key: cord-0949999-irr02zeb
authors: Haghjoo, Majid; Golipra, Reza; Kheirkhah, Jalal; Golabchi, Allahyar; Shahabi, Javad; Oni‐Heris, Saeed; Sami, Ramin; Tajmirriahi, Marzieh; Saravi, Mehrdad; Khatami, Mozhdeh; Varnasseri, Mehran; Kiarsi, Mohammadreza; Hejazi, Seyed Fakhreddin; Yousefzadeh Rahaghi, Mojtaba; Taherkhani, Maryam; Ashraf, Haleh; Keshmiri, Mohammad Sadegh; Akbarzadeh, Mohammad Ali; Bozorgi, Ali; Mottaghizadeh, Fateme; Hedayat, Behnam; Heidarali, Mona; Hajhossein Talasaz, Azita
title: Effect of COVID‐19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey
date: 2021-03-30
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14182
sha: bf79ba2dba5dcfe3fb01fbbf2e7b7de14cc50fca
doc_id: 949999
cord_uid: irr02zeb

BACKGROUND: There are some data showing that repurposed drugs used for the Coronavirus disease‐19 (COVID‐19) have potential to increase the risk of QTc prolongation and torsade de pointes (TdP), and these arrhythmic side effects have not been adequately addressed in COVID‐19 patients treated with these repurposed medications. METHODS: This is the prospective study of 2403 patients hospitalised at 13 hospitals within the COVID‐19 epicentres of the Iran. These patients were treated with chloroquine, hydroxychloroquine, lopinavir/ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir and remdesivir alone or in combination with azithromycin. The primary outcome of the study was incidence of critical QTc prolongation, and secondary outcomes were incidences of TdP and death. RESULTS: Of the 2403 patients, 2365 met inclusion criteria. The primary outcome of QTc ≥ 500 ms and ∆QTc ≥ 60 ms was observed in 11.2% and 17.6% of the patients, respectively. The secondary outcomes of TdP and death were reported in 0.38% and 9.8% of the patients, respectively. The risk of critical QT prolongation increased in the presence of female gender, history of heart failure, treatment with hydroxychloroquine, azithromycin combination therapy, simultaneous furosemide or beta‐blocker therapy and acute renal or hepatic dysfunction. However, the risk of TdP was predicted by treatment with lopinavir‐ritonavir, simultaneous amiodarone or furosemide administration and hypokalaemia during treatment. CONCLUSION: This cohort showed significant QTc prolongation with all COVID‐19 medications studied, however, life‐threatening arrhythmia of TdP occurred rarely. Among the repurposed drugs studied, hydroxychloroquine or lopinavir‐ritonavir alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation and/or TdP.

As the coronavirus disease 2019 (COVID-19) global pandemic spreads across the world, the use of off-label repurposed drugs, such as chloroquine/hydroxychloroquine with and without azithromycin, have gained attraction, appearing in international and domestic therapeutic guidelines. The presumed efficacies of these drugs mainly originated from in vitro investigations 1-3 and small non-randomised studies. 4, 5 However, subsequent randomised studies have failed to confirm these findings. [6] [7] [8] [9] Simultaneously, a group of antiviral agents including lopinavir/ritonavir, atazanavir/ ritonavir, oseltamivir, favipiravir and remdesivir have been tested in prospective observational and randomised clinical trials in different countries. [10] [11] [12] Although these repurposed drugs are generally well-tolerated in clinical practice, some of these drugs such as chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir have been clearly shown to increase the risk of QT interval prolongation and torsade de pointes (TdP). 13 There are no adequate clinical data on chloroquine, hydroxychloroquine, lopinavir/ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir and remdesivir alone or in combination with azithromycin. The primary outcome of the study was incidence of critical QTc prolongation, and secondary outcomes were incidences of TdP and death.

Of the 2403 patients, 2365 met inclusion criteria. The primary outcome of QTc ≥ 500 ms and ∆QTc ≥ 60 ms was observed in 11.2% and 17.6% of the patients, respectively. The secondary outcomes of TdP and death were reported in 0.38% and 9.8% of the patients, respectively. The risk of critical QT prolongation increased in the presence of female gender, history of heart failure, treatment with hydroxychloroquine, azithromycin combination therapy, simultaneous furosemide or beta-blocker therapy and acute renal or hepatic dysfunction. However, the risk of TdP was predicted by treatment with lopinavir-ritonavir, simultaneous amiodarone or furosemide administration and hypokalaemia during treatment.

