key: cord-328714-jg562twk
authors: Oscanoa, Teodoro J.; Vidal, Xavier; Kanters, Jørgen K.; Romero-Ortuno, Roman
title: Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: a Meta-analysis
date: 2020-10-24
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106212
sha: 
doc_id: 328714
cord_uid: jg562twk

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.

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.

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

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.

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.

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.

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.

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).

After screening 833 citations, 28 studies (27 observational and 1 RCT) [8, 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).

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] . 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.

In 5/28 studies, a subgroup analysis was performed that suggested several risk factors related to the frequency of HCQassociated 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] .

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 HCQinduced 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] . 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.

Ethical Approval: Not required

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