaire, et al.Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients-An Observational Study

medRxiv. (2020 n)

Google Scholar

[14]

S. Singh, A. Khan, M. Chowdhry, A. ChatterjeeOutcomes of Hydroxychloroquine Treatment Among Hospitalized COVID-19 Patients in the United States-Real-World Evidence From a Federated Electronic Medical Record Network

medRxiv (2020)

n.d.

Google Scholar

[15]

S. Jain, V. Workman, R. Ganeshan, E.R. Obasare, A. Burr, R.M. DeBiasi, et al.Enhanced ECG monitoring of COVID-19 patients

Hear Rhythm (2020)

https://doi.org/10.1016/j.hrthm.2020.04.047

Google Scholar

[16]

A.K. Sharma, A. Ahmed, V.N. Baig, P. Dhakad, G. Dalela, S. Kacker, …, R. GuptaCharacteristics and Outcomes of Hospitalized Young Adults with Mild to Moderate Covid-19 at a University Hospital in India

medRxiv (2020)

n.d.

Google Scholar

[17]

N.J. Rhodes, A. Dairem, W. Moore, A. Shah, M.J. Postelnick, M.E. Badowski, …, E.S. SpivekMulticenter point-prevalence evaluation of the utilization and safety of drug therapies for COVID-19

medRxiv. (2020)

n.d.

Google Scholar

[18]

C.P. Hor, N. Hussin, S. Nalliah, W.T. Ooi, X.Y. Tang, S. Zachariah, et al.Experience of short-term hydroxychloroquine and azithromycin in COVID-19 patients and effect on QTc trend

J Infect (2020)

https://doi.org/10.1016/j.jinf.2020.05.058

Google Scholar

[19]

I. Maraj, J.P. Hummel, R. Taoutel, R. Chamoun, V. Workman, C. Li, et al.Incidence and determinants of QT interval prolongation in COVID‐19 patients treated with hydroxychloroquine and azithromycin

J Cardiovasc Electrophysiol (2020)

jce.14594

https://doi.org/10.1111/jce.14594

Google Scholar

[20]

V.H. Chong, P.L. Chong, D. Metussin, R. Asli, R.N. Momin, B.I. Mani, et al.Conduction abnormalities in hydroxychloroquine add on therapy to lopinavir/ritonavir in COVID‐19

J Med Virol (2020)

jmv.26004

https://doi.org/10.1002/jmv.26004

Google Scholar

[21]

A. Mazzanti, M. Briani, D. Kukavica, F. Bulian, S. Marelli, A. Trancuccio, et al.Association of Hydroxychloroquine with QTc Interval in Patients with COVID-19

Circulation (2020)

CIRCULATIONAHA.120.048476

https://doi.org/10.1161/CIRCULATIONAHA.120.048476

Google Scholar

[22]

J.A. Oteo, P. Marco, L.P. de León, A. Roncero, T. Lobera, V. LisaA short therapeutic regimen based on hydroxychloroquine plus azithromycin for the treatment of COVID-19 in patients with non-severe disease. A strategy associated with a reduction in hospital admissions and complications

medRxiv. (2020)

n.d.

Google Scholar

[23]

F. Bessière, H. Roccia, A. Delinière, R. Charrière, P. Chevalier, L. Argaud, 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

JAMA Cardiol (2020)

https://doi.org/10.1001/jamacardio.2020.1787

Google Scholar

[24]

A.R. Sridhar, N.A. Chatterjee, B. Saour, D. Nguyen, E. Starnes, C. Johnston, et al.QT Interval and Arrhythmic Safety of Hydroxychloroquine Monotherapy in Coronavirus Disease 2019

Hear Rhythm (2020)

O2

https://doi.org/10.1016/j.hroo.2020.06.002

Google Scholar

[25]

O. Voisin, le Lorc'h E, A. Mahé, P. Azria, M.-F. Borie, S. Hubert, et al.ACUTE QT INTERVAL MODIFICATIONS DURING HYDROXYCHLOROQUINE-AZITHROMYCIN TREATMENT IN THE CONTEXT OF COVID-19 INFECTION