Conclusion: This cohort showed significant QTc prolongation with all COVID-19 medications studied, however, life-threatening arrhythmia of TdP occurred rarely. Among the repurposed drugs studied, hydroxychloroquine or lopinavir-ritonavir alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation and/or TdP.

• Hydroxychloroquine/chloroquine alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation or induction of Torsades de Pointes (TdP).

• This study clearly showed that other COVID-19 repurposed medications including lopinavir/ ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir, and remdesivir alone or in combination with azithromycin have potential to increase the risk of significant QTc prolongation.

• Although all the studied COVID-19 medications has potential for the significant QT prolongation, life-threatening arrhythmia of TdP occurred rarely.

• Among the repurposed drugs studied, hydroxychloroquine or lopinavir-ritonavir alone or in combination with azithromycin clearly demonstrated to increase the risk of critical QT prolongation or induction of TdP. Our country is seriously involved with the covid-19 outbreak and many patients received these drugs or are going to receive in the future. Therefore, we designed this study to evaluate the risk of QT interval prolongation, TdP and death among the hospitalised COVID-19 patients treated with chloroquine, hydroxychloroquine, lopinavir/ritonavir, atazanavir/ritonavir, oseltamivir, favipiravir and remdesivir alone or in combination with azithromycin.

In this multicentre national survey, we prospectively collected data 

Data were collected by patient interview and review of medical records. Collected data were entered into web-based electronic database (Regitory, Tehran, Iran: https://regit ory5.rhc.ac.ir). All information was kept confidential and password protected. We gathered all data related to patient demographics, associated comorbidities (ie heart disease, heart failure, renal failure, liver disease), laboratory data (ie electrolyte levels, renal function test and liver function tests), drug history (including COVID-19 drugs and other QT prolonging drugs), electrocardiographic findings at baseline ECG and after drug intake, and all important events during admission or follow-up (TdP, sudden death and mortality).

The decision to treat with above-mentioned drugs was based on the clinical decision of the treating physician and national guidelines.

The treatment regimens were as follows: (1) Chloroquine 500 mg by mouth twice daily for 1 day followed by 250 mg by mouth twice daily for 5-7 days; (2) Hydroxychloroquine 400 mg by mouth twice daily for 1 day followed by 200 mg by mouth twice daily for 5-7 days;

(3) Azithromycin 500 mg by mouth daily for 1 day and followed by 250 mg daily for 5 days; (4) Lopinavir/ritonavir 200/50 mg twice daily for 5 days; (5) Atazanavir/ritonavir 300/100 mg daily for 5 days; (6) Oseltamivir 75 mg twice daily for 5 days; (7) Favipiravir 1600 mg twice daily for 1 day and then 600-800 mg twice daily for 5 days;

(8) Remdesivir 200 mg daily for first day and then 100 mg daily for 5-7 days.

All decisions on patient care were taken by the hospital clinicians, and no attempt was made by research team to influence their decisions. Furthermore, decisions regarding situations such as critical QT prolongation and or TdP were at the sole discretion of the physicians responsible for patient care.

A baseline QTc was measured from a 12-lead ECG before treatment.

If no baseline ECGs were available, ECGs recorded within 30 days of drug initiation were used for the baseline measures. On-treatment QT measurements were done using 12-lead ECGs or single-lead rhythm strip of lead II.

QT measurements were independently reviewed and validated by 13 expert cardiologists who were blinded to other patient data.

The QT intervals were calculated manually from either lead II or V5 using the tangent method 17 and QT corrections were done using Bazett's formula. For patients with intraventricular conduction delays (paced rhythms or bundle branch block), a modified QTc was calculated using the formula: modified QTc = (QT-(QRS-120))/√RR. 18 Using ECGs recorded before and during treatment, we also assessed the change from baseline in QTc (∆QTc).

The primary outcome of the study was incidence of critical QTc prolongation, defined as maximum on-therapy QTc ≥ 500 ms (if QRS < 120 ms) or QTc ≥ 550 ms (if QRS ≥ 120 ms) and ∆QTc of ≥60 ms Secondary outcomes were incidences of documented TdP and all-cause mortality. Cause of death was adjudicated by review of the resuscitation records from all patients with attempted resuscitation, and the reviewers of these data were blinded to the QTc data. TdP should be clearly documented by a single-lead ECG tracing.

Fitness of interval variables with normal distribution was assessed by one-sample Kolmogorov-Smirnov test. Data are presented as mean ± SD for continuous and frequency (percentage) for categorical variables. Comparisons of characteristics were made using Pearson's chi-square or Fisher's exact test for categorical variables and unpaired Student t test for continuous variables. The ECG characteristics before versus during drug therapy were compared using paired t test. Independent predictors for prolonged QTc were identified by logistic regression models. P value < .05 was considered as statistically significant. Statistical analyses were performed using IBM SPSS Statistics 22 for Windows (IBM Corp, Armonk, NY).

Clinical characteristics of the study population were presented in Table 1 . Of the 2403 patients initially enrolled in the study, 2365 met inclusion criteria and 38 were excluded because of non-interpretable baseline ECG or incomplete clinical data. Of 2365 patients, 1311

(54.6%) were men and the mean age was 59.6 ± 16.4 years (range, 18-99 years). The most common comorbidities were hypertension (35.8%), diabetes mellitus (31%), non-ischemic structural heart disease (14.9%) and coronary artery disease (12.9%).

Hydroxychloroquine was prescribed to treat COVID-19 infection in 1430 (60.5%) of the patients. A minority of the patients (n = 9, 0.4%) received chloroquine. Azithromycin was added to 1080 (75.5%) patients in hydroxychloroquine group and 3 (33%) in chloroquine group. Lopinavir/ritonavir and atazanavir/ritonavir were administered to 689 (29%) and 16 (0.7%) of the patients, respectively.

Azithromycin was added to 206 (30%) patients in lopinavir/ritonavir group and 4 (25%) in atazanavir/ritonavir group. One-hundred twenty-one patients (5%) were treated with oseltamivir, including 103 monotherapy and 18 combination therapy with azithromycin.

Other antiviral agents favipiravir and remdesivir were also employed in 33 (1.4%) and 67 (2.8%) patients, respectively.

A 12-lead ECG was obtained from all patients before treatment. ECG characteristics were summarised in Table 2 . The mean baseline QTc interval was 399.5 ± 42.5 ms and 48 patients (2.0%) had a baseline QTc ≥ 500 ms On-treatment measurements showed significant increase in QTc interval (432.5 ± 53.8 ms, P < .001). All COVID-19 drug regimens were associated with significant increase in ontreatment QTc (all P < .05). Maximal increases in on-treatment QTc were observed following combination of azithromycin with either chloroquine, lopinavir/ritonavir or hydroxychloroquine (Table 3) .

Compared with monotherapy, combination therapy led to significantly more increase in on-treatment QTc (∆QTc: 26.4 ms vs 37.6 ms, P < .001) and higher number of the patients with QTc ≥ 500 ms (8.0% vs 13.5%, P < .001) and ∆QTc ≥ 60 ms (12% vs 212.6%, P < .001).

Primary and secondary outcome for different drug regimens were summarised in Table 4 . After receiving COVDI-19 medications, QTc ≥ 500 ms and ∆QTc ≥ 60 ms were detected in 11.2% (n = 266) and 17.6% (n = 417) of the patients respectively.

Compared with those with QTc < 500 ms, the patients with QTc ≥ 500 ms were more likely to have history of heart failure and chronic kidney disease (CKD), more likely to receive hydroxychloroquine, lopinavir-ritonavir, azithromycin, diuretics, beta-blockers and calcium antagonists and more likely to develop acute renal or hepatic dysfunction during treatment. However, female gender, history of heart failure, acute hepatic dysfunction, treatment with hydroxychloroquine, azithromycin combination therapy and simultaneous furosemide therapy remained as independent predictors of QTc ≥ 500 ms in multivariate analysis (Table 5 ).