Mayo Clin Proc (2020)

https://doi.org/10.1016/j.mayocp.2020.05.005

Google Scholar

[26]

A. Cipriani, A. Zorzi, D. Ceccato, F. Capone, M. Parolin, F. Donato, et al.Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin

Int J Cardiol (2020)

https://doi.org/10.1016/j.ijcard.2020.05.036

Google Scholar

[27]

M.R. Pereira, S. Mohan, D.J. Cohen, S.A. Husain, G.K. Dube, L.E. Ratner, et al.COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter

Am J Transplant, 20 (2020), pp. 1800-1808

https://doi.org/10.1111/ajt.15941

CrossRefView Record in ScopusGoogle Scholar

[28]

M. Fernández‐Ruiz, A. Andrés, C. Loinaz, J.F. Delgado, F. López‐Medrano, R. San Juan, et al.COVID‐19 in solid organ transplant recipients: A single‐center case series from Spain

Am J Transplant, 20 (2020), pp. 1849-1858

https://doi.org/10.1111/ajt.15929

CrossRefView Record in ScopusGoogle Scholar

[29]

J.-C. Lagier, M. Million, P. Gautret, P. Colson, S. Cortaredona, A. Giraud-Gatineau, et al.Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis

Travel Med Infect Dis (2020), Article 101791

https://doi.org/10.1016/j.tmaid.2020.101791

ArticleDownload PDFGoogle Scholar

[30]

Mfeukeu-Kuate, L. M., Ngatchou, W., Temgoua, M. N., Kouanfack, C., Lemogoum, D., Tochie, J. N., … & Sobngwi J.T. Electrocardiographic safety of daily Hydroxychloroquine 400mg plus Azithromycin 250mg as an ambulatory treatment for COVID-19 patients in Cameroon. medRxiv. https://doi.org/10.1101/2020.06.24.20139386 n.d.

Google Scholar

[31]

W. Tang, Z. Cao, M. Han, Z. Wang, J. Chen, W. Sun, et al.Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial

BMJ (2020)

m1849

https://doi.org/10.1136/bmj.m1849

Google Scholar

[32]

N.J. Mercuro, C.F. Yen, D.J. Shim, T.R. Maher, C.M. McCoy, P.J. Zimetbaum, 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)

JAMA Cardiol (2020)

https://doi.org/10.1001/jamacardio.2020.1834

Google Scholar

[33]

E. Chorin, L. Wadhwani, S. Magnani, M. Dai, E. Shulman, C. Nadeau-Routhier, et al.QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin

Hear Rhythm (2020)

https://doi.org/10.1016/j.hrthm.2020.05.014

Google Scholar

[34]

M. Mahevas, V. Tran, M. Roumier, et al.No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial

MedRxiv (2020)

Google Scholar

[35]

J.M. Molina, C. Delaugerre, J. Le Goff, B. Mela-Lima, D. Ponscarme, L. Goldwirt, 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

Médecine Mal Infect, 50 (2020), p. 384

https://doi.org/10.1016/j.medmal.2020.03.006

ArticleDownload PDFView Record in ScopusGoogle Scholar

[36]

S. Perinel, M. Launay, É. Botelho-Nevers, É. Diconne, A. Louf-Durier, R. Lachand, et al.Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients

Clin Infect Dis (2020)

https://doi.org/10.1093/cid/ciaa394

Google Scholar

[37]

E.S. Rosenberg, E.M. Dufort, T. Udo, L.A. Wilberschied, J. Kumar, J. Tesoriero, et al.Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State

JAMA, 323 (2020), p. 2493

https://doi.org/10.1001/jama.2020.8630

CrossRefView Record in ScopusGoogle Scholar

[38]

S. Louhaichi, A. Allouche, H. Baili, S. Jrad, A. Radhouani, D. Greb, et al.Features of patients with 2019 novel coronavirus admitted in a pneumology department: The first retrospective Tunisian case series