In comparison with those who had ∆QTc < 60 ms, patients with ∆QTc ≥ 60 ms were more likely to have history of CKD, more likely to develop acute renal or hepatic dysfunction during treatment, and more likely to receive hydroxychloroquine, lopinavir-ritonavir, oseltamivir, azithromycin combination therapy, furosemide and beta-blockers. In multivariate analysis, simultaneous beta-blocker therapy and acute renal failure remained as independent predictors for ∆QTc ≥ 60 ms (Table 6) . Note: Continuous variables were presented as mean ± SD. Categorical variables are presented as n (%). hypokalaemia during treatment remained as independent predictors of TdP (Table 7) .

Of the 2365 patients in the whole study cohort, 231 (9.8%) died during the study period. In comparison with those who survived, the patients who died were older, more likely to be men, more likely to have coronary artery disease, heart failure, CKD, diabetes, hypertension and more likely to receive hydroxychloroquine, lopinavir-ritonavir, combination therapy, furosemide, amiodarone, beta-blockers and digoxin, and more likely to experience hypokalaemia, acute renal or liver dysfunction, QTc ≥ 500 ms and ∆QTc ≥ 60 ms during treatment. However, age, azithromycin combination therapy, greater amiodarone exposure, furosemide therapy and acute renal dysfunction remained as independent predictors of mortality in multivariate analysis (Table 8 ). Survival analysis of the eight drug regimens showed clear increase in mortality among the patients who received hydroxychloroquine or lopinavir-ritonavir with and without azithromycin combination therapy (Figure 1 ).

In present cohort of 2365 patients with COVID-19, primary outcome of critical QT prolongation defined as QTc ≥ 500 ms or ∆QTc ≥ 60 ms was observed in 11.2% and 17.6% of the patients, respectively. Effect of chloroquine/hydroxychloroquine with and without azithromycin on QTc interval and TdP has been studied in several cohorts of COVID-19 patients. [14] [15] [16] In the present study, 1430 patients who were treated with hydroxychloroquine with or without azithromycin developed QTc ≥ 500 ms in 14%, ∆QTc ≥ 60 ms in 21%

and TdP in 0.3% of the patients. Female gender, history of heart failure, acute hepatic dysfunction, treatment with hydroxychloroquine, azithromycin combination therapy and simultaneous furosemide therapy were significant predictors of QTc ≥ 500 ms In largest published study, 415 patients with COVID-19 from 3 hospitals who were treated with hydroxychloroquine/azithromycin were prospectively included. 15 Critical QTc prolongation ≥500 ms was detected in 21% of patients and no instance of TdP was reported. Age, body mass index <30 kg/m 2 , heart failure, elevated creatinine and peak troponin >0.04 mg/ml were significant predictors of QTc ≥ 500 ms

Second important study reported the retrospective analysis of 251 patients with COVID-19 from 2 centres who were treated with combination of hydroxychloroquine and azithromycin. 16 On-treatment QTc ≥ 500 ms had developed in 23% of the patients, ∆QTc ≥ 60 ms in 22% was seen in 20% of the patients, and one patient experienced TdP (0.4%). Baseline QTc interval and simultaneous amiodarone therapy were predictors for QTc ≥ 500 ms and baseline creatinine level and simultaneous amiodarone therapy were predictors of simultaneous amiodarone therapy.

In addition to chloroquine/hydroxychloroquine with and without azithromycin, we studied the effect of five other antiviral repurposed drugs on QT interval prolongation and arrhythmic events.

Lopinavir-ritonavir and atazanavir-ritonavir, two fixed-dose combination antiretroviral medications, repurposed for COVID-19 treatment in the light of some efficacy in the SARS-CoV and the

Lopinavir/ritonavir and atazanavir/ritonavir were used 29% and 0.7% of our patients, respectively. Azithromycin was added to 30% of the patients in lopinavir/ritonavir group and 25% in atazanavir/ ritonavir group. Treatment with lopinavir-ritonavir increased the risk of TdP by more than 8 times; five cases of TdP occurred in patients who are receiving lopinavir-ritonavir and azithromycin combination, however, there was no report of TdP in atazanavir-ritonavir group.

Latter finding may be related to small number (n = 19) of the patients who were treated with atazanavir-ritonavir.

Oseltamivir, an antiviral to treat influenza, was used in the early days of the COVID-19 pandemic because there was some evidence that the active site of the spike protein of SARS-COV2 virus is similar to that of influenza virus neuraminidase, suggesting that neuraminidase inhibitors (eg oseltamivir) may be useful to treat COVID-19.

In the present study, it was used in 5% of the patients mainly as combination therapy with azithromycin. Oseltamivir use significantly increased baseline QT and led to critical QT prolongation as 25 In addition, concomitant cardiac injury from SARS-CoV-2 infection may increase the risk of adverse events from generally safe drugs. 26 We similarly showed that female gender, history of heart failure, treatment with hydroxychloroquine, azithromycin combination therapy, simultaneous furosemide or beta-blocker therapy, and acute renal or hepatic dysfunction were independent increased risk of the critical QT prolongation, however, the risk of TdP increased with lopinavir-ritonavir use, amiodarone or loop diuretic coadministration and hypokalaemia during treatment.

Drug-induced bradycardia is the common mechanism for the QT prolongation following amiodarone, beta-blocker and digoxin use, 25 however, amiodarone has also a known risk of prolonging QTc secondary to action potential prolongation. 27 We also observed that the risk of mortality increased independently by azithromycin combination therapy, simultaneous amiodarone or loop diuretic therapy, and acute renal dysfunction.

Importance of ECG monitoring has been studied in a recent multicentre study in 6476 hospitalised patients with COVID-19 who were treated with hydroxychloroquine with or without azithromycin. 28 Using a simplified approach to monitoring for QT prolongation and arrhythmia, TdP was observed in 1 (0.015%) patient and 67

(1.03%) patients had hydroxychloroquine with and without azithromycin held or discontinued as a result of excessive QT prolongation.

Practical recommendations for healthcare providers: (1) Considering the limited efficacy and important safety concerns, we think that chloroquine/hydroxychloroquine, fixed-dose com- 

Results of the present study should be interpreted in the light of certain limitations: first, patients without a baseline or postmedication ECGs were excluded from the analysis, which can represent a bias. We tried to minimise this bias by the consecutive inclusion of patients meeting study criteria. Second, the present cohort was consisted of hospitalised patients, and the results may not apply to outpatient setting or prophylactic treatments. Third, although a specific dosing schedule was recommended by national COVID-19 guidelines for all physicians, the decisions when and how to prescribe these drugs were deferred to the prescribing physicians. 

Authors contributing to this project have no conflict to disclose.

HAGHJOO et Al.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

https://orcid.org/0000-0002-9963-6628

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

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)

Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and proinflammatory cytokine production

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

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

Randomized doubleblinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe

Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial

Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial

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

A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19

Remdesivir for the treatment of Covid-19-Final report

Repurposed antiviral drugs for Covid-19-interim WHO Solidarity trial results

Considerations for drug interactions on QTc in exploratory COVID-19 treatment

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

Hydroxychloroquine/ Azithromycin therapy and QT prolongation in hospitalized patients with COVID-19

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

The measurement of the QT interval

A novel method for correcting QT interval for QRS duration, predicts all-cause mortality

Molecular dynamic simulations analysis of ritonavir and lopinavir as SARS-CoV 3CL(pro) inhibitors

Why we should be more careful using hydroxychloroquine in influenza season during COVID-19 pandemic?

QTc interval prolongation during favipiravir therapy in an Ebolavirusinfected patient

The effect of favipiravir on QTc interval in patients hospitalized with coronavirus disease 2019

Cardiac adverse events with remdesivir in COVID-19 infection

Risk assessment of druginduced long QT syndrome for some COVID-19 repurposed drugs

Development and validation of a risk score to predict QT interval prolongation in hospitalized patients

Cardiac safety of off-label COVID-19 drug therapy: a review and proposed monitoring protocol. Eur Heart J Acute Cardiovasc Care

QT prolongation and the antiarrhythmic efficacy of amiodarone

Safely administering potential QTc prolonging therapy across a large health care system in the COVID-19 era

Effect of COVID-19 medications on corrected QT interval and induction of torsade de pointes: Results of a multicenter national survey