Tunis Med, 98 (2020), pp. 261-265

View Record in ScopusGoogle Scholar

[39]

L. Jankelson, G. Karam, M.L. Becker, L.A. Chinitz, M.-C. TsaiQT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: A systematic review

Hear Rhythm (2020)

https://doi.org/10.1016/j.hrthm.2020.05.008

Google Scholar

[40]

M.S. Kim, M.H. An, W.J. Kim, T.H. HwangComparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis of confounder-adjusted 20212 hospitalized patients

medRxiv. (2020)

https://doi.org/10.1101/2020.06.15.2013

n.d

Google Scholar

[41]

I. Tleyjeh, Z. Kashour, O. AlDosary, M. Riaz, H. Tlayjeh, M.A. Garbati, et al.The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis

medRxiv. (2020)

https://doi.org/10.1101/2020.06.16.20132878

n.d

Google Scholar

[42]

M.P.H. van den Broek, J.E. Möhlmann, B.G.S. Abeln, M. Liebregts, V.F. van Dijk, E.M.W. van de GardeChloroquine-induced QTc prolongation in COVID-19 patients

Netherlands Hear J (2020)

https://doi.org/10.1007/s12471-020-01429-7

Google Scholar

[43]

M.G.S. Borba, F.F.A. Val, V.S. Sampaio, M.A.A. Alexandre, G.C. Melo, M. Brito, 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

JAMA Netw Open, 3 (2020), Article e208857

https://doi.org/10.1001/jamanetworkopen.2020.8857

CrossRefView Record in ScopusGoogle Scholar

[44]

L. Isaksen Jonas, Anders Gaarsdal Holst, Adrian Pietersen, Jonas Bille Nielsen, J.K.K. Claus GraffChloroquine, but not hydroxychlorquine, prolongs the QT interval in a primary care population

medRxiv (2020), Article 20135475

06.19

https://doi.org/10.1101/2020.06.19.20135475

n.dhttps://doi.org/10.1101/2020.06.19.20135475

Google Scholar

[45]

N. Matsunaga, P.A. Oki YA case of QT-interval prolongation precipitated by azithromycin

N Z Med J, 116 (2003), p. U666

Google Scholar

[46]

P. SAMARENDRA, S. KUMARI, S.J. EVANS, T.J. SACCHI, V. NAVARROQT Prolongation Associated with Azithromycin/Amiodarone Combination

Pacing Clin Electrophysiol, 24 (2001), pp. 1572-1574

https://doi.org/10.1046/j.1460-9592.2001.01572.x

View Record in ScopusGoogle Scholar

[47]

V. Russo, S.N. Puzio GAzithromycin-induced QT prolongation in elderly patient

Acta Biomed, 77 (2006), pp. 30-32

View Record in ScopusGoogle Scholar

[48]

B.-H. HUANG, C.-H. WU, C.-P. HSIA, C. YIN CHENAzithromycin-Induced Torsade De Pointes

Pacing Clin Electrophysiol, 30 (2007), pp. 1579-1582

https://doi.org/10.1111/j.1540-8159.2007.00912.x

CrossRefView Record in ScopusGoogle Scholar

[49]

M.H. KIM, C. BERKOWITZ, R.G. TROHMANPolymorphic Ventricular Tachycardia with a Normal QT Interval Following Azithromycin

Pacing Clin Electrophysiol, 28 (2005), pp. 1221-1222

https://doi.org/10.1111/j.1540-8159.2005.50146.x

CrossRefView Record in ScopusGoogle Scholar

[50]

Z. Yang, J.K. Prinsen, K.R. Bersell, W. Shen, L. Yermalitskaya, T. Sidorova, et al.Azithromycin Causes a Novel Proarrhythmic Syndrome

Circ Arrhythmia Electrophysiol, 10 (2017)

https://doi.org/10.1161/CIRCEP.115.003560

Google Scholar

[51]

W.A. Ray, K.T. Murray, K. Hall, P.G. Arbogast, C.M. SteinAzithromycin and the Risk of Cardiovascular Death

N Engl J Med, 366 (2012), pp. 1881-1890

https://doi.org/10.1056/NEJMoa1003833

View Record in ScopusGoogle Scholar

[52]

Meeting WERG. The cardiotoxicity of antimalarials. 2016. https://www.who.int/malaria/mpac/mpac-mar2017-erg-cardiotoxicity-report-session2.pdf n.d.

Google Scholar

[53]

O. Bouchaud, P. Imbert, J.E. Touze, A.N. Dodoo, M. Danis, F. LegrosFatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base

Malar J, 8 (2009), p. 289

https://doi.org/10.1186/1475-2875-8-289

Google Scholar

[54]

E. Monlun, O. Pillet, J.F. Cochard, L.B.M. Favarel Garrigues JCProlonged QT interval with halofantrine

Lancet, 342 (1993), pp. 1541-1542

Google Scholar

[55]

N.J. WhiteCardiotoxicity of antimalarial drugs

Lancet Infect Dis, 7 (2007), pp. 549-558

https://doi.org/10.1016/S1473-3099(07)70187-1

ArticleDownload PDFView Record in ScopusGoogle Scholar

[56]

A. Negoescu, A. Thornback, E. Wong, A.J. OstorLong QT and hydroxychloroquine; a poorly recognised problem in rheumatology patients

ACR/ARHP Annual Meeting (2013)

Abstract number 2045 n.d

Google Scholar

[57]

C. Chatre, F. Roubille, H. Vernhet, C. Jorgensen, Y.-M. PersCardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature

Drug Saf, 41 (2018), pp. 919-931

https://doi.org/10.1007/s40264-018-0689-4

CrossRefView Record in ScopusGoogle Scholar

[58]

T.K. McGhie, P. Harvey, J. Su, N. Anderson, G.T.Z. TomlinsonElectrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus

Clin Exp Rheumatol, 36 (2018), pp. 545-551

View Record in ScopusGoogle Scholar

[59]

M. Hooks, B. Bart, O. Vardeny, A. Westanmo, S. AdabagEffects of hydroxychloroquine treatment on QT interval

Hear Rhythm (2020)

https://doi.org/10.1016/j.hrthm.2020.06.029

Google Scholar

[60]

G. Sarganas, E. Garbe, A. Klimpel, R.C. Hering, E. Bronder, W. HaverkampEpidemiology of symptomatic drug-induced long QT syndrome and torsade de pointes in Germany

Europace, 16 (2014), pp. 101-108

https://doi.org/10.1093/europace/eut214

CrossRefView Record in ScopusGoogle Scholar

[61]

D.M. RodenPredicting drug-induced QT prolongation and torsades de pointes

J Physiol, 594 (2016), pp. 2459-2468

https://doi.org/10.1113/JP270526

CrossRefView Record in ScopusGoogle Scholar

[62]

R. Wilders, A.O. VerkerkLong QT Syndrome and Sinus Bradycardia–A Mini Review

Front Cardiovasc Med, 5 (2018)

https://doi.org/10.3389/fcvm.2018.00106

Google Scholar

[63]

Q. Khan, M. Ismail, I. HaiderHigh prevalence of the risk factors for QT interval prolongation and associated drug–drug interactions in coronary care units

Postgrad Med, 130 (2018), pp. 660-665

https://doi.org/10.1080/00325481.2018.1516106

CrossRefView Record in ScopusGoogle Scholar

[64]

National Medicines. Information Centre. ST. JAMES'S HOSPITAL D. DRUG-INDUCED QT INTERVAL PROLONGATION. Vol. 21. NUMBER 6. 2015. www.nmic.ie. http://www.stjames.ie/GPsHealthcareProfessionals/Newsletters/NMICBulletins/NMICBulletins2015/NMIC%20Bulletin%20February%202016%20-%20Drug-Induced%20QT%20Interval%20Prolongation% n.d.

Google Scholar

View Abstract

© 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.